TGR5 modulators and methods of use thereof
The application relates to compounds of formula A: or a salt, solvate, ester, tautomer, amino acid conjugate, or metabolite thereof. The compounds of formula A are TGR5 modulators useful for the treatment of various diseases, including metabolic disease, inflammatory disease, autoimmune disease, cardiac disease, kidney disease, cancer, and gastrointestinal disease.
1. A compound of formula A:
or a pharmaceutically acceptable salt, ester, tautomer, or amino acid conjugate, thereof, wherein:
A is
oxadiazolonyl, or isoxazolonyl, wherein the carbon atom marked with “*” is bonded to the carbon atom to which A is bonded;
n is 0, 1, or 2;
R 1 is H or OH;
R 2 is H or OH;
R 3 is CR 11 R 12 C(O)OH, C(O)NHR 31 , tetrazolyl, oxadiazolyl, oxadiazolonyl, or thiazolidine-dionyl optionally substituted with NHS(O) 2 —(C 1 -C 3 )alkyl;
R 11 and R 12 are each independently H, F, OH, CH 2 OH, or CH 2 F, provided that R 11 and R 12 are not both H;
R 31 is OH, (CH 2 ) p OH, or (CH 2 ) p OSO 3 H; and
p is 1 or 2.
2. The compound of claim 1 , wherein A is oxadiazolonyl or isoxazolonyl.
3. The compound of claim 1 , wherein A is
4. The compound of claim 1 , wherein R 1 and R 2 are each H.
5. The compound of claim 1 , wherein R 1 is H, and R 2 is OH.
6. The compound of claim 1 , wherein R 2 is H, and R 1 is OH.
7. The compound of claim 1 , wherein R 1 and R 2 are each OH.
8. The compound of claim 1 , wherein R 3 is CR 11 R 12 C(O)OH.
9. The compound of claim 1 , wherein n is 1.
10. The compound of claim 1 , wherein R 3 is C(O)NHR 31 .
11. The compound of claim 10 , wherein R 31 is OH.
12. The compound of claim 10 , wherein R 31 is (CH 2 ) p OH.
13. The compound of claim 10 , wherein R 31 is (CH 2 ) p OSO 3 H.
14. The compound of claim 1 , wherein the compound is of formula I:
or a pharmaceutically acceptable salt, ester, tautomer, or amino acid conjugate thereof, wherein:
R 11 and R 12 are each independently H, F, OH, CH 2 OH, or CH 2 F, provided that R 11 and R 12 are not both H; and
R 13 is H or OH.
15. The compound of claim 1 , wherein the compound is of formula II:
or a pharmaceutically acceptable salt, ester, tautomer, or amino acid conjugate thereof, wherein:
q is 0, 1, or 2;
R 21 and R 22 are each independently H or OH; and
R 23 is tetrazolyl, oxadiazolyl, oxadiazolonyl, or thiazolidine-dionyl optionally substituted with NHS(O) 2 —(C 1 -C 3 )alkyl.
16. The compound of claim 1 , wherein the compound is of formula III:
or a pharmaceutically acceptable salt, ester, tautomer, or amino acid conjugate thereof, wherein:
R 31 is OH, (CH 2 ) p OH, or (CH 2 ) p OSO 3 H; and
p is 1 or 2.
17. A pharmaceutical composition comprising the compound of claim 1 , and at least one pharmaceutically acceptable excipient.