Inhibitors of histone deacetylase

Patent metadata

Field	Value
Publication number	US-9365498-B2
Application number	US-201314065278-A
Country	US
Kind code	B2
Filing date	Oct 28, 2013
Priority date	Apr 28, 2011
Publication date	Jun 14, 2016
Grant date	Jun 14, 2016

Abstract

The present invention relates to compounds of formula (I):

or a pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof, wherein U, J, V, X, R 2a , R 2b , R 2c , R 5 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.

First claim

The invention claimed is:

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 NR 2d ;
V is selected from C and N, provided that when V is N, one of R 2a , R 2b , or R 2c is absent;
each X is independently selected from hydrogen, deuterium, methyl, CF 3 , and halogen;
R 2a is selected from hydrogen, halogen, OH, NH 2 , and C 1 -C 8 alkyl;
R 2b is selected from hydrogen, halogen, OH, NH 2 , and C 1 -C 8 alkyl;
R 2c is selected from hydrogen, halogen, OH, NH 2 , and C 1 -C 8 alkyl;
R 2d is selected from NH 2 and C 1 -C 8 alkyl;
provided that:
taken together two of R 2a , R 2b , and R 2c form a C 3 -C 8 cycloalkyl ring, C 4 -C 8 cycloalkenyl ring, or 3 to 8 membered saturated or partially unsaturated heterocyclic ring containing 1, 2, 3, or 4 nitrogen atoms, and the remaining R 2a , R 2b , or R 2c is absent or selected from hydrogen, halogen, OH, NH 2 , and C 1 -C 8 alkyl, further wherein:
said cycloalkyl ring formed by taking together two of R 2a , R 2b , and R 2c is substituted with two or more R x , wherein two R x are taken together to form a C 3 -C 8 cycloalkyl ring that is substituted with one or more R z or is unsubstituted, C 4 -C 8 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 R z , 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 R z ; and
said cycloalkenyl ring formed by taking together two of R 2a , R 2b , and R 2c , and heterocyclic ring formed by taking together two of R 2a , R 2b , and R 2c are unsubstituted or substituted with one or more R x ;

or taken together R 2d and one of R 2a , R 2b ,and R 2c form a 3 to 8 membered saturated or partially unsaturated heterocyclic ring, and: the remaining R 2a , R 2b , or R 2c is selected from hydrogen, halogen, OH, NH 2 , and C 1 -C 8 alkyl, or taken together two of the remaining R 2a , R 2b , and R 2c form ═O; further wherein said heterocyclic ring is unsubstituted or substituted with one or more R x ;
or taken together two of R 2a , R 2b , and R 2c form an aromatic or heteroaromatic ring and the remaining R 2a , R 2b , or R 2c is absent, provided that when two of R 2a , R 2b ,and R 2c form an aromatic or heteroaromatic ring and the remaining R 2a , R 2b , or R 2c 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 R x ; and said heteroaromatic ring is monocyclic or bicyclic, and is unsubstituted or substituted with one or more R x ;

each R x is independently selected from (CH 2 ) z NH 2 , (CH 2 ) z NHR 3 , (CH 2 ) z NR 3 R 3 , OR 3 , OCF 3 , OCH 2 F, OCHF 2 , (CH 2 ) z -aromatic ring, (CH 2 ) z -heterocyclic ring, hydroxyl, halogen, C 1 -C 8 alkyl, (C 1 -C 8 alkyl)CF 3 , (C 1 -C 8 alkyl)OH, C(O)R 3 ′(CH 2 ) z C(O)NH 2 , (CH 2 ) z C(O)NHR 3 , (CH 2 ) z C(O)NR 3 R 3 , (CH 2 ) z NHC(O)R 4 , and (CH 2 ) z NR 4 C(O)R 4 ; wherein the aromatic ring is monocyclic, bicyclic, or tricyclic, and the heterocyclic ring is 3 or 8 membered;
or taken together two R x attached to the same carbon atom of a cycloalkyl, cycloalkenyl or heterocyclic ring form ═O;
or taken together two R x form a C 3 -C 8 cycloalkyl ring, C 4 -C 8 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 R z ;
or taken together two R x 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 R z ; and said heteroaromatic ring is monocyclic or bicyclic, and is unsubstituted or substituted with one or more R z ;
each R z is independently selected from halogen, C 1 -C 4 alkyl, OH, OR 3 , CF 3 , OCF 3 , OCH 2 F, OCHF 2 , NH 2 , NHR 3 , NR 3 R 3 , and C(O)CH 3 ;
R 3 is C 1 -C 8 alkyl;
R 4 is selected from C 1 -C 8 alkyl and CF 3 ;
R 5 is selected from hydrogen, deuterium, halogen, OH, OCH 3 , CF 3 , CH 3 , and cyclopropyl;
t is selected from 0, 1, and
z is selected from 0, 1, 2, and 3.

2. The compound of claim 1 , wherein the compound is of the formula:

or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein:
the moiety

 is of the formula:

 and
U is a single bond.

3. The compound of claim 1 , or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein:
R 2a R 2b R 2c V— is of the formula:

wherein:
J is selected from N and C;
R u is selected from hydrogen, C 1 -C 8 alkyl, (C 1 -C 8 alkyl)CF 3 , (C 1 -C 8 alkyl)OH, and C(O)R 3a ;
R 3a is C 1 -C 8 alkyl;
v is selected from 0, 1, 2, 3, 4, 5, 6, 7, and 8; and

d and d′ are each independently selected from 0, 1, 2, and 3, provided that the ring formed by taking together R 2a and R 2b is a 3 to 8 membered ring; and further provided that when J is C:
v is selected from 2, 3, 4, 5, 6, 7, and 8; and
taken together two R x form a C 3 -C 8 cycloalkyl ring, C 4 -C 8 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 R z ;
or taken together two R x 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 R z ; and said heteroaromatic ring is monocyclic or bicyclic, and is unsubstituted or substituted with one or more R z .

4. The compound of claim 1 or a pharmaceutically acceptable salt, hydrate, solvate, or thereof, wherein R 2a R 2b R 2c V is

wherein w is selected from 1, 2, and 3.

5. The compound of claim 1 or a pharmaceutically acceptable salt, hydrate, or solvate, thereof, wherein R 2a R 2b R 2c V— is of the formula:

wherein:
J is selected from N, O, C, and S;
when J is N or C, R u is selected from hydrogen, C 1 -C 8 alkyl, (C 1 -C 8 alkyl)CF 3 , (C 1 -C 8 alkyl)OH, and C(O)R 3a ; and when J is O or S, R u is absent;
R 3a is C 1 -C 8 alkyl;
n is 1, 2, or 3; and
v is selected from 0, 1, 2, 3, 4, 5, 6, 7, and 8;
provided that when J is C:
each R x is independently selected from (CH 2 ) z NH

Assignees

• Broad Inst Inc
• Gen Hospital Corp
• Massachusetts Inst Technology

Inventors

• Holson Edward
• Wagner Florence Fevrier
• Weiwer Michel
• Tsai Li-Huei
• Haggarty Stephen
• Zhang Yan-Ling

Classifications

• A61P43/00

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

• A61P7/06

  Antianaemics · CPC title

• A61P7/00

  Drugs for disorders of the blood or the extracellular fluid · CPC title

• A61P25/28

  for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia · CPC title

• A61P35/02

  specific for leukemia · CPC title