Spiropiperidine beta-secretase inhibitors for the treatment of Alzheimer's disease
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Abstract
The present invention is directed to spiropiperidine compounds of formula (I)
-
Citations
28 Claims
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1. A compound of formula (I):
- View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28)
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2. A compound of claim 1 of formula (I) or (I′
- ), wherein Y is O.
-
3. A compound of claim 1 of formula (I) wherein X is N, or of formula (I′
- ), wherein X′
is NH.
- ), wherein X′
-
4. A compound of claim 1, wherein R1 is selected from the group consisting of optionally substituted C1-6 alkyl or C3-6 cycloalkyl.
-
5. A compound of claim 1, wherein R2 is phenyl, wherein the phenyl is optionally substituted with one or more
(i) halo, (ii) — - OH,
(iii) —
CN,(iv) —
C1-10 alkyl, and(v) phenyl optionally substituted with (A) halo, (B) —
OH,(C) —
CN,(D) —
C1-10 alkyl,(E) —
OC1-10 alkyl,(F) —
SO2C1-3 alkyl,(G) —
SO2NR5R5′
,(H) —
NR5SO2C1-3alkyl,(I) —
CO2R5, and(J) —
CONR5R5′
.
- OH,
-
6. A compound of claim 1, wherein Q is C1-3 alkylene and R3 is phenyl, wherein the phenyl is optionally substituted with one or more
(A) halo, (B) — - OH,
(C) —
CN,(D) —
C1-10 alkyl,(E) —
OC10 alkyl, and(F) phenyl optionally substituted with (i) —
C1-6 alkyl,(ii) —
OC1-6 alkyl, and(iii) —
NR5R5′
.
- OH,
-
7. A compound of claim 6, wherein Q is —
- CH2—
.
- CH2—
-
8. A compound of claim 1, wherein R4 is —
- C1-6 alkyl.
-
9. A compound of claim 1, which is a compound of formula (II)
-
10. A compound of claim 9 of formula (11) wherein X is N, or of formula (II′
- ), wherein X′
is NH.
- ), wherein X′
-
11. A compound of claim 9, wherein R2 is phenyl which is optionally substituted with one or more
(i) halo, (ii) — - OH,
(iii) —
CN,(iv) —
C1-10 alkyl, or(v) phenyl, optionally substituted with (A) halo, (B) —
OH,(C) —
CN,(D) —
C1-10 alkyl,(E) —
OC1-10alkyl,(F) —
SO2C1-3 alkyl,(G) —
SO2NR5R5′
,(H) —
NR5SO2C1-3alkyl,(I) —
CO2R5, and(J) —
CONR5R5′
.
- OH,
-
12. A compound of claim 9, wherein R4 is —
- C1-6 alkyl.
-
13. A compound of claim 1 which is a compound of formula (III)
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14. A compound of claim 13 of formula (III) wherein X is N, or of formula (III′
- ) wherein X′
is NH.
- ) wherein X′
-
15. A compound of claim 13, wherein Q is C1-3 alkylene, and R3 is phenyl, wherein the phenyl is optionally substituted with one or more
(A) halo, (B) — - OH,
(C) —
CN,(D) —
C1-10 alkyl,(E) —
OC10 alkyl, and(F) phenyl optionally substituted with (i) —
C1-6 alkyl,(ii) —
OC1-6 alkyl, and(iii) —
NR5R5′
.
