Claims for Patent: 9,949,994

Summary for Patent: 9,949,994

Title:	Methods for treating Filoviridae virus infections
Abstract:	Provided are compounds, methods, and pharmaceutical compositions for treating Filoviridae virus infections by administering ribosides, riboside phosphates and prodrugs thereof, of Formula IV: The compounds, compositions, and methods provided are particularly useful for the treatment of Marburg virus, Ebola virus and Cueva virus infections.
Inventor(s):	Byoung Kwon Chun, Michael O'Neil Hanrahan Clarke, Edward Doerffler, Hon Chung Hui, Robert Jordan, Richard L. Mackman, Jay P. Parrish, Adrian S. Ray, Dustin Siegel
Assignee:	Gilead Sciences Inc
Application Number:	US15/246,240
Patent Claims:	1. A method of treating a Filoviridae infection in a human in need thereof comprising administering a therapeutically effective amount of a compound of Formula IV: or a pharmaceutically acceptable salt thereof; wherein, R7 is selected from the group consisting of a) H, —C(═O)R11, —C(═O)OR11, —C(═O)NR11R12, —C(═O)SR11, —S(O)R11, —S(O)2R11, —S(O)(OR11), —S(O)2(OR11), or —SO2NR11R12; c) a group selected from: wherein: Rc is selected from the group of phenyl, 1-naphthyl, 2-naphthyl, Rd is selected from the group of H and CH3; Re1 and Re2 are each independently selected from the group of H, (C1-C6)alkyl and benzyl; Rf is selected from the group of H, (C1-C8)alkyl, benzyl, (C3-C6)cycloalkyl, and —CH2—(C3-C6)cycloalkyl; Rg is selected from the group of (C1-C8)alkyl, —O—(C1-C8)alkyl, benzyl, —O-benzyl, —CH2—(C3-C6)cycloalkyl, —O—CH2—(C3-C6)cycloalkyl, and CF3; and n′ is an integer selected from the group of 1, 2, 3, and 4; and d) a group of the formula: wherein: Q is selected from the group of O, S, NR, +N(O)(R), N(OR), +N(O)(OR), and N—NR2; Z1 and Z2, when taken together, are -Q1(C(RY)2)3Q1-; wherein each Q1 is independently selected from the group of O, S, and NR; and each Ry is independently selected from the group of H, F, Cl, Br, I, OH, R, —C(=Q2)R, —C(=Q2)OR, —C(=Q2)N(R)2, —N(R)2, —+N(R)3, —SR, —S(O)R, —S(O)2R, —S(O)(OR), —S(O)2(OR), —OC(=Q1)R, —OC(=Q2)OR, —OC(=Q2)(N(R)2), —SC(=Q2)R, —SC(=Q2)OR, —SC(=Q2)(N(R)2), —N(R)C(=Q2)R, —N(R)C(=Q2)OR, —N(R)C(=Q2)N(R)2, —SO2NR2, —CN, —N3, —NO2, —OR, and Z3; or when taken together, two Ry on the same carbon atom form a carbocyclic ring of 3 to 7 carbon atoms; each Q2 is independently, O, S, NR, +N(O)(R), N(OR), +N(O)(OR), or N—NR2; or Z1 and Z2 are each, independently, a group of the Formula Ia: wherein: each Q3 is independently selected from the group of a bond, O, CR2, NR, +N(O)(R), N(OR), +N(O)(OR), N—NR2, S, S—S, S(O), and S(O)2; M2 is an integer selected from the group of 0, 1 and 2; each Rx is independently Ry or the formula: wherein: each M1a, M1c, and M1d is an integer independently selected from the group of 0 and 1; M12c is an integer selected from the group of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12; Z3 is Z4 or Z5; Z4 is R, —C(Q2)Ry, —C(Q2)Z5, —SO2Ry, or —SO2Z5; and Z5 is a carbocycle or a heterocycle wherein Z5 is independently substituted with 0 to 3 Ry groups; each R11 or R12 is independently H, (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C4-C8)carbocyclylalkyl, (C6-C20)optionally substituted aryl, optionally substituted heteroaryl, —C(═O)(C1-C8)alkyl, —S(O)n(C1-C8)alkyl or (C6-C20)aryl(C1-C8)alkyl; or R11 and R12 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—or —NRa—; each Ra is independently selected from the group of H, (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C6-C20)aryl(C1-C8)alkyl, (C4-C8)carbocyclylalkyl, —C(═O)R, —C(═O)OR, —C(═O)NR2, —C(═O)SR, —S(O)R, —S(O)2R, —S(O)(OR), —S(O)2(OR), and —SO2NR2; wherein each R is independently selected from the group of H, (C1-C8) alkyl, (C1-C8) substituted alkyl, (C2-C8)alkenyl, (C2-C8) substituted alkenyl, (C2-C8) alkynyl, (C2-C8) substituted alkynyl, (C6-C20)aryl, (C6-C20)substituted aryl, (C2-C20)heterocyclyl, (C2-C20)substituted heterocyclyl, (C6-C20)aryl(C1-C8)alkyl and substituted (C6-C20)aryl(C1-C8)alkyl; each n is an integer independently selected from the group of 0, 1, and 2; and wherein each (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl or (C6-C20)aryl(C1-C8)alkyl of each R11 or R12 is, independently, optionally substituted with one or more substituents selected from the group of halo, hydroxy, CN, N3, N(Ra)2 and ORa; and wherein one or more of the non-terminal carbon atoms of each said (C1-C8)alkyl may be optionally replaced with —O—, —S—or —NRa—. 2. The method of claim 1 wherein R7 is H. 3. The method of claim 1 wherein R7 is wherein Rf is selected from the group of H, C1-C8 alkyl, benzyl, C3-C6 cycloalkyl, and —CH2—C3-C6 cycloalkyl; and Rg is selected from the group of C1-C8 alkyl, —O—C1-C8 alkyl, benzyl, —O-benzyl, —CH2—C3-C6 cycloalkyl, —O—CH2—C3-C6 cycloalkyl, and CF3. 4. The method of claim 1 wherein R7 is 5. The method of claim 1 wherein the compound of Formula IV is: or a pharmaceutically acceptable salt thereof. 6. The method of claim 1 wherein the compound of Formula IV is: or a pharmaceutically acceptable salt thereof. 7. The method of claim 1 further comprising administering a therapeutically effective amount of at least one other therapeutic agent or composition thereof selected from the group consisting of a corticosteroid, an anti-inflammatory signal transduction modulator, a β2-adrenoreceptor agonist bronchodilator, an anticholinergic, a mucolytic agent, hypertonic saline and other drugs for treating Filoviridae virus infections; or mixtures thereof. 8. The method of claim 7 wherein the at least one other therapeutic agent is ribavirin, palivizumab, motavizumab, RSV-IGIV (RespiGam®), MEDI-557, A-60444, MDT-637, BMS-433771, amiodarone, dronedarone, verapamil, Ebola Convalescent Plasma (ECP), TKM-100201, BCX4430((2S,3S,4R,5R)-2-(4-amino-5H-pyrrolo[3,2-d]pyrimidin-7-yl)-5-(hydroxymethyl)pyrrolidine-3,4-diol), favipiravir (also known as T-705 or Avigan), T-705 monophosphate, T-705 diphosphate, T-705 triphosphate, FGI-106 (1-N,7-N-bis[3-(dimethylamino)propyl]-3,9-dimethylquinolino[8,7-h]quinolone-1,7-diamine), JK-05, TKM-Ebola, ZMapp, rNAPc2, VRC-EBOADC076-00-VP, OS-2966, MVA-BN filo, brincidofovir, Vaxart adenovirus vector 5-based ebola vaccine, Ad26-ZEBOV, FiloVax vaccine, GOVX-E301, GOVX-E302, ebola virus entry inhibitors (NPC1 inhibitors), or rVSV-EBOV or mixtures thereof. 9. The method of claim 1 wherein the Filoviridae infection is caused by a Filoviridae virus. 10. The method of claim 1 wherein the Filoviridae infection is caused by an ebolavirus. 11. The method of claim 1 wherein the Filoviridae infection is caused by Bundibugyo ebolavirus, Reston ebolavirus, Sudan ebolavirus, Tai Forest ebolavirus, or Zaire ebolavirus. 12. The method of claim 1 wherein the Filoviridae infection is caused by a Marburg virus. 13. A compound: or a pharmaceutically acceptable salt thereof. 14. A method of treating a Filoviridae infection in a human in need thereof comprising administering a pharmaceutical composition comprising a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable carrier or excipient; the method 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 (RespiGam®), MEDI-557, A-60444, MDT-637, BMS-433771, amiodarone, dronedarone, verapamil, Ebola Convalescent Plasma (ECP), TKM-100201, BCX4430((2S,3S,4R,5R)-2-(4-amino-5H-pyrrolo[3,2-d]pyrimidin-7-yl)-5-(hydroxymethyl)pyrrolidine-3,4-diol), favipiravir (also known as T-705 or Avigan), T-705 monophosphate, T-705 diphosphate, T-705 triphosphate, FGI-106 (1-N,7-N-bis[3-(dimethylamino)propyl]-3,9-dimethylquinolino[8,7-h]quinolone-1,7-diamine), JK-05, TKM-Ebola, ZMapp, rNAPc2, VRC-EBOADC076-00-VP, OS-2966, MVA-BN filo, brincidofovir, Vaxart adenovirus vector 5-based ebola vaccine, Ad26-ZEBOV, FiloVax vaccine, GOVX-E301, GOVX-E302, ebola virus entry inhibitors (NPC1 inhibitors), rVSV-EBOV and mixtures thereof. 15. The method of claim 14 wherein the at least one other therapeutic agent is ZMapp.