MODULATORS OF TOLL-LIKE RECEPTORS

• US 20110098248A1
• Filed: 10/15/2010
• Published: 04/28/2011
• Est. Priority Date: 10/22/2009
• Status: Active Grant

• Current Assignee: Gilead Sciences Inc.
• Original Assignee: Gilead Sciences Inc.
• Inventors: Roethle, Paul A., Halcomb, Randall L.
• Granted Patent: US 8,507,507 B2
• Time in Patent Office: Days
• US Class Current: 514/64
• CPC Class Codes: A61K 31/437 the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
• CPC Class Codes: A61K 31/522 having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
• CPC Class Codes: A61K 31/5377 not condensed and containing further heterocyclic rings, e.g. timolol
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/02 Nasal agents, e.g. decongestants
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 31/14 for RNA viruses
• CPC Class Codes: A61P 31/16 for influenza or rhinoviruses
• CPC Class Codes: A61P 31/18 for HIV
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/08 Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 471/04 Ortho-condensed systems
• CPC Class Codes: C07D 473/16 two nitrogen atoms
• CPC Class Codes: C07D 473/18 one oxygen and one nitrogen atom, e.g. guanine
• CPC Class Codes: C07D 473/24 one nitrogen and one sulfur atom
• CPC Class Codes: C07D 473/34 : attached in position 6, e.g. adenine
• 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 application includes novel modulators of TLRs, compositions containing such compounds, therapeutic methods that include the administration of such compounds.

Claims

1. A compound of Formula I:

2. A compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein:

L¹ is —

NH—

or —

O—

;

R¹ is H, alkyl, substituted alkyl, heteroalkyl, substituted heteroalkyl, carbocylyl, substituted carbocyclyl, heterocyclyl, substituted heterocyclyl, carbocyclylalkyl, substituted carbocyclylalkyl, heterocyclylalkyl, or substituted heterocycylalkyl;

X¹ is alkylene, substituted alkylene, heteroalkylene, or substituted heteroalkylene;

D¹ is aryl or heteroaryl;

D² is aryl or heteroaryl;

n is 0, 1, or 2;

each R³ and R⁴ is independently alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, halogen, haloalkyl, haloalkoxy, heteroalkyl, substituted heteroalkyl, ═

O, —

OR⁸, —

SR⁸, —

NR⁹R¹⁰, ═

NR⁸, ═

NOR⁸, ═

NNR⁸R⁹, —

CN, —

OCN, —

SCN, —

N═

C═

O, —

NCS, —

NO, —

NO₂, ═

N₂, —

N₃, —

NR⁸C(═

O)R⁹, —

NR⁸C(═

O)OR⁹, —

NR⁸C(═

O)NR⁹R¹⁰, —

C(═

O)NR⁹R¹⁰, —

C(═

O)OR⁸, —

OC(═

O)NR⁹R¹⁰, —

OC(═

O)OR⁸, —

C(═

O)R⁸, —

S(═

O)₂OR⁸, —

S(═

O)₂R⁸, —

OS(═

O)₂OR⁸, —

S(═

O)₂NR⁹R¹⁰, —

S(═

O)R⁸, —

NR⁸S(═

O)₂R⁹, —

NR⁸S(═

O)₂NR⁹R¹⁰, —

NR⁸S(═

O)₂OR⁹, —

OS(O)₂NR⁹R¹⁰, —

OP(═

O)(OR⁸)₂, —

P(═

O)(OR⁸)₂, —

P(O)(OR⁸)(R⁹), —

P(O)R⁹R¹⁰, —

OP(═

))R⁹R¹⁰, —

C(═

S)R⁸, —

C(═

S)OR⁸, —

C(═

O)SR⁸, —

C(═

S)SR⁸, —

C(═

S)NR⁹R¹⁰, —

C(═

NR⁸)NR⁹R¹⁰, or —

NR⁸C(═

NR⁸)NR⁹R¹⁰;

m is 1 or 2;

L² is alkylene or heteroalkylene;

X² is N or C—

R⁵;

R⁵ is H, halogen, alkyl, substituted alkyl, haloalkyl, heteroalkyl, substituted heteroalkyl, cyano, azido, —