- OH,
-
16. A compound of claim 13, wherein R4 is C1-6 alkyl.
-
18. A compound of claim 1, or a pharmaceutically acceptable salt thereof, or an individual enantiomer thereof, wherein the compound of formula (I) and (I′
- ) is a compound of formula (IB)
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19. A compound of claim 1 which is selected from the group consisting of
Racemic 5(R,S)7(R,S)-8-benzyl-4-(cyclohexylamino)-1-(3-fluorophenyl)-7-methyl 1,3,8-triazaspiro[4.5]dec-3-en-2-one diastereomer A; -
Racemic 5(R,S)7(S,R)-8-benzyl-4-(cyclohexylamino)-1-(3-fluorophenyl)-7-methyl-1,3,8-triazaspiro[4.5]dec-3-en-2-one Diastereomer B;
Racemic 5(R,S)7(R,S)-4-(cyclohexylamino)-1-(3-fluorophenyl)-8-(3-isopropoxybenzyl)-7-methyl-1,3,8-triazaspiro[4.5]dec-3-en-2-one Diastereomer A;
Racemic 5(R,S)7(S,R)-4-(cyclohexylarmino)-1-(3-fluorophenyl)-8-(3-isopropoxybenzyl)-7-methyl-1,3,8-triazaspiro[4.5]dec-3-en-2-one Diastereomer B;
Racemic 5(R,S)7(R,S)-8-benzyl-4-(cyclohexylamino)-7-methyl-1-phenyl-1,3,8-triazaspiro[4.5]dec-3-en-2-one Diastereomer A;
Racemic 5(R,S)7(S,R)-8-benzyl-4-(cyclohexylamino)-7-methyl-1-phenyl-1,3,8-triazaspiro[4.5]dec-3-en-2-one Diastereomer B;
Racemic 5(R,S)7(R,S)-8-(3-isopropoxybenzyl)-4-(isopropylamino)-7-methyl-1-(3-methylphenyl)-1,3,8-triazaspiro[4.5]dec-3-en-2-one Diastereomer A;
Racemic 5(R,S)7(S,R)-8-(3-isopropoxybenzyl)-4-(isopropylamino)-7-methyl-1-(3-methylphenyl)-1,3,8-triazaspiro[4.5]dec-3-en-2-one Diastereomer B;
5(R,S)7(R,S)-8-benzyl-4-(cyclohexylamino)-1,7-dimethyl-1,3,8-triazaspiro[4.5]dec-3-en-2-one Diastereomer A; and
5(R,S)7(S,R)-8-benzyl-4-(cyclohexylamino)-1,7-dimethyl-1,3,8-triazaspiro[4.5]dec-3-en-2-one Diastereomer B; and
enantiomers thereof, and pharmaceutically acceptable salts thereof.
-
-
20. A compound of claim 1, which is selected from the group consisting of
(5R,7S)-4-(cyclohexylamino)-1-(3-fluorophenyl)-8-(3-isopropoxybenzyl)-7-methyl-1,3,8-triazaspiro[4.5]dec-3-en-2-one; -
(5R,7S)-4-(cyclohexylamino)-1-(3-fluorophenyl)-7-methyl-8-(3-thienylmethyl)-1,3,8-triazaspiro[4.5]dec-3-en-2-one;
(5R,7S)-4-(cyclohexylamino)-8-(2-fluorobenzyl)-1-(3-fluorophenyl)-7-methyl-1,3,8-triazaspiro[4.5]dec-3-en-2-one;
(5R,7S)-4-(cyclohexylamino)-1-(3-fluorophenyl)-7-methyl-8-[3-(1H-pyrrol-1-yl)benzyl]-1,3,8-triazaspiro[4.5]dec-3-en-2-one;
