US 11,834,467 B2
Substituted indazoles as hematopoietic progenitor kinase 1 (HPK1) inhibitors
Jinhwa Lee, Gyeonggi-do (KR); Suyeon Jo, Gyeonggi-do (KR); Keonseung Lim, Gyeonggi-do (KR); A Yeong Park, Gyeonggi-do (KR); Gadhe Changdev Gorakshnath, Seoul (KR); Hwajung Nam, Busan (KR); Yeonguk Jeon, Gyeonggi-do (KR); Yejin Hwang, Gyeonggi-do (KR); Jae Eun Kim, Gyeonggi-do (KR); Misoon Kim, Gyeonggi-do (KR); and Seung Mook Lim, Gyeonggi-do (KR)
Assigned to 1ST Biotherapeutics, Inc., Gyeonggi-do (KR)
Filed by 1ST Biotherapeutics, Inc., Gyeonggi-do (KR)
Filed on Sep. 27, 2021, as Appl. No. 17/485,653.
Claims priority of provisional application 63/084,059, filed on Sep. 28, 2020.
Prior Publication US 2022/0098219 A1, Mar. 31, 2022
Int. Cl. A61K 31/416 (2006.01); C07D 231/56 (2006.01); C07F 7/08 (2006.01); C07D 487/04 (2006.01); C07D 417/04 (2006.01); C07D 417/14 (2006.01); C07D 471/04 (2006.01); C07D 513/04 (2006.01); C07F 9/6558 (2006.01)
CPC C07F 7/0812 (2013.01) [C07D 417/04 (2013.01); C07D 417/14 (2013.01); C07D 471/04 (2013.01); C07D 487/04 (2013.01); C07D 513/04 (2013.01); C07F 9/65583 (2013.01); C07B 2200/05 (2013.01)] 24 Claims
 
1. A compound of Formula (I):

OG Complex Work Unit Chemistry
or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof,
wherein:
R1 is alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl;
wherein the alkyl is optionally substituted with one or more substituents independently selected from the group consisting of halo, CN, C(O)R9, C(O)NR10R11, C(O)OR9, NR10R11, NR6C(O)R9, NR6C(O)NR10R11, NR6C(O)OR9, NR6NR10R11, NR6OR9, NR6S(O)2R9, NR6S(O)2NR10R11, OR9, OC(O)R9, OC(O)NR10R11, ═O, P(O)R12R13, SR9, S(O)R9, S(O)(NH)R10, S(O)2R9, S(O)2NR10R11, cycloalkyl, heterocyclyl, aryl, and heteroaryl; and
wherein the cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more independently selected R7 substituents;
each R7 is independently halo, CN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C(O)R9, C(O)NR10R11, C(O)OR9, NR10R11, NR6C(O)R9, NR6C(O)NR10R11, NR6C(O)OR9, NR6NR10R11, NR6OR9, NR6S(O)2R9, NR6S(O)2NR10R11, OR9, OC(O)R9, OC(O)NR10R11, ═O, P(O)R12R13, SR9, S(O)R9, S(O)(NH)R10, S(O)2R9, S(O)2NR10R11, cycloalkyl, heterocyclyl, aryl, or heteroaryl;
L is a bond, —NR6—, —O—, or —S—;
X is O or S;
Het is:

