US 9,790,184 B2 · Inhibitors of histone deacetylase

Abstract

The present invention relates to compounds of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof, wherein X1, X2, X3, X4, X5, W1, W2, W3, and W4 are as described. The present invention relates generally to inhibitors of histone deacetylase and to methods of making and using them. In one aspect, the invention relates to selective HDAC3 inhibitors useful for protecting β-cells and improving insulin resistance. The selective HDAC3 inhibitors are also useful for promoting cognitive function and enhancing learning and memory formation. Compounds of the invention are useful for treating, alleviating, and/or preventing various conditions, including for example, a metabolic disorder such as type 1 or type 2 diabetes, dyslipidemias, lipodystrophies, liver disease associated with metabolic syndrome, polycystic ovarian syndrome, or obesity; inflammatory disease; neurological disorder; a memory or cognitive function disorder/impairment; an extinction learning disorder; fungal disease or infection; viral disease or infection such as HIV; hematological disease; liver disease; lysosomal storage disease; or neoplastic disease in humans or animals.

A compound of formula I:

or a pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof, wherein:
X3 is NR1C(O)R2, wherein R2 is unsubstituted C1-C8 alkyl, CF3, CH2F, or CF2H;
W1, W2, W3, and W4 are each independently selected from hydrogen, fluorine, chlorine, bromine, CF3, CH3, and deuterium, provided that at least one of W1, W2, W3, and W4 is not hydrogen;
X1 and X5 are each independently selected from hydrogen, halogen, and C1-C3 alkyl;
X2 and X4 are each independently selected from hydrogen, halogen, OR5, C(O)R6, OS(O)pR7, NR3R4, NR1C(O)R2, NR1S(O)pR7, S(O)qR10, C(O)OR11, C(O)NR12R13, OC(O)OR14, OC(O)NR15R16, NR17C(O)OR18, NR19C(O)NR20R21, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, C4-C8 cycloalkenyl, aromatic ring, 3-8 membered heteroaromatic ring, and 3-8 membered, saturated or partially saturated, heterocyclic ring, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aromatic ring, heteroaromatic ring, and heterocyclic ring are unsubstituted or substituted with one or more Ra, provided that one or two of X2 and X4 is hydrogen;
Ra is selected from halogen, OR25, C1-C8 alkyl, CF3, CHF2, CH2F, NR26C(O)R27, and NR28R29;
or
R1 and R26 are each independently selected from hydrogen and C1-C8 alkyl;
R2 is selected from hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C3-C8 alkynyl, C3-C8 cycloalkyl, C4-C8 cycloalkenyl, aromatic ring, 3-8 membered heteroaromatic ring, and 3-8 membered, saturated or partially saturated, heterocyclic ring, wherein said alkyl, alkynyl, cycloalkyl, cycloalkenyl, aromatic ring, heteroaromatic ring, and heterocyclic ring are unsubstituted or substituted with one or more Rb;
R27 is selected from hydrogen, C1-C8 alkyl, C3-C8 alkynyl, C3-C8 cycloalkyl, C4-C8 cycloalkenyl, aromatic ring, 3-8 membered heteroaromatic ring, and 3-8 membered, saturated or partially saturated, heterocyclic ring, wherein said alkyl, alkynyl, cycloalkyl, cycloalkenyl, aromatic ring, heteroaromatic ring, and heterocyclic ring are unsubstituted or substituted with one or more Rb;
