Compounds and methods for inducing chondrogenesis

1. A method of (a) ameliorating arthritis or joint injury in a mammal, the method comprising administering to a joint of the mammal a composition comprising a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt, solvate, polymorph, ester, N-oxide, or stereoisomer thereof; or (b) inducing differentiation of mesenchymal stem cells into chondrocytes, the method comprising contacting mesenchymal stem cells with a sufficient amount of a compound of Formula I, or a pharmaceutically acceptable salt, solvate, polymorph, ester, N-oxide, or stereoisomer thereof:

wherein

each R 1 is independently halo, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted aryloxy, CN, NO 2 , SR 4 , S(O)R 4 , SO 2 R 4 , NR 4 R 11 , or CO 2 R 4 ;

n is 0, 1, 2, 3, or 4;

m is 1, 2, 3, or 4;

B is CO 2 R 4 , CH 2 CO 2 H, CH 2 CO 2 R 4 , or optionally substituted phenyl;

Y is a bond, —(CR 5 R 6 )—, —(CR 7 R 8 )(CR 9 R 10 )—, or —(CR 7 R 8 )(CR 9 R 10 )X—;

X is O or CR 5 R 6 ;

R 2 is halo, C(O)R 4 , CO 2 R 4 , C(O)NR 4 R 11 , alkyl, optionally substituted alkoxy, haloalkyl, SO 2 R 4 , (CR 7 R 8 )OR 4 , (CR 7 R 8 )NR 4 R 11 , (CR 7 R 8 )(CR 9 R 10 )OR 4 , X(CR 7 R 8 )(CR 9 R 10 )OR 4 , X(CR 7 R 8 )(CR 9 R 10 )NR 4 R 11 , (CR 7 R 8 )C(O)R 4 , (CR 7 R 8 )C(O)OR 4 , (CR 7 R 8 )C(O)NR 4 R 11 , X(CR 7 R 8 )C(O)R 4 , X(CR 7 R 8 )C(O)OR 4 , X(CR 7 R 8 )C(O)NR 4 R 11 , X(CR 7 R 8 )(CR 9 R 10 )C(O)R 4 , X(CR 7 R 8 )(CR 9 R 10 )C(O)OR 4 , X(CR 7 R 8 )(CR 9 R 10 )C(O)NR 4 R 11 , (CR 7 R 8 )NR 4 SO 2 R 4 , or C(═NOR 4 )R 4 ;

each R 3 is independently selected from H, CN, halo, C(O)R 4 , CO 2 R 4 , C(O)NR 4 R 11 , alkyl, optionally substituted alkoxy, SO 2 R 4 , (CR 7 R 8 )OR 4 , (CR 7 R 8 )NR 4 R 11 , (CR 7 R 8 )(CR 9 R 10 )OR 4 , X(CR 7 R 8 )(CR 9 R 10 )OR 4 , X(CR 7 R 8 )(CR 9 R 10 )NR 4 R 11 , (CR 7 R 8 )C(O)R 4 , (CR 7 R 8 )C(O)OR 4 , (CR 7 R 8 )C(O)NR 4 R 11 , X(CR 7 R 8 )C(O)R 4 , X(CR 7 R 8 )C(O)OR 4 , X(CR 7 R 8 )C(O)NR 4 R 11 , X(CR 7 R 8 )(CR 9 R 10 )C(O)R 4 , X(CR 7 R 8 )(CR 9 R 10 )C(O)OR 4 , X(CR 7 R 8 )(CR 9 R 10 )C(O)NR 4 R 11 , (CR 7 R 8 )NR 4 SO 2 R 4 , and C(═NOR 4 )R 4 ;

or R 3 together with an adjacent R 3 or with R 2 form a ring;

each R 4 is independently selected from H and optionally substituted alkyl;

each R 5 , R 6 , R 7 , R 8 , R 9 , and R 10 is independently selected from H, halo, optionally substituted alkyl, OH, CO 2 R 4 , NR 4 R 11 , and optionally substituted alkoxy; and

R 11 is H, optionally substituted alkyl, C(O)R 4 , C(O)OR 4 , C(O)NR 4 R 4 , or SO 2 R 4 ;

provided that

a) if Y is a bond and R 3 is H, then R 2 is selected from C(O)NR 4 R 11 , (CR 7 R 8 )OR 4 , (CR 7 R 8 )(CR 9 R 10 )OR 4 , X(CR 7 R 8 )(CR 9 R 10 )OR 4 , X(CR 7 R 8 )(CR 9 R 10 )NR 4 R 11 , (CR 7 R 8 )C(O)R 4 , (CR 7 R 8 )C(O)OR 4 , (CR 7 R 8 )C(O)NR 4 R 11 , X(CR 7 R 8 )C(O)R 4 , X(CR 7 R 8 )C(O)OR 4 , X(CR 7 R 8 )C(O)NR 4 R 11 , X(CR 7 R 8 )(CR 9 R 10 )C(O)R 4 , X(CR 7 R 8 )(CR 9 R 10 )C(O)OR 4 , X(CR 7 R 8 )(CR 9 R 10 )C(O)NR 4 R 11 , (CR 7 R 8 )NR 4 SO 2 R 4 , and C(═NOR 4 )R 4 ; and

