# US 2014/0194402 A1 · Pyruvate kinase activators for use in therapy

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- Number: US 2014/0194402 A1
- Document ID: US20140194402A1
- Status: Published application
- Kind: A1
- Application number: 14/115,289
- Filed: 2012-05-03
- Published: 2014-07-10
- Earliest claimed: 2011-05-03
- Assignees: Agios Pharmaceuticals, Inc.
- Inventors: Shin-San M. Su
- Web page: https://patentgrep.com/patent/US20140194402A1

## CPC

- A61K 31/496: Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
- A61K 31/4965: Non-condensed pyrazines
- A61K 31/497: containing further heterocyclic rings
- A61K 31/535: having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61P 7/06: Antianaemics
- C07C 307/10: having nitrogen atoms of the sulfamide groups bound to carbon atoms of six-membered aromatic rings
- C07D 205/04: having no double bonds between ring members or between ring members and non-ring members
- C07D 213/81: Amides; Imides
- C07D 215/14: Radicals substituted by oxygen atoms
- C07D 235/06: with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
- C07D 241/04: having no double bonds between ring members or between ring members and non-ring members
- C07D 241/20: Nitrogen atoms (nitro radicals C07D241/16)
- C07D 271/12: condensed with carbocyclic rings or ring systems
- C07D 295/192: from aromatic carboxylic acids
- C07D 333/24: Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D 401/12: linked by a chain containing hetero atoms as chain links
- C07D 405/12: linked by a chain containing hetero atoms as chain links
- C07D 417/12: linked by a chain containing hetero atoms as chain links
- A61K 31/415: 1,2-Diazoles
- A61K 31/4406: only substituted in position 3, e.g. zimeldine (nicotinic acid A61K31/455)
- A61K 31/47: Quinolines; Isoquinolines
- C07C 13/04: with a three-membered ring
- C07D 307/14: Radicals substituted by nitrogen atoms not forming part of a nitro radical
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07C: ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

Described herein are methods for using compounds that activate pyruvate kinase.

## Claims

### Claim 1

A method for increasing lifetime of the red blood cells (RBCs) in need thereof comprising contacting blood with an effective amount of (1) a compound of formula I or a pharmaceutically acceptable salt thereof; (2) a composition comprising a compound of formula I or a salt thereof, and a carrier or (3) a pharmaceutically acceptable composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier:
formula (I):
or a pharmaceutically acceptable salt thereof, wherein:
W, X, Y and Z are each independently selected from CH or N;
D and D1 are independently selected from a bond or NRb;
A is optionally substituted aryl or optionally substituted heteroaryl;
L is a bond, —C(O)—, —(CRcRc)m—, —OC(O)—, —(CRcRc)m—OC(O)—, —(CRcRc)m—C(O)—, —NRbC(S)—, or —NRbC(O)— (wherein the point of the attachment to R1 is on the left-hand side);
R1 is selected from alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl; each of which is substituted with 0-5 occurrences of Rd;
each R3 is independently selected from halo, haloalkyl, alkyl, hydroxyl and —ORa, or two adjacent R3 taken together with the carbon atoms to which they are attached form an optionally substituted heterocyclyl; each Ra is independently selected from alkyl, acyl, hydroxyalkyl and haloalkyl;
each Rb is independently selected from hydrogen and alkyl;
each Rc is independently selected from hydrogen, halo, alkyl, alkoxy and halo alkoxy or two Rc taken together with the carbon atoms to which they are attached form an optionally substituted cycloalkyl;
each Rd is independently selected from halo, haloalkyl, haloalkoxy, alkyl, alkynyl, nitro, cyano, hydroxyl, —C(O)Ra, —OC(O)Ra, —C(O)ORa, —SRa, —NRaRb and —ORa, or two Rd taken together with the carbon atoms to which they are attached form an optionally substituted heterocyclyl;
n is 0, 1, or 2;
m is 1, 2 or 3;
h is 0, 1, 2; and
g is 0, 1 or 2.

### Claim 2 (depends on 1)

The method of claim 1, wherein the compound is added directly to whole blood or packed cells extracorporeally.

### Claim 3 (depends on 1)

The method of claim 1, wherein the pharmaceutical composition is administered to a subject in need thereof.

### Claim 4 (depends on 1)

A method for regulating 2,3-diphosphoglycerate levels in blood in need thereof comprising contacting blood an effective amount of (1) a compound of formula I or a pharmaceutically acceptable salt thereof; (2) a composition comprising a compound of formula I or a salt thereof, and a carrier or (3) a pharmaceutically acceptable composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier; wherein formula I is as defined in claim 1.

### Claim 5 (depends on 1)

A method for treating hereditary non-spherocytic hemolytic anemia comprising administering to a subject in need thereof a therapeutically effective amount of an effective amount of (1) a compound of formula II or a pharmaceutically acceptable salt thereof; or (2) a pharmaceutically acceptable composition comprising a compound of formula II or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier; wherein formula II is as defined in claim 1.

