BICYCLIC, SUBSTITUTED TRIAZOLES AS MODULATORS OF PPAR AND METHODS OF THEIR PREPARATION
First Claim
Patent Images
1. A compound having the formula:
- wherein Ar1 is a monocyclic or bicyclic aromatic ring system selected from the group consisting of phenyl, naphthyl, imidazolyl, benzimidazoyl, pyrrolyl, indolyl, thienyl, benzothienyl, furanyl, benzofuranyl, and benzodioxole each of which is optionally substituted with from one to five R7 substituents independently selected from the group consisting of halogen, (C1-C8)alkyl, halo(C1-C8)alkyl, —
OR2, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3-C7)cycloalkyl, (C3-C7)cycloalkyl(C1-C4)alkyl, aryl, aryl(C1-C4)alkyl, aryl(C2-C8)alkenyl, aryl(C2-C8)alkynyl, heterocyclyl, heterocyclyl(C1-C4)alkyl, —
COR2, —
CO2R2, —
NR2R3, —
NO2, —
CN, —
S(O)r1R2;
—
X1OR2, —
X1COR2, —
X1CO2R2, —
X1NR2R3, —
X1NO2, —
X1CN, and —
X1S(O)r1R2;
Ar2 is a bicyclic aromatic ring system selected from the group having the formula;
wherein the dashed line indicates that the bond may be a double or single bond;
each of which is optionally substituted with from one to four R8 substituents independently selected from the group consisting of halogen, (C1-C8)alkyl, halo(C1-C8)alkyl, —
OR2, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3-C7)cycloalkyl, (C3-C7)cycloalkyl(C1-C4)alkyl, aryl, aryl(C1-C4)alkyl, aryl(C2-C8)alkenyl, aryl(C2-C8)alkynyl, heterocyclyl, heterocyclyl(C1-C4)alkyl, —
COR2, —
CO2R2, —
NR2R3, —
NO2, —
CN, —
S(O)r1R25;
—
X2OR2, —
X2COR2O—
X2CO2R2, —
X2NR2R3, —
X2NO2, —
X2CN, and —
X2S(O)r1R2;
L is a member selected from the group consisting of a covalent bond and a linking group having from one to six main chain atoms and having the formula —
Y1m1Y2m2Y3m3—
wherein L can be attached to any available ring member of Ar2;
K is a member selected from the group consisting of a covalent bond and a linking group having from one to six main chain atoms and having the formula —
Y4m4Y5m5Y6m6—
wherein K can be attached to any available ring member of Ar2;
each Y1, Y2, Y3, Y4, Y5, and Y6 is a member independently selected from the group consisting of (CR4R5)p, C═
O, C═
ONR2, C═
NOR2, NR2C═
O, NR2, O, S(O)r2, NR2SO2, and SO2NR2;
Z is selected from the group consisting of CH2OR6, CO2R6, CN, tetrazol-5-yl, CONHSO2R2 and CHO;
R1 is selected from the group consisting of H, halogen, (C1-C8)alkyl, halo(C1-C8)alkyl, (C3-C7)cycloalkyl, (C3-C7)cycloalkyl(C1-C4)alkyl, aryl, aryl(C1-C4)alkyl, heterocyclyl, and heterocyclyl(C1-C4)alkyl;
each R2 and R3 is a member independently selected from the group consisting of H, (C1-C8)alkyl, halo(C1-C8)alkyl, —
X3OR9, aryl, aryl(C1-C4)alkyl, and heteroaryl, or optionally, if both present on the same substituent, may be joined together to form a three- to eight-membered ring system;
each R4 and R5 is a member independently selected from the group consisting of H, halogen, (C1-C8)alkyl, halo(C1-C8)alkyl, OR2, aryl, heteroaryl, and aryl(C1-C4)alkyl, or optionally, if both present on the same substituent, may be joined together to form a three- to eight-membered ring system, or if present on adjacent carbon atoms are combined to form a double bond or triple bond between the atoms to which they are attached;
R6 is a member selected from the group consisting of H, (C1-C8)alkyl, halo(C1-C8)alkyl, —
X4OR2, —
X4NR2R3, (C2-C8)alkenyl, (C3-C7)cycloalkyl, heterocyclyl, aryl(C1-C4)alkyl; and
aryl(C2-C8)alkenyl;
R9 is a member selected from the group consisting of H, (C1-C8)alkyl, halo(C1-C8)alkyl, aryl, aryl(C1-C4)alkyl, and heteroaryl;
each X1, X2, X3, and X4 is a member independently selected from the group consisting of (C1-C4)alkylene, (C2-C4)alkenylene, and (C2-C4)alkynylene;
the subscripts m1, m2, m3, m4, m5 and m6 are each integers of from 0 to 1;
the subscripts r1 and r2 are integers of from 0 to 2;
the subscript p is an integer of from 1 to 2; and
pharmaceutically acceptable salts, solvates, hydrates and prodrugs thereof.
