Heterocyclic modulators of lipid synthesis
Compounds that are fatty acid synthesis modulators are provided. The compounds may be used to treat disorders characterized by disregulation of the fatty acid synthase function by modulating the function and/or the fatty acid synthase pathway. Methods are provided for treating such disorders including viral infections, such as hepatitis C infection, cancer and metabolic disorders.
1. A compound of the Formula (X):
or a pharmaceutically acceptable salt thereof,
wherein:
R 1 is H, —CN, halogen, C 1 -C 4 straight or branched alkyl, —O—(C 3 -C 5 cycloalkyl), —O—(C 1 -C 4 straight or branched alkyl) wherein:
the C 3 -C 5 cycloalkyl optionally includes an oxygen or nitrogen heteroatom; and
when R 1 is not H, —CN or halogen, it is optionally substituted with one or more halogens;
each R 2 is independently hydrogen, halogen or C 1 -C 4 straight or branched alkyl;
R 3 is H, —OH or halogen;
L 3 is C(R 60 ) 2 , O or NR 50 ;
each R 60 is independently H, —OH, —CN, —O t —(C 3 -C 5 cycloalkyl), —O—(C 1 -C 4 straight or branched alkyl), or —C(O)—N(R 601 ) 2 wherein:
t is 0 or 1, and
the C 3 -C 5 cycloalkyl optionally includes an oxygen or nitrogen heteroatom;
each R 50 is independently H, —C(O)—O t —(C 1 -C 4 straight or branched alkyl), —C(O)—O t —(C 3 -C 5 cyclic alkyl), —C 3 -C 5 cyclic alkyl optionally containing an oxygen or nitrogen heteroatom, —C(O)—N(R 501 ) 2 , C 1 -C 4 straight or branched alkyl wherein:
t is 0 or 1, and
the C 3 -C 5 cycloalkyl optionally includes an oxygen or nitrogen heteroatom;
n is 1, 2 or 3;
m is 1 or 2;
R 21 is H, halogen, C 1 -C 4 straight or branched alkyl, C 3 -C 5 cycloalkyl wherein the C 3 -C 5 cycloalkyl optionally includes an oxygen or nitrogen heteroatom;
R 22 is H, halogen, C 1 -C 2 alkyl;
each R 26 is independently —OH, —CN, halogen, C 1 -C 4 straight or branched alkyl, —(C 1 -C 4 alkyl) t -O t —(C 3 -C 5 cycloalkyl), —(C 1 -C 4 alkyl) t -O—(C 1 -C 4 straight or branched alkyl), —C(O)—O t —(C 1 -C 4 alkyl), or —C(O)—N(R 501 ) 2 wherein:
t is 0 or 1, and
the C 3 -C 5 cycloalkyl optionally includes an oxygen or nitrogen heteroatom;
s is 0, 1 or 2;
each R 601 and R 501 is independently H or C 1 -C 4 straight or branched alkyl; and
wherein two of R 26 , R 60 , R 50 , R 501 and R 601 optionally join to form a ring wherein the two of R 26 , R 60 , R 50 , R 501 and R 601 may be two R 26 , two R 60 , two R 50 , two R 501 or two R 601 .
2. The compound of claim 1 , wherein R 21 is halogen, C 1 -C 4 straight or branched alkyl or C 3 -C 5 cycloalkyl.
3. The compound of claim 1 , wherein R 1 is —CN or C 1 -C 2 haloalkyl.
4. The compound of claim 1 , wherein R 3 is H or F.
5. The compound of claim 1 , wherein R 1 is —CN.
6. The compound of claim 1 , wherein R 1 is —CF 3 .
7. The compound of claim 1 , wherein n is 1 or 2.
8. The compound of claim 1 , wherein m is 1.
9. The compound of claim 1 , wherein m is 2.
10. The compound of claim 1 , wherein R 21 is C 1 -C 2 alkyl or C 3 -C 5 cycloalkyl and R 22 is C 1 -C 2 alkyl.
11. The compound of claim 1 , wherein R 21 is C 3 -C 5 cycloalkyl and R 22 is C 1 -C 2 alkyl.
12. The compound of claim 1 , wherein n is 2, m is 1, L 3 is —N—C(O)—O—(C 1 -C 2 alkyl).
13. The compound of claim 1 , wherein L 3 is NR 50 ; R 50 is C 1 -C 2 alkyl; R 21 is cyclobutyl; R 22 is H or methyl; R 3 is H; R 1 is —CN; m is 2 and n is 1 or 2.
14. The compound of claim 1 , wherein n is 2, m is 1, L 3 is O and s is 0.
15. The compound of claim 1 , wherein R 22 is H, methyl or ethyl.
16. The compound of claim 1 , wherein R 1 is —CN, each R 2 is H, R 3 is H or F, R 21 is C 3 -C 4 cycloalkyl, R 22 is methyl, n is 2 and L 3 is NR 50 wherein R 50 is methyl or ethyl.
17. The compound of claim 1 , wherein R 1 is —CN, each R 2 is H, R 3 is H or F, R 21 is C 3 -C 4 cycloalkyl, R 22 is methyl, n is 2 and L 3 is O.
18. The compound of claim 1 , having a formula selected from the group consisting of:
19. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier, excipient, or diluent.