(5R,7S)-4-(cyclohexylamino)-1-(3-fluorophenyl)-7-methyl-8-[3-(trifluoromethyl)benzyl]-1,3,8-triazaspiro[4.5]dec-3-en-2-one;
(5R,7S)-8-(3-tert-butoxybenzyl)-4-(cyclohexylamino)-1-(3-fluorophenyl)-7-methyl 1,3,8-triazaspiro[4.5]dec-3-en-2-one;
(5R,7S)-4-(cyclohexylamino)-8-[(2E)-3,7-dimethylocta-2,6-dien-1-yl]-1-(3-fluorophenyl)-7-methyl-1,3,8-triazaspiro[4.5]dec-3-en-2-one;
(5R,7S)-4-(cyclohexylamino)-1-(3-fluorophenyl)-7-methyl-8-(3-methylbut-2-en-1-yl)-1,3,8-triazaspiro[4.5]dec-3-en-2-one;
(5R,7S)-4-(cyclohexylamino)-1-(3-fluorophenyl)-7-methyl-8-[(trimethylsilyl)methyl]-1,3,8-triazaspiro[4.5]dec-3-en-2-one;
(5R,7S)-4-(cyclohexylamino)-1-(3-fluorophenyl)-7-methyl-8-[2-(trimethylsilyl)ethyl]-1,3,8-triazaspiro[4.5]dec-3-en-2-one;
(5R,7S)-4-(cyclohexylamino)-8-[3-(1-cyclopropylethoxy)benzyl]-1-(3-fluorophenyl)-7-methyl-1,3,8-triazaspiro[4.5]dec-3-en-2-one;
(5R,7S)-4-(cyclohexylamino)-1-(3-fluorophenyl)-7-methyl-8-(3-{[(1R)-1-methylpropyl]oxy}benzyl)-1,3,8-triazaspiro[4.5]dec-3-en-2-one;
(5R,7S)-4-(cyclohexylaniino)-8-(2-fluoro-5-{[(1R)-1-methylpropyl]oxy}benzyl)-1-(3-fluorophenyl)-7-methyl-1,3,8-triazaspiro[4.5]dec-3-en-2-one;
(5R,7S)-4-(cyclohexylamino)-8-[3-(cyclopropylmethyl)benzyl]1-(3-fluorophenyl)-7-methyl-1,3,8-triazaspiro[4.5]dec-3-en-2-one;
(5R,7S)-4-(cyclohexylamino)-1-(3-fluorophenyl)-7-methyl-8-[(2E)-3-methylpent-2-en-1-yl]-1,3,8-triazaspiro[4.5]dec-3-en-2-one;
(5R,7S)-4-(cyclohexylamino)-8-[3-(cyclopropyloxy)benzyl]-1-(3-fluorophenyl)-7-methyl-1,3,8-triazaspiro[4.5]dec-3-en-2-one;
(5R,7S)-4-(cyclohexylamino)-8-{3-[(1 s)-1-cyclopropylethyl]benzyl}-1-(3-fluorophenyl)-7-methyl-1,3,8-triazaspiro[4.5]dec-3-en-2-one;
(5R,7S)-4-(cyclohexylamino)-8-{3-[(1R)-1-cyclopropylethyl]benzyl}-1-(3-fluorophenyl)-7-methyl-1,3,8-triazaspiro[4.5]dec-3-en-2-one;
(5R,7S)-8-(cyclohex-1-en-1-ylmethyl)-4-(cyclohexylamino)-1-(3-fluorophenyl)-7-methyl-1,3,8-triazaspiro[4.5]dec-3-en-2-one;
(5R,7S)-4-(cyclohexylamino)-8-(cyclopent-1-en-1-ylmethyl)-1-(3-fluorophenyl)-7-methyl-1,3,8-triazaspiro[4.5]dec-3-en-2-one;
(5R,7S)-4-(cyclohexylamino)-1-(3-fluorophenyl)-8-[(1-isopropyl-1H-indol-6-yl)methyl]-7-methyl-1,3,8-triazaspiro[4.5]dec-3-en-2-one;
(5R,7S)-4-(cyclohexylamino)-1-(3-fluorophenyl)-7-methyl-8-[(2-methylcyclopent-1-en-1-yl)methyl]-1,3,8-triazaspiro[4.5]dec-3-en-2-one;
(5R,7S)-4-[(1R,4R)-bicyclo[2.2.1]hept-2-ylamino]-1-(3-fluorophenyl)-7-methyl-8-(3-{[(1R)-1-methylpropyl]oxy}benzyl)-1,3,8-triazaspiro[4.5]dec-3-en-2-one;
