Bisphosphonate compounds

1. A compound of Formula III,

or a pharmaceutically acceptable salt thereof,

wherein R 1 , R 2 , R 3 , R 4 and R 5 are each independently

a) hydrogen;

b) halogen, —CN, —CF 3 , or —NO 2 ;

c) C 1 -C 8 alkyl or C 1 -C 8 haloalkyl;

d) C 2 -C 8 alkenyl or C 2 -C 8 haloalkenyl;

e) C 2 -C 8 alkynyl or C 2 -C 8 haloalkynyl;

f) optionally substituted aryl or optionally substituted heteroaryl;

g) —C(O)R 6 ;

h) —C(O)OR 6 , or —CO 2 R 6 ;

i) —OR 6 , —O-L-OC(O)R 6 , or —O-L-OC(O)OR 6 ;

j) —OC(O)R 6 , or —OC(O)-L-OC(O)R 6 ;

k) —OC(O)OR 6 , —OC(O)O-L-C(O)R 7 , —OC(O)O-L-C(O)OR 7 , or -L-OC(O)R 6 ;

l) —C(O)NR 6 R 7 , or —CNR 6 R 7 ;

m) —OC(O)NR 6 R 7 , —OC(O)N(R 6 )-L-OC(O)R 7 , —OC(O)O-L-(R 6 )-L-C(O)R 7 , —OC(O)-C(R 6 )(R 7 )-L-OC(O)R 8 , —OC(O)N(-L-OC(O)R 7 )(-L-OC(O)R 8 );

n) —SR 6 , or —NR 6 R 7 ;

o) —NR 6 C(O)R 7 ;

p) —NR 6 C(O)OR 7 ;

q) —NR 6 C(O)NR 7 ;

r) —OSO 2 R 6 ;

s) —SO 2 OR 6 ;

t) —SO 2 R 6 ;

u) —NR 6 SO 2 R 7 ;

v) —SO 2 NR 6 R 7 ;

R 1 and R 2 , R 2 and R 3 , R 3 and R 4 , or R 4 and R 5 taken together form an optionally substituted 4- to 8-membered carbocyclic or heterocyclic ring, wherein the ring is saturated, unsaturated or aromatic;

R 6 is independently hydrogen, C 1 -C 8 alkyl, C 1 -C 8 haloalkyl, C 2 -C 8 alkenyl, C 2 -C 8 haloalkenyl, C 2 -C 8 alkynyl, C 2 -C 8 haloalkynyl, an optionally substituted 4-8 membered saturated carbocyclic or heterocyclic ring, optionally substituted aryl, optionally substituted heteroaryl, -L-optionally substituted aryl or -L-optionally substituted heteroaryl;

R 7 and R 8 are each independently hydrogen or C 1 -C 8 alkyl; and L is C 1 -C 8 alkyl; or

R 6 and R 7 taken together form an optionally substituted 4- to 8-membered carbocyclic or heterocyclic ring, wherein the ring is saturated, unsaturated or aromatic;

and R 9 and R 10 are each independently hydrogen, halogen, oxygen, C 1 -C 8 alkyl, C 1 -C 8 haloalkyl, C 2 -C 8 alkenyl, C 2 -C 8 haloalkenyl, C 2 -C 8 alkynyl, C 2 -C 8 haloalkynyl, optionally substituted aryl, optionally substituted heteroaryl, —OR 6 , —SR 6 , —NR 6 R 7 , —(C 1 -C 8 alkyl)-NR 6 R 7 , —(C 1 -C 8 haloalkyl)-NR 6 R 7 , —(C 2 -C 8 alkenyl)-NR 6 R 7 , —(C 2 -C 8 haloalkenyl) -NR 6 R 7 , —(C 2 -C 8 alkynyl)-NR 6 R 7 , —(C 2 -C 8 haloalkyl)-NR 6 R 7 , -L-R 11 ; or R 9 and R 10 taken together form a monocyclic or bicyclic optionally substituted carbocyclic or heterocyclic ring, wherein the ring is saturated, unsaturated or aromatic;

wherein R 11 is optionally substituted aryl or optionally substituted heteroaryl.

2. The compound of claim 1 , wherein R 9 is hydrogen, oxygen, —F, —Cl, —CH 3 , —OH, —SH, —NH 2 , —CH 2 —R 11 , or —N—(C 1 -C 8 alkyl);

R 10 is —Cl, —CH 3 , —S-phenyl, —S(p-chlorophenyl), —(CH 2 ) q NH 2 , —(CH 2 ) q NR 6 R 7 ,

q is an integer from 0 to 8;

R 12 is hydrogen, —OH, C 1 -C 8 alkyl, —CH 3 , or —F; and

R 13 is hydrogen, —OH, C 1 -C 8 alkyl, —OCH 3 , —OCH 2 -phenyl, —CF 3 , —NH 2 , —F, or —Br.

