Therapeutic pyrazolyl thienopyridines

1. A method of treating a TGFβ-mediated condition, comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of Formula I

or a pharmaceutically acceptable salt thereof, wherein:

R 1 is a thieno[3,2-c]pyridinyl, a thieno[3,2-b]pyridinyl, thieno[2,3-c]pyridinyl, or a thieno[2,3-b]pyridinyl, each of 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, wherein R 30 and R 31 are each independently selected from the group consisting of: H, and C 1 -C 3 alkyl;

or R 2 and R 3 may be taken together to form a 5 or 6 membered heteroaryl, a phenyl, a C 4 -C 6 -cycloalkyl, or a 4-6-membered heterocycloalkyl, wherein said C 4 -C 6 -cycloalkyl or 4-6-membered heterocycloalkyl may be optionally substituted with one to three substituents independently selected from halo, —OH, oxo, and C 1 -C 3 alkyl, wherein said 5 or 6-membered heteroaryl, or phenyl may be optionally substituted with one to three substituents independently selected from halo, —CN, —OH, —O—C 1 -C 3 alkyl 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)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;

and wherein the TGFβ-mediated condition is dermal scarring.

2. The method of claim 1 , wherein R 2 and R 3 are taken together to form a C 4 -C 6 -cyoloalkyl, or a 4-6-membered heterocycloalkyl, wherein said C 4 -C 6 -cycloalkyl or 4-6-membered heterocycloalkyl may be optionally substituted with one to three substituents independently selected from oxo and C 1 -C 3 alkyl.

3. The method of claim 2 , wherein R 2 and R 3 are taken together to form a C 5 -cycloalkyl, or a 4-6-membered heterocycloalkyl, wherein said 4-6-membered heterocycloalkyl is selected from the group consisting of: a tetrahydrofuranyl, a tetrahydrothienyl, a imidazlidinyl, an oxazolidinyl, an imidazolinyl, an isoxazolidinyl, and a pyrrolidinyl.

4. The method of claim 3 , wherein R 1 is a thieno[3,2-c]pyridinyl or 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.

5. The method of claim 4 , wherein said compound is 2-(2-(6-methylpyridin-2-yl)-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)thieno[3,2-d]pyridine, or a pharmaceutically acceptable salt thereof.

6. The method of claim 4 , wherein said compound is 2-(2-(6-methylpyridin-2-yl)-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)thieno[2,3-c]pyridine, or a pharmaceutically acceptable salt thereof.

7. The method of claim 1 , 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 1 -cycloalkyl.

8. The method of claim 7 , wherein R 2 and R 3 are independently selected from the group consisting of: hydrogen, and C 1 -C 3 alkyl.

9. The method of claim 8 , wherein R 2 is C 1 -C 2 alkyl and R 3 is hydrogen.

10. The method of claim 9 , wherein R 5 , R 6 , and R 7 are H, and R 9 is C 1 -C 3 -alkyl.

11. The method of claim 10 , wherein R 4 is methyl.

12. The method of claim 11 , wherein R 1 is a thieno[3,2-c]pyridinyl or 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.

13. The method of claim 12 , wherein R 1 is a thieno[3,2-c]pyridin-2-yl or 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.

14. The method of claim 13 , wherein R 1 is a thieno[3,2-c]pyridin-2-yl.

15. The method of claim 1 , wherein said compound is 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)-1H-pyrazol-5-yl]thieno[3,2-c]pyridine;

2-[3-methyl-1-(6-methylpyridin-2-yl)-1H-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

pharmaceutically acceptable salts thereof.

16. The method of claim 1 , 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.

17. The method of claim 13 , wherein R 1 is a thieno[2,3-c]pyridin-2-yl.