Modulators of toll-like receptor 7

• US 20090047249A1
• Filed: 06/26/2008
• Published: 02/19/2009
• Est. Priority Date: 06/29/2007
• Status: Active Grant

• Current Assignee: Gilead Sciences Inc.
• Original Assignee: Gilead Sciences Inc.
• Inventors: Graupe, Micheal, Halcomb, Randall L.
• Granted Patent: US 7,968,544 B2
• Time in Patent Office: Days
• US Class Current: 424/85.600
• 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: A61K 31/55 having seven-membered rings, e.g. azelastine, pentylenetetrazole
• CPC Class Codes: A61K 31/551 having two nitrogen atoms, e.g. dilazep
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• 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 31/20 for DNA viruses
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 473/18 one oxygen and one nitrogen atom, e.g. guanine
• 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 a compound of Formula I or II:

or a pharmaceutically acceptable-salt, solvate, and/or ester thereof, compositions containing such compounds, therapeutic methods that include the administration of such compounds, and therapeutic methods that include the administration of such compounds with at least one additional active agent.

Claims

1. A compound of Formula I or II:

2. The compound of claim 1, wherein:

X¹ is alkylene or substituted alkylene;

wherein the substituted alkylene comprises an alkylene substituted with one or more substituents selected from the group consisting of halo, hydroxyl, amino, heteroalkyl, substituted heteroalkyl, cyano, azido, nitro, alkyl, substituted alkyl, and combinations thereof.

3. The compound of claim 1, wherein:

m is 1;

D is D is arylene or heteroarylene;

L²-R¹ of Formula I is —

OH;

R¹ is —

NR⁴R⁵; and

R⁴ and R⁵, taken together with the nitrogen to which they are both attached, form a substituted or unsubstituted heterocycle;

wherein the heterocycle is a 4- to 6-membered monocyclic fully saturated or partially unsaturated ring containing at least one hetero atom selected from N, O, and S;

or a 10- to 12-membered fused bicyclic fully saturated or partially unsaturated ring containing at least one hetero atom selected from N, O, and S.

4. The compound of claim 3, wherein:

-L³-R³ is —

O-alkyl or —

O-alkylene-O-alkyl.

5. The compound of claim 1, wherein Formula I is represented by Formula Ia:

6. The compound of claim 5, wherein:

R¹ is NR⁴R⁵; and

R⁴ and R⁵, taken together with the nitrogen to which they are both attached, form a substituted or unsubstituted heterocycle;

wherein the heterocycle is a 4- to 6-membered monocyclic fully saturated, partially unsaturated, or heteraryl ring containing at least one hetero atom selected from N, O, and S;

or a 10- to 12-membered fused bicyclic fully saturated or partially unsaturated ring containing at least one hetero atom selected from N, O, and S.

7. The compound of claim 6, wherein the heterocycle is selected from the group consisting of:

8. The compound of claim 5, wherein:

R¹ is NR⁴R⁵;

R⁴ is H, alkyl, substituted alkyl, carbocyclylalkyl, or substituted carbocyclylalkyl; and

R⁵ is alkyl, substituted alkyl, carbocyclyl, substituted carbocyclyl, carbocyclylalkyl, substituted carbocyclylalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclylalkyl, substituted heterocyclylalkyl, —

C(O)H, —

C(O)R³, —

C(O)OR³, or —

C(O)NR⁷R⁸.

9. The compound of claim 5, wherein:

R² is H, —

C(O)R⁶, —

C(O)OR⁶—

C(O)NR⁷R⁸, —

S(O)OR⁷, —

S(O)NR⁷R⁸, —

S(O)₂OR⁷, or —

S(O)₂NR⁷R⁸.

10. The compound of claim 5, wherein:

-L³-R³ is —

O-alkyl, —

O-(substituted alkyl), —

O-carbocyclyl, —

O-heterocyclyl, —

O-carbocyclylalkyl, —

O-heterocyclylalkyl, or —

O-alkylene-O-alkyl; and

R² is H.

11. The compound of claim 10, wherein R¹ is NR⁴R⁵ and R⁴ and R⁵, taken together with the nitrogen to which they are both attached, form a heterocycle selected from the group consisting of:

12. The compound of claim 10, wherein R¹ is NR⁴R⁵ and R⁴ and R⁵, taken together with the nitrogen to which they are both attached, form a heterocycle selected from the group consisting of:

13. The compound of claim 5, wherein:

R¹ is —

NR⁴R⁵;

R² is H, —

C(O)R⁶, —

C(O)OR⁶, —

C(O)NR⁷R⁸, —

S(O)₂OR⁷, or —

S(O)₂NR⁷R⁸;

L³ is —

O—

;

