PPAR agonists, compounds, pharmaceutical compositions, and methods of use thereof
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).
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 pharmaceutical composition comprising a pharmaceutically acceptable excipient and the compound of claim 6 , or a pharmaceutically acceptable salt thereof.
21. A method of treating a PPARδ 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 6 , 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).
22. 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 6 , or a pharmaceutically acceptable salt thereof.
23. A method of treating a 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 muscular dystrophy.
24. A method of treating a 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 6 , or a pharmaceutically acceptable salt thereof, wherein the disease or condition is muscular dystrophy.
25. A method of treating a PPARδ related disease or condition in a subject, comprising administering to the subject in need thereof a therapeutically effective amount of a pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable excipient, 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).
26. A method of increasing or maintaining muscle mass or muscle tone in a subject, comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable excipient.
27. A method of treating a PPARδ related disease or condition in a subject, comprising administering to the subject in need thereof a therapeutically effective amount of a pharmaceutical composition comprising the compound of claim 6 and a pharmaceutically acceptable excipient, 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).
28. A method of increasing or maintaining muscle mass or muscle tone in a subject, comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising the compound of claim 6 and a pharmaceutically acceptable excipient.