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Claims for Patent: 6,552,065

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Claims for Patent: 6,552,065

Title: Deacetylase inhibitors
Abstract:The present invention provides hydroxamate compounds which are deacetylase inhibitors. The compounds are suitable for pharmaceutical compositions having anti-proliferative properties.
Inventor(s): Remiszewski; Stacy William (Washington Township, NJ), Bair; Kenneth Walter (Mountain Lakes, NJ), Versace; Richard William (Wanaque, NJ), Perez; Lawrence Blas (Hackettstown, NJ), Green; Michael Alan (Easton, PA), Sambucetti; Lidia Cristina (Pacifica, CA), Sharma; Sushil (West Orange, NJ)
Assignee: Novartis AG (Basel, CH)
Application Number:09/944,275
Patent Claims: 1. A compound of the formula (I) ##STR309##

wherein R.sub.1 is H, halo, or a straight chain C.sub.1 -C.sub.6 alkyl; R.sub.2 is selected from H, C.sub.1 -C.sub.10 alkyl, C.sub.4 -C.sub.9 cycloalkyl, C.sub.4 -C.sub.9 heterocycloalkyl, C.sub.4 -C.sub.9 heterocycloalkylalkyl, cycloalkylalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, --(CH.sub.2).sub.n C(O)R.sub.6, --(CH.sub.2).sub.n OC(O)R.sub.6, amino acyl, HON--C(O)--CH.dbd.C(R.sub.1)-aryl-alkyl- and --(CH.sub.2).sub.n R.sub.7 ; R.sub.3 and R.sub.4 are the same or different and independently H, C.sub.1 -C.sub.6 alkyl, acyl or acylamino, or R.sub.3 and R.sub.4 together with the carbon to which they are bound represent C.dbd.O, C.dbd.S, or C.dbd.NR.sub.8 ; R.sub.5 is selected from polyheteroaryl which is substituted or unsubstituted indol-3-yl; n, n.sub.1, n.sub.2 and n.sub.3 are the same or different and independently selected from 0-6, when n, is 1-6, each carbon atom can be optionally and independently substituted with R.sub.3 and/or R.sub.4 ; X and Y are the same or different and independently selected from H, halo, C.sub.1 -C.sub.4 alkyl, NO.sub.2, C(O)R.sub.1, OR.sub.9, SR.sub.9, CN, and NR.sub.10 R.sub.11 ; R.sub.6 is selected from H, C.sub.1 -C.sub.6 alkyl, C.sub.4 -C.sub.9 cycloalkyl, C.sub.4 -C.sub.9 heterocycloalkyl, cycloalkylalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, OR.sub.12, and NR.sub.13 R.sub.14 ; R.sub.7 is selected from OR.sub.15, SR.sub.15, S(O)R.sub.16, SO.sub.2 R.sub.17, NR.sub.13 R.sub.14, and NR.sub.12 SO.sub.2 R.sub.6 ; R.sub.8 is selected from H, OR.sub.15, NR.sub.13 R.sub.14, C.sub.1 -C.sub.6 alkyl, C.sub.4 -C.sub.9 cycloalkyl, C.sub.4 -C.sub.9 heterocycloalkyl, aryl, heteroaryl, arylalkyl, and heteroarylalkyl; R.sub.9 is selected from C.sub.1 -C.sub.4 alkyl and C(O)-alkyl; R.sub.10 and R.sub.11 are the same or different and independently selected from H, C.sub.1 -C.sub.4 alkyl, and --C(O)-alkyl; R.sub.12 is selected from H, C.sub.1 -C.sub.6 alkyl, C.sub.4 -C.sub.9 cycloalkyl, C.sub.4 -C.sub.9 heterocycloalkyl, C.sub.4 -C.sub.9 heterocycloalkylalkyl, aryl, mixed aryl and non-aryl polycycle, heteroaryl, arylalkyl, and heteroarylalkyl; R.sub.13 and R.sub.14 are the same or different and independently selected from H, C.sub.1 -C.sub.6 alkyl, C.sub.4 -C.sub.9 cycloalkyl, C.sub.4 -C.sub.9 heterocycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, amino acyl, or R.sub.13 and R.sub.14 together with the nitrogen to which they are bound are C.sub.4 -C.sub.9 heterocycloalkyl, heteroaryl, polyheteroaryl, non-aromatic polyheterocycle or mixed aryl and non-aryl polyheterocycle; R.sub.15 is selected from H, C.sub.1 -C.sub.6 alkyl, C.sub.4 -C.sub.9 cycloalkyl, C.sub.4 -C.sub.9 heterocycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl and (CH.sub.2).sub.m ZR.sub.12 ; R.sub.16 is selected from C.sub.1 -C.sub.6 alkyl, C.sub.4 -C.sub.9 cycloalkyl, C.sub.4 -C.sub.9 heterocycloalkyl, aryl, heteroaryl, polyheteroaryl, arylalkyl, heteroarylalkyl and (CH.sub.2).sub.m ZR.sub.12 ; R.sub.17 is selected from C.sub.1 -C.sub.6 alkyl, C.sub.4 -C.sub.9 cycloalkyl, C.sub.4 -C.sub.9 heterocycloalkyl, aryl, aromatic polycycle, heteroaryl, arylalkyl, heteroarylalkyl, polyheteroaryl and NR.sub.13 R.sub.14 ; m is an integer selected from 0 to 6; and Z is selected from O, NR.sub.13, S and S(O);

or a pharmaceutically acceptable salt thereof.

2. A compound of claim 1 wherein each of R.sub.1, X, Y, R.sub.3, and R.sub.4 is H.

3. A compound of claim 2 one of n.sub.2 and n.sub.3 is zero and the other is 1.

4. A compound of claim 3 wherein R.sub.2 is H or --CH.sub.2 --CH.sub.2 --OH.

5. A compound of claim 1 of the formula (Ia) ##STR310##

wherein n.sub.4 is 0-3, R.sub.2 is selected from H, C.sub.1 -C.sub.6 alkyl, C.sub.4 -C.sub.9 cycloalkyl, C.sub.4 -C.sub.9 heterocycloalkyl, alkylcycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, --(CH.sub.2).sub.n C(O)R.sub.6, amino acyl and --(CH.sub.2).sub.n R.sub.7 ; R.sub.5 ' is polyheteroaryl which is substituted or unsubstituted indol-3-yl,

or a pharmaceutically acceptable salt thereof.

6. A compound of claim 1 of formula Ib: ##STR311##

wherein R.sub.2 ' is selected from H, C.sub.1 -C.sub.6 alkyl, C.sub.4 -C.sub.6 cycloalkyl, alkylcycloalkyl, and (CH.sub.2).sub.2-4 OR.sub.21 where R.sub.21 is H, methyl, ethyl, propyl, or isopropyl, and R.sub.5 " is unsubstituted or substituted 1H-indol-3-yl,

or a pharmaceutically acceptable salt thereof.

7. A compound of claim 1 of formula (Id) ##STR312##

wherein Z.sub.1 is N--R.sub.20 ; R18 is H, halo, C.sub.1 -C.sub.6 alkyl, C.sub.3 -C.sub.7 cycloalkyl, aryl, or heteroaryl; R.sub.20 is H, C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 alkyl-C.sub.3 -C.sub.9 cycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, acyl or sulfonyl; A, is 1, 2 or 3 substituents which are independently H, C.sub.1 --C.sub.6 alkyl, --OR.sub.19, halo, alkylamino, aminoalkyl, halo, or heteroarylalkyl, R.sub.2 is selected from H, C.sub.1 -C.sub.6 alkyl, C.sub.4 -C.sub.9 cycloalkyl, C.sub.4 -C.sub.9 heterocycloalkyl, alkylcycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, --(CH.sub.2).sub.n C(O)R.sub.6, amino acyl and --(CH.sub.2).sub.n R.sub.7 ; R.sub.19 is selected from H, C.sub.1 -C.sub.6 alkyl, C.sub.4 -C.sub.9 cycloalkyl, C.sub.4 -C.sub.9 heterocycloalkyl, aryl, heteroaryl, arylalkyl, and heteroarylalkyl; p is 0-3, and q is 1-5 and r is 0 or q is 0 and r is 1-5