C(O)H, —

C(O)R⁸, —

S(O)R⁸, —

S(O)₂R⁸, —

S(O)₂NR⁸R⁹, —

C(O)OR⁸, or —

C(O)NR⁹R¹⁰;

R² is —

NR⁶R⁷; and

each of R⁸ and R⁷ independently is H, alkyl, substituted alkyl, heteroalkyl, substituted heteroalkyl, carbocyclyl, substituted carbocyclyl, heterocyclyl, substituted heterocyclyl, carbocylylalkyl, substituted carbocyclylalkyl, heterocyclylalkyl, substituted heterocyclylalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, arylalkyl, substituted arylalkyl, heteroarylalkyl, or substituted heteroarylalkyl;

or together with the nitrogen to which they are attached form a substituted or unsubstituted 3 to 8 membered heterocyclyl, which may contain one or more additional heteroatoms selected from N, O, S, or P; and

R⁸, R⁹, and R¹⁰ are each independently H, alkyl, substituted alkyl, haloalkyl, heteroalkyl, substituted heteroalkyl, carbocyclyl, substituted carbocyclyl, carbocyclylalkyl, substituted carbocyclylalkyl, heterocyclyl, substituted heterocyclyl, heterocyclylalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, substituted heterocyclylalkyl, arylalkyl, substituted arylalkyl, heteroarylalkyl, substituted heteroarylalkyl, carbocyclylalkenyl, substituted carbocyclylalkenyl, carbocyclyl alkynyl, substituted carbocyclylalkynyl, heterocyclylalkenyl, substituted heterocyclylalkenyl, heterocyclylalkynyl, substituted heteroalkynyl, arylalkenyl, substituted arylalkenyl, arylalkynyl, substituted arylalkynyl, heteroarylalkenyl, substituted heteroarylalkenyl, heteroarylalkynyl, substituted heteroarylalkynyl, carbocyclylheteroalkyl, substituted carbocyclylheteroalkyl, heterocyclylheteroalkyl, substituted heterocyclylheteroalkyl, arylheteroalkyl, substituted arylheteroalkyl, heteroarylheteroalkyl, or substituted heteroarylheteroalkyl.

3. A compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein:

L¹ is —

NH—

or —

O—

;

R¹ is H, alkyl, substituted alkyl, heteroalkyl, substituted heteroalkyl, carbocylyl, substituted carbocyclyl, heterocyclyl, substituted heterocyclyl, carbocyclylalkyl, substituted carbocyclylalkyl, heterocyclylalkyl, or substituted heterocycylalkyl;

X¹ is alkylene, substituted alkylene, heteroalkylene, or substituted heteroalkylene;

D¹ is aryl or heteroaryl;

D² is aryl or heteroaryl;

n is 0, 1, or 2;

each R³ and R⁴ is independently alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, halogen, haloalkyl, haloalkoxy, heteroalkyl, substituted heteroalkyl, ═

O, —

OR⁸, —

SR⁸, —

NR⁹R¹⁰, ═

NR⁸, ═

NOR⁸, ═

NNR⁸R⁹, —

CN, —

OCN, —

SCN, —

N═

C═

O, —

NCS, —

NO, —

NO₂, ═

N₂, —

N₃, —

NR⁸C(═

O)R⁹, —

NR⁸C(═

O)OR⁹, —

NR⁸C(═

O)NR⁹R¹⁰, —

C(═

O)NR⁹R¹⁰, —

C(═

O)OR⁸, —

OC(═

O)NR⁹R¹⁰, —

OC(═

O)OR⁸, —

C(═

O)R⁸, —

S(═

O)₂OR⁸, —

S(═

O)₂R⁸, —

OS(═

O)₂OR⁸, —

S(═

O)₂NR⁹R¹⁰, —

S(═

O)R⁸, —

NR⁸S(═

O)₂R⁹, —

NR⁸S(═

O)₂NR⁹R¹⁰, —

NR⁸S(═

O)₂OR⁹, —

OS(O)₂NR⁹R¹⁰, —

OP(═

O)(OR⁸)₂, —

P(═

O)(OR⁸)₂, —

P(O)(OR⁸)(R⁹), —

P(O)R⁹R¹⁰, —

OP(═

))R⁹R¹⁰, —

C(═

S)R⁸, —

C(═

S)OR⁸, —

C(═

O)SR⁸, —

C(═

S)SR⁸, —

C(═

S)NR⁹R¹⁰, —

C(═

NR⁸)NR⁹R¹⁰, or —

NR⁸C(═

NR⁸)NR⁹R¹⁰;

m is 1 or 2;

L² is alkylene or heteroalkylene;

X² is N or C—

R⁵;

R⁵ is H, halogen, alkyl, substituted alkyl, haloalkyl, heteroalkyl, substituted heteroalkyl, cyano, azido, —

C(O)H, —

C(O)R⁸, —

S(O)R⁸, —

S(O)₂R⁸, —

S(O)₂NR⁸R⁹, —

C(O)OR⁸, or —

C(O)NR⁹R¹⁰;

R² is —

NR⁶R⁷;

R⁶ and R⁷ together with the nitrogen to which they are attached form a substituted or unsubstituted 3 to 8 membered heterocyclyl, which may contain one or more additional heteroatoms selected from N, O, S, or P; and

R⁸, R⁹, and R¹⁰ are each independently H, alkyl, substituted alkyl, haloalkyl, heteroalkyl, substituted heteroalkyl, carbocyclyl, substituted carbocyclyl, carbocyclylalkyl, substituted carbocyclylalkyl, heterocyclyl, substituted heterocyclyl, heterocyclylalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, substituted heterocyclylalkyl, arylalkyl, substituted arylalkyl, heteroarylalkyl, substituted heteroarylalkyl, carbocyclylalkenyl, substituted carbocyclylalkenyl, carbocyclylalkynyl, substituted carbocyclylalkynyl, heterocyclylalkenyl, substituted heterocyclylalkenyl, heterocyclylalkynyl, substituted heterocyclylalkynyl, arylalkenyl, substituted arylalkenyl, arylalkynyl, substituted arylalkynyl, heteroarylalkenyl, substituted heteroarylalkenyl, heteroarylalkynyl, substituted heteroarylalkynyl, carbocyclylheteroalkyl, substituted carbocyclylheteroalkyl, heterocyclylheteroalkyl, substituted heterocyclytheteroalkyl, arylheteroalkyl, substituted arylheteroalkyl, heteroarylheteroalkyl, or substituted heteroarylheteroalkyl.

4. A compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein:

L¹ is —

NH—

or —

O—

;

R¹ is H, alkyl, substituted alkyl, heteroalkyl, substituted heteroalkyl, carbocylyl, substituted carbocyclyl, heterocyclyl, substituted heterocyclyl, carbocyclylalkyl, substituted carbocyclylalkyl, heterocyclylalkyl, or substituted heterocycylalkyl;

X¹ is alkylene, substituted alkylene, heteroalkylene, or substituted heteroalkylene;

D¹ is aryl or heteroaryl;

D² is aryl or heteroaryl;

n is 0, 1, or 2;

each R³ and R⁴ is independently alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, halogen, haloalkyl, haloalkoxy, heteroalkyl, substituted heteroalkyl, ═

O, —

OR⁸, —

SR⁸, —

NR⁹R¹⁰, ═

NR⁸, ═

NOR⁸, ═

NNR⁸R⁹, —

CN, —

OCN, —

SCN, —

N═

C═

O, —

NCS, —

NO, —

NO₂, ═

N₂, —

N₃, —

NR⁸C(═

O)R⁹, —

NR⁸C(═

O)OR⁹, —

NR⁸C(═

O)NR⁹R¹⁰, —

C(═

O)NR⁹R¹⁰, —

C(═

O)OR⁸, —

OC(═

O)NR⁹R¹⁰, —

OC(═

O)OR⁸, —

C(═

O)R⁸, —

S(═

O)₂OR⁸, —

S(═

O)₂R⁸, —

OS(═

O)₂OR⁸, —

S(═

O)₂NR⁹R¹⁰, —

S(═

O)R⁸, —

NR⁸S(═

O)₂R⁹, —

NR⁸S(═

O)₂NR⁹R¹⁰, —

NR⁸S(═

O)₂OR⁹, —

OS(O)₂NR⁹R¹⁰, —

OP(═

O)(OR⁸)₂, —

P(═

O)(OR⁸)₂, —

P(O)(OR⁸)(R⁹), —

P(O)R⁹R¹⁰, —

OP(═

))R⁹R¹⁰, —

C(═

S)R⁸, —

C(═

S)OR⁸, —

C(═

O)SR⁸, —

C(═

S)SR⁸, —

C(═

S)NR⁹R¹⁰, —

C(═

NR⁸)NR⁹R¹⁰, or —

NR⁸C(═

NR⁸)NR⁹R¹⁰;

m is 1 or 2;

L² is alkylene or heteroalkylene;

X² is N or C—

R⁵;

R⁵ is H, halogen, alkyl, substituted alkyl, haloalkyl, heteroalkyl, substituted heteroalkyl, cyano, azido, —

C(O)H, —

C(O)R⁸, —

S(O)R⁸, —

S(O)₂R⁸, —

S(O)₂NR⁸R⁹, —

C(O)OR⁸, or —

C(O)NR⁹R¹⁰;

R² is —

NR⁶R⁷; and

R⁶ is H, alkyl, substituted alkyl, heteroalkyl, substituted heteroalkyl, carbocyclyl, substituted carbocyclyl, heterocyclyl, substituted heterocyclyl, carbocylylalkyl, substituted carbocyclylalkyl, heterocyclylalkyl, substituted heterocyclylalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, arylalkyl, substituted arylalkyl, heteroarylalkyl, or substituted heteroarylalkyl;

or together with R⁷ and the nitrogen to which they are attached form a substituted or unsubstituted 3 to 8 membered heterocyclyl, which may contain one or more additional heteroatoms selected from N, O, S, or P;

or

R⁷ taken together with D², L², and the N to which both R⁷ and L² are attached forms a substituted or unsubstitued 5 to 15 membered heterocycle or heteroaryl which may contain one or more additional heteroatoms selected from N, O, S, or P; and

R⁸, R⁹, and R¹⁰ are each independently H, alkyl, substituted alkyl, haloalkyl, heteroalkyl, substituted heteroalkyl, carbocyclyl, substituted carbocyclyl, carbocyclylalkyl, substituted carbocyclylalkyl, heterocyclyl, substituted heterocyclyl, heterocyclylalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, substituted heterocyclylalkyl, arylalkyl, substituted arylalkyl, heteroarylalkyl, substituted heteroarylalkyl, carbocyclylalkenyl, substituted carbocyclylalkenyl, carbocyclylalkynyl, substituted carbocyclylalkynyl, heterocyclylalkenyl, substituted heterocyclylalkenyl, heterocyclylalkynyl, substituted heterocyclylalkynyl, arylalkenyl, substituted arylalkenyl, arylalkynyl, substituted arylalkynyl, heteroarylalkenyl, substituted heteroarylalkenyl, heteroarylalkynyl, substituted heteroarylalkynyl, carbocyclylheteroalkyl, substituted carbocyclylheteroalkyl, heterocyclylheteroalkyl, substituted heterocyclylheteroalkyl, arylheteroalkyl, substituted arylheteroalkyl, heteroarylheteroalkyl, or substituted heteroarylheteroalkyl.

5. The compound of claim 1, wherein X² is N.

6. The compound of claim 1, wherein X² is C—

R⁵.

7. The compound of claim 1, wherein L¹ is oxygen.

8. The compound of claim 1, wherein X¹ is alkylene.

9. The compound of claim 1, wherein D¹ is aryl.

10. The compound of claim 9, wherein D¹ is phenyl.

11. The compound of claim 1, wherein D² is aryl.

12. The compound of claim 1, wherein L² is alkylene.

13. A pharmaceutical composition comprising a compound according to claim 1, and one or more pharmaceutically acceptable carrier or excipient.

14. The pharmaceutical composition of claim 13, further comprising one or more additional therapeutic agent.

15. A method for treating a viral infection comprising administering a compound according to claim 1.

16. The method of claim 15, wherein the treatment results in one or more of a reduction in viral load or clearance of viral RNA.

17. A method for treating or preventing melanoma, non-small cell lung carcinoma, hepatocellular carcinoma, basal cell carcinoma, renal cell carcinoma, myeloma, allergic rhinitis, asthma, COPD, ulcerative colitis, hepatic fibrosis, HBV, HCV, HPV, RSV, SARS, HIV, or influenza comprising administering a compound according to claim 1.