Inhibiting fatty acid synthase (FASN)
The present disclosure is directed to inhibitors of FASN. The compounds can be useful in the treatment of disease or disorders associated with the inhibition of FASN. For instance, the disclosure is concerned with compounds and compositions for inhibition of FASN, methods of treating, preventing, or ameliorating diseases or disorders associated with the inhibition of FASN, and methods of synthesis of these compounds.
1. A method for preparing a compound of formula (VII-A):
or a pharmaceutically acceptable salt thereof, wherein:
Ring B is phenyl, fused bicyclic 8-10 membered aryl, or fused bicyclic 8-10 membered heteroaryl containing 1-2 heteroatoms independently selected from the group consisting of O, N, and S;
R 1 is 3-membered cycloalkyl optionally substituted with —OH, or 5-membered heterocyclyl containing 1-3 heteroatoms independently selected from the group consisting of O, N, and S;
each R d is independently halogen, —CO 2 H, —OR 3 , SO 2 NHCOR 3 , C 1-3 aliphatic, or 5-membered heteroaryl containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S; and
each R 3 is independently hydrogen or C 1-3 alkyl;
comprising:
treating a compound of formula (A):
with a compound of formula (B):
Ar—X (B)
to afford a compound of formula (C):
wherein:
PG is hydrogen or Boc;
X is halogen; and
Ar is a substituted phenyl, fused bicyclic 8-10 membered aryl, or fused bicyclic 8-10 membered heteroaryl containing 1-2 heteroatoms independently selected from the group consisting of O, N, and S; and
converting the compound of formula (C) to the compound of formula (VII-A), or a pharmaceutically acceptable salt thereof.
2. The method of claim 1 , wherein said treating the compound of formula (A) with the compound of formula (B) is performed in the presence of a palladium catalyst and a base.
3. The method of claim 1 , wherein the compound of formula (VII-A) is
4. The method of claim 3 , wherein the compound of formula (C) is
5. The method of claim 4 , wherein the compound of formula (A) is
and
the compound of formula (B) is
6. The method of claim 4 , wherein said converting the compound of formula (C) to the compound of formula (VII-A) comprises:
treating the compound of formula (C) with trifluoroacetic acid to afford a compound of formula (D)
coupling the compound of formula (D) with 1-hydroxycyclopropane-1-carboxylic acid to afford a compound of formula (E)
treating the compound of formula (E) with trifluoroacetic acid to afford a compound of formula (F)
and
separating enantiomers of the compound of formula (F) by chiral HPLC to afford the compound of formula (VII-A).
7. The method of claim 1 , wherein the compound of formula (VII-A) is
8. The method of claim 7 , wherein the compound of formula (C) is
9. The method of claim 8 , wherein the compound of formula (A) is
and
the compound of formula (B) is
10. The method of claim 8 , wherein said converting the compound of formula (C) to the compound of formula (VII-A) comprises:
treating the compound of formula (C) with trifluoroacetic acid to afford a compound of formula (D)
coupling the compound of formula (D) with 1-hydroxycyclopropane-1-carboxylic acid to afford a compound of formula (E)
treating the compound of formula (E) with trifluoroacetic acid to afford a compound of formula (F)
and
separating enantiomers of the compound of formula (F) by chiral HPLC to afford the compound of formula (VII-A).
11. The method of claim 1 , wherein the compound of formula (VII-A) is
12. The method of claim 11 , wherein the compound of formula (C) is
13. The method of claim 12 , wherein the compound of formula (A) is
and
the compound of formula (B) is
14. The method of claim 12 , wherein said converting the compound of formula (C) to the compound of formula (VII-A) comprises:
coupling the compound of formula (C) with 1-hydroxycyclopropane-1-carboxylic acid to afford the compound of formula (VII-A).
15. The method of claim 1 , wherein the compound of formula (VII-A) is
16. The method of claim 15 , wherein the compound of formula (C) is
17. The method of claim 16 , wherein the compound of formula (A) is
and
the compound of formula (B) is
18. The method of claim 16 , wherein said converting the compound of formula (C) to the compound of formula (VII-A) comprises:
treating the compound of formula (C) with sodium azide and zinc chloride to afford a compound of formula (D)
treating the compound of formula (D) with trifluoroacetic acid to afford a compound of formula (E)
or a trifluoroacetate salt thereof;
coupling the compound of formula (E), or a trifluoroacetate salt thereof, with (2R)-tetrahydrofuran-2-carboxylic acid to afford a compound of formula (F)
and
separating diastereomers of the compound of formula (F) by HPLC to afford the compound of formula (VII-A).
19. The method of claim 1 , wherein the compound of formula (VII-A) is
20. The method of claim 19 , wherein the compound of formula (C) is
21. The method of claim 20 , wherein the compound of formula (A) is
and
the compound of formula (B) is
22. The method of claim 20 , wherein said converting the compound of formula (C) to the compound of formula (VII-A) comprises:
treating the compound of formula (C) with sodium azide and zinc chloride to afford a compound of formula (D)
treating the compound of formula (D) with trifluoroacetic acid to afford a compound of formula (E)
or a trifluoroacetate salt thereof;
coupling the compound of formula (E), or a trifluoroacetate salt thereof, with (2R)-tetrahydrofuran-2-carboxylic acid to afford a compound of formula (F)
and
separating diastereomers of the compound of formula (F) by HPLC to afford the compound of formula (VII-A).