US 11,939,347 B2
1′-cyano nucleoside analogs and uses thereof
Daniel H. Byun, Foster City, CA (US); Byoung-Kwon Chun, Pleasanton, CA (US); Michael O. Clarke, Redwood City, CA (US); Petr Jansa, Foster City, CA (US); Rao V. Kalla, Cupertino, CA (US); Dmitry Koltun, Foster City, CA (US); Richard L. Mackman, Millbrae, CA (US); Thao D. Perry, San Jose, CA (US); Dustin S. Siegel, Half Moon Bay, CA (US); and Scott P. Simonovich, San Francisco, CA (US)
Assigned to Gilead Sciences, Inc., Foster City, CA (US)
Filed by Gilead Sciences, Inc., Foster City, CA (US)
Filed on Jun. 23, 2021, as Appl. No. 17/355,813.
Claims priority of provisional application 63/139,648, filed on Jan. 20, 2021.
Claims priority of provisional application 63/043,349, filed on Jun. 24, 2020.
Prior Publication US 2023/0040586 A1, Feb. 9, 2023
Int. Cl. A61K 31/675 (2006.01); A61K 45/06 (2006.01); A61P 31/12 (2006.01); C07F 9/6561 (2006.01)
CPC C07F 9/6561 (2013.01) [A61K 45/06 (2013.01)] 45 Claims
 
1. A compound of Formula I:

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or a pharmaceutically acceptable salt thereof, wherein
each R1 and R2 is independently H, —(CO)C1-C6 alkyl or —(CO)OC1-C6 alkyl, wherein the —(C(O)C1-C6 alkyl or —(CO)OC1-C6 alkyl is optionally substituted with a NH2 group; or
R1 and R2 are combined to form —CO—, —CO—CO—, or —C(O)—C(R1A)(R1B)—C(O)—;
wherein each R1A and R1B is independently H or C1-C6 alkyl;
R3A is H or C1-C6 alkyl; wherein the C1-C6 alkyl is optionally substituted with a —OH or phenyl;
R3B is H or C1-C3 alkyl; and
R4 is (i) C1-C8 alkyl, (ii) (CR8R9CR10R11O)mR12, (iii) C3-C10 cycloalkyl, (iv) 4 to 6 membered heterocyclyl having 1 to 3 heteroatoms independently selected from N, O and S, or (v) 5 to 6 membered heteroaryl having 1 to 3 heteroatoms independently selected from N, O and S; wherein the C1-C8 alkyl, C3-C10 cycloalkyl, 4 to 6 membered heterocyclyl, or 5 to 6 membered heteroaryl is optionally substituted with one or two R4A groups; wherein
each R4A is independently C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C3-C10 cycloalkyl, C6-C10 aryl, or 4 to 6 membered heterocyclyl having 1 to 3 heteroatoms independently selected from N, O and S; wherein the C3-C10 cycloalkyl, C6-C10 aryl, or 4 to 6 membered heterocyclyl is optionally substituted with one or two substituents independently selected from the group consisting of C1-C6 alkyl, halo, C1-C6 haloalkyl, and C1-C6 alkoxy;
Base is

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 wherein
R6 is —N(H)R6A; and
each R6A, R7A and R7B is independently H or —CH2OP(O)(OH)2;
Ar is C6-C10 aryl or 5 to 10 membered heteroaryl containing one, two, or three heteroatoms selected from the group consisting of O, N, and S;
n is 0, 1, 2, or 3;
each R5 is independently halo, cyano, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C3-C6 cycloalkoxy, —COOR5A, —SO2R5A, 4 to 6 membered heterocycloalkyl containing one, two or three heteroatoms selected from N, O, and S, or 5 to 6 membered heteroaryl containing one, two or three heteroatoms selected from N, O, and S; wherein the C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, C3-C6 cycloalkoxy, C1-C6 alkoxy, 4 to 6 membered heterocycloalkyl and 5 to 6 membered heteroaryl is optionally substituted with one or two R5B groups; or
two R5 groups on adjacent carbon atoms are joined to form a C5-C6 cycloalkyl;
each R5A is independently C1-C6 alkyl;
each R5B is independently —OH, —OR5C, —COOR5c and —NHCOOR5D; wherein R5C is C1-C6 alkyl and R5D is C1-C3 alkyl optionally substituted with a phenyl group;
each R8, R9, R10, R11 and R12 is independently H or C1-C3 alkyl;
m is 1, 2, 3, 4, or 5;
provided that when R1 and R2 are both H then:
(i) n is 1, 2, or 3; or
(ii) R4 is C1-C8 alkyl substituted with one or two groups independently selected from C1-C3 alkoxy, C1-C3 haloalkyl, C3-C10 cycloalkyl, C6-C10 aryl, or 4 to 6 membered heterocyclyl having 1 to 3 heteroatoms independently selected from N, O and S;
 wherein the C3-C10 cycloalkyl, C6-C10 aryl, or 4 to 6 membered heterocyclyl is optionally substituted with one or two substituents independently selected from the group consisting of C1-C6 alkyl, halo, C1-C6 haloalkyl, and C1-C6 alkoxy; or
(iii) R4 is (a) —(CR8R9CR10R11O)mR12, (b) monocyclic C3-C10 cycloalkyl substituted with substituted with one or two R4A groups, (c) bicyclic C3-C10 cycloalkyl, (d) 4 to 6 membered heterocyclyl having 1 to 3 heteroatoms independently selected from N, O and S, or (e) 5 to 6 membered heteroaryl having 1 to 3 heteroatoms independently selected from N, O and S;
wherein the bicyclic C3-C10 cycloalkyl, 4 to 6 membered heterocyclyl, or 5 to 6 membered heteroaryl is optionally substituted with one or two R4A groups; or
(iv) Base is

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 and at least one of R6A and R7A is —CH2OP(O)(OH)2; or Base is

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«and at least one of R6A and R7B is —CH2OP(O)(OH)2.