Therapeutic pyrazolyl thienopyridines
View Patent ↗The present invention provides for compounds of Formula I, and pharmaceutically acceptable salts thereof, wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 have any of the values defined therefor in the specification, and pharmaceutically acceptable salts thereof, that are useful as therapeutic agents in the treatment of TGFβ-mediated conditions, including cancer and fibrotic disorders. Also provided are pharmaceutical compositions comprising one or more compounds of Formula I.
1. A compound of Formula I
or a pharmaceutically acceptable salt thereof, wherein:
R 1 is a thieno[2,3-c]pyridinyl, which may be optionally substituted with one to three substituents each independently selected from the group consisting of: C 1 -C 3 -alkyl, —(C 1 -C 3 -alkyl)-S—(C 1 -C 3 -alkyl), —S—C 1 -C 3 -alkyl, —(C 1 -C 3 -alkyl)-O—(C 1 -C 3 -alkyl), —O—C 1 -C 3 -alkyl, —C(O)O—C 1 -C 3 -alkyl, —C(O)O—H, —C(O) NR 30 R 31 , halo, —CN, and —OH, wherein R 30 and R 31 are each independently selected from the group consisting of: H, C 1 -C 3 alkyl-OH, C 1 -C 3 -alkyl, halo, and —O—C 1 -C 3 -alkyl;
R 2 and R 3 are independently selected from the group consisting of: hydrogen, C 1 -C 3 -alkyl, —(C 1 -C 3 -alkyl)-S—(C 1 -C 3 -alkyl), —S—C 1 -C 3 -alkyl, —(C 1 -C 3 -alkyl)-O—(C 1 -C 3 -alkyl), —O—C 1 -C 3 -alkyl, —C(O)O—C 1 -C 3 -alkyl, —C(O)O—H, C(O)NH 2 , —C(O)NH(C 1 -C 3 alkyl), —C(O)N(C 1 -C 3 alkyl) 2 , halo, —CN, —OH, and a C 3 -C 6 -cycloalkyl;
R 4 , R 5 , R 6 , and R 7 are selected from the group consisting of: H, —OH, C 3 -cycloalkyl, C 1 -C 3 -alkyl), —(C 1 -C 3 -alkyl)-S—(C 1 -C 3 -alkyl), —S—C 1 -C 3 -alkyl, —(C 1 -C 3 -alkyl)-O—(C 1 -C 3 -alkyl), —O—C 1 -C 3 -alkyl, —C(O)O—C 1 -C 3 -alkyl, —C(O)O—H, C(O)NH 2 , —C(O)NH(C 1 -C 3 -alkyl), —C(O)NH(O—C 1 -C 3 alkyl), —C(O)N(H)(halo), —C(O)N(C 1 -C 3 alkyl) 2 , —C(O)N(C 1 -C 3 alkyl)(O—C 1 -C 3 alkyl), —C(O)N(C 1 -C 3 alkyl)(halo), —C(O)N(O—C 1 -C 3 alkyl) 2 , —C(O)N(O—C 1 -C 3 alkyl)(halo), —C(O)N(halo) 2 , halo, —CN, and —OH.
2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof wherein R 1 is a thieno[2,3-c]pyridinyl, which may be optionally substituted with one to three substituents each independently selected from the group consisting of: —OH, C 1 -C 3 alkyl, halo, and —O—C 1 -C 3 alkyl.
3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 and R 3 are independently selected from the group consisting of: hydrogen, C 1 -C 3 -alkyl, —(C 1 -C 3 -alkyl)-O—(C 1 -C 3 -alkyl), —O—C 1 -C 3 -alkyl, —C(O)O—C 1 -C 3 -alkyl, —C(O)O—H, C(O)NH 2 , —C(O)NH(C 1 -C 3 alkyl), —C(O)N(C 1 -C 3 alkyl) 2 , halo, —CN, —OH, and a C 3 -C 6 -cycloalkyl.
4. The compound of claim 3 , or a pharmaceutically acceptable salt thereof, wherein R 2 and R 3 are independently selected from the group consisting of hydrogen, and C 1 -C 3 alkyl.
5. The compound of claim 4 , or a pharmaceutically acceptable salt thereof, wherein R 2 is C 1 -C 2 alkyl and R 3 is hydrogen.
6. The compound of claim 5 , or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof wherein R 5 , R 6 , and R 7 are H, and R 4 is C 1 -C 3 -alkyl.
7. The compound of claim 6 , or a pharmaceutically acceptable salt thereof, wherein R 4 is methyl.
8. The compound of claim 7 , or a pharmaceutically acceptable salt thereof wherein R 1 is a thieno[2,3-c]pyridinyl, which may be optionally substituted with one to three substituents each independently selected from the group consisting of: —OH, C 1 -C 3 alkyl, halo, and —O—C 1 -C 3 alkyl.
9. The compound of claim 8 , or a pharmaceutically acceptable salt thereof wherein R 1 is a thieno[2,3-c]pyridin-2-yl, which may be optionally substituted with one to three substituents each independently selected from the group consisting of: —OH, C 1 -C 3 alkyl, halo, and —O—C 1 -C 3 alkyl.
10. The compound of claim 9 , or a pharmaceutically acceptable salt thereof wherein R 1 is a thieno[2,3-c]pyridin-2-yl.
11. The compound of claim 1 , wherein said compound is
or a pharmaceutically acceptable salt thereof.
12. A pharmaceutical composition comprising: a therapeutically effective amount of a compound of claim 1 , or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
13. A topical pharmaceutical composition comprising: a therapeutically effective amount of a compound of claim 1 , or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient suitable for topical application.
14. The pharmaceutical composition of claim 12 , wherein the compound is
or a pharmaceutically acceptable salt thereof.
15. The topical pharmaceutical composition of claim 14 , wherein the compound is
or a pharmaceutically acceptable salt thereof.
16. A method of inhibiting scar formation, comprising administering to a mammal in need of such treatment a therapeutically effective amount of compound of claim 1 , or pharmaceutically acceptable salt thereof.
17. The method of claim 16 , wherein the compound is administered topically.
18. The method of claim 16 , wherein the compound is
or a pharmaceutically acceptable salt thereof.