(5R,7S)-4-[(1S,4S)-bicyclo[2.2.1]hept-2-ylamino]-1-(3-fluorophenyl)-7-methyl-8-(3-{[(1R)-1-methylpropyl]oxy}benzyl)-1,3,8-triazaspiro[4.5]dec-3-en-2-one;
(5R,7S)-4-(cyclobutylamino)-1-(3-fluorophenyl)-7-methyl-8-(3-{[(1S,2R)-2-methylcyclopropyl]oxy}benzyl)-1,3,8-triazaspiro[4.5]dec-3-en-2-one;
(5R,7S)-4-(cyclobutylamino)-1-(3-fluorophenyl)-7-methyl-8-(3-{[(1R,2S)-2-methylcyclopropyl]oxy}benzyl)-1,3,8-triazaspiro[4.5]dec-3-en-2-one;
(5R,7S)-8-(cyclopentylmethyl)-4-{[(1S,2S)-2-fluorocyclohexyl]amino}-1-(3-fluorophenyl)-7-methyl-1,3,8-triazaspiro[4.5]dec-3-en-2-one;
(5R,7S)-8-(cyclopentylmethyl)-4-{[(1R,2R)-2-fluorocyclohexyl]amino}-1-(3-fluorophenyl)-7-methyl-1,3,8-triazaspiro[4.5]dec-3-en-2-one;
(5R,7S)-4-(cyclopentylamino)-1-(3-fluorophenyl)-8-(3-isopropoxybenzyl)-7-methyl-1,3,8-triazaspiro[4.5]dec-3-en-2-one;
(5R,7S)-8-benzyl-1-(3-fluorophenyl)-7-methyl-4-(spiro[2.5]oct-6-ylamino)-1,3,8-triazaspiro[4.5]dec-3-en-2-one;
(5R,7S)-1-(3-fluorophenyl)-8-(3-isopropoxybenzyl)-7-methyl-4-{[(5S,6R)-6-phenylspiro[2.4]hept-5-yl]amino}-1,3,8-triazaspiro[4.5]dec-3-en-2-one;
(5R,7S)-1-(3-fluorophenyl)-8-(3-isopropoxybenzyl)-7-methyl-4-{[(5R,6S)-6-phenylspiro[2.4]hept-5-yl]amino}-1,3,8-triazaspiro[4.5]dec-3-en-2-one;
(5R,7S)-4-[(4,4-difluorocyclohexyl)amino]-1-(3-fluorophenyl)-8-(3-isopropoxybenzyl)-7-methyl-1,3,8-triazaspiro[4.5]dec-3-en-2-one;
(5R,7S)-8-benzyl-4-[(4,4-difluorocyclohexyl)amino]-1-(3-fluorophenyl)-7-methyl-1,3,8-triazaspiro[4.5]dec-3-en-2-one;
(5R,7S)-8-(cyclobutylmethyl)-4-{[(3R)-1,1-dimethylsilolan-3-yl]amino}-1-(3-fluorophenyl)-7-methyl-1,3,8-triazaspiro[4.5]dec-3-en-2-one;
(5R,7S)-8-(cyclobutylmethyl)-4-{[(3S)-1,1-dimethylsilolan-3-yl]amino}-1-(3-fluorophenyl)-7-methyl-1,3,8-triazaspiro[4.5]dec-3-en-2-one;
this is example 41(5R,7S)-8-(cyclobutylmethyl)-4-{[(1R,2R)-2-fluorocyclohexyl]amino}-1-(3-fluorophenyl)-7-methyl-1,3,8-triazaspiro[4.5]dec-3-en-2-one;
(5R,7S)-8-(cyclobutylmethyl)-4-{[(1S,2S)-2-fluorocyclohexyl]amino}-1-(3-fluorophenyl)-7-methyl-1,3,8-triazaspiro[4.5]dec-3-en-2-one;
(5R,7S)-4-{[(1R)-1,2-dimethylpropyl]amino}-1-(3-fluorophenyl)-7-methyl-8-(3-methylbut-2-en-1-yl)-1,3,8-triazaspiro[4.5]dec-3-en-2-one;
(5R,7S)-4-{[(1S)-1,2-dimethylpropyl]amino}-1-(3-fluorophenyl)-7-methyl-8-(3-methylbut-2-en-1-yl)-1,3,8-triazaspiro[4.5]dec-3-en-2-one;