R 2 is not p-CH 2 OR 4 , p-CH 2 CH 2 OH, or p-CH 2 CH 2 CH 2 OH; and

b) the compound is not selected from

2. A method of (a) ameliorating arthritis or joint injury in a mammal, the method comprising administering to a joint of the mammal a composition comprising a therapeutically effective amount of a compound of Formula Ib, or a pharmaceutically acceptable salt, solvate, polymorph, ester, N-oxide, or stereoisomer thereof; or (b) inducing differentiation of mesenchymal stem cells into chondrocytes, the method comprising contacting mesenchymal stem cells with a sufficient amount of a compound of Formula Ib, or a pharmaceutically acceptable salt, solvate, polymorph, ester, N-oxide, or stereoisomer thereof:

wherein

each R 1 is independently halo, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted aryloxy, CN, NO 2 , SR 4 , S(O)R 4 , SO 2 R 4 , NR 4 R 11 , or CO 2 R 4 ;

n is 0, 1, 2, 3, or 4;

B is CO 2 R 4 ;

R 2 is C(O)NR 4 R 11 , (CR 7 R 8 )OR 4 , (CR 7 R 8 )(CR 9 R 10 )OR 4 , X(CR 7 R 8 )(CR 9 R 10 )OR 4 , X(CR 7 R 8 )(CR 9 R 10 )NR 4 R 11 , (CR 7 R 8 )C(O)R 4 , (CR 7 R 8 )C(O)OR 4 , (CR 7 R 8 )C(O)NR 4 R 11 , X(CR 7 R 8 )C(O)R 4 , X(CR 7 R 8 )C(O)OR 4 , X(CR 7 R 8 )C(O)NR 4 R 11 , X(CR 7 R 8 )(CR 9 R 10 )C(O)R 4 , X(CR 7 R 8 )(CR 9 R 10 )C(O)OR 4 , X(CR 7 R 8 )(CR 9 R 10 )C(O)NR 4 R 11 , (CR 7 R 8 )NR 4 SO 2 R 4 , or C(═NOR 4 )R 4 ;

R 3 is H;

X is O or CR 5 R 6 ;

each R 4 is independently selected from H and optionally substituted alkyl;

each R 5 , R 6 , R 7 , R 8 , R 9 , and R 10 is independently selected from H, halo, optionally substituted alkyl, OH, NR 4 R 11 , and optionally substituted alkoxy; and

R 11 is H, optionally substituted alkyl, C(O)R 4 , C(O)OR 4 , C(O)NR 4 R 4 , or SO 2 R 4 ;

provided that if n is 0, then R 2 is not p-CH 2 OR 4 , p-CH 2 CH 2 OH, or p-CH 2 CH 2 CH 2 OH.

3. A method of (a) ameliorating arthritis or joint injury in a mammal, the method comprising administering to a joint of the mammal a composition comprising a therapeutically effective amount of a compound of Formula Ic, or a pharmaceutically acceptable salt, solvate, polymorph, ester, N-oxide, or stereoisomer thereof; or (b) inducing differentiation of mesenchymal stem cells into chondrocytes, the method comprising contacting mesenchymal stem cells with a sufficient amount of a compound of Formula Ic, or a pharmaceutically acceptable salt, solvate, polymorph, ester, N-oxide, or stereoisomer thereof:

wherein

each R 1 is independently halo, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted aryloxy, CN, NO 2 , SR 4 , S(O)R 4 , SO 2 R 4 , NR 4 R 11 , CO 2 H, or CO 2 R 4 ;

n is 0, 1, 2, 3, or 4;

m is 1, 2, 3, or 4;

B is CO 2 R 4 ;

Y is —(CR 5 R 6 )—;

C is phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, thiazolyl, isoxazolyl, or pyrazolyl;

X is O or CR 5 R 6 ;

R 2 is halo, C(O)R 4 , CO 2 R 4 , C(O)NR 4 R 11 , alkyl, optionally substituted alkoxy, haloalkyl, SO 2 R 4 , SO 2 NH 2 , SO 3 H, (CR 7 R 8 )OR 4 , (CR 7 R 8 )NR 4 R 11 , (CR 7 R 8 )(CR 9 R 10 )OR 4 , X(CR 7 R 8 )(CR 9 R 10 )OR 4 , X(CR 7 R 8 )(CR 9 R 10 )NR 4 R 11 , (CR 7 R 8 )C(O)R 4 , (CR 7 R 8 )C(O)OR 4 , (CR 7 R 8 )C(O)NR 4 R 11 , X(CR 7 R 8 )C(O)R 4 , X(CR 7 R 8 )C(O)OR 4 , X(CR 7 R 8 )C(O)NR 4 R 11 , X(CR 7 R 8 )(CR 9 R 10 )C(O)R 4 , X(CR 7 R 8 )(CR 9 R 10 )C(O)OR 4 , X(CR 7 R 8 )(CR 9 R 10 )C(O)NR 4 R 11 , (CR 7 R 8 )NR 4 SO 2 R 4 , or C(═NOR 4 )R 4 ;

each R 3 is independently selected from H, CN, halo, C(O)R 4 , CO 2 R 4 , C(O)NR 4 R 11 , alkyl, optionally substituted alkoxy, haloalkyl, SO 2 R 4 , (CR 7 R 8 )OR 4 , (CR 7 R 8 )NR 4 R 11 , (CR 7 R 8 )(CR 9 R 10 )OR 4 , X(CR 7 R 8 )(CR 9 R 10 )OR 4 , X(CR 7 R 8 )(CR 9 R 10 )NR 4 R 11 , (CR 7 R 8 )C(O)R 4 , (CR 7 R 8 )C(O)OR 4 , (CR 7 R 8 )C(O)NR 4 R 11 , X(CR 7 R 8 )C(O)R 4 , X(CR 7 R 8 )C(O)OR 4 , X(CR 7 R 8 )C(O)NR 4 R 11 , X(CR 7 R 8 )(CR 9 R 10 )C(O)R 4 , X(CR 7 R 8 )(CR 9 R 10 )C(O)OR 4 , X(CR 7 R 8 )(CR 9 R 10 )C(O)NR 4 R 11 , (CR 7 R 8 )NR 4 SO 2 R 4 , and C(═NOR 4 )R 4 ;

or R 3 together with an adjacent R 3 or with R 2 form a ring;

each R 4 is independently selected from H and optionally substituted alkyl;

each R 5 , R 6 , R 7 , R 8 , R 9 , and R 10 is independently selected from H, halo, optionally substituted alkyl, OH, CO 2 R 4 , NR 4 R 11 , and optionally substituted alkoxy; and

R 11 is H, optionally substituted alkyl, C(O)R 4 , C(O)OR 4 , C(O)NR 4 R 4 , or SO 2 R 4 ;

provided that the compound is not

4. The method of claim 1 , wherein:

R 2 is halo, C(O)R 4 , alkyl, optionally substituted alkoxy, haloalkyl, (CR 7 R 8 )OR 4 , (CR 7 R 8 )(CR 9 R 10 )OR 4 , X(CR 7 R 8 )(CR 9 R 10 )OR 4 , X(CR 7 R 8 )C(O)OR 4 , or X(CR 7 R 8 )C(O)NR 4 R 11 ; and

each R 3 is independently selected from CN, halo, C(O)R 4 , CO 2 H, C(O)NR 4 R 11 , alkyl, or optionally substituted alkoxy;

or R 3 together with an adjacent R 3 or with R 2 form a ring.

5. The method of claim 4 , wherein:

R 2 is F, Cl, C(O)CH 3 , CH 3 , CF 3 , OCH 3 , OEt, OPr, OCF 3 , OCHF 2 , (CR 7 R 8 )OR 4 , (CR 7 R 8 )(CR 9 R 10 )OR 4 , X(CR 7 R 8 )(CR 9 R 10 )OR 4 , X(CR 7 R 8 )C(O)OR 4 , or X(CR 7 R 8 )C(O)NR 4 R 11 ; and

each R 3 is independently selected from CN, F, Cl, C(O)CH 3 , CO 2 H, C(O)NH 2 , CH 3 , OCF 3 , or OCH 3 ;

or R 3 together with an adjacent R 3 or with R 2 form a ring.

6. The method of claim 5 wherein R 2 is F, Cl, C(O)CH 3 , CH 3 , CF 3 , OCH 3 , OEt, OPr, OCF 3 , OCHF 2 , CH 2 OCH 3 , CH 2 OH, CH 2 CH 2 OH, CHOHCH 2 OH, CH 2 CH 2 CH 2 OH, CH 2 CHOHCH 2 OH, OCH 2 C(O)OH, or OCH 2 C(O)NH 2 .

7. The method of claim 6 , wherein each R 3 is independently selected from CN, F, Cl, C(O)CH 3 , or CO 2 H.

8. The method of claim 1 , wherein:

R 2 is (CR 7 R 8 )(CR 9 R 10 )OR 4 , X(CR 7 R 8 )(CR 9 R 10 )OR 4 , X(CR 7 R 8 )(CR 9 R 10 )NR 4 R 11 , (CR 7 R 8 )C(O)R 4 , (CR 7 R 8 )C(O)NR 4 R 11 , X(CR 7 R 8 )C(O)R 4 , X(CR 7 R 8 )C(O)NR 4 R 11 , (CR 7 R 8 )NR 4 SO 2 R 4 , or C(═NOR 4 )R 4 ; and

R 3 is H.

9. The method of claim 2 , wherein:

R 2 is (CR 7 R 8 )(CR 9 R 10 )OR 4 , X(CR 7 R 8 )(CR 9 R 10 )OR 4 , X(CR 7 R 8 )(CR 9 R 10 )NR 4 R 11 , (CR 7 R 8 )C(O)R 4 , (CR 7 R 8 )C(O)NR 4 R 11 , X(CR 7 R 8 )C(O)R 4 , X(CR 7 R 8 )C(O)NR 4 R 11 , (CR 7 R 8 )NR 4 SO 2 R 4 , or C(═NOR 4 )R 4 ; and

R 3 is H.

10. The method of claim 3 , wherein C is phenyl.

11. The method of claim 3 , wherein C is pyridinyl, pyrimidinyl, pyridazinyl, or pyrazinyl.

12. The method of claim 3 , wherein:

R 2 is halo, C(O)R 4 , CO 2 R 4 , C(O)NR 4 R 11 , alkyl, optionally substituted alkoxy, haloalkyl, SO 2 NH 2 , SO 3 H, (CR 7 R 8 )C(O)R 4 , (CR 7 R 8 )C(O)OR 4 , (CR 7 R 8 )C(O)NR 4 R 11 , X(CR 7 R 8 )C(O)OR 4 , or X(CR 7 R 8 )C(O)NR 4 R 11 ; and

each R 3 is independently selected from H, CN, halo, CO 2 H, or haloalkyl.

13. The method of claim 1 , wherein B is CO 2 R 4 and R 4 is optionally substituted alkyl.

14. The method of claim 2 , wherein B is CO 2 R 4 and R 4 is optionally substituted alkyl.

15. The method of claim 3 , wherein B is CO 2 R 4 and R 4 is optionally substituted alkyl.

16. The method of claim 1 , wherein B is CO 2 R 4 and R 4 is hydrogen.

17. The method of claim 2 , wherein B is CO 2 R 4 and R 4 is hydrogen.

18. The method of claim 3 , wherein B is CO 2 R 4 and R 4 is hydrogen.

19. The method of claim 1 , wherein n is 0, 1, or 2.

20. The method of claim 19 , wherein R 1 is independently selected from Cl, F, CH 2 OH, CH 2 NH 2 , OCH 3 , OCF 3 , OCHF 2 , CN, NO 2 , CO 2 H, and CO 2 CH 3 .

21. The method of claim 2 , wherein n is 0, 1, or 2.

22. The method of claim 21 , wherein R 1 is independently selected from Cl, F, CH 2 OH, CH 2 NH 2 , OCH 3 , OCF 3 , OCHF 2 , CN, NO 2 , CO 2 H, and CO 2 CH 3 .

23. The method of claim 3 , wherein n is 0, 1, or 2.

24. The method of claim 23 , wherein R 1 is independently selected from Cl, F, CH 2 OH, CH 2 NH 2 , OCH 3 , OCF 3 , OCHF 2 , CN, NO 2 , CO 2 H, and CO 2 CH 3 .

25. The method of claim 1 , wherein the compound, or a pharmaceutically acceptable salt, solvate, polymorph, ester, N-oxide, or stereoisomer thereof, is selected from:

26. The method of claim 1 , wherein the mammal is a human, a dog, a cat, or a horse.

27. The method of claim 2 , wherein the mammal is a human, a dog, a cat, or a horse.

28. The method of claim 3 , wherein the mammal is a human, a dog, a cat, or a horse.

29. The method of claim 2 , wherein the compound, or a pharmaceutically acceptable salt, solvate, polymorph, ester, N-oxide, or stereoisomer thereof, is selected from

30. The method of claim 3 , wherein the compound, or a pharmaceutically acceptable salt, solvate, polymorph, ester, N-oxide, or stereoisomer thereof, is selected from: