Histone deacetylase inhibitors based on alpha-chalcogenmethylcarbonyl compounds

A compound having the formula (II):

• 15
• wherein
• A is a cyclic moiety selected from the group consisting of C3-14 cycloalkyl, 3-14 membered heterocycloalkyl, C4-14 cycloalkenyl, 3-8 membered heterocycloalkenyl, aryl, and heteroaryl;
• the cyclic moiety being optionally substituted with alkyl, alkenyl, alkynyl, alkoxy, hydroxyl, hydroxylalkyl, halo, haloalkyl, amino, thio, alkylthio, arylthio, aralkylthio, acylthio, alkylcarbonyloxy, alkyloxycarbonyl, alkylcarbonyl, alkylsulfonylamino, aminosulfonyl, or alkylsulfonyl;
• L is a straight C2-12 hydrocarbon chain containing at least one double bond, at least one triple bond, or at least one double bond and one triple bond;
• the hydrocarbon chain being optionally interrupted by —O—, —S—, —N(Ra)—, —C(O)—, —N(Ra)—SO2—, —SO2—N(Ra)—, —N(Ra)—C(O)—O—, —O—C(O)—N(Ra)—, —N(Ra)—C(O)—N(Rb)—, —O—C(O)—, —C(O)—O—, —O—SO2—, —SO2—O—, or —O—C(O)—O—, where each of Ra and Rb, independently, is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, hydroxylalkyl, hydroxyl, or haloalkyl;
• and being optionally substituted with alkyl, alkenyl, alkynyl, alkoxy, hydroxyl, hydroxylalkyl, halo, haloalkyl, amino, alkylcarbonyloxy, alkyloxycarbonyl, alkylcarbonyl, alkylsulfonylamino, aminosulfonyl, or alkylsulfonyl;
• X1 is O or S;
• and
• X2 is —OR1, or —SR1, wherein R1 is hydrogen, alkyl, acyl, aryl or aralkyl;
• provided that when L is a C2 hydrocarbon chain having at least one double bond, A is not C3 cycloalkyl;
• or a salt thereof.

A method of inhibiting histone deacetylation activity in cells comprising contacting the cells with an effective amount of a compound of formula (I), thereby treating one or more disorders mediated by histone deacetylase or stimulating hematopoietic cells ex vivo, wherein the compound of formula (I) is:

• 16
• wherein
• A is a cyclic moiety selected from the group consisting of C3-14 cycloalkyl, 3-14 membered heterocycloalkyl, C4-14 cycloalkenyl, 3-8 membered heterocycloalkenyl, aryl, and heteroaryl;
• the cyclic moiety being optionally substituted with alkyl, alkenyl, alkynyl, alkoxy, hydroxyl, hydroxylalkyl, halo, haloalkyl, amino, thio, alkylthio, arylthio, aralkylthio, acylthio, alkylcarbonyloxy, alkyloxycarbonyl, alkylcarbonyl, alkylsulfonylamino, aminosulfonyl, or alkylsulfonyl;
• or A is a saturated C1-12 hydrocarbon chain or an unsaturated C2-12 hydrocarbon chain optionally interrupted by —O—, —S—, —N(Ra)—, —C(O)—, —N(Ra)—SO2—, —SO2—N(Ra)—, —N(Ra)—C(O)—O—, —O—C(O)—N(Ra)—, —N(Ra)—C(O)—N(Rb)—, —O—C(O)—, —C(O)—O—, —O—SO2—, —SO2—O—, or —O—C(O)—O—, where each of Ra and Rb, independently, is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, hydroxylalkyl, hydroxyl, or haloalkyl;
• each of the saturated and the unsaturated branched hydrocarbon chain being optionally substituted with alkyl, alkenyl, alkynyl, alkoxy, hydroxyl, hydroxylalkyl, halo, haloalkyl, amino, alkylcarbonyloxy, alkyloxycarbonyl, alkylcarbonyl, alkylsulfonylamino, aminosulfonyl, or alkylsulfonyl;
• each of Y1 and y2, independently, is —CH2—, —O—, —S—, —N(Rc)—, —N(Rc)—C(O)—O—, —C(O)—, —C(NORc)—, —N(Rc)—C(O)—, —C(O)—N(Rc)—, —O—C(O)—N(Rc)—, —N(Rc)—C(O)—N(Rd)—, —O—C(O)—O—, or a bond;
• each of Rc and Rd, independently, being hydrogen, alkyl, alkenyl, alkynyl, alkoxy, hydroxylalkyl, hydroxyl, or haloalkyl;
• L is a straight C1-2 hydrocarbon chain optionally containing at least one double bond, at least one triple bond, or at least one double bond and one triple bond;
• the hydrocarbon chain being optionally substituted with C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 alkoxy, hydroxyl, halo, amino, nitro, cyano, C3-5 cycloalkyl, 3-5 membered heterocycloalkyl, monocyclic aryl, 5-6 membered heteroaryl, C1-4 alkylcarbonyloxy, C1-4 alkyloxycarbonyl, C1-4 alkylcarbonyl, or formyl;
• and further being optionally interrupted by —O—, —N(Re)—, —N(Re)—C(O)—O—, —O—C(O)—N(Re)—, —N(Re)—C(O)—N(Rf)—, or —O—C(O)—O—;
• each of Re and Rf, independently, being hydrogen, alkyl, alkenyl, alkynyl, alkoxy, hydroxylalkyl, hydroxyl, or haloalkyl;
• X1 is O or S;
• and
• X2 is —OR1, —SR1, or —SeR1, wherein R1 is hydrogen, alkyl, acyl, aryl or aralkyl;
• or a salt thereof,
• provided that when Y1 is a bond and L is saturated, the carbon adjacent to Y1 is not substituted with C1-4 alkoxy or hydroxyl and when Y1 is —C(O)—, —C(NORc)—, L is not saturated, and
• determining whether the level of acetylated histones in the treated cells is higher than in untreated cells under the same conditions.