US 12,110,305 B2
Prodrugs of phosphonamide nucleotide analogues and their pharmaceutical use
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); Devan Naduthambi, San Bruno, CA (US); and Neil H. Squires, San Francisco, CA (US)
Assigned to Gilead Sciences, Inc., Foster City, CA (US)
Filed by Gilead Sciences, Inc., Foster City, CA (US)
Filed on Aug. 5, 2021, as Appl. No. 17/394,630.
Claims priority of provisional application 63/062,899, filed on Aug. 7, 2020.
Prior Publication US 2022/0119426 A1, Apr. 21, 2022
Int. Cl. C07F 9/36 (2006.01); A61K 45/06 (2006.01); A61P 31/18 (2006.01); A61P 31/20 (2006.01); C07F 9/6561 (2006.01)
CPC C07F 9/36 (2013.01) [A61K 45/06 (2013.01); A61P 31/18 (2018.01); A61P 31/20 (2018.01); C07F 9/65616 (2013.01)] 45 Claims
 
1. A compound of formula (I):

OG Complex Work Unit Chemistry
or a pharmaceutically acceptable salt thereof, wherein
R1 and R2 are independently chosen from C1-12alkyl, aryl-C1-4alkylene, C3-7cycloalkyl, C3-7cycloalkyl-C1-4alkylene, aryl-C3-7cycloalkylene, C7-12spirocycloalkyl, C7-12spirocycloalkyl-C1-4alkylene, bridged C5-10bicycloalkyl, bridged C5-10bicycloalkyl-C1-4alkylene, fused C5-10bicycloalkyl, C10-16dispirocycloalkyl, C10-16dispirocycloalkyl-C1-4alkylene, bridged C9-12tricycloalkyl, bridged C9-12tricycloalkyl-C1-4alkylene, C3-7cycloalkyl-C3-7cycloalkylene, and 5- to 7-membered monocyclic heterocyclyl having from 1 to 3 heteroatoms chosen from N, O, and S, wherein each C1-12alkyl, aryl-C1-4alkylene, C3-7cycloalkyl, C3-7cycloalkyl-C1-4alkylene, aryl-C3-7cycloalkylene, C7-12spirocycloalkyl, and C7-12spirocycloalkyl-C1-4alkylene is optionally substituted with from one to three Ra;
R3, R4, R5, and R6 are independently chosen from C1-4alkyl, C3-6cycloalkyl, and aryl-C1-4alkylene, wherein each C1-4alkyl, C3-6cycloalkyl, and aryl-C1-4alkylene is optionally substituted with from one to three Rb; or optionally:
R3 and R4 together with the carbon atom to which they are attached form a 3- to 6-membered saturated or partially unsaturated carbocyclic ring optionally substituted with from one to three Rb; and R5 and R6 are independently chosen from C1-4alkyl, C3-6cycloalkyl, and aryl-C1-4alkylene, wherein each C1-4alkyl, C3-6cycloalkyl, and aryl-C1-4alkylene is optionally substituted with from one to three Rb; or
R3 and R4 are independently chosen from C1-4alkyl, C3-6cycloalkyl, and aryl-C1-4alkylene, wherein each C1-4alkyl, C3-6cycloalkyl, and aryl-C1-4alkylene is optionally substituted with from one to three Rb; and R5 and R6 together with the carbon atom to which they are attached form a 3- to 6-membered saturated or partially unsaturated carbocyclic ring optionally substituted with from one to three Rb; or
R3 and R4 together with the carbon atom to which they are attached form a 3- to 6-membered saturated or partially unsaturated carbocyclic ring optionally substituted with from one to three Rb; and R5 and R6 together with the carbon atom to which they are attached form a 3- to 6-membered saturated or partially unsaturated carbocyclic ring optionally substituted with from one to three Rb;
B is

OG Complex Work Unit Chemistry
R7 is hydrogen or R8;
R8 is -L1-(L2)m-(L3)n-R8a;
L1 is chosen from a bond, —C(O)—, and —C(O)O—;
L2 is C1-6alkylene;
L3 is —C(O)O— or

OG Complex Work Unit Chemistry
R8a is chosen from C1-12alkyl, aryl, —C(O)-aryl, —C(O)—C1-4alkyl, —S—C(O)—C1-4alkyl,

OG Complex Work Unit Chemistry
 wherein aryl and —C(O)-aryl are optionally substituted with one or two Rc;
each Ra is independently chosen from C1-4alkyl, halo, C1-4haloalkyl, and —O—C1-4alkyl;
each Rb is independently C1-4alkyl;
each Rc is independently C1-4alkyl or —OC(O)—C1-4alkyl;
m and n are independently 0 or 1; and
p is 0, 1, or 2.