# US 2014/0155408 A1 · Pyruvate kinase activators for use in therapy

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- Number: US 2014/0155408 A1
- Document ID: US20140155408A1
- Status: Published application
- Kind: A1
- Application number: 14/115,292
- Filed: 2012-05-03
- Published: 2014-06-05
- Earliest claimed: 2011-05-03
- Assignees: Agios Pharmaceuticals, Inc.
- Inventors: Shin-San Michael Su
- Web page: https://patentgrep.com/patent/US20140155408A1

## CPC

- C12N 5/0641: {Erythrocytes}
- A61K 31/4965: Non-condensed pyrazines
- A61K 31/497: containing further heterocyclic rings
- A61P 7/00: Drugs for disorders of the blood or the extracellular fluid
- A61P 7/06: Antianaemics
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 215/36: Sulfur atoms (C07D215/24 takes precedence)
- 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 413/12: linked by a chain containing hetero atoms as chain links
- C07D 417/12: linked by a chain containing hetero atoms as chain links
- C07D 451/02: containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
- C12N: MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA (microbiological testing media C12Q1/00)
- 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
- 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;
Q and Q1 are independently selected from a bond or NRb;
A is optionally substituted bicyclic aryl or optionally substituted bicyclic heteroaryl;
L is a bond, —C(O)—, —(CRcRc)m—, —C(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, carbocycle, 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 R4 is independently selected from halo, haloalkyl, alkyl, hydroxyl, ═O, —ORa and phenyl, or two R4 taken together with the carbon atoms to which they are attached form a bridged, fused or spyro-fused carbocycle, an aryl or a heteroaryl;
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 carbocycle;
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;
g is 0, 1 or 2;
the sum of g+h is equal to or greater than 2; and
p 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 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 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 not:
N-[3-[(3,5-dimethoxyphenyl)amino]-2-quinoxalinyl]-4-[(4-methyl-1-piperazinyl)carbonyl]-benzenesulfonamide;
N-[4-[[4-(2-furanylmethyl)-1-piperazinyl]carbonyl]phenyl]-2,3-dihydro-2-oxo-1H-benzimidazole-5-sulfonamide;
2,3-dihydro-2-oxo-N-[4-[[4-(2,2,2-trifluoroethyl)-1-piperazinyl]carbonyl]phenyl]-1H-benzimidazole-5-sulfonamide;
2,3-dihydro-N-[4-[[4-(4-nitrophenyl)-1-piperazinyl]carbonyl]phenyl]-2-oxo-1H-benzimidazole-5-sulfonamide;
N-[4-[[4-(2-ethoxyphenyl)-1-piperazinyl]carbonyl]phenyl]-2,3-dihydro-2-oxo-1H-benzimidazole-5-sulfonamide;
2,3-dihydro-2-oxo-N-[4-[[4-(3-thienylmethyl)-1-piperazinyl]carbonyl]phenyl]-1H-benzimidazole-5-sulfonamide;
N-[4-[[4-(2,3-dimethylphenyl)-1-piperazinyl]carbonyl]phenyl]-2,3-dihydro-2-oxo-1H-benzimidazole-5-sulfonamide;
2,3-dihydro-N-[4-[[4-(2-hydroxyphenyl)-1-piperazinyl]carbonyl]phenyl]-2-oxo-1H-benzimidazole-5-sulfonamide;
4-[4-[[(2,3-dihydro-2-oxo-1H-benzimidazol-5-yl)sulfonyl]amino]benzoyl]-1-piperazinecarboxylic acid ethyl ester;
N-[4-[(4-acetyl-1-piperazinyl)carbonyl]phenyl]-2,3-dihydro-2-oxo-1H-benzimidazole-5-sulfonamide;
N-[4-[[4-(4-fluorophenyl)-1-piperazinyl]carbonyl]phenyl]-2,3-dihydro-2-oxo-1H-benzimidazole-5-sulfonamide;
2,3-dihydro-2-oxo-N-[4-[(4-phenyl-1-piperazinyl)carbonyl]phenyl]-1H-benzimidazole-5-sulfonamide; or
2,3-dihydro-2-oxo-N-[4-[[4-(2-pyridinyl)-1-piperazinyl]carbonyl]phenyl]-1H-benzimidazole-5-sulfonamide.

### Claim 8 (depends on 1)

The method of claim 1, wherein p is 1 or 2.

### Claim 9 (depends on 1, 8)

The method of claim 8, wherein p is 2 and the compound has the formula Ia:
or formula Ib:
wherein R1, L, R3, W, X, Y, Z, Q, Q1, A, and n are as defined in claim 1.

### Claim 10 (depends on 8)

The method of claim 8, wherein:
each R4 is independently selected from alkyl, phenyl, (S)-alkyl, (R)-alkyl, (S)-phenyl, and (R)-phenyl.

### Claim 11 (depends on 10)

The method of claim 10, wherein:
g is 1;
h is 1; and
each R4 is independently selected from methyl, (S)-methyl, (R)-methyl, ethyl, (S)-ethyl, (R)-ethyl, isopropyl, (S)-isopropyl, (R)-isopropyl, phenyl, (S)-phenyl, and (R)-phenyl.

### Claim 12 (depends on 1)

The method of claim 1, wherein A is

### Claim 13 (depends on 1)

The method of claim 1, wherein W, X, Y, Z and the carbons to which they are attached form a phenyl ring.

### Claim 14 (depends on 1)

The method of claim 1, wherein:
n is 1; and
R3 is selected from fluoro, chlororo, methyl, ethyl, CF3, methoxy, and OCF3.

### Claim 15 (depends on 1)

The method of claim 1, wherein:
Q is NH; and
Q1 is a bond.

### Claim 16 (depends on 1)

The method of claim 1, wherein L is selected from a bond, —C(O)—, —OC(O)—, —CH2—OC(O)—, —(CH2)2—OC(O)—, —C(CH3)2—C(O)—, —CH2—, —(CH2)2—, —(CH2)3—, —CH(CH3)—, —CH(CF3)—, —C(CH3)2—, —CHD-, —CD2-,

### Claim 17 (depends on 1)

The method of claim 1, wherein R1 is selected from methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, 1,2,3-thiadiazol-5-yl, 1,2,3-thiadiazol-4-yl, thiazol-4-yl, thiazol-5-yl, 1H-imidazol-4-yl, 1H-imidazol-2-yl, 1H-pyrazol-3-yl, 1H-pyrazol-4-yl, 1H-pyrazol-5-yl, pyrazin-2-yl, oxazol-4-yl, isoxazol-5-yl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydro-2H-pyran-4-yl, tetrahydro-2H-pyran-3-yl, and tetrahydro-2H-pyran-2-yl.

### Claim 18 (depends on 1)

The method of claim 1, wherein the compound is selected from a compound of Tables 1-2 and 3-4.