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Abstract
The present invention is directed to certain novel triazole compounds represented by Formula I and pharmaceutically acceptable salts, solvates, hydrates, and prodrugs thereof. The present invention is also directed to methods of making and using such compounds and pharmaceutical compositions containing such compounds to treat or control a number of diseases mediated by PPAR such as glucose metabolism, lipid metabolism and insulin secretion, specifically Type 2 diabetes, hyperinsulemia, hyperlipidemia, hyperuricemia, hypercholesteremia, atherosclerosis, one or more risk factors for cardiovascular disease, Syndrome X, hypertriglyceridemia, hyperglycemia, obesity, and eating disorders.
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Citations
68 Claims
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1. A compound having the formula:
-
wherein Ar1 is a monocyclic or bicyclic aromatic ring system selected from the group consisting of phenyl, naphthyl, imidazolyl, benzimidazoyl, pyrrolyl, indolyl, thienyl, benzothienyl, furanyl, benzofuranyl, and benzodioxole each of which is optionally substituted with from one to five R7 substituents independently selected from the group consisting of halogen, (C1-C8)alkyl, halo(C1-C8)alkyl, —
OR2, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3-C7)cycloalkyl, (C3-C7)cycloalkyl(C1-C4)alkyl, aryl, aryl(C1-C4)alkyl, aryl(C2-C8)alkenyl, aryl(C2-C8)alkynyl, heterocyclyl, heterocyclyl(C1-C4)alkyl, —
COR2, —
CO2R2, —
NR2R3, —
NO2, —
CN, —
S(O)r1R2;
—
X1OR2, —
X1COR2, —
X1CO2R2, —
X1NR2R3, —
X1NO2, —
X1CN, and —
X1S(O)r1R2;
Ar2 is a bicyclic aromatic ring system selected from the group having the formula;
wherein the dashed line indicates that the bond may be a double or single bond;
each of which is optionally substituted with from one to four R8 substituents independently selected from the group consisting of halogen, (C1-C8)alkyl, halo(C1-C8)alkyl, —
OR2, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3-C7)cycloalkyl, (C3-C7)cycloalkyl(C1-C4)alkyl, aryl, aryl(C1-C4)alkyl, aryl(C2-C8)alkenyl, aryl(C2-C8)alkynyl, heterocyclyl, heterocyclyl(C1-C4)alkyl, —
COR2, —
CO2R2, —
NR2R3, —
NO2, —
CN, —
S(O)r1R25;
—
X2OR2, —
X2COR2O—
X2CO2R2, —
X2NR2R3, —
X2NO2, —
X2CN, and —
X2S(O)r1R2;
L is a member selected from the group consisting of a covalent bond and a linking group having from one to six main chain atoms and having the formula —
Y1m1Y2m2Y3m3—
wherein L can be attached to any available ring member of Ar2;
K is a member selected from the group consisting of a covalent bond and a linking group having from one to six main chain atoms and having the formula —
Y4m4Y5m5Y6m6—
wherein K can be attached to any available ring member of Ar2;
each Y1, Y2, Y3, Y4, Y5, and Y6 is a member independently selected from the group consisting of (CR4R5)p, C═
O, C═
ONR2, C═
NOR2, NR2C═
O, NR2, O, S(O)r2, NR2SO2, and SO2NR2;
Z is selected from the group consisting of CH2OR6, CO2R6, CN, tetrazol-5-yl, CONHSO2R2 and CHO;
R1 is selected from the group consisting of H, halogen, (C1-C8)alkyl, halo(C1-C8)alkyl, (C3-C7)cycloalkyl, (C3-C7)cycloalkyl(C1-C4)alkyl, aryl, aryl(C1-C4)alkyl, heterocyclyl, and heterocyclyl(C1-C4)alkyl;
each R2 and R3 is a member independently selected from the group consisting of H, (C1-C8)alkyl, halo(C1-C8)alkyl, —
X3OR9, aryl, aryl(C1-C4)alkyl, and heteroaryl, or optionally, if both present on the same substituent, may be joined together to form a three- to eight-membered ring system;
each R4 and R5 is a member independently selected from the group consisting of H, halogen, (C1-C8)alkyl, halo(C1-C8)alkyl, OR2, aryl, heteroaryl, and aryl(C1-C4)alkyl, or optionally, if both present on the same substituent, may be joined together to form a three- to eight-membered ring system, or if present on adjacent carbon atoms are combined to form a double bond or triple bond between the atoms to which they are attached;
R6 is a member selected from the group consisting of H, (C1-C8)alkyl, halo(C1-C8)alkyl, —
X4OR2, —
X4NR2R3, (C2-C8)alkenyl, (C3-C7)cycloalkyl, heterocyclyl, aryl(C1-C4)alkyl; and
aryl(C2-C8)alkenyl;
R9 is a member selected from the group consisting of H, (C1-C8)alkyl, halo(C1-C8)alkyl, aryl, aryl(C1-C4)alkyl, and heteroaryl;
each X1, X2, X3, and X4 is a member independently selected from the group consisting of (C1-C4)alkylene, (C2-C4)alkenylene, and (C2-C4)alkynylene;
the subscripts m1, m2, m3, m4, m5 and m6 are each integers of from 0 to 1;
the subscripts r1 and r2 are integers of from 0 to 2;
the subscript p is an integer of from 1 to 2; and
pharmaceutically acceptable salts, solvates, hydrates and prodrugs thereof. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68)
wherein X is a halogen; - and
the dashed line indicates the point of attachment to the remainder of the molecule.
-
-
4. A compound of claim 3, wherein Ar1 is
wherein the dashed line indicates the point of attachment to the remainder of the molecule. -
5. A compound of claim 1, wherein R1 is selected from the group consisting of (C1-C8)alkyl, halo(C1-C8)alkyl, aryl and heterocyclyl(C1-C4)alkyl.
-
6. A compound of claim 5, wherein R1 is selected from the group consisting of CH3, CH(CH3)2, CF3, CF3CH2, phenyl and
R10 is a halogen or (C1-C8)alkoxy; - and the dashed line indicates the point of attachment to the remainder of the molecule.
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7. A compound of claim 6, wherein R10 is Cl, Oi—
- Pr or OCH3.
-
8. A compound of claim 5, wherein R1 is CH3.
-
9. A compound of claim 1, wherein Y1, Y2, Y3, Y4, Y5, and Y6 is a member independently selected from the group consisting of (CR4R5)p, C═
- O, NR2, O, and S(O)r2;
R2 is H;
each R4 and R5 is a member independently selected from the group consisting of H, (C1-C8)alkyl, halo(C1-C8)alkyl, or optionally, if both present on the same substituent, may be joined together to form a three- to eight-membered ring system or if present on adjacent carbon atoms are combined to form a double bond or triple bond between the atoms to which they are attached; and
r2 is 0.
- O, NR2, O, and S(O)r2;
-
10. A compound of claim 9, wherein Y1 is (CR4R5)p, Y2 is CH2 or C═
- O and Y3 is NH, O, or S.
-
11. A compound of claim 9, wherein Y1 is CH2, Y2 is (CH2)2 and Y3 is O or S.
-
12. A compound of claim 1, wherein at least one of m1, m2, or m3 is 0.
-
13. A compound of claim 1, wherein L is a member selected from the group consisting of:
- CH2, (CH2)2, —
CH2S, CH(CH3)S, C(CH3)2S, (CH2)2S, CH(CH3)CH2S, C(CH3)2CH2S, (CH2)3S, CH2O, —
CH(CH3)O, C(CH3)2O, (CH2)2O, CH(CH3)CH2O, C(CH3)2CH2O, (CH2)3S and —
(C═
O)NH.
- CH2, (CH2)2, —
-
14. A compound of claim 9, wherein Y4 is CR4R5 or O, Y5 is CR4R5 and m6 is 0.
-
15. A compound of claim 1, wherein K is a member selected from the group consisting of:
- —
CH2—
, —
CH(CH3)—
, —
C(CH3)2—
, —
CH═
CH2E—
, —
CH═
CH2Z—
, —
CH≡
CH—
, —
OCH2—
, —
OCH(CH3)— and
—
OC(CH3)2—
, wherein E represents the entgegen isomer and Z represents the zusammen isomer.
- —
-
16. A compound of claim 1, wherein each R4 and R5 is independently H, CH3, CF3, or joined together to form a three- to six-membered ring system selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
-
17. A compound of claim 16, wherein R4 and R1 are H.
-
18. A compound of claim 1, wherein Z is CO2R6.
-
19. A compound of claim 18, wherein R6 is H.
-
20. A compound of claim 1, wherein Ar2 is selected from the group having the formula:
-
each of which is optionally substituted with from one to three R8 substituents each independently selected from the group consisting of halogen, (C1-C8)alkyl, halo(C1-C8)alkyl, (C3-C7)cycloalkyl, aryl, aryl(C1-C4)alkyl, —
OR2, —
X2OR2, heterocyclyl, heterocyclyl(C1-C4)alkyl, —
COR2, —
CO2R2, —
NR2R3, —
NO2, —
X2NR2R3, —
CN and —
S(O)r1R2.
-
-
21. A compound of claim 20, wherein Ar2 is selected from the group having the formula:
-
each of which is optionally substituted with from one to three R8 substituents each independently selected from the group consisting of halogen, (C1-C8)alkyl, halo(C1-C8)alkyl, (C3-C7)cycloalkyl, aryl, aryl(C1-C4)alkyl, —
OR2, —
X2OR2, heterocyclyl, heterocyclyl(C1-C4)alkyl, —
COR2, —
CO2R2, —
NR2R3, —
NO2, —
X2NR2R3, —
CN and —
S(O)r, R2.
-
-
22. A compound of claim 20, wherein Ar2 is optionally substituted with from one to two R8 substituents each independently selected from the group consisting of H, halogen, (C1-C8)alkyl, heterocyclyl, heterocyclyl(C1-C4)alkyl, and halo(C1-C8)alkyl.
-
23. A compound of claim 20, wherein Y1, Y2, Y3, Y4, Y5, and Y6 is a member independently selected from the group consisting of (CR4R5)p, C═
- O, NR2, O, and S(O)r2;
R2 is H;
each R4 and R5 is a member independently selected from the group consisting of H, (C1-C8)alkyl, halo(C1-C8)alkyl, or optionally, if both present on the same substituent, may be joined together to form a three- to eight-membered ring system or if present on adjacent carbon atoms are combined to form a double bond or triple bond between the atoms to which they are attached; and
r2 is 0.
- O, NR2, O, and S(O)r2;
-
24. A compound of claim 23, wherein Y1 is (CR4R5)p, Y2 is CH2 or C═
- O and Y3 is NH, O, or S.
-
25. A compound of claim 23, wherein Y1 is CH2, Y2 is (CH2)2 and Y3 is O or S.
-
26. A compound of claim 20, wherein at least one of m1, m2, or m3 is 0.
-
27. A compound of claim 20, wherein L is a member selected from the group consisting of:
- CH2, (CH2)2, —
CH2S, CH(CH3)S, C(CH3)2S, (CH2)2S, CH(CH3)CH2S, C(CH3)2CH2S, (CH2)3S, CH2O, CH(CH3)O, C(CH3)2O, (CH2)2O, CH(CH3)CH2O, C(CH3)2CH2O, (CH2)3S and —
(C═
O)NH.
- CH2, (CH2)2, —
-
28. A compound of claim 23, wherein Y4 is CR4R5 or O, Y5 is CR4R5 and m6 is 0.
-
29. A compound of claim 20, wherein K is a member selected from the group consisting of:
- —
CH2—
, —
CH(CH3)—
, —
C(CH3)2—
, —
CH═
CH2E—
, —
CH═
CH2Z—
, —
CH≡
CH—
, —
OCH2—
, —
OCH(CH3)— and
—
OC(CH3)2—
, wherein E represents the entgegen isomer and Z represents the zusamen isomer.
- —
-
30. A compound of claim 20, wherein each R4 and R5 is independently H, CH3, CF3, or joined together to form a three- to six-membered ring system selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
-
31. A compound of claim 30, wherein R4 and R5 are H.
-
32. A compound of claim 20, wherein Ar2 has the formula:
optionally substituted with from one to two R8 substituents each independently selected from the group consisting of halogen, (C1-C8)alkyl, halo(C1-C8)alkyl, (C3-C7)cycloalkyl, aryl, aryl(C1-C4)alkyl, —
OR2, —
X2OR2, —
COR2, —
CO2R2, —
NR2R3, —
NO2, —
X2NR2R3, —
CN, and —
S(O)r1R2.
-
33. A compound of claim 20, wherein Ar2 has the formula:
-
optionally substituted with from one to two R8 substituents each independently selected from the group consisting of halogen, (C1-C8)alkyl, halo(C1-C8)alkyl, (C3-C7)cycloalkyl, aryl, aryl(C1-C4)alkyl, —
OR2, —
X2OR2, heterocyclyl, heterocyclyl(C1-C4)alkyl, —
COR2, —
CO2R2, —
NR2R3, —
NO2, —
X2NR1R3, —
CN and —
S(O)r1R2.
-
-
34. A compound of claim 1, having the formula:
has the formula;
each R8 is independently selected from the group consisting of halogen, (C1-C8)alkyl, halo(C1-C8)alkyl, (C3-C7)cycloalkyl, aryl, aryl(C1-C4)alkyl, —
OR2, —
X2OR2, heterocyclyl, heterocyclyl(C1-C4)alkyl, —
COR2, —
CO2R2, —
NR2R3, —
NO2, —
X2NR2R3, —
CN, and —
S(O)r1R2; and
1 is 0 to 2.
-
35. A compound of claim 34, wherein R8 is independently selected from the group consisting of halogen, (C11-C8)alkyl, (C3-C7)cycloalkyl, heterocyclyl, heterocyclyl(C1-C4)alkyl, and —
- OR2; and
1 is 0 to 2.
- OR2; and
-
36. A compound of claim 34 wherein
has the formula: R8 is independently selected from the group consisting of halogen, (C1-C8)alkyl, halo(C1-C8)alkyl, (C3-C7)cycloalkyl, aryl, aryl(C1-C4)alkyl, —
OR2, —
X2OR2, heterocyclyl, heterocyclyl(C1-C4)alkyl, —
COR2, —
CO2R2, —
NR2R3, —
NO2, —
X2NR2R3, —
CN and —
S(O)r1R2;
1 is 0 to 2; and
the dashed line indicates the point of attachment to L and the wavy line indicates the point of attachment to K.
-
37. A compound of claim 36, wherein Ar2 has the formula:
R8 is independently selected from the group consisting of halogen, (C1-C8)alkyl, halo(C1-C8)alkyl, (C3-C7)cycloalkyl, aryl, aryl(C1-C4)alkyl, —
OR2, —
X2OR2, heterocyclyl, heterocyclyl(C1-C4)alkyl, —
COR2, —
CO2R2, —
NR2R3, —
NO2, —
X2NR2R3, —
CN and —
S(O)r1R2;
1 is 0 to 2; and
the dashed line indicates the point of attachment to L and the wavy line indicates the point of attachment to K.
-
38. A compound of claim 36, wherein Ar2 has the formula:
R8 is independently selected from the group consisting of halogen, (C1-C8)alkyl, halo(C1-C8)alkyl, (C3-C7)cycloalkyl, aryl, aryl(C1-C4)alkyl, —
OR2, —
X2OR2, heterocyclyl, heterocyclyl(C1-C4)alkyl, —
COR2, —
CO2R2, —
NR2R3, —
NO2, —
X2NR2R3, —
CN and —
S(O)r1R2;
1 is 0 to 2; and
the dashed line indicates the point of attachment to L and the wavy line indicates the point of attachment to K.
-
39. A compound of claim 37, wherein the compound is
-
40. A compound of claim 34 wherein
has the formula: -
R8 is independently selected from the group consisting of halogen, (C1-C8)alkyl, halo(C1-C8)alkyl, (C3-C7)cycloalkyl, aryl, aryl(C1-C4)alkyl, —
OR2, —
X2OR2, heterocyclyl, heterocyclyl(C1-C4)alkyl, —
COR2, —
CO2R2, —
NR2R3, —
NO2, —
X2NR2R3, —
CN and —
S(O)r1R2;
1 is 0 to 2; and
the dashed line indicates the point of attachment to L and the wavy line indicates the point of attachment to K.
-
-
41. A compound of claim 40, wherein Ar2 has the formlula:
R8 is independently selected from the group consisting of halogen, (C1-C8)alkyl, halo(C1-C8)alkyl, (C3-C7)cycloalkyl, aryl, aryl(C1-C4)alkyl, —
OR2, —
X2OR2, heterocyclyl, heterocyclyl(C1-C4)alkyl, —
COR2, —
CO2R2, —
NR2R3, —
NO2, —
X2NR2R3, —
CN and —
S(O)r1R2;
1 is 0 to 2; and
the dashed line indicates the point of attachment to L and the wavy line indicates the point of attachment to K.
-
42. A compound of claim 34 wherein
R8 is independently selected from the group consisting of halogen, (C1-C8)alkyl, halo(C1-C8)alkyl, (C3-C7)cycloalkyl, aryl, aryl(C1-C4)alkyl, — - OR2, —
X2OR2, heterocyclyl, heterocyclyl(C1-C4)alkyl, —
COR2, —
CO2R2, —
NR2R2, —
NO2, —
X2NR2R3, —
CN and —
S(O)r1R2;
1 is 0 to 2; and
the dashed line indicates the point of attachment to K and the wavy line indicates the point of attachment to L.
- OR2, —
-
43. A compound of claim 42, wherein Ar2 has the formula:
R8 is independently selected from the group consisting of halogen, (C1-C8)alkyl, halo(C1-C8)alkyl, (C3-C7)cycloalkyl, aryl, aryl(C1-C4)alkyl, —
OR2, —
X2OR2, heterocyclyl, heterocyclyl(C1-C4)alkyl, —
COR2, —
CO2R2, —
NR2R3, —
NO2, —
X2NR2R3, —
CN, and —
S(O)r1R2;
1 is 0 to 2; and
the dashed line indicates the point of attachment to K and the wavy line indicates the point of attachment to L.
-
44. A compound of claim 42, wherein Ar2 has the formula:
R8 is independently selected from the group consisting of halogen, (C1-C8)alkyl, halo(C1-C8)alkyl, (C3-C7)cycloalkyl, aryl, aryl(C1-C4)alkyl, —
OR2, —
X2OR2, —
COR2, —
CO2R2, —
NR2R3, —
NO2, —
X2NR2R3, —
CN, and —
S(O)r1R2;
1 is 0 to 2; and
the dashed line indicates the point of attachment to K and the wavy line indicates the point of attachment to L.
-
45. A compound of claim 34 wherein
has the formula: -
R8 is independently selected from the group consisting of halogen, (C1-C8)alkyl, halo(C1-C8)alkyl, (C3-C7)cycloalkyl, aryl, aryl(C1-C4)alkyl, —
OR2, —
X2OR2, heterocyclyl, heterocyclyl(C1-C4)alkyl, —
COR2, —
CO2R2, —
NR2R3, —
NO2, —
X2NR2R3, —
CN and —
S(O)r1R2;
1 is 0 to 2; and
the dashed line indicates the point of attachment to K and the wavy line indicates the point of attachment to L.
-
-
46. A compound of claim 45, wherein Ar2 has the formula:
R8 is independently selected from the group consisting of halogen, (C1-C8)alkyl, halo(C1-C8)alkyl, (C3-C7)cycloalkyl, aryl, aryl(C1-C4)alkyl, —
OR2, —
X2OR2, heterocyclyl, heterocyclyl(C1-C4)alkyl, —
COR2, —
CO2R2, —
NR2R3, —
NO2, —
X2NR2R3, —
CN and —
S(O)r, R2;
1 is 0 to 2; and
the dashed line indicates the point of attachment to K and the wavy line indicates the point of attachment to L.
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49. A composition comprising one or more pharmaceutically acceptable carriers, diluents, or excipients and a compound of claim 1.
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50. A method of modulating a peroxisome proliferators activated receptor, comprising the step of contacting the receptor with at least one compound of claim 1.
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51. A method of treating Type 2 diabetes in a subject, said method comprising administering to said subject a therapeutically effective amount of a compound of claim 1.
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52. A method for modulating insulin resistance in a subject, said method comprising administering to said subject a therapeutically effective amount of a compound of claim 1.
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53. A method of treating hyperinsulemia in a subject, said method comprising administering to said subject a therapeutically effective amount of a compound of claim 1.
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54. A method of treating hyperlipidemia in a subject, said method comprising administering to said subject a therapeutically effective amount of a compound of claim 1.
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55. A method of treating hyperuricemia in a subject, said method comprising administering to said subject a therapeutically effective amount of a compound of claim 1.
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56. A method of treating hypercholesteremia in a subject, said method comprising administering to said subject a therapeutically effective amount of a compound of claim 1.
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57. A method of treating atherosclerosis in a subject, said method comprising administering to said subject a therapeutically effective amount of a compound of claim 1.
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58. A method of treating one or more risk factors for cardiovascular disease in a subject, said method comprising administering to said subject a therapeutically effective amount of a compound of claim 1.
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59. A method of treating Syndrome X in a subject, said method comprising administering to said subject a therapeutically effective amount of a compound of claim 1.
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60. A method of treating hypertriglyceridemia in a subject, said method comprising administering to said subject a therapeutically effective amount of a compound of claim 1.
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61. A method of treating hyperglycemia in a subject, said method comprising administering to said subject a therapeutically effective amount of a compound of claim 1.
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62. A method of decreasing fibrinogen levels in a subject, said method comprising administering to said subject a therapeutically effective amount of a compound of claim 1.
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63. A method of decreasing LDLc in a subject, said method comprising administering to said subject a therapeutically effective amount of a compound of claim 1.
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64. A method of shifting LDL particle size from small dense to normal dense LDL in a subject, said method comprising administering to said subject a therapeutically effective amount of a compound of claim 1.
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65. A method of treating obesity in a subject, said method comprising administering to said subject a therapeutically effective amount of a compound of claim 1.
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66. A method of treating eating disorders in a subject, said method comprising administering to said subject a therapeutically effective amount of a compound of claim 1.
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67. A method of suppressing appetite in a subject, said method comprising administering to said subject a therapeutically effective amount of a compound of claim 1.
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68. A method of modulating leptin levels in a subject, said method comprising administering to said subject a therapeutically effective amount of a compound of claim 1.
