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:
R1 is a thieno[3,2-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, —OH, wherein R 30 and R 31 are each independently selected from the group consisting of: H, and 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)NR 30 R 31 , halo, —CN, —OH, and a C 3 -C 6 -cycloalkyl, wherein R 30 and R 31 are each independently selected from the group consisting of: H, and C 1 -C 3 alkyl; and
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)NR 30 R 31 , halo, —CN, —OH, wherein R 30 and R 31 are each independently selected from the group consisting of: H, and C 1 -C 3 alkyl, C 1 -C 3 -alkyl, —O—C 1 -C 3 -alkyl, and halo.
2. 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)NR 30 R 31 , halo, —CN, and —OH, wherein R 30 and R 31 are each independently selected from the group consisting of: H, and C 1 -C 3 alkyl.
3. The compound of claim 2 , 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.
4. The compound of claim 3 , or a pharmaceutically acceptable salt thereof, wherein R 2 is C 1 -C 2 alkyl and R 3 is hydrogen.
5. The compound of claim 4 , 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.
6. The compound of claim 5 , or a pharmaceutically acceptable salt thereof, wherein R 4 is methyl.
7. The compound of claim 6 , or a pharmaceutically acceptable salt thereof wherein R 1 is a thieno[3,2-c]pyridinyl which may be optionally substituted with one to three substituents each independently selected from the group consisting of: —OH, C l -C 3 alkyl, halo, and —O—C 1 -C 3 alkyl.
8. A compound selected from the group consisting of:
2-[1-(6-methylpyridin-2-yl)-1H-pyrazol-5-yl]thieno[3,2-c]pyridine;
2-[3,4-dimethyl-1-(6-methylpyridin-2-yl)-1 H-pyrazol-5-yl]thieno[3,2-c]pyridine; 2-[3-methyl-1-(6-methylpyridin-2-yl)-1 H-pyrazol-5-yl]thieno[3,2-c]pyridine;
2-[3-ethyl-1-(6-methylpyridin-2-yl)-1H-pyrazol-5-yl]thieno[3,2-c]pyridine;
2-[4-ethyl-1-(6-methylpyridin-2-yl)-1H-pyrazol-5-yl]thieno[3,2-c]pyridine; and a pharmaceutically acceptable salt of any one of the foregoing.
9. 2-[4-methyl-1 -(6-methylpyridin-2-yl)-1H-pyrazol-5-yl]thieno[3,2-c]pyridine or a pharmaceutically acceptable salt thereof.
10. A pharmaceutical composition comprising: a therapeutically effective amount of a compound of claim 1 , or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
11. The pharmaceutical composition of claim 10 , wherein said compound is 2-[4-methyl-1-(6-methylpyridin-2-yl)-1H-pyrazol-5-yl]thieno[3,2-c]pyridine; or a pharmaceutically acceptable salt thereof.
12. 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.