NOVEL PHARMACEUTICALS

Abstract

The present invention relates to immune response modifiers of formula (I), which act selectively through agonism, of Toll-Like Receptors (TLRs), uses thereof, processes for the preparation thereof, intermediates used in the preparation thereof and compositions containing said inhibitors. These inhibitors have utility in a variety of therapeutic areas including the treatment of infectious disease such as Hepatitis (e.g. HCV, HBV), genetically related viral infection and cancer.

Description

Claims

1. A compound of formula (I)

2. A compound according to claim 1 wherein R1 is selected from: (a) H;(b) CN;(c) halo(d) (C1-C6)alkyl optionally substituted by one to three halo atoms;(e) tetrahydrofuranoxy;(f) (C1-C6)alkyl substituted by a 3 to 6 membered saturated heterocycyl containing 1 to 3 hetero atoms independently selected from N, O and S wherein said heterocyclyl is optionally substituted by one to three groups independently selected from CF3, (C1-C6)alkyl, (C1-C6)alkoxy and —(C1-C6)alkylene-O—(C1-C6)alkyl;(g) —(C1-C4)alkylene-O—(C1-C6)alkyl;(h) —(C1-C4)alkylene-N(H)—(C1-C4)alkylene-O—(C1-C4)alkyl;(i) (C1-C6)alkoxy optionally substituted by OH or cyclopropyl;(j) (C3-C7)cycloalkyl;(k) —(C1-C4)alkylene(C3-C7)cycloalkyl;(l) —C(O)NR6R7;(m) —CO2R6;(n) —C(O)R6;(o) a 5 membered aromatic heterocyclyl comprising (i) 1 to 4 nitrogen atoms, or (ii) 1 to 2 nitrogen atoms and 1 oxygen or sulphur atom, or (iii) 1 oxygen or sulphur atom; or a 6-membered aromatic heterocyclyl comprising 1 to 3 nitrogen atoms, said 5 and 6 membered aromatic heterocyclyl being optionally substituted by one to three atoms or groups independently selected from halo, OH, CF3, (C1-C6)alkyl, (C1-C6)alkoxy, —(C1-C6)alkylene-O—(C1-C6)alkyl, —(C1-C6)alkylene-OH , —NR11R12 and —(C1-C6)alkylene-NR11R12;(p) phenyl optionally substituted by 1 to 3 halo atoms;(q) —NR6R7; and(r) —NH—(C1-C4)alkylene-O—(C1-C6)alkyl; ora pharmaceutically acceptable salt or solvate thereof, wherein R6, R7, R11 and R12 are as defined in claim 1.

3. A compound according to claim 1, wherein R1 is selected from methyl or ethyl substituted by one to three fluoro atoms; cyclopropyl; —(C1-C2)alkylene-O—(C1-C2)alkyl; (C1-C4)alkoxy optionally substituted by OH or cyclopropyl; —COCH3; —CH2OCH3; and —CO2CH3; or a pharmaceutically acceptable salt or solvate thereof.

4. A compound according to claim 1, wherein R1 is cyclopropyl or CF3, or a pharmaceutically acceptable salt or solvate thereof.

5. A compound according to claim 1, wherein R1 is a 5 membered aromatic heterocyclyl comprising (i) 1 to 4 nitrogen atoms, or (ii) 1 to 2 nitrogen atoms and 1 oxygen or sulphur atom, or (iii) 1 oxygen or sulphur atom, said 5 membered aromatic heterocyclyl being optionally substituted by one to three atoms or groups independently selected from halo, OH, CF3, (C1-C6)alkyl, (C1-C6)alkoxy, —(C1-C3)alkylene-O—(C1-C4)alkyl, —(C1-C4)alkylene-OH, —NR11R12 and —(C1-C3)alkylene-NR11R12, or a pharmaceutically acceptable salt or solvate thereof, wherein R11 and R12 are as defined in claim 1.

6. A compound according to claim 5, wherein R1 is selected from imadazolyl, oxazolyl, oxadiazolyl, triazole, pyrazole and thiazole, all of which are optionally substituted by by one to three atoms or groups independently selected from halo, OH, CF3, (C1-C6)alkyl, (C1-C6)alkoxy, —(C1-C3)alkylene-O—(C1-C4)alkyl, —(C1-C4)alkylene-OH and —(C1-C3)alkylene-NR11R12, or a pharmaceutically acceptable salt or solvate thereof, wherein R11 and R12 are as defined in claim 1.

7. A compound according to claim 6, wherein R1 is selected from unsubstituted oxazolyl, triazole, pyrazole and thiazole, or a pharmaceutically acceptable salt or solvate thereof.

8. A compound according to claim 1, wherein R2 is selected from: (a) H;(b) halo;(c) (C1-C6)alkyl optionally substituted by one to three halo atoms;(d) tetrahydrofuranoxy;(e) (C1-C6)alkyl substituted by a 3 to 6 membered saturated heterocycyl containing 1 to 3 hetero atoms independently selected from N, O and S wherein said heterocyclyl is optionally substituted by one to three groups independently selected from CF3, (C1-C6)alkyl, (C1-C6)alkoxy and —(C1-C6)alkylene-O—(C1-C6)alkyl;(f) —(C1-C4)alkylene-O—(C1-C6)alkyl;(g) —(C1-C4)alkylene-N(H)—(C1-C4)alkylene-O—(C1-C4)alkyl;(h) (C1-C6)alkoxy optionally substituted by OH or cyclopropyl;(i) (C3-C7)cycloalkyl;(j) —(C1-C4)alkylene(C3-C7)cycloalkyl;(k) —C(O)NR 6R7;(l) —CO2R6;(m) —C(O)R6;(n) a 5 membered aromatic heterocyclyl comprising (i) 1 to 4 nitrogen atoms, or (ii) 1 to 2 nitrogen atoms and 1 oxygen or sulphur atom, or (iii) 1 oxygen or sulphur atom; or a 6-membered aromatic heterocyclyl comprising 1 to 3 nitrogen atoms, said 5 and 6 membered aromatic heterocyclyl being optionally substituted by one to three atoms or groups independently selected from halo, OH, CF3, (C1-C6)alkyl, (C1-C6)alkoxy, —(C1-C6)alkylene-O—(C1-C6)alkyl, —(C1-C6)alkylene-OH, —NR11R12 and —(C1-C6)alkylene-NR11R12;(o) phenyl optionally substituted by 1 to 3 halo atoms;(p) —NR6R7; and(q) —NH—(C1-C4)alkylene-O—(C1-C6)alkyl; ora pharmaceutically acceptable salt or solvate thereof, wherein R6, R7, R11 and R12 are as defined in claim 1.

9. A compound according to claim 1, wherein R2 is H or methyl, or a pharmaceutically acceptable salt or solvate thereof.

10. A compound according to claim 1, wherein R2 is H, or a pharmaceutically acceptable salt or solvate thereof.

11. A compound according to claim 1, wherein Y is methylene; and R3 is selected from aryl; a 5 membered aromatic heterocyclyl comprising (i) 1 to 4 nitrogen atoms, or (ii) 1 to 2 nitrogen atoms and 1 oxygen or sulphur atom, or (iii) 1 oxygen or sulphur atom; and a 6-membered aromatic heterocyclyl comprising 1 to 3 nitrogen atoms; said aryl and aromatic heterocycle being optionally substituted by one to three atoms or groups independently selected from halo, OH, oxo, CF3, CN, (C1-C6)alkyl, (C3-C7)cycloalkyl, (C1-C6)alkoxy, —(C1-C6)alkylene-O—(C1-C6)alkyl, —(C1-C6)alkylene-OH, —NR11R12, —(C1-C6)alkylene-NR11R12, aryl and 3 to 10-membered heterocyclyl, or a pharmaceutically acceptable salt or solvate thereof, wherein R11 and R12 are as defined in claim 1.

12. A compound according to claim 1, wherein Y is methylene; and R3 is selected from phenyl, pyridyl, pyrimidyl, pyridizinyl and pyrazinyl, each of which are optionally substituted by one to three atoms or groups independently selected from halo, (C1-4)alkyl, (C1-C4)alkoxy and CF3, or a pharmaceutically acceptable salt or solvate thereof.

13. A compound according to claim 1, wherein Y is methylene; and R3 is selected from phenyl, pyridin-3-yl and 6-methyl-pyridin-3-yl, or a pharmaceutically acceptable salt or solvate thereof.

14. A compound according to claim 1, wherein R5 is absent; and R4 is selected from —(C1-C6)alkylene-O—C(O)R9, —(C1-C6)alkylene-O—CO2R9, —(C1-C6)alkylene-O—C(O)NR9R10 and —(C1-C6)alkylene-O—P(O)(OH)2, or a pharmaceutically acceptable salt or solvate thereof, wherein R9and R10 are as defined in claim 1.

15. A compound according to claim 1, wherein R4 is H and R5 is absent, or a pharmaceutically acceptable salt or solvate thereof.

16. A compound according to claim 1, wherein R4 is absent; and R5 is selected from —(C1-C6)alkylene-O—C(O)R9, —(C1-C6)alkylene-O—CO2R9), —(C1-C6)alkylene-O—C(O)NR9R10 and —(C1-C6)alkylene-O—P(O)(OH)2, or a pharmaceutically acceptable salt or solvate thereof, wherein R9 and R10 are as defined in claim 1.

17. A compound according to claim 1 wherein: Y is methylene;R1 is selected from CF3, cyclopropyl, and oxazole;R2 is H;R3 is selected from phenyl, pyridin-3-yl and 6-methyl-pyridin-3-yl.R4 is H; andR5 is absent; oror a pharmaceutically acceptable salt or solvate thereof.

18. A compound of formula (Ic)

19. A compound according to claim 1, selected from: 4-Amino-1-benzyl-6-cyclopropyl-1,3-dihydro-imidazo[4,5-c]pyridin-2-one4-Amino-1-benzyl-6-oxazol-2-yl-1,3-dihydro-imidazo[4,5-c]pyridin-2-one; and4-Amino-1-benzyl-6-trifluoromethyl-1,3-dihydro-imidazo[4,5-c]pyridine-2-one ; ora pharmaceutically acceptable salt or solvate thereof.

20. A pharmaceutical composition, comprising a compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof, and one or more pharmaceutically acceptable excipients.

21. A pharmaceutical composition according to claim 20, further comprising one or more additional therapeutic agents.

22. A pharmaceutical composition according to claim 21, wherein said additional therapeutic agent is selected from inhibitors of HCV NS3A protein, HCV NS5A protein, HCV NS4B protein, HCV polymerase, HCV metalloprotease, HCV serine protease, HCV helicase and p7 protein.

23. A method of treating a disorder or condition in a mammal where modulation of TLR7 receptor is implicated, comprising administering to said mammal a therapeutically effective amount of a compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof.