PPAR agonists

Patent metadata

Field	Value
Publication number	US-9938234-B2
Application number	US-201514874008-A
Country	US
Kind code	B2
Filing date	Oct 2, 2015
Priority date	Apr 5, 2013
Publication date	Apr 10, 2018
Grant date	Apr 10, 2018

Abstract

Provided herein are compounds and compositions useful in increasing PPARδ activity. The compounds and compositions provided herein are useful for the treatment of PPARδ related diseases (e.g., muscular diseases, vascular disease, demyelinating disease, and metabolic diseases).

First claim

We claim:

1. A compound, having a formula

wherein:
L 2 is selected from

L 3 is selected from a bond or C 1 -C 3 alkylene;
L 4 R 3 is isopropyl;
R 2 is heteroaryl;
each R 22 independently is selected from deuterium, halogen, aryl, heteroaryl, aliphatic, heteroaliphatic, cycloaliphatic, NO 2 , OH, amino, amide, aminosulfonyl, carboxyl, carboxyl ester, alkylsulfonyl, SO 3 H, or acyl;
X is O, NR 30 , sulfonyl, or S;
n is 1;
m is from 0 to 4;
L 1 is a bond or —NR 30 —;
R 1 is hydrogen or —OR 1A ;
R 1A is hydrogen or aliphatic; and
R 30 is selected from H or, aliphatic, aryl, or cycloaliphatic.

2. The compound of claim 1 , wherein L 3 is C 1 -C 3 alkylene.

3. The compound of claim 1 , wherein X is O.

4. The compound of claim 1 , wherein R 2 is furan-2-yl or furan-3-yl.

5. A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of claim 1 .

6. A compound, having a formula

wherein:
L 2 is selected from

L 3 is selected from a bond or C 1 -C 3 alkylene;
L 4 R 3 is isopropyl;
each R 22 independently is selected from Br, F, methyl, trifluoromethyl, cyano, methoxy, cyclopropyl or azetidine;
each R 2 independently is selected from methyl, trifluoromethyl, methoxy, trifluoromethoxy, dimethylamino, acetyl, methane sulfonyl, cyano, cyclopropoxy, furan-2-yl, furan-3-yl, thiophen-2-yl, thiophen-3-yl, 3-pyridyl, 4-pyridyl, pyrrolidin-1-yl,

L 1 is a bond or NR 30 —;
m is from 0 to 4;
n is from 0 to 5;
R 1 is hydrogen or —OR 1A ;
R 1A is hydrogen or aliphatic;
R 30 is selected from H or, aliphatic, aryl, or cycloaliphatic; and
X is O, NR 30 , sulfonyl, or S.