(5R,7S)-1-(3-chlorophenyl)-8-(cyclobutylmethyl)-4-(cyclohexylamino)-7-methyl-1,3,8-triazaspiro[4.5]dec-3-en-2-one;
(5R,7S)-1-(3-bromophenyl)-8-(cyclobutylmethyl)-4-(cyclohexylamino)-7-methyl-1,3,8-triazaspiro[4.5]dec-3-en-2-one;
(5R,7S)-4-(cyclohexylaniino)-1-(3-fluorophenyl)-8-(3-isopropoxybenzyl)-7-methyl-1,3,8-triazaspiro[4,5]dec-3-ene-2-thione;
(5R,7S)-4-(cyclohexylamino)-8-[(2,2-dimethyl-1,2-dihydroquinolin-8-yl)methyl]-1-(3-fluorophenyl)-7-methyl-1,3,8-triazaspiro[4.5]dec-3-en-2-one;
(5R,7S)-4-(cyclohexylamino)-8-[(2,2-dimethyl-1,2,3,4-tetrahydroquinolin-8-yl)methyl]-1-(3-fluorophenyl)-7-methyl-1,3,8-triazaspiro[4.5]dec-3-en-2-one;
(5R,7R)-4-(cyclohexylamino)-1-(3-fluorophenyl)-8-(3-isopropoxybenzyl)-7-vinyl-1,3,8-triazaspiro[4.5]dec-3-en-2-one;
(5R,7R)-8-benzyl-4-(cyclohexylamino)-1-(3-fluorophenyl)-7-vinyl-1,3,8-triazaspiro[4.5]dec-3-en-2-one;
(5R,7R)-4-(cyclohexylamino)-1-(3-fluorophenyl)-8-(3-{[(1R)-1-methylpropyl]oxy}benzyl)-7-vinyl-1,3,8-triazaspiro[4.5]dec-3-en-2-one;
(5R,7R)-4-(cyclohexylamino)-1-(3-fluorophenyl)-8-(3-isopropoxybenzyl)-7-[(1E)-prop-1-en-1-yl]-1,3,8-triazaspiro[4.5]dec-3-en-2-one;
(5R,7R)-4-(cyclohexylamino)-1-(3-fluorophenyl)-8-(3-isopropoxybenzyl)-7-[(1Z)-prop-1-en-1-yl]-1,3,8-triazaspiro[4.5]dec-3-en-2-one;
(5R,7S)-1-(3-fluorophenyl)-7-methyl-4-(methylamino)-8-[(2′
-methylbiphenyl-3-yl)methyl]-1,3,8-triazaspiro[4.5]dec-3-en-2-one;
(5R,7S)-8-(cyclobutylmethyl)-4-(cyclohexylamino)-1-[4′
-(isopropylsulfonyl)biphenyl-2-yl]-7-methyl-1,3,8-triazaspiro[4.5]dec-3-en-2-one;
(5R,7S)-8-benzyl-4-(cyclohexylamino)-1-(cyclopropylmethyl)-7-methyl-1,3,8-triazaspiro[4.5]dec-3-en-2-one;
(5R,7S)-(5S,7R)-8-benzyl-4-(cyclohexylamino)-1-cyclopropyl-7-methyl-1,3,8-triazaspiro[4.5]dec-3-en-2-one;
(5R,7S)-(5S,7R)-8-benzyl-1-cyclobutyl-4-(cyclohexylamino)-7-methyl-1,3,8-triazaspiro[4.5]dec-3-en-2-one;
(5R,7S)-(5S,7R)-8-benzyl-4-(cyclohexylamino)-1-cyclopentyl-7-methyl-1,3,8-triazaspiro[4.5]dec-3-en-2-one;
(5R,7S)-(5S,7R)-8-benzyl-1-cyclohexyl-4-(cyclohexylamino)-7-methyl-1,3,8-triazaspiro[4.5]dec-3-en-2-one;
(5R,7S)-(5S,7R)-8-benzyl-4-(cyclohexylamino)-7-methyl-1-(2-methylprop-2-en-1-yl)-1,3,8-triazaspiro[4.5]dec-3-en-2-one;
(5R,7S)-(5S,7R)-8-benzyl-4-(cyclohexylamino)-7-methyl-1-(tetrahydrofuran-3-yl)-1,3,8-triazaspiro[4.5]dec-3-en-2-one;
(5R,7S)-1-(3-fluorophenyl)-8-(3-isopropoxybenzyl)-7-methyl-4-{[(3S)-1-(methylsulfonyl)pyrrolidin-3-yl]amino}-1,3,8-triazaspiro[4.5]dec-3-en-2-one;
