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Last Updated: August 7, 2020

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Claims for Patent: 9,504,689

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Summary for Patent: 9,504,689
Title:Compounds and methods for antiviral treatment
Abstract: Compounds and pharmaceutically acceptable salts and esters and compositions thereof, for treating viral infections are provided. The compounds and compositions are useful for treating Pneumovirinae virus infections. The compounds, compositions, and methods provided are particularly useful for the treatment of Human respiratory syncytial virus infections.
Inventor(s): Siegel; Dustin (San Carlos, CA), Sperandio; David (Palo Alto, CA), Yang; Hai (San Mateo, CA), Sangi; Michael (San Mateo, CA), Parrish; Jay P. (El Dorado Hills, CA), Hui; Hon Chung (San Mateo, CA)
Assignee: GILEAD SCIENCES, INC. (Foster City, CA)
Application Number:14/635,830
Patent Claims:1. A method of treating a Pneumovirinae virus infection in a human in need thereof comprising administering to the human a therapeutically effective amount of a compound of formula Im: ##STR00304## wherein: Ar is a C.sub.2-C.sub.20 heterocyclyl group or a C.sub.6-C.sub.20 aryl group, wherein the C.sub.2-C.sub.20 heterocyclyl group or the C.sub.6-C.sub.20 aryl group is optionally substituted with 1 to 5 R.sup.6; X is --C(R.sup.13)(R.sup.14)--, --N(CH.sub.2R.sup.14)-- or --NH--, or X is absent; R.sup.1 is H, --OR.sup.11, --NR.sup.11R.sup.12, --NR.sup.11C(O)R.sup.11, --NR.sup.11C(O)OR.sup.11, --NR.sup.11C(O)NR.sup.11R.sup.12, N.sub.3, CN, --NO.sub.2, --SR.sup.11, --S(O).sub.pR.sup.a, NR.sup.11S(O).sub.pR.sup.a, --C(.dbd.O)R.sup.11, --C(.dbd.O)OR.sup.11, --C(.dbd.O)NR.sup.11R.sup.12, --C(.dbd.O)SR.sup.11, --S(O).sub.p(OR.sup.11), --SO.sub.2NR.sup.11R.sup.12, --NR.sup.11S(O).sub.p(OR.sup.11), --NR.sup.11SO.sub.pNR.sup.11R.sup.12, --NR.sup.11C(.dbd.NR.sup.11)NR.sup.11R.sup.12, halogen, (C.sub.1-C.sub.8)alkyl, (C.sub.2-C.sub.8)alkenyl, (C.sub.2-C.sub.8)alkynyl, aryl(C.sub.1-C.sub.8)alkyl, C.sub.6-C.sub.20 aryl, C.sub.2-C.sub.20 heterocyclyl, C.sub.2-C.sub.20 heterocyclyl(C.sub.1-C.sub.8)alkyl, (C.sub.3-C.sub.7)cycloalkyl or (C.sub.3-C.sub.7)cycloalkyl(C.sub.1-C.sub.8)alkyl; R.sup.2 is H, CN, NO.sub.2, halogen or (C.sub.1-C.sub.8)alkyl; R.sup.7 is H, OR.sup.11, --NR.sup.11R.sup.12, --NR.sup.11C(O)R.sup.11, --NR.sup.11C(O)OR.sup.11, --NR.sup.11C(O)NR.sup.11R.sup.12, N.sub.3, CN, NO.sub.2, --SR.sup.11, --S(O).sub.pR.sup.a, --NR.sup.11S(O).sub.pR.sup.a, --C(.dbd.O)R.sup.11, --C(.dbd.O)OR.sup.11, --C(.dbd.O)NR.sup.11R.sup.12, --C(.dbd.O)SR.sup.11, --S(O).sub.p(OR.sup.11), --SO.sub.2NR.sup.11R.sup.12, --NR.sup.11S(O).sub.p(OR.sup.11), --NR.sup.11SO.sub.pNR.sup.11R.sup.12, --NR.sup.11C(.dbd.NR.sup.11)NR.sup.11R.sup.12, halogen, (C.sub.1-C.sub.8)alkyl, (C.sub.2-C.sub.8)alkenyl, (C.sub.2-C.sub.8)alkynyl, aryl(C.sub.1-C.sub.8)alkyl, C.sub.6-C.sub.20 aryl, C.sub.2-C.sub.20 heterocyclyl, C.sub.2-C.sub.20 heterocyclyl(C.sub.1-C.sub.8)alkyl, (C.sub.3-C.sub.7)cycloalkyl or (C.sub.3-C.sub.7)cycloalkyl(C.sub.1-C.sub.8)alkyl; R.sup.8 is H, --OR.sup.11, --NR.sup.11R.sup.12, NR.sup.11C(O)R.sup.11, --NR.sup.11C(O)OR.sup.11, --NR.sup.11C(O)NR.sup.11R.sup.12, N.sub.3, CN, NO.sub.2, --SR.sup.11, --S(O).sub.pR.sup.a, --NR.sup.11S(O).sub.pR.sup.a, --C(.dbd.O)R.sup.11, --C(.dbd.O)OR.sup.11, --C(.dbd.O)NR.sup.11R.sup.12, --C(.dbd.O)SR.sup.11, --S(O)(OR.sup.11), --SO.sub.2NR.sup.11R.sup.12, --NR.sup.11S(O).sub.p(OR.sup.11), --NR.sup.11SO.sub.pNR.sup.11R.sup.12, NR.sup.11C(.dbd.NR.sup.11)NR.sup.11R.sup.12, halogen, (C.sub.1-C.sub.8)alkyl, (C.sub.2-C.sub.8)alkenyl, (C.sub.2-C.sub.8)alkynyl, aryl(C.sub.1-C.sub.8)alkyl, C.sub.6-C.sub.20 aryl, C.sub.2-C.sub.20 heterocyclyl, C.sub.2-C.sub.20 heterocyclyl(C.sub.1-C.sub.8)alkyl, (C.sub.3-C.sub.7)cycloalkyl or (C.sub.3-C.sub.7)cycloalkyl(C.sub.1-C.sub.8)alkyl; each R.sup.11 or R.sup.12 is independently H, (C.sub.1-C.sub.8)alkyl, (C.sub.2-C.sub.8)alkenyl, (C.sub.2-C.sub.8)alkynyl, aryl(C.sub.1-C.sub.8)alkyl, C.sub.6-C.sub.20 aryl, C.sub.2-C.sub.20 heterocyclyl, (C.sub.3-C.sub.7)cycloalkyl, (C.sub.3-C.sub.7)cycloalkyl(C.sub.1-C.sub.8)alkyl, --C(.dbd.O)R.sup.a or --S(O).sub.pR.sup.a; or when R.sup.11 and R.sup.12 are attached to a nitrogen they may optionally be taken together with the nitrogen to which they are both attached to form a 3 to 7 membered heterocyclic ring wherein any one carbon atom of said heterocyclic ring can optionally be replaced with --O--, --S--, --S(O).sub.p--, --NH--, --NR.sup.a-- or --C(O)--; R.sup.13 is H or (C.sub.1-C.sub.8)alkyl; R.sup.14 is H, (C.sub.1-C.sub.8)alkyl, NR.sup.11R.sup.12, NR.sup.11C(O)R.sup.11, NR.sup.11C(O)OR.sup.11, NR.sup.11C(O)NR.sup.11R.sup.12, NR.sup.11S(O).sub.pR.sup.a, --NR.sup.11S(O).sub.p(OR.sup.11) or NR.sup.11SO.sub.pNR.sup.11R.sup.12; and wherein each (C.sub.1-C.sub.8)alkyl, (C.sub.2-C.sub.8)alkenyl, (C.sub.2-C.sub.8)alkynyl, aryl(C.sub.1-C.sub.8)alkyl, C.sub.6-C.sub.20 aryl, C.sub.2-C.sub.20 heterocyclyl, C.sub.2-C.sub.20 heterocyclyl(C.sub.1-C.sub.8)alkyl, (C.sub.3-C.sub.7)cycloalkyl or (C.sub.3-C.sub.7)cycloalkyl(C.sub.1-C.sub.8)alkyl of each R.sup.1, R.sup.2, R.sup.7, R.sup.8, R.sup.8', R.sup.11 or R.sup.12 is independently, optionally substituted with one or more oxo, halogen, hydroxy, --NH.sub.2, CN, N.sub.3, --N(R.sup.a).sub.2, --NHR.sup.a, --SH, --SR.sup.a, --S(O).sub.pR.sup.a, --OR.sup.a, (C.sub.1-C.sub.8)alkyl, (C.sub.1-C.sub.8)haloalkyl, --C(O)R.sup.a, --C(O)H, --C(.dbd.O)OR.sup.a, --C(.dbd.O)OH, --C(.dbd.O)N(R.sup.a).sub.2, --C(.dbd.O)NHR.sup.a, --C(.dbd.O)NH.sub.2, --NHS(O).sub.pR.sup.a, --NR.sup.aS(O).sub.pR.sup.a, --NHC(O)R.sup.a, --NR.sup.aC(O)R.sup.a, --NHC(O)OR.sup.a, --NR.sup.aC(O)OR.sup.a, --NR.sup.aC(O)NHR.sup.a, --NR.sup.aC(O)N(R.sup.a).sub.2, --NR.sup.aC(O)NH.sub.2, --NHC(O)NHR.sup.a, --NHC(O)N(R.sup.a).sub.2, --NHC(O)NH.sub.2, .dbd.NH, .dbd.NOH, .dbd.NOR.sup.a, --NR.sup.aS(O).sub.pNHR.sup.a, --NR.sup.aS(O).sub.pN(R.sup.a).sub.2, --NR.sup.aS(O).sub.pNH.sub.2, --NHS(O).sub.pNHR.sup.a, --NHS(O).sub.pN(R.sup.a).sub.2, --NHS(O).sub.pNH.sub.2, --OC(.dbd.O)R.sup.a, --OP(O)(OH).sub.2 or R.sup.a; each R.sup.a is independently (C.sub.1-C.sub.8)alkyl, (C.sub.1-C.sub.8)haloalkyl, (C.sub.2-C.sub.8)alkenyl, (C.sub.2-C.sub.8)alkynyl, aryl(C.sub.1-C.sub.8)alkyl, C.sub.6-C.sub.20 aryl, C.sub.2-C.sub.20 heterocyclyl, C.sub.2-C.sub.20 heterocyclyl(C.sub.1-C.sub.8)alkyl, (C.sub.3-C.sub.7)cycloalkyl or (C.sub.3-C.sub.7)cycloalkyl(C.sub.1-C.sub.8)alkyl wherein any (C.sub.1-C.sub.8)alkyl, (C.sub.1-C.sub.8)haloalkyl, (C.sub.2-C.sub.8)alkenyl or (C.sub.2-C.sub.8)alkynyl of R.sup.a is optionally substituted with one or more OH, NH.sub.2, CO.sub.2H, C.sub.2-C.sub.20 heterocyclyl, and wherein any aryl(C.sub.1-C.sub.8)alkyl, C.sub.6-C.sub.20 aryl, C.sub.2-C.sub.20 heterocyclyl, (C.sub.3-C.sub.7)cycloalkyl or (C.sub.3-C.sub.7)cycloalkyl(C.sub.1-C.sub.8)alkyl of R.sup.a is optionally substituted with one or more --OH, --NH.sub.2, CO.sub.2H, C.sub.2-C.sub.20 heterocyclyl or (C.sub.1-C.sub.8)alkyl; and p is 1 or 2; or a pharmaceutically acceptable salt thereof.

2. The method of claim 1 wherein R.sup.2 is H.

3. The method of claim 1 wherein X is --C(R.sup.13)(R.sup.14)-- or X is absent.

4. The method of claim 3 wherein R.sup.13 is H and R.sup.14 is --NHS(O).sub.2(C.sub.1-C.sub.3)alkyl.

5. The method of claim 1 wherein X is absent.

6. The method of claim 1 wherein R.sup.7 is H or (C.sub.1-C.sub.8)alkyl, wherein (C.sub.1-C.sub.8)alkyl is optionally substituted with one or more substituents selected from the group of oxo, halogen, hydroxy, --NH.sub.2, CN, N.sub.3, --N(R.sup.a).sub.2, --NHR.sup.a, --SH, --SR.sup.a, --S(O).sub.pR.sup.a, --OR.sup.a, (C.sub.1-C.sub.8)alkyl, (C.sub.1-C.sub.8)haloalkyl, --C(O)R.sup.a, --C(O)H, --C(.dbd.O)OR.sup.a, --C(.dbd.O)OH, --C(.dbd.O)N(R.sup.a).sub.2, --C(.dbd.O)NHR.sup.a, --C(.dbd.O)NH.sub.2, --NHS(O).sub.pR.sup.a, --NR.sup.aS(O).sub.pR.sup.a, --NHC(O)R.sup.a, --NR.sup.aC(O)R.sup.a, --NHC(O)OR.sup.a, --NR.sup.aC(O)OR.sup.a, --NR.sup.aC(O)NHR.sup.a, --NR.sup.aC(O)N(R.sup.a).sub.2, --NR.sup.aC(O)NH.sub.2, --NHC(O)NHR.sup.a, --NHC(O)N(R.sup.a).sub.2, --NHC(O)NH.sub.2, .dbd.NH, .dbd.NOH, .dbd.NOR.sup.a, --NR.sup.aS(O).sub.pNHR.sup.a, --NR.sup.aS(O).sub.pN(R.sup.a).sub.2, --NR.sup.aS(O).sub.pNH.sub.2, --NHS(O).sub.pNHR.sup.a, --NHS(O).sub.pN(R.sup.a).sub.2, --NHS(O).sub.pNH.sub.2, --OC(.dbd.O)R.sup.a, --OP(O)(OH).sub.2 and R.sup.a.

7. The method of claim 1 wherein R.sup.7 is H or methyl.

8. The method of claim 1 wherein R.sup.1 is H, --NR.sup.11R.sup.12, (C.sub.1-C.sub.8)alkyl or C.sub.2-C.sub.20 heterocyclyl wherein (C.sub.1-C.sub.8)alkyl or C.sub.2-C.sub.20 heterocyclyl is optionally substituted with one or more substituents selected from the group of oxo, halogen, hydroxy, --NH.sub.2, CN, N.sub.3, --N(R.sup.a).sub.2, --NHR.sup.a, --SH, --SR.sup.a, --S(O).sub.pR.sup.a, --OR.sup.a, (C.sub.1-C.sub.8)alkyl, (C.sub.1-C.sub.8)haloalkyl, --C(O)R.sup.a, --C(O)H, --C(.dbd.O)OR.sup.a, --C(.dbd.O)OH, --C(.dbd.O)N(R.sup.a).sub.2, --C(.dbd.O)NHR.sup.a, --C(.dbd.O)NH.sub.2, --NHS(O).sub.pR.sup.a, --NR.sup.aS(O).sub.pR.sup.a, --NHC(O)R.sup.a, --NR.sup.aC(O)R.sup.a, --NHC(O)OR.sup.a, --NR.sup.aC(O)OR.sup.a, --NR.sup.aC(O)NHR.sup.a, --NR.sup.aC(O)N(R.sup.a).sub.2, --NR.sup.aC(O)NH.sub.2, --NHC(O)NHR.sup.a, --NHC(O)N(R.sup.a).sub.2, --NHC(O)NH.sub.2, .dbd.NH, .dbd.NOH, .dbd.NOR.sup.a, --NR.sup.aS(O).sub.pNHR.sup.a, --NR.sup.aS(O).sub.pN(R.sup.a).sub.2, --NR.sup.aS(O).sub.pNH.sub.2, --NHS(O).sub.pNHR.sup.a, --NHS(O).sub.pN(R.sup.a).sub.2, --NHS(O).sub.pNH.sub.2, --OC(.dbd.O)R.sup.a, --OP(O)(OH).sub.2 and R.sup.a.

