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 IIb, or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, ester, metabolite, N-oxide, stereoisomer, or isomer 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 IIb, or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, ester, metabolite, N-oxide, stereoisomer, or isomer 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 , NHR 5 , NR 4 R 5 , CO 2 H, or CO 2 R 4 ;

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

B is NHC(O)R 2 ;

R 2 is optionally substituted phenyl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted aralkyl, or optionally substituted alkyl;

R 4 is optionally substituted phenyl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted aralkyl, or optionally substituted alkyl;

R 5 is H, optionally substituted alkyl, C(O)R 4 , C(O)OR 4 , C(O)NR 4 R 4 , or SO 2 R 4 ;

A is SO 2 NR a R b ; and

each R a and R b is independently optionally substituted alkyl or together with the N to which they are attached make a ring.

2. The method of claim 1 , wherein each R a and R b is independently optionally substituted alkyl.

3. The method of claim 1 , wherein R a and R b together with the N to which they are attached make a ring.

4. The method of claim 1 , wherein R 2 is optionally substituted phenyl.

5. The method of claim 1 , wherein the phenyl of R 2 is monosubstituted or disubstituted.

6. The method of claim 5 , wherein substitution on the phenyl of R 2 is independently selected from F, Cl, CO 2 H, CN, OCH 3 , C(O)CH 3 , CF 3 , CH 3 , CH 2 OH, CH 2 CH 2 OH, and CH 2 CH 2 CH 2 OH.

7. The method of claim 1 , wherein the compound is:

or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, ester, metabolite, N-oxide, stereoisomer, or isomer thereof.

8. 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 III, or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, ester, metabolite, N-oxide, stereoisomer, or isomer 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 III, or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, ester, metabolite, N-oxide, stereoisomer, or isomer 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 , NHR 5 , NR 4 R 5 , CO 2 H, or CO 2 R 4 ;

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

X is O or NH and A is CH—CR 3 R 4 —C(O)R 2 ; or

X is NR 6 and A is C(O) or CH 2 ;

R 2 is optionally substituted aryl or optionally substituted heteroaryl;

each R 3 and R 4 is independently H or optionally substituted alkyl;

R 5 is H, optionally substituted alkyl, C(O)R 4 , C(O)OR 4 , C(O)NR 4 R 4 , or SO 2 R 4 ; and

R 6 is optionally substituted phenyl;

provided that

if n is 0, A is CHCH 2 C(O)R 2 and X is O, then R 2 is not

and

if A is C(O) or CH 2 , then X is NR 6 and R 6 is not

9. The method of claim 8 , wherein R 2 is phenyl and the phenyl of R 2 is monosubstituted or disubstituted.

10. The method of claim 9 , wherein substitution on the phenyl is independently selected from F, Cl, CO 2 H, CN, OCH 3 , C(O)CH 3 , CF 3 , CH 3 , CH 2 OH, CH 2 CH 2 OH, and CH 2 CH 2 CH 2 OH.

11. The method of claim 8 , wherein n is 0 or 1.

12. The method of claim 11 , 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 .

13. The method of claim 8 , wherein the compound is

or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, ester, metabolite, N-oxide, stereoisomer, or isomer thereof.