# US 7,608,639 B2 · Phenoxyether derivatives as PPAR modulators

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- Number: US 7,608,639 B2
- Document ID: US7608639B2
- Status: Granted
- Kind: B2
- Application number: 10/571,961
- Filed: 2004-10-08
- Published: 2007-02-15
- Granted: 2009-10-27
- Earliest claimed: 2003-10-14
- Assignees: Eli Lilly and Company
- Inventors: Leonard Larry Winneroski, Jr.; Yanping Xu; Jeremy Schulenburg York
- Web page: https://patentgrep.com/patent/US7608639B2

## CPC

- C07D 213/30: Oxygen atoms
- A61P 3/04: Anorexiants; Antiobesity agents
- A61P 3/06: Antihyperlipidemics
- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- A61P 9/04: Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
- A61P 9/12: Antihypertensives
- C07C 59/68: the oxygen atom of the ether group being bound to a non-condensed six-membered aromatic ring
- C07C 59/70: Ethers of hydroxy-acetic acid {, e.g. substitutes on the ring}
- C07C 59/90: containing singly bound oxygen-containing groups
- C07C 317/22: with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
- C07C 323/52: the carbon skeleton being acyclic and saturated
- C07D 213/64: attached in position 2 or 6
- C07D 213/643: 2-Phenoxypyridines; Derivatives thereof
- C07D 213/69: Two or more oxygen atoms
- C07D 239/26: with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07C: ACYCLIC OR CARBOCYCLIC COMPOUNDS

## Abstract

The present invention is directed to a compound of formula (I), or a pharmaceutically acceptable salt, solvate, hydrate or stereoisomer thereof, which is useful in treating or preventing disorders mediated by a peroxisome proliferator activated receptor (PPAR), such as syndrome X, type II diabetes, hyperglycemia, hyperlipidemia, obesity, coagaulopathy, hypertension, arteriosclerosis, and other disorders related to syndrome X and cardiovascular diseases.

## Claims

### Claim 1

The compound having a structural formula III,
or a pharmaceutically acceptable salt thereof wherein:
A is: a bond, CH2, (CH2)2, O, S; or A and R1 or A and R2 together being a 3- to 6-membered carbocyclyl when A is a carbon;
n is: 1, 2, 3, 4, 5 or 6
p is: 1 or 2;
r is: 1, 2, 3, or 4;
R1 and R2 are each independently:
hydrogen, C1-C6 alkyl, or R1 and R2 together being a 3- to 8-membered carbocyclic ring;
R3 and R4 are each independently:
hydrogen,
nitro,
cyano,
hydroxyl,
halo,
haloalkyl,
haloalkyloxy,
C1-C6 alkyl,
C1-C6 alkoxy, or
C3-C8 cycloalkyl
R5 is: hydrogen,
nitro,
cyano,
hydroxyl,
halo,
haloalkyl,
haloalkyloxy,
aryloxy,
C1-C6 alkyl,
C1-C6 alkoxy,
[T]-aryl,
[T]-heteroaryl,
[T]-heterocyclyl,
[T]-(CH2)n, C3-C8 cycloalkyl,
C(O)pR7,
O(CH2)nR7,
SR7,
S(O)pR7 or
OS(O)pR7,
wherein aryl, aryloxy, alkyl, heteroaryl, heterocyclyl and cycloalkyl are being optionally substituted with one or more substituents independently selected from R8;
[T] is: a bond, O, C(O), S, NR7, or C1-C6 alkyl;
R6 is: hydrogen, C1-C6 alkyl or aminoalkyl;
R7 is: hydrogen,
C1-C6 alkyl,
C3-C8 cycloalkyl,
aryl,
heteroaryl or
heterocyclyl,
wherein alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl being optionally substituted with one or more substituents independently selected from R8; and
R8 is: hydrogen, nitro, cyano, hydroxyl, halo, haloalkyl, haloalkyloxy, aryloxy, oxo, acyl, C1-C6 alkyl, C1-C6 alkoxy or C3-C8 cycloalkyl.

