Histone deacetylase inhibitors
The compounds provided herein are phenyl analine amides and are useful for inhibiting histone deacteylase (“HDAC”) enzymes, such as HDAC1, HDAC2, and HDAC3.
1. A method of inhibiting HDAC1, HDAC2, or HDAC3 in a subject, comprising administering to the subject an effective amount of a compound having a structure of formula (II):
wherein:
R A is H or F;
R C is H, Cl, or F;
Het is selected from oxetanyl, azetindinyl, piperidinyl, and 8-azabicyclo[3.2.1]octanyl, and when Het is azetindinyl, piperidinyl, or 8-azabicyclo[3.2.1]octanyl, the ring nitrogen is substituted with R B ; and
R B is C 1 -C 6 alkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 3 alkylene-C 3 -C 6 cycloalkyl, C 1 -C 3 alkylene-phenyl, or C 1 -C 3 alkylene-pyridyl; wherein the phenyl or pyridyl ring is optionally substituted with methyl;
or a pharmaceutically acceptable salt thereof.
2. The method of claim 1 , wherein R A is H.
3. The method of claim 1 , wherein R A is F.
4. The method of claim 1 , wherein Het is oxetanyl.
5. The method of claim 1 , wherein Het is azetindinyl, piperidinyl, or 8-azabicyclo [3.2.1]octanyl.
6. The method of claim 1 , wherein Het is azetindinyl or piperidinyl.
7. The method of claim 1 , wherein R B is C 1-6 alkyl, C 1-6 hydroxyalkyl, CH 2 -cyclopropyl, CH 2 -phenyl, or CH 2 -pyridyl, and the pyridyl is optionally substituted with methyl.
8. The method of claim 1 , wherein R B is methyl, CH 2 C(CH 3 ) 3 , CH 2 C(CH 3 ) 2 OH, CH 2 -cyclopropyl, CH 2 -phenyl, CH 2 -pyridyl, or CH 2 -methylpyridyl.
9. The method of claim 1 , wherein Het is azetindinyl, piperidinyl, or 8-azabicyclo [3.2.1]octanyl; and R B is C 1-6 alkyl, C 1-6 hydroxyalkyl, CH 2 -cyclopropyl, CH 2 -phenyl, or CH 2 -pyridyl, or CH 2 -methylpyridyl.
10. The method of claim 9 , wherein Het is azetindinyl, and R B is C 1-6 alkyl, CH 2 C(CH 3 ) 2 OH, CH 2 -cyclopropyl, CH 2 -phenyl, or CH 2 -methylpyridyl.
11. The method of claim 9 , wherein Het is piperidinyl, and R B is C 1-6 alkyl, CH 2 C(CH 3 ) 2 OH, CH 2 -cyclopropyl, CH 2 -phenyl, CH 2 -pyridyl, or CH 2 -methylpyridyl.
12. The method of claim 9 , wherein Het is 8-azabicyclo [3.2.1]octanyl and R B is C 1-6 alkyl.
13. The method of claim 1 , wherein the subject suffers from a neurological disease.
14. The method of claim 13 , wherein the neurological disease is Friedreich's ataxia.
15. A method of treating a neurological disease or disorder selected from Friedreich's ataxia, myotonic dystrophy, spinal muscular atrophy, fragile X syndrome, Huntington's disease, spinocerebellar ataxia, Kennedy's disease, amyotrophic lateral sclerosis, spinal and bulbar muscular atrophy, and Alzheimer's disease; cutaneous T-cell lymphoma; a B cell lymphoma; colorectal cancer; psoriasis; rheumatoid arthritis; osteoarthritis; a long-term memory impairment condition; or a drug addiction in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound having a structure of formula (II):
wherein:
R A is H or F;
R C is H, Cl, or F;
Het is selected from oxetanyl, azetindinyl, piperidinyl, and 8-azabicyclo[3.2.1]octanyl, and when Het is azetindinyl, piperidinyl, or 8-azabicyclo[3.2.1]octanyl, the ring nitrogen is substituted with R B ;
R B is C 1 -C 6 alkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 3 alkylene-C 3 -C 6 cycloalkyl, C 1 -C 3 alkylene-phenyl, or C 1 -C 3 alkylene-pyridyl; wherein the phenyl or pyridyl ring is optionally substituted with methyl;
or a pharmaceutically acceptable salt thereof.
16. The method of claim 15 , wherein Het is azetindinyl, piperidinyl, or 8-azabicyclo [3.2.1]octanyl.
17. The method of claim 15 , wherein Het is azetindinyl or piperidinyl.
18. The method of claim 15 , wherein R B is C 1-6 alkyl, C 1-6 hydroxyalkyl, CH 2 -cyclopropyl, CH 2 -phenyl, or CH 2 -pyridyl, wherein the pyridyl is optionally substituted with methyl.
19. The method of claim 15 , wherein Het is azetindinyl, piperidinyl, or 8-azabicyclo [3.2.1]octanyl; and R B is C 1-6 alkyl, CH 2 C(CH 3 ) 2 OH, CH 2 -cyclopropyl, CH 2 -phenyl, or CH 2 -pyridyl, wherein the pyridyl is optionally substituted with methyl.
20. A method of treating a neurological disease or disorder selected from Friedreich's ataxia, myotonic dystrophy, spinal muscular atrophy, fragile X syndrome, Huntington's disease, spinocerebellar ataxia, Kennedy's disease, amyotrophic lateral sclerosis, spinal and bulbar muscular atrophy, and Alzheimer's disease; cutaneous T-cell lymphoma; a B cell lymphoma; colorectal cancer; psoriasis; rheumatoid arthritis; osteoarthritis; a long-term memory impairment condition; or a drug addiction in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
21. The method of claim 20 , wherein the disease or disorder is Friedreich's ataxia.
22. A method of inhibiting HDAC1, HDAC2, or HDAC3 in a subject, the method comprising administering to the subject an effective amount of a compound selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
23. The method of claim 22 , wherein the subject suffers from a neurological disease.
24. The method of claim 23 , wherein the neurological disease is Friedreich's ataxia.