Rb is selected from halogen, C1-C8 alkyl, CF3, CHF2, CH2F, OR25, NH2, NHCH3, N(CH3)2, C3-C8 cycloalkyl, C4-C8 cycloalkenyl, aromatic ring, 3-8 membered heteroaromatic ring, and 3-8 membered, saturated or partially saturated, heterocyclic ring, wherein said cycloalkyl, cycloalkenyl, aromatic ring, heteroaromatic ring, and heterocyclic ring are unsubstituted or substituted with one or more Rb1;
Rb1 is selected from halogen, C1-C3 alkyl, CF3, CHF2, CH2F, OH, OCH3, S(O)CH3, S(O)2CH3, NH2, NHCH3, and N(CH3)2;
R3 and R4 are each independently selected from hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C3-C8 alkynyl, C3-C8 cycloalkyl, C4-C8 cycloakenyl, aromatic ring, 3-8 membered heteroaromatic ring, and 3-8 membered, saturated or partially saturated, heterocyclic ring, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aromatic ring, heteroaromatic ring, and heterocyclic ring are unsubstituted or substituted with one or more Rg;
R28 and R29 are each independently selected from hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C3-C8 alkynyl, C3-C8 cycloalkyl, C4-C8 cycloakenyl, aromatic ring, 3-8 membered heteroaromatic ring, and 3-8 membered, saturated or partially saturated, heterocyclic ring, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aromatic ring, heteroaromatic ring, and heterocyclic ring are unsubstituted or substituted with one or more Rg;
Rg is selected from halogen, C1-C3 alkyl, CF3, CHF2, CH2F, OH, OCH3, NH2, NHCH3, N(CH3)2, C3-C8 cycloalkyl, C4-C8 cycloalkenyl, aromatic ring, 3-8 membered heteroaromatic ring, and 3-8 membered, saturated or partially saturated, heterocyclic ring, wherein said cycloalkyl, cycloalkenyl, aromatic ring, heteroaromatic ring, and heterocyclic ring are unsubstituted or substituted with one or more Rh;
Rh is selected from halogen, C1-C3 alkyl, CF3, CHF2, CH2F, OH, OCH3, S(O)CH3, S(O)2CH3, NH2, NHCH3, and N(CH3)2;
R5 and R25 are each independently selected from hydrogen, C(O)R6, C1-C8 alkyl, CF3, CHF2, CH2F, C2-C8 alkenyl, C3-C8 alkynyl, C3-C8 cycloalkyl, C4-C8 cycloalkenyl, aromatic ring, 3-8 membered heteroaromatic ring, and 3-8 membered, saturated or partially saturated, heterocyclic ring, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aromatic ring, heteroaromatic ring, and heterocyclic ring are unsubstituted or substituted with one or more Rc;
Rc is selected from halogen, C1-C3 alkyl, CF3, CHF2, CH2F, OH, OCH3, NH2, NHCH3, N(CH3)2, C3-C8 cycloalkyl, C4-C8 cycloalkenyl, aromatic ring, 3-8 membered heteroaromatic ring, and 3-8 membered, saturated or partially saturated, heterocyclic ring, wherein said cycloalkyl, cycloalkenyl, aromatic ring, heteroaromatic ring, and heterocyclic ring are unsubstituted or substituted with one or more Rd;
Rd is selected from halogen, C1-C3 alkyl, CF3, CHF2, CH2F, OH, OCH3, S(O)CH3, S(O)2CH3, NH2, NHCH3, and N(CH3)2;
R6 is selected from hydrogen, OR25, C1-C8 alkyl, CF3, CHF2, CH2F, C2-C8 alkenyl, C3-C8 alkynyl, C3-C8 cycloalkyl, C4-C8 cycloalkenyl, aromatic ring, 3-8 membered heteroaromatic ring, and 3-8 membered, saturated or partially saturated, heterocyclic ring;
wherein said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aromatic ring, heteroaromatic ring, and heterocyclic ring are unsubstituted or substituted with one or more Re;
Re is selected from halogen, C1-C3 alkyl, CF3, CHF2, CH2F, OH, OCH3, NH2, NHCH3, N(CH3)2, C3-C8 cycloalkyl, C4-C8 cycloalkenyl, aromatic ring, 3-8 membered heteroaromatic ring, and 3-8 membered, saturated or partially saturated, heterocyclic ring, wherein said cycloalkyl, cycloalkenyl, aromatic ring, heteroaromatic ring, and heterocyclic ring are unsubstituted or substituted with one or more Rf;