(5R,7S)-4-[(3,3-difluorocyclohexyl)amino]-1-(3-fluorophenyl)-8-(3-isopropoxybenzyl)-7-methyl-1,3,8-triazaspiro[4.5]dec-3-en-2-one;
(5R,7S)-(5S,7R)-4-[(2-fluoro-1-methylethyl)amino]-1-(3-fluorophenyl)-8-(3-isopropoxybenzyl)-7-methyl-1,3,8-triazaspiro[4.5]dec-3-en-2-one;
(5R,7S)-(5S,7R)-4-{[(1S)-1,2-dimethylpropyl]amino}-1-(3-fluorophenyl)-8-(3-isopropoxybenzyl)-7-methyl-1,3,8-triazaspiro[4.5]dec-3-en-2-one;
(5R,7S)-4-{[(1R,2R)-2-fluorocyclohexyl]amino}-1-(3-fluorophenyl)-8-(3-isopropoxybenzyl)-7-methyl-1,3,8-triazaspiro[4.5]dec-3-en-2-one;
(5R,7S)-4-{[(1S,2S)-2-fluorocyclohexyl]amino}-1-(3-fluorophenyl)-8-(3-isopropoxybenzyl)-7-methyl-1,3,8-triazaspiro[4.5]dec-3-en-2-one;
(5R,7S)-1-(3-fluorophenyl)-8-(3-isopropoxybenzyl)-4-[(2-isopropylcyclopropyl)amino]-7-methyl-1,3,8-triazaspiro[4.5]dec-3-en-2-one;
(5R,7S)-4-{[(1R,2R)-2-fluorocyclopentyl]amino}-1-(3-fluorophenyl)-8-(3-isopropoxybenzyl)-7-methyl-1,3,8-triazaspiro[4.5]dec-3-en-2-one;
(5R,7S)-4-{[(1S,2S)-2-fluorocyclopentyl]amino}-1-(3-fluorophenyl)-8-(3-isopropoxybenzyl)-7-methyl-1,3,8-triazaspiro[4.5]dec-3-en-2-one;
(5R,7S)-1-(3-fluorophenyl)-8-(3-isopropoxybenzyl)-7-methyl-4-[(2-propylcyclopropyl)amino]-1,3,8-triazaspiro[4.5]dec-3-en-2-one;
(5R,7S)-4-{[(1R)-2,2-difluorocyclohexyl]amino}-1-(3-fluorophenyl)-8-(3-isopropoxybenzyl)-7-methyl-1,3,8-triazaspiro[4.5]dec-3-en-2-one;
(5R,7S)-4-{[(1S)-2,2-difluorocyclohexyl]amino}-1-(3-fluorophenyl)-8-(3-isopropoxybenzyl)-7-methyl-1,3,8-triazaspiro[4.5]dec-3-en-2-one;
(5R,7S)-4-{[(1R)-2,2-difluorocyclopentyl]amino}-1-(3-fluorophenyl)-8-(3-isopropoxybenzyl)-7-methyl-1,3,8-triazaspiro[4.5]dec-3-en-2-one;
(5R,7S)-4-{[(1S)-2,2-difluorocyclopentyl]amino}-1-(3-fluorophenyl)-8-(3-isopropoxybenzyl)-7-methyl-1,3,8-triazaspiro[4.5]dec-3-en-2-one;
(5R,7S)-4-{[(1R,2S)-2-fluorocyclohexyl]amino}-1-(3-fluorophenyl)-8-(3-isopropoxybenzyl)-7-methyl-1,3,8-triazaspiro[4.5]dec-3-en-2-one;
(5R,7S)-4-{[(1S,2R)-2-fluorocyclohexyl]amino}-1-(3-fluorophenyl)-8-(3-isopropoxybenzyl)-7-methyl-1,3,8-triazaspiro[4.5]dec-3-en-2-one;
(5R,7S)-8-benzyl-1-(3-fluorophenyl)-7-methyl-4-{[(1S)-1,2,2-trimethylpropyl]amino}-1,3,8-triazaspiro[4.5]dec-3-en-2-one;
(5R,7S)-4-(cyclohexylimino)-1-(3-fluorophenyl)-8-(3-isopropoxybenzyl)-3,7-dimethyl-1,3,8-triazaspiro[4.5]decan-2-one; and
pharmaceutically acceptable salts thereof.
