Isoxazole derivatives as FXR agonists and methods of use thereof
The present invention provides compounds of Formula (I): pharmaceutical compositions comprising these compounds and methods of using these compounds to treat or prevent a disease or disorder mediated by FXR. Specifically, the present invention relates to isoxazole derivatives useful as agonists for FXR, and methods for their preparation and use.
1. A compound represented by Formula (Ib), or a pharmaceutically acceptable salt thereof:
wherein:
R 1 is hydrogen, halogen, cyano, optionally substituted —C 1 -C 6 alkyl, optionally substituted —C 2 -C 6 alkenyl, optionally substituted —C 2 -C 6 alkynyl, optionally substituted —C 3 -C 6 cycloalkyl or optionally substituted 3- to 6-membered heterocycloalkyl;
R 2 is an optionally substituted aryl, optionally substituted heteroaryl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, or optionally substituted cycloalkyl;
m is 0, 1 or 2;
n is 1 or 2;
is selected from the groups set forth below:
Each R 3 is independently selected from the group consisting of halo, hydroxy, —OMe, —OCH 2 F, OCF 3 , —C 2 -C 6 -alkoxy, —C 1 -C 6 -alkyl, —C 1 -C 6 haloalkyl, —C 2 -C 6 alkenyl, —C 2 -C 6 alkynyl, —C 3 -C 6 cycloalkyl, —O—C 1 -C 2 alkylphenyl, cyano, —CH 2 F, —CHF 2 , —CF 3 , —SCF 3 , —NH 2 , —NHMe, and —NMe 2 ;
c is 0, 1, or 2;
R 4 is
wherein
R 5 and R 7 are independently selected from the group consisting of:
1) Hydrogen;
2) Optionally substituted —C 1 -C 8 alkyl;
3) Optionally substituted —C 2 -C 8 alkenyl;
4) Optionally substituted —C 2 -C 8 alkynyl; and
5) Optionally substituted —C 3 -C 8 cycloalkyl;
R 6 is selected from the group consisting of:
1) Optionally substituted —C 1 -C 8 alkyl;
2) Optionally substituted —C 2 -C 8 alkenyl;
3) Optionally substituted —C 2 -C 8 alkynyl;
4) Optionally substituted —C 3 -C 8 cycloalkyl;
5) Optionally substituted aryl;
6) Optionally substituted arylalkyl;
7) Optionally substituted heterocycloalkyl;
8) Optionally substituted heteroaryl;
9) Optionally substituted heteroarylalkyl; and
10) NR 8 R 9 ; wherein R 8 and R 9 are each independently selected from hydrogen, optionally substituted —C 1 -C 8 alkyl, optionally substituted —C 2 -C 8 alkenyl, optionally substituted vC 2 -C 8 alkynyl, optionally substituted —C 3 -C 8 cycloalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heterocycloalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, alternatively, R 8 and R 9 are taken together with the nitrogen atom to which they are attached to form a heterocyclic ring; and
R 10 is hydrogen, optionally substituted —C 1 -C 6 alkyl, optionally substituted —C 2 -C 6 alkenyl, optionally substituted —C 2 -C 6 alkynyl, optionally substituted —C 3 -C 6 cycloalkyl, or R 11 C(O)—, where R 11 is hydrogen or C 1 -C 4 -alkyl.
2. The compound of claim 1 , wherein R 2 is selected from the groups set forth below:
3. The compound of claim 1 ,
wherein R 4 is
4. The compound of claim 1 ,
wherein R 4 is
5. The compound of claim 1 ,
wherein R 4 is
6. The compound of claim 1 ,
wherein R 1 is cyclopropyl.
7. The compound of claim 1 , represented by Formula (VIa) or Formula (VIb), or a pharmaceutically acceptable salt thereof,
wherein R 2 ,
c, R 3 , and R 10 are as defined in claim 1 .
8. The compound of claim 7 , selected from compounds according to Formula (VIa) or Formula (VIb), or a pharmaceutically acceptable salt thereof, wherein R 2 , R 10 , and
are delineated for each compound in Table 1:
TABLE 1
Entry
R 2
R 10
1a
H
2a
H
3a
H
4a
H
5a
H
6a
H
7a
Me
8a
Me
9a
Me
10a
Me
11a
Me
12a
Me
13a
H
14a
H
15a
H
16a
H
17
H
18
H
19a
Me
20a
Me
21a
Me
22a
Me
23a
Me
24a
Me
25a
H
26a
H
27a
H
28a
H
29a
H
30a
H
31a
Me
32a
Me
33a
Me
34a
Me
35a
Me
36a
Me
9. The compound of claim 1 , represented by Formula (VIIa-b) or Formula (VIIb-b), or a pharmaceutically acceptable salt thereof,
wherein p is 0 or 1; and R 2 , m, R 3 , and R 10 are as defined in claim 1 .
10. The compound of claim 9 , selected from compounds according to Formula (VIIa-b) or Formula (VIIb-b), or a pharmaceutically acceptable salt thereof, wherein p is 1, and R 2 , m, R 10 and R 3 are delineated for each compound in Table 2:
TABLE 2
Entry
R 2
m
R 10
R 3
1b
0
H
F
2b
0
H
Oi-Pr
3b
0
Me
F
4b
0
Me
Oi-Pr
5b
0
F
6b
0
Oi-Pr
7b
1
H
F
8b
1
H
Oi-Pr
9b
1
Me
F
10b
1
Me
Oi-Pr
11b
1
F
12b
1
Oi-Pr
13b
2
H
F
14b
2
H
Oi-Pr
15b
2
Me
F
16b
2
Me
Oi-Pr
17b
2
F
18b
2
Oi-Pr
19b
0
H
F
20b
0
H
Oi-Pr
21b
0
Me
F
22b
0
Me
Oi-Pr
23b
0
F
24b
0
Oi-Pr
25b
1
H
F
26b
1
H
Oi-Pr
27b
1
Me
F
28b
1
Me
Oi-Pr
29b
1
F
30b
1
Oi-Pr
31b
2
H
F
32b
2
H
Oi-Pr
33b
2
Me
F
34b
2
Me
Oi-Pr
35b
2
F
36b
2
Oi-Pr
37b
0
H
F
38b
0
H
Oi-Pr
39b
0
Me
F
40b
0
Me
Oi-Pr
41b
0
F
42b
0
Oi-Pr
43b
1
H
F
44b
1
H
Oi-Pr
45b
1
Me
F
46b
1
Me
Oi-Pr
47b
1
F
48b
1
Oi-Pr
49b
2
H
F
50b
2
H
Oi-Pr
51b
2
Me
F
52b
2
Me
Oi-Pr
53b
2
F
54b
2
Oi-Pr.
11. The compound of claim 1 , represented by Formula (VIIIa), Formula (VIIIb), Formula (VIIIc), or Formula (VIIId), or a pharmaceutically acceptable salt thereof,
wherein p is 0 or 1; and R 3 and R 6 are as defined in claim 1 .
12. The compound of claim 11 , selected from compounds according to Formula (VIIIa), Formula (VIIIb), Formula (VIIIc), or Formula (VIIId), or a pharmaceutically acceptable salt thereof, wherein p is 1 and R 3 and R 6 are delineated for each compound in Table 3
TABLE 3
Entry
R 3
R 6
1c
Oi-Pr
Methyl
2c
Oi-Pr
Ethyl
3c
Oi-Pr
Isopropyl
4c
Oi-Pr
Butyl
5c
Oi-Pr
t-Butyl
6c
Oi-Pr
Propyl
7c
Oi-Pr
Benzyl
8c
Oi-Pr
Vinyl
9c
Oi-Pr
Allyl
10c
Oi-Pr
—CF 3
11c
Oi-Pr
12c
Oi-Pr
13c
Oi-Pr
14c
Oi-Pr
15c
Oi-Pr
16c
Oi-Pr
17c
Oi-Pr
18c
Oi-Pr
19c
Oi-Pr
20c
Oi-Pr
21c
Oi-Pr
22c
Oi-Pr
23c
Oi-Pr
24c
Oi-Pr
—NH 2
25c
Oi-Pr
—NHCH 3
26c
Oi-Pr
—N(CH 3 ) 2
27c
Oi-Pr
28c
Oi-Pr
29c
Oi-Pr
30c
F
Methyl
31c
F
Ethyl
32c
F
Isopropyl
33c
F
Butyl
34c
F
t-Butyl
35c
F
Propyl
36c
F
Benzyl
37c
F
Vinyl
38c
F
Allyl
39c
F
—CF 3
40c
F
41c
F
42c
F
43c
F
44c
F
45c
F
46c
F
47c
F
48c
F
49c
F
50c
F
51c
F
52c
F
53c
F
—NH 2
54c
F
—NHCH 3
55c
F
—N(CH 3 ) 2
56c
F
57c
F
58c
F
13. The compound of claim 1 , represented by Formula (IXa-b), (IXb-b), (IXc-b) or (IXd-b), or a pharmaceutically acceptable salt thereof,
wherein R 2 , c, R 3 , R 6 and R 10 are as defined in claim 1 .
14. A compound, selected from the compounds set forth below or a pharmaceutically acceptable salt thereof:
Com-
Com-
pound
Structure
pound
Structure
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15. A method for treating an FXR-mediated disease or condition selected from the group consisting of primary biliary cirrhosis, cerebrotendinous xanthomatosis, primary sclerosing cholangitis, alcoholic liver disease, nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, atherosclerosis, hypercholesterolemia, hypertriglyceridemia, and Type II diabetes in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound according to claim 1 .
16. The method according to claim 15 , wherein the FXR-mediated disease or condition is selected from the group consisting of primary biliary cirrhosis, primary sclerosing cholangitis, and cerebrotendinous xanthomatosis.
17. A pharmaceutical composition comprising a compound of claim 1 , and a pharmaceutically acceptable excipient or carrier.
18. A method for treating nonalcoholic steatohepatitis in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound according to claim 1 .
19. A method for treating primary biliary cirrhosis in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound according to claim 1 .
20. A method for treating nonalcoholic fatty liver disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound according to claim 1 .
21. The compound according to claim 1 selected from compounds 16-20 set forth below, or a pharmaceutically acceptable salt thereof:
Compound
Structure
16
17
18
19
20