or a pharmaceutically acceptable salt thereof.

8. A compound of claim 7 wherein R.sub.2 is H or --CH.sub.2 --CH.sub.2 --OH and the sum of q and r is 1.

9. A compound of claim 1 of the formula (Id) ##STR313##

wherein Z.sub.1 is N--R.sub.20, R18 is H, halo, C.sub.1 -C.sub.6 alkyl, C.sub.3 -C.sub.7 cycloalkyl, unsubstituted phenyl, substituted phenyl, or heteroaryl, R.sub.20 is H, C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 alkyl-C.sub.3 -C.sub.9 cycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, acyl or sulfonyl; A.sub.1 is 1, 2 or 3 substituents which are independently H, C.sub.1 -C-.sub.6 alkyl, --OR.sub.19, or halo, R.sub.19 is selected from H, C.sub.1 -C.sub.6 alkyl, C.sub.4 -C.sub.9 cycloalkyl, C.sub.4 -C.sub.9 heterocycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl and --(CH.sub.2 CH.dbd.CH(CH.sub.3)(CH.sub.2)).sub.1-3 H; p is 0-3, and q is 1-5 and r is 0 or q is 0 and r is 1-5,

or a pharmaceutically acceptable salt thereof.

10. A compound of claim 9 wherein R.sub.2 is H or --CH.sub.2 --CH.sub.2 --OH and the sum of q and r is 1.

11. A compound of claim 9 wherein R18 is H, fluoro, chloro, bromo, a C.sub.1 -C.sub.4 alkyl group, a C.sub.3 -C.sub.7 cycloalkyl group, phenyl or a heteroaryl ring.

12. A compound of claim 9 wherein R.sub.2 is H, or --(CH.sub.2).sub.s CH.sub.2 OH and wherein s is 1-3.

13. A compound of claim 12 wherein R.sub.1 is H and X and Y are each H, and wherein q is 1-3 and r is 0 or wherein q is 0 and r is 1-3.

14. A compound of claim 9 wherein R18 is H, methyl, ethyl, t-butyl, trifluoromethyl, cyclohexyl, phenyl, 4-methoxyphenyl, 4-trifluoromethylphenyl, 2-furanyl, 2-thiophenyl, or 2-, 3- or 4-pyridyl.

15. A compound of claim 14 wherein R.sub.2 is H, or --(CH.sub.2).sub.5 CH.sub.2 OH and wherein s is 1-3.

16. A compound of claim 15 wherein p is 1-3.

17. A compound of claim 16 wherein R.sub.1 is H and X and Y are each H, and wherein q is 1-3 and r is 0 or wherien q is 0 and r is 1-3.

18. A compound of claim 17 wherein R.sub.2 H or --CH.sub.2 --CH.sub.2 --OH and the sum of q and r is 1.

19. A compound of claim 9 wherein R.sub.20 is H or C.sub.1 -C.sub.6 alkyl.

20. A compound of claim 9 selected from the group consisting of N-hydroxy-3-[4-[[(2-hydroxyethyl)[2-(1H-indol-3-yl)ethyl]-amino]methyl]phe nyl]-2E-2-propenamide, or a pharmaceutically acceptable salt thereof.

21. A pharmaceutical composition comprising a pharmaceutically effective amount of a compound of formula (I) ##STR314##

wherein R.sub.1 is H, halo, or a straight chain C.sub.1 -C.sub.6 alkyl; R.sub.2 is selected from H, C.sub.1 -C.sub.10 alkyl, C.sub.4 -C.sub.9 cycloalkyl, C.sub.4 -C.sub.9 heterocycloalkyl, C.sub.4 -C.sub.9 heterocycloalkylalkyl, cycloalkylalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, --(CH.sub.2).sub.n C(O)R.sub.6, --(CH.sub.2).sub.n OC(O)R.sub.6, amino acyl, HON--C(O)--CH.dbd.C(R.sub.1)-aryl-alkyl- and --(CH.sub.2).sub.n R.sub.7 ; R.sub.3 and R.sub.4 are the same or different and independently H, C.sub.1 -C.sub.6 alkyl, acyl or acylamino, or R.sub.3 and R.sub.4 together with the carbon to which they are bound represent C.dbd.O, C.dbd.S, or C.dbd.NR.sub.8 g; R.sub.5 is polyheteroaryl which is substituted or unsubstituted indol-3-yl; n, n.sub.1, n.sub.2 and n.sub.3 are the same or different and independently selected from 0-6, when n, is 1-6, each carbon atom can be optionally and independently substituted with R.sub.3 and/or R.sub.4 ; X and Y are the same or different and independently selected from H, halo, C.sub.1 -C.sub.4 alkyl, NO.sub.2, C(O)R.sub.1, OR.sub.9, SR.sub.9, CN, and NR.sub.10 R.sub.11 ; R.sub.6 is selected from H, C.sub.1 -C.sub.6 alkyl, C.sub.4 -C.sub.9 cycloalkyl, C.sub.4 -C.sub.9 heterocycloalkyl, cycloalkylalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, OR.sub.12, and NR.sub.13 R.sub.14 ; R.sub.7 is selected from OR.sub.15, SR.sub.15, S(O)R.sub.16, SO.sub.2 R.sub.17, NR.sub.13 R.sub.14, and NR.sub.12 SO.sub.2 R.sub.6 ; R.sub.8 is selected from H, OR.sub.15, NR.sub.13 R.sub.14, C.sub.1 -C.sub.6 alkyl, C.sub.4 -C.sub.9 cycloalkyl, C.sub.4 -C.sub.9 heterocycloalkyl, aryl, heteroaryl, arylalkyl, and heteroarylalkyl; R.sub.9 is selected from C.sub.1 -C.sub.4 alkyl and C(O)-alkyl; R.sub.10 and R.sub.11 are the same or different and independently selected from H, C.sub.1 -C.sub.4 alkyl, and --C(O)-alkyl; R.sub.12 is selected from H, C.sub.1 -C.sub.6 alkyl, C.sub.4 -C.sub.9 cycloalkyl, C.sub.4 -C.sub.9 heterocycloalkyl, C.sub.4 -C.sub.9 heterocycloalkylalkyl, aryl, mixed aryl and non-aryl polycycle, heteroaryl, arylalkyl, and heteroarylalkyl; R.sub.13 and R.sub.14 are the same or different and independently selected from H, C.sub.1 -C.sub.6 alkyl, C.sub.4 -C.sub.9 cycloalkyl, C.sub.4 -C.sub.9 heterocycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, amino acyl, or R.sub.13 and R.sub.14 together with the nitrogen to which they are bound are C.sub.4 -C.sub.9 heterocycloalkyl, heteroaryl, polyheteroaryl, non-aromatic polyheterocycle or mixed aryl and non-aryl polyheterocycle; R.sub.15 is selected from H, C.sub.1 -C.sub.6 alkyl, C.sub.4 -C.sub.9 cycloalkyl, C.sub.4 -C.sub.9 heterocycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl and (CH.sub.2).sub.m ZR.sub.12 ; R.sub.16 is selected from C.sub.1 -C.sub.6 alkyl, C.sub.4 -C.sub.9 cycloalkyl, C.sub.4 -C.sub.9 heterocycloalkyl, aryl, heteroaryl, polyheteroaryl, arylalkyl, heteroarylalkyl and (CH.sub.2).sub.m ZR.sub.12 ; R.sub.17 is selected from C.sub.1 -C.sub.6 alkyl, C.sub.4 -C.sub.9 cycloalkyl, C.sub.4 -C.sub.9 heterocycloalkyl, aryl, aromatic polycycle, heteroaryl, arylalkyl, heteroarylalkyl, polyheteroaryl and NR.sub.13 R.sub.14 ; m is an integer selected from 0 to 6; and Z is selected from O, NR.sub.13, S and S(O);

