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Last Updated: March 29, 2024

Claims for Patent: 9,353,100


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Summary for Patent: 9,353,100
Title:Macrocyclic serine protease inhibitors, pharmaceutical compositions thereof, and their use for treating HCV infections
Abstract: Provided herein are macrocyclic serine protease inhibitor compounds, for example, of Formula I, and pharmaceutical compositions and processes of preparation thereof. Also provided are methods of their use for the treatment of an HCV infection in a host in need thereof. ##STR00001##
Inventor(s): Parsy; Christophe Claude (Jacou, FR), Alexandre; Francois-Rene (Montpellier, FR), Convard; Thierry (Sathonay-Camp, FR), Surleraux; Dominique (Wauthier-Braine, BE)
Assignee: Idenix Pharmaceuticals LLC (Cambridge, MA)
Application Number:13/370,198
Patent Claims:1. A compound of Formula I: ##STR00160## or an isotopic variant thereof; or a pharmaceutically acceptable salt, thereof; wherein: R.sup.A is (i) hydrogen or halogen; or (ii) C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-10 cycloalkyl, C.sub.6-14 aryl, C.sub.7-15 aralkyl, heteroaryl, or heterocyclyl; and R.sup.B is a moiety (Ia) or (Ib): ##STR00161## wherein: each Z is independently CR.sup.1 or N; R.sup.1, R.sup.2, R.sup.5, R.sup.6, R.sup.7, and R.sup.8 are each independently (i) hydrogen, halo, cyano, trifluoromethyl, or nitro; (ii) C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-10 cycloalkyl, C.sub.6-14 aryl, C.sub.7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) --C(O)R.sup.1a, --C(O)OR.sup.1a, --C(O)NR.sup.1bR.sup.1c, --C(NR.sup.1a)NR.sup.1bR.sup.1c, --OR.sup.1a, --OC(O)R.sup.1a, --OC(O)OR.sup.1a, --OC(O)NR.sup.1bR.sup.1c, --OC(.dbd.NR.sup.1a)NR.sup.1bR.sup.1c, --OS(O)R.sup.1a, --OS(O).sub.2R.sup.1a, --OS(O)NR.sup.1bR.sup.1c, --OS(O).sub.2NR.sup.1bR.sup.1c, --NR.sup.1bR.sup.1c, --NR.sup.1aC(O)R.sup.1d, --NR.sup.1aC(O)OR.sup.1d, --NR.sup.1aC(O)NR.sup.1bR.sup.1c, --NR.sup.1aC(.dbd.NR.sup.1d)NR.sup.1bR.sup.1c, --NR.sup.1aS(O)R.sup.1d, NR.sup.1aS(O).sub.2R.sup.1d, --NR.sup.1aS(O)NR.sup.1bR.sup.1c, --NR.sup.1aS(O).sub.2NR.sup.1bR.sup.1c, --P(O)R.sup.1aR.sup.1d, --P(O)(OR.sup.1a)R.sup.1d, --P(O)(OR.sup.1a)(OR.sup.1d), --SR.sup.1a, --S(O)R.sup.1a, --S(O).sub.2R.sup.1a, --S(O)NR.sup.1bR.sup.1c, or --S(O).sub.2NR.sup.1bR.sup.1c; and each R.sup.1a, R.sup.1b, R.sup.1c, and R.sup.1d is independently hydrogen, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-10 cycloalkyl, C.sub.6-14 aryl, C.sub.7-15 aralkyl, heteroaryl, or heterocyclyl; or R.sup.1a and R.sup.1c together with the C and N atoms to which they are attached form heterocyclyl; or R.sup.1b and R.sup.1c together with the N atom to which they are attached form heterocyclyl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl, and heterocyclyl is optionally substituted with one or more substituents Q, where each Q is independently (a) oxo, cyano, halo, or nitro; (b) C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-10 cycloalkyl, C.sub.6-14 aryl, C.sub.7-15 aralkyl, heteroaryl, or heterocyclyl, each of which is further optionally substituted with one, two, three, or four, substituents Q.sup.a; or (c) --C(O)R.sup.a, --C(O)OR.sup.a, --C(O)NR.sup.bR.sup.c, --C(NR.sup.a)NR.sup.bR.sup.c, --OR.sup.a, --OC(O)R.sup.a, --OC(O)OR.sup.a, --OC(O)NR.sup.bR.sup.c, --OC(.dbd.NR.sup.a)NR.sup.bR.sup.c, --OS(O)R.sup.a, --OS(O).sub.2R.sup.a, --OS(O)NR.sup.bR.sup.c, --OS(O).sub.2NR.sup.bR.sup.c, --NR.sup.bR.sup.c, --NR.sup.aC(O)R.sup.d, --NR.sup.aC(O)OR.sup.d, --NR.sup.aC(O)NR.sup.bR.sup.c, --NR.sup.aC(.dbd.NR.sup.d)NR.sup.bR.sup.c, --NR.sup.aS(O)R.sup.d, --NR.sup.aS(O).sub.2R.sup.d, --NR.sup.aS(O)NR.sup.bR.sup.c, --NR.sup.aS(O).sub.2NR.sup.bR.sup.c, --P(O)R.sup.aR.sup.d, --P(O)(OR.sup.a)R.sup.d, --P(O)(OR.sup.a)(OR.sup.d), --SR.sup.a, --S(O)R.sup.a, --S(O).sub.2R.sup.a, --S(O)NR.sup.bR.sup.c, or --S(O).sub.2NR.sup.bR.sup.c, wherein each R.sup.a, R.sup.b, R.sup.c, and R.sup.d is independently (i) hydrogen; (ii) C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-10 cycloalkyl, C.sub.6-14 aryl, C.sub.7-15 aralkyl, heteroaryl, or heterocyclyl, each optionally substituted with one, two, three, or four, substituents Q.sup.a; or (iii) R.sup.b and R.sup.c together with the N atom to which they are attached form heterocyclyl, optionally substituted with one, two, three, or four, substituents Q.sup.a; wherein each Q.sup.a is independently (a) oxo, cyano, halo, or nitro; (b) C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-10 cycloalkyl, C.sub.6-14 aryl, C.sub.7-15 aralkyl, heteroaryl, or heterocyclyl; or (c) --C(O)R.sup.e, --C(O)OR.sup.e, --C(O)NR.sup.fR.sup.g, --C(NR.sup.e)NR.sup.fR.sup.g, --OR.sup.e, --OC(O)R.sup.e, --OC(O)OR.sup.e, --OC(O)NR.sup.fR.sup.g, --OC(.dbd.NR.sup.e)NR.sup.fR.sup.g, --OS(O)R.sup.e, --OS(O).sub.2R.sup.e, --OS(O)NR.sup.fR.sup.g, --OS(O).sub.2NR.sup.fR.sup.g, --NR.sup.fR.sup.g, --NR.sup.eC(O)R.sup.h, --NR.sup.eC(O)OR.sup.f, --NR.sup.eC(O)NR.sup.fR.sup.g, --NR.sup.eC(.dbd.NR.sup.h)NR.sup.fR.sup.g, --NR.sup.eS(O)R.sup.h, --NR.sup.eS(O).sub.2R.sup.h, --NR.sup.eS(O)NR.sup.fR.sup.g, --NR.sup.eS(O).sub.2NR.sup.fR.sup.g, --P(O)R.sup.eR.sup.h, --P(O)(OR.sup.e)R.sup.h, --P(O)(OR.sup.e)(OR.sup.h), --SR.sup.e, --S(O)R.sup.e, --S(O).sub.2R.sup.e, --S(O)NR.sup.fR.sup.g, or --S(O).sub.2NR.sup.fR.sup.g; wherein each R.sup.e, R.sup.f, R.sup.g, and R.sup.h is independently (i) hydrogen; (ii) C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-10 cycloalkyl, C.sub.6-14 aryl, C.sub.7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) R.sup.f and R.sup.g together with the N atom to which they are attached form heterocyclyl.

