# US 9,751,863 B2 · Therapeutically active compounds and their methods of use

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- Number: US 9,751,863 B2
- Document ID: US9751863B2
- Status: Granted
- Kind: B2
- Application number: 15/229,011
- Filed: 2016-08-04
- Published: 2017-02-09
- Granted: 2017-09-05
- Earliest claimed: 2015-08-05
- Assignees: Agios Pharmaceuticals, Inc.
- Applicants: Agios Pharmaceuticals, Inc.
- Inventors: Shijie Zhang
- Web page: https://patentgrep.com/patent/US9751863B2

## CPC

- C07D 401/14: containing three or more hetero rings
- C07D 401/04: directly linked by a ring-member-to-ring-member bond
- C07D 401/12: linked by a chain containing hetero atoms as chain links
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

Provided are compounds useful for treating cancer and methods of making the compounds and intermediates described herein.

## Claims

### Claim 1

A method of preparing a compound having the formula (I):
wherein ring A is pyridinyl substituted with trifluoromethyl, comprising reacting a compound of formula (II):
wherein R is alkyl, alkenyl or alkynyl;
with
(biuret) in the presence of a dehydrating agent, wherein the dehydrating agent comprises (i) trimethyl orthoformate and a catalytic amount of trifluoroacetic acid or (ii) titanium(IV) ethoxide.

### Claim 2

A method of preparing a compound of formula (Ia):
comprising reacting a compound of formula (IIa):
with
with (biuret) in the presence of a dehydrating reagent to provide the compound of formula (Ia), wherein the dehydrating agent comprises (i) trimethyl orthoformate and a catalytic amount of trifluoroacetic acid or (ii) titanium(IV) ethoxide.

### Claim 3 (depends on 2)

The method of claim 2, wherein the reaction is in the presence of a base.

### Claim 4 (depends on 3)

The method of claim 3, wherein the base is sodium ethoxide.

### Claim 5 (depends on 1)

The method of claim 1, wherein the compound of formula (II) is prepared by reacting a compound of formula (III)
with an acid halide and an alcohol.

### Claim 6 (depends on 2)

The method of claim 2, wherein the compound of formula (IIa) is prepared by reacting a compound of formula (IIIa):
with hydrogen chloride and methanol.

### Claim 7 (depends on 1)

The method of claim 1, further comprising halogenating the compound of formula (I) to give a compound of formula (IV)
wherein X is a halogen.

### Claim 8 (depends on 2)

The method of claim 2, further comprising reacting the compound of formula (Ia) with benzyltriethylammonium chloride and POCl3 to give a compound of formula (IVb)

### Claim 9 (depends on 8)

The method of claim 8, further comprising reacting the compound of formula (IVb) with a compound of formula (Va)
to give a compound of formula (VIb)

### Claim 10

A method of preparing a compound of formula (VIIIa)
comprising a) reacting compound (Ia)
with benzyltriethylammonium chloride and POCl3 to obtain compound (IVb)
b) reacting compound (IVb) with 2-(trifluoromethyl)pyridin-4-amine to obtain compound (VIb)
and
c) reacting compound (VIb) with 1-amino-2-methylpropan-2-ol to obtain the compound of formula (VIIIa), wherein compound (Ia) is prepared by reacting
with
in the presence of a dehydrating reagent, wherein the dehydrating agent comprises (i) trimethyl orthoformate and a catalytic amount of trifluoroacetic acid or (ii) titanium(IV) ethoxide.

### Claim 11 (depends on 10)

The method of claim 10, wherein step a) comprises heating to about 95-98° C. for about 18 hours.

### Claim 12 (depends on 10)

The method of claim 10, wherein step b) comprises aging at about 20° C. for about 3 h and then heating to about 60-65° C. for about 15.5 h.

### Claim 13 (depends on 10)

The method of claim 10, wherein step b) is conducted in methyltetrahydrofuran.

### Claim 14 (depends on 10)

The method of claim 10, wherein step c) is conducted at about 20-30° C.

### Claim 15 (depends on 10)

The method of claim 10, wherein step c) is conducted in presence of diisopropylethylamine.

### Claim 16 (depends on 10)

The method of claim 10, wherein the reaction of (IIa) is conducted in the presence of a base.

### Claim 17 (depends on 16)

The method of claim 16, wherein the base is sodium ethoxide.