Imidazolyl pyrimidinylamine compounds as CDK2 inhibitors

Patent metadata

Field	Value
Publication number	US-12312331-B2
Application number	US-202217816271-A
Country	US
Kind code	B2
Filing date	Jul 29, 2022
Priority date	Aug 14, 2019
Publication date	May 27, 2025
Grant date	May 27, 2025

Abstract

The present application provides imidazolyl pyrimidinylamine inhibitors of cyclin-dependent kinase 2 (CDK2), as well as pharmaceutical compositions thereof, and methods of treating cancer using the same.

First claim

What is claimed is:

1. A compound of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein:
n is 0, 1, 2, 3, or 4;
Ring moiety A is 4-14 membered heterocycloalkyl, wherein Ring moiety A is attached to the —NH— group of Formula (I) at a ring member of a saturated or partially saturated ring of said 4-14 membered heterocycloalkyl;
R 1 is selected from H, D, halo, CN, C 1-4 alkyl, C 1-4 haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl, OH, C 1-3 alkoxy, C 1-3 haloalkoxy, amino, C 1-3 alkylamino, di(C 1-3 alkyl)amino, cyano-C 1-4 alkyl, HO—C 1-4 alkyl, C 1-3 alkoxy-C 1-4 alkyl, and C 3-4 cycloalkyl;
R 2 , R 3 , and R 4 are defined as shown in Group (a), Group (b), or Group (c);
Group (a):
R 2 is selected from H, D, halo, CN, C 1-4 alkyl, C 1-4 haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl, OH, C 1-4 alkoxy, C 1-4 haloalkoxy, amino, C 1-3 alkylamino, di(C 1-3 alkyl)amino, cyano-C 1-4 alkyl, HO—C 1-4 alkyl, C 1-3 alkoxy-C 1-4 alkyl, and C 3-4 cycloalkyl;
R 3 is selected from H, D, halo, CN, C 1-4 alkyl, C 1-4 haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl, OH, C 1-3 alkoxy, C 1-3 haloalkoxy, amino, C 1-3 alkylamino, di(C 1-3 alkyl)amino, cyano-C 1-4 alkyl, HO—C 1-4 alkyl, C 1-3 alkoxy-C 1-4 alkyl, and C 3-4 cycloalkyl; and
R 4 is selected from C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, 6-10 membered aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C 3-10 cycloalkyl-C 1-4 alkyl, 6-10 membered aryl-C 1-4 alkyl, 4-10 membered heterocycloalkyl-C 1-4 alkyl, 5-10 membered heteroaryl-C 1-4 alkyl, C(O)R b4 , C(O)NR c4 R d4 , C(O)NR c4 (OR a4 ), C(O)OR a4 , C(═NR e4 )R b4 , C(═NR e4 )NR c4 R d4 , S(O) 2 R b4 , and S(O) 2 NR c4 R d4 , wherein said C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, 6-10 membered aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C 3-10 cycloalkyl-C 1-4 alkyl, 6-10 membered aryl-C 1-4 alkyl, 4-10 membered heterocycloalkyl-C 1-4 alkyl, and 5-10 membered heteroaryl-C 1-4 alkyl are each optionally substituted by 1, 2, 3, or 4 independently selected R 4A substituents;
Group (b):
R 2 is selected from H, D, halo, NO 2 , CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 6-10 membered aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C 3-10 cycloalkyl-C 1-4 alkyl, 6-10 membered aryl-C 1-4 alkyl, 4-10 membered heterocycloalkyl-C 1-4 alkyl, 5-10 membered heteroaryl-C 1-4 alkyl, OR a2 , SR a2 , NHOR a2 , C(O)R b2 , C(O)NR c2 R d2 , C(O)NR c2 (OR a2 ), C(O)OR a2 , OC(O)R b2 , OC(O)NR c2 R d2 , NR c2 R d2 , NR c2 NR c2 R d2 , NR c2 C(O)R b2 , NR c2 C(O)OR a2 , NR c2 C(O)NR c2 R d2 , C(═NR e2 )R b2 , C(═NR e2 )NR c2 R d2 , NR c2 C(═NR e2 )NR c2 R d2 , NR c2 C(═NR e2 )R b2 , NR c2 S(O)NR c2 R d2 , NR c2 S(O)R b2 , NR c2 S(O) 2 R b2 , NR c2 S(O)(═NR e2 )R b2 , NR c2 S(O) 2 NR c2 R d2 , S(O)R b2 , S(O)NR c2 R d2 , S(O) 2 R b2 , S(O) 2 NR c2 R d2 , OS(O)(═NR e2 )R b2 , OS(O) 2 R b2 , S(O)(═NR e2 )R b2 , SF 5 , P(O)R f2 R g2 , OP(O)(OR h2 )(OR i2 ), P(O)(OR h2 )(OR i2 ), and BR j2 R k2 , wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 6-10 membered aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C 3-10 cycloalkyl-C 1-4 alkyl, 6-10 membered aryl-C 1-4 alkyl, 4-10 membered heterocycloalkyl-C 1-4 alkyl, and 5-10 membered heteroaryl-C 1-4 alkyl are each optionally substituted by 1, 2, 3, or 4 independently selected R 2A substituents;
R 3 is selected from H, D, halo, CN, C 1-4 alkyl, C 1-4 haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl, OH, C 1-3 alkoxy, C 1-3 haloalkoxy, amino, C 1-3 alkylamino, di(C 1-3 alkyl)amino, cyano-C 1-4 alkyl, HO—C 1-4 alkyl, C 1-3 alkoxy-C 1-4 alkyl, and C 3-4 cycloalkyl; and
R 4 is selected from C 1-4 alkyl, C 1-4 haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl, cyano-C 1-4 alkyl, HO—C 1-4 alkyl, C 1-3 alkoxy-C 1-4 alkyl, and C 3-4 cycloalkyl;
Group (c):
R 2 is selected from H, D, halo, CN, C 1-4 alkyl, C 1-4 haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl, OH, C 1-3 alkoxy, C 1-3 haloalkoxy, amino, C 1-3 alkylamino, di(C 1-3 alkyl)amino, cyano-C 1-4 alkyl, HO—C 1-4 alkyl, C 1-3 alkoxy-C 1-4 alkyl, and C 3-4 cycloalkyl; and
R 3 and R 4 , together with the atoms to which they are attached, form a 5-7 membered heterocycloalkyl ring, which is optionally substituted by 1, 2, 3, or 4 independently selected R 4A substituents;

each R a2 , R c2 , and R d2 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, 6-10 membered aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C 3-10 cycloalkyl-C 1-4 alkyl, 6-10 membered aryl-C 1-4 alkyl, 4-10 membered heterocycloalkyl-C 1-4 alkyl, and 5-10 membered heteroaryl-C 1-4 alkyl, wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 6-10 membered aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C 3-10 cycloalkyl-C 1-4 alkyl, 6-10 membered aryl-C 1-4 alkyl, 4-10 membered heterocycloalkyl-C 1-4 alkyl, and 5-10 membered heteroaryl-C 1-4 alkyl are each optionally substituted with 1, 2, 3, or 4 independently selected R 2A substituents;
or, any R c2 and R d2 attached to the same N atom, together with the N atom to which they are attached, form a 4-10 membered heterocycloalkyl group, which is optionally substituted with 1, 2, 3, or 4 independently selected R 2A substituents;
each R b2 is independently selected from C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, 6-10 membered aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C 3-10 cycloalkyl-C 1-4 alkyl, 6-10 membered aryl-C 1-4 alkyl, 4-10 membered heterocycloalkyl-C 1-4 alkyl, and 5-10 membered heteroaryl-C 1-4 alkyl, which are each optionally substituted with 1, 2, 3, or 4 independently selected R 2A substituents;
each R e2 is independently selected from H, OH, CN, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, 6-10 membered aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C 3-10 cycloalkyl-C 1-4 alkyl, 6-10 membered aryl-C 1-4 alkyl, 4-10 membered heterocycloalkyl-C 1-4 alkyl, and 5-10 membered heteroaryl-C 1-4 alkyl;
each R f2 and R g2 is independently selected from H, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, 6-10 membered aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C 3-10 cycloalkyl-C 1-4 alkyl, 6-10 membered aryl-C 1 -4 alkyl, 4-10 membered heterocycloalkyl-C 1-4 alkyl, and 5-10 membered heteroaryl-C 1-4 alkyl;
each R h2 and R i2 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, 6-10 membered aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C 3-10 cycloalkyl-C 1-4 alkyl, 6-10 membered aryl-C 1-4 alkyl, 4-10 membered heterocycloalkyl-C 1-4 alkyl, and 5-10 membered heteroaryl-C 1-4 alkyl;
each R j2 and R k2 is independently selected from OH, C 1-6 alkoxy, and C 1-6 haloalkoxy;
or any R j2 and R k2 attached to the same B atom, together with the B atom to which they are attached, form a 5- or 6-membered heterocycloalkyl group optionally substituted with 1, 2, 3, or 4 substituents independently selected from C 1-6 alkyl and C 1-6 haloalkyl;
each R 2A is independently selected from D, halo, CN, NO 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 6-10 membered aryl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl, C 3-10 cycloalkyl-C 1-4 alkyl, 6-10 membered

Assignees

• Incyte Corp

Inventors

• Ye Qinda
• Li Jingwei
• Mukai Ken
• Smith Brandon
• Wu Liangxing
• Yao Wenqing
• Ye Min
• Chen Yingnan
• Favata Margaret
• Lo Yvonne

Classifications

• G01N33/57557

  of other specific parts of the body, e.g. brain · CPC title

• G01N33/5758

  involving compounds serving as markers for tumours, cancers or neoplasias, e.g. cellular determinants, receptors, heat shock/stress proteins, A-protein, oligosaccharides or metabolites · CPC title

• C12Q1/6886

  for cancer (immunoassay for cancer G01N33/575) · CPC title

• C12Q1/6865

  Promoter-based amplification, e.g. nucleic acid sequence amplification [NASBA], self-sustained sequence replication [3SR] or transcription-based amplification system [TAS] · CPC title

• C07D498/08

  Bridged systems · CPC title