IP Library › Patent Application 12209419

Patent Application

App. No. 12/209,419

Combination Therapy

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Patent No.: US None
App. No.: 12/209,419

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Abstract

The invention relates to the treatment of mammalian diseases manifested by abnormal cell growth and/or abnormal cell proliferation. More particularly, the invention relates to the use of combination therapies to control abnormal cell growth and/or abnormal cell proliferation. In particular, the invention relates to the use of isotype-selective inhibitors of histone deacetylases 1, 2 and/or 3 (HDACs 1-3), as well as isotype-selective inhibitors of HDAC1 and/or HDAC2, to potentiate therapeutic activity of microtubule-stabilization agents.

Claims (226)

1 . A method for inhibiting abnormal cell growth and/or abnormal cell proliferation in a mammal, comprising administering to a mammal in need thereof an effective amount of a selective inhibitor of histone deacetylase (HDAC)1, HDAC2 and/or HDAC3 in combination with an effective amount of a compound that stabilizes microtubules.

2 . The method according to claim 1 , wherein the selective inhibitor of HDAC1, HDAC2 and/or HDAC 3 has a structure represented by Formula (I), Formula (II) or Formula (III) and N-oxides, hydrates, solvates, pharmaceutically acceptable salts, prodrugs and complexes thereof, and racemic and scalemic mixtures, diastereomers, enantiomers and tautomers thereof, wherein

Formula (I) has the structure

wherein

X is H, halo-, C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy, —CH 2 F, —CHF 2 , —CF 3 , aryl or heteroaryl, each of which is optionally substituted (preferably with one to three substituents independently selected from halo, —CN, —CH═N(OH), hydroxy, C 1 -C 3 -hydrocarbyl, —O—C 1 -C 4 alkyl, methoxy, or mono-, di-, or tri-halo substituted alkyl),

Y is —NH 2 or OH;

Ar is arylene or heteroarylene, each of which is optionally substituted;

A is selected from the group consisting of a covalent bond, M 1 -L 2 -Ml, and L 2 -M 2 -L 2 wherein

L 2 , at each occurrence, is independently selected from the group consisting of a chemical bond, C 0 -C 4 hydrocarbyl, C 0 -C 4 -hydrocarbyl-(NH)-C 0 -C 4 -hydrocarbyl, C 0 -C 4 -hydrocarbyl-(S)—C 0 -C 4 -hydrocarbyl, C 0 -C 4 -hydrocarbyl-(O)—C 0 -C 4 -hydrocarbyl, C 0 -C 4 -hydrocarbyl-SO—C 0 -C 4 -hydrocarbyl, C 0 -C 4 -hydrocarbyl-SO 2 -C 0 -C 4 -hydrocarbyl, C 0 -C 4 -hydrocarbyl-NH—CO—C 0 -C 4 -hydrocarbyl, and C 0 -C 4 -hydrocarbyl-CO—NH—C 0 -C 4 -hydrocarbyl, provided that L 2 is not a chemical bond when X 1 is M 1 -L 2 -M 1 ;

M 1 , at each occurrence, is independently selected from the group consisting of —O—, —N(R 7 )—, —S—, —S(O)—, S(O) 2 —, —S(O) 2 N(R 7 )—, —N(R 7 )—S(O) 2 —, —C(O)—, —C(O)—NH—, —NH—C(O)—, —NH—C(O)—O— and —O—C(O)—NH—, wherein R 7 is selected from the group consisting of hydrogen, alkyl, aryl, aralkyl, acyl, heterocyclyl, and heteroaryl; and

M 2 is selected from the group consisting of M 1 , heteroarylene, and heterocyclylene, either of which rings optionally is substituted; and

L is selected from the group consisting of H, cycloalkyl, aryl, heteroaryl, or heterocyclyl, each of which is optionally substituted and each of which is optionally fused to one or more aryl or heteroaryl rings, or to one or more saturated or partially unsaturated cycloalkyl or heterocyclic rings, each of which rings is optionally substituted;

Formula (II) has the structure:

wherein

X is H, phenyl, thienyl, furanyl, pyridyl or pyrimidyl, each of which is optionally substituted;

Y is —NH 2 ;

A is —N(R 7 )—(CH 2 )—; and

L is -heteroaryl-heteroaryl, -alkyl or heteroaryl, each of which is optionally substituted; wherein

R 7 is selected from the group consisting of hydrogen, alkyl, aryl, aralkyl, acyl, heterocyclyl, and heteroaryl; and

Formula (III) has the structure:

wherein

Cy 5 is aryl, or heteroaryl, each of which is optionally substituted and wherein each of aryl and heteroaryl is optionally fused to one or more aryl or heteroaryl rings, or to one or more saturated or partially unsaturated cycloalkyl or heterocyclic rings, each of which rings is optionally substituted;

X 1 is selected from the group consisting of: a covalent bond, C 0 -C 4 -hydrocarbyl, C 0 -C 4 -hydrocarbyl-(CO)—C 0 -C 4 -hydrocarbyl, C 0 -C 4 -hydrocarbyl-N(R 8 )—C 0 -C 4 -hydrocarbyl, C 0 -C 4 -hydrocarbyl-(S)—C 0 -C 4 -hydrocarbyl, C 0 -C 4 -hydrocarbyl-(O)—C 0 -C 4 -hydrocarbyl, C 0 -C 4 -hydrocarbyl-(SO)—C 0 -C 4 -hydrocarbyl, C 0 -C 4 -hydrocarbyl-(SO 2 )-C 0 -C 4 -hydrocarbyl, C 0 -C 4 -hydrocarbyl-(NH)—(CO)—C 0 -C 4 -hydrocarbyl, C 0 -C 4 -hydrocarbyl -(CO)—(NH)—C 0 -C 4 -hydrocarbyl, —NH—CO—NH—, —NH—CS—NH—, —O—CO—O—, —O—CS—O—, —NH—C(NH)—NH—, —S(O) 2 —N(R 8 )—, —N(R 8 )—S(O) 2 —, —NH—C(O)—O—, and —O—C(O)—NH—;

wherein R 8 is selected from the group consisting of hydrogen, C 1 -C 5 -alkyl, aryl, aralkyl, acyl, heterocyclyl, heteroaryl, SO 2 -alkyl, SO 2 -aryl, CO-alkyl, CO-aryl, CO—NH-alkyl, CO—NH-aryl, CO—O-alkyl and CO—O-aryl, each of which is optionally substituted;

n is 0 to 4;

Y 1 is N or CH; and

T is NH 2 or OH.

3 . The method according to claim 1 , wherein the selective inhibitor of HDAC1, HDAC2 and/or HDAC 3 has the structure

4 . The method according to claim 1 , wherein the compound that stabilizes microtubules is a taxane, an epothilone or an elpothilone analog.

5 . The method according to claim 4 , wherein the taxane is taxol or taxotere.

6 . A method for inhibiting abnormal cell growth and/or abnormal cell proliferation in a mammal, comprising administering to a mammal in need thereof an effective amount of a selective inhibitor of histone deacetylase (HDAC)1, and/or HDAC2 in combination with an effective amount of a compound that stabilizes microtubules.

