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US-20260125391-A1 - PYRIMIDINE INDOLES AS CDK4 INHIBITORS

US20260125391A1US 20260125391 A1US20260125391 A1US 20260125391A1US-20260125391-A1

Abstract

The present application provides compounds of Formula (I): or a pharmaceutically acceptable salt thereof, that are inhibitors of cyclin-dependent kinase 4 (CDK4), as well as pharmaceutical compositions thereof, and methods of treating cancer using the same.

Inventors

  • Peter Niels Carlson
  • Bo Wei
  • LIANA HIE
  • Joshua Hummel
  • Jacob J. Lacharity
  • XIAOLEI LI
  • Sharada Manns
  • Eli Ortiz
  • Robert Susick
  • Xiaozhao Wang

Assignees

  • INCYTE CORPORATION

Dates

Publication Date
20260507
Application Date
20251104

Claims (20)

  1. 1 . A compound of Formula (I): or a pharmaceutically acc b s hereof, wherein n is 0, 1, 2, 3, 4, 5, or 6; X is O, S, S(O) 2 , S(O)NR c , or N(-L-R 4 ); L is S(O) 2 , S(O)(═NR b ), or S(O) 2 NR a ; R a , R b , and R c are each independently selected from H, C 1-6 alkyl, and C 1-6 haloalkyl; or, alternatively, R a and R 4 , taken together with the nitrogen atom to which they are attached, form a 4-7 membered heterocycloalkyl ring or 5-6 membered heteroaryl ring, each of which is optionally substituted by 1, 2, 3, or 4 independently selected R 4A substituents; R 1 is selected from C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 6-14 membered aryl, 4-15 membered heterocycloalkyl, 5-14 membered heteroaryl, C 3-10 cycloalkyl-C 1-4 alkyl, 6-14 membered aryl-C 1-4 alkyl, 4-15 membered heterocycloalkyl-C 1-4 alkyl, and 5-14 membered heteroaryl-C 1-4 alkyl, which are each optionally substituted with 1, 2, 3, or 4 independently selected R 1A substituents; each R 1A is independently selected from H, D, halo, CN, NO 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4 alkyl, 4-7 membered heterocycloalkyl-C 1-4 alkyl, 5-6 membered heteroaryl-C 1-4 alkyl, OR a11 , SR a11 , NHOR a11 , C(O)R b11 , C(O)NR c11 R a11 , C(O)NR c11 (OR a11 ), C(O)OR a11 , OC(O)R b11 , OC(O)NR c11 R d11 , NR c11 R d11 , NR c11 NR c11 R d11 , NR c11 C(O)R b11 , NR c11 C(O)OR a11 , NR c11 C(O)NR c11 R d11 , C(═NR e11 )R b11 , C(═NR e11 )NR c11 R d11 , NR c11 C(═NR e11 )NR c11 R d11 , NR c11 C(═NR e11 )R b11 , NR c11 S(O)NR c11 R d11 , NR c11 S(O)R b11 , NR c11 S(O) 2 R b11 , NR c11 S(O)(═NR e11 )R b11 , NR c11 S(O) 2 NR c11 R d11 , S(O)R b11 , S(O)NR c11 R d11 , S(O) 2 R b11 , S(O) 2 NR c11 R d11 , OS(O)(═NR e11 )R b11 , OS(O) 2 R b11 , S(O)(═NR e11 )R b11 , SF 5 , P(O)R f11 R g11 , OP(O)(OR h11 )(OR i11 ), P(O)(OR h11 )(OR i11 ) and BR j11 R k11 , wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4 alkyl, 4-7 membered heterocycloalkyl-C 1-4 alkyl, and 5-6 membered heteroaryl-C 1-4 alkyl are each optionally substituted with 1, 2, 3, or 4 independently selected R 11 substituents; each R a11 , R c11 , and R d11 , is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4 alkyl, 4-7 membered heterocycloalkyl-C 1-4 alkyl, and 5-6 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 3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4 alkyl, 4-7 membered heterocycloalkyl-C 1-4 alkyl, and 5-6 membered heteroaryl-C 1-4 alkyl are each optionally substituted with 1, 2, 3, or 4 independently selected R 1B substituents; or, any R C11 and R d11 , attached to the same N atom, together with the N atom to which they are attached, form a 4-7 membered heterocycloalkyl group, wherein the 4-7 membered heterocycloalkyl group is optionally substituted with 1, 2, 3, or 4 independently selected R 1B substituents; each R b11 is independently selected from C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4 alkyl, 4-7 membered heterocycloalkyl-C 1-4 alkyl, and 5-6 membered heteroaryl-C 1-4 alkyl, which are each optionally substituted with 1, 2, 3, or 4 independently selected R 1B substituents; each R e11 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 3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4 alkyl, 4-7 membered heterocycloalkyl-C 1-4 alkyl, and 5-6 membered heteroaryl-C 1-4 alkyl; each R f11 and R g11 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 3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4 alkyl, 4-7 membered heterocycloalkyl-C 1-4 alkyl, and 5-6 membered heteroaryl-C 1-4 alkyl; each R h11 and R i11 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4 alkyl, 4-7 membered heterocycloalkyl-C 1-4 alkyl, and 5-6 membered heteroaryl-C 1-4 alkyl; each R j11 and R k11 is independently selected from OH, C 1-6 alkoxy, and C 1-6 