Modulators of toll-like receptors
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.
1. A compound of Formula II:
or a pharmaceutically acceptable salt or tautomeric enol thereof, wherein:
Y—Z is —CR 4 R 5 —;
L 1 is —NR 8 —, —O—, —N(R 8 )C(O)—, or a covalent bond;
R 1 is alkyl, substituted alkyl, haloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, C 1 -C 6 substituted or unsubstituted heteroalkyl containing one or more heteroatoms (selected from N, O, or S), -cyclopropyl, substituted cyclopropyl, cyclobutyl, substituted cyclobutyl, cyclopentyl, substituted cyclopentyl, cyclohexyl, substituted cyclohexyl, bicyclo[3.1.0]cyclohexyl, tetrahydropyranyl, substituted tetrahydropyranyl, furanyl, substituted furanyl, pyrrolidinyl, or substituted pyrrolidinyl;
X 1 is alkylene, substituted alkylene, heteroalkylene, substituted heteroalkylene, or a bond;
D is phenylene, biphenylene, or pyridinyl, wherein said phenylene, biphenylene, or pyridinyl is substituted with one or two -L 2 -NR 6 R 7 ;
each L 2 is independently alkylene, substituted alkylene, heteroalkylene, substituted heteroalkylene, or a covalent bond;
each R 3 is independently halogen, cyano, azido, nitro, alkyl, substituted alkyl, hydroxyl, amino, alkoxy, haloalkyl, haloalkoxy, —CHO, —C(O)OR 8 , —S(O)R 8 , —S(O) 2 R 8 ; —C(O)NR 9 R 10 , —N(R 9 )C(O)R 8 , alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, —S(O) 2 NR 9 R 10 , —N(R 9 )S(O) 2 R 8 , —N(R 9 )S(O) 2 OR 10 , or —OS(O) 2 NR 9 R 10 ;
n is 0, 1, 2, 3, 4 or 5;
R 4 and R 5 taken together with the carbon to which they are attached is —C(O)—;
R 6 and R 7 are each independently H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, haloalkyl, C 1 -C 6 substituted or unsubstituted heteroalkyl containing one or more heteroatoms (selected from N, O, or S), C(O)H, —C(O)R 8 , —S(O)R 8 , —S(O) 2 R 8 , —C(O)OR 8 , or —C(O)NR 9 R 10 , S(O) 2 NR 9 R 10 ; or
R 6 and R 7 , taken together with the nitrogen to which they are both attached, form a substituted or unsubstituted heterocycle, which may contain one or more additional heteroatoms selected from N, O, P, or S; or
R 7 taken together with L 2 , and the N to which they are both attached, forms a substituted or unsubstituted 3 to 8 membered heterocycle which may contain one or more additional heteroatoms selected from N, O, S, or P;
R 8 is H, alkyl, substituted alkyl, haloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, or C 1 -C 6 substituted or unsubstituted heteroalkyl containing one or more heteroatoms (selected from N, O, or S); and
R 9 and R 10 are each independently H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, haloalkyl, C 1 -C 6 substituted or unsubstituted heteroalkyl containing one or more heteroatoms (selected from N, O, or S);
wherein each substituted alkyl, substituted alkenyl, substituted alkynyl, substituted cyclopropyl, substituted cyclobutyl, substituted cyclopentyl, substituted cyclohexyl, substituted tetrahydropyranyl, substituted furanyl, or substituted pyrrolidinyl, substituted alkylene, substituted heteroalkylene, substituted alkenylene, substituted alkynylene is independently substituted with one to four substituents selected from the group consisting of -halogen, —R, —O − , ═OR, —SR, —S − , —NR 2 , —N(+)R 3 , ═NR, —C(halogen) 3 , —CR(halogen) 2 , —CR 2 (halogen), —CN, —OCN, —SCN, —N═C═O, —NCS, —NO, —NO 2 , ═N 2 , —N 3 , —NRC(═O)R, —NRC(═O)OR, —NRC(═O)NRR, —C(═O)NRR, —C(═O)OR, —OC(═O)NRR, —OC(═O)OR, —C(═O)R, —S(═O) 2 OR, —S(═O) 2 R, —OS(═O) 2 OR, —S(═O) 2 NR, —S(═O)R, —NRS(═O) 2 R, —NRS(═O) 2 NRR, —NRS(═O) 2 OR, —OP(═O)(OR) 2 , —P(═O)(OR) 2 , —P(O)(OR)(O)R, —C(═O)R, —C(═S)R, —C(═O)OR, —C(═S)OR, —C(═O)SR, —C(═S)SR, —C(═O)NRR, —C(═S)NRR, —C(═NR)NRR, and —NRC(═NR)NRR; wherein each R is independently H or alkyl.