7 . The method according to claim 6 , wherein the selective inhibitor of HDAC1 and/or HDAC2 has a structure represented by Formula (IV), Formula (IVa) or Formula (V) and N-oxides, hydrates, solvates, pharmaceutically acceptable salts, prodrugs and complexes thereof, and racemic and scalemic mixtures, diastereomers, enantiomers and tautomers thereof, wherein

Formula (IV) has the structure.

wherein

X 2 is aryl, cycloalkyl, heteroaryl or heterocyclyl, each of which is optionally substituted;

Ar 1 is aryl, heteroaryl, cycloalkyl or heterocyclyl, each of which is optionally substituted;

R a is H or an optional substituent, preferably halo;

R b , R c and R d are each independently hydrogen, C 1 -C 8 alkyl, aryl, heteroaryl, cycloalkyl, heterocyclyl or halo; or

R b and R c together with the atoms to which they are bonded, optionally form a 5- or 6-membered cycloalkyl or heterocycloalkyl having 1 or 2 annular heteroatoms; each of which is optionally substituted with from 1 to 3 substituents;

Y 2 is —NH 2 or —OH;

Y b is —N— or —CH—;

Y a is a direct

bond, —O—, —N(R 34 )—, —C(O)—, —OC(O)—, —C(O)O—, —N(R 34 )—C(O)—, —C(O)—N(R 34 )—, —N(R 34 )—C(S) —, —C(S)—N(R 34 )—, —N(R 34 )—C(O)—N(R 35 )—, —N(R 34 )—C(NR 34 )—N(R 35 )—, —N(R 34 )—C(NR 35 ), —C(NR 35 )—N(R 34 )—, —N(R 34 )—C(S)—N(R 35 )—, —N(R 34 )—C(O)—O—, —O—C(O)—N(R 34 )—, —N(R 34 )—C(S)O—, —O—-C(S)—N(R 35 )—, —S(O) 0-2 , —SO 2 N(R 35 )—, —N(R 35 )—SO 2 —, N(R 34 )—S(O) 2 —N(R 35 )—, —O—C 1 -C 3 alkyl-, —N(R 34 )—C 1 -C 3 alkyl-, —C(O)—C 1 -C 3 alkyl- or —O—C(O)—C 1 -C 3 alkyl-;

X a is C 1 -C 8 alkyl-, C 1 -C 8 alkenyl-, C 1 -C 8 alkynyl-, C 0 -C 3 alkyl-C 1 -C 8 alkenyl-C 0 -C 3 alkyl-, C 0 -C 3 alkyl-C 1 -C 8 alkynyl-C 0 -C 3 alkyl-, C 1 -C 3 alkyl-O—C 1 -C 3 alkyl-, HO—C 1 -C 3 alkyl-, C 1 -C 4 alkyl-N(R 34 )—C 0 -C 3 alkyl-, N(R 34 )(R 35 )—C 0 -C 3 alkyl-, C 1 -C 3 alkyl-S(O) 0-2 —C 1 -C 3 alkyl-, CF 3 —C 0 -C 3 alkyl-, CF 2 H-C 0 -C 3 alkyl-, C 1 -C 8 heteroalkyl-, aryl, cycloalkyl, heterocyclyl, heteroaryl, aryl-C 1 -C 3 alkyl-, cycloalkyl-C 1 -C 3 alkyl-, heterocyclyl-C 1 -C 3 alkyl-, heteroaryl-C 1 -C 3 alkyl-, aryl-C 0 -C 2 alkyl-heterocyclyl-C 0 -C 2 alkyl-, heteroaryl-C 0 -C 2 alkyl-heterocyclyl-C 0 -C 2 alkyl-, N(R 34 )(R 35 )-heterocyclyl-C 0 -C 3 alkyl-, heteroaryl-C 0 -C 3 alkyl-heterocyclyl- or C 1 -C 4 alkyl-CH(N(R 34 )(R 35 ))—C(O)—N(R 34 )-aryl-, wherein the aryl, cycloalkyl, heteroaryl and heterocycyl are optionally substituted with from 1 to 3 independently selected substituents;

