Inhibitors of histone deacetylase

Patent metadata

Field	Value
Publication number	US-10662199-B2
Application number	US-201715786134-A
Country	US
Kind code	B2
Filing date	Oct 17, 2017
Priority date	Apr 28, 2011
Publication date	May 26, 2020
Grant date	May 26, 2020

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:
U is a single bond;
J′ is NH 2 ;
V is C;
X is hydrogen;
taken together two of R 2a , R 2b , and R 2c form a C 4 -C 5 cycloalkyl ring or C 4 -C 5 cycloalkenyl ring, 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, wherein said cycloalkyl ring formed by taking together two of R 2a , R 2b , and R 2c is substituted with one or more R x , and said cycloalkenyl ring formed by taking together two of R 2a , R 2b , and R 2c 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 -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 ;
or:
taken together only two R x form: i) a C 3 -C 4 or C 7 -C 8 , cycloalkyl ring, or 3 to 8 membered, saturated or partially unsaturated, heterocyclic ring, wherein said cycloalkyl ring and heterocyclic ring are unsubstituted or substituted with one or more R z ; or ii) an aromatic ring or heteroaromatic ring, wherein said aromatic ring and heteroaromatic ring are unsubstituted or substituted with one or more R z ; and
optionally each remaining 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 -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 ;
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 ;
each instance of R 3 is C 1 -C 8 alkyl;
each instance of R 4 is independently selected from C 1 -C 8 alkyl and CF 3;
R 5 is hydrogen;
t is 0; and
z is selected from 0, 1, 2, and 3.

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

wherein w is selected from 1 and 2.

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

No.
Formula

219

223

or a pharmaceutically acceptable salt, hydrate, or solvate thereof.

4. The compound of claim 1 , or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein the cycloalkenyl ring formed by taking together two of R 2a , R 2b , and R 2c is unsubstituted.

5. The compound of claim 1 , or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein:
the cycloalkyl ring and cycloalkenyl ring formed by taking together two of R 2a , R 2b , and R 2c are substituted with one or more R x ; and
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 -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 .

6. The compound of claim 1 , or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein:
the cycloalkyl ring and cycloalkenyl ring formed by taking together two of R 2a , R 2b , and R 2c are substituted with two or more R x ;
taken together only two R x form a C 3 -C 4 or C 7 -C 8 , cycloalkyl ring, or 3 to 8 membered, saturated or partially unsaturated, heterocyclic ring, wherein said cycloalkyl ring and heterocyclic ring are unsubstituted or substituted with one or more R z ; and optionally:
each remaining 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 -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 .

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

wherein:
J is selected from N, O, CH, C, and S;
when J is N, CH, 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 0; and
is selected from 0, 1, 2, 3, 4, 5, 6, and 7.

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

wherein:
J is selected from CH 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;
n is 0; and
is selected from 0, 1, 2, 3, 4, 5, 6, and 7.

9. The compound of claim 1 , or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein:
the cycloalkyl ring and cycloalkenyl ring formed by taking together two of R 2a , R 2b , and R 2c are substituted with two or more R x ;
taken together only two R x form an aromatic ring, wherein said aromatic ring is unsubstituted or substituted with one or more R z ; and optionally:
each remaining 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 -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)N H R 3 , (CH 2 ) z C(O)NR 3 R 3 , (CH 2 ) z N HC(O) R 4 , and (CH 2 ) z NR 4 C(O)R 4 .

10. The compound of claim 1 , or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein

Assignees

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

Inventors

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

Classifications

• C07C2602/08

  the other ring being five-membered, e.g. indane · CPC title

• C07C237/20

  the carbon skeleton containing six-membered aromatic rings · CPC title

• A61K31/4545

  containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine · CPC title

• A61K31/439

  the ring forming part of a bridged ring system, e.g. quinuclidine (8-azabicyclo [3.2.1] octanes A61K31/46) · CPC title

• A61K31/167

  having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol · CPC title