Claims for Patent: 9,675,694

Summary for Patent: 9,675,694

Title:	Polycyclic agents for the treatment of respiratory syncytial virus infections
Abstract:	The present invention relates to polycyclic antiviral compounds, and salts thereof, methods for their preparation and compositions containing them, and the use of the compounds and composition in the treatment of viral infections.
Inventor(s):	Mitchell; Jeffrey Peter (Alpharetta, GA), Draffan; Alistair George (Alpharetta, GA), Sanford; Vanessa Anne (Alpharetta, GA), Bond; Silas (Alpharetta, GA), Lim; Chin Lim (Alpharetta, GA), Mayes; Penelope Anne (Alpharetta, GA)
Assignee:	BIOTA SCIENTIFIC MANAGEMENT PTY LTD (Notting Hill, Victoria, AU)
Application Number:	14/015,790
Patent Claims:	1. A compound of formula I or salt thereof ##STR00203## wherein: R.sub.1 is selected from C.sub.1-12 alkyl, C.sub.2-12 alkenyl, C.sub.2-12 alkynyl, --(CH.sub.2).sub.nC.sub.3-7 cycloalkyl, --(CH.sub.2).sub.nC.sub.4-7 cycloalkenyl, --(CH.sub.2).sub.n aryl, --(CH.sub.2).sub.n arylC.sub.1-12 alkyl, --(CH.sub.2).sub.n arylC.sub.2-12 alkenyl, --(CH.sub.2).sub.narylC.sub.2-12 alkynyl, and --(CH.sub.2), heterocyclyl; n is 0-6 and said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl and heterocyclyl groups are optionally substituted; R.sub.2 is selected from H, O, --CH.sub.2R.sub.3, --C(.dbd.Y)R.sub.3, --C(.dbd.Y)OR.sub.3, --C(.dbd.Y)N(R.sub.4)R.sub.3, --C(.dbd.Y)CH.sub.2N(R.sub.4)R.sub.3, --C(.dbd.Y)CH.sub.2SR.sub.3 and --S(O).sub.wR.sub.5, where R.sub.3 is selected from hydrogen, C.sub.1-12 alkyl, C.sub.2-12 alkenyl, C.sub.2-12 alkynyl, --(CH.sub.2).sub.mC.sub.3-7 cycloalkyl, --(CH.sub.2).sub.mC.sub.4-7 cycloalkenyl, --(CH.sub.2).sub.m aryl, --(CH.sub.2).sub.m arylC.sub.1-12 alkyl, --(CH.sub.2).sub.m arylC.sub.2-12 alkenyl, --(CH.sub.2).sub.m arylC.sub.2-12 alkynyl and --(CH.sub.2).sub.n heterocyclyl; and when R.sub.2 is --CH.sub.2R.sub.3, or --C(.dbd.Y)R.sub.3, R.sub.3 may also be selected from --S--R.sub.5 and --O--R.sub.5; m is 0-6; R.sub.4 is hydrogen or C.sub.1-6 alkyl; R.sub.5 is C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-7 cycloalkyl, C.sub.4-7 cycloalkenyl, benzyl, aryl or heterocyclyl; w is 0, 1 or 2, and the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl and heterocyclyl groups are optionally substituted; X is O and Y is selected from O, S and NR.sub.6, where R.sub.6 is independently selected from hydrogen, C.sub.1-6 alkyl, hydroxy and C.sub.1-6 alkoxy; A together with the atoms to which it is attached, forms an optionally substituted unsaturated 6-membered nitrogen containing heterocyclic ring; B-C is --CH.sub.2--CH.sub.2--; and D is --CH.sub.2--. 2. A compound according to claim 1 wherein ring A is an optionally substituted heteroaryl ring selected from a pyridyl, pyridazinyl, pyrimidinyl or pyrazinyl ring. 3. A compound according to claim 1 wherein ring A is an optionally substituted pyridyl ring. 4. A compound according to claim 1 wherein R.sub.1 represents an optionally substituted aryl, optionally substituted alkyl or optionally substituted heterocyclyl. 5. A compound according to claim 4 wherein R.sub.1 represents an optionally substituted phenyl, optionally substituted thienyl, optionally substituted pyrrolyl or optionally substituted pyridyl. 6. A compound according to claim 5 wherein R.sub.1 represents an optionally substituted phenyl ring. 7. A compound according to claim 1, wherein R.sub.1 is optionally substituted phenyl where the substituents are each independently selected from halo, hydroxy or alkoxy; cycloalkyl; or optionally substituted pyridyl or an N-oxide thereof where the substituents are each independently selected from halo. 8. A compound according to claim 7, wherein R.sub.1 is optionally substituted phenyl where the substituents are each independently selected from chloro, hydroxy or methoxy; lower cycloalkyl; or optionally substituted pyridyl or an N-oxide thereof where the substituents are each independently selected from chloro. 9. A compound according to claim 7, wherein R.sub.1 is phenyl, 4-chlorophenyl, 4-methoxyphenyl, 4-hydroxyphenyl, 5-chloro-2-pyridyl, 4-pyridyl or 4-pyridyl N-oxide. 10. A compound according to claim 1, wherein R.sub.2 is selected from O, --CH.sub.2R.sub.3, --C(.dbd.Y)R.sub.3, --C(.dbd.Y)OR.sub.3, --C(.dbd.Y)N(R.sub.4)R.sub.3, --C(.dbd.Y)CH.sub.2N(R.sub.4)R.sub.3, --C(.dbd.Y)CH.sub.2SR.sub.3 and --S(O).sub.wR.sub.5, where R.sub.3 is selected from hydrogen, C.sub.1-12 alkyl, C.sub.2-12 alkenyl, C.sub.2-12 alkynyl, --(CH.sub.2).sub.mC.sub.3-7 cycloalkyl, --(CH.sub.2).sub.mC.sub.4-7cycloalkenyl, --(CH.sub.2).sub.m aryl, --(CH.sub.2).sub.m arylC.sub.1-12 alkyl, --(CH.sub.2).sub.m arylC.sub.2-12 alkenyl, --(CH.sub.2).sub.m arylC.sub.2-12alkynyl and --(CH.sub.2).sub.m heterocyclyl; and when R.sub.2 is --CH.sub.2R.sub.3, or --C(.dbd.Y)R.sub.3; R.sub.3 may also be selected from --S--R.sub.5 and --O--R.sub.5; m is 0-6; R.sub.4 is hydrogen or C.sub.1-6 alkyl; R.sub.5 is C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-7 cycloalkyl, C.sub.4-7 cycloalkenyl, benzyl, aryl or heterocyclyl; w is 0, 1 or 2, and the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl and heterocyclyl groups are optionally substituted. 11. A compound according to claim 1, where R.sub.2 is --CH.sub.2--R.sub.3, wherein R.sub.3 is --(CH.sub.2).sub.m optionally substituted aryl or --(CH.sub.2).sub.m optionally substituted heterocyclyl and m is 0 to 3. 12. A compound according to claim 1, where R.sub.2 is --C(.dbd.Y)CH.sub.2N(R.sub.4)R.sub.3 or --C(.dbd.Y)CH.sub.2SR.sub.3, wherein R.sub.3 is --(CH.sub.2).sub.m optionally substituted aryl or --(CH.sub.2).sub.m optionally substituted heterocyclyl, m is 0 to 3, Y is O and R.sub.4 is H or C.sub.1-C.sub.6 alkyl. 13. A compound according to claim 1, where R.sub.2 is --CON(R.sub.4)R.sub.3, wherein R.sub.4 is H, R.sub.3 is --(CH.sub.2).sub.m optionally substituted aryl or --(CH.sub.2).sub.m optionally substituted heteroaryl and m is 0 to 2. 14. A compound according to claim 1, where R.sub.2 is --C(.dbd.Y)R.sub.3, wherein Y is O or S, R.sub.3 is --(CH.sub.2).sub.m optionally substituted aryl or --(CH.sub.2).sub.m optionally substituted heteroaryl, and m is 0 to 3. 15. A compound according to claim 14 wherein Y is O, m is 0, and R.sub.3 is an optionally substituted 5 or 6 membered monocyclic heterocycle, an optionally substituted 9 or 10 membered bicyclic heterocycle or an optionally substituted aryl group. 16. A compound according to claim 1, wherein R.sub.2 is --CH.sub.2R.sub.3, --C(.dbd.O)R.sub.3, --C(.dbd.O)N(R.sub.4)R.sub.3 or --SO.sub.2R.sub.5; where a. R.sub.3 in --CH.sub.2R.sub.3 or --C(.dbd.O)R.sub.3 is (i) optionally substituted alkyl where the substituents are each independently selected from --COOH, --SCH.sub.2CONHaryl, --NHSO.sub.2aryl, heteroaryl and aryl, each further optionally independently substituted with halo or alkoxy; (ii) optionally substituted phenyl where the substituents are each independently selected from halo; (iii) optionally substituted 5- or 6-membered heteroaryl where the substituents are each independently selected from halo, alkyl, haloalkyl, cycloalkyl, aryl, heteroaryloxy, and heteroaryl optionally substituted with alkyl or haloalkyl; or (iv) optionally substituted alkenyl where the substituents are each independently selected from heteroaryl; b. R.sub.4 is H; c. R.sub.3 in --C(.dbd.O)N(R.sub.4)R.sub.3 is cycloalkyl, heteroaralkyl, alkyl, aralkyl heteroaryl; and d. R.sub.5 is heteroaryl. 17. A compound according to claim 1, wherein R.sub.2 is --CH.sub.2R3, --C(.dbd.O)R.sub.3, --C(.dbd.O)N(R.sub.4)R.sub.3 or --SO.sub.2R.sub.5; where a. R.sub.3 in --CH.sub.2R.sub.3 or --C(.dbd.O)R.sub.3 is (i) optionally substituted methyl, ethyl, or propyl, where the substituents are each independently selected from --COOH, --SCH.sub.2CONH--3,4-dimethoxyphenyl, --NHSO.sub.2-4-fluorophenyl, pyridyloxy, benzisoxazolyl, pyridyl, furyl, 4-fluorophenyl, or 4-methoxyphenyl; (ii) optionally substituted phenyl where the substituents are each independently selected from methoxy, F and Cl; (iii) optionally substituted thiazolyl, pyridyl, furyl, thienyl, isoxazolyl, isothiazolyl, 1,2,3-thiadiazolyl, or pyrazolyl where the substituents are each independently selected from pyridyloxy, cyclopropyl, Me, CF.sub.3, phenyl, thienyl, pyridyl, F, Cl, Br, 5-CF.sub.3-3-methyl-1-pyrazolyl; or (iv) 2-furylethen-1-yl; b. R.sub.4 is H; c. R.sub.3 in --C(.dbd.O)N(R.sub.4)R.sub.3 is 2-pheneth-1-yl, benzyl, cyclohexyl, 2-furylmethyl, methyl, or 4-methylbenzyl; and d. R.sub.5 is pyridyl. 18. A compound according to claim 15 wherein R.sub.3 is selected from phenyl, furyl, thienyl, pyridyl, oxazolyl, thiazolyl, pyrazolyl, furazanyl, isoxazolyl, isothiazolyl, 1,2,3-triazolyl, 1,3,4-triazolyl, 1,2,3-thiadiazolyl, 1,3,4-thiadiazolyl, pyridazinyl, pyrimidinyl, benzo[b]furanyl, benzo[b]thiophenyl and benzoisoxazolyl; each of which may be optionally substituted. 19. A compound according to claim 1 where R.sub.2 is --COR.sub.3, fused ring A is an optionally substituted pyridyl ring, R.sub.3 is selected from phenyl, furyl, thienyl, pyridyl, oxazolyl, thiazolyl, pyrazolyl, furazanyl, isoxazolyl, isothiazolyl, 1,2,3-triazolyl, 1,3,4-triazolyl, 1,2,3-thiadiazolyl, 1,3,4-thiadiazolyl, pyridazinyl, pyrimidinyl, benzo[b]furanyl, benzo[b]thiophenyl and benzoisoxazolyl; each of which may be optionally substituted. 20. A compound according to claim 1 wherein R.sub.1 is an optionally substituted phenyl, A together with the atoms to which it is attached forms an optionally substituted phenyl or optionally substituted pyridyl ring, and R.sub.2 is --C(O)optionally substituted aryl or --C(O)optionally substituted heterocyclyl. 