Claims for Patent: 8,946,238
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Summary for Patent: 8,946,238
Title: | Pyrazolo[1,5-A]pyrimidines as antiviral agents |
Abstract: | The invention provides compounds and pharmaceutically acceptable salts and esters and compositions thereof, for treating viral infections. The compounds and compositions are useful for treating Pneumovirinae virus infection including Human respiratory syncytial virus infections. |
Inventor(s): | Boojamra; Constantine G. (San Franciso, CA), Hui; Hon Chung (San Mateo, CA), Jansa; Petr (San Mateo, CA), Mackman; Richard L. (Millbrae, CA), Parrish; Jay P. (Redwood City, CA), Sangi; Michael (Oakland, CA), Siegel; Dustin (Foster City, CA), Sperandio; David (Palo Alto, CA), Yang; Hai (San Mateo, CA) |
Assignee: | Gilead Sciences, Inc. (Foster City, CA) |
Application Number: | 13/722,962 |
Patent Litigation and PTAB cases: | See patent lawsuits and PTAB cases for patent 8,946,238 |
Patent Claims: | 1. A compound of formula I: ##STR00362## or a salt or ester, thereof; wherein: A is --(C(R.sup.4).sub.2).sub.n-- wherein any one C(R.sup.4).sub.2 of said
--(C(R.sup.4).sub.2).sub.n-- may be optionally replaced with --O--, --S--, --S(O).sub.p--, NH or NR.sup.a; n is 3, 4, 5 or 6; each p is 1 or 2; 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, 2, 3, 4 or 5 R.sup.6; each R.sup.3, R.sup.4 or R.sup.6 is independently H, oxo, 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(.dbd.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.3-C.sub.7)cycloalkyl or (C.sub.4-C.sub.8)carbocyclylalkyl; or two R.sup.4 on adjacent carbon atoms, when taken together, may optionally form a double bond between
the two carbons to which they are attached or may form a (C.sub.3-C.sub.7)cycloalkyl ring wherein one carbon atom of said (C.sub.3-C.sub.7)cycloalkyl ring may be optionally replaced by --O--, --S--, --S(O).sub.p--, --NH-- or --NR.sup.a--; or four
R.sup.4 on adjacent carbon atoms, when taken together, may optionally form an optionally substituted C.sub.6 aryl ring; or two R.sup.4 on the same carbon atom, when taken together, may optionally form a (C.sub.3-C.sub.7)cycloalkyl ring wherein one
carbon atom of said (C.sub.3-C.sub.7)cycloalkyl ring may be optionally replaced by --O--, --S--, --S(O).sub.p--, --NH-- or --NR.sup.a--; or two R.sup.6 on adjacent carbon atoms, when taken together, may optionally form a (C.sub.3-C.sub.7)cycloalkyl ring
wherein one carbon atom of said (C.sub.3-C.sub.7)cycloalkyl ring may be optionally replaced by --O--, --S--, --S(O).sub.p--, --NH-- or --NR.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.3-C.sub.7)cycloalkyl or (C.sub.4-C.sub.8)carbocyclylalkyl 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.4-C.sub.8)carbocyclylalkyl 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; 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.4-C.sub.8)carbocyclylalkyl,
--C(.dbd.O)R.sup.a, --S(O).sub.pR.sup.a or aryl(C.sub.1-C.sub.8)alkyl; or R.sup.11 and R.sup.12 taken together with a nitrogen to which they are both attached 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)--; 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.3-C.sub.7)cycloalkyl or (C.sub.4-C.sub.8)carbocyclylalkyl of each R.sup.6, 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; provided the compound is not: ##STR00363##
2. The compound of claim 1 wherein each R.sup.3 is H. 3. The compound of claim 1 wherein n is 3. 4. The compound of claim 1 wherein each R.sup.4 is H. 5. The compound of claim 1 wherein A is --(CH.sub.2).sub.3--. 6. The compound of claim 1 wherein the compound of formula I is a compound of formula Ia: ##STR00364## or a salt or ester, thereof. 7. The compound of claim 1 wherein Ar is phenyl, pyridyl, 1,2,3,4-tetrahydronaphthyl, indazolyl, 1,6-naphthyridyl, 2,3,-dihydroindanyl, quinolyl, indolyl, 4H-benzo][d][1,3]dioxanyl, pyrazolo[1,5-a]pyridinyl, imidazo[1,2-a]pyridinyl, 1,2,3,4-tetrahydroquinolyl, benzo[d][1,3]dioxolyl, quinoxalyl, isoquinolyl, naphthyl, thiophenyl, pyrazolyl, 4,5,6,7-tetrahydrobenzothiophenyl or pyrazolo[3,4,b]pyridinyl, wherein any phenyl, pyridyl, 1,2,3,4-tetrahydronaphthyl, indazolyl, 1,6-naphthyridyl, 2,3,-dihydroindanyl, quinolyl, indolyl, 4H-benzo][d][1,3]dioxanyl, pyrazolo[1,5-a]pyridinyl, imidazo[1,2-a]pyridinyl, 1,2,3,4-tetrahydroquinolyl, benzo[d][1,3]dioxolyl, quinoxalyl, isoquinolyl, naphthyl, thiophenyl, pyrazolyl, 4,5,6,7-tetrahydrobenzothiophenyl or pyrazolo[3,4,b]pyridinyl of A is optionally substituted with 1 to 5 R.sup.6. 8. The compound of claim 1 wherein each R.sup.6 is independently OR.sup.11, CN, S(O).sub.pR.sup.a, halogen, (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.4-C.sub.8)carbocyclylalkyl, NR.sup.11C(O)R.sup.11 or NR.sup.11S(O).sub.pR.sup.a, wherein any (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.4-C.sub.8)carbocyclylalkyl of R.sup.6 is 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, NH--S(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. 9. The compound of claim 1 wherein each R.sup.6 is independently OR.sup.11, CN, S(O).sub.pR.sup.a, halogen, (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.4-C.sub.8)carbocyclylalkyl, wherein any (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.4-C.sub.8)carbocyclylalkyl of R.sup.6 is 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, NH--S(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. 10. The compound of claim 1 selected from: ##STR00365## ##STR00366## ##STR00367## ##STR00368## ##STR00369## ##STR00370## ##STR00371## ##STR00372## ##STR00373## ##STR00374## ##STR00375## ##STR00376## ##STR00377## and salts and esters, thereof. 11. The compound of claim 1 selected from: ##STR00378## ##STR00379## ##STR00380## and salts and esters, thereof. 12. A compound of formula: ##STR00381## wherein W is: ##STR00382## ##STR00383## or a salt, or stereoisomer thereof. 13. The compound of claim 12 selected from: ##STR00384## ##STR00385## ##STR00386## ##STR00387## ##STR00388## ##STR00389## and salts thereof. 14. A compound of formula: ##STR00390## wherein Y is: ##STR00391## ##STR00392## ##STR00393## ##STR00394## ##STR00395## or a salt, or stereoisomer thereof. 15. The compound of claim 14 selected from: ##STR00396## ##STR00397## ##STR00398## ##STR00399## ##STR00400## ##STR00401## ##STR00402## ##STR00403## ##STR00404## ##STR00405## ##STR00406## ##STR00407## ##STR00408## ##STR00409## ##STR00410## ##STR00411## and salts thereof. 16. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt or ester thereof and a pharmaceutically acceptable carrier. 17. The pharmaceutical composition of claim 16 further comprising a therapeutic agent selected from ribavirin, palivizumab, motavizumab, RSV-IGIV, MEDI-557, A-60444, MDT-637, BMS-433771, ALN-RSV0 and ALX-0171 and mixtures thereof. 18. A method of treating a Pneumovirinae virus infection in a mammal in need thereof comprising administering to the mammal a therapeutically effective amount of a compound of claim 1, or a pharmaceutically acceptable salt or ester thereof. 19. The method of claim 18 wherein the Pneumovirinae virus infection is caused by a respiratory syncytial virus. 20. The method of claim 18 further comprising administering a therapeutically effective amount of a therapeutic agent or composition thereof selected from the group consisting of ribavirin, palivizumab, motavizumab, RSV-IGIV, MEDI-557, A-60444, MDT-637, BMS-433771, ALN-RSV0 and ALX-0171 and mixtures thereof. 21. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 12, or a pharmaceutically acceptable salt or ester thereof and a pharmaceutically acceptable carrier. 22. The pharmaceutical composition of claim 21 further comprising a therapeutic agent selected from ribavirin, palivizumab, motavizumab, RSV-IGIV, MEDI-557, A-60444, MDT-637, BMS-433771, ALN-RSV0 and ALX-0171 and mixtures thereof. 23. A method of treating a Pneumovirinae virus infection in a mammal in need thereof comprising administering to the mammal a therapeutically effective amount of a compound of claim 12, or a pharmaceutically acceptable salt or ester thereof. 24. The method of claim 23 wherein the Pneumovirinae virus infection is caused by a respiratory syncytial virus. 25. The method of claim 14 further comprising administering a therapeutically effective amount of a therapeutic agent or composition thereof selected from the group consisting of ribavirin, palivizumab, motavizumab, RSV-IGIV, MEDI-557, A-60444, MDT-637, BMS-433771, ALN-RSV0 and ALX-0171 and mixtures thereof. 26. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 14, or a pharmaceutically acceptable salt or ester thereof and a pharmaceutically acceptable carrier. 27. The pharmaceutical composition of claim 26 further comprising a therapeutic agent selected from ribavirin, palivizumab, motavizumab, RSV-IGIV, MEDI-557, A-60444, MDT-637, BMS-433771, ALN-RSV0 and ALX-0171 and mixtures thereof. 28. A method of treating a Pneumovirinae virus infection in a mammal in need thereof comprising administering to the mammal a therapeutically effective amount of a compound of claim 14, or a pharmaceutically acceptable salt or ester thereof. 29. The method of claim 28 wherein the Pneumovirinae virus infection is caused by a respiratory syncytial virus. 30. The method of claim 29 further comprising administering a therapeutically effective amount of a therapeutic agent or composition thereof selected from the group consisting of ribavirin, palivizumab, motavizumab, RSV-IGIV, MEDI-557, A-60444, MDT-637, BMS-433771, ALN-RSV0 and ALX-0171 and mixtures thereof. |
Details for Patent 8,946,238
Applicant | Tradename | Biologic Ingredient | Dosage Form | BLA | Approval Date | Patent No. | Expiredate |
---|---|---|---|---|---|---|---|
Swedish Orphan Biovitrum Ab (publ) | SYNAGIS | palivizumab | For Injection | 103770 | 06/19/1998 | ⤷ Try a Trial | 2031-12-22 |
Swedish Orphan Biovitrum Ab (publ) | SYNAGIS | palivizumab | Injection | 103770 | 07/23/2004 | ⤷ Try a Trial | 2031-12-22 |
Hoffmann-la Roche Inc. | PEGASYS COPEGUS COMBINATION PACK | peginterferon alfa-2a and ribavirin | 125083 | 06/04/2004 | ⤷ Try a Trial | 2031-12-22 | |
>Applicant | >Tradename | >Biologic Ingredient | >Dosage Form | >BLA | >Approval Date | >Patent No. | >Expiredate |
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