2. The compound of claim 1 wherein L 1 is —NH— or —O—.
3. The compound of claim 2 wherein X 1 is C 1 -C 6 alkylene, C 1 -C 6 heteroalkylene or C 1 -C 6 substituted heteroalkylene.
4. The compound of claim 3 wherein L 1 is —O—.
5. The compound of claim 4 wherein L 2 is C 1 -C 6 alkylene or a covalent bond.
6. The compound of claim 5 wherein X 1 is —CH 2 —.
7. The compound of claim 6 wherein R 6 and R 7 independently are H, alkyl, C 1 -C 6 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 R 6 and R 7 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 L 2 is —CH 2 —.
10. The compound of claim 4 wherein D is pyridinyl.
11. The compound of claim 9 wherein D is optionally substituted pyridinyl, optionally substituted piperidinyl, optionally substituted piperazinyl or optionally substituted 1,2,3,4-tetrahydroisoquinolinyl.
12. A compound represented by Formula Ia:
or a pharmaceutically acceptable salt or tautomeric enols thereof, wherein:
L 1 is —NH— or —O—;
R 1 is alkyl, substituted alkyl, C 1 -C 6 substituted or unsubstituted heteroalkyl containing one or more heteroatoms (selected from N, O, or S), cyclopropyl, substituted cyclopropyl, cyclobutyl, substituted cyclobutyl, cyclopentyl, substituted cyclopentyl, cyclohexyl, substituted cyclohexyl, bicyclo[3.1.0]cyclohexyl, tetrahydropyranyl, substituted tetrahydropyranyl, furanyl, substituted furanyl, pyrrolidinyl, or substituted pyrrolidinyl;
R 4 and R 5 taken together with the carbon to which they are attached is —C(O)—;
X 1 is C 1 -C 6 alkylene, C 1 -C 6 heteroalkylene or C 1 -C 6 substituted heteroalkylene;
D is phenyl, biphenyl or pyridinyl, wherein said phenyl, biphenyl or pyridinyl is substituted with -L 2 -NR 6 R 7 ; or
D is pyridinyl, piperidinyl, piperazinyl or 1,2,3,4-tetrahydroisoquinolinyl, wherein said pyridinyl, piperidinyl, piperazinyl or 1,2,3,4-tetrahydroisoquinolinyl is substituted with one or two -L 2 -NR 6 R 7 ; or
D is pyridinyl, piperidinyl, piperazinyl or 1,2,3,4-tetrahydroisoquinolinyl;
n is 0 or 1;
R 3 is halogen, cyano, alkyl, haloalkyl, —C(O)OR 8 , —C(O)NR 9 R 10 or —CHO;
L 2 is C 1 -C 6 alkylene or a covalent bond;
each of R 6 and R 7 independently is H, or alkyl; or
R 6 and R 7 taken together with the nitrogen to which they are attached form a substituted or unsubstituted 4-6 membered heterocycle comprising 0 to 2 heteroatoms selected from N, O or S.
13. A compound of claim 12 wherein L 1 is —O—.
14. A compound selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
15. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 and a pharmaceutically acceptable carrier or excipient.
16. The pharmaceutical composition of claim 15 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.
17. 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-2b, 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.
18. A method for treating a Hepatitis C viral infection comprising administering to a human subject infected with Hepatitis C virus a therapeutically effective amount of a compound of claim 1 .
19. The method of claim 18 further comprising administering 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.