9. The method of claim 1 wherein R.sup.1 is H, (C.sub.1-C.sub.3)alkyl or --NR.sup.11R.sup.12, wherein each R.sup.11 or R.sup.12 is independently H or (C.sub.1-C.sub.3)alkyl; or R.sup.11 and R.sup.12 together with the nitrogen to which they are both attached to form a 3 to 7 membered heterocyclic ring wherein any one carbon atom of said heterocyclic ring can optionally be replaced with --O--, --S--, --S(O).sub.p--, --NH--, --NR.sup.a-- or --C(O)--.

10. The method of claim 1 wherein R.sup.1 is H, methyl or azetidinyl.

11. The method of claim 1 wherein R.sup.8 is --NR.sup.11R.sup.12, (C.sub.1-C.sub.8)alkyl or C.sub.2-C.sub.20 heterocyclyl wherein (C.sub.1-C.sub.8)alkyl or C.sub.2-C.sub.20 heterocyclyl is optionally substituted with one or more substituents selected from the group of oxo, halogen, hydroxy, --NH.sub.2, CN, N.sub.3, --N(R.sup.a).sub.2, --NHR.sup.a, --SH, --SR.sup.a, --S(O).sub.pR.sup.a, --OR.sup.a, (C.sub.1-C.sub.8)alkyl, (C.sub.1-C.sub.8)haloalkyl, --C(O)R.sup.a, --C(O)H, --C(.dbd.O)OR.sup.a, --C(.dbd.O)OH, --C(.dbd.O)N(R.sup.a).sub.2, --C(.dbd.O)NHR.sup.a, --C(.dbd.O)NH.sub.2, --NHS(O).sub.pR.sup.a, --NR.sup.aS(O).sub.pR.sup.a, --NHC(O)R.sup.a, --NR.sup.aC(O)R.sup.a, --NHC(O)OR.sup.a, --NR.sup.aC(O)OR.sup.a, --NR.sup.aC(O)NHR.sup.a, --NR.sup.aC(O)N(R.sup.a).sub.2, --NR.sup.aC(O)NH.sub.2, --NHC(O)NHR.sup.a, --NHC(O)N(R.sup.a).sub.2, --NHC(O)NH.sub.2, .dbd.NH, .dbd.NOH, .dbd.NOR.sup.a, --NR.sup.aS(O).sub.pNHR.sup.a, --NR.sup.aS(O).sub.pN(R.sup.a).sub.2, --NR.sup.aS(O).sub.pNH.sub.2, --NHS(O).sub.pNHR.sup.a, --NHS(O).sub.pN(R.sup.a).sub.2, --NHS(O).sub.pNH.sub.2, --OC(.dbd.O)R.sup.a, --OP(O)(OH).sub.2 and R.sup.a.

12. The method of claim 1 wherein R.sup.8 is (C.sub.1-C.sub.8)alkyl, azetidinyl or pyrrolidinyl, wherein azetidinyl or pyrrolidinyl is optionally substituted with one or more substituents selected from the group of oxo, halogen, hydroxy, --NH.sub.2, CN, N.sub.3, --N(R.sup.a).sub.2, --NHR.sup.a, --SH, --SR.sup.a, --S(O).sub.pR.sup.a, --OR.sup.a, (C.sub.1-C.sub.8)alkyl, (C.sub.1-C.sub.8)haloalkyl, --C(O)R.sup.a, --C(O)H, --C(.dbd.O)OR.sup.a, --C(.dbd.O)OH, --C(.dbd.O)N(R.sup.a).sub.2, --C(.dbd.O)NHR.sup.a, --C(.dbd.O)NH.sub.2, --NHS(O).sub.pR.sup.a, --NR.sup.aS(O).sub.pR.sup.a, --NHC(O)R.sup.a, --NR.sup.aC(O)R.sup.a, --NHC(O)OR.sup.a, --NR.sup.aC(O)OR.sup.a, --NR.sup.aC(O)NHR.sup.a, --NR.sup.aC(O)N(R.sup.a).sub.2, --NR.sup.aC(O)NH.sub.2, --NHC(O)NHR.sup.a, --NHC(O)N(R.sup.a).sub.2, --NHC(O)NH.sub.2, .dbd.NH, .dbd.NOH, .dbd.NOR.sup.a, --NR.sup.aS(O).sub.pNHR.sup.a, --NR.sup.aS(O).sub.pN(R.sup.a).sub.2, --NR.sup.aS(O).sub.pNH.sub.2, --NHS(O).sub.pNHR.sup.a, --NHS(O).sub.pN(R.sup.a).sub.2, --NHS(O).sub.pNH.sub.2, --OC(.dbd.O)R.sup.a, --OP(O)(OH).sub.2 and R.sup.a.

13. The method of claim 1 wherein R.sup.8 is methyl, azetidinyl or pyrrolidinyl, wherein azetidinyl or pyrrolidinyl is optionally substituted with one or more substituents selected from the group of hydroxy, NH.sub.2 and CN.

14. The method of claim 1 wherein Ar is a phenyl or 5-6 membered monocyclic heteroaryl, wherein phenyl or 5-6 membered monocyclic heteroaryl is optionally substituted with 1 to 5 R.sup.6.

15. The method of claim 1 wherein Ar is a phenyl, pyridinyl or thienyl, wherein phenyl, pyridinyl or thienyl is optionally substituted with 1 to 5 R.sup.6.

16. The method of claim 1 wherein each R.sup.6 is --NR.sup.11S(O).sub.pR.sup.a, halogen, or (C.sub.1-C.sub.8)alkyl.

17. The method of claim 1 wherein each R.sup.6 is --NHS(O).sub.2CH.sub.3, chloro, bromo or methyl.

18. The method of claim 1 wherein the compound of formula Im is selected from the group of: ##STR00305## ##STR00306## or a pharmaceutically acceptable salt thereof.

19. The method of claim 1 wherein the Pneumovirinae virus infection is caused by a respiratory syncytial virus.

20. The method of claim 1 further comprising administering a therapeutically effective amount of at least one other therapeutic agent selected from the group consisting of ribavirin, palivizumab, motavizumab, RSV-IGIV, MEDI-557, A-60444, MDT-637, BMS-433771, ALN-RSV01 and ALX-0171 and mixtures thereof.

Details for Patent 9,504,689

Applicant Tradename Biologic Ingredient Dosage Form BLA Number Approval Date Patent No. Assignee Estimated Patent Expiration Status Orphan Source
Medimmune SYNAGIS palivizumab VIAL 103770 001 1998-06-19   Start Trial GILEAD SCIENCES, INC. (Foster City, CA) 2032-04-17 RX search
Medimmune SYNAGIS palivizumab VIAL 103770 002 1998-06-19   Start Trial GILEAD SCIENCES, INC. (Foster City, CA) 2032-04-17 RX search
>Applicant >Tradename >Biologic Ingredient >Dosage Form >BLA >Number >Approval Date >Patent No. >Assignee >Estimated Patent Expiration >Status >Orphan >Source

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