Inhibitors of histone deacetylase

Patent metadata

Field	Value
Publication number	US-9790184-B2
Application number	US-201314417477-A
Country	US
Kind code	B2
Filing date	Jul 29, 2013
Priority date	Jul 27, 2012
Publication date	Oct 17, 2017
Grant date	Oct 17, 2017

Abstract

The present invention relates to compounds of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof, wherein X 1 , X 2 , X 3 , X 4 , X 5 , W 1 , W 2 , W 3 , and W 4 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.

First claim

We claim:

1. A compound of formula I:

or a pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof, wherein:
X 3 is NR1C(O)R2, wherein R2 is unsubstituted C1-C8 alkyl, CF3, CH2F, or CF2H;
W 1 , W 2 , W 3 , and W 4 are each independently selected from hydrogen, fluorine, chlorine, bromine, CF 3 , CH 3 , and deuterium, provided that at least one of W 1 , W 2 , W 3 , and W 4 is not hydrogen;
X 1 and X 5 are each independently selected from hydrogen, halogen, and C 1 -C 3 alkyl;
X 2 and X 4 are each independently selected from hydrogen, halogen, OR 5 , C(O)R 6 , OS(O) p R 7 , NR 3 R 4 , NR 1 C(O)R 2 , NR 1 S(O) p R 7 , S(O) q R 10 , C(O)OR 11 , C(O)NR 12 R 13 , OC(O)OR 14 , OC(O)NR 15 R 16 , NR 17 C(O)OR 18 , NR 19 C(O)NR 20 R 21 , C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 3 -C 8 cycloalkyl, C 4 -C 8 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 R a , provided that one or two of X 2 and X 4 is hydrogen;
R a is selected from halogen, OR 25 , C 1 -C 8 alkyl, CF 3 , CHF 2 , CH 2 F, NR 26 C(O)R 27 , and NR 28 R 29 ; or
R 1 and R 26 are each independently selected from hydrogen and C 1 -C 8 alkyl;
R 2 is selected from hydrogen, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 3 -C 8 alkynyl, C 3 -C 8 cycloalkyl, C 4 -C 8 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 R b ;
R 27 is selected from hydrogen, C 1 -C 8 alkyl, C 3 -C 8 alkynyl, C 3 -C 8 cycloalkyl, C 4 -C 8 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 R b ;
R b is selected from halogen, C 1 -C 8 alkyl, CF 3 , CHF 2 , CH 2 F, OR 25 , NH 2 , NHCH 3 , N(CH 3 ) 2 , C 3 -C 8 cycloalkyl, C 4 -C 8 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 R b1 ;
R b1 is selected from halogen, C 1 -C 3 alkyl, CF 3 , CHF 2 , CH 2 F, OH, OCH 3 , S(O)CH 3 , S(O) 2 CH 3 , NH 2 , NHCH 3 , and N(CH 3 ) 2 ;
R 3 and R 4 are each independently selected from hydrogen, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 3 -C 8 alkynyl, C 3 -C 8 cycloalkyl, C 4 -C 8 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 R g ;
R 28 and R 29 are each independently selected from hydrogen, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 3 -C 8 alkynyl, C 3 -C 8 cycloalkyl, C 4 -C 8 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 R g ;
R g is selected from halogen, C 1 -C 3 alkyl, CF 3 , CHF 2 , CH 2 F, OH, OCH 3 , NH 2 , NHCH 3 , N(CH 3 ) 2 , C 3 -C 8 cycloalkyl, C 4 -C 8 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 R h ;
R h is selected from halogen, C 1 -C 3 alkyl, CF 3 , CHF 2 , CH 2 F, OH, OCH 3 , S(O)CH 3 , S(O) 2 CH 3 , NH 2 , NHCH 3 , and N(CH 3 ) 2 ;
R 5 and R 25 are each independently selected from hydrogen, C(O)R 6 , C 1 -C 8 alkyl, CF 3 , CHF 2 , CH 2 F, C 2 -C 8 alkenyl, C 3 -C 8 alkynyl, C 3 -C 8 cycloalkyl, C 4 -C 8 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 R c ;
R c is selected from halogen, C 1 -C 3 alkyl, CF 3 , CHF 2 , CH 2 F, OH, OCH 3 , NH 2 , NHCH 3 , N(CH 3 ) 2 , C 3 -C 8 cycloalkyl, C 4 -C 8 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 R d ;
R d is selected from halogen, C 1 -C 3 alkyl, CF 3 , CHF 2 , CH 2 F, OH, OCH 3 , S(O)CH 3 , S(O) 2 CH 3 , NH 2 , NHCH 3 , and N(CH 3 ) 2 ;
R 6 is selected from hydrogen, OR 25 , C 1 -C 8 alkyl, CF 3 , CHF 2 , CH 2 F, C 2 -C 8 alkenyl, C 3 -C 8 alkynyl, C 3 -C 8 cycloalkyl, C 4 -C 8 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 R e ;
R e is selected from halogen, C 1 -C 3 alkyl, CF 3 , CHF 2 , CH 2 F, OH, OCH 3 , NH 2 , NHCH 3 , N(CH 3 ) 2 , C 3 -C 8 cycloalkyl, C 4 -C 8 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 R f ;
R f is selected from halogen, C 1 -C 3 alkyl, CF 3 , CHF 2 , CH 2 F, OH, OCH 3 , S(O)CH 3 , S(O) 2 CH 3 , NH 2 , NHCH 3 , and N(CH 3 ) 2 ;
R 7 is selected from C 1 -C 8 alkyl, C 3 -C 8 cycloalkyl, C 4 -C 8 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 R i ;
R i is selected from halogen, C 1 -C 3 alkyl, CF 3 , CHF 2 , CH 2 F, OH, OCH 3 , NH 2 , NHCH 3 , and N(CH 3 ) 2 ;
R 10 is selected from C 1 -C 8 alkyl, C 3 -C 8 cycloalkyl, C 4 -C 8 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 R j ;
R j is selected from halogen, C 1 -C 3 alkyl, CF 3 , CHF 2 , CH 2 F, OH, OCH 3 , NH 2 , NHCH 3 , and N(CH 3 ) 2 ;
R 11 is selected from hydrogen, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 3 -C 8 cycloalkyl, C 4 -C 8 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 R k ;
R k is selected from halog

Assignees

• Massachusetts Gen Hospital
• Broad Inst Inc

Inventors

• Holson Edward
• Wagner Florence Fevrier
• Haggarty Stephen J
• Zhang Yan-Ling
• Lundh Morten
• Wagner Bridget
• Lewis Michael C
• Petryshen Tracey Lynn

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P35/02

  specific for leukemia · CPC title

• A61P25/14

  for treating abnormal movements, e.g. chorea, dyskinesia · CPC title

• A61P3/04

  Anorexiants; Antiobesity agents · CPC title