COMPOUNDS FOR MODULATING TLR2

• US 20110152251A1
• Filed: 11/17/2010
• Published: 06/23/2011
• Est. Priority Date: 11/18/2009
• Status: Active Grant

• Current Assignee: University Of Massachusetts
• Original Assignee: University Of Massachusetts
• Inventors: Finberg, Robert W., Zhou, Shenghua, Kurt-Jones, Evelyn A.
• Granted Patent: US 8,609,663 B2
• Time in Patent Office: Days
• US Class Current: 514/220
• CPC Class Codes: A61K 31/42 Oxazoles
• CPC Class Codes: A61K 31/423 condensed with carbocyclic rings
• CPC Class Codes: A61K 31/4245 Oxadiazoles
• CPC Class Codes: A61K 31/429 condensed with heterocyclic ring systems
• CPC Class Codes: A61K 31/443 containing a five-membered ring with oxygen as a ring hetero atom
• CPC Class Codes: A61K 31/4433 containing a six-membered ring with oxygen as a ring hetero atom
• CPC Class Codes: A61K 31/4439 containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole nicotine A61K31/465
• CPC Class Codes: A61K 31/4535 containing a heterocyclic ring having sulfur as a ring hetero atom, e.g. pizotifen
• CPC Class Codes: A61K 31/454 containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
• CPC Class Codes: A61K 31/4725 containing further heterocyclic rings
• CPC Class Codes: A61K 31/4745 condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines yohimbine derivatives, vinblastine A61K31/475; ergoline derivatives A61K31/48
• CPC Class Codes: A61K 31/496 Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
• CPC Class Codes: A61K 31/505 Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
• CPC Class Codes: A61K 31/506 not condensed and containing further heterocyclic rings
• CPC Class Codes: A61K 31/551 having two nitrogen atoms, e.g. dilazep
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: Y02A 50/30 Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

The present invention is directed to methods, kits, and uses of inhibitors of LCMV mediated NF-κB activation to treat viral infections and inflammatory conditions.

Claims

1. A method of treating a viral infection or inflammatory condition in an individual in need thereof, comprising administering to said individual a therapeutically effective amount of a compound of Formula I:

2. The method according to claim 1, wherein Ar¹ is selected from:

3. The method according to claim 1, wherein each R² 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.

4. The method according to claim 1, wherein each R² is independently selected from C_1-6 alkyl.

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

6. The method according to claim 1, wherein Ar¹ is selected from:

7. The method according to claim 1, wherein each R¹ is independently selected from —

OR^a, —

C(O)R^b, —

C(O)NR^eR^f, —

C(O)OR^a, —

NR^eR^f, —

NR^cC(O)R^d, —

S(O)₂R^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.

8. The method according to claim 1, wherein each R¹ 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.

9. The method according to claim 1, wherein each R¹ is independently selected from chloro, trifluoromethyl, methoxy, methoxycarbonyl, 4-methylpiperazinyl, and (4-methylpiperidinyl)methyl.

10. The method according to claim 1, wherein each R^1′

is independently C_1-4 alkyl.

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

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

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

14. The method according to claim 1, wherein:

Ar¹ is selected from;

15. The method according to claim 1, wherein:

Ar¹ is selected from;

16. The method according to claim 1, wherein:

Ar¹ is selected from;

17. The method according to claim 1, wherein Ar¹ is:

18. 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;

14(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-(4-((4-methylpiperidin-1-yl)methyl)phenyl)-3-(thiophen-2-yl)urea;

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

14(5-methylbenzo[d]isoxazol-3-yl)methyl)-3-(2-(4-methylpiperazin-1-yl)phenyl)urea;

or a pharmaceutically acceptable salt thereof.

19. 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.

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, West Nile virus, reovirus, Coxsackie B virus, papillomavirus, measles, and viral encephalitis.

21. The method according to claim 1, wherein said inflammatory condition is selected from chronic joint disease, chronic active gastritis, chronic mucosal inflammation, and sepsis.

22. A compound of Formula I:

23. A method of treating a viral infection or inflammatory condition in an individual in need thereof, comprising administering to said individual a therapeutically effective amount of an agent;

wherein said agent is selected from;

(a) compounds of Formula II;