	US 12,247,004 B2
	2-amino-N-(amino-oxo-aryl-lambda⁶-sulfanylidene)acetamide compounds and their therapeutic use
Grace Edmund, London (GB); Michael H. Charlton, Oxford (GB); Paul William Finn, Faringdon (GB); Aigars Jirgensons, Riga (LV); Marija Skvorcova, Riga (LV); Janis Veliks, Riga (LV); and Liene Grigorjeva, Riga (LV)
Assigned to Oxford Drug Design Limited, London (GB)
Appl. No. 17/786,089
Filed by Oxford Drug Design Limited, London (GB)
PCT Filed Dec. 18, 2020, PCT No. PCT/EP2020/087126 § 371(c)(1), (2) Date Jun. 16, 2022, PCT Pub. No. WO2021/123237, PCT Pub. Date Jun. 24, 2021.
Claims priority of provisional application 62/950,311, filed on Dec. 19, 2019.
Prior Publication US 2023/0114875 A1, Apr. 13, 2023
Int. Cl. C07C 381/10 (2006.01); C07C 313/06 (2006.01); C07D 213/71 (2006.01); C07D 215/36 (2006.01); C07D 231/18 (2006.01); C07D 277/16 (2006.01); C07D 307/79 (2006.01); C07D 317/50 (2006.01); C07D 333/34 (2006.01); C07D 333/52 (2006.01); C07D 495/04 (2006.01)

CPC C07C 381/10 (2013.01) [C07C 313/06 (2013.01); C07D 213/71 (2013.01); C07D 215/36 (2013.01); C07D 231/18 (2013.01); C07D 277/16 (2013.01); C07D 307/79 (2013.01); C07D 317/50 (2013.01); C07D 333/34 (2013.01); C07D 333/52 (2013.01); C07D 495/04 (2013.01)]

24 Claims

1. A compound selected from compounds of the following formula, and pharmaceutically acceptable salts thereof:

wherein:

-A is independently -A^Cor -A^H;

-A^Cis independently phenyl or naphthyl, and is optionally substituted with one or more substituents —R^X;

-A^His independently C_5-12heteroaryl, and is optionally substituted with one or more substituents —R^X;

and wherein:

each —R^Xis independently selected from:

—R^XX, —R^XXU, —R^XXV,

—F, —Cl, —Br, —I,

—OH, —OR^XX,

-L^XX-OH, -L^XX-OR^XX,

—CF₃, —CHF₂, —OCF₃, —OCHF₂,

—NH₂, —NHR^XX, —NR^XX₂, —R^XM,

-L^XX-NH₂, -L^XX-NHR^XX, -L^XX-NR^XX₂, -L^XX-R^XM,

—C(═O)OH, —C(═O)OR^XX, —OC(═O)R^XX,

—C(═O)NH₂, —C(═O)NHR^XX, —C(═O)NR^XX₂, —C(═O)R^XM,

—NHC(═O)R^XX, —NR^XNC(═O)R^XX,

—NHC(═O)NH₂, —NHC(═O)NHR^XX, —NHC(═O)NR^XX₂, —NHC(═O)R^XM,

—NR^XNC(═O)NH₂, —NR^XNC(═O)NHR^XX, —NR^XNC(═O)NR^XX₂, —NR^XNC(═O)R^XM,

—NHC(═O)OR^XX, —NR^XNC(═O)OR^XX,

—OC(═O)NH₂, —OC(═O)NHR^XX, —OC(═O)NR^XX₂, —OC(═O)R^XM,

—NHC(═NH)NH₂,

—C(═O)R^XX,

—S(═O)NH₂, —S(═O)NHR^XX, —S(═O)NR^XX₂, —S(═O)R^XM,

—S(═O)₂NH₂, —S(═O)₂NHR^XX, —S(═O)₂NR^XX₂, —S(═O)₂R^XM,

—NHS(═O)R^XX, —NR^XNS(═O)R^XX,

—NHS(═O)₂R^XX, —NR^XNS(═O)₂R^XX,

—S(═O)R^XX, —S(═O)₂R^XX,

—SH, —SR^XX, —CN, and —NO₂;

and additionally, two adjacent groups —R^X, if present, may together form:

—O—CH₂—O—, —O—CH₂CH₂—O—, —CH₂—CH₂—O—, —CH₂—CH₂CH₂—O—,

—CH₂—O—CH₂—, or —CH₂—CH₂—O—CH₂—;

wherein:

each -L^XX- is linear or branched saturated C_1-4alkylene;

each —R^XXis independently linear or branched saturated C_1-4alkyl, phenyl, or —CH₂-phenyl, wherein each phenyl is optionally substituted with one or more groups selected from —F, —Cl, —Br, -Me, —OH, —OMe, —CF₃, and —OCF₃;

each —R^XXUis independently linear or branched C_2-4alkenyl;

each —R^XXVis independently linear or branched C_2-4alkynyl;

each —R^XNis linear or branched saturated C_1-4alkyl;

each —R^XMis independently azetidino, pyrrolidino, piperidino, piperazino, morpholino, azepano, or diazepano, and is:

optionally substituted with one or more groups selected from:

—R^XMM, —C(═O)R^XMM, —C(═O)OR^XMM, and —S(═O)₂R^XMM;

wherein each —R^XMMis independently linear or branched saturated C_1-4alkyl, phenyl, or —CH₂-phenyl, wherein each phenyl is optionally substituted with one or more groups selected from —F, —Cl, —Br, -Me, —OH, —OMe, —CF₃, and —OCF₃;

—R¹is independently —H or —R¹¹;

—R¹¹is independently —R^11Aor —R^11B;

—R^11Ais independently:

—R^A1, —R^A2, —R^A3, —R^A4, —R^A5, -L^A-R^A2, -L^A-R^A3, -L^A-R^A4, or -L^A-R^A5;

each —R^A1is linear or branched saturated C_1-6alkyl, and is optionally substituted with one or more groups —R^AA2;

each —R^A2is saturated C_3-6cycloalkyl, and is optionally substituted with one or more groups —R^AA1and one or more groups —R^AA2;

each —R^A3is non-aromatic C_3-7heterocyclyl, and is optionally substituted with one or more groups —R^AA1and one or more groups —R^AA2;

each —R^A4is independently phenyl or naphthyl, and is optionally substituted with one or more groups —R^AA1and one or more groups —R^AA2;

each —R^A5is C_5-10heteroaryl, and is optionally substituted with one or more groups —R^AA1and one or more groups —R^AA2;

each -L^A- is linear or branched saturated C_1-4alkylene;

each —R^AA1is independently selected from:

—R^AA,

-L^AA-OH, -L^AA-OR^AA,

-L^AA-NH₂, -L^AA-NHR^AA, -L^AA-N(R^AA)₂, and -L^AA-R^AM;

each —R^AA2is independently selected from:

—F, —Cl, —Br, —I,

—OH, —OR^AA,

—CF₃, —CHF₂, —OCF₃, —OCHF₂,

—NH₂, —NHR^AA, —N(R^AA)₂, —R^AM,

—C(═O)OH, —C(═O)OR^AA, —OC(═O)R^AA,

—C(═O)NH₂, —C(═O)NHR^AA, —C(═O)N(R^AA)₂, —C(═O)R^AM,

—NHC(═O)R^AA, —NR^ANC(═O)R^AA,

—NHC(═O)NH₂, —NHC(═O)NHR^AA, —NHC(═O)N(R^AA)₂, —NHC(═O)R^AM,

—NR^ANC(═O)NH₂, —NR^ANC(═O)NHR^AA, —NR^ANC(═O)N(R^AA)₂, —NR^ANC(═O)R^AM,

—NHC(═O)OR^AA, —NR^ANC(═O)OR^AA,

—OC(═O)NH₂, —OC(═O)NHR^AA, —OC(═O)N(R^AA)₂, —OC(═O)R^AM,

—NHC(═NH)NH₂,

—C(═O)R^AA,

—S(═O)NH₂, —S(═O)NHR^AA, —S(═O)N(R^AA)₂, —S(═O)R^AM,

—S(═O)₂NH₂, —S(═O)₂NHR^AA, —S(═O)₂N(R^AA)₂, —S(═O)₂R^AM,

—NHS(═O)R^AA, —NR^ANS(═O)R^AA,

—NHS(═O)₂R^AA, —NR^ANS(═O)₂R^AA,

—S(═O)R^AA, —S(═O)₂R^AA,

—SH, —SR^AA, —CN, and —NO₂;

wherein:

each -L^AA- is linear or branched saturated C_1-4alkylene;

each —R^AAis independently linear or branched saturated C_1-4alkyl, phenyl, or —CH₂-phenyl, wherein each phenyl is optionally substituted with one or more groups selected from —F, —Cl, —Br, -Me, —OH, —OMe, —CF₃, and —OCF₃;

each —R^ANis linear or branched saturated C_1-4alkyl;

each —R^AMis independently azetidino, pyrrolidino, piperidino, piperazino, morpholino, azepano, or diazepano, and is:

optionally substituted with one or more groups selected from:

—R^AMM, —C(═O)R^AMM, —C(═O)OR^AMM, and —S(═O)₂R^AMM;

wherein each —R^AMMis independently linear or branched saturated C_1-4alkyl, phenyl, or —CH₂-phenyl, wherein each phenyl is optionally substituted with one or more groups selected from —F, —Cl, —Br, -Me, —OH, —OMe, —CF₃, and —OCF₃;

—R^11Bis independently selected from:

—F, —Cl, —Br, —I,

—OH, —OR^BB,

—CF₃, —CHF₂, —OCF₃, —OCHF₂,

—NH₂, —NHR^BB, —NR^BB₂, —R^BM,

—C(═O)OH, —C(═O)OR^BB, —OC(═O)R^BB,

—C(═O)NH₂, —C(═O)NHR^BB, —C(═O)NR^BB₂, —C(═O)R^BM,

—NHC(═O)R^BB, —NR^BNC(═O)R^BB,

—NHC(═O)NH₂, —NHC(═O)NHR^BB, —NHC(═O)NR^BB₂, —NHC(═O)R^BM,

—NR^BNC(═O)NH₂, —NR^BNC(═O)NHR^BB, —NR^BNC(═O)NR^BB₂, —NR^BNC(═O)R^BM,

—NHC(═O)OR^BB, —NR^BNC(═O)OR^BB,

—OC(═O)NH₂, —OC(═O)NHR^BB, —OC(═O)NR^BB₂, —OC(═O)R^BM,

—NHC(═NH)NH₂,

—C(═O)R^BB,

—S(═O)NH₂, —S(═O)NHR^BB, —S(═O)NR^BB₂, —S(═O)R^BM,

—S(═O)₂NH₂, —S(═O)₂NHR^BB, —S(═O)₂NR^BB₂, —S(═O)₂R^BM,

—NHS(═O)R^BB, —NR^BNS(═O)R^BB,

—NHS(═O)₂R^BB, —NR^BNS(═O)₂R^BB,

—S(═O)R^BB, —S(═O)₂R^BB,

—SH, —SR^BB, —CN, and —NO₂;

wherein:

each —R^BBis independently linear or branched saturated C_1-4alkyl, phenyl, or —CH₂-phenyl, wherein each phenyl is optionally substituted with one or more groups selected from —F, —Cl, —Br, -Me, —OH, —OMe, —CF₃, and —OCF₃;

each —R^BNis linear or branched saturated C_1-4alkyl;

each —R^BMis independently azetidino, pyrrolidino, piperidino, piperazino, morpholino, azepano, or diazepano, and is:

optionally substituted with one or more groups selected from:

—R^BMM, —C(═O)R^BMM, —C(═O)OR^BMM, and —S(═O)₂R^BMM;

wherein each —R^BMMis independently linear or branched saturated C_1-4alkyl, phenyl, or —CH₂-phenyl, wherein each phenyl is optionally substituted with one or more groups selected from —F, —Cl, —Br, -Me, —OH, —OMe, —CF₃, and —OCF₃;

—R²is independently —H or —R²²;

—R²²is independently —R^22Cor —R^22D;

—R^22Cis independently:

—R^C1, —R^C2, —R^C3, —R^C4, —R^C5, -L^C-R^C2, -L^C-R^C3, -L^C-R^C4, or -L^C-R^C5;

each —R^C1is linear or branched saturated C_1-6alkyl, and is optionally substituted with one or more groups —R^CC2;

each —R^C2is saturated C_3-6cycloalkyl, and is optionally substituted with one or more groups —R^CC1and one or more groups —R^CC2;

each —R^C3is non-aromatic C_3-6heterocyclyl, and is optionally substituted with one or more groups —R^CC1and one or more groups —R^CC2;

each —R^C4is independently phenyl or naphthyl, and is optionally substituted with one or more groups —R^CC1and one or more groups —R^CC2;

each —R^C5is C_5-10heteroaryl, and is optionally substituted with one or more groups —R^CC1and one or more groups —R^CC2;

each -L^C- is linear or branched saturated C_1-4alkylene;

each —R^CC1is independently selected from:

—R^CC,

-L^CC-OH, -L^CC-OR^CC,

-L^CC-NH₂, -L^CC-NHR^CC, -L^CC-N(R^CC)₂, and -L^CC-R^CM;

each —R^CC2is independently selected from:

—F, —Cl, —Br, —I,

—OH, —OR^CC,

—CF₃, —CHF₂, —OCF₃, —OCHF₂,

—NH₂, —NHR^CC, —N(R^CC)₂, —R^CM,

—C(═O)OH, —C(═O)OR^CC, —OC(═O)R^CC,

—C(═O)NH₂, —C(═O)NHR^CC, —C(═O)N(R^CC)₂, —C(═O)R^CM,

—NHC(═O)R^CC, —NR^CNC(═O)R^CC,

—NHC(═O)NH₂, —NHC(═O)NHR^CC, —NHC(═O)N(R^CC)₂, —NHC(═O)R^CM,

—NR^CNC(═O)NH₂, —NR^CNC(═O)NHR^CC, —NR^CNC(═O)N(R^CC)₂,

—NR^CNC(═O)R^CM,

—NHC(═O)OR^CC, —NR^CNC(═O)OR^CC,

—OC(═O)NH₂, —OC(═O)NHR^CC, —OC(═O)N(R^CC)₂, —OC(═O)R^CM,

—NHC(═NH)NH₂,

—C(═O) R^CC,

—S(═O)NH₂, —S(═O)NHR^CC, —S(═O)N(R^CC)₂, —S(═O)R^CM,

—S(═O)₂NH₂, —S(═O)₂NHR^CC, —S(═O)₂N(R^CC)₂, —S(═O)₂R^CM,

—NHS(═O)R^CC, —NR^CNS(═O)R^CC,

—NHS(═O)₂R^CC, —NR^CNS(═O)₂R^CC,

—S(═O)R^CC, —S(═O)₂R^CC,

—SH, —SR^CC, —CN, and —NO₂;

wherein:

each -L^CC- is linear or branched saturated C_1-4alkylene;

each —R^CCis independently linear or branched saturated C_1-4alkyl, phenyl, or —CH₂-phenyl, wherein each phenyl is optionally substituted with one or more groups selected from —F, —Cl, —Br, -Me, —OH, —OMe, —CF₃, and —OCF₃;

each —R^CNis linear or branched saturated C_1-4alkyl;

each —R^CMis independently azetidino, pyrrolidino, piperidino, piperazino, morpholino, azepano, or diazepano, and is:

optionally substituted with one or more groups selected from:

—R^CMM, —C(═O)R^CMM, —C(═O)OR^CMM, and —S(═O)₂R^CMM;

wherein each —R^CMMis independently linear or branched saturated C_1-4alkyl, phenyl, or —CH₂-phenyl, wherein each phenyl is optionally substituted with one or more groups selected from —F, —Cl, —Br, -Me, —OH, —OMe, —CF₃, and —OCF₃;

—R^22Dis independently selected from:

—F, —Cl, —Br, —I,

—OH, —OR^DD,

—CF₃, —CHF₂, —OCF₃, —OCHF₂,

—NH₂, —NHR^DD, —NR^DD₂, —R^DM,

—C(═O)OH, —C(═O)OR^DD, —OC(═O)R^DD,

—C(═O)NH₂, —C(═O)NHR^DD, —C(═O)NR^DD₂, —C(═O)R^DM,

—NHC(═O)R^DD, —NR^DNC(═O)R^DD,

—NHC(═O)NH₂, —NHC(═O)NHR^DD, —NHC(═O)NR^DD₂, —NHC(═O)R^DM,

—NR^DNC(═O)NH₂, —NR^DNC(═O)NHR^DD, —NR^DNC(═O)NR^DD₂, —NR^DNC(═O)R^DM,

—NHC(═O)OR^DD, —NR^DNC(═O)OR^DD,

—OC(═O)NH₂, —OC(═O)NHR^DD, —OC(═O)NR^DD₂, —OC(═O)R^DM,

—NHC(═NH)NH₂,

—C(═O)R^DD,

—S(═O)NH₂, —S(═O)NHR^DD, —S(═O)NR^DD₂, —S(═O)R^DM,

—S(═O)₂NH₂, —S(═O)₂NHR^DD, —S(═O)₂NR^DD₂, —S(═O)₂R^DM,

—NHS(═O)R^DD, —NR^DNS(═O)R^DD,

—NHS(═O)₂R^DD, —NR^DNS(═O)₂R^DD,

—S(═O)R^DD, —S(═O)₂R^DD,

—SH, —SR^DD, —CN, and —NO₂;

wherein:

each —R^DDis independently linear or branched saturated C_1-4alkyl, phenyl, or —CH₂-phenyl, wherein each phenyl is optionally substituted with one or more groups selected from —F, —Cl, —Br, -Me, —OH, —OMe, —CF₃, and —OCF₃;

each —R^DNis linear or branched saturated C_1-4alkyl;

each —R^DMis independently azetidino, pyrrolidino, piperidino, piperazino, morpholino, azepano, or diazepano, and is:

optionally substituted with one or more groups selected from:

—R^DMM, —C(═O)R^DMM, —C(═O)OR^DMM, and —S(═O)₂R^DMM;

wherein each —R^DMMis independently linear or branched saturated C_1-4alkyl, phenyl, or —CH₂-phenyl, wherein each phenyl is optionally substituted with one or more groups selected from —F, —Cl, —Br, -Me, —OH, —OMe, —CF₃, and —OCF₃;

or —R¹and —R², together with the carbon atom to which they are attached, form a saturated C_3-6cycloalkyl or a non-aromatic C_3-7heterocyclyl, and is optionally substituted with one or more groups —R^CC2;

and wherein:

—R^N1is independently —H or —R^N;

—R^N2is independently —H or —R^N;

each —R^Nis independently linear or branched saturated C_1-6alkyl, phenyl, or —CH₂-phenyl, wherein each phenyl is optionally substituted with one or more groups selected from —F, —Cl, —Br, -Me, —OH, —OMe, —CF₃, and —OCF₃; or

—R^N1and R^N2, taken together, form C_2-6alkylene.