2. The compound of claim 1, having the structure of Formula IA: ##STR00162## or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

3. The compound of claim 1, wherein Z is CR.sup.1.

4. The compound of claim 3, wherein Z is CH.

5. The compound of claim 1, wherein Z is N.

6. The compound of claim 1, wherein R.sup.5 is hydrogen.

7. The compound of claim 1, wherein R.sup.6 is hydrogen.

8. The compound of claim 1, wherein R.sup.7 is --OR.sup.1a.

9. The compound of claim 8, wherein R.sup.7 is C.sub.1-6 alkoxy, optionally substituted with one or more substituents Q.

10. The compound of claim 8, wherein R.sup.7 is methoxy.

11. The compound of claim 1, wherein R.sup.8 is C.sub.1-6 alkyl, optionally substituted with one or more substituents Q.

12. The compound of claim 11, wherein R.sup.8 is methyl.

13. The compound of claim 1, having the structure of Formula IB: ##STR00163## or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

14. The compound of claim 13, wherein Z is CR.sup.1.

15. The compound of claim 13, wherein Z is CH.

16. The compound of claim 13, wherein Z is N.

17. The compound of claim 13, wherein R.sup.2 is heteroaryl, optionally substituted with one or more substituents Q.

18. The compound of claim 17, wherein R.sup.2 is monocyclic heteroaryl, optionally substituted with one or more substituents Q.