haloalkoxy; or, any R j11 and R k11 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 1B is independently selected from H, D, halo, CN, NO 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4 alkyl, 4-7 membered heterocycloalkyl-C 1-4 alkyl, 5-6 membered heteroaryl-C 1-4 alkyl, OR a12 , SR a12 , NHOR a12 , C(O)R b12 , C(O)NR c12 R d12 , C(O)NR c12 (OR a12 ), C(O)OR a12 , OC(O)R b12 , OC(O)NR c12 R d12 , NR c12 R d12 , NR c12 NR e12 R d12 , NR c12 C(O)R b12 , NR c12 C(O)OR a12 , NR c12 C(O)NR c12 R d12 , C(═NR e12 )R b12 , C(═NR e12 )NR c12 R d12 , NR e12 C(═NR e12 )NR c12 R d12 , NR c12 C(═NR e12 )R b12 , NR c12 S(O)NR c12 R d12 , NR c12 S(O)R b12 NR c12 S(O) 2 R b12 , NR c12 S(O)(═NR e12 )R b12 , NR c12 S(O) 2 NR c12 R d12 , S(O)R b12 , S(O)NR c12 R d12 , S(O) 2 R b12 , S(O) 2 NR c12 R d12 , OS(O)(═NR e12 )R b12 , OS(O) 2 R b12 , S(O)(═NR e12 )R b12 , SF 5 , P(O)R f12 R g12 , OP(O)(OR h12 )(OR i12 ), P(O)(OR h12 )(OR i12 ), and BR j12 R k12 , wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4 alkyl, 4-7 membered heterocycloalkyl-C 1-4 alkyl, and 5-6 membered heteroaryl-C 1-4 alkyl are each optionally substituted with 1, 2, 3, or 4 independently selected R G substituents; each R a12 , R c12 , and R d12 , is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4 alkyl, 4-7 membered heterocycloalkyl-C 1-4 alkyl, and 5-6 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 3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4 alkyl, 4-7 membered heterocycloalkyl-C 1-4 alkyl, and 5-6 membered heteroaryl-C 1-4 alkyl are each optionally substituted with 1, 2, 3, or 4 independently selected R G substituents; or, any R e12 and R d12 , attached to the same N atom, together with the N atom to which they are attached, form a 4-7 membered heterocycloalkyl group, wherein the 4-7 membered heterocycloalkyl group is optionally substituted with 1, 2, 3, or 4 independently selected R G substituents; each R b12 , is independently selected from C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4 alkyl, 4-7 membered heterocycloalkyl-C 1-4 alkyl, and 5-6 membered heteroaryl-C 1-4 alkyl, which are each optionally substituted with 1, 2, 3, or 4 independently selected R G substituents; each R e12 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 3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4 alkyl, 4-7 membered heterocycloalkyl-C 1-4 alkyl, and 5-6 membered heteroaryl-C 1-4 alkyl; each R f12 and R g12 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 3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4 alkyl, 4-7 membered heterocycloalkyl-C 1-4 alkyl, and 5-6 membered heteroaryl-C 1-4 alkyl; each R h12 and R i12 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4 alkyl, 4-7 membered heterocycloalkyl-C 1-4 alkyl, and 5-6 membered heteroaryl-C 1-4 alkyl; each R j12 and R k12 is independently selected from OH, C 1-6 alkoxy, and C 1-6 haloalkoxy; or, any R j12 and R k12 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; R 2A , R 2B , and R 2C are each independently selected from H, D, halo, CN, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, phenyl, 4-8 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3 -7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4 alkyl, 4-8 membered heterocycloalkyl-C 1-4 alkyl, 5-6 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 )R 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 e2 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 , and S(O) 2 NR c2 R d2 , wherein said C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, phenyl, 4-8 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4 alkyl, 4-8 membered heterocycloalkyl-C 1-4 alkyl, and 5-6 membered heteroaryl-C 1-4 alkyl are each optionally substituted with 1, 2, 3, or 4 independently selected R G substituents; each R a2 , R c2 , and R d2 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, phenyl, 4-8 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4 alkyl, 4-8 membered heterocycloalkyl-C 1-4 alkyl, and 5-6 membered heteroaryl-C 1-4 alkyl, wherein said C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, phenyl, 4-8 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4 alkyl, 4-8 membered heterocycloalkyl-C 1-4 alkyl, and 5-6 membered heteroaryl-C 1-4 alkyl are each optionally substituted with 1, 2, 3, or 4 independently selected R G 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 4-8 membered heterocycloalkyl group, which is optionally substituted with 1, 2, 3, or 4 independently selected R G substituents; each R b2 is