3. The compound of claim 2 , wherein R 10 is —CH 2 CH 2 NH 2 , —(CH 2 ) 3 NH 2 , —(CH 2 ) 2 N(CH 3 )((CH 2 ) 4 CH 3 ),

4. The compound of claim 2 , wherein R 9 is —OH.

5. The compound of claim 1 , wherein R 9 is hydrogen, —F, or —Cl;

R 10 is

R 12 is hydrogen, —OH, C 1 -C 8 alkyl, —OCH 3 , or —F; and

R 13 is hydrogen, —OH, C 1 -C 8 alkyl, or —F.

6. The compound of claim 5 , wherein R 9 is hydrogen or —F; and R 12 and R 13 are each independently hydrogen, —OH, —CH 3 , —CH 2 CH 3 , —C(CH 3 ) 3 , or —F.

7. The compound of claim 5 , wherein R 9 is hydrogen or —F; and R 12 and R 13 are each hydrogen.

8. The compound of claim 1 , wherein R 1 and R 5 are each independently halogen;

R 3 is —OR 6 , —O-L-OC(O)R 6 , —O-L-OC(O)OR 6 , —OC(O)R 6 , —OC(O)-L-OC(O)R 6 , —OC(O)OR 6 , —OC(O)O-L-C(O)R 7 , —OC(O)NR 6 R 7 , —OC(O)N(R 6 )-L-OC(O)R 7 , or —OC(O)N(-L-OC(O)R 7 )(-L-OC(O)R 8 )

and R 2 and R 4 are each hydrogen.

9. The compound of claim 1 , wherein R 1 is —OR 6 , —O-L-OC(O)R 6 , —O-L-OC(O)OR 6 , —OC(O)R 6 , —OC(O)-L-OC(O)R 6 , —OC(O)OR 6 , —OC(O)O-L-C(O)R 7 , —OC(O)NR 6 R 7 , —OC(O)N(R 6 )-L-OC(O)R 7 , or —OC(O)N(-L-OC(O)R 7 )(-L-OC(O)R 8 )

one of R 2 , R 3 , R 4 and R 5 is halogen, —CF 3 , C 1 -C 8 alkyl, phenyl, —OR 6 , or —C(O)OR 6 ;

and each remaining R-group of R 2 , R 3 , R 4 and R 5 is hydrogen.

10. The compound of claim 1 , wherein R 3 is —OR 6 , —O-L-OC(O)R 6 , —O-L-OC(O)OR 6 , —OC(O)R 6 , —OC(O)-L-OC(O)R 6 , —OC(O)OR 6 , —OC(O)O-L-C(O)R 7 , —OC(O)NR 6 R 7 , —OC(O)N(R 6 )-L-OC(O)R 7 , or —OC(O)N(-L-OC(O)R 7 )(-L-OC(O)R 8 )

one of R 1 , R 2 , R 4 and R 5 is halogen, —CF 3 , C 1 -C 8 alkyl, phenyl, —OR 6 , or —C(O)OR 6 ;

and each remaining R-group of R 1 , R 2 , R 4 and R 5 is hydrogen.

11. The compound of claim 1 , wherein R 1 is —OR 6 , —O-L-OC(O)R 6 , —O-L-OC(O)OR 6 , —OC(O)R 6 , —OC(O)-L-OC(O)R 6 , —OC(O)OR 6 , —OC(O)O-L-C(O)R 7 , —OC(O)NR 6 R 7 , —OC(O)N(R 6 )-L-OC(O)R 7 , or —OC(O)N(-L-OC(O)R 7 )(-L-OC(O)R 8 ),

and R 2 , R 3 , R 4 , and R 5 are each hydrogen.

12. The compound of claim 1 , wherein R 3 is —OR 6 , —O-L-OC(O)R 6 , —O-L-OC(O)OR 6 , —OC(O)R 6 , —OC(O)-L-OC(O)R 6 , —OC(O)OR 6 , —OC(O)O-L-C(O)R 7 , —OC(O)NR 6 R 7 , —OC(O)N(R 6 )-L-OC(O)R 7 , or —OC(O)N(-L-OC(O)R 7 )(-L-OC(O)R 8 )

and R 1 , R 2 , R 4 , and R 5 are each hydrogen.

13. A pharmaceutical composition comprising a compound of claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

14. The pharmaceutical composition of claim 13 , wherein the composition further comprises at least one pharmaceutically active ingredient selected from the group consisting of: an anti-inflammatory, an immunomodulator, a chelator, a musculoskeletal anabolic agent, and a combination thereof.

15. A method of treating osteoporosis, rheumatoid arthritis, osteoarthritis, Paget's disease, or alveolar bone loss comprising administering an effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof to a patient in need of such treatment.