Modulators of toll-like receptor 7

Abstract

The present invention includes therapeutic methods that include the administration of a compound of Formula I or II: or a pharmaceutically acceptable salt, solvate, and/or ester thereof, to a subject in need of such, and therapeutic methods that include the administration of such compounds with at least one additional active agent.

1 . 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 of a compound of Formula I or II:   
       
         
           
           
               
               
           
         
         wherein:
 X 1  is —NH—, —O—, alkylene, substituted alkylene, alkenylene, substituted alkenylene, alkynylene, substituted alkynylene, carbocyclylene, substituted carbocyclylene, heterocyclylene, or substituted heterocyclylene; 
 D is carbocyclylene or heterocyclylene; 
 each L 1  is independently alkylene or substituted alkylene; 
 each R 1  is independently —NR 4 R 5 ; 
 m is 1 or 2; 
 L 2  is a covalent bond, —NH—, —O—, or —S—; 
 R 2  is H, halo, alkyl, substituted alkyl, alkenyl, substituted alkenyl, carbocyclyl, substituted carbocyclyl, carbocyclylalkyl, substituted carbocyclylalkyl, arylalkyl, substituted arylalkyl, heterocyclylalkyl, substituted heterocyclylalkyl,
 —C(O)R 6 , —C(O)OR 6 , —C(O)NR 7 R 8 , —S(O)OR 7 , —S(O)NR 7 R 8 , —S(O) 2 R 7 , —S(O)R 7 , —S(O) 2 OR 7 , or —S(O) 2 NR 7 R 8 ; 
 
 L 3  is —NH—, —O—, —S—, —N(R 9 )C(O)—, —S(O) 2 —, —S(O)—, or a covalent bond; 
 R 3  is alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, heteroalkyl, substituted heteroalkyl, carbocyclyl, substituted carbocyclyl, carbocyclylalkyl, substituted carbocyclylalkyl, heterocyclyl, substituted heterocyclyl, heterocyclylalkyl, or substituted heterocyclylalkyl; 
 R 4  and R 5  are each independently H, alkyl, substituted alkyl, carbocyclyl, substituted carbocyclyl, carbocyclylalkyl, substituted carbocyclylalkyl, heterocyclyl, substituted heterocyclyl, heterocyclylalkyl, substituted heterocyclylalkyl, —C(O)H, —C(O)R 3 , —S(O)R 3 , —S(O) 2 R 3 , —C(O)OR 3 , or —C(O)NR 7 R 8 ; or 
 R 4  and R 5 , taken together with the nitrogen to which they are both attached, form a substituted or unsubstituted heterocycle; 
 R 6  is alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, heteroalkyl, substituted heteroalkyl, carbocyclyl, substituted carbocyclyl, carbocyclylalkyl, substituted carbocyclylalkyl, heterocyclyl, substituted heterocyclyl, heterocyclylalkyl, or substituted heterocyclylalkyl; 
 R 7  and R 8  are each independently H, alkyl, substituted alkyl, carbocyclyl, substituted carbocyclyl, carbocyclylalkyl, substituted carbocyclylalkyl, heterocyclyl, substituted heterocyclyl, heterocyclylalkyl, or substituted heterocyclylalkyl; or 
 R 7  and R 8 , taken together with the nitrogen to which they are both bonded, form a substituted or unsubstituted heterocycle; 
 R 9  is H, alkyl, substituted alkyl, carbocyclyl, substituted carbocyclyl, carbocyclylalkyl, substituted carbocyclylalkyl, heterocyclyl, substituted heterocyclyl, heterocyclylalkyl, or substituted heterocyclylalkyl; 
 R 10  is halogen, cyano, azido, nitro, alkyl, substituted alkyl, hydroxyl, amino, heteroalkyl, or substituted heteroalkyl; 
 n is an integer from 0 to 5; and 
 with the following provisos: 
 (a) When X 1  is —CH 2 —, D is 1,4-phenylene, R 3 -L 3 - is CHSCH 2 CH 2 CH 2 O— or CH 3 —O—CH 2 CH 2 —O, n=0, m=1, then NR 4 R 5  is not: (1) a 4-substituted or 4,4-disubstituted piperidine or piperazine (2) —NHCH 3 ; 
 (b) When X 1  is —CH 2 —, D is 1,4-phenylene or 1,4-piperidinylene, R 3 -L 3 - is CH 3 CH 2 CH 2 CH 2 O— or CH 3 —O—CH 2 CH 2 —O, n=0, m=1, then neither R 4  nor R 5  are substituted alkyl, substituted heterocycyl, substituted benzyl; and 
 (c) When X 1  is —CH 2 —, D is 2,5-pyridylene, R 3 -L 3 - is CH 3 CH 2 CH 2 CH 2 O— or CH 3 —O—CH 2 CH 2 —O, n=0, m=1, then NR 4 R 5  is not pyrrolyl, piperazyl, N(CH 3 ) 2 , 
 
       
       or a pharmaceutically acceptable salt, solvate, and/or ester thereof. 
     
     
         2 . The method of  claim 1 , 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.   
     
     
         3 . The method of  claim 2 , 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.   
     
     
         4 . 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 Formula I or II:   
       
         
           
           
               
               
           
         
         wherein:
 X 1  is —NH—, —O—, alkylene, substituted alkylene, alkenylene, substituted alkenylene, alkynylene, substituted alkynylene, carbocyclylene, substituted carbocyclylene, heterocyclylene, or substituted heterocyclylene; 
 D is carbocyclylene or heterocyclylene; 
 each L 1  is independently alkylene or substituted alkylene; 
 each R 1  is independently —NR 4 R 5 ; 
 m is 1 or 2; 
 L 2  is a covalent bond, —NH—, —O—, or —S—; 
 R 2  is H, halo, alkyl, substituted alkyl, alkenyl, substituted alkenyl, carbocyclyl, substituted carbocyclyl, carbocyclylalkyl, substituted carbocyclylalkyl, arylalkyl, substituted arylalkyl, heterocyclylalkyl, substituted heterocyclylalkyl,
 —C(O)R 6 , —C(O)OR 6 , —C(O)NR 7 R 8 , —S(O)OR 7 , —S(O)NR 7 R 8 , —S(O) 2 R 7 , —S(O)R 7 , —S(O) 2 OR 7 , or —S(O) 2 NR 7 R 8 ; 
 
 L 3  is —NH—, —O—, —S—, —N(R 9 )C(O)—, —S(O) 2 —, —S(O)—, or a covalent bond; 
 R 3  is alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, heteroalkyl, substituted heteroalkyl, carbocyclyl, substituted carbocyclyl, carbocyclylalkyl, substituted carbocyclylalkyl, heterocyclyl, substituted heterocyclyl, heterocyclylalkyl, or substituted heterocyclylalkyl; 
 R 4  and R 5  are each independently H, alkyl, substituted alkyl, carbocyclyl, substituted carbocyclyl, carbocyclylalkyl, substituted carbocyclylalkyl, heterocyclyl, substituted heterocyclyl, heterocyclylalkyl, substituted heterocyclylalkyl, —C(O)H, —C(O)R 3 , —S(O)R 3 , —S(O) 2 R 3 , —C(O)OR 3 , or —C(O)NR 7 R 8 ; or 
 R 4  and R 5 , taken together with the nitrogen to which they are both attached, form a substituted or unsubstituted heterocycle; 
 R 6  is alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, heteroalkyl, substituted heteroalkyl, carbocyclyl, substituted carbocyclyl, carbocyclylalkyl, substituted carbocyclylalkyl, heterocyclyl, substituted heterocyclyl, heterocyclylalkyl, or substituted heterocyclylalkyl; 
 R 7  and R 8  are each independently H, alkyl, substituted alkyl, carbocyclyl, substituted carbocyclyl, carbocyclylalkyl, substituted carbocyclylalkyl, heterocyclyl, substituted heterocyclyl, heterocyclylalkyl, or substituted heterocyclylalkyl; or 
 R 7  and R 8 , taken together with the nitrogen to which they are both bonded, form a substituted or unsubstituted heterocycle; 
 R 9  is H, alkyl, substituted alkyl, carbocyclyl, substituted carbocyclyl, carbocyclylalkyl, substituted carbocyclylalkyl, heterocyclyl, substituted heterocyclyl, heterocyclylalkyl, or substituted heterocyclylalkyl; 
 R 10  is halogen, cyano, azido, nitro, alkyl, substituted alkyl, hydroxyl, amino, heteroalkyl, or substituted heteroalkyl; 
 n is an integer from 0 to 5; and 
 with the following provisos: 
 (a) When X 1  is —CH 2 —, D is 1,4-phenylene, R 3 -L 3 - is CH 3 CH 2 CH 2 CH 2 O— or CH 3 —O—CH 2 CH 2 —O, n=0, m=1, then NR 4 R 5  is not: (1) a 4-substituted or 4,4-disubstituted piperidine or piperazine (2) —NHCH 3 ; 
 (b) When X 1  is —CH 2 —, D is 1,4-phenylene or 1,4-piperidinylene, R 3 -L 3 - is CH 3 CH 2 CH 2 CH 2 O— or CH 3 —O—CH 2 CH 2 —O, n=0, m=1, then neither R 4  nor R 5  are substituted alkyl, substituted heterocycyl, substituted benzyl; and 
 (c) When X 1  is —CH 2 —, D is 2,5-pyridylene, R 3 -L 3 - is CH 3 CH 2 CH 2 CH 2 O— or CH 3 —O—CH 2 CH 2 —O, n=0, m=1, then NR 4 R 5  is not pyrrolyl, piperazyl, N(CH 3 ) 2 , or a pharmaceutically acceptable salt, solvate, and/or ester thereof.