independently selected from C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, phenyl, 4-8 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4 alkyl, 4-8 membered heterocycloalkyl-C 1-4 alkyl, and 5-6 membered heteroaryl-C 1-4 alkyl, which are each optionally substituted with 1, 2, 3, or 4 independently selected R G substituents; each R e2 is independently selected from H, OH, CN, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, and C 1-6 haloalkoxy; each R 3 is independently selected from D, halo, CN, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4 alkyl, 4-7 membered heterocycloalkyl-C 1-4 alkyl, 5-6 membered heteroaryl-C 1-4 alkyl, OR a3 , SR a3 , NHOR a3 , C(O)R b3 , C(O)NR c3 R d3 , C(O)NR c3 (OR a3 ), C(O)OR a3 , OC(O)R b3 , OC(O)NR c3 R d3 , NR c3 R d3 NR c3 NR c3 R d3 NR c3 C(O)R b3 NR c3 C(O)OR a3 NR c3 C(O)NR c3 R d3 , C(═NR e3 )R b3 , C(═NR e3 )NR c3 R d3 NR c3 C(═NR e3 )NR c3 R d3 NR c3 C(═NR e3 )R b3 NR c3 S(O)NR c3 R d3 , NR c3 S(O)R b3 , NR c3 S(O) 2 R b3 , NR c3 S(O)(═NR e3 )R b3 , NR c3 S(O) 2 NR c3 R d3 S(O)R b3 , S(O)NR c3 R d3 , S(O) 2 R b3 , and S(O) 2 NR c3 R d3 , wherein said C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4 alkyl, 4-7 membered heterocycloalkyl-C 1-4 alkyl, and 5-6 membered heteroaryl-C 1-4 alkyl are each optionally substituted with 1, 2, 3, or 4 independently selected R G substituents; each R a3 , R c3 , and R d3 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4 alkyl, 4-7 membered heterocycloalkyl-C 1-4 alkyl, and 5-6 membered heteroaryl-C 1-4 alkyl, wherein said C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4 alkyl, 4-7 membered heterocycloalkyl-C 1-4 alkyl, and 5-6 membered heteroaryl-C 1-4 alkyl are each optionally substituted with 1, 2, 3, or 4 independently selected R G substituents; each R b3 is independently selected from C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4 alkyl, 4-7 membered heterocycloalkyl-C 1-4 alkyl, and 5-6 membered heteroaryl-C 1-4 alkyl, which are each optionally substituted with 1, 2, 3, or 4 independently selected R G substituents; each R e3 is independently selected from H, OH, CN, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, and C 1-6 haloalkoxy; R 4 is selected from C 1-6 alkyl, 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, wherein said C 1-6 alkyl, 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 4A substituents; each R 4A is independently selected from D, halo, CN, NO 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4 alkyl, 4-7 membered heterocycloalkyl-C 1-4 alkyl, 5-6 membered heteroaryl-C 1-4 alkyl, OR a41 , SR a41 , NHOR a41 , C(O)R b41 , C(O)NR c41 R d41 , C(O)NR c41 (OR a41 ) C(O)OR a41 , OC(O)R b41 , OC(O)NR c41 R d41 , NR c41 R d41 NR c41 NR c41 R d41 NR c41 C(O)R b41 NR c41 C(O)OR a41 NR c41 C(O)NR c41 R d41 , C(═NR e41 )R b41 , C(═NR e41 )NR c41 R d41 , NR c41 C(═NR e41 )NR c41 R d41 NR c41 C(═NR e41 )R b41 , NR c41 S(O)NR c41 R d41 , NR c41 S(O)R b41 NR c41 S(O) 2 R b41 , NR c41 S(O)(═NR e41 )R b41 , NR c41 S(O) 2 NR c41 R d41 , S(O)R b41 , S(O)NR c41 R d41 , S(O) 2 R b41 , S(O) 2 NR c41 R d41 , OS(O)(═NR e41 )R b41 , OS(O) 2 R b41 , and S(O)(═NR e41 )R b41 , wherein said C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4 alkyl, 4-7 membered heterocycloalkyl-C 1-4 alkyl, and 5-6 membered heteroaryl-C 1-4 alkyl are each optionally substituted with 1, 2, 3, or 4 independently selected R 4B substituents; each R a41 , R c41 , and R d41 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4 alkyl, 4-7 membered heterocycloalkyl-C 1-4 alkyl, and 5-6 membered heteroaryl-C 1-4 alkyl, wherein said C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4 alkyl, 4-7 membered heterocycloalkyl-C 1-4 alkyl, and 5-6 membered heteroaryl-C 1-4 alkyl are each optionally substituted with 1, 2, 3, or 4 independently selected R 4B substituents; or, any R c41 and R d41 attached to the same N atom, together with the N atom to which they are attached, form a 4-7 membered heterocycloalkyl group, which is optionally substituted with 1, 2, 3, or 4 independently selected R 4B substituents; each R b41 is independently selected from C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4 alkyl, 4-7 membered heterocycloalkyl-C 1-4 alkyl, and 5-6 membered heteroaryl-C 1-4 alkyl, which are each optionally substituted with 1, 2, 3, or 4 independently selected R 4B substituents; each R e41 is independently selected from H, OH, CN, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4 alkyl, 4-7 membered heterocycloalkyl-C 1-4 alkyl, and 5-6 membered heteroaryl-C 1-4 alkyl; each R 4B is independently selected from D, halo, CN, NO 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4 alkyl, 4-7 membered heterocycloalkyl-C 1-4 alkyl, 5-6 membered heteroaryl-C 1-4 alkyl, OR a42 , SR a42 , NHOR a42 , C(O)R b42 , C(O)NR c42 R d42 , C(O)NR e42 (OR a42 ) C(O)OR a42 , OC(O)R b42 , OC(O)NR c42 R d42 , NR c42 R d42 , NR c42 NR c42 R d42 , NR c42 C(O)R b42 , NR c42 C(O)OR a42 , NR c42 C(O)NR c42 R d42 , C(═NR e42 )R b42 , C(═NR e42 )NR c42 R d42 , NR c42 C(═NR e42 )NR c42 R d42 , NR c42 C(═NR e42 )R b42 , NR c42 S(O)NR c42 R d42 , NR c42 S(O)R b42 , NR c42 S(O) 2 R b42 , NR c42 S(O)(═NR e42 )R b42 , NR c42 S(O) 2 NR c42 R d42 , S(O)R b42 , S(O)NR c42 R d42 , S(O) 2 R b42 , S(O) 2 NR c42 R d42 , 0S(O)(═NR e42 )R b42 , OS(O) 2 R b42 , and S(O)(═NR e42 )R b42 , wherein said C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4 alkyl, 4-7 membered heterocycloalkyl-C 1-4 alkyl, and 5-6 membered heteroaryl-C 1-4 alkyl are each optionally substituted with 1, 2, 3, or 4 independently selected R G substituents; each R a42 , R c42 , and R d42 , is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4 alkyl, 4-7 membered heterocycloalkyl-C 1-4 alkyl, and 5-6 membered heteroaryl-C 1-4 alkyl, wherein said C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4 alkyl, 4-7 membered heterocycloalkyl-C 1-4 alkyl, and 5-6 membered heteroaryl-C 1-4 alkyl are each optionally substituted with 1, 2, 3, or 4 independently selected R G substituents; each R b42 is independently selected from C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4 alkyl, 4-7 membered heterocycloalkyl-C 1-4 alkyl, and 5-6 membered heteroaryl-C 1-4 alkyl, which are each optionally substituted with 1, 2, 3, or 4 independently selected R G substituents; each R e42 is independently selected from H, OH, CN, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4 alkyl, 4-7 membered heterocycloalkyl-C 1-4 alkyl, and 5-6 membered heteroaryl-C 1-4 alkyl; R 5 is selected from halo, CN, C 1-4 alkyl, C 1-4 haloalkyl, C 2-4 alkenyl, C 2-4 alkynyl, 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 6 is selected from 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, which are each optionally substituted by 1, 2, 3, 4, 5, or 6 independently selected R 6A substituents; R 7 is selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, phenyl, 4-8 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4 alkyl, 4-8 membered heterocycloalkyl-C 1-4 alkyl, and 5-6 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 3-7 cycloalkyl, phenyl, 4-8 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4 alkyl, 4-8 membered heterocycloalkyl-C 1-4 alkyl, and 5-6 membered heteroaryl-C 1-4 alkyl are each optionally substituted with 1, 2, 3, or 4 independently selected R G substituents; or, R 6 and R 7 , together with the nitrogen atom to which they are attached, form a 4-15 membered heterocycloalkyl moiety or a 5-10 membered heteroaryl moiety, each of which is optionally substituted by 1, 2, 3, 4, 5, or 6 independently selected R 6A substituents; each R 6A 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 aryl-C 1-4 alkyl, 4-10 membered heterocycloalkyl-C 1-4 alkyl, 5-10 membered heteroaryl-C 1-4 alkyl, OR a61 , SR a61 NHOR a61 , C(O)R b61 , C(O)NR c61 R d61 , C(O)NR c61 (OR a61 ), C(O)OR a61 , OC(O)R b61 , OC(O)NR c61 R d61 , NR c61 R d61 , NR c61 NR c61 R d61 NR c61 C(O)R b61 , NR c61 C(O)OR a61 , NR c61 C(O)NR e61 R d61 , C(═NR e61 )R b61 , C(═NR e61 )NR c61 R d61 , NR c61 C(═NR e61 )NR e61 R d61 , NR e61 C(═NR e61 )R b61 , NR c61 S(O)NR c61 R d61 , NR c61 S(O)R b61 , NR c61 S(O) 2 R b61 , NR c61 S(O)(═NR e61 )R b61 , NR c61 S(O) 2 NR c61 R d61 , S(O)R b61 , S(O)NR c61 R d61 , S(O) 2 R b61 , S(O) 2 NR c61 R d61 , OS(O)(═NR e61 )R b61 , OS(O) 2 R b61 , S(O)(═NR e61 )R b61 , SF 5 , P(O)R f61 R g61 OP(O)(OR h61 )(OR i61 ), P(O)(OR h61 )(OR i61 ), and BR j61 R k61 , 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 61 substituents; each R a61 , R c61 , and R d61 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 6B substituents; or, any R c61 and R d61 attached to the same N atom, together with the N atom to which they are attached, form a 4-7 membered heterocycloalkyl group, which is optionally substituted with 1, 2, 3, or 4 independently selected R 61 substituents; each R b61 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 6B substituents; each R e61 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 f61 and R g61 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 