Inhibiting fatty acid synthase (FASN)

Patent metadata

Field	Value
Publication number	US-11299484-B2
Application number	US-202017021759-A
Country	US
Kind code	B2
Filing date	Sep 15, 2020
Priority date	Oct 10, 2018
Publication date	Apr 12, 2022
Grant date	Apr 12, 2022

Abstract

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.

First claim

We claim:

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 ,

Assignees

• Forma Therapeutics Inc

Inventors

• Martin Matthew W
• Zablocki Mary-Margaret
• Mente Scot
• Dinsmore Christopher
• Wang Zhongguo
• Zheng Xiaozhang

Classifications

• C07D405/14 Primary

  containing three or more hetero rings · CPC title

• C07D413/14

  containing three or more hetero rings · CPC title

• C07D409/14

  containing three or more hetero rings · CPC title

• A61K31/4709

  Non-condensed quinolines and containing further heterocyclic rings · CPC title

• C07D405/06

  linked by a carbon chain containing only aliphatic carbon atoms · CPC title