X a -Y a - is selected from the group consisting of H—, halo-, HO—, HS—, HC(O)—, HOC(O)—, C 1 -C 4 alkyl-, H 2 N—, (R 34 )(R 35 )N—, C 1 -C 4 alkyl-NH—, (C 1 -C 4 alkyl) 2 -N—, HC(O)N(R 34 )—, (R 34 )(R 35 )N—S(O) 2 —N(R 36 )—, (R 34 )(R 35 )N—C(O)—, H 2 N—C(O)—, HC(S)N(R 34 )—, (R 34 )(R 35 )N—C(S)—, H 2 N—C(S)—, (R 34 )(R 35 )N—C(O)—O—, (R 34 )(R 35 )N—C(S)—O—, (R 34 )(R 35 )N—C(O)—N(R 36 )—, (C 1 -C 3 alkylN) 2 —C═N—, (R 34 )(R 35 )N—C(NR 37 )—N(R 36 )—, (R 34 )(R 35 )N—C(NR 36 )—, cycloalkyl-C 0 -C 2 alkyl-C(NR 36 )—, heterocyclyl-C 0 -C 2 alkyl-C(NR 36 )—, aryl-C 0 -C 2 alkyl-C(NR 36 )—, heteroaryl-C 0 -C 2 alkyl-C(NR 36 )—, C 0 -C 3 alkyl-C(NR 36 )—, C 1 -C 4 alkyl-S(O) 2 —N(R 36 )—, CF 3 —C 0 -C 4 alkyl-S(O) 2 —N(R 36 )—, CF 3 —C 0 -C 4 alkyl-C(O)—N(R 36 )—, aryl-C 0 -C 4 alkyl-S(O) 2 —N(R 36 )—, heteroaryl-C 0 -C 4 alkyl-S(O) 2 —N(R 3 )—, cycloalkyl-C 0 -C 4 alkyl-S(O) 2 —N(R 36 )—, heterocyclyl-C 0 -C 4 allyl-O S(O) 2 —N(R 36 )—, C 1 -C 4 alkyl-O—C(O)—NH—, C 1 -C 4 alkyl-O—C(O)—N(H)—C 1 -C 4 alkyl-, C 1 -C 4 alkyl-N(H)—C(O)—N(H)—, C 1 -C 4 alkyl-NH—C(O)—O—, C 1 -C 4 alkyl-C(O)—N(H)—, C 1 -C 4 alkyl-O—C(S)—N(H)—, C 1 -C 4 alkyl-N(H)—C(S)—N(H)—, C 1 -C 4 alkyl-N(H)—C(S)—O—, C 1 -C 4 alkyl-C(S)—N(H)—, Me-C(O)—O—, Me-C(O)—N(H)—, aryl-C 0 -C 4 alkyl-O—C(O)—N(H)—, aryl-C 0 -C 4 alkyl-O—C(O)—N(C 1 -C 4 alkyl)-, aryl-C 0 -C 4 alkyl-C(O)—N(H)—, heteroaryl-C 0 -C 4 alkyl-O—C(O)—N(H)—, heteroaryl-C 0 -C 4 alkyl-O—C(O)—N(C 1 -C 4 alkyl)-, heteroaryl-C 0 -C 4 alkyl-C(O)—N(H)—, aryl-C 0 -C 4 alkyl-N(H)—C(O)—O—, heteroaryl-C 0 -C 4 alkyl-N(H)—C(O)—O—, heterocyclyl-C 0 -C 4 alkyl-O—C(O)—N(H)—, heterocyclyl-C 0 -C 4 alkyl-O—C(O)—N(C 1 -C 4 alkyl)-, heterocyclyl-C 0 -C 4 alkyl-C(O)—N(H)—, cycloalkyl-C 0 -C 4 alkyl-O—C(O)—N(H)—, cycloalkyl-C 0 -C 4 alkyl-O—C(O)—N(C 1 -C 4 alkyl)-, cycloalkyl-C 0 -C 4 alkyl-C(O)—N(H)—, heterocyclyl-C 0 -C 4 alkyl-N(H)—C(O)—O—, cycloalkyl-C 0 -C 4 alkyl-N(H)—C(O)—O—, heterocyclyl-C 0 -C 4 alkyl-C(O)—N(H)—, aryl-C 0 -C 4 alkyl-N(H)—C(O)—N(H)—, aryl-C 0 -C 4 alkyl-N(H)—, aryl-C 0 -C 4 alkyl-O—, aryl-C 0 -C 4 alkyl-S(O) 0-2 —, heteroaryl-C 0 -C 4 alkyl-N(H)—C(O)—N(H)—, heteroaryl-C 0 -C 4 alkyl-N(H)—, heteroaryl-C 0 -C 4 alkyl-O—, heteroaryl-C 0 -C 4 alkyl-S(O) 0-2 —, heterocyclyl-C 0 -C 4 alkyl-N(H)—C(O)—N(H)—, heterocyclyl-C 0 -C 4 alkyl-N(H)—, heterocyclyl-C 0 -C 4 alkyl-O—, heterocyclyl-C 0 -C 4 alkyl-S(O) 0-2 —, cycloalkyl-C 0 -C 4 alkyl-N(H)—C(O)—N(H)—, cycloalkyl-C 0 -C 4 alkyl-N(H)—, cycloalkyl-C 0 -C 4 alkyl-O—, cycloalkyl-C 0 -C 4 alkyl-S(O) 0-2 —, aryl-C 0 -C 4 alkyl-C(S)—N(H)—, heteroaryl-C 0 -C 4 alkyl-C(S)—N(H)—, aryl-C 0 -C 4 alkyl-O—C(S)—N(H)—, heteroaryl-C 0 -C 4 alkyl-O—C(S)—N(H)—, aryl-C 0 -C 4 alkyl-N(H)—C(S)—O—, heteroaryl-C 0 -C 4 alkyl-N(H)—C(S)—O—, heterocyclyl-C 0 -C 4 alkyl-C(S)—N(H)—, cycloalkyl-C 0 -C 4 alkyl-C(S)—N(H)—, heterocyclyl-C 0 -C 4 alkyl-O—C(S)—N(H)—, cycloalkyl-C 0 -C 4 alkyl-O—C(S)—N(H)—, heterocyclyl-C 0 -C 4 alkyl-N(H)—C(S)—O—, cycloalkyl-C 0 -C 4 alkyl-N(H)—C(S)—O—, heterocyclyl-C 0 -C 4 alkyl-C(S)—N(H)—, aryl-C 0 -C 4 alkyl-N(H)—C(S)—NH—, heteroaryl-C 0 -C 4 alkyl-N(H)—C(S)—N(H)—, heterocyclyl-C 0 -C 4 alkyl-N(H)—C(S)—N(H)—, cycloalkyl-C 0 -C 4 alkyl-N(H)—C(S)—N(H)—, C 1 -C 4 alkyl-O—C 1 -C 4 alkyl-C(O)—N(H)—, C 1 -C 4 alkyl-O—C 2 -C 4 alkyl-O—C(O)—N(H)—, C 1 -C 4 alkyl-O—C 2 -C 4 alkyl-N(H)—C(O)—N(H)—, C 1 -C 4 alkyl-O—C 2 -C 4 alkyl-N(H)—, C 1 -C 4 alkyl-O—C 2 -C 4 alkyl-O—, C 1 -C 4 alkyl-O—C 2 -C 4 alkyl-N(H)—C(O)—O—, HO—C 1 -C 4 alkyl-C(O)—N(H)—, HO—C 1 -C 4 alkyl-N(H)—, HO—C 1 -C 4 alkyl-N(R 3 )—, HO—C 1 -C 4 alkyl-O—, HO—C 1 -C 4 alkyl-S(O) 0-2 —, HO—C 2 -C 4 alkyl-O—C(O)—N(H)—, HO—C 2 -C 4 alkyl-N(H)—C(O)—N(H)—, HO—C 2 -C 4 alkyl-N(H)—C(O)—O—, C 1 -C 4 alkyl-O—C 1 -C 4 alkyl-C(S)—N(H)—, C 1 -C 4 alkyl-O—C 2 -C 4 alkyl-O—C(S)—N(H)—, C 1 -C 4 alkyl-O—C 2 -C 4 alkyl-N(H)C(S)—N(H)—, C 1 -C 4 alkyl-O—C 2 -C 4 alkyl-N(H)—C(S)—O—, HO—C 2 -C 4 alkyl-O—C(S)—N(H)—, HO—C 2 -C 4 alkyl-N(H)—C(S)—N(H)—, HO—C 2 -C 4 alkyl-N(H)—C(S)—O—, (C 1 -C 4 alkyl) 2 N—C 1 -C 4 alkyl-C(O)—N(H)—, (CO—C 4 alkyl)-O—C 1 -C 4 alkyl-C(O)—N(H)—, (CO—C 4 alkyl)-O—C 1 -C 4 alkyl-C(S)—N(H)—, (CO—C 4 alkyl)-O—C 1 -C 4 alkyl-C(O)—O—, (CO—C 4 alkyl)-O—C 2 -C 4 alkyl-N(H)—C(O)—N(H)—, (CO—C 4 alkyl)-O—C 2 -C 4 alkyl-O—C(O)—N(H)—, (CO—C 4 alkyl)-O—C 2 -C 4 alkyl-N(H)—C(NH)—N(H)—, (CO—C 4 alkyl)-O—C 2 -C 4 alkyl-N(H)—C(O)—, (C 1 -C 4 alkyl) 2 N—C 2 -C 4 alkyl-O—C(O)—N(H)—, (C 1 -C 4 alkyl) 2 N—C 2 -C 4 alkyl-N(H)—, (C 1 -C 4 alkyl) 2 N—C 2 -C 4 alkyl-O—, (C 1 -C 4 alkyl) 2 N—C 2 -C 4 alkyl-S(O) 0-2 —, (C 1 -C 4 alkyl) 2 N—C 2 -C 4 alkyl-N(H)—C(O)—N(H)—, (C 1 -C 4 alkyl) 2 N—C 2 -C 4 alkyl-N(H)—C(O)—O—, (C 1 -C 4 alkyl) 2 N—C 1 -C 4 alkyl-C(S)—N(H)—, (C 1 -C 4 alkyl) 2 N—C 2 -C 4 alkyl-N(H)—C(S)—N(H)—, (C 1 -C 4 alkyl) 2 N—C 2 -C 4 alkyl-N(H)—C(S)—O—, (C 1 -C 4 alkyl)-O—C(O)C 1 -C 8 alkyl-C(O)—(H)—, HO—C(O)C 1 -C 8 alkyl-C(O)—N(H)—, HO—NH—C(O)C 1 -C 8 alkyl-C(O)—N(H)—, CF 2 H—C 0 -C 4 alkyl-C(O)—N(H)—, CF 3 —C 0 -C 4 alkyl-C(O)—N(H)—, CF 3 —C 0 -C 4 alkyl-N(H)—, CF 3 —C 0 -C 4 alkyl-N(R 3 )—, CF 3 —C 0 -C 4 alkyl-O—, CF 3 —C 0 -C 4 alkyl-S(O) 0-2 —, CF 3 —C 0 -C 4 alkyl-O—C(O)—N(H)—, CF 3 —C 0 -C 4 alkyl-N(H)C(O)—N(H)—, CF 3 —C 0 -C 4 alkyl-N(H)—C(O)—O—, CF 3 —C 0 -C 4 alkyl-O—C(S)—N(H)—, CF 3 —C 0 -C 4 alkyl-N(H)—C(S)—N(H)—, CF 3 —C 0 -C 4 alkyl-N(H)—C(S)—O—, CF 3 -C 0 -C 4 alkyl-C(S)—N(H)—, CF 2 H—C 0 -C 4 alkyl-N(H)—, CF 2 H—C 0 -C 4 alkyl-O—, CF 2 H—C 0 -C 4 alkyl-S(O) 0-2 —, CF 2 H—C 0 -C 4 alkyl-O—C(O)—N(H)—, CF 2 H—C 0 -C 4 alkyl-N(H)C(O)—N(H)—, CF 2 H—C 0 -C 4 alkyl-N(H)—C(O)—O—, CF 2 H—C 0 -C 4 alkyl-O—C(S)—N(H)—, CF 2 H—C 0 -C 4 alkyl-N(H)—C(S)—N(H)—, CF 2 H—C 0 -C 4 alkyl-N(H)—C(S)—O—, CF 2 H—C 0 -C 4 alkyl-C(S)—N(H)—, (H)(R 34 )N—C 1 -C 3 alkyl-, (H)(R 34 )N—C 1 -C 3 alkyl-, HO—C 1 -C 3 alkyl-, (H)(R 34 )N—S(O) 2 —N(R 35 )—, (H)(R 35 )N—S(O) 2 —, (H)(R 34 )N—C(S)—O—, (H)(R 34 )N—C(O)—O—, (H)(R 34 )N—C(S)—N(R 35 )—, (H)(R 34 )N—C(NR 35 )—, (H)(R 34 )N—C(NR 34 )—N(R 38 )—, (H)(R 34 )N—C(O)—N(R 35 )—, HO—C(O)—C 1 -C 3 alkyl-, C 1 -C 4 alkyl-S(O) 2 —NH— and ((R 34 )(R 35 )N) 2 —C═N—;