Rf is selected from halogen, C1-C3 alkyl, CF3, CHF2, CH2F, OH, OCH3, S(O)CH3, S(O)2CH3, NH2, NHCH3, and N(CH3)2;
R7 is selected from C1-C8 alkyl, C3-C8 cycloalkyl, C4-C8 cycloalkenyl, aromatic ring, 3-8 membered heteroaromatic ring, and 3-8 membered, saturated or partially saturated, heterocyclic ring;
wherein said alkyl, cycloalkyl, cycloalkenyl, aromatic ring, heteroaromatic ring, and heterocyclic ring are unsubstituted or substituted with one or more Ri;
Ri is selected from halogen, C1-C3 alkyl, CF3, CHF2, CH2F, OH, OCH3, NH2, NHCH3, and N(CH3)2;
R10 is selected from C1-C8 alkyl, C3-C8 cycloalkyl, C4-C8 cycloalkenyl, aromatic ring, 3-8 membered heteroaromatic ring, and 3-8 membered, saturated or partially saturated, heterocyclic ring;
wherein said alkyl, cycloalkyl, cycloalkenyl, aromatic ring, heteroaromatic ring, and heterocyclic ring are unsubstituted or substituted with one or more Rj;
Rj is selected from halogen, C1-C3 alkyl, CF3, CHF2, CH2F, OH, OCH3, NH2, NHCH3, and N(CH3)2;
R11 is selected from hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, C4-C8 cycloalkenyl, aromatic ring, 3-8 membered heteroaromatic ring, and 3-8 membered, saturated or partially saturated, heterocyclic ring;
wherein said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aromatic ring, heteroaromatic ring, and heterocyclic ring are unsubstituted or substituted with one or more Rk;
Rk is selected from halogen, C1-C3 alkyl, CF3, CHF2, CH2F, OH, OCH3, NH2, NHCH3, N(CH3)2, C3-C8 cycloalkyl, C4-C8 cycloalkenyl, aromatic ring, 3-8 membered heteroaromatic ring, and 3-8 membered, saturated or partially saturated, heterocyclic ring, wherein said cycloalkyl, cycloalkenyl, aromatic ring, heteroaromatic ring, and heterocyclic ring are unsubstituted or substituted with one or more Rk1;
Rk1 is selected from halogen, C1-C3 alkyl, CF3, CHF2, CH2F, OH, OCH3, SO2CH3, NH2, NHCH3, and N(CH3)2;
R12 and R13 are each independently selected from hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C3-C8 alkynyl, C3-C8 cycloalkyl, C4-C8 cycloalkenyl, aromatic ring, 3-8 membered heteroaromatic ring, and 3-8 membered, saturated or partially saturated, heterocyclic ring, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aromatic ring, heteroaromatic ring, and heterocyclic ring are unsubstituted or substituted with one or more Rl;
Rl is selected from halogen, C1-C3 alkyl, CF3, CHF2, CH2F, OH, OCH3, NH2, NHCH3, N(CH3)2, C3-C8 cycloalkyl, C4-C8 cycloalkenyl, aromatic ring, 3-8 membered heteroaromatic ring, and 3-8 membered, saturated or partially saturated, heterocyclic ring, wherein said cycloalkyl, cycloalkenyl, aromatic ring, heteroaromatic ring, and heterocyclic ring are unsubstituted or substituted with one or more Rm;
Rm is selected from halogen, C1-C3 alkyl, CF3, CHF2, CH2F, OH, OCH3, S(O)CH3, S(O)2CH3, NH2, NHCH3, and N(CH3)2;
R14 is selected from C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, C4-C8 cycloalkenyl, and aromatic ring;
wherein said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, and aromatic ring are unsubstituted or substituted with one or more Rn;
Rn is selected from halogen, C1-C3 alkyl, CF3, CHF2, CH2F, OH, OCH3, NH2, NHCH3, N(CH3)2, C3-C8 cycloalkyl, C4-C8 cycloalkenyl, aromatic ring, 3-8 membered heteroaromatic ring, and 3-8 membered, saturated or partially saturated, heterocyclic ring, wherein said cycloalkyl, cycloalkenyl, aromatic ring, heteroaromatic ring, and heterocyclic ring are unsubstituted or substituted with one or more Rn1;
