Claims for Patent: 10,695,361

Summary for Patent: 10,695,361

Title:	Methods for treating arenaviridae and coronaviridae virus infections
Abstract:	Provided are methods for treating Arenaviridae and Coronaviridae virus infections by administering nucleosides and prodrugs thereof, of Formula I: wherein the 1′ position of the nucleoside sugar is substituted. The compounds, compositions, and methods provided are particularly useful for the treatment of Lassa virus and Junin virus infections.
Inventor(s):	Michael O'Neil Hanrahan Clarke, Joy Yang Feng, Robert Jordan, Richard L. Mackman, Adrian S. Ray, Dustin Siegel
Assignee:	Gilead Sciences Inc
Application Number:	US16/265,016
Patent Claims:	1. A method for treating a Coronaviridae 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) —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), and —SO2NR11R12, wherein each R11 and R12 is independently H, (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C4-C8)carbocyclylalkyl, optionally substituted aryl, optionally substituted heteroaryl, —C(═O)(C1-C8)alkyl, —S(O)n(C1-C8)alkyl or 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 is optionally replaced with —O—, —S— or —NRa—; each Ra is independently H, (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, 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), or —SO2NR2; wherein each R is independently 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, arylalkyl or substituted arylalkyl; and wherein each (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl or aryl(C1-C8)alkyl of each R11 and R12 is, independently, optionally substituted with one or more halo, hydroxy, CN, N3, N(Ra)2 or ORa; and wherein one or more of the non-terminal carbon atoms of each said (C1-C8)alkyl is optionally replaced with —O—, —S— or —NRa—, wherein: Rc is selected from the group consisting of phenyl, 1-naphthyl, 2-naphthyl, Rd is H or CH3; Re1 and Re2 are each independently H, C1-C6 alkyl or benzyl; and Rf is selected from the group consisting of H, C1-C8 alkyl, benzyl, C3-C6 cycloalkyl, and —CH2—C3-C6 cycloalkyl; and d) a group of the formula: wherein Q is O, S, NR, +N(O)(R), N(OR), +N(O)(OR), or N—NR2; Z1 and Z2, when taken together, are -Q1(C(Ry)2)3Q1-; wherein each Q1 is independently O, S, or NR; and each Ry is independently 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(=Q2)R, —OC(=Q2)OR, —OC(=Q2)(N(R)2), —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, or 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 a bond, O, CR2, NR, +N(O)(R), N(OR), +N(O)(OR), N—NR2, S—S, S(O), or S(O)2; M2 is 0, 1 or 2; each Rx is independently Ry or the formula: wherein: each M1a, M1c, and M1d is independently 0 or 1; M12c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 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. 2. The method of claim 1 wherein R7 is selected from the group consisting of a) 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), and —SO2NR11R12, wherein: Rc is selected from the group consisting of phenyl, 1-naphthyl, 2-naphthyl, Rd is H or CH3; Re1 and Re2 are each independently H or C1-C6 alkyl; and Rf is selected from the group consisting of H, C1-C8 alkyl, benzyl, C3-C6 cycloalkyl, and —CH2—C3-C6 cycloalkyl. 3. The method of claim 1 wherein R7 is wherein Z1 and Z2 are each, independently, a group having the structure: and Z3 is Z5. 4. The method of claim 1 wherein R7 is wherein each Q3b is, independently, O or N(R). 5. The method of claim 4 wherein each Q3b is O and each Rx is independently: wherein M12c is 1, 2 or 3 and each Q3 is independently a bond, O, or CR2. 6. The method of claim 1 wherein R7 is 7. The method of claim 1 wherein R7 is 8. The method of claim 1 wherein R7 is wherein Rf is selected from the group consisting of H, C1-C8 alkyl, benzyl, C3-C6 cycloalkyl, and —CH2—C3-C6 cycloalkyl; and Rg is selected from the group consisting of —O—C1-C8 alkyl, benzyl, —O-benzyl, —CH2—C3-C6 cycloalkyl, —O—CH2—C3-C6 cycloalkyl, and CF3. 9. The method of claim 1 wherein R7 is wherein Rf is selected from the group consisting of H, C1-C8 alkyl, benzyl, C3-C6 cycloalkyl, and —CH2—C3-C6 cycloalkyl. 10. The method of claim 9 wherein Rf is C1-C8 alkyl. 11. The method of claim 9 wherein Rf is C1-C6 alkyl. 12. The method of claim 1 wherein the compound of Formula IV is: or a pharmaceutically acceptable salt thereof. 13. The method of claim 1 wherein the compound of Formula IV is: or a pharmaceutically acceptable salt thereof. 14. The method of claim 1 wherein the compound of Formula IV is: or a pharmaceutically acceptable salt thereof. 15. The method of claim 1 wherein the compound of formula IV is: or a pharmaceutically acceptable salt thereof. 16. The method of claim 1 further comprising a pharmaceutically acceptable carrier or excipient. 17. 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 a Coronaviridae virus infection; or mixtures thereof. 18. The method of claim 1 wherein the Coronaviridae infection is caused by a Coronaviridae virus. 19. The method of claim 1 wherein the Coronaviridae infection is caused by a Coronaviridae virus selected from SARS, MERS, 229E, NL63, OC43, and HKU1. 20. The method of claim 1, wherein the compound of Formula IV is or a pharmaceutically acceptable salt thereof.