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US 2019/0241523 A1Published application
Therapeutic compounds and compositions
AssigneeAgios Pharmaceuticals, Inc.
InventorsFrancesco G. Salituro, Jeffrey O. Saunders, Shunqi Yan
Life of this patent
Estimating the term…
Abstract
Compounds and 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.
Claims30
A compound of 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 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.
14 more elements
A pharmaceutical composition comprising a compound 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.
14 more elements
A pharmaceutical composition comprising a compound represented in FIG. 1 or pharmaceutically acceptable salt thereof.
A compound of 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 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;
- for use as a medicament.
15 more elements
A use of a compound of 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 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;
- in the manufacture of a medicament for modulating PKM2 activity in a subject in need thereof or for treating cancer associated with PKM2 activity in a subject in need thereof.
15 more elements
Dependencies are inferred from the claim text.