m and n are independently 0, 1, 2 or 3;

q is 0, 1 or 2; and

R 34 , R 35 , R 36 and R 37 are each independently selected from the group consisting of hydrogen, cyano, oxo, hydroxyl, —C 1 -C 8 alkyl, C 1 -C 8 heteroalkyl, C 1 -C 8 alkenyl, carboxamido, C 1 -C 3 alkyl-carboxamido-, carboxamido-C 1 -C 3 alkyl-, amidino, C 2 -C 8 hydroxyalkyl, C 1 -C 3 alkylaryl-, aryl-C 1 -C 3 alkyl-, C 1 -C 3 alkylheteroaryl-, heteroaryl-C 1 -C 3 alkyl-, C 1 -C 3 alkylheterocyclyl-, heterocyclyl-C 1 -C 3 alkyl-, C 1 -C 3 alkylcycloalkyl-, cycloalkyl-C 1 -C 3 alkyl-, C 2 -C 8 alkoxy-, C 2 -C 8 alkoxy-C 1 -C 4 alkyl-, C 1 -C 8 alkoxycarbonyl-, aryloxycarbonyl-, aryl-C 1 -C 3 alkoxycarbonyl-, heteroaryloxycarbonyl-, heteroaryl-C 1 -C 3 alkoxycarbonyl-, C 1 -C 8 acyl, C 0 -C 8 alkyl-carbonyl-, aryl-C 0 -C 8 alkyl-carbonyl-, heteroaryl-C 0 -C 8 alkyl-carbonyl-, cycloalkyl-C 0 -C 8 alkyl-carbonyl-, C 0 -C 8 alkyl-N(H)-carbonyl-, aryl-C 0 -C 8 alkyl-N(H)-carbonyl-, heteroaryl-C 0 -C 8 alkyl-N(H)-carbonyl-, cycloalkyl-C 0 -C 8 alkyl-N(H)-carbonyl-, C 0 -C 8 alkyl-O-carbonyl-, aryl-C 0 -C 8 alkyl-O-carbonyl-, heteroaryl-C 0 -C 8 alkyl-O-carbonyl-, cycloalkyl-C 0 -C 8 alkyl-O-carbonyl-, C 1 -C 8 alkylsulfonyl-, arylalkylsulfonyl-, arylsulfonyl-, heteroarylalkylsulfonyl-, heteroarylsulfonyl-, C 1 -C 8 alkyl-N(H)-sulfonyl-, arylalkyl-N(H)-sulfonyl-, aryl-N(H)-sulfonyl-, heteroarylalkyl-N(H)-sulfonyl-, heteroaryl-N(H)-sulfonyl, aroyl, aryl, cycloalkyl, heterocyclyl, heteroaryl, aryl-C 1 -C 3 alkyl-, cycloalkyl-C 1 -C 3 alkyl-, heterocyclyl-C 1 -C 3 alkyl-, heteroaryl-C 1 -C 3 alkyl-, and a protecting group, wherein each of the foregoing is further optionally substituted with one more moieties; or

R 34 and R 35 taken together with the N to which they are attached form a heterocyclyl or heteroaryl, each of which is optionally substituted with from 1 to 3 substituents, wherein the heterocyclyl may also be bridged (forming a bicyclic moiety with a methylene, ethylene or propylene bridge),

provided that 1) when Y b is N, then m is not 0 if Y a is bound to the ring comprising Y, via a N, S or O in Y a , or 2) when m and n are both 0 then Y b is —CH—;

Formula (IVa) has the structure:

wherein m, n, R 34 and R 35 are as defined for formula (IV); and

Formula (V) has the structure:

wherein

X 3 is aryl, cycloalkyl, heteroaryl or heterocyclyl, each of which is optionally substituted;

Y 3 is —NH 2 or —OH;

Ar 2 is optionally substituted aryl or optionally substituted heteroaryl; and

Het is an optionally substituted heterocyclyl.

8 . The method according to claim 6 , wherein the selective inhibitor of HDAC1 and/or HDAC2 has the structure

9 . The method according to claim 6 , wherein the compound that stabilizes microtubules is a taxane, an epothilone or an elpothilone analog.

10 . The method according to claim 9 , wherein the taxane is taxol or taxotere.

11 . A method for inhibiting abnormal cell growth and/or abnormal cell proliferation in a mammal, comprising up-regulating the expression of metalothionene 3 (MT3) in the cells and/or up-regulating the expression of thrombospondin-1 (TSP1) in the cells, in combination with administering a compound that stabilizes microtubules.

12 . The method according to claim 11 , wherein the compound that stabilizes microtubules is a taxane, an epothilone or an elpothilone analog.

13 . The method according to claim 12 , wherein the taxane is taxol or taxotere.

14 . A method for inhibiting abnormal cell growth and/or abnormal cell proliferation in a mammal, the method comprising administering to a mammal in need thereof an agonist of TSP1 receptor in combination with a compound that stabilizes microtubules.

15 . The method according to claim 14 , wherein the compound that stabilizes microtubules is a taxane, an epothilone or an elpothilone analog.

16 . The method according to claim 15 , wherein the taxane is taxol or taxotere.

17 . A method for inhibiting abnormal cell growth and/or abnormal cell proliferation in a mammal, the method comprising up-regulating the expression of thrombospondin-1 (TSP1) in the cell, in combination with administering a compound that stabilizes microtubules.

18 . The method according to claim 17 , wherein the compound that stabilizes microtubules is a taxane, an epothilone or an elpothilone analog.

19 . The method according to claim 18 , wherein the taxane is taxol or taxotere.

20 . A method for inhibiting abnormal cell growth and/or abnormal cell proliferation in a mammal, comprising up-regulating the expression of metalothionene 3 (MT3) in the cell and/or up-regulating the expression of thrombospondin-1 (TSP1) in the cell, in combination with administering a compound that stabilizes microtubules.

21 . The method according to claim 20 , wherein the compound that stabilizes microtubules is a taxane, an epothilone or an elpothilone analog.

22 . The method according to claim 21 , wherein the taxane is taxol or taxotere.

23 . A method for inhibiting angiogenesis in a mammal, comprising administering an effective amount of a selective inhibitor of histone deacetylase (HDAC)1, HDAC2 and/or HDAC3.

