Alpha-cinnamide compounds and compositions as HDAC8 inhibitors
The present invention relates to inhibitors of histone deacetylases, in particular HDAC8, that are useful for the treatment of cancer and other diseases and disorders, as well as the synthesis and applications of said inhibitors.
1. A compound of Formula I:
or a pharmaceutically acceptable salt thereof,
wherein:
X 1 , X 2 , X 3 , and X 4 are each CH;
R a is hydrogen;
R b is —C(O)R c ;
or alternatively, R a and R b are combined to form a heterocycle, wherein said heterocycle is optionally substituted with one or more R d ;
R c is aryl, optionally substituted with one or more R d or R e ;
R d is hydrogen, C 1 -C 6 alkyl, oxo, C 3 -C 8 cycloalkyl, or —OR e ,
or two R d when attached to the same carbon atom can form a C 3 -C 12 spirocycle or a 3- to 12-membered spiroheterocycle;
R e is aryl; and
A is hydrogen;
with the proviso that:
when R a is H and R b is —C(O)R c , then R c cannot be phenyl, 1-naphthyl, 2-naphthyl, or 4-biphenyl.
2. The compound of claim 1 , wherein R a and R b are combined to form a heterocycle, wherein said heterocycle is optionally substituted with one or more R d .
3. The compound of claim 2 , wherein R d is at least one of hydrogen, C 1 -C 6 alkyl, oxo, or C 3 -C 8 cycloalkyl.
4. The compound of claim 2 , wherein R d is at least one of hydrogen, oxo, C 3 -C 8 cycloalkyl, or two R d when attached to the same carbon atom can form a C 3 -C 12 spirocycle or a 3- to 12-membered spiroheterocycle.
5. The compound of claim 1 , wherein R c is aryl, optionally substituted with one or more R d .
6. The compound of claim 5 , wherein R d is —OR e .
7. The compound of claim 1 , wherein the compound is (E)-N-(2-(3 -(hydroxyamino)-3 -oxoprop-1-en-1-yl)phenyl)-2-phenoxybenzamide.
8. A pharmaceutical composition comprising a compound of claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
9. A composition comprising a compound of Formula I:
or a pharmaceutically acceptable salt thereof,
wherein:
X 1 , X 2 , X 3 , and X 4 are each CH;
R a is hydrogen;
R b is —C(O)R c ;
or alternatively, R a and R b are combined to form a heterocycle, wherein said heterocycle is optionally substituted with one or more R d ;
R c is aryl, optionally substituted with one or more R d or R e ;
R d is hydrogen, C 1 -C 6 alkyl, oxo, C 3 -C 8 cycloalkyl, or —OR e ,
or two R d when attached to the same carbon atom can form a C 3 -C 12 spirocycle or a 3- to 12-membered spiroheterocycle;
R e is aryl; and
A is hydrogen;
with the proviso that:
when R a is H and R b is —C(O)R c , then R c cannot be phenyl, 1-naphthyl, 2-naphthyl, or 4-biphenyl; and
wherein the compound is obtained by a process comprising a step of treating a compound 2:
with hydroxylamine and sodium hydroxide to form the compound of Formula I.
10. The composition of claim 9 , wherein the process further comprises a step of treating a compound 1:
wherein Hal is halogen,
with an amine under palladium- or copper-mediated cross-coupling conditions to form the compound 2:
11. The composition of claim 9 , wherein the process further comprises a step of treating a compound 4:
with a carboxylic acid to form the compound 2:
12. A composition comprising a compound of Formula I:
or a pharmaceutically acceptable salt thereof,
wherein:
X 1 , X 2 , X 3 , and X 4 are each CH;
R a is hydrogen;
R b is —C(O)R c ;
or alternatively, R a and R b are combined to form a heterocycle, wherein said heterocycle is optionally substituted with one or more R d ;
R c is aryl, optionally substituted with one or more R d or R e ;
R d is hydrogen, C 1 -C 6 alkyl, oxo, C 3 -C 8 cycloalkyl, or —OR e ,
or two R d when attached to the same carbon atom can form a C 3 -C 12 spirocycle or a 3- to 12-membered spiroheterocycle;
R e is aryl; and
A is hydrogen;
with the proviso that:
when R a is H and R b is —C(O)R c , then R c cannot be phenyl, 1-naphthyl, 2-naphthyl, or 4-biphenyl; and
a compound 2:
13. The composition of claim 12 , wherein R a and R b are combined to form a heterocycle, wherein said heterocycle is optionally substituted with one or more R d .
14. The composition of claim 13 , wherein R d is at least one of hydrogen, C 1 -C 6 alkyl, oxo, C 3 -C 8 cycloalkyl, or two R d when attached to the same carbon atom can form a C 3 -C 12 spirocycle or a 3- to 12-membered spiroheterocycle.
15. The composition of claim 12 , wherein R c is aryl optionally substituted with —OR e .
16. The composition of claim 12 , wherein the compound of Formula I is (E)-N-(2-(3-(hydroxyamino)-3-oxoprop-1-en-l-yl)phenyl)-2-phenoxybenzamide.