Rn1 is selected from halogen, C1-C3 alkyl, CF3, CHF2, CH2F, OH, OCH3, SO2CH3, NH2, NHCH3, and N(CH3)2;
R15 and R16 are each independently selected from hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C3-C8 alkynyl, C3-C8 cycloalkyl, C4-C8 cycloalkenyl, aromatic ring, 3-8 membered heteroaromatic ring, and 3-8 membered, saturated or partially saturated, heterocyclic ring, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aromatic ring, heteroaromatic ring, and heterocyclic ring are unsubstituted or substituted with one or more Ro;
Ro is selected from halogen, C1-C3 alkyl, CF3, CHF2, CH2F, OH, OCH3, NH2, NHCH3, N(CH3)2, C3-C8 cycloalkyl, C4-C8 cycloalkenyl, aromatic ring, 3-8 membered heteroaromatic ring, and 3-8 membered, saturated or partially saturated, heterocyclic ring, wherein said cycloalkyl, cycloalkenyl, aromatic ring, heteroaromatic ring, and heterocyclic ring are unsubstituted or substituted with one or more Rp;
Rp is selected from halogen, C1-C3 alkyl, CF3, CHF2, CH2F, OH, OCH3, S(O)CH3, S(O)2CH3, NH2, NHCH3, and N(CH3)2;
R17 and R19 are each independently selected from hydrogen and C1-C8 alkyl;
R18 is selected from C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, C4-C8 cycloalkenyl, aromatic ring, 3-8 membered heteroaromatic ring, and 3-8 membered saturated heterocyclic ring;
wherein said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heteroaromatic ring, heterocyclic ring, and aromatic ring are unsubstituted or substituted with one or more Rq;
Rq is selected from halogen, C1-C3 alkyl, CF3, CHF2, CH2F, OH, OCH3, NH2, NHCH3, N(CH3)2, C3-C8 cycloalkyl, C4-C8 cycloalkenyl, aromatic ring, 3-8 membered heteroaromatic ring, and 3-8 membered, saturated or partially saturated, heterocyclic ring, wherein said cycloalkyl, cycloalkenyl, aromatic ring, heteroaromatic ring, and heterocyclic ring are unsubstituted or substituted with one or more Rq1;
Rq1 is selected from halogen, C1-C3 alkyl, CF3, CHF2, CH2F, OH, OCH3, SO2CH3, NH2, NHCH3, and N(CH3)2;
R20 and R21 are each independently selected from selected from hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C3-C8 alkynyl, C3-C8 cycloalkyl, C4-C8 cycloalkenyl, aromatic ring, 3-8 membered heteroaromatic ring, and 3-8 membered, saturated or partially saturated, heterocyclic ring, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aromatic ring, heteroaromatic ring, and heterocyclic ring are unsubstituted or substituted with one or more Rr;
Rr is selected from halogen, C1-C3 alkyl, CF3, CHF2, CH2F, OH, OCH3, NH2, NHCH3, N(CH3)2, C3-C8 cycloalkyl, C4-C8 cycloalkenyl, aromatic ring, 3-8 membered heteroaromatic ring, and 3-8 membered, saturated or partially saturated, heterocyclic ring, wherein said cycloalkyl, cycloalkenyl, aromatic ring, heteroaromatic ring, and heterocyclic ring are unsubstituted or substituted with one or more Rs;
Rs is selected from halogen, C1-C3 alkyl, CF3, CHF2, CH2F, OH, OCH3, S(O)CH3, SO2CH3, NH2, NHCH3, and N(CH3)2;
and
p and q are each independently selected from 0, 1, and 2.

50 more elements

Inhibitors of histone deacetylase

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Inhibitors of histone deacetylase

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Abstract

Claims25