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47. A compound selected from the group consisting of:
{5-[5-Methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-ylmethoxy]-indol-1-yl}-acetic acid;
3-{5-[5-Methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-ylmethoxy]-indol-1-yl}-propionic acid;
2-{5-[5-Methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-ylmethoxy]-indol-1-yl}-propionic acid;
2-Methyl-2-{5-[5-methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-ylmethoxy]-indol-1-yl}-propionic acid;
{5-[5-Methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-ylmethoxy]-indazol-1-yl}-acetic acid;
{5-[5-Methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-ylmethylsulfanyl]-indazol-1-yl}-acetic acid;
{6-[5-Methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-ylmethoxy]-indazol-1-yl}-acetic acid;
{6-[5-Methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-ylmethylsulfanyl]-indazol-1-yl}-acetic acid;
{5-[5-Methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-ylmethoxy]-benzothiazol-2-yl}-acetic acid;
{6-[5-Methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-ylmethoxy]-benzothiazol-2-yl}-acetic acid;
{5-[5-Methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-ylmethoxy]-1H-indol-3-yl}-acetic acid;
{6-[5-Methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-ylmethoxy]-indol-1-yl}-acetic acid;
5-[5-Methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-ylmethoxy]-1-(1H-tetrazol-5-ylmethyl)-1H-indole;
{5-[5-Methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-ylmethylsulfanyl]-indol-1-yl}-acetic acid;
{6-[5-Methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-ylmethoxy]-benzofuran-3-yl}-acetic acid;
{6-[5-Methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-ylmethylsulfanyl]-benzo[b]thiophen-3-yl}-acetic acid;
{5-[5-Methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-ylmethoxy]-benzofuran-3-yl}-acetic acid;
{5-[5-Methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-ylmethoxy]-benzo[b]thiophen-3-yl}-acetic acid;
{5-[5-Methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-ylmethylsulfanyl]-benzo[b]thiophen-3-yl}-acetic acid;
{5-[5-Methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-ylmethoxy]-benzooxazol-2-yl}-acetic acid;
{6-[5-Methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-ylmethoxy]-benzooxazol-2-yl}-acetic acid;
{6-[5-Methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-ylmethoxy]-1H-indol-3-yl}-acetic acid;
{5-[5-Methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-ylmethoxy]-1H-benzoimidazol-2-yl}-acetic acid;
(5-{2-[5-Methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-yl]-ethoxy}-indol-1-yl)-acetic acid;
(5-{2-[5-Methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-yl]-ethoxy}-indazol-1-yl)-acetic acid;
(6-{2-[5-Methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-yl]-ethoxy}-benzofuran-3-yl)-acetic acid;
(6-{2-[5-Methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-yl]-ethoxy}-benzo[b]thiophen-3-yl)-acetic acid;
(5-{2-[5-Methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-yl]-ethoxy}-benzo[b]thiophen-3-yl)-acetic acid;
(5-{2-[5-Methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-yl]-ethoxy}-benzofuran-3-yl)-acetic acid;
(5-{2-Methyl-2-[5-methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-yl]-propoxy}-indol-1-yl)-acetic acid;
(6-{2-Methyl-2-[5-methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-yl]-propoxy}-indol-1-yl)-acetic acid;
(5-{2-[5Trifluoromethyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-yl]-ethoxy}-indol-1-yl)-acetic acid;
(5-{2-[2-(3,4-Bis-trifluoromethyl-phenyl)-5-methyl-2H-[1,2,3]triazol-4-yl]-ethoxy}-indol-1-yl)-acetic acid;
(5-{2-[2-(3-Chloro-4-trifluoromethyl-phenyl)-5-methyl-2H-[1,2,3]triazol-4-yl]-ethoxy}-indol-1-yl)-acetic acid;
(5-{2-[2-(3,5-Bis-trifluoromethyl-phenyl)-5-methyl-2H-[1,2,3]triazol-4-yl]-ethoxy}-indol-1-yl)-acetic acid;
(5-{2-[2-(3,5-Dichloro-phenyl)-5-methyl-2H-[1,2,3]triazol-4-yl]-ethoxy}-indol-1-yl)-acetic acid;
{5-[5-Ethyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-ylmethoxy]-indol-1-yl}-acetic acid;
{5-[5-Isopropyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-ylmethoxy]-indol-1-yl}-acetic acid;
{5-[5-(2,2,2-Trifluoro-ethyl)-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-ylmethoxy]-indol-1-yl}-acetic acid;
{5-[5-Phenyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-ylmethoxy]-indol-1-yl}-acetic acid;
{5-[2-(3,4-Bis-trifluoromethyl-phenyl)-5-methyl-2H-[1,2,3]triazol-4-ylmethoxy]-indol-1-yl}-acetic acid;
{5-[2-(3-Chloro-4-trifluoromethyl-phenyl)-5-methyl-2H-[1,2,3]triazol-4-ylmethoxy]-indol-1-yl}-acetic acid;
{5-[2-(3-Fluoro-4-trifluoromethyl-phenyl)-5-methyl-2H-[1,2,3]triazol-4-ylmethoxy]-indol-1 yl}-acetic acid;
{5-[5-Trifluoromethyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-ylmethoxy]-indol-1-yl}-acetic acid;
{5-[2-(4-Chloro-3-fluoro-phenyl)-5-methyl-2H-[1,2,3]triazol-4-ylmethoxy]-indol-1-yl}-acetic acid;
{5-[2-(3,4-Dichloro-phenyl)-5-methyl-2H-[1,2,3]triazol-4-ylmethoxy]-indol-1-yl}-acetic acid;
{5-[2-(4-Chloro-3-trifluoromethyl-phenyl)-5-methyl-2H-[1,2,3]triazol-4-ylmethoxy]-indol-1-yl}-acetic acid;
{5-[2-(3,5-Bis-trifluoromethyl-phenyl)-5-methyl-2H-[1,2,3]triazol-4-ylmethoxy]-indol-1-yl}-acetic acid;
{5-[2-(2-Fluoro-4-trifluoromethyl-phenyl)-5-methyl-2H-[1,2,3]triazol-4-ylmethoxy]-indol-1-yl}-acetic acid;
{5-[2-(3,5-Dichloro-phenyl)-5-methyl-2H-[1,2,3]triazol-4-ylmethoxy]-indol-1-yl}-acetic acid;
{1-[5-Methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-ylmethyl]-1H-indol-5-yloxy}-acetic acid;
2-{1-[5-Methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-ylmethyl]-1H-indol-5-yloxy}-propionic acid;
2-Methyl-2-{1-[5-methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-ylmethyl]-1H-indol-5-yloxy}-propionic acid;
{1-[5-Methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-ylmethyl]-1H-indol-6-yloxy}-acetic acid;
{3-[5-Methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-ylmethyl]-benzofuran-5-yloxy}-acetic acid;
{3-[5-Methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-ylmethyl]-benzo[b]thiophen-5-yloxy}-acetic acid;
{1-[5-Methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-ylmethyl]-1H-indazol-5-yloxy}-acetic acid;
{1-[5-Methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-ylmethyl]-1H-indazol-6-yloxy}-acetic acid;
(1-{2-[5-Methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-yl]-ethyl}-1H-indol-5-yloxy)-acetic acid;
(1-{2-[5-Methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-yl]-ethyl}-1H-indol-6-yloxy)-acetic acid;
{5-[5-Methyl-2-(3-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-ylmethoxy]-indol-1-yl}-acetic acid;
{5-[2-(4-Methoxy-phenyl)-5-methyl-2H-[1,2,3]triazol-4-ylmethoxy]-indol-1-yl}-acetic acid;
{1-[5-Isopropyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-ylmethyl]-1H-indol-5-yloxy}-acetic acid;
{6-[5-Phenyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-ylmethoxy]-benzofuran-3-yl}-acetic acid;
{6-[2-(3,4-Dichloro-phenyl)-5-methyl-2H-[1,2,3]triazol-4-ylmethoxy]-benzofuran-3-yl}-acetic acid;
{6-[2-(3,5-Bis-trifluoromethyl-phenyl)-5-methyl-2H-[1,2,3]triazol-4-ylmethoxy]-benzofuran-3-yl}-acetic acid;
2-{6-[5-Methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-ylmethoxy]-benzofuran-3-yl}-propionic acid;
1-{5-[5-Methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-ylmethylsulfanyl]-indol-1-yl}-cyclopropanecarboxylic acid;
1-{5-[5-Methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-ylmethylsulfanyl]-indol-1-yl}-cyclobutanecarboxylic acid;
1-{5-[5-Methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-ylmethylsulfanyl]-indol-1-yl}-cyclopentanecarboxylic acid;
1-{5-[5-Methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-ylmethylsulfanyl]-indol-1-yl}-cyclohexanecarboxylic acid;
2-{5-[5-[4-(4-Methoxy-phenyl)-piperazin-1-ylmethyl]-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-ylmethylsulfanyl]-indol-1-yl}-2-methyl-propionic acid;
{5-[2-(2-Fluoro-4-thiophen-2-yl-phenyl)-5-methyl-2H-[1,2,3]triazol-4-ylmethylsulfanyl]-indol-1-yl}-acetic acid; and
{1-Methyl-6-[5-methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-ylmethoxy]-1H-indol-3-yl}-acetic acid.
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48. A compound selected from the group consisting of:
{6-[5-Phenyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-ylmethoxy]-benzofuran-3-yl}-acetic acid;
{6-[2-(3,4-Dichloro-phenyl)-5-methyl-2H-[1,2,3]triazol-4-ylmethoxy]-benzofuran-3-yl}-acetic acid;
{6-[2-(3,5-Bis-trifluoromethyl-phenyl)-5-methyl-2H-[1,2,3]triazol-4-ylmethoxy]-benzofuran-3-yl}-acetic acid; and
2-Methyl-2-{6-[5-methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-ylmethoxy]-benzofuran-3-yl}-propionic acid.
Specification