24 . The method according to claim 23 wherein the selective inhibitor of HDAC1, HDAC2 and/or HDAC 3 has a structure represented by Formula (I), Formula (II) or Formula (III) and N-oxides, hydrates, solvates, pharmaceutically acceptable salts, prodrugs and complexes thereof, and racemic and scalemic mixtures, diastereomers, enantiomers and tautomers thereof, wherein

Formula (I) has the structure

wherein

Y is —NH 2 or OH;

Ar is arylene or heteroarylene, each of which is optionally substituted;

A is selected from the group consisting of a covalent bond, M 1 -L 2 -M 1 , and L 2 -M 2 -L 2 wherein

L 2 , at each occurrence, is independently selected from the group consisting of a chemical bond, C 0 -C 4 hydrocarbyl, C 0 -C 4 -hydrocarbyl-(NH)—C 0 -C 4 -hydrocarbyl, C 0 -C 4 -hydrocarbyl-(S)—C 0 -C 4 -hydrocarbyl, C 0 -C 4 -hydrocarbyl-(O)—C 0 -C 4 -hydrocarbyl, C 0 -C 4 -hydrocarbyl-SO—C 0 -C 4 -hydrocarbyl, C 0 -C 4 -hydrocarbyl-SO 2 —C 0 -C 4 -hydrocarbyl, C 0 -C 4 -hydrocarbyl-NH—C 0 -C 0 -C 4 -hydrocarbyl, and C 0 -C 4 -hydrocarbyl-CO—NH—C 0 -C 4 -hydrocarbyl, provided that L 2 is not a chemical bond when X 1 is M 1 -L 2 -M 1 ;

M 2 is selected from the group consisting of M 1 , heteroarylene, and heterocyclylene, either of which rings optionally is substituted; and

Formula (II) has the structure:

wherein

X is H, phenyl, thienyl, furanyl, pyridyl or pyrimidyl, each of which is optionally substituted;

Y is —NH 2 ;

A is —N(R 7 )—(CH 2 )—; and

L is -heteroaryl-heteroaryl, -alkyl or heteroaryl, each of which is optionally substituted; wherein

R 7 is selected from the group consisting of hydrogen, alkyl, aryl, aralkyl, acyl, heterocyclyl, and heteroaryl; and

Formula (III) has the structure:

wherein

wherein R 8 is selected from the group consisting of hydrogen, C 1 -C 8 -alkyl, aryl, aralkyl, acyl, heterocyclyl, heteroaryl, SO 2 -alkyl, SO 2 -aryl, CO-alkyl, CO-aryl, CO—NH-alkyl, CO—NH-aryl, CO—O-alkyl and CO—O-aryl, each of which is optionally substituted;

n is 0 to 4;

Y 1 is N or CH; and

T is NH 2 or OH.

25 . The method according to claim 23 , wherein the selective inhibitor of HDAC1, HDAC2 and/or HDAC 3 has the structure

26 . The method according to claim 23 , wherein the compound that stabilizes microtubules is a taxane, an epothilone or an elpothilone analog.

27 . The method according to claim 26 , wherein the taxane is taxol or taxotere.

28 . A method for inducing expression of an anti-angiogenesis factor in a cell, the method comprising administering to the cell a selective inhibitor of histone deacetylase (HDAC)1, HDAC2 and/or HDAC3.

29 . The method according to claim 28 , wherein the selective inhibitor of HDAC1, HDAC2 and/or HDAC 3 has a structure represented by Formula (I), Formula (II) or Formula (III) and N-oxides, hydrates, solvates, pharmaceutically acceptable salts, prodrugs and complexes thereof, and racemic and scalemic mixtures, diastereomers, enantiomers and tautomers thereof, wherein

Formula (I) has the structure

wherein

Y is —NH 2 or OH;

Ar is arylene or heteroarylene, each of which is optionally substituted;

A is selected from the group consisting of a covalent bond, M 1 -L 2 -Ml, and L 2 -M 2 -L 2 wherein

L 2 , at each occurrence, is independently selected from the group consisting of a chemical bond, C 0 -C 4 hydrocarbyl, C 0 -C 4 -hydrocarbyl-(NH)—C 0 -C 4 -hydrocarbyl, C 0 -C 4 -hydrocarbyl-(S)—C 0 -C 4 -hydrocarbyl, C 0 -C 4 -hydrocarbyl-(O)—C 0 -C 4 -hydrocarbyl, C 0 -C 4 -hydrocarbyl-SO—C 0 -C 4 -hydrocarbyl, C 0 -C 4 -hydrocarbyl-SO 2 —C 0 -C 4 -hydrocarbyl, C 0 -C 4 -hydrocarbyl-NH—CO—C 0 -C 4 -hydrocarbyl, and C 0 -C 4 -hydrocarbyl-CO—NH—C 0 -C 4 -hydrocarbyl, provided that L 2 is not a chemical bond when X 1 is M 1 -L 1 -M 1 ;

M 2 is selected from the group consisting of M 1 , heteroarylene, and heterocyclylene, either of which rings optionally is substituted; and

Formula (II) has the structure:

wherein

X is H, phenyl, thienyl, furanyl, pyridyl or pyrimidyl, each of which is optionally substituted;

Y is —NH 2 ;

A is —N(R 7 )—(CH 2 )—; and

L is -heteroaryl-heteroaryl, -alkyl or heteroaryl, each of which is optionally substituted; wherein R 7 is selected from the group consisting of hydrogen, alkyl, aryl, aralkyl, acyl, heterocyclyl, and heteroaryl; and

Formula (III) has the structure:

wherein

n is 0 to 4;

Y 1 is N or CH; and

T is NH 2 or OH.

30 . The method according to claim 28 , wherein the selective inhibitor of HDAC1, HDAC2 and/or HDAC 3 has the structure

31 . The method according to claim 28 , wherein the compound that stabilizes microtubules is a taxane, an epothilone or an elpothilone analog.

32 . The method according to claim 31 , wherein the taxane is taxol or taxotere.

33 . A method for inhibiting expression of an angiogenesis factor in a cell, the method comprising administering to the cell a selective inhibitor of histone deacetylase (HDAC)1, HDAC2 and/or HDAC3.

34 . The method according to claim 33 , wherein the selective inhibitor of HDAC1, HDAC2 and/or HDAC 3 has a structure represented by Formula (I), Formula (II) or Formula (III) and N-oxides, hydrates, solvates, pharmaceutically acceptable salts, prodrugs and complexes thereof, and racemic and scalemic mixtures, diastereomers, enantiomers and tautomers thereof, wherein

Formula (I) has the structure

wherein

Y is —NH 2 or OH;

Ar is arylene or heteroarylene, each of which is optionally substituted;

A is selected from the group consisting of a covalent bond, M 1 -L 2 -M 1 , and L 2 -M 2 -L 2 wherein

L 2 , at each occurrence, is independently selected from the group consisting of a chemical bond, C 0 -C 4 hydrocarbyl, C 0 -C 4 -hydrocarbyl-(NH)—C 0 -C 4 -hydrocarbyl, C 0 -C 4 -hydrocarbyl-(S)—C 0 -C 4 -hydrocarbyl, C 0 -C 4 -hydrocarbyl-(O)—C 0 -C 4 -hydrocarbyl, C 0 -C 4 -hydrocarbyl-SO—C 0 -C 4 -hydrocarbyl, C 0 -C 4 -hydrocarbyl-SO 2 —C 0 -C 4 -hydrocarbyl, C 0 -C 4 -hydrocarbyl-NH—CO—C 0 -C 4 -hydrocarbyl, and C 0 -C 4 -hydrocarbyl-CO—NH—C 0 -C 4 -hydrocarbyl, provided that L 2 is not a chemical bond when X 1 is M 1 -L 2 -M 1 ;

M 2 is selected from the group consisting of M 1 , heteroarylene, and heterocyclylene, either of which rings optionally is substituted; and

Formula (II) has the structure:

wherein

X is H, phenyl, thienyl, furanyl, pyridyl or pyrimidyl, each of which is optionally substituted;

Y is —NH 2 ;

A is —N(R 7 )—(CH 2 )—; and

L is -heteroaryl-heteroaryl, -alkyl or heteroaryl, each of which is optionally substituted; wherein

R 7 is selected from the group consisting of hydrogen, alkyl, aryl, aralkyl, acyl, heterocyclyl, and heteroaryl; and

Formula (III) has the structure:

wherein

n is 0 to 4;

Y 1 is N or CH; and

T is NH 2 or OH.

35 . The method according to claim 33 , wherein the selective inhibitor of HDAC1, HDAC2 and/or HDAC 3 has the structure

36 . The method according to claim 33 , wherein the compound that stabilizes microtubules is a taxane, an epothilone or an elpothilone analog.

37 . The method according to claim 36 , wherein the taxane is taxol or taxotere.

38 . A method for controlling abnormal cell growth and/or abnormal cell proliferation in a patient, comprising administering to a patient in need thereof an effective amount of a selective inhibitor of histone deacetylase (HDAC)1, HDAC2 and/or HDAC3 in combination with an effective amount of a compound that stabilizes microtubules.

39 . The method according to claim 38 , wherein the selective inhibitor of HDAC1, HDAC2 and/or HDAC 3 has a structure represented by Formula (I), Formula (II) or Formula (III) and N-oxides, hydrates, solvates, pharmaceutically acceptable salts, prodrugs and complexes thereof, and racemic and scalemic mixtures, diastereomers, enantiomers and tautomers thereof, wherein

Formula (I) has the structure

wherein

Y is —NH 2 or OH;

Ar is arylene or heteroarylene, each of which is optionally substituted;

A is selected from the group consisting of a covalent bond, M 1 -L 2 -M 1 , and L 2 -M 2 -L 2 wherein

L 2 , at each occurrence, is independently selected from the group consisting of a chemical bond, C 0 -C 4 hydrocarbyl, C 0 -C 4 -hydrocarbyl-(NH)—C 0 -C 4 -hydrocarbyl, C 0 -C 4 -hydrocarbyl-(S)—C 0 -C 4 -hydrocarbyl, C 0 -C 4 -hydrocarbyl-(O)—C 0 -C 4 -hydrocarbyl, C 0 -C 4 -hydrocarbyl-SO—C 0 -C 4 -hydrocarbyl, C 0 -C 4 -hydrocarbyl-SO 2 —C 0 -C 4 -hydrocarbyl, C 0 -C 4 -hydrocarbyl-NH—CO—C 0 -C 4 -hydrocarbyl, and C 0 -C 4 -hydrocarbyl-CO—NH—C 0 -C 4 -hydrocarbyl, provided that L 2 is not a chemical bond when X 1 is M 1 -L 2 -M 1 ;

M 2 is selected from the group consisting of M 1 , heteroarylene, and heterocyclylene, either of which rings optionally is substituted; and

Formula (II) has the structure:

wherein

X is H, phenyl, thienyl, furanyl, pyridyl or pyrimidyl, each of which is optionally substituted;

Y is —NH 2 ;

A is —N(R 7 )—(CH 2 )—; and

L is -heteroaryl-heteroaryl, -alkyl or heteroaryl, each of which is optionally substituted; wherein

R 7 is selected from the group consisting of hydrogen, alkyl, aryl, aralkyl, acyl, heterocyclyl, and heteroaryl; and

Formula (III) has the structure:

wherein

n is 0 to 4;

Y 1 is N or CH; and

T is NH 2 or OH.

40 . The method according to claim 38 , wherein the selective inhibitor of HDAC1, HDAC2 and/or HDAC 3 has the structure

41 . The method according to claim 38 , wherein the compound that stabilizes microtubules is a taxane, an epothilone or an elpothilone analog.

42 . The method according to claim 41 , wherein the taxane is taxol or taxotere.

43 . A method for controlling abnormal cell growth and/or abnormal cell proliferation in a patient, comprising administering to a patient in need thereof an effective amount of a selective inhibitor of histone deacetylase (HDAC)1 and/or HDAC2 in combination with an effective amount of a compound that stabilizes microtubules.

44 . The method according to claim 43 , wherein the selective inhibitor of HDAC1 and/or HDAC2 has a structure represented by Formula (IV), Formula (IVa) or Formula (V) and N-oxides, hydrates, solvates, pharmaceutically acceptable salts, prodrugs and complexes thereof, and racemic and scalemic mixtures, diastereomers, enantiomers and tautomers thereof, wherein

Formula (IV) has the structure.

wherein

X 2 is aryl, cycloalkyl, heteroaryl or heterocyclyl, each of which is optionally substituted;

Ar 1 is aryl, heteroaryl, cycloalkyl or heterocyclyl, each of which is optionally substituted;

R a is H or an optional substituent, preferably halo;

R b , R c and R d are each independently hydrogen, C 1 -C 8 alkyl, aryl, heteroaryl, cycloalkyl, heterocyclyl or halo; or

Y 2 is —NH 2 or —OH;

Y b is —N— or —CH—;

Y a is a direct

bond, —O—, —N(R 34 )—, —C(O)—, —OC(O)—, —C(O)O—, —N(R 34 )—C(O)—, —C(O)—N(R 34 )—, —N(R 34 )—C(S)—, —C(S)—N(R 34 ), —N(R 34 )—C(O)—N(R 3 )—, —N(R 34 )—C(NR 34 )—N(R 35 )—, —N(R 34 )—C(R 35 )—, —C(NR 35 ) —N(R 34 )—, —N(R 34 )—C(S)—N(R 35 )—, —N(R 34 )—C(O)—O—, —O—C(O)—N(R 34 )—, —N(R 34 )—C(S)O—, —O—C(S) —N(R 35 )—, —S(O) 0-2 , —SO 2 N(R 35 )—, —N(R 35 )—SO 2 —N(R 34 )—S(O) 2 —N(R 35 )—, —O—C 1 -C 3 alkyl-, —N(R 34 )—C 1 -C 3 alkyl-, —C(O)—C 1 -C 3 alkyl- or —O—C(O)—C 1 -C 3 alkyl-;

X a is C 1 -C 8 alkyl-, C 1 -C 8 alkenyl-, C 1 -C 8 alkynyl-, C 0 -C 3 alkyl-C 1 -C 8 alkenyl-C 0 -C 3 alkyl-, C 0 -C 3 alkyl-C 1 -C 8 alkynyl-C 0 -C 3 alkyl-, C 1 -C 3 alkyl-O—C 1 -C 3 alkyl-, HO—C 1 -C 3 alkyl-, C 1 -C 4 alkyl-N(R 34 )—C 0 -C 3 alkyl-, N(R 34 )(R 35 )—C 0 -C 3 alkyl-, C 1 -C 3 alkyl-S(O) 0-2 —C 1 -C 3 alkyl-, CF 3 —C 0 -C 3 alkyl-, CF 2 H—C 0 -C 3 alkyl-, C 1 -C 8 heteroalkyl-, aryl, cycloalkyl, heterocyclyl, heteroaryl, aryl-C 1 -C 3 alkyl-, cycloalkyl-C 1 -C 3 alkyl-, heterocyclyl-C 1 -C 3 alkyl-, heteroaryl-C 1 -C 3 alkyl-, aryl-C 0 -C 2 alkyl-heterocyclyl-C 0 -C 2 alkyl-, heteroaryl-C 0 -C 2 alkyl-heterocyclyl-C 0 -C 2 alkyl-, N(R 34 )(R 35 )-heterocyclyl-C 0 -C 3 alkyl-, heteroaryl-C 0 -C 3 alkyl-heterocyclyl- or C 1 -C 4 alkyl-CH(N(R 34 )(R 35 ))—C(O)—N(R 34 )-aryl-, wherein the aryl, cycloalkyl, heteroaryl and heterocycyl are optionally substituted with from 1 to 3 independently selected substituents;

X a -Y a - is selected from the group consisting of H—, halo-, HO—, HS—, HC(O)—, HOC(O)—, C 1 -C 4 alkyl-, H 2 N—, (R 34 )(R 35 )N—, C 1 -C 4 alkyl-NH—, (C 1 -C 4 alkyl) 2 -N—, HC(O)N(R 34 )—, (R 34 )(R 35 )N—S(O) 2 —N(R 36 )—, (R 34 )(R 35 )N—C(O)—, H 2 N—C(O)—, HC(S)N(R 34 )—, (R 34 )(R 35 )N—C(S)—, H 2 N—C(S)—, (R 34 )(R 35 )N—C(O)—O—, (R 34 )(R 35 )N—C(S)—O—, (R 34 )(R 35 )N—C(O)—N(R 36 )—, (C 1 -C 3 alkylN) 2 —C═N—, (R 34 )(R 35 )N—C(NR 37 )—N(R 36 ), (R 34 )(R 35 )N—C(NR 36 )—, cycloalkyl-C 0 -C 2 alkyl-C(NR 36 )—, heterocyclyl-C 0 -C 2 alkyl-C(NR 36 )—, aryl-C 0 -C 2 alkyl-C(NR 36 )—, heteroaryl-C 0 -C 2 alkyl-C(NR 36 )—, C 0 -C 3 alkyl-C(NR 36 )—, C 1 -C 4 alkyl-S(O) 2 —N(R 36 )—, CF 3 —C 0 -C 4 alkyl-S(O) 2 —N(R 36 )—, CF 3 —C 0 -C 4 alkyl-C(O)—N(R 36 )—, aryl-C 0 -C 4 alkyl-S(O) 2 —N(R 36 )—, heteroaryl-C 0 -C 4 alkyl-S(O) 2 —N(R 36 )—, cycloalkyl-C 0 -C 4 alkyl-S(O) 2 —N(R 36 )—, heterocyclyl-C 0 -C 4 alkyl-S(O) 2 —N(R 36 )—, C 1 -C 4 alkyl-O—C(O)—NH—, C 1 -C 4 alkyl-O—C(O)—N(H)—C 1 -C 4 alkyl-, C 1 -C 4 alkyl-N(H)—C(O)—N(H)—, C 1 -C 4 alkyl-NH—C(O)—O—, C 1 -C 4 alkyl-C(O)—N(H)—, C 1 -C 4 alkyl-O—C(S)—N(H)—, C 1 -C 4 alkyl-N(H)—C(S)—N(H)—, C 1 -C 4 alkyl-N(H)—C(S)—O—, C 1 -C 4 alkyl-C(S)—N(H)—, Me-C(O)—O—, Me-C(O)—N(H)—, aryl-C 0 -C 4 alkyl-O—C(O)—N(H)—, aryl-C 0 -C 4 alkyl-O—C(O)—N(C 1 -C 4 alkyl)-, aryl-C 0 -C 4 alkyl-C(O)—N(H)—, heteroaryl-C 0 -C 4 alkyl-O—C(O)—N(H)—, heteroaryl-C 0 -C 4 alkyl-O—C(O)—N(C 1 -C 4 alkyl)-, heteroaryl-C 0 -C 4 alkyl-C(O)—N(H)—, aryl-C 0 -C 4 alkyl-N(H)—C(O)—O—, heteroaryl-C 0 -C 4 alkyl-N(H)—C(O)—O—, heterocyclyl-C 0 -C 4 alkyl-O—C(O)—N(H)—, heterocyclyl-C 0 -C 4 alkyl-O—C(O)—N(C 1 -C 4 alkyl)-, heterocyclyl-C 0 -C 4 alkyl-C(O)—N(H)—, cycloalkyl-C 0 -C 4 alkyl-O—C(O)—N(H)—, cycloalkyl-C 0 -C 4 alkyl-O—C(O)—N(C 1 -C 4 alkyl)-, cycloalkyl-C 0 -C 4 alkyl-C(O)—N(H)—, heterocyclyl-C 0 -C 4 alkyl-N(H)—C(O)—O—, cycloalkyl-C 0 -C 4 alkyl-N(H)—C(O)—O—, heterocyclyl-C 0 -C 4 alkyl-C(O)—N(H)—, aryl-C 0 -C 4 alkyl-N(H)—C(O)—N(H)—, aryl-C 0 -C 4 alkyl-N(H)—, aryl-C 0 -C 4 alkyl-O—, aryl-C 0 -C 4 alkyl-S(O) 0-2 —, heteroaryl-C 0 -C 4 alkyl-N(H)—C(O)—N(H)—, heteroaryl-C 0 -C 4 alkyl-N(H)—, heteroaryl-C 0 -C 4 alkyl-O—, heteroaryl-C 0 -C 4 alkyl-S(O) 0-2 —, heterocyclyl-C 0 -C 4 alkyl-N(H)—C(O)—N(H)—, heterocyclyl-C 0 -C 4 alkyl-N(H)—, heterocyclyl-C 0 -C 4 alkyl-O—, heterocyclyl-C 0 -C 4 alkyl-S(O) 0-2 —, cycloalkyl-C 0 -C 4 alkyl-N(H)—C(O)—N(H)—, cycloalkyl-C 0 -C 4 alkyl-N(H)—, cycloalkyl-C 0 -C 4 alkyl-O—, cycloalkyl-C 0 -C 4 alkyl-S(O) 0-2 —, aryl-C 0 -C 4 alkyl-C(S)—N(H)—, heteroaryl-C 0 -C 4 alkyl-C(S)—N(H)—, aryl-C 0 -C 4 alkyl-O—C(S)—N(H)—, heteroaryl-C 0 -C 4 alkyl-O—C(S)—N(H)—, aryl-C 0 -C 4 alkyl-N(H)—C(S)—O—, heteroaryl-C 0 -C 4 alkyl-N(H)—C(S)—O—, heterocyclyl-C 0 -C 4 alkyl-C(S)—N(H)—, cycloalkyl-C 0 -C 4 alkyl-C(S)—N(H)—, heterocyclyl-C 0 -C 4 alkyl-O—C(S)—N(H)—, cycloalkyl-C 0 -C 4 alkyl-O—C(S)—N(H)—, heterocyclyl-C 0 -C 4 alkyl-N(H)—C(S)—O—, cycloalkyl-C 0 -C 4 alkyl-N(H)—C(S)—O—, heterocyclyl-C 0 -C 4 alkyl-C(S)—N(H)—, aryl-C 0 -C 4 alkyl-N(H)—C(S)—NH—, heteroaryl-C 0 -C 4 alkyl-N(H)—C(S)—N(H)—, heterocyclyl-C 0 -C 4 alkyl-N(H)—C(S)—N(H)—, cycloalkyl-C 0 -C 4 alkyl-N(H)—C(S)—N(H)—, C 1 -C 4 alkyl-O—C 1 -C 4 alkyl-C(O)—N(H)—, C 1 -C 4 alkyl-O—C 2 -C 4 alkyl-O—C(O)—N(H)—, C 1 -C 4 alkyl-O—C 2 -C 4 alkyl-N(H)—C(O)—N(H)—, C 1 -C 4 alkyl-O—C 2 -C 4 alkyl-N(H)—, C 1 -C 4 alkyl-O—C 2 -C 4 alkyl-O—, C 1 -C 4 alkyl-O—C 2 -C 4 alkyl-N(H)—C(O)—O—, HO—C 1 -C 4 alkyl-C(O)—N(H)—, HO—C 1 -C 4 alkyl-N(H)—, HO—C 1 -C 4 alkyl-N(R 3 )—, HO—C 1 -C 4 alkyl-O—, HO—C 1 -C 4 alkyl-S(O) 0-2 —, HO—C 2 -C 4 alkyl-O—C(O)—N(H)—, HO—C 2 -C 4 alkyl-N(H)—C(O)—N(H)—, HO—C 2 -C 4 alkyl-N(H)—C(O)—O—, C 1 -C 4 alkyl-O—C 1 -C 4 alkyl-C(S)—N(H)—, C 1 -C 4 alkyl-O—C 2 -C 4 alkyl-O—C(S)—N(H)—, C 1 -C 4 alkyl-O—C 2 -C 4 alkyl-N(H)C(S)—N(H)—, C 1 -C 4 alkyl-O—C 2 -C 4 alkyl-N(H)—C(S)—O—, HO—C 2 -C 4 alkyl-O—C(S)—N(H)—, HO—C 2 -C 4 alkyl-N(H)—C(S)—N(H)—, HO—C 2 -C 4 alkyl-N(H)—C(S)—O—, (C 1 -C 4 alkyl) 2 N—C 1 -C 4 alkyl-C(O)—N(H)—, (C 0 -C 4 alkyl)-O—C 1 -C 4 alkyl-C(O)—N(H)—, (C 0 -C 4 alkyl)-O—C 1 -C 4 alkyl-C(S)—N(H)—, (C 0 -C 4 alkyl)-O—C 1 -C 4 alkyl-C(O)—O—, (C 0 -C 4 alkyl)-O—C 2 -C 4 alkyl-N(H)—C(O)—N(H)—, (C 0 -C 4 alkyl)-O—C 2 -C 4 alkyl-O—C(O)—N(H)—, (C 0 -C 4 alkyl)-O—C 2 -C 4 alkyl-N(H)—C(NH)—N(H)—, (C 0 -C 4 alkyl)-O—C 2 -C 4 alkyl-N(H)—C(O)—, (C 1 -C 4 alkyl) 2 N—C 2 -C 4 alkyl-O—C(O)—N(H)—, (C 1 -C 4 alkyl) 2 N—C 2 -C 4 alkyl-N(H)—, (C 1 -C 4 alkyl) 2 N—C 2 -C 4 alkyl-O—, (C 1 -C 4 alkyl) 2 N—C 2 -C 4 alkyl-S(O) 0-2 —, (C 1 -C 4 alkyl) 2 N—C 2 -C 4 alkyl-N(H)—C(O)—N(H)—, (C 1 -C 4 alkyl) 2 N—C 2 -C 4 alkyl-N(H)—C(O)—O—, (C 1 -C 4 alkyl) 2 N—C 1 -C 4 alkyl-C(S)—N(H)—, (C 1 -C 4 alkyl) 2 N—C 2 -C 4 alkyl-N(H)—C(S)—N(H)—, (C 1 -C 4 alkyl) 2 N—C 2 -C 4 alkyl-N(H)—C(S)—O—, (C 1 -C 4 alkyl)-O—C(O)C 1 -C 8 alkyl-C(O)—(H)—, HO—C(O)C 1 -C 8 alkyl-C(O)—N(H)—, HO—NH—C(O)C 1 -C 8 alkyl-C(O)—N(H)—, CF 2 H—C 0 -C 4 alkyl-C(O)—N(H)—, CF 3 —C 0 -C 4 alkyl-C(O)—N(H)—, CF 3 —C 0 -C 4 alkyl-N(H)—, CF 3 —C 0 -C 4 alkyl-N(R 3 )—, CF 3 —C 0 -C 4 alkyl-O—, CF 3 —C 0 -C 4 alkyl-S(O) 0-2 —, CF 3 —C 0 -C 4 alkyl-O—C(O)—N(H)—, CF 3 —C 0 -C 4 alkyl-N(H)C(O)—N(H)—, CF 3 —C 0 -C 4 alkyl-N(H)—C(O)—O—, CF 3 —C 0 -C 4 alkyl-O—C(S)—N(H)—, CF 3 —C 0 -C 4 alkyl-N(H)—C(S)—N(H)—, CF 3 —C 0 -C 4 alkyl-N(H)—C(S)—O—, CF 3 —C 0 -C 4 alkyl-C(S)—N(H)—, CF 2 H—C 0 -C 4 alkyl-N(H)—, CF 2 H—C 0 -C 4 alkyl-O—, CF 2 H-C 0 -C 4 alkyl-S(O) 0-2 —, CF 2 H—C 0 -C 4 alkyl-O—C(O)—N(H)—, CF 2 H—C 0 -C 4 alkyl-N(H)C(O)—N(H)—, CF 2 H—C 0 -C 4 alkyl-N(H)—C(O)—O—, CF 2 H—C 0 -C 4 alkyl-O—C(S)—N(H)—, CF 2 H—C 0 -C 4 alkyl-N(H)—C(S)—N(H)—, CF 2 H—C 0 -C 4 alkyl-N(H)—C(S)—O—, CF 2 H-C 0 -C 4 alkyl-C(S)—N(H)—, (H)(R 34 )N—C 1 -C 3 alkyl-, (H)(R 34 )N—C 1 -C 3 alkyl-, HO—C 1 -C 3 alkyl-, (H)(R 34 )N—S(O) 2 —N(R 35 )—, (H)(R 35 )N—S(O) 2 —, (H)(R 34 )N—C(S)—O—, (H)(R 34 )N—C(O)—O—, (H)(R 34 )N—C(S)—N(R 35 )—, (H)(R 34 )N—C(NR 35 )—, (H)(R 4 )N—C(NR 34 )—N(R 38 )—, (H)(R 34 )N—C(O)—N(R 35 )—, HO—C(O)—C 1 -C 3 alkyl-, C 1 -C 4 alkyl-S(O) 2 —NH— and ((R 34 )(R 35 )N) 2 —C═N—;

m and n are independently 0, 1, 2 or 3;

q is 0, 1 or 2; and

provided that 1) when Y b is N, then m is not 0 if Y a is bound to the ring comprising Y, via a N, S or O in Y a , or 2) when m and n are both 0 then Y b is —CH—;

Formula (IVa) has the structure:

wherein m, n, R 34 and R 35 are as defined for formula (IV); and

Formula (V) has the structure:

wherein

X 3 is aryl, cycloalkyl, heteroaryl or heterocyclyl, each of which is optionally substituted;

Y 3 is —NH 2 or —OH;

Ar 2 is optionally substituted aryl or optionally substituted heteroaryl; and

Het is an optionally substituted heterocyclyl.

45 . The method according to claim 44 , wherein the selective inhibitor of HDAC1 and/or HDAC2 has the structure

46 . The method according to claim 43 , wherein the compound that stabilizes microtubules is a taxane, an epothilone or an elpothilone analog.

47 . The method according to claim 46 , wherein the taxane is taxol or taxotere.

48 . Use of a selective inhibitor of histone deacetylase (HDAC)1, HDAC2 and/or HDAC3, in combination with a compound that stabilizes microtubules for the manufacture of a medicament to inhibit abnormal cell growth and/or abnormal cell proliferation, or to treat cancer in a patient.

Assignments (2)

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Nov 17, 2008

From: LI, ZUOMEI

To: METHYLGENE, INC.

Reel/Frame 021856/0919 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Nov 17, 2008

From: MURAKAMI, KOJI

To: TAIHO PHARMACEUTICALS CO., LTD.

Reel/Frame 021858/0304 →