Benzoazepin-oxy-acetic acid derivatives as PPAR-delta agonists used for the increase of HDL-C, lower LDL-C and lower cholesterol
View Patent ↗The invention is directed to compounds of Formula (I) useful as PPAR agonists. Pharmaceutical compositions and methods of treating one or more conditions including, but not limited to, diabetes, nephropathy, neuropathy, retinopathy, polycystic ovary syndrome, hypertension, ischemia, stroke, irritable bowel disorder, inflammation, cataract, cardiovascular diseases, Metabolic X Syndrome, hyper-LDL-cholesterolemia, dyslipidemia (including hypertriglyceridemia, hypercholesterolemia, mixed hyperlipidemia, and hypo-HDL-cholesterolemia), atherosclerosis, obesity, and other disorders related to lipid metabolism and energy homeostasis complications thereof, using compounds of the invention are also described.
1. A compound of Formula (I)
wherein:
X is a covalent bond, O, or S;
R 1 and R 2 are independently selected from the group consisting of H, C 1-8 alkyl, and substituted C 1-8 alkyl, or R 1 , R 2 and the carbon atom to which they are attached together may form C 3-7 cycloalkyl;
R 3 is H;
R 4 and R 5 are independently selected from the group consisting of H, halo, C 1-8 alkyl, C 3-7 cycloalkyl, C 3-7 cycloalkyl-C 1-4 alkyl, C 3-7 cycloalkyloxy-C 1-4 alkyl, C 1-6 alkoxy-C 1-4 alkyl, C 6-10 aryl, heteroaryl, halo substituted C 1-4 alkyl, amino substituted C 1-4 alkyl, C 6-10 aryl substituted C 1-4 alkyl, cyano substituted C 1-4 alkyl, and hydroxy substituted C 1-4 alkyl;
R 6 and R 7 are independently selected from the group consisting of H, halo, C 1-3 alkyl, halo substituted C 1-3 alkyl, C 1-3 alkoxy, and halo substituted C 1-3 alkoxy;
n is 1; and
Q is selected from the group consisting of
and enantiomers, diastereomers, tautomers, or pharmaceutically acceptable salts thereof.
2. The compound according to claim 1 wherein R 1 and R 2 are independently selected from the group consisting of H and C 1-8 alkyl, or R 1 , R 2 and the carbon atom to which they are attached together may form C 3-5 cycloalkyl.
3. The compound according to claim 1 wherein R 1 and R 2 are independently selected from the group consisting of H and CH 3 , or R 1 , R 2 and the carbon atom to which they are attached together may form
4. The compound according to claim 1 wherein R 6 and R 7 are independently selected from the group consisting of H, halo, halo substituted C 1-3 alkyl, C 1-3 alkoxy, and halo substituted C 1-3 alkoxy.
5. The compound according to claim 1 wherein R 6 is H and R 7 is selected from the group consisting of halo, halo substituted C 1-3 alkyl, and halo substituted C 1-3 alkoxy.
6. The compound according to claim 5 wherein R 7 is selected from the group consisting of F, CF 3 , and —O—CF 3 .
7. The compound according to claim 1 wherein R 4 and R 5 are independently selected from the group consisting of H and C 1-8 alkyl.
8. The compound according to claim 1 wherein R 5 is H, CH 3 , or —CH 2 CH 3 .
9. The compound according to claim 1 wherein Q is selected from the group consisting of
10. The compound according to claim 1 wherein Q is selected from the group consisting of
11. The compound according to claim 1 wherein X is O.
12. A compound according to claim 1 wherein
X is 0;
R 1 , R 2 , R 4 , and R 5 are independently selected from the group consisting of H and C 1-3 alkyl, or R 1 , R 2 and the carbon atom to which they are attached together may form
and
R 6 and R 7 are independently selected from the group consisting of H, halo, C 1-3 alkoxy, and halo substituted C 1-3 alkyl, and halo substituted C 1-3 alkoxy;
and enantiomers, diastereomers, tautomers, or pharmaceutically acceptable salts thereof.
13. A compound of Formula (Ia)
wherein
R 1 and R 2 are independently selected from the group consisting of H and C 1-8 alkyl, or R 1 , R 2 and the carbon atom to which they are attached together may form C 3-5 cycloalkyl;
R 6 and R 7 are independently selected from the group consisting of H, C 1-3 alkyl, halo, and halo substituted C 1-3 alkyl;
R 4 and R 5 are independently selected from the group consisting of H and C 1-8 alkyl; and
Q is selected from the group consisting of
and enantiomers, diastereomers, tautomers, or pharmaceutically acceptable salts thereof.
14. A compound of Formula (Ib)
wherein
R 1 and R 2 are independently selected from the group consisting of H and CH 3 , or R 1 , R 2 and the carbon atom to which they are attached together may form
R 4 and R 5 are independently selected from the group consisting of H, CH 3 , and —CH 2 CH 3 ; and
Q is selected from the group consisting of
and enantiomers, diastereomers, tautomers, or pharmaceutically acceptable salts thereof.
15. A compound of Formula (Ic)
R 1 , R 2 , and R 4 , are independently selected from the group consisting of H and CH 3 , or R 1 , R 2 and the carbon atom to which they are attached together may form
R 5 is selected from the group consisting of H, CH 3 , and —CH 2 CH 3 ;
R 7 is halo or halo substituted C 1-3 alkyl; and
Q is selected from the group consisting of
and enantiomers, diastereomers, tautomers, or pharmaceutically acceptable salts thereof.
16. A compound according to claim 15 wherein:
(a) R 1 or R 2 is H;
(b) R 1 and R 2 are both H;
(c) R 1 or R 2 is CH 3 ;
(d) R 1 and R 2 are both CH 3 ;
(e) R 1 , R 2 and the carbon atom to which they are attached together form
(f) R 4 is H or CH 3 ;
(g) R 5 is H, CH 3 , or —CH 2 CH 3 ;
(h) R 1 or R 2 is H and R 4 is H or CH 3 ;
(i) R 1 and R 2 are both H and R 4 is H or CH 3 ;
(j) R 1 or R 2 is H and R 5 is H, CH 3 , or —CH 2 CH 3 ;
(k) R 1 and R 2 are both H and R 5 is H, CH 3 , or —CH 2 CH 3 ;
(l) R 1 or R 2 is CH 3 and R 5 is H, CH 3 , or —CH 2 CH 3 ;
(m) R 1 and R 2 are both CH 3 and R 5 is H, CH 3 , or —CH 2 CH 3 ;
(n) R 1 or R 2 is H, R 4 is H, and R 5 is H, CH 3 , or —CH 2 CH 3 ;
(o) R 1 and R 2 are both H, R 4 is H, and R 5 is H, CH 3 , or —CH 2 CH 3 ;
(p) R 1 or R 2 is CH 3 , R 4 is H, and R 5 is H, CH 3 , or —CH 2 CH 3 ;
(q) R 1 and R 2 are both CH 3 , R 4 is H, and R 5 is H, CH 3 , or —CH 2 CH 3 ;
(r) R 1 , R 2 and the carbon atom to which they are attached together form
R 4 is H, and R 5 is H, CH 3 , or —CH 2 CH 3 ;
(s) R 7 is CF 3 ;
(t) R 7 is Cl;
(u) R 1 or R 2 is H, R 7 is CF 3 , and R 4 is H or CH 3 ;
(v) R 1 and R 2 are both H, R 7 is CF 3 , and R 4 is H or CH 3 ;
(w) R 1 or R 2 is H, R 7 is CF 3 , and R 5 is H, CH 3 , or —CH 2 CH 3 ;
(x) R 1 and R 2 are both H, R 7 is CF 3 , and R 5 is H, CH 3 , or —CH 2 CH 3 ;
(y) R 1 or R 2 is CH 3 , R 7 is CF 3 , and R 5 is H, CH 3 , or —CH 2 CH 3 ;
(z) R 1 and R 2 are both CH 3 , R 7 is CF 3 , and R 5 is H, CH 3 , or —CH 2 CH 3 ;
(aa) R 1 or R 2 is H, R 4 is H, R 7 is CF 3 , and R 5 is H, CH 3 , or —CH 2 CH 3 ;
(bb) R 1 and R 2 are both H, R 4 is H, R 7 is CF 3 , and R 5 is H, CH 3 , or —CH 2 CH 3 ;
(cc) R 1 or R 2 is CH 3 , R 4 is H, R 7 is CF 3 , and R 5 is H, CH 3 , or —CH 2 CH 3 ;
(dd) R 1 and R 2 are both CH 3 , R 4 is H, R 7 is CF 3 , and R 5 is H, CH 3 , or —CH 2 CH 3 ;
(ee) R 1 , R 2 and the carbon atom to which they are attached together form
R 4 is H, R 7 is CF 3 , and R 5 is H, CH 3 , or —CH 2 CH 3 ;
(ff) Q is selected from the group consisting of
(gg) R 1 or R 2 is H and Q is selected from the group consisting of
(hh) R 1 and R 2 are both H and Q is selected from the group consisting of
(ii) R 1 or R 2 is CH 3 and Q is selected from the group consisting of
(jj) R 1 and R 2 are both CH 3 and Q is selected from the group consisting of
(kk) R 4 is H or CH 3 and Q is selected from the group consisting of
(ll) R 5 is H, CH 3 , or —CH 2 CH 3 and Q is selected from the group consisting of
(mm) R 1 or R 2 is H and R 4 is H or CH 3 and Q is selected from the group consisting of
(nn) R 1 and R 2 are both H and R 4 is H or CH 3 and Q is selected from the group consisting of
(oo) R 1 or R 2 is H and R 5 is H, CH 3 , or —CH 2 CH 3 and Q is selected from the group consisting of
(pp) R 1 and R 2 are both H and R 5 is H, CH 3 , or —CH 2 CH 3 and Q is selected from the group consisting of
(qq) R 1 or R 2 is CH 3 and R 5 is H, CH 3 , or —CH 2 CH 3 and Q is selected from the group consisting of
(rr) R 1 and R 2 are both CH 3 , R 5 is H, CH 3 , or —CH 2 CH 3 , and Q is selected from the group consisting of
(ss) R 1 or R 2 is H, R 4 is H, R 5 is H, CH 3 , or —CH 2 CH 3 , and Q is selected from the group consisting of
(tt) R 1 and R 2 are both H, R 4 is H, R 5 is H, CH 3 , or —CH 2 CH 3 , and Q is selected from the group consisting of
(uu) R 1 or R 2 is CH 3 , R 4 is H, R 5 is H, CH 3 , or —CH 2 CH 3 , and Q is selected from the group consisting of
(vv) R 1 and R 2 are both CH 3 , R 4 is H, R 5 is H, CH 3 , or —CH 2 CH 3 , and Q is selected from the group consisting of
(ww) R 1 , R 2 and the carbon atom to which they are attached together form
R 4 is H, R 5 is H, CH 3 , or —CH 2 CH 3 , and Q is selected from the group consisting of
(xx) R 7 is CF 3 and Q is selected from the group consisting of
(yy) R 7 is Cl and Q is selected from the group consisting of
(zz) R 1 or R 2 is H, R 7 is CF 3 , R 4 is H or CH 3 , and Q is selected from the group consisting of
(aaa) R 1 and R 2 are both H, R 7 is CF 3 , R 4 is H or CH 3 , and Q is selected from the group consisting of
(bbb) R 1 or R 2 is H, R 7 is CF 3 , R 5 is H, CH 3 , or —CH 2 CH 3 , and Q is selected from the group consisting of
(ccc) R 1 and R 2 are both H, R 7 is CF 3 , R 5 is H, CH 3 , or —CH 2 CH 3 , and Q is selected from the group consisting of
(ddd) R 1 or R 2 is CH 3 , R 7 is CF 3 , R 5 is H, CH 3 , or —CH 2 CH 3 , and Q is selected from the group consisting of
(eee) R 1 and R 2 are both CH 3 , R 7 is CF 3 , R 5 is H, CH 3 , or —CH 2 CH 3 , and Q is selected from the group consisting of
(fff) R 1 or R 2 is H, R 4 is H, R 7 is CF 3 , R 5 is H, CH 3 , or —CH 2 CH 3 , and Q is selected from the group consisting of
(ggg) R 1 and R 2 are both H, R 4 is H, R 7 is CF 3 , R 5 is H, CH 3 , or —CH 2 CH 3 , and Q is selected from the group consisting of
(hhh) R 1 or R 2 is CH 3 , R 4 is H, R 7 is CF 3 , R 5 is H, CH 3 , or —CH 2 CH 3 , and Q is selected from the group consisting of
(iii) R 1 and R 2 are both CH 3 , R 4 is H, R 7 is CF 3 , R 5 is H, CH 3 , or —CH 2 CH 3 , and Q is selected from the group consisting of
and enantiomers, diastereomers, tautomers, or pharmaceutically acceptable salts thereof.
17. A compound selected from the group consisting of
and enantiomers, diastereomers, tautomers, or pharmaceutically acceptable salts thereof.
18. A compound selected from the group consisting of
wherin the compound is substantially free from the corresponding other enantiomer.
19. A compound of the formula
20. A pharmaceutical composition comprising a compound, or salt according to claim 1 admixed with a pharmaceutically acceptable carrier, excipient or diluent.
21. A compound of Formula (I)
wherein:
X is a covalent bond, O, or S;
R 1 and R 2 are independently selected from the group consisting of H, C 1-8 alkyl, and substituted C 1-8 alkyl, or R 1 , R 2 and the carbon atom to which they are attached together may form C 3-7 cycloalkyl;
R 3 is H;
R 4 and R 5 are independently selected from the group consisting of H, halo, C 1-8 alkyl, C 3-7 cycloalkyl, C 3-7 cycloalkyl-C 1-4 alkyl, C 3-7 cycloalkyloxy-C 1-4 alkyl, C 1-6 alkoxy-C 1-4 alkyl, C 6-10 aryl, heteroaryl, halo substituted C 1-4 alkyl, amino substituted C 1-4 alkyl, C 6-10 aryl substituted C 1-4 alkyl, heteroaryl substituted C 1-4 alkyl, cyano substituted C 1-4 alkyl, and hydroxy substituted C 1-4 alkyl;
R 6 and R 7 are independently selected from the group consisting of H, halo, C 1-3 alkyl, halo substituted C 1-3 alkyl, C 1-3 alkoxy, and halo substituted C 1-3 alkoxy;
n is 1; and
Q is C 6-10 aryl;
and enantiomers, diastereomers, tautomers, or pharmaceutically acceptable salts thereof.
22. A compound of Formula (I)
wherein:
X is a covalent bond, O, or S;
R 1 and R 2 are independently selected from the group consisting of H, C 1-8 alkyl, and substituted C 1-8 alkyl, or R 1 , R 2 and the carbon atom to which they are attached together may form C 3-7 cycloalkyl;
R 3 is H;
R 4 and R 5 are independently selected from the group consisting of H, halo, C 1-8 alkyl, C 3-7 cycloalkyl, C 3-7 cycloalkyl-C 1-4 alkyl, C 3-7 cycloalkyloxy-C 1-4 alkyl, C 1-6 alkoxy-C 1-4 alkyl, C 6-10 aryl, heteroaryl, halo substituted C 1-4 alkyl, amino substituted C 1-4 alkyl, C 6-10 aryl substituted C 1-4 alkyl, heteroaryl substituted C 1-4 alkyl, cyano substituted C 1-4 alkyl, and hydroxy substituted C 1-4 alkyl;
R 6 and R 7 are independently selected from the group consisting of H, halo, C 1-3 alkyl, halo substituted C 1-3 alkyl, C 1-3 alkoxy, and halo substituted C 1-3 alkoxy;
n is 1 or 2; and
Q is selected from the group consisting of
and enantiomers, diastereomers, tautomers, or pharmaceutically acceptable salts thereof.
23. A compound of Formula (I)
wherein:
X is a covalent bond, O, or S;
R 1 and R 2 are independently selected from the group consisting of H, C 1-8 alkyl, and substituted C 1-8 alkyl, or R 1 , R 2 and the carbon atom to which they are attached together may form C 3-7 cycloalkyl;
R 3 is H;
R 4 and R 5 are independently selected from the group consisting of H, halo, C 1-8 alkyl, C 3-7 cycloalkyl, C 3-7 cycloalkyl-C 1-4 alkyl, C 3-7 cycloalkyloxy-C 1-4 alkyl, C 1-6 alkoxy C 1-4 alkyl, C 6-10 aryl, heteroaryl, halo substituted C 1-4 alkyl, amino substituted C 1-4 alkyl, C 6-10 aryl substituted C 1-4 alkyl, cyano substituted C 1-4 alkyl, and hydroxy substituted C 1-4 alkyl;
R 6 and R 7 are independently selected from the group consisting of H, halo, C 1-3 alkyl, halo substituted C 1-3 alkyl, C 1-3 alkoxy, and halo substituted C 1-3 alkoxy;
n is 2; and
Q is selected from the group consisting of
and enantiomers, diastereomers, tautomers, or pharmaceutically acceptable salts thereof.
24. A compound selected from the group consisting of