US 12,173,026 B2
PRMT5 inhibitors
Michelle Machacek, Belmont, MA (US); David Witter, Norfolk, MA (US); Craig Gibeau, Northborough, MA (US); Chunhui Huang, Arlington, MA (US); Shuhei Kawamura, Cambridge, MA (US); David L. Sloman, Brookline, MA (US); Phieng Siliphaivanh, Newton, MA (US); Ryan Quiroz, Boston, MA (US); Murray Wan, Watertown, MA (US); Sebastian Schneider, Boston, MA (US); Charles S. Yeung, Dedham, MA (US); Michael H. Reutershan, Brighton, MA (US); Timothy J. Henderson, Beaulieu, MA (US); Jean-Laurent Paparin, Vendemian (FR); Houcine Rahali, Beaulieu (FR); Jonathan M. E. Hughes, Hoboken, NJ (US); Sulagna Sanyal, Belmont, MA (US); Yingchun Ye, Belmont, MA (US); David A. Candito, Wrentham, MA (US); Patrick S. Fier, Monroe Township, NJ (US); and Steven M. Silverman, Jersey City, NJ (US)
Assigned to Merck Sharp & Dohme LLC, Rahway, NJ (US); and MSD International GmbH, Lucerne (CH)
Appl. No. 17/266,521
Filed by Merck Sharp & Dohme LLC, Rahway, NJ (US); and MSD International GmbH, Lucerne (CH)
PCT Filed Aug. 5, 2019, PCT No. PCT/US2019/045050
§ 371(c)(1), (2) Date Feb. 5, 2021,
PCT Pub. No. WO2020/033288, PCT Pub. Date Feb. 13, 2020.
Claims priority of provisional application 62/715,446, filed on Aug. 7, 2018.
Claims priority of provisional application 62/792,623, filed on Jan. 15, 2019.
Claims priority of provisional application 62/859,490, filed on Jun. 10, 2019.
Prior Publication US 2022/0363707 A1, Nov. 17, 2022
Int. Cl. C07H 19/14 (2006.01); A61P 35/00 (2006.01); C07D 487/04 (2006.01)
CPC C07H 19/14 (2013.01) [A61P 35/00 (2018.01); C07D 487/04 (2013.01)] 20 Claims
 
1. A compound of formula I,

OG Complex Work Unit Chemistry
or a pharmaceutically acceptable salt thereof, wherein
X is CH2 or O;
Y is CH2, NH, or O;
Z1 is CR4 or N;
Z2, Z3, Z4, and Z5 are independently selected from N and CR9;
A1 is CH or N;
A2 is CR 10 or N
A3 is CH or N;
A4 is CR8 or N;
R1 and R7 taken together to form a five membered carbon ring optionally substituted with 1-3 halogens or a five membered heterocycloalkyl ring comprising one O atom;
R2 is H, OH, CH3, CHF2, or F;
R3 is H, halogen, NH2, NHCH3, CN, OH, OCH3, C1-4alkyl optionally substituted with 1-3 halogen or OH, or C3-5cycloalkyl optionally substituted with 1-3 halogens or OH;
R5 is H, NH2, or NHR6; and R4, when present, is H, halogen, CH3, CHF2, or CF3; or
R4 and R5 taken together with the carbon atoms to which they are attached, join to form a 5 membered heterocycloalkyl comprising one N atom, wherein the heterocycloalkyl is optionally substituted with one to four substituents independently selected from halogen, CH3, CF3, and CF2H;
R6, when present, is CH3, C2H5, CH2CH2CH3, CH (CH3)2, CH2CHF2, CH2CF3, or CH2-cyclopropyl;
R8, when present, is H, halogen, C1-4alkyl optionally substituted with 1-3 halogens, C3-5cycloalkyl optionally substituted with 1-3 halogens, or aryl optionally substituted with 1-3 halogens;
each R9, when present, is independently selected from H and halogen; and
R10, when present, is H, C1-6alkyl, NH2, or halogen.