Compounds for modulating TLR2

1. A method of treating a viral infection selected from Tacaribe virus, Rift Valley Fever Virus, herpes simplex virus-1 (HSV-1), herpes simplex virus-2 (HSV-2), lymphocytic choriomenigitis virus (LCMV), human cytomegalovirus (HCMV), respiratory syncytial virus (RSV), vesicular stomatitis virus (VSV), varicella zoster virus (VZV), influenza, Lassa hemorrhagic fever (HF), Argentine HF virus, West Nile virus, reovirus, Coxsackie B virus, papillomavirus, measles, and viral encephalitis 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 (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 l 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 viral infection is selected from Tacaribe virus, Rift Valley Fever Virus, herpes simplex virus-1 (HSV-1), herpes simplex virus-2 (HSV-2), and lymphocytic choriomenigitis virus (LCMV).

20. The method according to claim 1 , wherein said viral infection is selected from Tacaribe virus, Rift Valley Fever Virus, herpes simplex virus-1 (HSV-1), herpes simplex virus-2 (HSV-2), lymphocytic choriomenigitis virus (LCMV), human cytomegalovirus (HCMV), respiratory syncytial virus (RSV), vesicular stomatitis virus (VSV), varicella zoster virus (VZV), influenza, Lassa hemorrhagic fever (HF), Argentine HF virus, measles, and viral encephalitis.

21. The method according to claim 1 , wherein said viral infection is selected from Tacaribe virus, Rift Valley Fever Virus, herpes simplex virus-1 (HSV-1) and lymphocytic choriomenigitis virus (LCMV).

22. The method according to claim 1 , wherein said viral infection is lymphocytic choriomenigitis virus (LCMV).