### Claim 2 (depends on 1)

The compound of claim 1, wherein the compound is structural formula IV,
or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:
A is: CH2, O, S;
[T] is: a bond, O, C(O) or C1-C3 alkyl;
R3 and R4 are each independently:
hydrogen, C1-C3 alkyl, halo, haloalkyl or haloalkyloxy;
R5 and R8 are each independently:
hydrogen, C1-C6 alkyl, halo, haloalkyl or haloalkyloxy; and
r is 1 or 2.

### Claim 3 (depends on 2)

The compound of claim 2, wherein the compound is structural formula V,
or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:
R3 and R4 are each independently: hydrogen, methyl, ethyl, Br, Cl or F;
R5 and R8 are each independently: hydrogen, C1-C4 alkyl, Br, Cl, F or CF3; and
r is 1 or 2.

### Claim 4 (depends on 2)

The compound of claim 2, wherein the compound is structural formula VI,
or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:
R3 and R4 are each independently: hydrogen, methyl, ethyl, Br, Cl or F;
R5 and R8 are each independently: hydrogen, C1-C4 alkyl, Br, Cl, F or CF3; and
r is 1 or 2.

### Claim 5 (depends on 4)

The compound of claim 4, wherein the compound is structural formula VII,
or a pharmaceutically acceptable salt thereof.

### Claim 6 (depends on 4)

The compound of claim 4, wherein the compound is structural formula VIII,
or a pharmaceutically acceptable salt thereof.

### Claim 7 (depends on 2)

The compound of claim 2, wherein the compound is structural formula IX,
or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:
R3 and R4 are each independently: hydrogen, methyl, ethyl, Br, Cl or F;
R5 and R8 are each independently: hydrogen, C1-C4 alkyl, Br, Cl, F or CF3; and
r is 1 or 2.

### Claim 8

The compound having the structural formula X,
or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:
is a 5- or 6-membered heteroaryl or heterocyclyl, wherein heteroaryl and heterocyclyl being optionally substituted with one or more substituents independently selected from R8;
A is: a bond, CH2, (CH2)2, O, S; or A and R1 or A and R2 together being a 3- to 6-membered carbocyclyl when A is a carbon;
n is: 1,2,3,4,5 or 6;
p is: 1 or 2;
r is: 1,2,3, or 4;
R1 and R2 are each independently:
hydrogen, C1-C6 alkyl, or R1 and R2 together being a 3- to 8-membered carbocyclic ring;
R3 and R4 are each independently:
hydrogen,
nitro,
cyano,
hydroxyl,
halo,
haloalkyl,
haloalkyloxy,
C1-C6 alkyl,
C1-C6 alkoxy, or
C3-C8 cycloalkyl
R5 is: hydrogen,
nitro,
cyano,
hydroxyl,
halo,
haloalkyl,
haloalkyloxy,
aryloxy,
C1-C6 alkyl,
C1-C6 alkoxy,
[T]-aryl,
[T]-heteroaryl,
[T]-heterocyclyl,
[T]-(CH2)nC3-C8 cycloalkyl,
C(O)pR7,
O(CH2)nR7,
SR7,
S(O)pR7 or
OS(O)pR7,
wherein aryl, aryloxy, alkyl, heteroaryl, heterocyclyl and cycloalkyl are being optionally substituted with one or more substituents independently selected from R8;
[T] is: a bond, O, C(O), S, NR7, or C1-C6 alkyl;
R6 is: hydrogen, C1-C6 alkyl or aminoalkyl;
R7 is: hydrogen,
C1-C6 alkyl,
C3-8 cycloalkyl,
aryl,
heteroaryl or
heterocyclyl,
wherein alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl being optionally substituted with one or more substituents independently selected from R8, and
R8 is: hydrogen, nitro, cyano, hydroxyl, halo, haloalkyl, haloalkyloxy, aryloxy, oxo, acyl, C1-C6 alkyl, C1-C6 alkoxy or C3-C8 cycloalkyl.

### Claim 9 (depends on 8)

The compound of claim 8, wherein the heteroaryl is pyrazolyl, pyrrolyl, pyrazinyl, pyridyl, pyrimidyl, or pyrimidinyl.

### Claim 10 (depends on 8)

The compound of claim 8, wherein the compound is structural formula XI,
or a pharmaceutically acceptable salt, solvate, hydrate or stereoisomer thereof, wherein:
[T] is: a bond, O, C(O) or C1-C3 alkyl;
R3 and R4 are each independently: hydrogen, methyl, ethyl, Br, Cl or F;
R5 and R8 are each independently: hydrogen, C1-C4 alkyl, Br, Cl, F or CF3; and
r is 1 or 2.

### Claim 11

The compound having the structural formula XII,
or a pharmaceutically acceptable salt or stereoisomer thereof;
A is: a bond, CH2, (CH2)2, O, S; or A and R1 or A and R2 together being a 3- to 6-membered carbocyclyl when A is a carbon;
Q is COOR6;
n is: 1,2,3,4,5 or 6;
p is: 1 or 2;
r is: 1,2,3, or 4;
R1 and R2 are each independently:
hydrogen, C1-C6 alkyl, or R1 and R2 together being a 3- to 8-membered carbocyclic ring;
R3 and R4 are each independently:
hydrogen,
nitro,
cyano,
hydroxyl,
halo,
haloalkyl,
haloalkyloxy,
C1-C6 alkyl,
C1-C6 alkoxy, or
C3-C8 cycloalkyl
R5 is: hydrogen,
nitro,
cyano,
hydroxyl,
halo,
haloalkyl, haloalkyloxy,
aryloxy,
C1-C6 alkyl,
C1-C6 alkoxy,
[T]-aryl,
[T]-heteroaryl,
[T]-heterocyclyl,
[T]-(CH2)nC3-C8 cycloalkyl,
C(O)pR7,
O(CH2)nR7,
SR7,
S(O)pR7, or
OS(O)pR7,
wherein aryl, aryloxy, alkyl, heteroaryl, heterocyclyl and cycloalkyl are being optionally substituted with one or more substituents independently selected from R8;
[T] is: a bond, O, C(O), S, NR7, or C1-C6 alkyl;
R6 is: hydrogen, C1-C6 alkyl or aminoalkyl;
R7 is: hydrogen,
C1-C6 alkyl,
C3-C8 cycloalkyl,
aryl,
heteroaryl or
heterocyclyl,
wherein alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl being optionally substituted with one or more substituents independently selected from R8; and
R8 is: hydrogen, nitro, cyano, hydroxyl, halo, haloalkyl, haloalkyloxy, aryloxy, oxo, acyl, C1-C6 alkyl, C1-C6 alkoxy or C3-C8 cycloalkyl.

### Claim 12 (depends on 11)

The compound of claim 11, wherein the compound is formula XIII,
or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:
A is: CH2, O, S;
[T] is: a bond, O, C(O) or C1-C3 alkyl;
R3 and R4 are each independently:
hydrogen, C1-C3 alkyl, halo, haloalkyl or haloalkyloxy;
R5 and R8 are each independently:
hydrogen, C1-C6 alkyl, halo, haloalkyl or haloalkyloxy; and
R6 is: hydrogen or C1-C6 alkyl; and
r is 1 or 2.

### Claim 13 (depends on 12)

The compound of claim 12, wherein the compound is formula XIV,
or a pharmaceutically-acceptable salt or stereoisomer thereof, wherein:
[T] is: a bond, O or C1-C3 alkyl;
R3 and R4 are each independently: hydrogen, methyl, ethyl, Br, Cl or F;
R5 and R8 are each independently: hydrogen, C1-C4 alkyl, Br, Cl, F or CF3; and
r is 1 or 2.

### Claim 14

A compound selected from the group consisting of the following compounds:
No.
Structure
Name
1
3-{4-[3-(4-Chloro-2- phenoxy-phenoxy)- phenoxy]-2-methyl- phenyl}-propionic acid
2
3-{4-[3-(2-Benzoyl-4- ethyl-phenoxy)-phenoxy]- 2-methyl-phenyl}- propionic acid
3
3-{4-[3-(4-Ethyl-2- phenoxy-phenoxy)- phenoxy]-2-methyl- phenyl}-propionic acid
4
3-{4-[3-(2-Benzoyl-4- chloro-phenoxy)- phenoxy]-2-methyl- phenyl}-propionic acid
5
3-{4-[3-(2-Benzoyl- phenoxy)-phenoxy]-2- methyl-phenyl}-propionic acid
6
3-{2-Methyl-4-[3-(2- phenoxy-phenoxy)- phenoxy]-phenyl}- propionic acid
7
3-{2-Methyl-4-[3-(2- phenoxy-4- trifluoromethyl-phenoxy)- phenoxy]-phenyl}- propionic acid
8
3-{4-[3-(4-Chloro-2- phenoxy-phenoxy)-5- fluoro-phenoxy]-2-methyl- phenyl}-propionic acid
9
3-{4-[3-(4-Ethyl-2- phenoxy-phenoxy)-5- fluoro-phenoxy]-2-methyl- phenyl}-propionic acid
10
3-(4-{3-[4-Ethyl-2-(1- methyl-1-phenyl-ethyl)- phenoxy]-5-fluoro- phenoxy}-2-methyl- phenyl)-propionic acid
11
3-{4-[3-(4-Ethyl-2- phenoxy-phenoxy)-5- fluoro-phenoxy]-2-methyl- phenyl}-propionic acid
12
3-{4-[3-(4-Chloro-2- phenoxy-phenoxy)-5- methyl-phenoxy]-2- methyl-phenyl}-propionic acid
13
3-{4-[3-(2-Benzoyl-4- chloro-phenoxy)-5- methyl-phenoxy]-2- methyl-phenyl}-propionic acid
14
3-{2-Methyl-4-[3-methyl- 5-(2-pyridin-3-yl-4- trifluoromethyl-phenoxy)- phenoxy]-phenyl}- propionic acid
15
3-{2-Methyl-4-[3-methyl- 5-(2-pyridin-2-yl-4- trifluoromethyl-phenoxy)- phenoxy]-phenyl}- propionic acid
16
3-{4-[3-(2′-Acetyl-5- trifluoromethyl-biphenyl- 2-yloxy)-5-methyl- phenoxy]-2-methyl- phenyl}-propionic acid
17
3-{4-[3-(4′- Methanesulfonyl-5- trifluoromethyl-biphenyl- 2-yloxy)-5-methyl- phenoxy]-2-methyl- phenyl}-propionic acid
18
3-{2-Methyl-4-[3-methyl- 5-(2′-trifluoromethoxy-5- trifluoromethyl-biphenyl- 2-yloxy)-phenoxy]- phenyl}-propionic acid
19
3-{2-Methyl-4-[3-methyl- 5-(2-phenoxy-4- trifluoromethyl-phenoxy)- phenoxy]-phenyl}- propionic acid
20
3-(2-Methyl-4-{3-methyl- 5-[2-(pyridin-2-yloxy)-4- trifluoromethyl-phenoxy]- phenoxy}-phenyl)- propionic acid
21
3-(2-Methyl-4-{3-methyl- 5-[2-(2-oxo-2H-pyridin-1- yl)-4-trifluoromethyl- phenoxy]-phenoxy}- phenyl)-propionic acid
22
3-(2-Methyl-4-{3-methyl- 5-[2-(pyridin-3-yloxy)-4- trifluoromethyl-phenoxy]- phenoxy}-phenyl)- propionic acid
23
3-{2-Methyl-4-[3-methyl- 5-(2-o-tolyloxy-4- trifluoromethyl-phenoxy)- phenoxy]-phenyl}- propionic acid
24
3-{2-Methyl-4-[3-methyl- 5-(2-m-tolyloxy-4- trifluoromethyl-phenoxy)- phenoxy]-phenyl}- propionic acid
25
3-{2-Methyl-4-[3-methyl- 5-(2-p-tolyloxy-4- trifluoromethyl-phenoxy)- phenoxy]-phenyl}- propionic acid
26
3-(4-{3-[2-(3,5-Difluoro- phenoxy)-4- trifluoromethyl-phenoxy]- 5-methyl-phenoxy}-2- methyl-phenyl)-propionic acid
27
3-{4-[3-Fluoro-5-(2- phenoxy-4- trifluoromethyl-phenoxy)- phenoxy]-2-methyl- phenyl}-propionic acid
28
3-{4-[3-Fluoro-5-(2- pyridin-2-yl-4- trifluoromethyl-phenoxy)- phenoxy]-2-methyl- phenyl}-propionic acid
29
3-{4-[3-Fluoro-5-(2- pyridin-3-yl-4- trifluoromethyl-phenoxy)- phenoxy]-2-methyl- phenyl}-propionic acid
30
3-{4-[3-Chloro-5-(2- phenoxy-4- trifluoromethyl-phenoxy)- phenoxy]-2-methyl- phenyl}-propionic acid
31
3-(4-{3-Chloro-5-[2-(3- fluoro-phenoxy)-4- trifluoromethyl-phenoxy]- phenoxy}-2-methyl- phenyl)-propionic acid
32
3-{4-[3-Chloro-5-(2- pyridin-2-yl-4- trifluoromethyl-phenoxy)- phenoxy]-2-methyl- phenyl}-propionic acid
33
3-{4-[3-Chloro-5-(2- pyridin-3-yl-4- trifluoromethyl-phenoxy)- phenoxy]-2-methyl- phenyl}-propionic acid
34
{4-[3-(4-Chloro-2- phenoxy-phenoxy)- phenoxy]-2-methyl- phenylsulfanyl}-acetic acid
35
2-{4-[3-(4-Chloro-2- phenoxy-phenoxy)- phenoxy]-phenoxy}-2- methyl-propionic acid
36
2-{4-[3-(4-Chloro-2- phenoxy-phenoxy)- phenoxy]-2-methyl- phenoxy}-2-methyl- propionic acid
37
{4-[3-(4-Chloro-2- phenoxy-phenoxy)- phenoxy]-2-methyl- phenoxy}-acetic acid
38
3-{4-[3-(4-Chloro-2- phenoxy-phenoxy)- phenoxy]-2-fluoro- phenyl}-propionic acid
39
4-{4-[3-(4-Chloro-2- phenoxy-phenoxy)- phenoxy]-2-methyl- phenyl}-butyric acid
40
3-{4-[3-(4-Chloro-2- phenoxy-phenoxy)- phenoxy]-2-ethyl-phenyl}- propionic acid
41
3-{4-[3-(2-Benzyl-4- chloro-phenoxy)- phenoxy]-2-methyl- phenyl}-propionic acid
42
3-{4-[3-(2-Benzyl-4- chloro-phenoxy)-5- methyl-phenoxy]-2- methyl-phenyl}-propionic acid
43
3-{4-[3-(4-Chloro-2- cyclohexyl-phenoxy)-5- methyl-phenoxy]-2- methyl-phenyl}-propionic acid
44
3-{4-[3-(2-Benzyl-4- chloro-phenoxy)-5-fluoro- phenoxy]-2-methyl- phenyl}-propionic acid
45
3-{2-Methyl-4-[3-methyl- 5-(3-phenoxy-5- trifluoromethyl-pyridin-2- yloxy)-phenoxy]-phenyl}- propionic acid.

### Claim 15 (depends on 14)

The compound of claim 14, wherein the compound is 3-{4-[3-(4-chloro-2-phenoxy-phenoxy)-5-methyl-phenoxy]-2-methyl-phenyl}-propionic acid
or a pharmaceutically acceptable salt thereof.

### Claim 16 (depends on 14)

The compound of claim 14, wherein the compound is:
{4-[3-(4-chloro-2-phenoxy-phenoxy)-phenoxy]-2-methyl-phenoxy}-acetic acid
or a pharmaceutically acceptable salt thereof.

### Claim 17 (depends on 1)

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

### Claim 18 (depends on 1)

A method for lowering blood-glucose in a mammal in need thereof, comprising the step of administering an effective amount of a compound of claim 1.