OG Complex Work Unit Chemistry
Ra is H, D, halo, CN, CH2F, CHF2, CF3, NR10R11, or OR9;
Rb is H, D, halo, CN, CH2F, CHF2, CF3, NR10R11, or OR9;
Rc is H, D, halo, CN, CH2F, CHF2, CF3, NR10R11, or OR9;
R2 is H, D, halo, CN, NO2, CD3, CD2OH, CH2OCH[Si(CH3)3]CH3, CH2OCH2CH2Si(CH3)3, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C(O)R9, C(O)NR10R11, C(O)OR9, NR10R11, NR6C(O)R9, NR6C(O)NR10R11, NR6C(O)OR9, NR6NR10R11, NR6OR9, NR6S(O)2R9, NR6S(O)2NR10R11, OR9, OC(O)R9, OC(O)NR10R11, P(O)R12R13, SR9, S(O)R9, S(O)(NH)R10, S(O)2R9, S(O)2NR10R11, cycloalkyl, heterocyclyl, aryl, or heteroaryl;
wherein the C1-6 alkyl, C2-6 alkenyl, or C2-6 alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of halo, CN, NO2, C(O)R9, C(O)NR10R11, C(O)OR9, NR10R11, NR10C(O)R9, NR10C(O)NR10R11, NR10C(O)OR9, OR9, OC(O)R9, OC(O)NR10R11, and OC(O)OR9; and
wherein the cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of halo, CN, NO2, alkyl, haloalkyl, hydroxyalkyl, alkenyl, alkynyl, C(O)R9, C(O)NR10R11, C(O)OR9, NR10R11, NR10C(O)R9, NR10C(O)NR10R11, NR10C(O)OR9, OR9, OC(O)R9, OC(O)NR10R11, and OC(O)OR9;
R3 is H, D, halo, CN, NO2, CD3, CH2OH, CD2OH, C1-6 alkyl, haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C(O)R9, C(O)NR10R11, C(O)OR9, NR10R11, NR6C(O)R9, NR6C(O)NR10R11, NR6C(O)OR9, NR6NR10R11, NR6OR9, NR6S(O)2R9, NR6S(O)2NR10R11, OR9, OC(O)R9, OC(O)NR10R11, P(O)R12R13, SR9, S(O)R9, S(O)(NH)R10, S(O)2R9, S(O)2NR10R11, cycloalkyl, heterocyclyl, aryl, or heteroaryl;
R5 is H, D, halo, CN, CD3, CH2OH, CD2OH, C1-6 alkyl, haloalkyl, C2-6 alkenyl, C2-6 alkynyl, OH, or cycloalkyl;
M is a bond, —NR6—, —O—, or —S—;
each R6 is independently H or C1-6 alkyl;
R4 is H, D, halo, CN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C(O)R9, C(O)NR10R11, C(O)OR9, OH, P(O)R12R13, S(O)(NH)R10, S(O)2R9, S(O)2NR10R11, cycloalkyl, heterocyclyl, aryl, or heteroaryl;
wherein the C1-6 alkyl, C2-6 alkenyl, or C2-6 alkynyl is optionally substituted with one or more substituents independently selected from the group consisting of D, halo, CN, NO2, C(O)R9, C(O)NR10R11, C(O)OR9, NR10R11, NR10C(O)R9, NR10C(O)NR10R11, NR10C(O)OR9, NR10S(O)2R9, OR9, OC(O)R9, OC(O)NR10R11, and OC(O)OR9; and
wherein the cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of halo, CN, NO2, CD3, alkyl, haloalkyl, hydroxyalkyl, alkenyl, alkynyl, C(O)R9, C(O)NR10R11, C(O)OR9, NR10R11, NR10C(O)R9, NR10C(O)NR10R11, NR10C(O)OR9, NR10S(O)2R9, OR9, OC(O)R9, OC(O)NR10R11, and OC(O)OR9;
each R10 is independently H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl;
each R11 is independently H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; or
each R10 and R11, taken together with the nitrogen atom to which they are attached, independently form a 4- to 12-membered heterocyclyl, wherein the 4- to 12-membered heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of halo, CN, NO2, alkyl, haloalkyl, hydroxyalkyl, alkenyl, alkynyl, C(O)R9, C(O)NR10R11, C(O)OR9, NR10R11, NR10C(O)R9, NR10C(O)NR10R11, NR10C(O)OR9, OR9, OC(O)R9, OC(O)NR10R11, and OC(O)OR9;
each R12 is independently C1-6 alkyl, OC1-6 alkyl, C3-8 cycloalkyl, heterocyclyl, aryl, or heteroaryl;
each R13 is independently C1-6 alkyl, OC1-6 alkyl, C3-8 cycloalkyl, heterocyclyl, aryl, or heteroaryl; or
each R12 and R13, taken together with the phosphorus atom to which they are attached, independently form a 4- to 8-membered heterocyclyl, wherein the 4- to 8-membered heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of halo, CN, NO2, alkyl, haloalkyl, hydroxyalkyl, alkenyl, alkynyl, C(O)R9, C(O)NR10R11, C(O)OR9, NR10R11, NR10C(O)R9, NR10C(O)NR10R11, NR10C(O)OR9, OR9, OC(O)R9, OC(O)NR10R11, and OC(O)OR9; and
each R9 is independently H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl.