# US 2017/0283401 A1 · Therapeutic compositions and related methods of use

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- Number: US 2017/0283401 A1
- Document ID: US20170283401A1
- Status: Published application
- Kind: A1
- Application number: 15/488,174
- Filed: 2017-04-14
- Published: 2017-10-05
- Earliest claimed: 2009-04-06
- Assignees: Agios Pharmaceuticals, Inc.
- Applicants: Agios Pharmaceuticals, Inc.
- Inventors: Francesco G. Salituro; Jeffrey O. Saunders
- Web page: https://patentgrep.com/patent/US20170283401A1

## CPC

- C07D 405/14: containing three or more hetero rings
- A61P 3/04: Anorexiants; Antiobesity agents
- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- A61P 13/08: of the prostate
- A61P 35/00: Antineoplastic agents
- A61P 37/02: Immunomodulators
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 401/04: directly linked by a ring-member-to-ring-member bond
- C07D 403/04: directly linked by a ring-member-to-ring-member bond
- C07D 409/04: directly linked by a ring-member-to-ring-member bond
- C07D 417/04: directly linked by a ring-member-to-ring-member bond
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

Compositions comprising compounds that modulate pyruvate kinase M2 (PKM2) are described herein. Also described herein are methods of using the compounds that modulate PKM2 in the treatment of cancer.

## Claims

### Claim 1

A compound of Formula (IV) or pharmaceutically acceptable salt thereof, wherein:
R1 (IV),
X1 is N or CE;
X2 is N or CD;
X3 is N or CB;
X4 is N or CA, wherein at least one of X, X2, X3 and X4 is N; and at least one of X1, X2, X3, X4, is C—SO2—NR4R5;
A, B, D and E are each independently selected from H and —SO2—NR4R5;
each R4 is independently selected from C1-8 alkyl, aryl and heteroaryl, each of which is substituted with n occurrences of R2;
n is 0, 1, 2 or 3;
each R5 is independently hydrogen or C1-8 alkyl;
each R1 is independently selected from hydrogen, C1-8 alkyl, C1-8 alkoxy, halogen, haloalkyl and haloalkoxy;
each R2 is independently selected from halo, haloalkyl, C1-4alkyl, C2-4 alkenyl, C2-4 alkynylheteroaryl, aryl, aralkyl, heteroaralkyl, cyano, —ORa, —COORb and —CONRcRc′; wherein two R2, together with the carbons to which they are attached, may form an optionally substituted ring, each of which can be further substituted;
each R3 is independently selected from C1-8 alkyl, —ORa, halogen, haloalkyl, haloalkoxy or optionally substituted heteroaryl;
Ra is independently selected from alkyl, haloalkyl, optionally substituted heteroaryl and optionally substituted heterocyclyl;
each Rb is independently alkyl; and
each Rc is independently selected from hydrogen and alkyl.

### Claim 2 (depends on 1)

The compound of claim 1 or pharmaceutically acceptable salt thereof, wherein at least one of X3 and X4 are CH.

### Claim 3 (depends on 1)

The compound of claim 1 or pharmaceutically acceptable salt thereof, wherein at least one of A, B, D and E are H.

### Claim 4 (depends on 1)

The compound of claim 1 or pharmaceutically acceptable salt thereof, wherein B is —SO2—NH—R4.

### Claim 5 (depends on 1)

The compound of claim 1 or pharmaceutically acceptable salt thereof having Formula (IVa):

### Claim 6 (depends on 1)

The compound of claim 1 or pharmaceutically acceptable salt thereof having Formula (IVb):

### Claim 7 (depends on 1)

The compound of claim 1 or pharmaceutically acceptable salt thereof, wherein each R1 is independently selected from halogen or haloalkyl.

### Claim 8 (depends on 1)

The compound of claim 1 or pharmaceutically acceptable salt thereof, wherein each R1 is independently selected from chlorine and trifluoroalkyl.

### Claim 9 (depends on 1)

The compound of claim 1 or pharmaceutically acceptable salt thereof, wherein R4 is aryl substituted with n occurrences of R2.

### Claim 10 (depends on 1)

The compound of claim 1 or pharmaceutically acceptable salt thereof, wherein R2 is selected from halo, C1-4 alkyl, cyano, haloalkyl, —ORa or two R2, taken together with the carbon atoms to which they are attached form an optionally substituted ring, each of which can be further substituted.

### Claim 11 (depends on 1)

The compound of claim 1 or pharmaceutically acceptable salt thereof, wherein R2 is selected from halo and C1-4 alkyl.

### Claim 12 (depends on 1)

The compound of claim 1 or pharmaceutically acceptable salt thereof, wherein n is 2.

### Claim 13 (depends on 1)

The compound of claim 1 or pharmaceutically acceptable salt thereof selected from:

### Claim 14

A compound of Formula (II) or pharmaceutically acceptable salt thereof, wherein:
A, B, D and E are each independently selected from H, —SO2—NR4R5 and R3; wherein at least one of A, B, D, or E is —SO2—NR4R5;
Y1, Y2, Y3 and Y4 are each independently selected from N and CR1, wherein at least one of Y1, Y2, Y3 and Y4 are N;
each R4 is independently selected from C1-8 alkyl, aryl and heteroaryl, each of which is substituted with n occurrences of R2;
each R5 is independently hydrogen or C1-8 alkyl;
each R1 is independently selected from hydrogen, C1-8 alkyl, C1-8 terminal alkynyl, C1-8 alkoxy, halogen, haloalkyl and haloalkoxy;
each R2 is independently selected from halo, haloalkyl, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, aryl, heteroaryl, aralkyl, heteroaralkyl, cyano, —ORa, —COORb and —CONRcRc′; wherein two R2, together with the carbons to which they are attached, may form an optionally substituted ring, each of which can be further substituted;
each R3 is independently selected from C1-8 alkyl, —ORa, halogen, haloalkyl, haloalkoxy and optionally substituted heteroaryl;
each Ra is independently selected from alkyl, haloalkyl, optionally substituted heteroaryl and optionally substituted heterocyclyl;
each Rb is independently alkyl;
each Rc is independently selected from hydrogen and alkyl; and
n is 0, 1, 2 or 3.

### Claim 15 (depends on 14)

The compound of claim 14 or pharmaceutically acceptable salt thereof having Formula (IIa):

### Claim 16 (depends on 14)

The compound of claim 14 or pharmaceutically acceptable salt thereof having Formula (IIb):

### Claim 17 (depends on 14)

The compound of claim 14 or pharmaceutically acceptable salt thereof, wherein R4 is aryl substituted with n occurrences of R2.

### Claim 18 (depends on 14)

The compound of claim 14 or pharmaceutically acceptable salt thereof, wherein R2 is halo, C1-4 alkyl or haloalkyl; or two R2, together with the carbon atoms to which they are attached, form a 5-membered heterocyclic ring.

### Claim 19 (depends on 14)

The compound of claim 14 or pharmaceutically acceptable salt thereof selected from:

### Claim 20 (depends on 1)

A pharmaceutical composition comprising a compound of claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.