Modulators of toll-like receptors

• US 8,367,670 B2
• Filed: 12/07/2009
• Issued: 02/05/2013
• Est. Priority Date: 12/09/2008
• Status: Active Grant

• Current Assignee: Gilead Sciences Inc.
• Original Assignee: Gilead Sciences Inc.
• Inventors: Desai, Manoj C., Halcomb, Randall L., Hrvatin, Paul, Hui, Hon Chung, McFadden, Ryan, Roethle, Paul A., Yang, Hong
• Primary Examiner(s): Kifle, Bruck
• Application Number:
  US12/632,194
• Publication Number:
  US 20100143301A1
• Time in Patent Office: 1,156 Days
• Field of Search: 544/258, 544/259, 514/249
• US Class Current: 514/249
• CPC Class Codes: A61K 31/519 ortho- or peri-condensed with heterocyclic rings
• CPC Class Codes: A61K 31/527 spiro-condensed
• CPC Class Codes: A61K 31/5377 not condensed and containing further heterocyclic rings, e.g. timolol
• CPC Class Codes: A61K 31/551 having two nitrogen atoms, e.g. dilazep
• CPC Class Codes: A61K 31/573 substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
• CPC Class Codes: A61K 31/683 Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols
• CPC Class Codes: A61K 31/7056 containing five-membered rings with nitrogen as a ring hetero atom
• CPC Class Codes: A61K 31/7072 having two oxo groups directly attached to the pyrimidine ring, e.g. uridine, uridylic acid, thymidine, zidovudine
• CPC Class Codes: A61K 31/708 having oxo groups directly attached to the purine ring system, e.g. guanosine, guanylic acid
• CPC Class Codes: A61K 38/16 Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof enzyme inhibitors A61K38/005
• CPC Class Codes: A61K 38/21 Interferons [IFN]
• CPC Class Codes: A61K 38/212 IFN-alpha
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• 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 31/20 : for DNA viruses
• 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: C07D 403/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 475/06 : with a nitrogen atom directly attached in position 4
• CPC Class Codes: C07D 475/08 : with a nitrogen atom directly attached in position 2
• CPC Class Codes: C07D 475/10 : with an aromatic or hetero-aromatic ring directly attached in position 2
• CPC Class Codes: C07D 475/12 : containing pteridine ring systems condensed with carbocyclic rings or ring systems
• CPC Class Codes: C07D 487/04 : Ortho-condensed systems
• 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

Provided are modulators of TLRs of Formula II:

pharmaceutically acceptable salts thereof, compositions containing such compounds, and therapeutic methods that include the administration of such compounds.

Claims

1. A compound of Formula II:

2. The compound of claim 1 wherein L¹ is —

NH—

or —

O—

.

3. The compound of claim 2 wherein X¹ is C₁-C₆ alkylene, C₁-C₆ heteroalkylene or C₁-C₆ substituted heteroalkylene.

4. The compound of claim 3 wherein L¹ is —

O—

.

5. The compound of claim 4 wherein L² is C₁-C₆ alkylene or a covalent bond.

6. The compound of claim 5 wherein X¹ is —

CH₂—

.

7. The compound of claim 6 wherein R⁶ and R⁷ independently are H, alkyl, C₁-C₆ substituted or unsubstituted heteroalkyl containing one or more heteroatoms (selected from N, O, or S), or, together with the nitrogen atom to which they are attached, form a substituted or unsubstituted pyrrolidine, piperidine or piperazine.

8. The compound of claim 7 wherein R⁶ and R⁷ taken together with the nitrogen to which they are attached form a 4- to 10-membered mono- or bicyclic, saturated, partially saturated, or unsaturated ring containing from 0 to 3 additional heteroatoms selected from N, O, or S.

9. The compound of claim 8 wherein L² is —

CH₂—

.

10. The compound of claim 9 wherein Y—

Z is —

CH₂—

.

11. The compound of claim 4 wherein D is pyridinyl.

16. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 and a pharmaceutically acceptable carrier or excipient.

17. The pharmaceutical composition of claim 16 further comprising at least one additional therapeutic agent selected from the group consisting of interferons, ribavirin or its analogs, HCV NS3 protease inhibitors, alpha-glucosidase 1 inhibitors, hepatoprotectants, nucleoside or nucleotide inhibitors of HCV NS5B polymerase, non-nucleoside inhibitors of HCV NS5B polymerase, HCV NS5A inhibitors, TLR-7 agonists, cyclophilin inhibitors, HCV IRES inhibitors, pharmacokinetic enhancers, and other drugs for treating HCV, or mixtures thereof.

18. The pharmaceutical composition of claim 16 further comprising at least one additional therapeutic agent selected from the group consisting of lamivudine, adefovir, tenofovir, telbivudine, entecavir, interferon alpha-21), pegylated interferon alpha-2a, interferon alpha 2a, interferon alpha N1, prednisone, predinisolone, Thymalfasin®

, retinoic acid receptor agonists, 4-methylumbelliferone, Alamifovir®

, Metacavir®

, Albuferon®

, cytokines and agonists of TLRs.

19. A method of treating a viral infection caused by Hepatitis C virus comprising administering to a mammal in need thereof a therapeutically effective amount of a compound of claim 1.

12. A compound represented by Formula Ia:

13. A compound of claim 12 wherein each R⁴ or R⁵ is independently H or CH₃.

14. A compound of claim 12 wherein L¹ is —

O—

.

15. A compound selected from the group consisting of