21. A compound according to claim 1, wherein ring A is an unsubstituted pyridyl ring. 22. A pharmaceutical composition comprising a compound of formula Ia or salt thereof ##STR00204## wherein: R.sub.1 is selected from C.sub.1-12 alkyl, C.sub.2-12 alkenyl, C.sub.2-12 alkynyl, --(CH.sub.2).sub.nC.sub.3-7 cycloalkyl, --(CH.sub.2).sub.nC.sub.4-7cycloalkenyl, --(CH.sub.2).sub.n aryl, --(CH.sub.2).sub.n arylC.sub.1-12 alkyl, --(CH.sub.2).sub.n arylC.sub.2-12 alkenyl, --(CH.sub.2).sub.narylC.sub.2-12 alkynyl, and --(CH.sub.2).sub.n heterocyclyl; n is 0-6 and said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl and heterocyclyl groups are optionally substituted; R.sub.2 is selected from H, O, --CH.sub.2R.sub.3, --C(.dbd.Y)R.sub.3, --C(.dbd.Y)OR.sub.3, --C(.dbd.Y)N(R.sub.4)R.sub.3, --C(.dbd.Y)CH.sub.2N(R.sub.4)R.sub.3, --C(.dbd.Y)CH.sub.2SR.sub.3 and --S(O).sub.wR.sub.5, where R.sub.3 is selected from hydrogen, C.sub.1-12 alkyl, C.sub.2-12 alkenyl, C.sub.2-12 alkynyl, --(CH2).sub.mC.sub.3-7cycloalkyl, --(CH.sub.2).sub.mC.sub.4-7 cycloalkenyl, --(CH.sub.2).sub.m aryl, --(CH.sub.2).sub.m arylC.sub.1-12 alkyl, --(CH.sub.2).sub.m arylC.sub.2-12alkenyl, --(CH.sub.2).sub.m arylC.sub.2-12 alkynyl and --(CH.sub.2).sub.m heterocyclyl; and when R.sub.2 is --CH.sub.2R.sub.3, or --C(.dbd.Y)R.sub.3; R.sub.3 may also be selected from --S--R.sub.5 and --O--R.sub.5; m is 0-6; R.sub.4 is hydrogen or C.sub.1-6 alkyl; R.sub.5 is C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-7 cycloalkyl, C.sub.4-7 cycloalkenyl, benzyl, aryl or heterocyclyl; w is 0, 1 or 2, and the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl and heterocyclyl groups are optionally substituted; X is O and Y is selected from O, S and NR.sub.6, where R.sub.6 is independently selected from hydrogen, C.sub.1-6 alkyl, hydroxy and lower C.sub.1-6 alkoxy; A together with the atoms to which it is attached, forms an optionally substituted unsaturated 6-membered nitrogen containing heterocyclic ring; B-C is --CH.sub.2--CH.sub.2--; and D is --CH.sub.2--, and at least one pharmaceutically acceptable adjuvant, carrier or diluent. 23. A pharmaceutical composition according to claim 22 further comprising one or more anti-viral actives, selected from ribavirin, respiratory syncytial virus immunoglobulin, and palivizumab. 24. A compound selected from the group consisting of: ##STR00205## ##STR00206## ##STR00207## ##STR00208## ##STR00209## ##STR00210## ##STR00211## ##STR00212## ##STR00213## ##STR00214## ##STR00215## ##STR00216## ##STR00217## or a salt thereof. 25. A compound according to claim 1, which contains a stereogenic center at the point of attachment of R.sub.1 according to the following structure: ##STR00218## 26. A pharmaceutical composition comprising a compound of claim 25, and at least one pharmaceutically acceptable adjuvant, carrier or diluent. 27. A compound according to claim 2, wherein ring A is an optionally substituted heteroaryl ring selected from ##STR00219##

Details for Patent 9,675,694

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		2026-09-28
Swedish Orphan Biovitrum Ab (publ)	SYNAGIS	palivizumab	Injection	103770	07/23/2004		2026-09-28