# US 11,299,484 B2 · Inhibiting fatty acid synthase (FASN)

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- Number: US 11,299,484 B2
- Document ID: US11299484B2
- Status: Granted
- Kind: B2
- Application number: 17/021,759
- Filed: 2020-09-15
- Published: 2021-01-28
- Granted: 2022-04-12
- Earliest claimed: 2018-10-10
- Assignees: FORMA Therapeutics, Inc.
- Applicants: FORMA Therapeutics, Inc.
- Inventors: Matthew W. Martin; Mary-Margaret Zablocki; Scot Mente; Christopher Dinsmore; Zhongguo Wang; Xiaozhang Zheng
- Web page: https://patentgrep.com/patent/US11299484B2

## CPC

- C07D 405/14: containing three or more hetero rings
- C07D 221/20: Spiro-condensed ring systems
- C07D 405/06: linked by a carbon chain containing only aliphatic carbon atoms
- C07D 409/14: containing three or more hetero rings
- C07D 413/14: containing three or more hetero rings
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## 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.

## Claims

### 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;
R1 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 Rd is independently halogen, —CO2H, —OR3, SO2NHCOR3, C1-3 aliphatic, or 5-membered heteroaryl containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S; and
each R3 is independently hydrogen or C1-3 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.

### Claim 2 (depends on 1)

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.

### Claim 3 (depends on 1)

The method of claim 1, wherein the compound of formula (VII-A) is

### Claim 4 (depends on 3)

The method of claim 3, wherein the compound of formula (C) is

### Claim 5 (depends on 4)

The method of claim 4, wherein the compound of formula (A) is
and
the compound of formula (B) is

### Claim 6 (depends on 4)

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).

### Claim 7 (depends on 1)

The method of claim 1, wherein the compound of formula (VII-A) is

### Claim 8 (depends on 7)

The method of claim 7, wherein the compound of formula (C) is

### Claim 9 (depends on 8)

The method of claim 8, wherein the compound of formula (A) is
and
the compound of formula (B) is

### Claim 10 (depends on 8)

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).

### Claim 11 (depends on 1)

The method of claim 1, wherein the compound of formula (VII-A) is

### Claim 12 (depends on 11)

The method of claim 11, wherein the compound of formula (C) is

### Claim 13 (depends on 12)

The method of claim 12, wherein the compound of formula (A) is
and
the compound of formula (B) is

### Claim 14 (depends on 12)

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).

### Claim 15 (depends on 1)

The method of claim 1, wherein the compound of formula (VII-A) is

### Claim 16 (depends on 15)

The method of claim 15, wherein the compound of formula (C) is

### Claim 17 (depends on 16)

The method of claim 16, wherein the compound of formula (A) is
and
the compound of formula (B) is

### Claim 18 (depends on 16)

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).

### Claim 19 (depends on 1)

The method of claim 1, wherein the compound of formula (VII-A) is

### Claim 20 (depends on 19)

The method of claim 19, wherein the compound of formula (C) is

### Claim 21 (depends on 20)

The method of claim 20, wherein the compound of formula (A) is
and
the compound of formula (B) is

### Claim 22 (depends on 20)

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).