US Patent No. 10,428,050

SUBSTITUTED REVERSE PYRIMIDINE BMI-1 INHIBITORS


Patent No. 10,428,050
Issue Date October 01, 2019
Title Substituted Reverse Pyrimidine Bmi-1 Inhibitors
Inventorship Chang-Sun Lee, Belle Mead, NJ (US)
Ramil Baiazitov, East Brunswick, NJ (US)
Liangxian Cao, East Brunswick, NJ (US)
Thomas W Davis, South Orange, NJ (US)
Wu Du, Cranbury, NJ (US)
Ronggang Liu, Berwyn, PA (US)
Young-choon Moon, Belle Mead, NJ (US)
Steven D. Paget, Hillsborough, NJ (US)
Hongyu Ren, Florence, NJ (US)
Nadiya Sydorenko, Princeton, NJ (US)
Richard Gerald Wilde, Somerville, NJ (US)
Assignee PTC THERAPEUTICS, INC., South Plainfield, NJ (US)

Claim of US Patent No. 10,428,050

1. A compound of Formula (I):
or a form thereof, wherein
R1 is bicyclic heteroaryl or bicyclic heterocyclyl substituted on a carbon atom ring member with one, two, three or four R5 substituents, or on a nitrogen atom ring member with an oxygen atom substituent to form an N-oxide;
X is N or N substituted with an oxygen atom substituent to form an N-oxide;
R2 is amino;
R3 is hydrogen, cyano, halo, C1-8alkyl, amino, C1-8alkyl-amino or (C1-8alkyl)2-amino;
R4 is phenyl, optionally substituted with one, two, three or four R6 substituents;
R5 is independently selected from the group consisting of cyano, halo, hydroxyl, nitro, oxo, C1-8alkyl, cyano-C1-8alkyl, halo-C1-8alkyl, hydroxyl-C1-8alkyl, C1-8alkoxy, C1-8alkoxy-C1-8alkyl, halo-C1-8alkoxy, C2-8alkenyl, C1-8alkoxy-C2-8alkenyl, C2-8alkynyl, C1-8alkoxy-C2-8alkynyl, carboxyl, amino, C1-8alkyl-amino, (C1-8alkyl)2-amino, amino-C1-8alkyl, C1-8alkyl-amino-C1-8alkyl, (C1-8alkyl)2-amino-C1-8alkyl, hydroxyl-C1-8alkyl-amino, hydroxyl-C1-8alkyl-amino-C1-8alkyl, hydroxyl-C1-8alkyl-amino-C1-8alkyl-amino, C1-8alkyl-thio, C1-8alkyl-carbonyl, C1-8alkyl-carbonyl-amino, C1-8alkyl-carbonyl-oxy, C1-8alkyl-carbonyl-oxy-C1-8alkyl, C1-8alkoxy-carbonyl, C1-8alkoxy-carbonyl-C1-8alkyl, C1-8alkoxy-carbonyl-amino, C1-8alkyl-sulfonyl, C3-14cycloalkyl, aryl, aryl-C1-8alkyl, aryl-amino, aryl-C1-8alkyl-amino, heteroaryl, heteroaryl-C1-8alkyl and heterocyclyl, wherein C3-14cycloalkyl, aryl, heteroaryl or heterocyclyl and the aryl and heteroaryl portions of aryl-C1-8alkyl, aryl-amino, aryl-C1-8alky-amino and heteroaryl-C1-8alkyl are each optionally substituted with one, two, three or four halo, C1-8alkyl, halo-C1-8alkyl, hydroxyl-C1-8alkyl, C1-8alkoxy, halo-C1-8alkoxy, hydroxyl-C1-8alkoxy or carboxyl substituents;
R6 is independently selected from the group consisting of cyano, halo, nitro, C1-8alkyl, halo-C1-8alkyl, hydroxyl-C1-8alkyl, C1-8alkoxy, halo-C1-8alkoxy, C2-8alkenyl, C1-8alkoxy-C2-8alkenyl, C2-8alkynyl, C1-8alkoxy-C2-8alkynyl, carboxyl, formyl, formyl-oxy, C1-8alkyl-carbonyl, halo-C1-8alkyl-carbonyl, C1-8alkyl-thio, halo-C1-8alkyl-thio, amino, C1-8alkyl-amino, (C1-8alkyl)2-amino, C1-8alkyl-carbonyl, C1-8alkyl-carbonyl-oxy, C1-8alkyl-carbonyl-oxy-C1-8alkyl, C1-8alkoxy-carbonyl, halo-C1-8alkoxy-carbonyl, C1-8alkoxy-carbonyl-C1-8alkyl, C1-8alkoxy-carbonyl-amino, C1-8alkoxy-carbonyl-amino-C1-8alkyl, amino-carbonyl, C1-8alkyl-amino-carbonyl, (C1-8alkyl)2-amino-carbonyl, C1-8alkyl-carbonyl-amino, C1-8alkyl-carbonyl-amino-C1-8alkyl, amino-C1-8alkyl, C1-8alkyl-amino-C1-8alkyl, (C1-8alkyl)2-amino-C1-8alkyl, amino-C1-8alkyl-amino, C1-8alkyl-amino-C1-8alkyl-amino, (C1-8alkyl)2-amino-C1-8alkyl-amino, hydroxyl-C1-8alkyl-amino, hydroxyl-C1-8alkyl-amino-C1-8alkyl, hydroxyl-C1-8alkyl-amino-C1-8alkyl-amino, imino-C1-8alkyl, hydroxyl-imino-C1-8alkyl, C1-8alkoxy-imino-C1-8alkyl, C1-8alkyl-sulfonyl, halo-C1-8alkyl-sulfonyl, amino-sulfonyl, C1-8alkyl-amino-sulfonyl, (C1-8alkyl)2-amino-sulfonyl, B(OR8)2, C3-14cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein C3-14cycloalkyl, heterocyclyl, aryl, and heteroaryl are each optionally substituted with one, two, three or four halo or C1-8alkyl substituents;
R8 is independently hydrogen or C1-8alkyl;
wherein the form of the compound is selected from the group consisting of a free acid, free base, salt, ester, hydrate, solvate, chelate, clathrate, isotopologue, stereoisomer, racemate, enantiomer, diastereomer and tautomer thereof.