PPAR agonists

Patent metadata

Field	Value
Publication number	US-11420934-B2
Application number	US-201916715711-A
Country	US
Kind code	B2
Filing date	Dec 16, 2019
Priority date	Apr 5, 2013
Publication date	Aug 23, 2022
Grant date	Aug 23, 2022

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

or a salt thereof, wherein:
Z is R 1 L 1 C(O)—, or a carboxyl bioisostere;
R 1 is hydrogen, aliphatic, OR 1A , —NR 1A R 1B , —C(O)R 1A , —S(O) 2 R 1A , —S(O) 2 NR 1A R 1B or —C(O)NR 1A R 1B ;
each of R 1A , R 1B R 3a and R 3b independently is hydrogen or aliphatic;
L 1 is a bond or —NR 30 —, where R 30 is H;
L 2 is aliphatic, heteroaliphatic, arylene, heteroarylene, cycloalkylene, or heterocycloalkylene;
X is O;
ring A is phenyl;
ring B is selected from a cycloalkylene, heterocycloalkylene, arylene or heteroarylene;
each R 2 independently is aryl, heteroaryl, aliphatic, heteroaliphatic, cyano, NO 2 , OH, or amino or two adjacent R 2 groups form a fused ring system with ring B;
L 3 ′ is —C(O)—;
L 3 is C 1 -C 5 alkylene;
L 4 is selected from a bond, aliphatic, heteroaliphatic, arylene, heteroarylene, cycloalkylene, or heterocycloalkylene;
R 3 is selected from —OH, —OR 3A , —NR 3A R 3B , —C(O)R 3A , —S(O) 2 R 3A , —C(O)OR 3A , —S(O) 2 NR 3A R 3B , or —C(O)NR 3A R 3B , aliphatic, heteroaliphatic, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
each R 22 independently is selected from halogen, aryl, heteroaryl, aliphatic, heteroaliphatic, cyano, NO 2 , OH, or amino;
n is from 1 to 5; and
m is from 0 to 4;

with the provisos that
if -L 3 N(L 4 R 3 )L 3 - is —CH 2 N(L 4 R 3 )C(O)—, L 4 R 3 is n-propyl or isopropyl, ring A is phenyl, and n is 1 then R 2 is not 4-bromo or 4-benzo[d][1,3]dioxole;
and where the compound is not
ethyl 6-(2-((4-bromo-N-propylbenzamido)methyl)phenoxy)hexanoate;
ethyl 6-(2-((4-(benzo[d][1,3]dioxol-5-yl)-N-propylbenzamido)methyl)phenoxy)hexanoate;
6-(2-((4-(benzo[d][1,3]dioxol-5-yl)-N-propylbenzamido)methyl)phenoxy)hexanoic acid;
ethyl 6-(2-((4-(benzo[d][1,3]dioxol-5-yl)-N-isopropylbenzamido)methyl)phenoxy)hexanoate;
6-(2-((4-(benzo[d][1,3]dioxol-5-yl)-N-isopropylbenzamido)methyl)phenoxy)hexanoic acid.

2. The compound of claim 1 , wherein ring B is selected from phenyl, pyridine, thiophene, thiazole, pyrazole, oxazole, isoxazole, benzo[b]furan, indazole, piperidine, cyclohexane, piperidin-2-one, piperazine-2,5-dione or quinazolin-4(3H)-one.

3. The compound of claim 1 , wherein the carboxyl bioisostere is selected from

and
X 7 , Y 7 , and Z 7 are each independently selected from N, CH 2 or CO;
X 8 is selected from 0, S or NMe; and
X 9 is selected from O, N, NH, S, CH or CH 2 .

4. The compound of claim 1 , wherein the compound has a formula selected from:

5. The compound of claim 1 , wherein R 3 is selected from alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl.

6. The compound of claim 1 , wherein L 2 is alkylene, and L 4 is selected from a bond or alkylene.

7. The compound of claim 1 , wherein L 4 R 3 is isopropyl, cyclopropyl, cyclopentyl, sec-butyl, benzyl, morpholinopropyl, or (2-pyridinyl)ethyl.

8. The compound of claim 1 , wherein each R 2 independently is cyano, NO 2 , or OH.

9. The compound of claim 1 , wherein each R 2 independently is alkyloxy, haloalkyloxy, cycloalkyloxy, haloalkyl, alkyl, amino, heterocyclic, aryl, cycloaliphatic or heteroaryl.

10. The compound of claim 1 , wherein n is from 2 to 4, and two adjacent R 2 groups form a fused ring system with ring B.

11. The compound of claim 1 , wherein at least one R 2 is para to L 3 and is selected from phenyl, 3-pyridinyl, 4-pyridinyl, furan-2-yl, furan-3-yl, thiophen-2-yl,

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

13. The compound of claim 1 , wherein L 2 is

14. The compound of claim 1 , wherein L 2 is C 1-6 linear or branched alkylene.

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

Assignees

• Salk Inst For Biological Studi
• Mitobridge Inc
• Salk Inst Biological Studies

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 Authur F
• Patane Mike A

Classifications

• C07D231/12 Primary

  with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms · CPC title

• A61K31/5377

  not condensed and containing further heterocyclic rings, e.g. timolol · CPC title

• C07D333/24

  Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals · CPC title

• C07D307/83

  Oxygen atoms · CPC title

• C07D209/34

  in position 2 · CPC title