h61 and R i61 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 j61 and R k61 is independently selected from OH, C 1-6 alkoxy, and C 1-6 haloalkoxy; or, any R j61 and R k61 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 6B 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 aryl-C 1-4 alkyl, 4-10 membered heterocycloalkyl-C 1-4 alkyl, 5-10 membered heteroaryl-C 1-4 alkyl, OR a62 , SR a62 , NHOR a62 , C(O)R b62 , C(O)NR c62 R d62 , C(O)NR c62 (OR a62 ), C(O)OR a62 , OC(O)R b62 , OC(O)NR c62 R d62 , NR c62 R d62 , NR e62 NR c62 R d62 , NR c62 C(O)R b62 , NR c62 C(O)OR a62 , NR c62 C(O)NR c62 R d62 , C(═NR e62 )R b62 , C(═NR e62 )NR c62 R d62 , NR c62 C(═NR e62 )NR c62 R d62 , NR e62 C(═NR e62 )R b62 , NR c62 S(O)NR c62 R d62 , NR e62 S(O)R b62 , NR c62 S(O) 2 R b62 , NR c62 S(O)(═NR e62 )R b62 , NR c62 S(O) 2 NR c62 R d62 , S(O)R b62 , S(O)NR c62 R d62 , S(O) 2 R b62 , S(O) 2 NR c62 R d62 , OS(O)(═NR e62 )R b62 , OS(O) 2 R b62 , S(O)(═NR e62 )R b62 , SF 5 , P(O)R f62 R g62 OP(O)(OR h62 )(OR i62 ), P(O)(OR h62 )(OR i62 ), and BR j62 R k62 , 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 6C substituents; each R a62 , R c62 , and R d62 , 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 6C substituents; or, any R c62 and R d62 , attached to the same N atom, together with the N atom to which they are attached, form a 4-7 membered heterocycloalkyl group, which is optionally substituted with 1, 2, 3, or 4 independently selected R 6C substituents; each R b62 , 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 6C substituents; each R e62 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 f62 and R g62 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 h62 and R i62 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 j62 and R k62 is independently selected from OH, C 1-6 alkoxy, and C 1-6 haloalkoxy; or, any R j62 and R k62 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 6C 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 3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4 alkyl, 4-7 membered heterocycloalkyl-C 1-4 alkyl, 5-6 membered heteroaryl-C 1-4 alkyl, OR a63 , SR a63 , NHOR a63 , C(O)R b63 , C(O)NR c63 R d63 , C(O)NR c63 (OR a63 ), C(O)OR a63 , OC(O)R b63 , OC(O)NR c63 R d63 , NR c63 R d63 , NR 63 NR c63 R d63 , NR c63 C(O)R b63 , NR c63 C(O)OR a63 , NR c63 C(O)NR c63 R d63 , C(═NR e63 )R b63 , C(═NR e63 )NR c63 R d63 , NR c63 C(═NR e63 )NR c63 R d63 , NR c63 C(═NR e63 )R b63 , NR c63 S(O)NR c63 R d63 , NR c63 S(O)R b63 , NR c63 S(O) 2 R b63 , NR c63 S(O)(═NR e63 )R b63 , NR c63 S(O) 2 NR c63 R d63 , S(O)R b63 , S(O)NR c63 R d63 , S(O) 2 R b63 , S(O) 2 NR c63 R d63 , OS(O)(═NR e63 )R b63 , OS(O) 2 R b63 , S(O)(═NR e63 )R b63 , SF 5 , P(O)R f63 R g63 , OP(O)(OR h63 )(OR i63 ), P(O)(OR h63 )(OR i63 ) and BR j63 R k63 , wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4 alkyl, 4-7 membered heterocycloalkyl-C 1-4 alkyl, and 5-6 membered heteroaryl-C 1-4 alkyl are each optionally substituted with 1, 2, 3, or 4 independently selected R G substituents; each R a63 , R c63 , and R d63 , is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4 alkyl, 4-7 membered heterocycloalkyl-C 1-4 alkyl, and 5-6 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 3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4 alkyl, 4-7 membered heterocycloalkyl-C 1-4 alkyl, and 5-6 membered heteroaryl-C 1-4 alkyl are each optionally substituted with 1, 2, 3, or 4 independently selected R G substituents; or, any R c63 and R d63 , attached to the same N atom, together with the N atom to which they are attached, form a 4-7 membered heterocycloalkyl group, which is optionally substituted with 1, 2, 3, or 4 independently selected R G substituents; each R b63 is independently selected from C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4 alkyl, 4-7 membered heterocycloalkyl-C 1-4 alkyl, and 5-6 membered heteroaryl-C 1-4 alkyl, which are each optionally substituted with 1, 2, 3, or 4 independently selected R G substituents; each R e63 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 3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4 alkyl, 4-7 membered heterocycloalkyl-C 1-4 alkyl, and 5-6 membered heteroaryl-C 1-4 alkyl; each R f63 and R g63 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 3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4 alkyl, 4-7 membered heterocycloalkyl-C 1-4 alkyl, and 5-6 membered heteroaryl-C 1-4 alkyl; each R h63 and R i63 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4 alkyl, 4-7 membered heterocycloalkyl-C 1-4 alkyl, and 5-6 membered heteroaryl-C 1-4 alkyl; each R j63 and R k63 is independently selected from OH, C 1-6 alkoxy, and C 1-6 haloalkoxy; or, any R j63 and R k63 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; R 8 is selected from H, D, halo, CN, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, phenyl, 4-8 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4 alkyl, 4-8 membered heterocycloalkyl-C 1-4 alkyl, 5-6 membered heteroaryl-C 1-4 alkyl, OR a8 , SR a8 , NHOR a8 , C(O)R b8 , C(O)NR c8 R d8 , C(O)NR c8 (OR a8 ), C(O)OR a8 , OC(O)R b8 , OC(O)NR c8 R d8 , NR c8 R d8 , NR c8 NR c8 R d8 NR c8 C(O)R b8 NR c8 C(O)OR a8 , NR c8 C(O)NR c8 R d8 , C(═NR e8 )R b8 , C(═NR e8 )NR c8 R d8 , NR c8 C(═NR e8 )NR c8 R d8 , NR c8 C(═NR e8 )R b8 , NR c8 S(O)NR c8 R d8 , NR e8 S(O)R b8 NR c8 S(O) 2 R b8 , NR c8 S(O)(═NR e8 )R b8 , NR c8 S(O) 2 NR c8 R d8 , S(O)R b8 , S(O)NR c8 R d8 , S(O) 2 R b8 , and S(O) 2 NR c8 R d8 , wherein said C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, phenyl, 4-8 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4 alkyl, 4-8 membered heterocycloalkyl-C 1-4 alkyl, and 5-6 membered heteroaryl-C 1-4 alkyl are each optionally substituted with 1, 2, 3, or 4 independently selected R G substituents; each R a8 , R c8 , and R d8 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, phenyl, 4-8 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4 alkyl, 4-8 membered heterocycloalkyl-C 1-4 alkyl, and 5-6 membered heteroaryl-C 1-4 alkyl, wherein said C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, phenyl, 4-8 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4 alkyl, 4-8 membered heterocycloalkyl-C 1-4 alkyl, and 5-6 membered heteroaryl-C 1-4 alkyl are each optionally substituted with 1, 2, 3, or 4 independently selected R G substituents; or, any R c8 and R d8 attached to the same N atom, together with the N atom to which they are attached, form a 4-8 membered heterocycloalkyl group, which is optionally substituted with 1, 2, 3, or 4 independently selected R G substituents; each R b8 is independently selected from C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, phenyl, 4-8 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4 alkyl, 4-8 membered heterocycloalkyl-C 1-4 alkyl, and 5-6 membered heteroaryl-C 1-4 alkyl, which are each optionally substituted with 1, 2, 3, or 4 independently selected R G substituents; each R e8 is independently selected from H, OH, CN, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, and C 1-6 haloalkoxy; and each R G is independently selected from OH, NO 2 , CN, halo, C 1-3 alkyl, C 2-3 alkenyl, C 2-3 alkynyl, C 1-3 haloalkyl, cyano-C 1-3 alkyl, HO—C 1-3 alkyl, C 1-3 alkoxy-C 1-3 alkyl, C 3-4 cycloalkyl, C 1-3 alkoxy, C 1-3 haloalkoxy, amino, C 1-3 alkylamino, di(C 1-3 alkyl)amino, thio, C 1-3 alkylthio, C 1-3 alkylsulfinyl, C 1-3 alkylsulfonyl, carbamyl, C 1-3 alkylcarbamyl, di(C 1-3 alkyl)carbamyl, carboxy, C 1-3 alkylcarbonyl, C 1-3 alkoxycarbonyl, C 1-3 alkylcarbonyloxy, C 1-3 alkylcarbonylamino, C 1-3 alkoxycarbonylamino, C 1-3 alkylaminocarbonyloxy, C 1-3 alkylsulfonylamino, aminosulfonyl, C 1-3 alkylaminosulfonyl, di(C 1-3 alkyl)aminosulfonyl, aminosulfonylamino, C 1-3 alkylaminosulfonylamino, di(C 1-3 alkyl)aminosulfonylamino, aminocarbonylamino, C 1-3 alkylaminocarbonylamino, and di(C 1-3 alkyl)aminocarbonylamino.
  2. 2 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein n is 0, 1, or 2.
  3. 3 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein n is 1.
  4. 4 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein X is O, S(O) 2 , or N(-L-R 4 ).
  5. 5 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein X is O.
  6. 6 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein X is N(-L-R 4 ).
  7. 7 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein L is S(O) 2 .
  8. 8 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4 alkyl, 4-7 membered heterocycloalkyl-C 1-4 alkyl, and 5-6 membered heteroaryl-C 1-4 alkyl, which are each optionally substituted with 1, 2, 3, or 4 independently selected R 1A substituents.
  9. 9 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, and 4-7 membered heterocycloalkyl, which are each optionally substituted with 1, 2, 3, or 4 independently selected R 1A substituents.
  10. 10 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from C 1-6 alkyl, C 1-6 haloalkyl, and C 3-7 cycloalkyl, which are each optionally substituted with 1, 2, 3, or 4 independently selected R 1A substituents.
