# US 8,785,450 B2 · Therapeutic compounds and compositions

> Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt

- Number: US 8,785,450 B2
- Document ID: US8785450B2
- Status: Granted
- Kind: B2
- Application number: 12/826,630
- Filed: 2010-06-29
- Published: 2010-12-30
- Granted: 2014-07-22
- Earliest claimed: 2009-06-29
- Assignees: Agios Pharmaceuticals, Inc.
- Applicants: Francesco G. Salituro; Jeffrey O. Saunders; Shunqi Yan
- Inventors: Francesco G. Salituro; Jeffrey O. Saunders; Shunqi Yan
- Web page: https://patentgrep.com/patent/US8785450B2

## CPC

- C07D 215/36: Sulfur atoms (C07D215/24 takes precedence)
- A61K 31/497: containing further heterocyclic rings
- A61K 31/5513: 1,4-Benzodiazepines, e.g. diazepam {or clozapine}
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 9/10: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
- A61P 35/00: Antineoplastic agents
- C07D 215/40: attached in position 8
- C07D 239/42: One nitrogen atom (nitro radicals C07D239/30)
- C07D 241/20: Nitrogen atoms (nitro radicals C07D241/16)
- C07D 243/08: not condensed with other rings
- C07D 271/12: condensed with carbocyclic rings or ring systems
- C07D 277/64: with only hydrocarbon or substituted hydrocarbon radicals attached in position 2
- C07D 277/68: with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
- C07D 295/192: from aromatic carboxylic acids
- C07D 319/18: Ethylenedioxybenzenes, not substituted on the hetero ring
- C07D 401/12: linked by a chain containing hetero atoms as chain links
- C07D 401/14: containing three or more hetero rings
- C07D 403/12: linked by a chain containing hetero atoms as chain links
- C07D 407/12: linked by a chain containing hetero atoms as chain links
- C07D 409/12: linked by a chain containing hetero atoms as chain links
- C07D 417/12: linked by a chain containing hetero atoms as chain links
- C07D 417/14: containing three or more hetero rings
- Y02P 20/582: Recycling of unreacted starting or intermediate materials
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- 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
- Y02P: CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS

## 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.

## Claims

### Claim 1

A compound of formula II 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;
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 1; and
g is 1.

### Claim 2 (depends on 1)

The compound of claim 1, wherein W, X, Y and Z are CH.

### Claim 3 (depends on 2)

The compound of claim 2, wherein D is NRb and D1 is a bond.

### Claim 4 (depends on 3)

The compound of claim 3, wherein Rb is H, methyl or ethyl.

### Claim 5 (depends on 1)

The compound of claim 1, wherein L is a bond, —(CRcRc)m—, —NRbC(O)—, —(CRcRc)m—C(O)—, —C(O)—, or —O(CO)—.

### Claim 6 (depends on 5)

The compound of claim 5, wherein L is a bond.

### Claim 7 (depends on 6)

The compound of claim 6, wherein R1 is alkyl, aryl or heteroaryl, each substituted with 0-5 occurrences of Rd.

### Claim 8 (depends on 5)

The compound of claim 5, wherein L is —(CRcRc)m—.

### Claim 9 (depends on 8)

The compound of claim 8, wherein R1 is cycloalkyl, aryl, heteroaryl or heterocyclyl, each substituted with 0-5 occurrences of Rd.

### Claim 10 (depends on 5)

The compound of claim 5, wherein L is —NRbC(O)— and Rb is hydrogen.

### Claim 11 (depends on 10)

The compound of claim 10, wherein R1 is aryl substituted with 0-5 occurrences of Rd.

### Claim 12 (depends on 5)

The compound of claim 5, wherein L is —(CRcRc)m—C(O)—.

### Claim 13 (depends on 12)

The compound of claim 12, wherein R1 is cycloalkyl, aryl or heteroaryl, each substituted with 0-5 occurrences of Rd.

### Claim 14 (depends on 5)

The compound of claim 5, wherein L is —C(O)—.

### Claim 15 (depends on 14)

The compound of claim 14, wherein R1 is aryl, alkyl, or heteroaryl, each substituted with 0-5 occurrences of Rd.

### Claim 16 (depends on 5)

The compound of claim 5, wherein L is —OC(O)—.

### Claim 17 (depends on 16)

The compound of claim 16, wherein R1 is alkyl, aryl or heterocyclyl, each substituted with 0-5 occurrences of Rd.

### Claim 18 (depends on 1)

The compound of claim 1, wherein L is —(CRcRc)m—OC(O)—.

### Claim 19 (depends on 18)

The compound of claim 18, wherein R1 is heterocyclyl or cycloalkyl, each substituted with 0-5 occurrences of Rd.

### Claim 20 (depends on 5)

The compound of claim 5, wherein n is 0.

### Claim 21 (depends on 5)

The compound of claim 5, wherein n is 1 and R3 is CH3, CH2CH3, OCH3, OCH2CH3, OH, F, Cl, or CF3.

### Claim 22

A pharmaceutical composition comprising a compound formula II 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;
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 1; and
g is 1.

### Claim 23 (depends on 22)

The pharmaceutical composition of claim 22, wherein the compound is a compound of formula:

### Claim 24 (depends on 1)

The compound of claim 1, wherein the compound is selected from the following:

### Claim 25 (depends on 1)

The compound of claim 1 selected from the following:

### Claim 26 (depends on 1)

The compound of claim 1 selected from:

### Claim 27 (depends on 1)

The compound of claim 1 selected from:

### Claim 28 (depends on 1)

The compound of claim 1 selected from:

### Claim 29 (depends on 1)

The compound of claim 1 selected from:

### Claim 30 (depends on 1)

The compound of claim 1 selected from:

### Claim 31 (depends on 1)

The compound of claim 1 selected from:

### Claim 32 (depends on 1)

The compound of claim 1 selected from:

### Claim 33 (depends on 1)

The compound of claim 1 selected from:

### Claim 34 (depends on 1)

The compound of claim 1 selected from:

### Claim 35 (depends on 1)

The compound of claim 1 selected from:

### Claim 36 (depends on 1)

The compound of claim 1 selected from:

### Claim 37 (depends on 1)

The compound of claim 1 selected from:

### Claim 38 (depends on 1)

The compound of claim 1 selected from:

### Claim 39 (depends on 1)

The compound of claim 1 selected from:

### Claim 40 (depends on 1)

The compound of claim 1 selected from:

### Claim 41 (depends on 1)

The compound of claim 1 selected from:

### Claim 42 (depends on 1)

The compound of claim 1 selected from:

### Claim 43 (depends on 1)

The compound of claim 1 selected from:

### Claim 44 (depends on 1)

The compound of claim 1 selected from:

### Claim 45 (depends on 1)

The compound of claim 1 selected from:

### Claim 46 (depends on 1)

The compound of claim 1 selected from:

### Claim 47 (depends on 1)

The compound of claim 1 selected from:

### Claim 48 (depends on 1)

The compound of claim 1 selected from:

### Claim 49

A compound selected from one of the following:

### Claim 50 (depends on 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 49)

A pharmaceutical composition comprising a compound of any one of claims 2 to 21, or a pharmaceutically acceptable salt thereof, or a compound of claim 49.

### Claim 51 (depends on 24)

A pharmaceutical composition comprising a compound of claim 24, or a pharmaceutically acceptable salt thereof.