### Claim 6 (depends on 1)

A method for treating sickle cell anemia comprising administering to a subject in need thereof a therapeutically effective amount of an effective amount of (1) a compound of formula I or a pharmaceutically acceptable salt thereof; or (2) a pharmaceutically acceptable composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier; wherein formula I is as defined in claim 1.

### Claim 7 (depends on 1)

The method of claim 1, wherein the compound is represented by formula (I):
wherein:
W, X, Y and Z are each independently selected from CH or N;
D and D1 are independently selected from a bond or NRb;
A is optionally substituted bicyclic heteroaryl;
L is a bond, —C(O)—, —(CRcRc)m—, —OC(O)—, —(CRcRc)m—OC(O)—, —(CRcRc)m—C(O)—, —NRbC(S)—, or —NRbC(O)—;
R1 is selected from alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl; each of which is substituted with 0-5 occurrences of Rd;
each R3 is independently selected from halo, haloalkyl, alkyl, hydroxyl and —ORa or two adjacent R3 taken together with the carbon atoms to which they are attached form an optionally substituted cyclyl;
each Ra is independently selected from alkyl, acyl, hydroxyalkyl and haloalkyl;
each Rb is independently selected from hydrogen and alkyl;
each Rc is independently selected from hydrogen, halo, alkyl, alkoxy and halo alkoxy or two Rc taken together with the carbon atoms to which they are attached form an optionally substituted cycloalkyl;
each Rd is independently selected from halo, haloalkyl, haloalkoxy, alkyl, alkynyl, nitro, cyano, hydroxyl, —C(O)Ra, —OC(O)Ra, —C(O)ORa, —SRa, —NRaRb and —ORa, or two Rd taken together with the carbon atoms to which they are attached form an optionally substituted heterocyclyl;
n is 0, 1, or 2;
m is 1, 2 or 3;
h is 0, 1, 2; and
g is 0, 1 or 2.

### Claim 8 (depends on 7)

The method of claim 7, wherein h is 1 and g is 1.

### Claim 9 (depends on 8)

The method of claim 8, wherein W, X, Y and Z are CH.

### Claim 10 (depends on 9)

The method of claim 9, wherein D is NRb and D1 is a bond.

### Claim 11 (depends on 10)

The method of claim 10, wherein Rb is H, methyl or ethyl.

### Claim 12 (depends on 7)

The method of claim 7, wherein L is a bond, —(CRcRc)m—, —NRbC(O)—, —(CRcRc)m—C(O)—, —C(O)—, or —O(CO)—.

### Claim 13 (depends on 12)

The method of claim 12, wherein L is a bond.

### Claim 14 (depends on 13)

The method of claim 13, wherein R1 is alkyl, aryl or heteroaryl substituted with 0-5 occurrences of Rd.

### Claim 15 (depends on 12)

The method of claim 12, wherein L is —(CRcRc)m—.

### Claim 16 (depends on 15)

The method of claim 15, wherein R1 is cycloalkyl, aryl, heteroaryl or heterocyclyl substituted with 0-5 occurrences of Rd.

### Claim 17 (depends on 12)

The method of claim 12, wherein L is —NRbC(O)— and Rb is hydrogen.

### Claim 18 (depends on 17)

The method of claim 17, wherein R1 is aryl substituted with 0-5 occurrences of Rd.

### Claim 19 (depends on 12)

The method of claim 12, wherein L is —(CRcRc)m—C(O)—.

### Claim 20 (depends on 19)

The method of claim 19, wherein R1 is cycloalkyl, aryl or heteroaryl substituted with 0-5 occurrences of Rd.

### Claim 21 (depends on 12)

The method of claim 12, wherein L is —C(O)—.

### Claim 22 (depends on 21)

The method of claim 21, wherein R1 is aryl, alkyl, or heteroaryl substituted with 0-5 occurrences of Rd.

### Claim 23 (depends on 12)

The method of claim 12, wherein L is —OC(O)—.

### Claim 24 (depends on 23)

The method of claim 23, wherein R1 is alkyl, aryl or heterocyclyl substituted with 0-5 occurrences of Rd.

### Claim 25 (depends on 12)

The method of claim 12, wherein L is —(CRcRc)m—OC(O)—.

### Claim 26 (depends on 25)

The method of claim 25, wherein R1 is heterocyclyl or cycloalkyl substituted with 0-5 occurrences of Rd.

### Claim 27 (depends on 12)

The method of claim 12, wherein n is 0.

### Claim 28 (depends on 12)

The method of claim 12, wherein n is 1 and R3 is CH3, CH2CH3, OCH3, OCH2CH3, OH, F, Cl, or CF3.

### Claim 29 (depends on 1)

The method of claim 1, wherein the compound is represented by formula (Id):

### Claim 30 (depends on 1)

The method of claim 1, wherein the compound is selected from FIG. 1.