3-aryl- heteroaryl substituted 5-trifluoromethyl oxadiazoles as histonedeacetylase 6 (HDAC6) inhibitors
The present invention is directed to substituted 5-trifluoromethyl oxadiazole compounds of generic formula (I) or a pharmaceutically acceptable salt thereof. In particular, the invention is directed to a class of aryl and heteroaryl substituted 5-trifluoromethyl oxadiazole compounds of formula I which may be useful as HDAC6 inhibitors for treating cellular proliferative diseases, including cancer, neurodegenerative diseases, such as schizophrenia and stroke, as well as other diseases.
1. A compound of formula (I):
or a pharmaceutically acceptable salt thereof wherein;
X represents phenyl, wherein said phenyl is optionally substituted with one or two fluoro;
Z is —N;
R 1 and R 2 can combine together with the nitrogen atom to which they are attached to form a six membered monocyclic, heterocyclic non-aromatic ring optionally interrupted by 1 heteroatoms O, wherein said heterocyclic ring is optionally substituted with 1 to 2 groups of R a ;
R a is selected from the group consisting of H, phenyl and ═O, wherein said phenyl is optionally substituted with 1 group R b ;
R b is halo,
n represents 0.
2. The compound according to claim 1 wherein R 1 and R 2 combine together with the nitrogen atom to which they are attached to form optionally substituted morpholinyl, morpholinonyl, piperidinonyl, or piperidinyl, wherein said groups are optionally substituted with 1 to 2 R a selected from the group consisting of phenyl, or a pharmaceutically acceptable salt thereof.
3. The compound according to claim 2 wherein R 1 and R 2 combine together with the nitrogen atom to which they are attached to form morpholinyl, morpholinonyl, piperidinonyl, or piperidinyl, and at least one R a is present which is positioned adjacent to the nitrogen atom to which R 1 and R 2 originally are attached, or a pharmaceutically acceptable salt thereof.
4. The compound according to claim 3 wherein the R a substituent attached adjacent to the nitrogen atom to which R 1 and R 2 are originally attached is phenyl, or a pharmaceutically acceptable salt thereof.
5. The compound according to claim 1 as represented by structural formula II:
or a pharmaceutically acceptable salt thereof, wherein
is defined as Q and Q is represented by structural formulas (c), (d), (e), or (f);
represents the bond that links the nitrogen to which it is attached to the rest of the molecule;
and R a′ is R a and R a is as defined in claim 1 .
6. The compound according to claim 5 wherein Q is (c), (d), (e), or (f), at least one R a is attached and is phenyl, or a pharmaceutically acceptable salt thereof.
7. The compound according to claim 6 wherein at least one R a present, is phenyl, and is located on the carbon atom directly adjacent to the linking nitrogen atom, or a pharmaceutically acceptable salt thereof.
8. A compound which is selected from the group consisting of:
(R)-5-phenyl-4-(4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)phenyl)morpholin-3-one,
(R)-4-(3-fluoro-4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)phenyl)-5-phenylmorpholin-3-one,
(R)-4-(2,5-difluoro-4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)phenyl)-5-phenylmorpholin-3-one,
(R)-4-(2-fluoro-4-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)phenyl)-5-phenylmorpholin-3-one,
or a pharmaceutically acceptable salt thereof.
9. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.