Methods using HDAC11 inhibitors
The present invention provides methods and uses of inhibitors of histone deacetylase 11 (HDAC11) in the treatment of diseases and/or disorders, such as, for example, cell proliferative diseases.
1. A compound of Formula I-A or a pharmaceutically acceptable salt thereof,
wherein:
X 1 , X 2 , X 3 , and X 4 are each independently, at each occurrence, N or CR 1 ;
wherein
(i) X 1 and X 4 are both N, and X 2 and X 3 are each independently CR 1 ;
(ii) X 2 and X 4 are both N, and X 1 and X 3 are each independently CR 1 ;
(iii) X 1 is N and X 2 , X 3 , and X 4 are each independently CR 1 ; or
(iv) X 1 , X 2 , X 3 , and X 4 are each CR 1 ;
R 1 is independently, at each occurrence, —H, —R 3 , —R 4 , —C 1 -C 6 alkyl, —C 2 -C 6 alkenyl, —C 4 -C 8 cycloalkenyl, —C 2 -C 6 alkynyl, —C 3 -C 8 cycloalkyl, heterocyclyl, aryl, heteroaryl containing 1-5 heteroatoms selected from the group consisting of N, S, P and O, —OH, —OR 3 , halogen, —NO 2 , —CN, —NHC 1 -C 6 alkyl, —N(C 1 -C 6 alkyl) 2 , —S(O) 2 NH 2 , —S(O) 2 N(C 1 -C 6 alkyl) 2 , —N(C 1 -C 6 alkyl)S(O) 2 R 5 , —S(O) 2 (C 1 -C 6 alkyl), —(C 1 -C 6 alkyl)S(O) 2 R 5 , —C(O)C 1 -C 6 alkyl, —C(O)OC 1 -C 6 alkyl, —N(C 1 -C 6 alkyl)S(O) 2 C 1 -C 6 alkyl, or —(CHR 5 ) p NR 3 R 4 , wherein each alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more —OH, halogen, —NO 2 , oxo, —CN, —R 3 , —R 5 , —SR 3 , —OR 3 , —NHR 3 , —NR 3 R 4 , —S(O) 2 N(R 3 ) 2 —, —S(O) 2 R 5 , —C(O)R 5 , —C(O)OR 5 , —NR 3 S(O) 2 R 5 , —S(O)R 5 , —S(O)NR 3 R 4 , —NR 3 S(O)R 5 , heterocycle, aryl, or heteroaryl;
or two occurrences of R 1 , when on adjacent atoms, can combine to form a cycloalkyl, a heterocycle, aryl, heteroaryl containing 1-5 heteroatoms selected from the group consisting of N, S, P and O, or a cycloalkenyl, each optionally substituted with one or more independent occurrences of R 3 and R 4 ;
R 3 and R 4 are independently, at each occurrence, —H, —C 1 -C 6 alkyl, —C 2 -C 6 alkenyl, —C 4 -C 8 cycloalkenyl, —C 2 -C 6 alkynyl, —C 3 -C 8 cycloalkyl, heterocyclyl, aryl, heteroaryl containing 1-5 heteroatoms selected from N, S, P, and O, —S(O) 2 N(C 1 -C 6 alkyl) 2 , —S(O) 2 (C 1 -C 6 alkyl), —(C 1 -C 6 alkyl)S(O) 2 R 5 , —C(O)C 1 -C 6 alkyl, —C(O)OC 1 -C 6 alkyl, oxo, or —(CHR 5 ) p N(C 1 -C 6 alkyl) 2 , wherein each alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more substituents selected from —OH, halogen, —NO 2 , oxo, —CN, —R 5 , —O(C 1 -C 6 )alkyl, —NH(C 1 -C 6 )alkyl, —N(C 1 -C 6 alkyl) 2 , —S(O) 2 N(C 1 -C 6 alkyl) 2 , —S(O) 2 NHC 1 -C 6 alkyl, —C(O)C 1 -C 6 alkyl, —C(O)OC 1 -C 6 alkyl, —N(C 1 -C 6 alkyl)S(O) 2 C 1 -C 6 alkyl, —S(O)R 5 , —S(O)N(C 1 -C 6 alkyl) 2 , —N(C 1 -C 6 alkyl)S(O)R 5 , heterocycle, aryl, or heteroaryl;
R 5 is independently, at each occurrence, —H, —C 1 -C 6 alkyl, —C 2 -C 6 alkenyl, —C 4 -C 8 cycloalkenyl, —C 2 -C 6 alkynyl, —C 3 -C 8 cycloalkyl, heterocyclyl, aryl, heteroaryl containing 1-5 heteroatoms selected from N, S, P and O, —OH, halogen, —NO 2 , —CN, —N(C 1 -C 6 alkyl) 2 , —S(O) 2 NH(C 1 -C 6 alkyl), —S(O) 2 N(C 1 -C 6 alkyl) 2 , —S(O) 2 C 1 -C 6 alkyl, —C(O)C 1 -C 6 alkyl, —C(O)OC 1 -C 6 alkyl, —N(C 1 -C 6 alkyl)SO 2 C 1 -C 6 alkyl, —S(O)(C 1 -C 6 alkyl), —S(O)N(C 1 -C 6 alkyl) 2 , —N(C 1 -C 6 alkyl)S(O)(C 1 -C 6 alkyl) or —(CH 2 ) p N(C 1 -C 6 alkyl) 2 ;
R 6 is —H, —C 2 -C 6 alkenyl, —C 4 -C 8 cycloalkenyl, —C 2 -C 6 alkynyl, —C 3 -C 8 cycloalkyl, heterocyclyl, aryl, heteroaryl containing 1-5 heteroatoms selected from the group consisting of N, S, P and O, —S(O) 2 N(C 1 -C 6 alkyl) 2 , —S(O) 2 (C 1 -C 6 alkyl), —(C 1 -C 6 alkyl)S(O) 2 R 5 , —C(O)C 1 -C 6 alkyl, —C(O)OC 1 -C 6 alkyl, or —(CHR 5 ) p NR 3 R 4 wherein each alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more substituents selected from —OH, halogen, —NO 2 , oxo, —CN, —R 5 , —O(C 1 -C 6 )alkyl, —NH(C 1 -C 6 )alkyl, —N(C 1 -C 6 alkyl) 2 , —S(O) 2 N(C 1 -C 6 alkyl) 2 , —S(O) 2 NHC 1 -C 6 alkyl, —C(O)C 1 -C 6 alkyl, —C(O)OC 1 -C 6 alkyl, —N(C 1 -C 6 alkyl)S(O) 2 C 1 -C 6 alkyl, —S(O)R 5 , —S(O)N(C 1 -C 6 alkyl) 2 , —N(C 1 -C 6 alkyl)S(O)R 5 , heterocycle, aryl, or heteroaryl;
and
p is 0, 1, 2, 3, 4, 5, or 6.
2. The compound of claim 1 , wherein X 1 , X 2 , X 3 , and X 4 are each CR 1 .
3. The compound of claim 2 , wherein each R 1 is independently H, halogen, —CF 3 , —OH, —CN, —SO 2 (C 1 -C 3 alkyl), phenyl, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, pyridyl, —C(O)C 1 -C 3 alkyl, —OC 1 -C 3 alkyl, —(C 1 -C 3 alkyl)O(C 1 -C 3 alkyl), —OCF 3 or —OCH 2 phenyl.
4. The compound of claim 3 , wherein each R 1 is independently H or halogen.
5. The compound of claim 1 , wherein R 6 is H, —(CHR 5 ) p NR 3 R 4 , or —C 1 -C 6 alkyl optionally substituted with one or more substituents selected from —OH, halogen, —NO 2 , oxo, —CN, —R 5 , —O(C 1 -C 6 )alkyl, —NH(C 1 -C 6 )alkyl, —N(C 1 -C 6 alkyl) 2 , —S(O) 2 N(C 1 -C 6 alkyl) 2 , —S(O) 2 NHC 1 -C 6 alkyl, —C(O)C 1 -C 6 alkyl, —C(O)OC 1 -C 6 alkyl, —N(C 1 -C 6 alkyl)S(O) 2 C 1 -C 6 alkyl, —S(O)R 5 , —S(O)N(C 1 -C 6 alkyl) 2 , or —N(C 1 -C 6 alkyl)S(O)R 5 .
6. The compound of claim 5 , wherein R 6 is H.
7. A compound selected from
8. The compound of claim 7 , wherein the compound is selected from:
9. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically accepted salt thereof, and a pharmaceutically accepted carrier.
10. A pharmaceutical composition comprising a compound of claim 7 , or a pharmaceutically accepted salt thereof, and a pharmaceutically accepted carrier.
11. A pharmaceutical composition comprising a compound of claim 8 , or a pharmaceutically accepted salt thereof, and a pharmaceutically accepted carrier.