  11. 11 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from C 1-6 alkyl, C 1-6 haloalkyl, and C 3-7 cycloalkyl.
  12. 12 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein: each R 1A is independently selected from H, D, halo, CN, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4 alkyl, 4-7 membered heterocycloalkyl-C 1-4 alkyl, 5-6 membered heteroaryl-C 1-4 alkyl, OR a11 , SR a11 , C(O)R b11 , C(O)NR c11 R d11 , C(O)OR a11 , OC(O)R b11 , OC(O)NR c11 R d11 , NR c11 R d11 , NR c11 C(O)R b11 , NR c11 C(O)OR a11 , NR c11 CHC(O)NR c11 R d11 , NR c11 S(O) 2 R b11 , NR c11 S(O) 2 NR c11 R d11 , S(O) 2 R b11 , and S(O) 2 NR c11 R d11 , wherein said C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4 alkyl, 4-7 membered heterocycloalkyl-C 1-4 alkyl, and 5-6 membered heteroaryl-C 1-4 alkyl are each optionally substituted with 1, 2, 3, or 4 independently selected R 1B substituents; each R a11 , R c11 , and R d11 , is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4 alkyl, 4-7 membered heterocycloalkyl-C 1-4 alkyl, and 5-6 membered heteroaryl-C 1-4 alkyl, wherein said C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4 alkyl, 4-7 membered heterocycloalkyl-C 1-4 alkyl, and 5-6 membered heteroaryl-C 1-4 alkyl are each optionally substituted with 1, 2, 3, or 4 independently selected R 1B substituents; each R b11 is independently selected from C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4 alkyl, 4-7 membered heterocycloalkyl-C 1-4 alkyl, and 5-6 membered heteroaryl-C 1-4 alkyl, which are each optionally substituted with 1, 2, 3, or 4 independently selected R 1B substituents; each R 1B is independently selected from H, D, halo, CN, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4 alkyl, 4-7 membered heterocycloalkyl-C 1-4 alkyl, 5-6 membered heteroaryl-C 1-4 alkyl, OR a12 , SR a12 , C(O)R b12 , C(O)NR e12 R d12 , C(O)OR a12 , OC(O)R b12 OC(O)NR c12 R d12 , NR c12 R d12 , NR c12 C(O)R b12 NR c12 C(O)OR a12 NR e12 C(O)NR e12 R d12 , NR c12 S(O) 2 R b12 , NR c12 S(O) 2 NR c12 R d12 , S(O) 2 R b12 , and S(O) 2 NR c12 R d12 ; each R a12 , R c12 , and R d12 , is independently selected from H, C 1-6 alkyl, and C 1-6 haloalkyl; and each R b12 , is independently selected from C 1-6 alkyl and C 1-6 haloalkyl.
  13. 13 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein: each R 1A is independently selected from H, D, halo, CN, C 1-6 alkyl, C 1-6 haloalkyl, OR a11 , and NR c11 R d11 ; and each R a11 , R c11 , and R d11 , is independently selected from H, C 1-6 alkyl, and C 1-6 haloalkyl.
  14. 14 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2A R 2B , and R 2C are each independently selected from H, D, halo, CN, C 1-6 alkyl, C 1-6 haloalkyl, C(O)R b2 , C(O)NR c2 R d2 , C(O)OR a2 , OC(O)R b2 , OC(O)NR c2 R d2 , NR c2 R d2 , NR c2 C(O)R b2 NR c2 C(O)OR a2 NR c2 C(O)NR c2 R d2 , NR c2 S(O) 2 R b2 , NR c2 S(O) 2 NR c2 R d2 , S(O) 2 R b2 , and S(O) 2 NR c2 R d2 , wherein said C 1-6 alkyl and C 1-6 haloalkyl are each optionally substituted with 1 or 2 independently selected R G substituents.
  15. 15 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2A R 2B , and R 2C are each independently selected from H, halo, and OR a2 .
  16. 16 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein: each R a2 , R c2 , and R d2 is independently selected from H, C 1-6 alkyl, and C 1-6 haloalkyl; and each R b2 is independently selected from C 1-6 alkyl and C 1-6 haloalkyl.
  17. 17 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein each R 3 is independently selected from —C 1-4 alkylene-OR a3 , —C 1-4 alkylene-NR c3 R d3 , OR a3 , and NR c3 R d3 .
  18. 18 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein each R 3 is OH.
  19. 19 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4 is selected from C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3-7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4 alkyl, 4-7 membered heterocycloalkyl-C 1-4 alkyl, and 5-6 membered heteroaryl-C 1-4 alkyl, wherein said C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, phenyl, 4-7 membered heterocycloalkyl, 5-6 membered heteroaryl, C 3 -7 cycloalkyl-C 1-4 alkyl, phenyl-C 1-4 alkyl, 4-7 membered heterocycloalkyl-C 1-4 alkyl, and 5-6 membered heteroaryl-C 1-4 alkyl are each optionally substituted by 1, 2, 3, or 4 independently selected R 4A substituents.
  20. 20 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4 is selected from C 1-6 alkyl and C 1-6 haloalkyl.