R³ is alkyl, substituted alkyl, heteroalkyl, substituted heteroalkyl, carbocyclyl, heterocyclyl, carbocyclylalkyl, heterocyclylalkyl; and

R⁴ and R⁵ are each independently H, alkyl, substituted alkyl, carbocyclyl, substituted carbocyclyl, carbocyclylalkyl, substituted carbocyclylalkyl, heterocyclyl, substituted heterocyclyl, heterocyclylalkyl, substituted heterocyclylalkyl, —

C(O)H, —

C(O)R³, —

S(O)R³, —

S(O)₂R³, —

C(O)OR³, or —

C(O)NR⁷R⁸;

or

R⁴ and R⁵, taken together with the nitrogen to which they are both attached, form a substituted or unsubstituted heterocycle.

14. The compound of claim 5, wherein -L³-R³ is —

OCH₂CH₂OCH₃, —

OCH₂CH₂CH₃, —

OCH₂CH₂CH₂CH₃, —

O-1-butyl, —

O-cyclobutyl, —

O-cyclopentyl, —

OCH₂-cyclopropyl, —

OCH₂-cyclobutyl, —

OCH₂CH₂-cyclopropyl, —

OCH₂CH₂CH₂CH₂OH, —

OCH₂CF₃, —

OCH₂CH₂CF₃, —

OCH₂CH₂CH₂CF₃, or (tetrahydrofuran-2-yl)methoxy; and

R² is H.

15. The compound of claim 14, wherein R¹ is NR⁴R⁵ and R⁴ and R⁵, taken together with the nitrogen to which they are both attached, form a heterocycle selected from the group consisting of:

16. The compound of claim 14, wherein R¹ is NR⁴R⁵ and R⁴ and R⁵, taken together with the nitrogen to which they are both attached, form a heterocycle selected from the group consisting of:

17. The compound of claim 16 wherein -L³-R³ is —

OCH₂CH₂CH₂CH₃, —

OCH₂CH₂OCH₃, —

OCH₂CH₂CF₃, —

OCH₂CH₂CH₂CH₂OH, or —

OCH₂-cyclopropyl.

18. The compound of claim 1, wherein Formula II is represented by Formula IIa:

19. The compound of claim 18, wherein:

R¹ is NR⁴R⁵; and

R⁴ and R⁵, taken together with the nitrogen to which they are both attached, form a substituted or unsubstituted heterocycle;

wherein the heterocycle is a 4- to 6-membered monocyclic fully saturated or partially unsaturated ring containing at least one hetero atom selected from N, O, and S;

or a 10- to 12-membered fused bicyclic fully saturated or partially unsaturated ring containing at least one hetero atom selected from N, O, and S.

20. The compound of claim 19, wherein the heterocycle is selected from the group consisting of:

21. The compound of claim 18, wherein:

R¹ is NR⁴R⁵;

R⁴ is H, alkyl, substituted alkyl, carbocyclylalkyl, substituted carbocyclylalkyl; and

R⁵ is carbocyclyl, substituted carbocyclyl, carbocyclylalkyl, substituted carbocyclylalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclylalkyl, substituted heterocyclylalkyl, —

C(O)H, —

C(O)R³, —

C(O)OR³, or —

C(O)NR⁷R⁸.

22. The compound of claim 18, wherein:

R² is alkyl, substituted alkyl, alkenyl, substituted alkenyl, carbocyclyl, substituted carbocyclyl, carbocyclylalkyl, substituted carbocyclylalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heterocyclylalkyl, or substituted heterocyclylalkyl.

23. The compound of claim 22, wherein:

-L³-R³ is —

O-alkyl or —

O-alkylene-O-alkyl.

24. The compound of claim 18, wherein:

R¹ is —

NR⁴R⁵;

R² is alkyl, substituted alkyl, alkenyl, substituted alkenyl, cyclylalkyl, substituted cyclylalkyl, cyclylalkylalkyl, substituted cyclylalkylalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heterocyclylalkyl or substituted heterocyclylalkyl;

L³ is —

O—

;

R³ is alkyl, substituted alkyl, heteroalkyl, substituted heteroalkyl; and

R⁴ and R⁵, taken together with the nitrogen to which they are both attached, form a substituted or unsubstituted heterocycle.

25. The compound of claim 1, wherein

L² is a covalent bond;

and R² is H or halo.

26. The compound of claim 1 selected from the group consisting of:

31. The compound of claim 1 selected from the group consisting of:

32. A pharmaceutical composition comprising:

at least one compound of claim 1, or a pharmaceutically acceptable salt, solvate, and/or ester thereof; and

a pharmaceutically acceptable carrier or excipient.

33. The pharmaceutical composition of claim 32, further comprising:

at least one additional active agent.

34. The pharmaceutical composition of claim 33, wherein:

the at least one additional active agent is 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, cyclophillin inhibitors, HCV IRES inhibitors, pharmacokinetic enhancers, and other drugs for treating HCV, or mixtures thereof.

35. The pharmaceutical composition of claim 34, wherein the at least one additional active agent is selected from the group consisting of:

(1) interferons selected from the group consisting of pegylated rIFN-alpha 2b, (PEG-Intron), pegylated rIFN-alpha-2a (Pegasys), rIFN-alpha 2b (Intron A), rIFN-alpha 2a (Roferon-A), interferon alpha (MOR-22, OPC-18, Alfaferone, Alfanative, Multiferon, subalin), interferon alfacon-1 (Infergen), interferon alpha-n1 (Wellferon), interferon alpha-n3 (Alferon), interferon-beta (Avonex, DL-8234), interferon-omega (omega DUROS, Biomed

     510), albinterferon alpha-2b (Albuferon), IFN alpha-2b XL, BLX-883 (Locteron), DA-3021, glycosylated interferon alpha-2b (AVI-005), PEG-Infergen, PEGylated interferon lambda-1 (PEGylated IL-29), belerofon, and mixtures thereof;

(2) ribavirin and its analogs selected from the group consisting of ribavirin (Rebetol, Copegus), taribavirin (Viramidine), and mixtures thereof;

(3) HCV NS3 protease inhibitors selected from the group consisting of boceprevir (SCH-503034, SCH-7), telaprevir (VX-950), TMC435350, BI-1335, BI-1230, MK-7009, VBY-376, VX-500, BMS-790052, BMS-605339, PHX-1766, AS-101, YH-5258, YH5530, YH5531, ITMN-191, and mixtures thereof;

(4) alpha-glucosidase 1 inhibitors selected from the group consisting of celgosivir (MX-3253), Miglitol, UT-231B, and mixtures thereof;

(5) hepatoprotectants selected from the group consisting of IDN-6556, ME 3738, LB-84451, silibilin, MitoQ, and mixtures thereof;

(6) nucleoside or nucleotide inhibitors of HCV NS5B polymerase selected from the group consisting of R1626, R7128 (R4048), IDX184, IDX-102, BCX-4678, valopicitabine (NM-283), MK-0608, and mixtures thereof;

(7) non-nucleoside inhibitors of HCV NS5B polymerase selected from the group consisting of PF-868554, VCH-759, VCH-916, JTK-652, MK-3281, VBY-708, VCH-222, A848837, ANA-598, GL60667, GL59728, A-63890, A-48773, A-48547, BC-2329, VCH-796 (nesbuvir), GSK625433, BILN-1941, XTL-2125, GS-9190, and mixtures thereof;

(8) HCV NS5A inhibitors selected from the group consisting of AZD-2836 (A-831), A-689, and mixtures thereof;

(9) TLR-7 agonists selected from the group consisting of ANA-975, SM-360320, and mixtures thereof;

(10) cyclophillin inhibitors selected from the group consisting of DEBIO-025, SCY-635, NIM811, and mixtures thereof;

(11) HCV IRES inhibitors selected from the group consisting of MCI-067,

(12) pharmacokinetic enhancers selected from the group consisting of BAS-100, SPI-452, PF-4194477, TMC-41629, roxythromycin, and mixtures thereof; and

(13) other drugs for treating HCV selected from the group consisting of thymosin alpha 1 (Zadaxin), nitazoxanide (Alinea, NTZ), BIVN-401 (virostat), PYN-17 (altirex), KPE02003002, actilon (CPG-10101), KRN-7000, civacir, GI-5005, XTL-6865, BIT225, PTX-111, ITX2865, TT-033i, ANA 971, NOV-205, tarvacin, EHC-18, VGX-410C, EMZ-702, AVI 4065, BMS-650032, BMS-791325, Bavituximab, MDX-1106 (ONO-4538), Oglufanide, VX-497 (merimepodib), and mixtures thereof.

36. A method for treating or preventing a viral infection comprising:

administering, to a patient in need thereof, a therapeutically effective amount of at least one compound of claim 1, or a pharmaceutically acceptable salt, solvate, and/or ester thereof.

37. The method of claim 36, further comprising:

co-administering at least one additional active 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, cyclophillin inhibitors, HCV IRES inhibitors, pharmacokinetic enhancers, and other drugs for treating HCV, or mixtures thereof.

38. The method of claim 37, wherein the at least one additional active agent is selected from the group consisting of:

(1) interferons selected from the group consisting of pegylated rIFN-alpha 2b (PEG-Intron), pegylated rIFN-alpha 2a (Pegasys), rIFN-alpha 2b (Intron A), rIFN-alpha 2a (Roferon-A), interferon alpha (MOR-22, OPC-18, Alfaferone, Alfanative, Multiferon, subalin), interferon alfacon-1 (Infergen), interferon alpha-n1 (Wellferon), interferon alpha-n3 (Alferon), interferon-beta (Avonex, DL-8234), interferon-omega (omega DUROS, Biomed

     510), albinterferon alpha-2b (Albuferon), IFN alpha-2b XL, BLX-883 (Locteron), DA-3021, glycosylated interferon alpha-2b (AVI-005), PEG-Infergen, PEGylated interferon lambda-1 (PEGylated IL-29), belerofon, and mixtures thereof;

(2) ribavirin and its analogs selected from the group consisting of ribavirin (Rebetol, Copegus), taribavirin (Viramidine), and mixtures thereof;

(3) HCV NS3 protease inhibitors selected from the group consisting of boceprevir (SCH-503034, SCH-7), telaprevir (VX-950), TMC435350, BI-1335, BI-1230, MK-7009, VBY-376, VX-500, BMS-790052, BMS-605339, PHX-1766, AS-101, YH-5258, YH5530, YH5531, ITMN-191, and mixtures thereof;

(4) alpha-glucosidase 1 inhibitors selected from the group consisting of celgosivir (MX-3253), Miglitol, UT-231B, and mixtures thereof;

(5) hepatoprotectants selected from the group consisting of IDN-6556, ME 3738, LB-84451, silibilin, MitoQ, and mixtures thereof;

(6) nucleoside or nucleotide inhibitors of HCV NS5B polymerase selected from the group consisting of R1626, R7128 (R4048), IDX184, IDX-102, BCX-4678, valopicitabine (NM-283), MK-0608, and mixtures thereof;

(7) non-nucleoside inhibitors of HCV NS5B polymerase selected from the group consisting of PF-868554, VCH-759, VCH-916, JTK-652, MK-3281, VBY-708, VCH-222, A848837, ANA-598, GL60667, GL59728, A-63890, A-48773, A-48547, BC-2329, VCH-796 (nesbuvir), GSK625433, BILN-1941, XTL-2125, GS-9190, and mixtures thereof;

(8) HCV NS5A inhibitors selected from the group consisting of AZD-2836 (A-831), A-689, and mixtures thereof;

(9) TLR-7 agonists selected from the group consisting of ANA-975, SM-360320, and mixtures thereof;

(10) cyclophillin inhibitors selected from the group consisting of DEBIO-025, SCY-635, NIM811, and mixtures thereof;

(11) HCV IRES inhibitors selected from the group consisting of MCI-067,

(12) pharmacokinetic enhancers selected from the group consisting of BAS-100, SPI-452, PF-4194477, TMC-41629, roxythromycin, and mixtures thereof; and

(13) other drugs for treating HCV selected from the group consisting of thymosin alpha 1 (Zadaxin), nitazoxanide (Alinea, NTZ), BIVN-401 (virostat), PYN-17 (altirex), KPE02003002, actilon (CPG-10101), KRN-7000, civacir, GI-5005, XTL-6865, BIT225, PTX-111, ITX2865, TT-033i, ANA 971, NOV-205, tarvacin, EHC-18, VGX-410C, EMZ-702, AVI 4065, BMS-650032, BMS-791325, Bavituximab, MDX-1106 (ONO-4538), Oglufanide, VX-497 (merimepodib), and mixtures thereof.

39. A method of agonizing toll-like receptor 7, comprising:

contacting a cell having a toll-like receptor 7 with an effective amount of a compound of claim 1, or a pharmaceutically acceptable salt, solvate, and/or ester thereof.

40. A combination pharmaceutical agent comprising:

a) a first pharmaceutical composition comprising a compound of any of claim 1, or a pharmaceutically acceptable salt, solvate, or ester thereof; and

b) a second pharmaceutical composition comprising at least one additional active 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, cyclophillin inhibitors, HCV IRES inhibitors, pharmacokinetic enhancers, and other drugs for treating HCV, or mixtures thereof.

27. A compound of Formula Ia:

28. The compound of claim 27 wherein -L³-R³ is —

OCH₂CH₂CH₂CH₃, —

OCH₂CH₂OCH₃, —

OCH₂CH₂CF₃, —

OCH₂CH₂CH₂CH₂OH, or —

OCH₂-cyclopropyl.

29. The compound of claim 28 wherein -L³-R³ is —

OCH₂CH₂CH₂CH₃.

30. The compound of claim 29 wherein R⁴ and R⁵, taken together with the nitrogen to which they are both attached form a heterocycle selected from the group consisting of: