US 12,410,160 B2
KHK inhibitors
James L. Bachman, Seattle, WA (US); Daniel H. Byun, Foster City, CA (US); Christopher T. Clark, Seattle, WA (US); Petr Jansa, Foster City, CA (US); Joshua A. Kaplan, Foster City, CA (US); Zachary A. Kasun, Seattle, WA (US); Jennifer R. Lo, Seattle, WA (US); Megan E. Neubig, San Diego, CA (US); Nathaniel H. Stanley, San Francisco, CA (US); and Kirk L. Stevens, Bothell, WA (US)
Assigned to Gilead Sciences, Inc., Foster City, CA (US)
Filed by Gilead Sciences, Inc., Foster City, CA (US)
Filed on Mar. 25, 2022, as Appl. No. 17/704,440.
Claims priority of provisional application 63/167,331, filed on Mar. 29, 2021.
Prior Publication US 2023/0079863 A1, Mar. 16, 2023
Int. Cl. C07D 409/14 (2006.01); A61K 45/06 (2006.01); C07D 401/14 (2006.01); C07D 403/04 (2006.01); C07D 403/14 (2006.01); C07D 405/14 (2006.01); C07D 413/14 (2006.01); C07D 491/107 (2006.01); C07D 493/10 (2006.01); C07D 495/04 (2006.01); C07D 513/04 (2006.01)
CPC C07D 409/14 (2013.01) [A61K 45/06 (2013.01); C07D 401/14 (2013.01); C07D 403/04 (2013.01); C07D 403/14 (2013.01); C07D 405/14 (2013.01); C07D 413/14 (2013.01); C07D 491/107 (2013.01); C07D 493/10 (2013.01); C07D 495/04 (2013.01); C07D 513/04 (2013.01)] 38 Claims
 
1. A compound of Formula II, or a pharmaceutically acceptable salt or stereoisomer thereof,

OG Complex Work Unit Chemistry
wherein m is 0-4;
each R1a is independently C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, OH, OR1b, CH2OH, CO2R12, halogen, oxo, CONH2, CN, NH2, NHR11, C1-6 alkyl-NHSO2R13, C1-6 alkyl-NHCOR13, C1-6 alkoxy or C1-6 haloalkyl, wherein the alkyl, alkenyl, or alkynyl are optionally substituted with up to three R1c, alternatively two R1a can be combined with the atoms to which they are attached to form a 3-6 membered spiro, fused or bridged ring;
R1b is H, or C1-6 alkyl, wherein the alkyl is optionally substituted with up to three halogens, CN, or OH;
each R1c is independently OH, OR11, halogen, oxo, SOR13, SO2R13, SR13, SO2NH2, CONH2, C1-6 alkoxy, C6-10 aryl, C6-10 aryloxy, 5-11 membered heteroaryl, or C3-7 cycloalkyl;
R2 is C6-10 aryl, or a 6-14 membered heteroaryl, wherein the aryl, or heteroaryl are optionally substituted with up to eight R2a, and wherein R2 is attached to the core through a carbon atom of R2;
each R2a is independently C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 haloalkyl, SO2R2c, SOR2c, SO2NH2, CONH2, COR2c, CONHR2e, CON(R2c)2, halogen, oxo, OH, CN, NH2, NHR2c, N(R2c)2, NHCOR2c, N(R2c) COR2c, NO2, SO2NHR2c, SO2N(R2c)2, NHSO2R2c, N(R2c) SO2R2c, S(O)(NH) R2c, S(O)(NH) NH2, NHS(O)(NH) R2c, NS(O) (NH2) R2c, NS(O) (R2c)2, S(O)(NR2c) R2c, S(O)(NR2c) NH2, S(O)(NH) NHR2c, S(O)(NR2c) NH(R2c), OR2c, C3-7 cycloalkyl, 4-7 membered heterocyclyl, C6-10 aryl, or 5-11 membered heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl are substituted with up to seven R2b, and wherein the cycloalkyl can be fused or spiro to the heteroaryl, or the cycloalkyl can be fused to the aryl; alternatively two R2a can be combined with the atoms to which they are attached to form a 3-7 membered spiro, fused or bridged ring;
each R2b is independently C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, OH, halogen, oxo, CONH2, NHCOR2c, N(R2c) COR2c, NHCO2R2c, NH2, N(R2c)2, NHR2c, S(O)(NH) R2c, S(O)(NH) NH2, NHS(O)(NH) R2c, NS(O) (NH2) R2c, NS(O) (R2c)2, S(O)(NR2c) R2c, S(O)(NR2c) NH2, S(O)(NH) NHR2c, S(O)(NR2c) NH(R2c), OR2c, NHSO2R2c, N(R2c) SO2R2c, C1-6 alkyl-CO2R12, C1-6 alkyl-CONH2, C1-6 alkyl-NHSO2R2c, CN, COR2c, NHCO2R2c, SO2NH2, SO2NHR2c, SO2R2c, C3-7 cycloalkyl, 4-7 membered heterocyclyl, C6-10 aryl or 5-11 membered heteroaryl, wherein the alkyl, alkoxy, haloalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl can be optionally substituted with up to four R2d; alternatively two R2b can be combined with the atoms to which they are attached to form a 3-7 membered spiro, fused or bridged ring;
each R2c is independently C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C6-10 aryl, 5-11 membered heteroaryl, or 4-7 membered heterocyclyl, wherein the alkyl, haloalkyl, alkoxy, aryl, heteroaryl or heterocyclyl are optionally substituted with up to four R2d;
each R2d is independently OH, halogen, NH2, C1-6 alkoxy, CONH2, SO2NH2, NHCOR13, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkyl-NH2, C1-6 alkyl-CO2R12, oxo, or CN;
R2e is C1-6 alkyl, C3-7 cycloalkyl, C6-10 aryl, C1-6 alkyl-C6-10 aryl, 4-7 membered heterocyclyl, or 5-11 membered heteroaryl, wherein the alkyl, cycloalkyl, aryl, alkyl-aryl, heterocyclyl or heteroaryl are optionally substituted with up to three R10;
R3, R4, R5, R6, R7, R8 are independently H, C1-6 alkyl, halogen, or C3-7 cycloalkyl;
alternatively R3, R4, R5, R6, R7 or R8 can be combined with the atoms to which they are attached to form a 3-6 membered spiro, bridged or fused ring;
each R10 is independently C1-6 alkoxy, CN, halogen, OH, NH2, NHR11, CONH2, SO2NH2, or NHCO2—C1-6 alkyl;
R11 is H, C1-6 alkyl, or C1-6 haloalkyl;
R12 is C1-6 alkyl, C1-6 haloalkyl, 3-7 cycloalkyl, 4-7 heterocyclyl, C6-10 aryl, or 5-11 heteroaryl; and
R13 is C1-6 alkyl, or C1-6 haloalkyl.