PPAR agonists, compounds, pharmaceutical compositions, and methods of use thereof

Patent metadata

Field	Value
Publication number	US-10188627-B2
Application number	US-201515517893-A
Country	US
Kind code	B2
Filing date	Oct 7, 2015
Priority date	Oct 8, 2014
Publication date	Jan 29, 2019
Grant date	Jan 29, 2019

Abstract

Provided herein are compounds of formula (I) useful for the treatment of PPAR-delta related diseases (e.g. mitochondrial diseases, muscular diseases, vascular diseases, demyelinating diseases and metabolic diseases).

First claim

We claim:

1. A compound of Formula (II):

or a pharmaceutically acceptable salt thereof, wherein:
Z is CH, N, or

R 1 is —OR 1A or —NR 1A R 1B ;
R 1A , R 1B are each independently hydrogen or C 1 -C 4 -alkyl;
W is O, CH 2 , CH═CH, or C≡C;
L is selected from the group consisting of:

Q 1 is CR 20 ═CR 20 , N═CH, CH═N,

or S;
Q 2 is CR 20 or N;
each R 20 is independently hydrogen, halogen, C 1 -C 4 -alkyl, CN, or C 1 -C 4 -alkoxy;
each R 10 is independently hydrogen, halogen, C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -haloalkoxy, or C 3 -C 6 -cycloalkyl;
p is an integer having a value of 1 or 2; and
R 2 is halogen, C 1 -C 4 -alkyl, C 3 -C 6 -cycloalkyl, CN, C 1 -C 4 -alkoxy, C 1 -C 4 -haloalkoxy, SO 2 (C 1 -C 4 -alkyl), 5- or 6-membered heterocycloalkyl, -≡-R 2A , —O(CH 2 ) m ,R 2B , NH(C 1 -C 4 -alkyl), N(C 1 -C 4 -alkyl) 2 , C(O)(C 1 -C 4 -alkyl), optionally substituted aryl, or optionally substituted 5-membered heteroaryl;
m is an integer having an a value of 0, 1, 2, or 3;
R 2A and R 2B are each independently C 1 -C 4 -alkyl, C 3 -C 6 -cycloalkyl, or C 1 -C 4 haloalkyl;
R 3 is C 1 -C 4 -alkyl,

 or C 1 -C 4 -haloalkyl; and
with the proviso that the compound is not selected from the group consisting of:

 or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 , wherein the compound has the structure of Formula (III):

or a pharmaceutically acceptable salt thereof, wherein:
t is an integer having a value of 1 or 2.

3. The compound of claim 1 , wherein the compound has the structure of Formula (VI) or (VII):

or a pharmaceutically acceptable salt thereof.

4. The compound of claim 1 , wherein the compound has the structure of Formula (VIII):

or a pharmaceutically acceptable salt thereof, wherein:
q is an integer having a value of 0 or 1;
X is O ⊖ ; and
Y is N ⊕ when q is 1; or
Y is N when q is 0; and
t is an integer having a value of 1 or 2.

5. The compound of claim 1 , wherein the compound has the structure of Formula (IX):

or a pharmaceutically acceptable salt thereof,
wherein:
q is an integer having a value of 0 or 1;
X is O ⊖ ; and
Y is N ⊕ when q is 1; or
Y is N when q is 0; and
t is an integer having a value of 1 or 2.

6. A compound of Formula (X):

or a pharmaceutically acceptable salt thereof, wherein:
Z is CH, N, or

R 1 is —OR 1A or —NR 1A R 1B ;
R 1A , R 1B are each independently hydrogen or C 1 -C 4 -alkyl;
W is O, CH 2 , CH═CH, or C≡C;
L is selected from the group consisting of:

