Substituted enaminones, their derivatives and uses thereof
View Patent ↗The invention relates to substituted enaminones of Formula I and their derivatives and the discovery that these compounds modulate the effect of γ-aminobutyric acid (GABA) on the GABA A receptor complex in a therapeutically relevant fashion and may be used to ameliorate CNS disorders amenable to modulation of the GABA A receptor complex.
1. A compound comprising the Formula I:
or a pharmaceutically acceptable salt thereof, wherein:
R 1 is selected from the group consisting of aryl, heteroaryl and aralkyl, each unsubstituted or substituted;
R 2 is selected from the group consisting of hydrogen and unsubstituted or substituted C 1-10 alkyl;
R 3 is selected from the group consisting of fluoro, chloro, bromo, iodo, C 1-10 alkoxy, nitro, haloC 1-10 alkyl, perhaloC 1-10 alkyl and unsubstituted or substituted C 1-10 alkyl;
each R 4 is independently selected from the group consisting of halogen, nitro, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 alkoxy, aralkyl, aryl, heteroaryl, cycloalkyl and heterocycloalkyl, each unsubstituted or substituted, or wherein R 3 and an adjacent R 4 together form a fused unsubstituted or substituted 5 or 6 membered cycloalkyl, aryl or heteroaryl ring;
R 5 is selected from the group consisting of —NH 2 , C 1-10 alkylamino, di(C 1-10 )alkylamino and aryl, each substituted or unsubstituted; and
m is 0, 1, 2, 3 or 4.
2. A compound according to claim 1 : wherein:
R 5 is selected from the group consisting of —NH 2 , C 1-10 alkylamino, di(C 1-10 )alkylamino and aryl, each unsubstituted or substituted.
3. A compound comprising the Formula Ib:
or a pharmaceutically acceptable salt thereof, wherein:
R 1 is selected from the group consisting of aryl, heteroaryl, and aralkyl and R 16 R 17 N—, each unsubstituted or substituted;
R 2 is selected from the group consisting of hydrogen and unsubstituted or substituted C 1-10 alkyl;
R 3 is selected from the group consisting of hydrogen, halo, haloC 1-10 alkyl, perhaloC 1-10 alkyl, amino, cyano, nitro, hydroxy, thio, C 1-20 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, C 1-10 alkoxy, aryloxy, heteroaryloxy, carbonyl group, sulfonyl group, sulfinyl group, imino group, each unsubstituted or substituted;
each R 4 is independently selected from the group consisting of hydrogen, halo, nitro, haloC 1-10 alkyl, perhaloC 1-10 alkyl, amino, cyano, hydroxy, thio, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, C 1-10 alkoxy, aryloxy, heteroaryloxy, carbonyl group, sulfonyl group, sulfinyl group, imino group, each unsubstituted or substituted, or wherein R 3 and an adjacent R 4 together form a fused unsubstituted or substituted 5 or 6 membered cycloalkyl, aryl or heteroaryl ring;
R 16 and R 17 are each independently C 3-12 cycloalkyl, aryl, heteroaryl, C 1-10 alkyl, each unsubstituted or substituted, or R 16 and R 17 together with the nitrogen atom to which they are attached form an unsubstituted or substituted 4, 5 or 6 membered ring; and
R 18 is selected from the group consisting of C 1-10 alkyl, aralkyl, and heterocycloalkyl, each substituted or unsubstituted; and
m is 0, 1, 2, 3 or 4.
4. The compound of claim 3 comprising the Formula Ic:
or a pharmaceutically acceptable salt thereof, wherein:
R 2 is selected from the group consisting of hydrogen, methyl and ethyl;
R 3 is selected from the group consisting of hydrogen, halo, haloC 1-10 alkyl, perhaloC 1-10 alkyl, amino, cyano, nitro, hydroxy, thio, C 1-20 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, C 1-10 alkoxy, aryloxy, heteroaryloxy, carbonyl group, sulfonyl group, sulfinyl group, imino group, each unsubstituted or substituted;
each R 4 is independently selected from the group consisting of hydrogen, halo, nitro, haloC 1-10 alkyl, perhaloC 1-10 alkyl, amino, cyano, hydroxy, thio, C 1-20 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, C 1-10 alkoxy, aryloxy, heteroaryloxy, carbonyl group, sulfonyl group, sulfinyl group, imino group, each unsubstituted or substituted, or wherein R 3 and an adjacent R 4 together form a fused unsubstituted or substituted 5 or 6 membered cycloalkyl, aryl or heteroaryl ring;
R 6 , R 7 , R 8 , R 9 and R 10 are each independently selected from the group consisting of hydrogen, halo, C 1-10 alkyl, C 2-10 alkynyl, C 1-10 alkoxy, aralkyl, cycloalkyl, arylC 1-10 alkyl and heteroarylC 1-10 alkyl; or R 6 and R 7 , or R 7 and R 8 , or R 8 and R 9 , or R 9 and R 10 are taken together with the carbon atoms to which they are attached to form an unsubstituted or substituted fused 5 or 6 membered saturated, partially unsaturated ring, aryl or heteroaryl;
R 18 is selected from the group consisting of C 1-10 alkyl, aralkyl, and heterocycloalky, each unsubstituted or substituted; and
m is 0, 1, 2, 3 or 4.
