Compounds for modulating TLR2

1. A method of treating an inflammatory condition selected from chronic joint disease, chronic active gastritis, chronic mucosal inflammation, and sepsis in an individual in need thereof, comprising administering to said individual a therapeutically effective amount of a compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein:

Ar 1 is selected from:

each R 1 is independently selected from —OR a , —SR b , —C(O)R b , —C(O)NR e R f , —C(O)OR a , —OC(O)R b , —OC(O)NR e R f , —NR e R f , —NR c C(O)R d , —NR c C(O)OR d , —NR c C(O)NR d , —S(O)R b , —S(O)NR e R f , —S(O) 2 R a , —NR c S(O) 2 R d , halogen, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-3 alkyl, C 2-9 heterocycloalkyl, C 2-9 heterocycloalkyl-C 1-3 alkyl, C 6-10 aryl, C 6-10 aryl-C 1-3 alkyl, C 1-9 heteroaryl, and C 1-9 heteroaryl-C 1-3 alkyl; wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-3 alkyl, C 2-9 heterocycloalkyl, C 2-9 heterocycloalkyl-C 1-3 alkyl, C 6-10 aryl, C 6-10 aryl-C 1-3 alkyl, C 1-9 heteroaryl, and C 1-9 heteroaryl-C 1-3 alkyl are each optionally substituted by 1, 2, 3, or 4 independently selected R 1′ groups;

each R 2 is independently selected from —OR m , —SR n , —C(O)R n , —C(O)NR q R r , —C(O)OR m , —OC(O)R n , —OC(O)NR q R r , —NR q R r , —NR o C(O)R p , —NR o C(O)OR p , —NR o C(O)NR p , —S(O)R n , —S(O)NR q R p , —S(O) 2 R m , —NR o S(O) 2 R p , halogen, cyano, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-3 alkyl, C 2-9 heterocycloalkyl, C 2-9 heterocycloalkyl-C 1-3 alkyl, C 6-10 aryl, C 6-10 aryl-C 1-3 alkyl, C 1-9 heteroaryl, and C 1-9 heteroaryl-C 1-3 alkyl; wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-3 alkyl, C 2-9 heterocycloalkyl, C 2-9 heterocycloalkyl-C 1-3 alkyl, C 6-10 aryl, C 6-10 aryl-C 1-3 alkyl, C 1-9 heteroaryl, and C 1-9 heteroaryl-C 1-3 alkyl are each optionally substituted by 1, 2, 3, or 4 independently selected R 2′ groups;

each R b and R n is independently selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, C 3-7 cycloalkyl-C 1-3 alkyl, C 2-6 heterocycloalkyl, C 2-6 heterocycloalkyl-C 1-3 alkyl, phenyl, phenyl-C 1-3 alkyl, C 1-6 heteroaryl, and C 1-6 heteroaryl-C 1-3 alkyl; wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, C 3-7 cycloalkyl-C 1-3 alkyl, C 2-6 heterocycloalkyl, C 2-6 heterocycloalkyl-C 1-3 alkyl, phenyl, phenyl-C 1-3 alkyl, C 1-6 heteroaryl, and C 1-6 heteroaryl-C 1-3 alkyl are each optionally substituted by 1, 2, 3, or 4 independently selected R g groups;

each R a , R c , R d , R e , R f , R m , R o , R p , R r , and R q is independently selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, C 3-7 cycloalkyl-C 1-3 alkyl, C 2-6 heterocycloalkyl, C 2-6 heterocycloalkyl-C 1-3 alkyl, phenyl, phenyl-C 1-3 alkyl, C 1-6 heteroaryl, and C 1-6 heteroaryl-C 1-3 alkyl; wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, C 3-7 cycloalkyl-C 1-3 alkyl, C 2-6 heterocycloalkyl, C 2-6 heterocycloalkyl-C 1-3 alkyl, phenyl, phenyl-C 1-3 alkyl, C 1-6 heteroaryl, and C 1-6 heteroaryl-C 1-3 alkyl are each optionally substituted by 1, 2, 3, or 4 independently selected R g groups;

each R 1′ , R 2′ , and R g is independently selected from halogen, cyano, nitro, hydroxyl, carboxy, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkylcarbonyl, C 1-4 alkoxycarbonyl, amino, C 1-4 alkylamino, di-C 1-4 alkylamino, and C 1-4 alkylsulfonyl;

n is an integer selected from 0, 1, and 2; and

m and p are each independently an integer selected from 0, 1, 2, 3, 4, and 5; provided that the proper valencies are not exceeded.

2. The method according to claim 1 , wherein each R 2 is independently selected from halogen, cyano, nitro, hydroxyl, carboxy, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkylcarbonyl, C 1-4 alkoxycarbonyl, amino, C 1-4 alkylamino, di-C 1-4 alkylamino, and C 1-4 alkylsulfonyl.

3. The method according to claim 1 , wherein each R 2 is independently selected from C 1-6 alkyl.

4. The method according to claim 1 , wherein p is 0 or 1.

5. The method according to claim 1 , wherein Ar 1 is selected from:

6. The method according to claim 1 , wherein each R 1 is independently selected from —OR a , —C(O)R b , —C(O)NR e R f , —C(O)OR a , —NR e R f , —NR c C(O)R d , —S(O) 2 R a , halogen, cyano, nitro, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-3 alkyl, C 2-9 heterocycloalkyl, and C 2-9 heterocycloalkyl-C 1-3 alkyl; wherein said C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-3 alkyl, C 2-9 heterocycloalkyl, and C 2-9 heterocycloalkyl-C 1-3 alkyl are each optionally substituted by 1, 2, 3, or 4 independently selected R 1′ groups.

7. The method according to claim 1 , wherein each R 1 is independently selected from —OR a , —C(O)OR a , halogen, C 1-6 haloalkyl, C 2-9 heterocycloalkyl, and C 2-9 heterocycloalkyl-C 1-3 alkyl, wherein said C 2-9 heterocycloalkyl, and C 2-9 heterocycloalkyl-C 1-3 alkyl are each optionally substituted with 1, 2, 3, or 4 independently selected R 1′ groups.

8. The method according to claim 1 , wherein each R 1 is independently selected from chloro, trifluoromethyl, methoxy, methoxycarbonyl, 4-methylpiperazinyl, and (4-methylpiperidinyl)methyl.

9. The method according to claim 1 , wherein each R 1′ is independently C 1-4 alkyl.

10. The method according to claim 1 , wherein m is 0, 1, or 2.

11. The method according to claim 1 , wherein n is 0.

12. The method according to claim 1 , wherein n is 1.

13. The method according to claim 1 , wherein:

Ar 1 is selected from:

each R 2 is independently selected from halogen, cyano, nitro, hydroxyl, carboxy, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkylcarbonyl, C 1-4 alkoxycarbonyl, amino, C 1-4 alkylamino, di-C 1-4 alkylamino, and C 1-4 alkylsulfonyl;

each R 1 is independently selected from —OR a , —C(O)R b , —C(O)NR e R f , —C(O)OR a , —NR e R f , —NR c C(O)R d , —S(O) 2 R a , halogen, cyano, nitro, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-3 alkyl, C 2-9 heterocycloalkyl, and C 2-9 heterocycloalkyl-C 1-3 alkyl; wherein said C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-3 alkyl, C 2-9 heterocycloalkyl, and C 2-9 heterocycloalkyl-C 1-3 alkyl are each optionally substituted by 1, 2, 3, or 4 independently selected R 1′ groups;

each R 1′ is independently C 1-4 alkyl;

m is 0, 1, or 2;

n is 0 or 1; and

p is 0 or 1.

14. The method according to claim 1 , wherein:

Ar 1 is selected from:

each R 2 is independently selected from C 1-6 alkyl;

each R 1 is independently selected from —OR a , —C(O)OR a , halogen, C 1-6 haloalkyl, C 2-9 heterocycloalkyl, and C 2-9 heterocycloalkyl-C 1-3 alkyl, wherein said C 2-9 heterocycloalkyl, and C 2-9 heterocycloalkyl-C 1-3 alkyl are each optionally substituted with 1, 2, 3, or 4 independently selected R 1′ groups;

each R 1′ is independently C 1-4 alkyl;

each R a is independently selected from H and C 1-6 alkyl;

m is 0, 1, or 2;

n is 0 or 1; and

p is 0 or 1.

15. The method according to claim 1 , wherein:

Ar 1 is selected from:

each R 2 is independently selected from methyl;

each R 1 is independently selected from chloro, trifluoromethyl, methoxy, methoxycarbonyl, 4-methylpiperazinyl, and (4-methylpiperidinyl)methyl;

m is 0, 1, or 2;

n is 0 or 1; and

p is 0 or 1.

16. The method according to claim 1 , wherein Ar 1 is:

17. The method according to claim 1 , wherein said compound is selected from:

1-(benzo[d]isoxazol-3-ylmethyl)-3-(4-((4-methylpiperidin-1-yl)methyl)phenyl)urea;

1-((5-methylbenzo[d]isoxazol-3-yl)methyl)-3-(4-((4-methylpiperidin-1-yl)methyl)phenyl)urea;

1-((5-methylbenzo[d]isoxazol-3-yl)methyl)-3-(3-(trifluoromethyl)phenyl)urea;

1-(3-chlorophenyl)-3-(benzo[d]isoxazol-3-ylmethyl)urea;

1-(benzo[d]isoxazol-3-ylmethyl)-3-(3-methoxyphenyl)urea;

methyl 4-(3-(benzo[d]isoxazol-3-ylmethyl)ureido)benzoate;

1-(2-methyl-1-oxo-1,2-dihydroisoquinolin-4-yl)-3-(4-((4-methylpiperidin-1-yl)methyl)phenyl)urea; and

1-((5-methylbenzo[d]isoxazol-3-yl)methyl)-3-(2-(4-methylpiperazin-1-yl)phenyl)urea;

or a pharmaceutically acceptable salt thereof.

18. The method according to claim 1 , wherein the compound is 1-(benzo[d]isoxazol-3-ylmethyl)-3-(4-((4-methylpiperidin-1-yl)methyl)phenyl)urea, or a pharmaceutically acceptable salt thereof.

19. The method according to claim 1 , wherein said inflammatory condition is sepsis.

20. The method according to claim 1 , wherein said inflammatory condition is chronic joint disease.

21. The method according to claim 1 , wherein said inflammatory condition is chronic active gastritis.

22. The method according to claim 1 , wherein said inflammatory condition is chronic mucosal inflammation.