Claims for Patent: 6,552,065

Summary 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):	Stacy William Remiszewski, Kenneth Walter Bair, Richard William Versace, Lawrence Blas Perez, Michael Alan Green, Lidia Cristina Sambucetti, Sushil Sharma
Assignee:	Secura Bio Inc
Application Number:	US09/944,275
Patent Claims:	1. A compound of the formula (I) wherein R1 is H, halo, or a straight chain C1-C6 alkyl; R2 is selected from H, C1-C10 alkyl, C4-C9 cycloalkyl, C4-C9 heterocycloalkyl, C4-C9 heterocycloalkylalkyl, cycloalkylalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, —(CH2)nC(O)R6, —(CH2)nOC(O)R6, amino acyl, HON—C(O)—CH═C(R1)-aryl-alkyl- and —(CH2)nR7; R3 and R4 are the same or different and independently H, C1-C6 alkyl, acyl or acylamino, or R3 and R4 together with the carbon to which they are bound represent C═O, C═S, or C═NR8; R5 is selected from polyheteroaryl which is substituted or unsubstituted indol-3-yl; n, n1, n2 and n3 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 R3 and/or R4; X and Y are the same or different and independently selected from H, halo, C1-C4 alkyl, NO2, C(O)R1, OR9, SR9, CN, and NR10R11; R6 is selected from H, C1-C6 alkyl, C4-C9 cycloalkyl, C4-C9 heterocycloalkyl, cycloalkylalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, OR12, and NR13R14; R7 is selected from OR15, SR15, S(O)R16, SO2R17, NR13R14, and NR12SO2R6; R8 is selected from H, OR15, NR13R14, C1-C6 alkyl, C4-C9 cycloalkyl, C4-C9 heterocycloalkyl, aryl, heteroaryl, arylalkyl, and heteroarylalkyl; R9 is selected from C1-C4 alkyl and C(O)-alkyl; R10 and R11 are the same or different and independently selected from H, C1-C4 alkyl, and —C(O)-alkyl; R12 is selected from H, C1-C6 alkyl, C4-C9 cycloalkyl, C4-C9 heterocycloalkyl, C4-C9 heterocycloalkylalkyl, aryl, mixed aryl and non-aryl polycycle, heteroaryl, arylalkyl, and heteroarylalkyl; R13 and R14 are the same or different and independently selected from H, C1-C6 alkyl, C4-C9 cycloalkyl, C4-C9 heterocycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, amino acyl, or R13 and R14 together with the nitrogen to which they are bound are C4-C9 heterocycloalkyl, heteroaryl, polyheteroaryl, non-aromatic polyheterocycle or mixed aryl and non-aryl polyheterocycle; R15 is selected from H, C1-C6 alkyl, C4-C9 cycloalkyl, C4-C9 heterocycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl and (CH2)mZR12; R16 is selected from C1-C6 alkyl, C4-C9 cycloalkyl, C4-C9 heterocycloalkyl, aryl, heteroaryl, polyheteroaryl, arylalkyl, heteroarylalkyl and (CH2)mZR12; R17 is selected from C1-C6 alkyl, C4-C9 cycloalkyl, C4-C9 heterocycloalkyl, aryl, aromatic polycycle, heteroaryl, arylalkyl, heteroarylalkyl, polyheteroaryl and NR13R14; m is an integer selected from 0 to 6; and Z is selected from O, NR13, S and S(O); or a pharmaceutically acceptable salt thereof. 2. A compound of claim 1 wherein each of R1, X, Y, R3, and R4 is H. 3. A compound of claim 2 one of n2 and n3 is zero and the other is 1. 4. A compound of claim 3 wherein R2 is H or —CH2—CH2—OH. 5. A compound of claim 1 of the formula (Ia) wherein n4 is 0-3, R2 is selected from H, C1-C6 alkyl, C4-C9 cycloalkyl, C4-C9 heterocycloalkyl, alkylcycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, —(CH2)nC(O)R6, amino acyl and —(CH2)nR7; R5′ 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: wherein R2′ is selected from H, C1-C6 alkyl, C4-C6 cycloalkyl, alkylcycloalkyl, and (CH2)2-4OR21 where R21 is H, methyl, ethyl, propyl, or isopropyl, and R5″ is unsubstituted or substituted 1H-indol-3-yl, or a pharmaceutically acceptable salt thereof. 7. A compound of claim 1 of formula (Id) wherein Z1 is N—R20; R18 is H, halo, C1-C6alkyl, C3-C7cycloalkyl, aryl, or heteroaryl; R20 is H, C1-C6alkyl, C1-C6alkyl-C3-C9cycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, acyl or sulfonyl; A, is 1, 2 or 3 substituents which are independently H, C1--C6alkyl, —OR19, halo, alkylamino, aminoalkyl, halo, or heteroarylalkyl, R2 is selected from H, C1-C6 alkyl, C4-C9 cycloalkyl, C4-C9 heterocycloalkyl, alkylcycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, —(CH2)nC(O)R6, amino acyl and —(CH2)nR7; R19 is selected from H, C1-C6alkyl, C4-C9cycloalkyl, C4-C9heterocycloalkyl, 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 R2 is H or —CH2—CH2—OH and the sum of q and r is 1. 9. A compound of claim 1 of the formula (Id) wherein Z1 is N—R20, R18 is H, halo, C1-C6alkyl, C3-C7cycloalkyl, unsubstituted phenyl, substituted phenyl, or heteroaryl, R20 is H, C1-C6alkyl, C1-C6alkyl-C3-C9cycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, acyl or sulfonyl; A1 is 1, 2 or 3 substituents which are independently H, C1-C-6alkyl, —OR19, or halo, R19 is selected from H, C1-C6alkyl, C4-C9cycloalkyl, C4-C9heterocycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl and —(CH2CH═CH(CH3)(CH2))1-3H; 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 R2 is H or —CH2—CH2—OH and the sum of q and r is 1. 11. A compound of claim 9 wherein R18 is H, fluoro, chloro, bromo, a C1-C4alkyl group, a C3-C7cycloalkyl group, phenyl or a heteroaryl ring. 12. A compound of claim 9 wherein R2 is H, or —(CH2)sCH2OH and wherein s is 1-3. 13. A compound of claim 12 wherein R1 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 R2 is H, or —(CH2)5CH2OH and wherein s is 1-3. 16. A compound of claim 15 wherein p is 1-3. 17. A compound of claim 16 wherein R1 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 R2 H or —CH2—CH2—OH and the sum of q and r is 1. 19. A compound of claim 9 wherein R20 is H or C1-C6alkyl. 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]phenyl]-2E-2-propenamide, or a pharmaceutically acceptable salt thereof. 21. A pharmaceutical composition comprising a pharmaceutically effective amount of a compound of formula (I) wherein R1 is H, halo, or a straight chain C1-C6 alkyl; R2 is selected from H, C1-C10 alkyl, C4-C9 cycloalkyl, C4-C9 heterocycloalkyl, C4-C9 heterocycloalkylalkyl, cycloalkylalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, —(CH2)nC(O)R6, —(CH2)nOC(O)R6, amino acyl, HON—C(O)—CH═C(R1)-aryl-alkyl- and —(CH2)nR7; R3 and R4 are the same or different and independently H, C1-C6 alkyl, acyl or acylamino, or R3 and R4 together with the carbon to which they are bound represent C═O, C═S, or C═NR8g; R5 is polyheteroaryl which is substituted or unsubstituted indol-3-yl; n, n1, n2 and n3 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 R3 and/or R4; X and Y are the same or different and independently selected from H, halo, C1-C4 alkyl, NO2, C(O)R1, OR9, SR9, CN, and NR10R11; R6 is selected from H, C1-C6 alkyl, C4-C9 cycloalkyl, C4-C9 heterocycloalkyl, cycloalkylalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, OR12, and NR13R14; R7 is selected from OR15, SR15, S(O)R16, SO2R17, NR13R14, and NR12SO2R6; R8 is selected from H, OR15, NR13R14, C1-C6 alkyl, C4-C9 cycloalkyl, C4-C9 heterocycloalkyl, aryl, heteroaryl, arylalkyl, and heteroarylalkyl; R9 is selected from C1-C4 alkyl and C(O)-alkyl; R10 and R11 are the same or different and independently selected from H, C1-C4 alkyl, and —C(O)-alkyl; R12 is selected from H, C1-C6 alkyl, C4-C9 cycloalkyl, C4-C9 heterocycloalkyl, C4-C9 heterocycloalkylalkyl, aryl, mixed aryl and non-aryl polycycle, heteroaryl, arylalkyl, and heteroarylalkyl; R13 and R14 are the same or different and independently selected from H, C1-C6 alkyl, C4-C9 cycloalkyl, C4-C9 heterocycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, amino acyl, or R13 and R14 together with the nitrogen to which they are bound are C4-C9 heterocycloalkyl, heteroaryl, polyheteroaryl, non-aromatic polyheterocycle or mixed aryl and non-aryl polyheterocycle; R15 is selected from H, C1-C6 alkyl, C4-C9 cycloalkyl, C4-C9 heterocycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl and (CH2)mZR12; R16 is selected from C1-C6 alkyl, C4-C9 cycloalkyl, C4-C9 heterocycloalkyl, aryl, heteroaryl, polyheteroaryl, arylalkyl, heteroarylalkyl and (CH2)mZR12; R17 is selected from C1-C6 alkyl, C4-C9 cycloalkyl, C4-C9 heterocycloalkyl, aryl, aromatic polycycle, heteroaryl, arylalkyl, heteroarylalkyl, polyheteroaryl and NR13R14; m is an integer selected from 0 to 6; and Z is selected from O, NR13, 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]phenyl]-2E-2-propenamide, or a pharmaceutically acceptable salt thereof. 23. A compound of claim 1 wherein R3 and R4 are each H. 24. A compound of claim 8, wherein R1, R3 and R4 are each H, X and Y are each H, R20 is H or C1-C4alkyl and p is 1. 25. A pharmaceutical composition of claim 21, which comprises a pharmaceutically effective amount of a compound of formula (Ic) wherein Z1 is N—R20; R18 is H, halo, C1-C6alkyl, C3-C7cycloalkyl, aryl, or heteroaryl; R20 is H, C1-C6alkyl, C1-C6alkyl-C3-C9cycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, acyl or sulfonyl; A1 is 1, 2 or 3 substituents which are independently H, C1-C-6alkyl, —OR19, halo, alkylamino, aminoalkyl, halo, or heteroarylalkyl, R2 is selected from H, C1-C6 alkyl, C4-C9 cycloalkyl, C4-C9 heterocycloalkyl, alkylcycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, —(CH2)nC(O)R6, amino acyl and —(CH2)nR7; R19 is selected from H, C1-C6alkyl, C4-C9cycloalkyl, C4-C9heterocycloalkyl, 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 R18 is H, halo, C1-C6alkyl, C3-C7cycloalkyl, unsubstituted phenyl, substituted phenyl, or heteroaryl, R20 is H, C1-C6alkyl-C1-C6alkyl-C3-C9 cycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, acyl or sulfonyl; A1 is 1, 2 or 3 substituents which are independently H, C1-C6alkyl, —OR19, or halo, or a pharmaceutically acceptable salt thereof. 27. A pharmaceutical composition of claim 25, wherein R1, R3 and R4 are each H, R2 is H or —CH2CH2OH, X and Y are each H, R20 is H or C1-C4alkyl, p is 1 and q is 1.