US 12,441,730 B2
PRMT5 inhibitors
Michelle Machacek, Belmont, MA (US); Michael D. Altman, Needham, MA (US); Shuhei Kawamura, Cambridge, MA (US); Michael H. Reutershan, Brighton, MA (US); David L. Sloman, Newton, MA (US); Phieng Siliphaivanh, Newton Highlands, MA (US); Sebastian E. Schneider, Boston, MA (US); Charles S. Yeung, Dedham, MA (US); David J. Witter, Ontario (CA); and Craig R. Gibeau, Northborough, MA (US)
Assigned to Merck Sharp & Dohme LLC, Rahway, NJ (US)
Appl. No. 17/783,967
Filed by Merck Sharp & Dohme LLC, Rahway, NJ (US)
PCT Filed Dec. 14, 2020, PCT No. PCT/US2020/064759
§ 371(c)(1), (2) Date Jun. 9, 2022,
PCT Pub. No. WO2021/126729, PCT Pub. Date Jun. 24, 2021.
Claims priority of provisional application 62/949,242, filed on Dec. 17, 2019.
Claims priority of provisional application 63/025,329, filed on May 15, 2020.
Prior Publication US 2023/0114091 A1, Apr. 13, 2023
This patent is subject to a terminal disclaimer.
Int. Cl. C07D 471/10 (2006.01); A61K 31/4747 (2006.01); C07D 519/00 (2006.01)
CPC C07D 471/10 (2013.01) [C07D 519/00 (2013.01)] 14 Claims
 
1. A compound of formula I,

OG Complex Work Unit Chemistry
or a pharmaceutically acceptable salt thereof, wherein
Y is H or OH;
Y1 is H or OH;
R1 is H, halogen, or C1-6alkyl optionally substituted with halogen;
R2 is H or D;
each t is independently 0, 1, or 2;
A is
(a) phenyl, optionally substituted with one or two moieties independently selected from OC1-6alkyl, halogen, C(O)R5, O-cyclopropyl, or an unsaturated heterocycle having 1-3 nitrogen atoms and 0-1 oxygen atoms wherein the unsaturated heterocycle is optionally substituted with C1-6alkyl, wherein R5 is a saturated heterocycle having 1 nitrogen atom and 1 oxygen atom;
(b) an unsaturated 6-membered heterocycle with 1-2 N atoms, wherein the heterocycle is substituted with NHR3, wherein the heterocycle is additionally optionally substituted with 1 or 2 halogens, wherein R3 is saturated heterocycle with 1 nitrogen atom, wherein the R3 nitrogen is substituted with C(O)C1-6alkyl and wherein the R3 heterocycle is optionally substituted with 1 or 2 halogens;
(c) an unsaturated 6-membered heterocycle with 1 N atom optionally substituted with one, two or three moieties independently selected from halogen, ═O, C1-6alkyl, C3-6cycloalkyl, C1-6fluoroalkyl, 5-membered unsaturated heterocycle having 3 or 4 N atoms, OH, OC1-6alkyl, OC1-6alkoxy, NC1-6alkyl, or NHR4, wherein R4 is saturated heterocycle having 1N atom optionally substituted with one or two C(O)C1-6alkyl and wherein the C(O)C1-6alkyl is optionally substituted with one or two fluoro atoms;
(d)
i. an unsaturated 5-membered heterocycle with 1 or 2 Nitrogen atoms and 0-1 Oxygen atom optionally substituted with a 5-membered unsaturated heterocycle with 1 nitrogen atom and 1 oxygen atom wherein each heterocycle is independently optionally substituted with C1-6alkyl,
ii. an unsaturated 5-membered heterocycle with 2 N atoms optionally substituted with CHF2, cyclopropyl, or a phenyl optionally mono-substituted, independently disubstituted, or independently trisubstituted with halogen, C1-6alkyl, OC1-6alkyl, or C1-6fluoroalkyl,
(e) an unsaturated 8-11-membered bicyclic heterocycle with 1-4 nitrogen atoms, 0-1 oxygen atoms, and 0-1 sulfur atoms, unsubstituted, mono-substituted, independently disubstituted, or independently trisubstituted with
i) CR6R7R8, wherein
R6 is H, C1-6alkyl, or halogen,
R7 is H, C1-6alkyl, halogen or OH, and
R8 is H, CN, C1-6alkyl optionally substituted with CN, halogen, OH, OC1-6alkyl, or C1-6haloalkyl;
ii) C(O)NR9R10, wherein
R9 is H, C1-6alkyl, halogen, or C1-6haloalkyl, and
R10 is H, C1-6alkyl, C1-6alkyl (C1-6alkyl)1-2, halogen, or C1-6haloalkyl,
iii) CN;
iv) C3 to C6 saturated or unsaturated carbocycle optionally mono-substituted, independently disubstituted, or independently trisubstituted with C1-6alkyl, 1-3 halogens, or CN;
v) halogen;
vi) C0-6alkylO(CH2)0-2R11, wherein:
R11 is H, C1-6alkyl, (C1-6alkyl)(OC1-6alkyl), OC1-6alkyl, C1-6alkyl(C1-6alkyl)1-2, C1-6alkyl(C1-6alkyl)1-2OH, C3-6heterocycle or C3-6cycloalkyl wherein the C3-6heterocycle or C3-6cycloalkyl are optionally mono-substituted, independently disubstituted, or independently trisubstituted with C1-6alkyl, halogen, CN, or ═O;
vii) ═O;
viii) C3-6heterocycle or C3-6cycloalkyl wherein the C3-6heterocycle or C3-6cycloalkyl are optionally mono-substituted, independently disubstituted, or independently trisubstituted with C1-6alkyl, C1-6cycloalkyl, halogen, CN, or ═O;
ix) N(C1-6alkyl)(C1-6alkyl)(OC1-6alkyl) or N(C1-6alkyl)(C1-6alkyl), wherein the alkyl moiety is optionally substituted with 5-membered unsaturated ring with 2 nitrogen atoms, 0-1 oxygen atom, wherein the ring is optionally substituted with C1-6alkyl, halogen, or C1-6haloalkyl;
xi) C3-6heterocycle optionally mono-substituted, independently disubstituted, or independently trisubstituted with 5-membered unsaturated ring with 2 nitrogen,
xii) an unsaturated 8-11 membered bicyclic heterocycle with 1-4 nitrogen atoms, 0-1 oxygen atoms, and 0-1 sulfur atoms, unsubstituted, mono-substituted, independently disubstituted, or independently trisubstituted with C1-6alkyl, or halogen,
xiii) unsaturated 5- or 6-membered heterocycle with 1-2 nitrogen atoms, 0-1 oxygen atoms, and 0-1 sulfur atoms optionally mono-substituted or independently disubstituted with C1-6alkyl or OC1-6alkyl, wherein the alkyl is optionally substituted with 1-3 halogens xiv) C1-6alkyl optionally substituted with CN or halogen; or
(f) unsaturated 13-membered tricyclic heterocycle with 1 oxygen, wherein the tricyclic heterocycle is optionally substituted with OH,
provided that the compound of formula I is not:

OG Complex Work Unit Chemistry