19. The compound of claim 17, wherein R.sup.2 is 5-membered heteroaryl, optionally substituted with one or more substituents Q.

20. The compound of claim 17, wherein R.sup.2 is furanyl, thienyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, thiazolyl, optionally substituted with one or two substituents Q.

21. The compound of claim 17, wherein R.sup.2 is thiazol-2-yl, optionally substituted with one or two substituents Q, and each Q is independently selected from cyano, methyl, ethyl, propyl, isopropyl, trifluoromethyl, ethynyl, phenyl, benzyl, pyrrolidinyl, and methoxy.

22. The compound of claim 17, wherein R.sup.2 is thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, 4-methyl-thiazol-2-yl, 5-methyl-thiazol-2-yl, 4-isopropyl-thiazol-2-yl, 4-trifluoromethyl-thiazol-2-yl, 2,4-dimethylthiazol-5-yl, 4,5-dimethylthiazol-2-yl, 4-ethynyl-thiazol-2-yl, 2-methoxy-thiazol-4-yl, or 2-pyrrolidin-1-yl-thiazol-4-yl.

23. The compound of claim 13, wherein R.sup.5 is hydrogen.

24. The compound of claim 13, wherein R.sup.6 is hydrogen.

25. The compound of claim 13, wherein R.sup.7 is --OR.sup.1a.

26. The compound of claim 25, wherein R.sup.7 is C.sub.1-6 alkoxy, optionally substituted with one or more substituents Q.

27. The compound of claim 25, wherein R.sup.7 is methoxy.

28. The compound of claim 1 selected from: ##STR00164## ##STR00165## and isotopic variants thereof; and pharmaceutically acceptable salts, solvates, and prodrugs thereof.

29. A pharmaceutical composition comprising the compound of claim 1, and one or more pharmaceutically acceptable carriers.

30. The pharmaceutical composition of claim 29, further comprising a second antiviral agent.

31. The pharmaceutical composition of claim 30, wherein the second antiviral agent is an interferon, ribavirin, an interleukin, an NS3 protease inhibitor, a cysteine protease inhibitor, a phenathrenequinone, a thiazolidine, a benzanilide, a helicase inhibitor, a polymerase inhibitor, a nucleotide analogue, a liotoxin, acerulenin, an antisense phosphorothioate oligodeoxynucleotide, an inhibitor of IRES-dependent translation, or a ribozyme.

32. The pharmaceutical composition of claim 30, wherein the second antiviral agent is an interferon.

33. The pharmaceutical composition of claim 32, wherein the interferon is pegylated interferon alpha 2a, interferon alfahcon-1, natural interferon, albuferon, interferon beta-1a, omega interferon, interferon alpha, interferon gamma, interferon tau, interferon delta, or interferon gamma-1b.

34. The pharmaceutical composition of claim 29, wherein the composition is formulated for single dose administration.

35. The pharmaceutical composition of claim 29, wherein the composition is formulated as oral, parenteral, or intravenous dosage form.

36. The pharmaceutical composition of claim 35, wherein the oral dosage form is a tablet or capsule.

37. The pharmaceutical composition of claim 29, wherein the compound is administered in a dose of about 0.5 milligram to about 1,000 milligram daily.

Details for Patent 9,353,100

Applicant Tradename Biologic Ingredient Dosage Form BLA Approval Date Patent No. Expiredate
Biogen Inc. AVONEX interferon beta-1a For Injection 103628 05/17/1996 ⤷  Try a Trial 2031-02-10
Biogen Inc. AVONEX interferon beta-1a Injection 103628 05/28/2003 ⤷  Try a Trial 2031-02-10
Biogen Inc. AVONEX interferon beta-1a Injection 103628 02/27/2012 ⤷  Try a Trial 2031-02-10
>Applicant >Tradename >Biologic Ingredient >Dosage Form >BLA >Approval Date >Patent No. >Expiredate

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