7. A compound, selected from:
6-(2-((N-cyclopropyl-2-oxo-2,3-dihydrobenzofuran-5-carboxamido)methyl)phenoxy)hexanoic acid;
6-(2-((N-cyclopropyl-5-(furan-2-yl)thiazole-2-carboxamido)methyl)phenoxy)hexanoic acid;
6-(2-((N-cyclopropyl-[2,3′-bifuran]-5′-carboxamido)methyl)phenoxy)hexanoic acid;
ethyl 6-(2-(1-(4-bromo-N-cyclopropylbenzamido)-2-(tert-butylamino)-2-oxoethyl)phenoxy)hexanoate;
ethyl 6-(2-(2-(tert-butylamino)-1-(N-cyclopropyl-[1,1′-biphenyl]-4-carboxamido)-2-oxoethyl)phenoxy)hexanoate;
ethyl 6-(2-(2-amino-1-(N-cyclopropyl-[1,1′-biphenyl]-4-carboxamido)-2-oxoethyl)phenoxy)hexanoate;
6-(2-(2-amino-1-(N-cyclopropyl-[1,1′-biphenyl]-4-carboxamido)-2-oxoethyl)phenoxy)hexanoic acid;
6-(2-(2-(tert-butylamino)-1-(N-cyclopropyl-[1,1′-biphenyl]-4-carboxamido)-2-oxoethyl)phenoxy)hexanoic acid;
6-(2-((N-cyclopropyl-[1,1′-biphenyl]-4-carboxamido)methyl)phenoxy)hexanoic acid;
N-(2-amino-1-(2-((6-(hydroxyamino)-6-oxohexyl)oxy)phenyl)-2-oxoethyl)-N-cyclopropyl-[1,1′-biphenyl]-4-carboxamide;
6-(2-((N-cyclopropyl-4-(pyridin-4-yl)benzamido)methyl)phenoxy)hexanoic acid;
6-(2-((N-cyclopropyl-4-(pyridin-3-yl)benzamido)methyl)phenoxy)hexanoic acid;
6-(2-((N-cyclopropyl-4-(1H-pyrazol-4-yl)benzamido)methyl)phenoxy)hexanoic acid;
6-(2-((N-cyclopropyl-4-(furan-2-yl)benzamido)methyl)phenoxy)hexanoic acid;
6-(2-((N-cyclopropyl-4-(furan-3-yl)benzamido)methyl)phenoxy)hexanoic acid;
6-(2-((N-cyclopropyl-4-(thiophen-2-yl)benzamido)methyl)phenoxy)hexanoic acid;
6-(2-((N-cyclopropyl-4-(thiophen-3-yl)benzamido)methyl)phenoxy)hexanoic acid;
6-(2-((N-benzyl-[1,1′-biphenyl]-4-carboxamido)methyl)phenoxy)hexanoic acid;
6-(2-((N-benzyl-4-(pyridin-3-yl)benzamido)methyl)phenoxy)hexanoic acid;
6-(2-((N-benzyl-4-(pyridin-4-yl)benzamido)methyl)phenoxy)hexanoic acid;
6-(2-((N-benzyl-4-(1H-pyrazol-4-yebenzamido)methyl)phenoxy)hexanoic acid;
6-(2-((N-benzyl-4-(thiophen-2-yl)benzamido)methyl)phenoxy)hexanoic acid;
6-(2-((N-benzyl-4-(furan-3-yl)benzamido)methyl)phenoxy)hexanoic acid;
6-(2-((N-benzyl-4-(furan-2-yl)benzamido)methyl)phenoxy)hexanoic acid;
6-(2-((N-benzyl-4-(thiophen-3-yl)benzamido)methyl)phenoxy)hexanoic acid;
N-benzyl-N-(2-((6-(hydroxyamino)-6-oxohexyl)oxy)benzyl)-4-(pyridin-4-yl)benzamide;
N-benzyl-N-(2-((6-(hydroxyamino)-6-oxohexyl)oxy)benzyl)-[1,1′-biphenyl]-4-carboxamide;
N-benzyl-N-(2-((6-(hydroxyamino)-6-oxohexyl)oxy)benzyl)-4-(pyridin-3-yl)benzamide;
N-benzyl-N-(2-((6-(hydroxyamino)-6-oxohexyl)oxy)benzyl)-4-(1H-pyrazol-4-yl)benzamide;
N-benzyl-N-(2-((6-(hydroxyamino)-6-oxohexyl)oxy)benzyl)-4-(thiophen-2-yl)benzamide;
N-benzyl-4-(furan-2-yl)-N-(2-((6-(hydroxyamino)-6-oxohexyl)oxy)benzyl)benzamide;
N-benzyl-4-(furan-3-yl)-N-(2-((6-(hydroxyamino)-6-oxohexyl)oxy)benzyl)benzamide;
6-(2-((N-(sec-butyl)-[1,1′-biphenyl]-4-carboxamido)methyl)phenoxy)hexanoic acid;
N-benzyl-N-(2-((6-(hydroxyamino)-6-oxohexyl)oxy)benzyl)-4-(thiophen-3-yl)benzamide;
6-(2-((N-(sec-butyl)-4-(pyridin-3-yebenzamido)methyl)phenoxy)hexanoic acid;
6-(2-((N-(sec-butyl)-4-(pyridin-4-yebenzamido)methyl)phenoxy)hexanoic acid;
6-(2-((N-(sec-butyl)-4-(1H-pyrazol-4-yl)benzamido)methyl)phenoxy)hexanoic acid;
6-(2-((N-(sec-butyl)-4-(furan-2-yl)benzamido)methyl)phenoxy)hexanoic acid;
6-(2-((N-(sec-butyl)-4-(furan-3-yl)benzamido)methyl)phenoxy)hexanoic acid;
6-(2-((N-(sec-butyl)-4-(thiophen-2-yl)benzamido)methyl)phenoxy)hexanoic acid;
6-(2-((N-(sec-butyl)-4-(thiophen-3-yl)benzamido)methyl)phenoxy)hexanoic acid;
6-(2-((4-bromo-N-(sec-butyl)benzamido)methyl)phenoxy)hexanoic acid;
6-(2-((N-(3-morpholinopropyl)-4-(pyridin-3-yl)benzamido)methyl)phenoxy)hexanoic acid;
6-(2-((N-(3-morpholinopropyl)-4-(pyridin-4-yl)benzamido)methyl)phenoxy)hexanoic acid;
6-(2-((N-(3-morpholinopropyl)-[1,1′-biphenyl]-4-carboxamido)methyl)phenoxy)hexanoic acid;
6-(2-((N-(3-morpholinopropyl)-4-(1H-pyrazol-4-yl)benzamido)methyl)phenoxy)hexanoic acid;
6-(2-((4-(furan-3-yl)-N-(3-morpholinopropyl)benzamido)methyl)phenoxy)hexanoic acid;
6-(2-((4-(furan-2-yl)-N-(3-morpholinopropyl)benzamido)methyl)phenoxy)hexanoic acid;
6-(2-((N-(2-(pyridin-2-yl)ethyl)-[1,1′-biphenyl]-4-carboxamido)methyl)phenoxy)hexanoic acid;
6-(2-((N-(3-morpholinopropyl)-4-(thiophen-3-yl)benzamido)methyl)phenoxy)hexanoic acid;
6-(2-((N-(3-morpholinopropyl)-4-(thiophen-2-yl)benzamido)methyl)phenoxy)hexanoic acid;
6-(2-((N-(2-(pyridin-2-yl)ethyl)-4-(pyridin-3-yl)benzamido)methyl)phenoxy)hexanoic acid;
6-(2-((N-(2-(pyridin-2-yl)ethyl)-4-(pyridin-4-yl)benzamido)methyl)phenoxy)hexanoic acid;
6-(2-((4-(1H-pyrazol-4-yl)-N-(2-(pyridin-2-yl)ethyl)benzamido)methyl)phenoxy)hexanoic acid;
6-(2-((4-(furan-3-yl)-N-(2-(pyridin-2-yl)ethyl)benzamido)methyl)phenoxy)hexanoic acid;
6-(2-((N-(2-(pyridin-2-yl)ethyl)-4-(thiophen-2-yl)benzamido)methyl)phenoxy)hexanoic acid;
6-(2-((4-(furan-2-yl)-N-(2-(pyridin-2-yl)ethyl)benzamido)methyl)phenoxy)hexanoic acid;
6-(2-((N-(2-(pyridin-2-yl)ethyl)-4-(thiophen-3-yl)benzamido)methyl)phenoxy)hexanoic acid;
6-(2-((N-isopropyl-4-(pyridin-4-yl)benzamido)methyl)phenoxy)hexanoic acid;
6-(2-((N-isopropyl-4-(1H-pyrazol-4-yl)benzamido)methyl)phenoxy)hexanoic acid;
6-(2-((4-(furan-2-yl)-N-isopropylbenzamido)methyl)phenoxy)hexanoic acid;
6-(2-((N-isopropyl-4-(pyridin-3-yl)benzamido)methyl)phenox

Assignees

• Salk Inst For Biological Studi
• Mitobridge Inc

Inventors

• Evans Ronald M
• Downes Michael
• Baiga Thomas J
• Noel Joseph P
• Embler Emi Kanakubo
• Fan Weiwei
• Keana John F W
• Bock Mark G
• Kluge Arthur F
• Patane Mike A

Classifications

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P9/14

  Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P3/06

  Antihyperlipidemics · CPC title