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: ##STR00001## The compounds, compositions, and methods provided are particularly useful for the treatment of Marburg virus, Ebola virus and Cueva virus infections.
Inventor(s):	Chun; Byoung Kwon (Pleasanton, CA), Clarke; Michael O'Neil Hanrahan (Redwood City, CA), Doerffler; Edward (Foster City, CA), Hui; Hon Chung (Foster City, CA), Jordan; Robert (Foster City, CA), Mackman; Richard L. (Millbrae, CA), Parrish; Jay P. (El Dorado Hills, CA), Ray; Adrian S. (Burlingame, CA), Siegel; Dustin (San Carlos, CA)
Assignee:	GILEAD SCIENCES, INC. (Foster City, CA)
Application Number:	15/246,240
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: ##STR00150## or a pharmaceutically acceptable salt thereof; wherein, R.sup.7 is selected from the group consisting of a) H, --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)R.sup.11, --S(O).sub.2R.sup.11, --S(O)(OR.sup.11), --S(O).sub.2(OR.sup.11), or --SO.sub.2NR.sup.11R.sup.12; ##STR00151## c) a group selected from: ##STR00152## wherein: R.sup.c is selected from the group of phenyl, 1-naphthyl, 2-naphthyl, ##STR00153## R.sup.d is selected from the group of H and CH.sub.3; R.sup.e1 and R.sup.e2 are each independently selected from the group of H, (C.sub.1-C.sub.6)alkyl and benzyl; R.sup.f is selected from the group of H, (C.sub.1-C.sub.8)alkyl, benzyl, (C.sub.3-C.sub.6)cycloalkyl, and --CH.sub.2--(C.sub.3-C.sub.6)cycloalkyl; R.sup.g is selected from the group of (C.sub.1-C.sub.8)alkyl, --O--(C.sub.1-C.sub.8)alkyl, benzyl, --O-benzyl, --CH.sub.2--(C.sub.3-C.sub.6)cycloalkyl, --O--CH.sub.2--(C.sub.3-C.sub.6)cycloalkyl, and CF.sub.3; and n' is an integer selected from the group of 1, 2, 3, and 4; and d) a group of the formula: ##STR00154## wherein: Q is selected from the group of O, S, NR, .sup.+N(O)(R), N(OR), .sup.+N(O)(OR), and N--NR.sub.2; Z.sup.1 and Z.sup.2, when taken together, are -Q.sup.1(C(R.sup.Y).sub.2).sub.3Q.sup.1-; wherein each Q.sup.1 is independently selected from the group of O, S, and NR; and each R.sup.y is independently selected from the group of H, F, Cl, Br, I, OH, R, --C(=Q.sup.2)R, --C(=Q.sup.2)OR, --C(=Q.sup.2)N(R).sub.2, --N(R).sub.2, --.sup.+N(R).sub.3, --SR, --S(O)R, --S(O).sub.2R, --S(O)(OR), --S(O).sub.2(OR), --OC(=Q.sup.1)R, --OC(=Q.sup.2)OR, --OC(=Q.sup.2)(N(R).sub.2), --SC(=Q.sup.2)R, --SC(=Q.sup.2)OR, --SC(=Q.sup.2)(N(R).sub.2), --N(R)C(=Q.sup.2)R, --N(R)C(=Q.sup.2)OR, --N(R)C(=Q.sup.2)N(R).sub.2, --SO.sub.2NR.sub.2, --CN, --N.sub.3, --NO.sub.2, --OR, and Z.sup.3; or when taken together, two R.sup.y on the same carbon atom form a carbocyclic ring of 3 to 7 carbon atoms; each Q.sup.2 is independently, O, S, NR, .sup.+N(O)(R), N(OR), .sup.+N(O)(OR), or N--NR.sub.2; or Z.sup.1 and Z.sup.2 are each, independently, a group of the Formula Ia: ##STR00155## wherein: each Q.sup.3 is independently selected from the group of a bond, O, CR.sub.2, NR, .sup.+N(O)(R), N(OR), .sup.+N(O)(OR), N--NR.sub.2, S, S--S, S(O), and S(O).sub.2; M2 is an integer selected from the group of 0, 1 and 2; each R.sup.x is independently R.sup.y or the formula: ##STR00156## 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; Z.sup.3 is Z.sup.4 or Z.sup.5; Z.sup.4 is R, --C(Q.sup.2)R.sup.y, --C(Q.sup.2)Z.sup.5, --SO.sub.2R.sup.y, or --SO.sub.2Z.sup.5; and Z.sup.5 is a carbocycle or a heterocycle wherein Z.sup.5 is independently substituted with 0 to 3 R.sup.y groups; 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, (C.sub.4-C.sub.8)carbocyclylalkyl, (C.sub.6-C.sub.20)optionally substituted aryl, optionally substituted heteroaryl, --C(.dbd.O)(C.sub.1-C.sub.8)alkyl, --S(O).sub.n(C.sub.1-C.sub.8)alkyl or (C.sub.6-C.sub.20)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--or --NR.sup.a--; each R.sup.a is independently selected from the group of H, (C.sub.1-C.sub.8)alkyl, (C.sub.2-C.sub.8)alkenyl, (C.sub.2-C.sub.8)alkynyl, (C.sub.6-C.sub.20)aryl(C.sub.1-C.sub.8)alkyl, (C.sub.4-C.sub.8)carbocyclylalkyl, --C(.dbd.O)R, --C(.dbd.O)OR, --C(.dbd.O)NR.sub.2, --C(.dbd.O)SR, --S(O)R, --S(O).sub.2R, --S(O)(OR), --S(O).sub.2(OR), and --SO.sub.2NR.sub.2; wherein each R is independently selected from the group of H, (C.sub.1-C.sub.8) alkyl, (C.sub.1-C.sub.8) substituted alkyl, (C.sub.2-C.sub.8)alkenyl, (C.sub.2-C.sub.8) substituted alkenyl, (C.sub.2-C.sub.8) alkynyl, (C.sub.2-C.sub.8) substituted alkynyl, (C.sub.6-C.sub.20)aryl, (C.sub.6-C.sub.20)substituted aryl, (C.sub.2-C.sub.20)heterocyclyl, (C.sub.2-C.sub.20)substituted heterocyclyl, (C.sub.6-C.sub.20)aryl(C.sub.1-C.sub.8)alkyl and substituted (C.sub.6-C.sub.20)aryl(C.sub.1-C.sub.8)alkyl; each n is an integer independently selected from the group of 0, 1, and 2; and wherein each (C.sub.1-C.sub.8)alkyl, (C.sub.2-C.sub.8)alkenyl, (C.sub.2-C.sub.8)alkynyl or (C.sub.6-C.sub.20)aryl(C.sub.1-C.sub.8)alkyl of each R.sup.11 or R.sup.12 is, independently, optionally substituted with one or more substituents selected from the group of halo, hydroxy, CN, N.sub.3, N(R.sup.a).sub.2 and OR.sup.a; and wherein one or more of the non-terminal carbon atoms of each said (C.sub.1-C.sub.8)alkyl may be optionally replaced with --O--, --S--or --NR.sup.a--. 2. The method of claim 1 wherein R.sup.7 is H. 3. The method of claim 1 wherein R.sup.7 is ##STR00157## wherein R.sup.f is selected from the group of H, C.sub.1-C.sub.8 alkyl, benzyl, C.sub.3-C.sub.6 cycloalkyl, and --CH.sub.2--C.sub.3-C.sub.6 cycloalkyl; and R.sup.g is selected from the group of C.sub.1-C.sub.8 alkyl, --O--C.sub.1-C.sub.8 alkyl, benzyl, --O-benzyl, --CH.sub.2--C.sub.3-C.sub.6 cycloalkyl, --O--CH.sub.2--C.sub.3-C.sub.6 cycloalkyl, and CF.sub.3. 4. The method of claim 1 wherein R.sup.7 is ##STR00158## 5. The method of claim 1 wherein the compound of Formula IV is: ##STR00159## ##STR00160## or a pharmaceutically acceptable salt thereof. 6. The method of claim 1 wherein the compound of Formula IV is: ##STR00161## 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 .beta.2-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.RTM.), 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-(hydr- oxymethyl)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: ##STR00162## ##STR00163## ##STR00164## 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 ##STR00165## 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.RTM.), 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-(hydr- oxymethyl)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.