5. The compound of claim 1 comprising the Formula II:
or a pharmaceutically acceptable salt thereof, wherein:
R 1 is selected from the group consisting of aryl, heteroaryl and aralkyl, each unsubstituted or substituted;
R 2 is selected from the group consisting of hydrogen and unsubstituted or substituted C 1-10 alkyl;
R 5 is selected from the group consisting of —NH 2 , C 1-10 alkylamino, di(C 1-10 )alkylamino and aryl, each unsubstituted or substituted;
R 19 and R 20 are each independently selected from the group consisting of halo, cyano, nitro, halo(C 1-10 )alkyl, perhalo(C 1-5 )alkyl, aryl, heteroaryl, cycloalkyl, C 1-10 alkyl, aryl(C 1-10 )alkyl, cycloalkyl(C 1-10 )alkyl, hydroxy(C 1-10 )alkyl, amino(C 1-10 )alkyl, alkoxy(C 1-10 )alkyl, amino, hydroxyl, thio, C 1-10 alkoxy and C 1-10 alkylthiol; and
v and w independently are 0, 1, 2 or 3.
6. The compound of claim 1 comprising the Formula III:
or a pharmaceutically acceptable salt thereof, wherein:
R 2 is selected from the group consisting of hydrogen and unsubstituted or substituted C 1-10 alkyl;
R 3 is selected from the group consisting of fluoro, chloro, bromo, iodo, C 1-10 alkoxy, nitro, haloC 1-10 alkyl, perhaloC 1-10 alkyl and unsubstituted or substituted C 1-10 alkyl;
each R 4 is independently selected from the group consisting of halogen, nitro, C 1-10 alkyl, C 2-10 alkynyl, C 1-10 alkoxy, aralkyl, aryl, heteroaryl, cycloalkyl and heterocycloalkyl, each unsubstituted or substituted, or wherein R 3 and an adjacent R 4 together form a fused unsubstituted or substituted 5 or 6 membered cycloalkyl, aryl or heteroaryl ring;
R 5 is selected from the group consisting of —NH 2 , C 1-10 alkylamino, di(C 1-10 )alkylamino and aryl, each unsubstituted or substituted;
R 6 , R 7 , R 8 , R 9 and R 10 are each independently selected from the group consisting of hydrogen, halo, C 1-10 alkyl, C 2-10 alkynyl, C 1-10 alkoxy, aralkyl, cycloalkyl, arylC 1-10 alkyl and heteroarylC 1-10 alkyl; or R 6 and R 7 , or R 7 and R 8 , or R 8 and R 9 , or R 9 and R 10 are taken together with the carbon atoms to which they are attached to form an unsubstituted or substituted fused 5 or 6 membered saturated, partially unsaturated ring, aryl or heteroaryl; and
m is 0, 1, 2, 3 or 4.
7. The compound of claim 1 comprising the Formula IV:
or a pharmaceutically acceptable salt thereof, wherein:
R 2 is selected from the group consisting of hydrogen and unsubstituted or substituted C 1-10 alkyl;
R 3 is selected from the group consisting of fluoro, chloro, bromo, iodo, C 1-10 alkoxy, nitro, haloC 1-10 alkyl, perhaloC 1-10 alkyl and unsubstituted or substituted C 1-10 alkyl;
each R 4 is independently selected from the group consisting of halogen, nitro, C 1-10 alkyl, C 2-10 alkynyl, C 1-10 alkoxy, aralkyl, aryl, heteroaryl, cycloalkyl and heterocycloalkyl, each unsubstituted or substituted, or wherein R 3 and an adjacent R 4 together form a fused unsubstituted or substituted 5 or 6 membered cycloalkyl, aryl or heteroaryl ring;
R 5 is selected from the group consisting of —NH 2 , C 1-10 alkylamino, di(C 1-10 )alkylamino and aryl, each unsubstituted or substituted;
R 6 , R 7 , R 8 , R 9 and R 10 are each independently selected from the group consisting of hydrogen, halo, C 1-10 alkyl, C 2-10 alkynyl, C 1-10 alkoxy, aralkyl, cycloalkyl, arylC 1-10 alkyl and heteroarylC 1-10 alkyl; or R 6 and R 7 , or R 7 and R 8 , or R 8 and R 9 , or R 9 and R 10 are taken together with the carbon atoms to which they are attached to form an unsubstituted or substituted fused 5 or 6 membered saturated, partially unsaturated ring, aryl or heteroaryl;
R 11 is hydrogen or is an unsubstituted or substituted C 1-10 alkyl;
m is 0, 1, 2, 3 or 4; and
n is 0, 1, 2, 3, 4 or 5.
8. The compound of claim 3 comprising the Formula IVa:
or a pharmaceutically acceptable salt thereof, wherein:
R 2 is selected from the group consisting of hydrogen, methyl and ethyl;
R 3 is selected from the group consisting of hydrogen, halo, haloC 1-10 alkyl, perhaloC 1-10 alkyl, amino, cyano, nitro, hydroxy, thio, C 1-20 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, C 1-10 alkoxy, aryloxy, heteroaryloxy, carbonyl group, sulfonyl group, sulfinyl group, imino group, each unsubstituted or substituted;
each R 4 is independently selected from the group consisting of halogen, nitro, C 1-10 alkyl, C 2-10 alkynyl, C 1-10 alkoxy, aralkyl, aryl, heteroaryl, cycloalkyl and heterocycloalkyl, each unsubstituted or substituted, or wherein R 3 and an adjacent R 4 together form a fused unsubstituted or substituted 5 or 6 membered cycloalkyl, aryl or heteroaryl ring;
R 6 , R 7 , R 8 , R 9 and R 10 are each independently selected from the group consisting of hydrogen, halo, C 1-10 alkyl, C 2-10 alkynyl, C 1-10 alkoxy, aralkyl, cycloalkyl, arylC 1-10 alkyl and heteroarylC 1-10 alkyl; or R 6 and R 7 , or R 7 and R 8 , or R 8 and R 9 , or R 9 and R 10 are taken together with the carbon atoms to which they are attached to form an unsubstituted or substituted fused 5 or 6 membered saturated, partially unsaturated ring, aryl or heteroaryl;
R 11 is hydrogen or is an unsubstituted or substituted C 1-10 alkyl;
R 18 is selected from the group consisting of C 1-10 alkyl, arylalkyl and heterocycloalkyl, each unsubstituted or substituted;
m is 0, 1, 2, 3 or 4; and
n is 0, 1, 2, 3, 4 or 5.
9. A compound comprising the Formula V:
or a pharmaceutically acceptable salt thereof, wherein:
R 3 is selected from the group consisting of hydrogen, halo, haloC 1-10 alkyl, perhaloC 1-10 alkyl, amino, cyano, nitro, hydroxy, thio, C 1-20 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, C 1-10 alkoxy, aryloxy, heteroaryloxy, carbonyl group, sulfonyl group, sulfinyl group, imino group, each unsubstituted or substituted;
each R 4 is independently selected from the group consisting of hydrogen, halo, haloC 1-10 alkyl, perhaloC 1-10 alkyl, amino, cyano, nitro, hydroxy, thio, C 1-20 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, C 1-10 alkoxy, aryloxy, heteroaryloxy, carbonyl group, sulfonyl group, sulfinyl group, imino group, each unsubstituted or substituted, or wherein R 3 and an adjacent R 4 together form a fused unsubstituted or substituted 5 or 6 membered cycloalkyl, aryl or heteroaryl ring;
R 5 is selected from the group consisting of alkyl, amino, alkylamino, dialkylamino and aryl, each unsubstituted or substituted;
each R 19 is independently selected from the group consisting of halogen, C 1-10 alkyl, C 2-10 alkynyl, C 1-10 alkoxy, aralkyl and cycloalkyl, each unsubstituted or substituted;
m is 0, 1, 2, 3 or 4; and
u is 0, 1 or 2.
10. The compound of claim 3 comprising the Formula Va:
or a pharmaceutically acceptable salt thereof, wherein:
R 2 is selected from the group consisting of hydrogen and unsubstituted or substituted C 1-10 alkyl;
R 3 is selected from the group consisting of hydrogen, halo, haloC 1-10 alkyl, perhaloC 1-10 alkyl, amino, cyano, nitro, hydroxy, thio, C 1-20 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, C 1-10 alkoxy, aryloxy, heteroaryloxy, carbonyl group, sulfonyl group, sulfinyl group, imino group, each unsubstituted or substituted;
each R 4 is independently selected from the group consisting of hydrogen, halo, haloC 1-10 alkyl, perhaloC 1-10 alkyl, amino, cyano, nitro, hydroxy, thio, C 1-20 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, C 1-10 alkoxy, aryloxy, heteroaryloxy, carbonyl group, sulfonyl group, sulfinyl group, imino group, each unsubstituted or substituted, or wherein R 3 and an adjacent R 4 together form a fused unsubstituted or substituted 5 or 6 membered cycloalkyl, aryl or heteroaryl ring;
R 16 and R 17 are each independently C 3-12 cycloalkyl, aryl, heteroaryl, C 1-10 alkyl, each unsubstituted or substituted, or R 16 and R 17 together with the nitrogen atom to which they are attached form an unsubstituted or substituted 4, 5, or 6 membered ring;
R 18 is selected from the group consisting of C 1-10 alkyl, arylalkyl, and heterocycloalkyl, each unsubstituted or substituted; and
m is 0, 1, 2, 3 or 4.
11. A compound comprising the Formula VI:
or a pharmaceutically acceptable salt thereof, wherein:
R 1 is selected from the group consisting of aryl, heteroaryl, aralkyl and R 16 R 17 N—, each unsubstituted or substituted;
R 2 is selected from the group consisting of hydrogen and unsubstituted or substituted C 1-10 alkyl;
R 3 is selected from the group consisting of hydrogen, halo, haloC 1-10 alkyl, perhaloC 1-10 alkyl, amino, cyano, nitro, hydroxy, thio, C 1-20 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, C 1-10 alkoxy, aryloxy, heteroaryloxy, carbonyl group, sulfonyl group, sulfinyl group, imino group, each unsubstituted or substituted;
each R 4 is independently selected from the group consisting of halogen, nitro, C 1-10 alkyl, C 2-10 alkynyl, C 1-10 alkoxy, aralkyl, aryl, heteroaryl, cycloalkyl and heterocycloalkyl, each unsubstituted or substituted, or wherein R 3 and an adjacent R 4 together form a fused unsubstituted or substituted 5 or 6 membered cycloalkyl, aryl or heteroaryl ring;
R 16 and R 17 are each independently C 3-12 cycloalkyl, aryl, heteroaryl, C 1-10 alkyl, each unsubstituted or substituted, or R 16 and R 17 together with the nitrogen atom to which they are attached form an unsubstituted or substituted 4, 5, or 6 membered ring;
each R 20 is independently selected from the group consisting of halo, cyano, nitro, halo(C 1-10 )alkyl, perhalo(C 1-5 )alkyl, aryl, heteroaryl, C 1-10 alkyl, aryl(C 1-10 )alkyl, alkoxy(C 1-10 )alkyl, amino, hydroxyl, thio and C 1-10 alkoxy and
m and p are each independently 0, 1, 2, 3 or 4.
12. The compound of claim 6 , wherein R 8 is selected from the group consisting of C 1-10 alkyl, halogen, and C 1-10 alkoxy; and R 6 , R 7 , R 9 and R 10 are hydrogen.
13. The compound of claim 12 , wherein R 3 is selected from the group consisting of methyl, trifluoromethyl and chloro; and m is 0.
14. The compound of claim 1 that is:
2-Chloro-α-[[(4-cyanophenyl)amino]methylene]—N-ethyl-β-oxo-benzenepropanamide;
2-Chloro-N-ethyl-α-[[(4-iodophenyl)amino]methylene]-β-oxo-benzenepropanamide;
2-Chloro-α-[[(4-iodophenyl)amino]methylene]-β-oxo-N-(2-propynyl)-benzenepropanamide;
2-Chloro-α-[[(4-ethynylphenyl)amino]methylene]-β-oxo-N-propyl-benzenepropanamide;
α-[[(4-Ethynylpheny)amino]methylene]-2-methyl-β-oxo-N-propyl-benzenepropanamide;
α-[[(4-Cyanophenyl)amino]methylene]-2-methyl-β-oxo-N-propyl-benzenepropanamide;
α-[[(4-Ethynylphenyeamino]methylene]-2-methyl-β-oxo-N-(2- propynyl)-benzenepropanamide;
2-Chloro-α-[[(4-cyanopheny)amino]methylene]-β-oxo-N-propyl-benzenepropanamide;
2-Chloro-N-ethyl-α[(isoxazolyl-3-amino)methylene]-β-oxo-benzenepropanamide;
α-[(4-EthynylphenyDaminomethylene]-β-oxo-N-propyl-1- naphthalenepropanamide;
2-Chloro-α-[(isoxazolyl-3-amino)methylene]-β-oxo-N-propyl-benzenepropanarnide;
2-Chloro-N-ethyl-β-oxo-α-[(1,2,4-triazolyl-4-amino)methylene]benzene-propanamide;
α-[(4Ethynylpheny)aminomethylene]-β-oxo-N-propyl-1-naphthalenepropanamide;
2-Chloro-N-ethyl-β-oxo-α-[(pyrazinyl)amino]benzenepropanamide;
α-[[(4-chlorophenyeamino]methylene]-N-isopropyl-β-oxobenzenepropanamide;
2-chloro-a-[[(4-chlorophenypamino]methylene]-N-isopropyl-β-oxobenzene-propanamide;
2-chloro-α-[[(4-chlorophenyl)amino]methylene]-N-ethyl-β-oxobenzenepropanamide;
2-chloro-α-[[(4ethoxyphenyl)amino]methylene]-N-ethyl-β-oxobenzene-propanamide;
2-chloro-α-[[(4chlorophenyl)amino]methylene]-N-propyl-β-oxobenzene-propanamide;
2-chloro-α-[[(4-chlorophenypamino]methylene]-N-(1-methylpropyl-β-oxobenzene-propanamide;
2-chloro-N-ethyl-α-[[(α-methyl-4fluorobenzyl)amino]methylene]-β-oxobenzene-propanamide;
2-chloro-N-ethyl-α-[[(α-methylbenzyl)amino]methylene]-β-oxobenzene-propanamide;
2-chloro-α-[[(4-iodophenyl)amino]methylene]-N-methyl-β-oxobenzene-propanamide;
2-chloro-α-[[(4-chlorophenyl)amino]methylene]-N-methyl-β-oxobenzene-propanamide; and 2-chloro-α-[[(4-chlorophenypamino]methylene]-N-(α-methylbenzyl)-β-oxobenzene-propanamide.
15. A pharmaceutical composition, comprising the compound of Formula I:
or a pharmaceutically acceptable salt thereof, wherein:
R 1 is selected from the group consisting of aryl, heteroaryl, aralkyl and R 16 R 17 N—, each unsubstituted or substituted;
R 2 is selected from the group consisting of hydrogen and unsubstituted or substituted C 1-10 alkyl;
R 3 is selected from the group consisting of fluoro, chloro, bromo, iodo, C 1-10 alkoxy, nitro, haloC 1-10 alkyl, perhaloC 1-10 alkyl and unsubstituted or substituted C 1-10 alkyl;
each R 4 is independently selected from the group consisting of halogen, nitro, C 1-10 alkyl, C 1-10 alkenyl, C 2-10 alkynyl, C 1-10 alkoxy, aralkyl, aryl, heteroaryl, cycloalkyl and heterocycloalkyl, each unsubstituted or substituted, or wherein R 3 and an adjacent R 4 together form a fused unsubstituted or substituted 5 or 6 membered cycloalkyl, aryl or heteroaryl ring;
R 5 is selected from the group consisting of C 1-10 alkyl, C 1-10 alkoxy,—NH 2 , C 1-10 alkylamino, di(C 1-10 )alkylamino and aryl, each substituted or unsubstituted;
R 16 and R 17 are each independently C 3-12 cycloalkyl, aryl, heteroaryl, C 1-10 alkyl, each unsubstituted or substituted, or R 16 and R 17 together with the nitrogen atom to which they are attached form an unsubstituted or substituted 4, 5, or 6 membered ring; and
m is 0, 1, 2, 3 or 4; with the proviso that when R 5 is —OEt, then R 4 is not halogen, and the compound of Formula I is not the compounds ethyl α-[(benzyl)aminomethylene]- 2-chloro-β-oxobenzenepropionate and 1-(2,4-dichloro-5-fluorophenye-2-[[(2,4-difluorophenyl)amino]methylene]-1,3-pentanedione; and
a pharmaceutically-acceptable carrier selected from the group consisting of excipients and auxiliaries.
16. A pharmaceutical composition comprising the compound of claim 14 and a pharmaceutically-acceptable carrier selected from the group consisting of excipients and auxiliaries.
17. A method for the treatment of a CNS disorder amenable to modulation of the GABA A receptor complex which comprises administering to a patient in need of such treatment a compound of Formula I:
or a pharmaceutically acceptable salt thereof, wherein:
R 1 is selected from the group consisting of aryl, heteroaryl, aralkyl and R 16 R 17 N—, each unsubstituted or substituted;
R 2 is selected from the group consisting of hydrogen and unsubstituted or substituted C 1-10 alkyl;
R 3 is selected from the group consisting of hydrogen, halo, haloC 1-10 alkyl, perhaloC 1-10 alkyl, amino, cyano, nitro, hydroxy, thio, C 1-20 alkyl, C 2-10 alkenyl, C 2-10 alkyenyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, C 1-10 alkoxy, aryloxy, heteroaryloxy, carbonyl group, sulfonyl group, sulfinyl group, imino group, each unsubstituted or substituted;
each R 4 is independently selected from the group consisting of hydrogen, halo, haloC 1-10 alkyl, perhaloC 1-10 alkyl, amino, cyano nitro, hydroxy, thio, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, C 1-10 alkoxy, aryloxy, heteroaryloxy, carbonyl group, sulfonyl group, sulfinyl group, imino group, each unsubstituted or substituted, or wherein R 3 and an adjacent R 4 together foam a fused unsubstituted or substituted 5 or 6 membered cycloalkyl, aryl or heteroaryl ring;
R 5 is selected from the group consisting of C 1-10 alkyl, C 1-10 alkoxy, —NH 2 , C 1-10 alkylamino, di(C 1-10 )alkylamino and aryl, each substituted or unsubstituted;
R 16 and R 17 are each independently C 3-12 cycloalkyl, aryl, heteroaryl, C 1-10 alkyl, each unsubstituted or substituted, or R 16 and R 17 together with the nitrogen atom to which they are attached form an unsubstituted or substituted 4, 5, or 6 membered ring; and
m is 0, 1, 2, 3 or 4;
wherein said CNS disorder is selected from the group consisting of anxiety disorder, insomnia, major depressive disorder, bipolar disorder, convulsions, withdrawal-induced convulsions from substance abuse, chronic pain, acute pain, neuroses, phobia, panic disorder, generalized anxiety disorder, obsessive-compulsive disorder, post traumatic stress disorder, acute stress disorder, migraine, depression, and epilepsy.
18. A method for the treatment of a sleep disorder involving reduced wakefulness comprising the steps of administering to a patient in need of such a treatment a compound of Formula I:
or a pharmaceutically acceptable salt thereof, wherein:
R 1 is selected from the group consisting of aryl, heteroaryl, aralkyl and R 16 R 17 N—, each unsubstituted or substituted;
R 2 is selected from the group consisting of hydrogen and unsubstituted or substituted C 1-10 alkyl;
R 3 is selected from the group consisting of hydrogen, halo, haloC 1-10 alkyl, perhaloC 1-10 alkyl, amino, cyano, nitro, hydroxy, thio, C 1-20 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, C 1-10 alkoxy, aryloxy, heteroaryloxy, carbonyl group, sulfonyl group, sulfinyl group, imino group, each unsubstituted or substituted;
each R 4 is independently selected from the group consisting of hydrogen, halo, haloC 1-10 alkyl, perhaloC 1-10 alkyl, amino, cyano, nitro, hydroxy, thio, C 1-20 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, C 1-10 alkoxy, aryloxy, heteroaryloxy, carbonyl group, sulfonyl group, sulfinyl group, imino group, each unsubstituted or substituted, or wherein R 3 and an adjacent R 4 together form a fused unsubstituted or substituted 5 or 6 membered cycloalkyl, aryl or heteroaryl ring;
R 5 is selected from the group consisting of C 1-10 alkyl, C 1-10 alkoxy, —NH 2 , C 1-10 alkylamino, di(C 1-10 )alkylamino and aryl, each substituted or unsubstituted;
R 16 and R 17 are each independently C 3-12 cycloalkyl, aryl, heteroaryl, C 1-10 alkyl, each unsubstituted or substituted, or R 16 and R 17 together with the nitrogen atom to which they are attached form an unsubstituted or substituted 4, 5, or 6 membered ring; and
m is 0, 1, 2, 3 or 4.
19. The method of claim 18 , wherein the sleep disorder involving reduced wakefulness is selected from the group consisting of narcolepsy and idiopathic hypersomnia.
20. The method of claim 17 , wherein:
R 5 is selected from the group consisting of —C 1-10 alkyl, CH 3 O—, C 3-10 alkoxy, —NH 2 , C 1-10 alkylamino, di(C 1-10 )alkylamino and aryl, each unsubstituted or substituted.
21. A method for the treatment of a neurodegenerative disorder, which comprises administering to a patient in need of such treatment an effective amount of compound of Formula I:
or a pharmaceutically acceptable salt thereof, wherein:
R 1 is selected from the group consisting of aryl, heteroaryl, aralkyl and R 16 R 17 N—, each unsubstituted or substituted;
R 2 is selected from the group consisting of hydrogen and unsubstituted or substituted C 1-10 alkyl;
R 3 is selected from the group consisting of hydrogen, halo, haloC 1-10 alkyl, perhaloC 1-10 alkyl, amino, cyano, nitro, hydroxy, thio, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, C 1-10 alkoxy, aryloxy, heteroaryloxy, carbonyl group, sulfonyl group, sulfinyl group, imino group, each unsubstituted or substituted;
each R 4 is independently selected from the group consisting of hydrogen, halo, haloC 1-10 alkyl, perhaloC 1-10 alkyl, amino, cyano, nitro, hydroxy, thio, C 1-20 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, C 1-10 alkoxy, aryloxy, heteroaryloxy, carbonyl group, sulfonyl group, sulfinyl group, imino group, each unsubstituted or substituted, or wherein R 3 and an adjacent R 4 together form a fused unsubstituted or substituted 5 or 6 membered cycloalkyl, aryl or heteroaryl ring;
R 5 is selected from the group consisting of C 1-10 alkyl, C 1-10 alkoxy, —NH 2 , C 1-10 alkylamino, di(C 1-10 )alkylamino and aryl, each substituted or unsubstituted;
R 16 and R 17 are each independently C 3-12 cycloalkyl, aryl, heteroaryl, C 1-10 alkyl, each unsubstituted or substituted, or R 16 and R 17 together with the nitrogen atom to which they are attached form an unsubstituted or substituted 4, 5, or 6 membered ring; and
m is 0, 1, 2, 3, or 4.
22. A method for the treatment of senile dementia, which comprises administering to a patient in need of such treatment an effective amount of compound of Formula I:
or a pharmaceutically acceptable salt thereof, wherein:
R 1 is selected from the group consisting of aryl, heteroaryl, aralkyl and R 16 R 17 N—, each unsubstituted or substituted;
R 2 is selected from the group consisting of hydrogen and unsubstituted or substituted C 1-10 alkyl;
R 3 is selected from the group consisting of hydrogen, halo, haloC 1-10 alkyl, perhaloC 1-10 alkyl, amino, cyano, nitro, hydroxy, thio, C 2-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, C 1-10 alkoxy, aryloxy, heteroaryloxy, carbonyl group, sulfonyl group, sulfinyl group, imino group, each unsubstituted or substituted;
each R 4 is independently selected from the group consisting of hydrogen, halo, haloC 1-10 alkyl, perhaloC 1-10 alkyl, amino, cyano, nitro, hydroxy, thio, C 1-20 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, C 1-10 alkoxy, aryloxy, heteroaryloxy, carbonyl group, sulfonyl group, sulfinyl group, imino group, each unsubstituted or substituted, or wherein R 3 and an adjacent R 4 together form a fused unsubstituted or substituted 5 or 6 membered cycloalkyl, aryl or heteroaryl ring;
R 5 is selected from the group consisting of C 1-10 alkyl, C 1-10 alkoxy, —NH 2 , C 1-10 alkylamino, di(C 1-10 )alkylamino and aryl, each substituted or unsubstituted;
R 16 and R 17 are each independently C 3-12 cycloalkyl, aryl, heteroaryl, C 1-10 alkyl, each unsubstituted or substituted, or R 16 and R 17 together with the nitrogen atom to which they are attached form an unsubstituted or substituted 4, 5, or 6 membered ring; and
m is 0, 1, 2, 3 or 4.
23. A method for the treatment of schizophrenia, which comprises administering to a patient in need of such treatment an effective amount of compound of Formula I:
or a pharmaceutically acceptable salt thereof, wherein:
R 1 is selected from the group consisting of aryl, heteroaryl, aralkyl and R 16 R 17 N—, each unsubstituted or substituted;
R 2 is selected from the group consisting of hydrogen and unsubstituted or substituted C 1-10 alkyl;
R 3 is selected from the group consisting of hydrogen, halo, haloC 1-10 alkyl, perhaloC 1-10 alkyl, amino, cyano, nitro, hydroxy, thio, C 1-20 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, C 1-10 alkoxy, aryloxy, heteroaryloxy, carbonyl group, sulfonyl group, sulfinyl group, imino group, each unsubstituted or substituted;
each R 4 is independently selected from the group consisting of hydrogen, halo, haloC 1-10 alkyl, perhaloC 1-10 alkyl, amino, cyano, nitro, hydroxy, thio, C 1-20 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, C 1-10 alkoxy, aryloxy, heteroaryloxy, carbonyl group, sulfonyl group, sulfinyl group, imino group, each unsubstituted or substituted, or wherein R 3 and an adjacent R 4 together form a fused unsubstituted or substituted 5 or 6 membered cycloalkyl, aryl or heteroaryl ring;
R 5 is selected from the group consisting of C 1-10 alkyl, C 1-10 alkoxy,NH 2 , C 1-10 alkylamino, di(C 1-10 )alkylamino and aryl, each substituted or unsubstituted;
R 16 and R 17 are each independently C 3-12 cycloalkyl, aryl, heteroaryl, C 1-10 alkyl, each unsubstituted or substituted, or R 16 and R 17 together with the nitrogen atom to which they are attached form an unsubstituted or substituted 4, 5, or 6 membered ring; and
m is 0, 1, 2, 3 or 4.
24. A method for the treatment of a cognition deficit disorder, which comprises administering to a patient in need of such treatment an effective amount of compound of Formula I:
or a pharmaceutically acceptable salt thereof, wherein:
R 1 is selected from the group consisting of aryl, heteroaryl, aralkyl and R 16 R 17 N—, each unsubstituted or substituted;
R 2 is selected from the group consisting of hydrogen and unsubstituted or substituted C 1-10 alkyl;
R 3 is selected from the group consisting of hydrogen, halo, haloC 1-10 alkyl, perhaloC 1-10 alkyl, amino, cyano, nitro, hydroxy, thio, C 1-20 alkyl, C 1-10 alkenyl, C 2-10 alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, C 1-10 alkoxy, aryloxy, heteroaryloxy, carbonyl group, sulfonyl group, sulfinyl group, imino group, each unsubstituted or substituted;
each R 4 is independently selected from the group consisting of hydrogen, halo, haloC 1-10 alkyl, perhaloC 1-10 alkyl, amino, cyano, nitro, hydroxy, thio, C 1-20 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, C 1-10 alkoxy, aryloxy, heteroaryloxy, carbonyl group, sulfonyl group, sulfinyl group, imino group, each unsubstituted or substituted, or wherein R 3 and an adjacent R 4 together form a fused unsubstituted or substituted 5 or 6 membered cycloalkyl, aryl or heteroaryl ring;
R 5 is selected from the group consisting of C 1-10 alkyl, C 1-10 alkoxy, —NH 2 , C 1-10 alkylamino, di(C 1-10 )alkylamino and aryl, each substituted or unsubstituted;
R 16 and R 17 are each independently C 3-12 cycloalkyl, aryl, heteroaryl, C 1-10 alkyl, each unsubstituted or substituted, or R 16 and R 17 together with the nitrogen atom to which they are attached form an unsubstituted or substituted 4, 5, or 6 membered ring; and
m is 0, 1, 2, 3 or 4.
25. A method for the treatment of mild cognitive impairment, age related cognitive decline, or Alzheimer's disease, which comprises administering to a patient in need of such treatment an effective amount of a compound of Formula I:
or a pharmaceutically acceptable salt thereof, wherein:
R 1 is selected from the group consisting of aryl, heteroaryl, aralkyl and R 16 R 17 N—, each unsubstituted or substituted;
R 2 is selected from the group consisting of hydrogen and unsubstituted or substituted C 1-10 alkyl;
R 3 is selected from the group consisting of hydrogen, halo, haloC i1-10 alkyl, perhaloC 1-10 alkyl, amino, cyano, nitro, hydroxy, thio, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, C 1-10 alkoxy, aryloxy, heteroaryloxy, carbonyl group, sulfonyl group, sulfinyl group, imino group, each unsubstituted or substituted;
each R 4 is independently selected from the group consisting of hydrogen, halo, haloC 1-10 alkyl, perhaloC 1-10 alkyl, amino, cyano, nitro, hydroxy, thio, C 1-20 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, C 1-10 alkoxy, aryloxy, heteroaryloxy, carbonyl group, sulfonyl group, sulfinyl group, imino group, each unsubstituted or substituted, or wherein R 3 and an adjacent R 4 together foul a fused unsubstituted or substituted 5 or 6 membered cycloalkyl, aryl or heteroaryl ring;
R 5 is selected from the group consisting of C 1-10 alkyl, C 1-10 alkoxy, —NH 2 , C 1-10 alkylamino, di(C 1-10 )alkylamino and aryl, each substituted or unsubstituted;
R 16 and R 17 are each independently C 3-12 cycloalkyl, aryl, heteroaryl, C 1-10 alkyl, each unsubstituted or substituted, or R 16 and R 17 together with the nitrogen atom to which they are attached form an unsubstituted or substituted 4, 5, or 6 membered ring; and
m is 0, 1, 2, 3 or 4.