Description

TECHNICAL FIELD This application is directed to pyrimidine indoles which inhibit cyclin-dependent kinase 4 (CDK4) and are useful for treating cancer. BACKGROUND Cyclin-dependent kinases (CDKs) are a family of serine/threonine kinases. Heterodimerized with regulatory subunits known as cyclins, CDKs become fully activated and regulate key cellular processes including cell cycle progression and cell division (Morgan, D. O. Annu. Rev. Cell Dev. Biol. 1997, 13:261-291). Uncontrolled proliferation is a hallmark of cancer cells. The deregulation of the CDK activity is associated with abnormal regulation of cell-cycle and is detected in virtually all forms of human cancers (Sherr, C. J. and Roberts, J. M., Genes Dev. 1999, 13(12): 1501-1512). CDK4, in complex with cyclin D, is crucial for the transition from the G1 phase to the S phase of the cell cycle. The availability and synthesis of cyclin D are influenced by extracellular signals such as growth factors and mitogens (Sherr, C. J. and Roberts, J. M., Genes Dev. 1999, 13(12): 1501-1512; and Malumbres, M. et al. Nat. Rev. Cancer 2009, 9(3): 153-166). This transition is essential for DNA replication and cell division. One of the primary targets of the CDK4/cyclin D complex is the retinoblastoma protein (Rb). In its hypophosphorylated form, Rb binds to and inhibits E2F transcription factors (Weinberg, R. A. Cell 1995, 81(3): 323-330; and Dyson, N., Genes Dev. 1998, 12(15): 2245-2262). CDK4/cyclin D phosphorylates Rb, leading to its inactivation. Phosphorylation of retinoblastoma protein (Rb) by the CDK4/cyclin D complex leads to the release of E2F transcription factors, which promote the expression of genes required for DNA synthesis and S phase entry, such as those coding for cyclin E and other proteins involved in DNA replication (Harbour, J. W. and Dean, D. C., Genes Dev., 2000, 14(19): 2393-2409; Nevins, J. R., Hum. Mol. Genet., 2001, 10(7): 699-703). The action of CDK4/cyclin D ensure that once the cell passes the G1/S checkpoint, it is committed to completing the cell cycle, thus ensuring controlled and regulated cell division. Overexpression or amplification of CDK4 can lead to abnormal activity, resulting in uncontrolled cell proliferation, a hallmark of cancer. The CDK4-cyclin D pathway is often deregulated in many cancers, leading to excessive cell division and tumor growth. Dysregulation of CCND1 in cancer can occur through gene amplification, chromosomal translocations, mutations in regulatory pathways, miRNA alterations, and changes in protein stability and degradation (Swerdlow, S. H. et al., Hum. Pathol., 1995 26(9): 999-1004; Knudsen, E. S. and Wang, J. Y, Mol. Cell Biol., 1997, 17(10): 5771-5783; Asghar, U., A. K. et al., Nat. Rev. Drug Discov., 2015, 14(2): 130-146; Zheng, N., Z. Wang and Wei, W., Int. J. Biochem. Cell Biol., 2016, 73: 99-110; and Lines, K. E. et al., J. Endocrinol., 2018, 240(1): 41-50). Additionally, mutations or alterations in the Rb pathway can enhance CDK4 activity, further contributing to cancer development (Weinberg, R. A. Cell 1995, 81(3): 323-330; Sherr, C. J. and Roberts, J. M., Genes Dev. 1999, 13(12): 1501-1512; Harbour, J. W. and Dean, D. C., Genes Dev., 2000, 14(19): 2393-2409; Nevins, J. R., Hum. Mol. Genet., 2001, 10(7): 699-703). Due to its central role in cell cycle regulation, CDK4 is a target for cancer therapy. CDK4/6 dual inhibitors, such as palbociclib, ribociclib, and abemaciclib, have been developed and approved for the treatment of certain cancers, including breast cancer. These inhibitors work by blocking the kinase activity of CDK4/6, blocking cell cycle progression, and inducing senescence thereby inhibiting tumor growth (Asghar, U., A. K. et al., Nat. Rev. Drug Discov., 2015, 14(2): 130-146). Further, a compound which is selective for CDK4 over CDK6 can be useful to minimize dose limiting toxicity. In particular, CDK4 is the primary oncogenic driver in certain breast cancers, the co-inhibition of CDK6-cyclin D3 can result in dose limiting toxicities due to associated hematological adverse events (Maurer, B. et al., Haematologica., 2021, 106(10): 2624-2632). Neutropenia is reported as the most common adverse events for CDK4/6 inhibitors, particularly palbociclib and ribociclib, and to a lesser extent abemaciclib (Liu, Y et al., BMC Cancer, 2023, 23(1): 816). Despite the clinical success of CDK4/6 inhibitors, such dose limiting toxicities limit the dosing regimen thus limiting effective target coverage. A selective CDK4 inhibitor would facilitate higher target coverage, thus maximizing efficacy while also minimizing the CDK6-associated toxicity profile, thus improving overall safety and tolerability. A next-generation CDK4 inhibitor could have clinical benefit in CDK4/6 refractory patients and could address acquired resistance to standard of care. Additionally, functional inhibition of CDK4, through a CDK4 molecule, has clinical opportunity in other indications besides breast cancers. CCND1 dysregulated