Inhibitors of histone deacetylase

摘要

The present invention relates to compounds of formula (I):;
or a pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof, wherein U, J, V, X, R2a, R2b, R2c, R5 and t are as described herein. The present invention relates generally to inhibitors of histone deacetylase and to methods of making and using them. These compounds are useful for promoting cognitive function and enhancing learning and memory formation. In addition, these compounds are useful for treating, alleviating, and/or preventing various conditions, including for example, neurological disorders, memory and cognitive function disorders/impairments, extinction learning disorders, fungal diseases and infections, inflammatory diseases, hematological diseases, and neoplastic diseases in humans and animals.

主权项

1. A compound having formula I:or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein:
the moiety  is of the formula: U is selected from single bond and NR2d; V is selected from C and N, provided that when V is N, one of R2a, R2b, or R2c is absent; each X is independently selected from hydrogen, deuterium, methyl, CF3, and halogen; R2a is selected from hydrogen, halogen, OH, NH2, and C1-C8 alkyl; R2b is selected from hydrogen, halogen, OH, NH2, and C1-C8 alkyl; R2c is selected from hydrogen, halogen, OH, NH2, and C1-C8 alkyl; R2d is selected from NH2 and C1-C8 alkyl; provided that:
taken together two of R2a, R2b, and R2c form a C3-C8 cycloalkyl ring, C4-C8 cycloalkenyl ring, or 3 to 8 membered saturated or partially unsaturated heterocyclic ring containing 1, 2, 3, or 4 nitrogen atoms, and the remaining R2a, R2b, or R2c is absent or selected from hydrogen, halogen, OH, NH2, and C1-C8 alkyl, further wherein:
said cycloalkyl ring formed by taking together two of R2a, R2b, and R2c is substituted with two or more Rx, wherein two Rx are taken together to form a C3-C8 cycloalkyl ring that is substituted with one or more Rz or is unsubstituted, C4-C8 cycloalkenyl ring, or 3 to 8 membered saturated or partially unsaturated heterocyclic ring, further wherein said cycloalkenyl ring and heterocyclic ring are unsubstituted or substituted with one or more Rz, or to form an aromatic ring or heteroaromatic ring, further wherein said aromatic ring and heteroaromatic ring are monocyclic or bicyclic, and are unsubstituted or substituted with one or more Rz; andsaid cycloalkenyl ring formed by taking together two of R2a, R2b, and R2c, and heterocyclic ring formed by taking together two of R2a, R2b, and R2c are unsubstituted or substituted with one or more Rx;or taken together R2d and one of R2a, R2b,and R2c form a 3 to 8 membered saturated or partially unsaturated heterocyclic ring, and: the remaining R2a, R2b, or R2c is selected from hydrogen, halogen, OH, NH2, and C1-C8 alkyl, or taken together two of the remaining R2a, R2b, and R2c form ═O; further wherein said heterocyclic ring is unsubstituted or substituted with one or more Rx;or taken together two of R2a, R2b, and R2c form an aromatic or heteroaromatic ring and the remaining R2a, R2b, or R2c is absent, provided that when two of R2a, R2b,and R2c form an aromatic or heteroaromatic ring and the remaining R2a, R2b, or R2c is absent, U is not a single bond, further wherein: said aromatic ring is monocyclic, bicyclic, or tricyclic, and is unsubstituted or substituted with one or more Rx; and said heteroaromatic ring is monocyclic or bicyclic, and is unsubstituted or substituted with one or more Rx; each Rx is independently selected from (CH2)zNH2, (CH2)zNHR3, (CH2)zNR3R3, OR3, OCF3, OCH2F, OCHF2, (CH2)z-aromatic ring, (CH2)z-heterocyclic ring, hydroxyl, halogen, C1-C8 alkyl, (C1-C8 alkyl)CF3, (C1-C8 alkyl)OH, C(O)R3′(CH2)zC(O)NH2, (CH2)zC(O)NHR3, (CH2)zC(O)NR3R3, (CH2)zNHC(O)R4, and (CH2)zNR4C(O)R4; wherein the aromatic ring is monocyclic, bicyclic, or tricyclic, and the heterocyclic ring is 3 or 8 membered; or taken together two Rx attached to the same carbon atom of a cycloalkyl, cycloalkenyl or heterocyclic ring form ═O; or taken together two Rx form a C3-C8 cycloalkyl ring, C4-C8 cycloalkenyl ring, or 3 to 8 membered saturated or partially unsaturated heterocyclic ring, further wherein said cycloalkyl ring cycloalkenyl ring, and heterocyclic ring are unsubstituted or substituted with one or more Rz; or taken together two Rx form an aromatic ring or heteroaromatic ring, further wherein: said aromatic ring is monocyclic, bicyclic, or tricyclic, and is unsubstituted or substituted with one or more Rz; and said heteroaromatic ring is monocyclic or bicyclic, and is unsubstituted or substituted with one or more Rz; each Rz is independently selected from halogen, C1-C4 alkyl, OH, OR3, CF3, OCF3, OCH2F, OCHF2, NH2, NHR3, NR3R3, and C(O)CH3; R3 is C1-C8 alkyl; R4 is selected from C1-C8 alkyl and CF3; R5 is selected from hydrogen, deuterium, halogen, OH, OCH3, CF3, CH3, and cyclopropyl; t is selected from 0, 1, and z is selected from 0, 1, 2, and 3.