-
-
21. A compound of claim 20, which is selected from the group consisting of
5(R),7(S)-8-benzyl-4-(cyclohexylamino)-1-(3-fluorophenyl)-7-methyl-1,3,8-triazaspiro[4.5]dec-3-en-2-one; -
(5R,7S)-4-(cyclohexylamino)-1-(3-fluorophenyl)-8-(3-isopropoxybenzyl)-7-methyl-1,3,8-triazaspiro[4.5]dec-3-en-2-one;
(5R,7S)-4-(cyclohexylamino)-8-[(2E)-3,7-dimethylocta-2,6-dien-1-yl]-1-(3-fluorophenyl)-7-methyl-1,3,8-triazaspiro[4.5]dec-3-en-2-one;
(5R,7S)-4-(cyclohexylamino)-1-(3-fluorophenyl)-7-methyl-8-(3-{[(1R)-1-methylpropyl]oxy}benzyl)-1,3,8-triazaspiro[4.5]dec-3-en-2-one;
(5R,7S)-4-(cyclohexylamino)-8-[3-(cyclopropylmethyl)benzyl]-1-(3-fluorophenyl)-7-methyl-1,3,8-triazaspiro[4.5]dec-3-en-2-one;
(5R,7S)-8-(cyclobutylmethyl)-4-{[(1R,2R)-2-fluorocyclohexyl]amino}-1-(3-fluorophenyl)-7-methyl-1,3,8-triazaspiro[4.5]dec-3-en-2-one;
(5R,7S)-8-(cyclobutylmethyl)-4-{[(1S,2S)-2-fluorocyclohexyl]amino}-1-(3-fluorophenyl)-7-methyl-1,3,8-triazaspiro[4.5]dec-3-en-2-one;
(5R,7S)-4-[(4,4-difluorocyclohexyl)amino]-1-(3-fluorophenyl)-8-(3-isopropoxybenzyl)-7-methyl-1,3,8-triazaspiro[4.5]dec-3-en-2-one;
(5R,7S)-1-(3-chlorophenyl)-8-(cyclobutylmethyl)-4-(cyclohexylamino)-7-methyl-1,3,8-triazaspiro[4.5]dec-3-en-2-one;
(5R,7S)-1-(3-bromophenyl)-8-(cyclobutylmethyl)-4-(cyclohexylamino)-7-methyl-1,3,8-triazaspiro[4.5]dec-3-en-2-one;
(5R,7S)-1-(3-fluorophenyl)-7-methyl-4-(methylamino)-8-[(2′
-methylbiphenyl-3-yl)methyl]-1,3,8-triazaspiro[4.5]dec-3-en-2-one;
(5R,7S)-4-[(3,3-difluorocyclohexyl)amino]-1-(3-fluorophenyl)-8-(3-isopropoxybenzyl)-7-methyl-1,3,8-triazaspiro[4.5]dec-3-en-2-one;
(5R,7S)-4-{[(1R,2R)-2-fluorocyclohexyl]amino}-1-(3-fluorophenyl)-8-(3-isopropoxybenzyl)-7-methyl-1,3,8-triazaspiro[4.5]dec-3-en-2-one;
(5R,7S)-4-{[(1R)-2,2-difluorocyclopentyl]amino}-1-(3-fluorophenyl)-8-(3-isopropoxybenzyl)-7-methyl-1,3,8-triazaspiro[4.5]dec-3-en-2-one;
(5R,7S)-4-{[(1S)-2,2-difluorocyclopentyl]amino}-1-(3-fluorophenyl)-8-(3-isopropoxybenzyl)-7-methyl-1,3,8-triazaspiro[4.5]dec-3-en-2-one;
and pharmaceutically acceptable salts thereof.
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22. A pharmaceutically acceptable salt of a compound of claim 20, wherein the salt is selected from the group consisting of sulfate, phosphate, citrate, malate, mandelate, hippurate, trifluoroacetate and hydrochloric acid salts.
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23. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
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24. The pharmaceutical composition of claim 23, further comprising a P450 inhibitor.
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25. The pharmaceutical composition of claim 24, wherein the P450 inhibitor is ritonavir.
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26. A method of treating Alzheimer'"'"'s disease in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
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27. A method of treating Alzheimer'"'"'s disease in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of claim 1, or a pharmaceutically acceptable salt thereof, in combination with a P-450 inhibitor, and a pharmaceutically acceptable carrier.
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28. The method of claim 27, wherein the P450 Inhibitor is ritonavir.
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2. A compound of claim 1 of formula (I) or (I′
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17. A compound of formula (I)
Specification
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Current AssigneeMerck Sharp & Dohme LLC (Merck & Co., Inc.), Sunesis Pharmaceuticals, Inc. (Viracta Therapeutics, Inc.)
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Original AssigneeMerck Sharp & Dohme Corporation (Merck & Co., Inc.)
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InventorsYang, Wenjin, Stauffer, Shaun, Nantermet, Philippe, Fahr, Bruce, Lu, Wanli, Coburn, Craig, Rajapakse, Hemaka, Egbertson, Melissa, Stachel, Shawn, McGaughey, Georgia, Graham, Samuel
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Granted Patent
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Time in Patent OfficeDays
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Field of Search
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US Class Current514/278
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CPC Class CodesA61P 1/18 for pancreatic disorders, e...A61P 25/00 Drugs for disorders of the ...A61P 25/28 for treating neurodegenerat...A61P 3/10 for hyperglycaemia, e.g. an...A61P 43/00 Drugs for specific purposes...A61P 9/10 for treating ischaemic or a...C07D 471/10 Spiro-condensed systems