US 11,655,254 B2
Substituted piperazines as BTK inhibitors
Guangxiu Dai, Shanghai (CN); and Kun Xiao, Shanghai (CN)
Assigned to HUTCHISON MEDIPHARMA LIMITED, Shanghai (CN)
Filed by HUTCHISON MEDIPHARMA LIMITED, Shanghai (CN)
Filed on Apr. 25, 2022, as Appl. No. 17/728,097.
Application 17/728,097 is a continuation of application No. PCT/CN2021/119056, filed on Sep. 17, 2021.
Claims priority of application No. 202010993583.8 (CN), filed on Sep. 21, 2020; application No. 202110175357.3 (CN), filed on Feb. 7, 2021; and application No. 202111077860.1 (CN), filed on Sep. 15, 2021.
Prior Publication US 2022/0332719 A1, Oct. 20, 2022
Int. Cl. A61K 31/496 (2006.01); C07D 241/04 (2006.01); C07D 487/04 (2006.01); A61P 19/02 (2006.01); A61K 45/06 (2006.01)
CPC C07D 487/04 (2013.01) [A61K 45/06 (2013.01); A61P 19/02 (2018.01)] 35 Claims
 
1. A compound of formula (I):

OG Complex Work Unit Chemistry
or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof,
wherein:
X1 is CH or N;
X2 is CH or N;
X3 is CH or N;
U is CR9 or N;
V is CR9 or N;
Y1 is CR10 or N;
Y2 is CR10 or N;
Z1 is CH or N;
Z2 is CH or N;
Z3 is CH or N;
Z4 is CH or N;
R1 is H, D, halogen, CN, C1-6 alkyl, C1-6 deuteroalkyl, haloalkyl, C2-6 alkynyl, OH, or C3-6 cycloalkyl;
R2 is H, D, halogen, CN, C1-6 alkyl, C1-6 deuteroalkyl, haloalkyl, C2-6 alkynyl, OH, or C3-6 cycloalkyl; or
R1 and R2, together with the carbon atom to which they are attached, form a C3-6 cycloalkyl;
R3 is H, D, halogen, CN, or C1-6 haloalkyl;
R4 is H, halogen, CN, C1-6 alkyl, C1-3 alkyl-OH, C1-3 alkyl-OC1-3 alkyl, C2-6 alkynyl, C(O)H, C(O)NH2, C(O)NHCH3, C(O)N(CH3)2, OC1-3 alkyl, or 3-hydroxyoxetan-3-yl, wherein the C1-6 alkyl, C1-3 alkyl-OH, C1-3 alkyl-OC1-3 alkyl, or OC1-3 alkyl is optionally substituted with one or more substituents independently selected from the group consisting of D and halogen;
R5 is H, C1-6 alkyl, or C3-6 cycloalkyl, wherein the C1-6 alkyl is optionally substituted with one or more substituents independently selected from the group consisting of D and halogen;
R6 is C1-6 alkyl;
R7 is C1-6 alkyl;
R8 is H, C1-6 alkyl, C3-6 cycloalkyl, or 4- to 8-membered heterocyclyl, wherein the C1-6 alkyl, C3-6 cycloalkyl, or 4- to 8-membered heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of D, halogen, C1-6 alkyl, CF3, NH2, NHC1-6 alkyl, N(C1-6 alkyl)2, OH, and OC1-6 alkyl;
R9 is H, D, or halogen;
R10 is H, D, halogen, CN, C1-6 alkyl, or C1-6 haloalkyl; and
n is 0, 1, or 2;
with the provisos that:
(1) at least one of Z1, Z2, Z3, and Z4 is N; and
(2) if n is 1, then R3 is not H.
 
17. A pharmaceutical composition comprising a pharmaceutically acceptable excipient and the compound according to claim 1, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.