R 2 is halogen, C 1 -C 4 -alkyl, C 3 -C 6 -cycloalkyl, CN, C 1 -C 4 -alkoxy, C 1 -C 4 -haloalkoxy, SO 2 (C 1 -C 4 -alkyl), 5- or 6-membered heterocycloalkyl, -≡-R 2A , —O(CH 2 ) m R 2B , NH(C 1 -C 4 -alkyl), N(C 1 -C 4 -alkyl) 2 , C(O)(C 1 -C 4 -alkyl), optionally substituted aryl, or optionally substituted 5-membered heteroaryl;
Q 2 is CR 20 or N;
p and t are integers each independently having a value of 1 or 2;
each R 10 is independently hydrogen, halogen, C 1 -C 4 -alkyl, C 1 -C 4 -haloalkoxy, C 1 -C 4 -alkoxy, C 1 -C 4 -haloalkoxy, or C 3 -C 6 -cycloalkyl; and
each R 20 is independently hydrogen, halogen, C 1 -C 4 -alkyl, CN, or C 1 -C 4 -alkoxy.

7. The compound of claim 6 , wherein the compound has the structure of Formula (XI):

or a pharmaceutically acceptable salt thereof.

8. The compound of claim 2 , wherein Z is CH.

9. The compound of claim 8 , wherein W is O.

10. The compound of claim 9 , wherein R 3 is methyl.

11. The compound of claim 10 , wherein R 2 is phenyl, furanyl, thienyl, -≡-CF 3 , OCF 3 , or OCHF 2 , wherein the phenyl can be optionally substituted with halogen, CN, C 1 -C 4 -alkyl, OH, C 1 -C 4 alkoxy, formyl, acetyl, acetoxy, or carboxyl, and wherein the furanyl and the thienyl each can be optionally substituted with C 1 -C 4 -alkyl.

12. The compound of claim 11 , wherein L is selected from the group consisting of:

13. The compound of claim 12 , wherein L is

14. The compound of claim 12 , wherein R 10 is hydrogen, halogen, methyl, OCH 3 , CF 3 , OCF 3 , OCHF 2 , or cyclopropyl.

15. The compound of claim 14 , wherein R 20 is hydrogen or halogen.

16. The compound of claim 2 , wherein:
R 1 is OH;
W is O;
Z is CH;
L is

R 2 is unsubstituted furanyl or 5-methyl-2-furanyl;
R 3 is methyl;
p and t are 1;
R 10 is hydrogen, fluorine, bromine, methyl, or OCH 3 ; and
R 20 is hydrogen, fluorine, or chlorine.

17. A pharmaceutical composition comprising a pharmaceutically acceptable excipient and the compound of claim 1 , or a pharmaceutically acceptable salt thereof.

18. A method of treating a PPARϵ related disease or condition in a subject, comprising administering to the subject in need thereof a therapeutically effective amount of one or more compounds of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the disease or condition is Duchenne muscular dystrophy (DMD), MELAS-Mitochondrial myopathy, Friedreich's Ataxia (FA), Adrenoleukodystrophy (ALD), nonalcoholic steatohepatitis (NASH), amyotrophic lateral sclerosis (ALS), or Kearns-Sayra Syndrome (KSS).

19. A method of increasing or maintaining muscle mass or muscle tone in a subject, comprising administering to the subject a therapeutically effective amount of one or more compounds of claim 1 , or a pharmaceutically acceptable salt thereof.

20. A

Assignees

• Mitobridge Inc
• Salk Inst For Biological Studi

Inventors

• Downes Michael
• Evans Ronald
• Kluge Arthur
• Lagu Bharat
• Miura Masanori
• Panigrahi Sunil Kumar
• Patane Michael
• Samajdar Susanta
• Senaiar Ramesh
• Takahashi Taisuke

Classifications

• C07D307/54

  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

• A61P3/00

  Drugs for disorders of the metabolism (of the blood or the extracellular fluid A61P7/00) · CPC title

• C07D307/38

  with substituted hydrocarbon radicals attached to ring carbon atoms · CPC title

• C07D235/20

  Two benzimidazolyl-2 radicals linked together directly or via a hydrocarbon or substituted hydrocarbon radical · CPC title

• A61K31/341 Primary

  not condensed with another ring, e.g. ranitidine, furosemide, bufetolol, muscarine · CPC title