or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

22. A pharmaceutical composition of claim 21 wherein the compound of formula (I) is selected from the group consisting of N-hydroxy-3-[4-[[(2-hydroxyethyl)[2-(1H-indol-3-yl)ethyl]-amino]methyl]phe nyl]-2E-2-propenamide, or a pharmaceutically acceptable salt thereof.

23. A compound of claim 1 wherein R.sub.3 and R.sub.4 are each H.

24. A compound of claim 8, wherein R.sub.1, R.sub.3 and R.sub.4 are each H, X and Y are each H, R.sub.20 is H or C.sub.1 -C.sub.4 alkyl and p is 1.

25. A pharmaceutical composition of claim 21, which comprises a pharmaceutically effective amount of a compound of formula (Ic) ##STR315##

wherein Z.sub.1 is N--R.sub.20 ; R.sub.18 is H, halo, C.sub.1 -C.sub.6 alkyl, C.sub.3 -C.sub.7 cycloalkyl, aryl, or heteroaryl; R.sub.20 is H, C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 alkyl-C.sub.3 -C.sub.9 cycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, acyl or sulfonyl; A.sub.1 is 1, 2 or 3 substituents which are independently H, C.sub.1 -C-.sub.6 alkyl, --OR.sub.19, halo, alkylamino, aminoalkyl, halo, or heteroarylalkyl, R.sub.2 is selected from H, C.sub.1 -C.sub.6 alkyl, C.sub.4 -C.sub.9 cycloalkyl, C.sub.4 -C.sub.9 heterocycloalkyl, alkylcycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, --(CH.sub.2).sub.n C(O)R.sub.6, amino acyl and --(CH.sub.2).sub.n R.sub.7 ; R.sub.19 is selected from H, C.sub.1 -C.sub.6 alkyl, C.sub.4 -C.sub.9 cycloalkyl, C.sub.4 -C.sub.9 heterocycloalkyl, aryl, heteroaryl, arylalkyl, and heteroarylalkyl; p is 0-3, and q is 1-5 and r is 0 or q is 0 and r is 1-5

or a pharmaceutically acceptable salt thereof.

26. A pharmaceutical composition of claim 25, which comprises a pharmaceutically effective amount a compound of formula (Ic)

wherein R.sub.18 is H, halo, C.sub.1 -C.sub.6 alkyl, C.sub.3 -C.sub.7 cycloalkyl, unsubstituted phenyl, substituted phenyl, or heteroaryl, R.sub.20 is H, C.sub.1 -C.sub.6 alkyl-C.sub.1 -C.sub.6 alkyl-C.sub.3 -C.sub.9 cycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, acyl or sulfonyl; A.sub.1 is 1, 2 or 3 substituents which are independently H, C.sub.1 -C.sub.6 alkyl, --OR.sub.19, or halo, or a pharmaceutically acceptable salt thereof.

27. A pharmaceutical composition of claim 25, wherein R.sub.1, R.sub.3 and R.sub.4 are each H, R.sub.2 is H or --CH.sub.2 CH.sub.2 OH, X and Y are each H, R.sub.20 is H or C.sub.1 -C.sub.4 alkyl, p is 1 and q is 1.
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