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EP-4735453-A1 - KRAS MODULATING COMPOUNDS

EP4735453A1EP 4735453 A1EP4735453 A1EP 4735453A1EP-4735453-A1

Abstract

Provided herein are compounds, and pharmaceutically acceptable salts thereof, useful as KRAS inhibitors, methods of making and using the same (singly or in combination with additional agents), and pharmaceutical compositions thereof.

Inventors

  • CORTOPASSI COELHO, Wilian Augusto
  • MEDLEY, Jonathan William
  • TSUI, VICKIE H.
  • WATKINS, WILLIAM J.
  • FARAND, JULIE
  • GUERRERO, JUAN A.
  • GRAUPE, MICHAEL
  • KATO, DARRYL
  • KIBURU, Irene N.
  • MACK, James B.C.
  • MARTIN, Joshua L.
  • MCAULEY, Erik P.

Assignees

  • GILEAD SCIENCES, INC.

Dates

Publication Date
20260506
Application Date
20240627

Claims (20)

  1. CLAIMS 1. A compound of Formula (I): Formula (I), or a pharmaceutically acceptable salt thereof, wherein X is N, CH, or CR x ; R x is (CH2)mCN or halo; m is 0, 1, 2 or 3; each R 3 and R 4 is independently H or C1-C3 alkyl; R A is phenyl, naphthyl, or 5- to 14-membered heteroaryl, wherein R A is substituted with 0, 1, 2, 3, 4, or 5 R A2 ; each R A2 is independently -OH, C 1 -C 10 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C 1 -C 10 alkoxy, C 1 -C 10 hydroxyalkyl, C2-C10 alkoxyalkyl, C 1 -C 6 alkyl-N(R A2a )(R A2b ), C 1 -C 10 thioalkyl, halo, C1- C6 haloalkyl, -CN, -C(O)R A2a , -C(O)OR A2a , -OC(O)R A2a , -OC(O)OR A2a , -C(O)N(R A2a )(R A2b ), - N(R A2a )C(O)(R A2b ), -OC(O)N(R A2a )(R A2b ), -N(R A2a )C(O)(OR A2b ), oxo, -OR A2a , -SR A2a , - S(O)2R A2a , -S(O)2OR A2a , -N(R A2a )(R A2b ), -(C0-C3 alkyl)-SF5, -OP(O)(OR A2a )(OR A2b ), C 3 -C 8 cycloalkyl, -(C 1 -C 6 alkyl)-(C 3 -C 8 cycloalkyl), 3- to 14-membered heterocyclyl, -(C 1 -C 6 alkyl)-(3- to 14-membered heterocyclyl), C6-C14 aryl, -(C 1 -C 6 alkyl)-(C6-C14 aryl), 5- to 14-membered heteroaryl, or -(C 1 -C 6 alkyl)-(5- to 14-membered heteroaryl), wherein each alkyl, alkenyl, alkynyl, alkoxy, hydroxyalkyl, and haloalkyl is substituted with 0, 1, 2, or 3 R A3 , and wherein each cycloalkyl, alkyl-cycloalkyl, heterocyclyl, alkyl-heterocyclyl, aryl, alkyl-aryl, heteroaryl, and alkyl-heteroaryl is substituted with 0, 1, 2, or 3 R A4 ; each R A2a and R A2b is independently H, C 1 -C 10 alkyl, C 1 -C 6 haloalkyl, or C 3 -C 8 cycloalkyl; each R A3 is independently halo, -CN, -OR A3a , -SR A3a , -N(R A3a )(R A3b ), C 3 -C 8 cycloalkyl, or 5- to 14-membered heteroaryl; each R A3a and R A3b is independently H, C 1 -C 10 alkyl, C 1 -C 6 haloalkyl, or C 3 -C 8 cycloalkyl; each R A4 is independently C 1 -C 6 alkoxy, C 1 -C 6 hydroxyalkyl, C2-C6 alkoxyalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, C 1 -C 6 haloalkylthio, C 3 -C 8 cycloalkyl, -(C 1 -C 6 alkyl)-(C6-C10 aryl), halo, -CN, -OH, or -N(R A4a )(R A4b ); each R A4a and R A4b is independently H or C 1 -C 6 alkyl; alternatively, two R A2 can combine to form a C3-C10 cycloalkyl, C6-C10 aryl, a 3- to 10-membered heterocyclyl, or 5- to 14-membered heteroaryl on two adjacent atoms on R A , wherein each cycloalkyl, aryl, heterocyclyl, and heteroaryl is substituted with 0, 1, 2, or 3 R A5 ; each R A5 is independently C 1 -C 10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, halo, C 1 -C 6 haloalkyl, - CN, or C 3 -C 8 cycloalkyl; R B is H; L C is a bond or ; Y is C or Si; n is 0, 1, 2, or 3; q is 0, 1, 2, or 3; R Y1 is H or C1-C3 alkyl; R Y2 is H or C1-C3 alkyl; alternatively, R Y1 and R Y2 combine to form a C3-C10 cycloalkyl or a 3- to 10-membered heterocyclyl; R C is H, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 hydroxyalkyl, C2-C6 alkoxyalkyl, C 1 -C 6 haloalkyl, C1- C6 haloalkoxy, -NH2, -NHR C1 , -N(R C1 )2, C 3 -C 8 cycloalkyl, 3- to 14-membered heterocyclyl, C6- C14 aryl, or 5- to 14-membered heteroaryl, wherein each C 3 -C 8 cycloalkyl, 3- to 14-membered heterocyclyl, C6-C14 aryl, and 5- to 14-membered heteroaryl is substituted with 0, 1, 2, 3, or 4 R C3 ; each R C1 is independently selected from C 1 -C 6 alkyl; each R C3 is independently C 1 -C 6 alkyl, C2-C6 alkenyl, C2-C8 alkynyl, C 1 -C 6 alkoxyalkyl, C 1 -C 6 hydroxyalkyl, halo, C 1 -C 6 haloalkyl, C 1 -C 6 heteroalkyl, -(C 1 -C 6 alkyl)-N(R C3a )(R C3b ), -CN, - C(O)R C3a , -C(O)OR C3a , -C(O)N(R C3a )(R C3b ), -N(R C3a )C(O)(R C3b ), -OC(O)N(R C3a )(R C3b ), -N(R C3a )C(O)(OR C3b ), =CH2, =CHF, =CF2, oxo, - OR C3a , -SR C3a , -N(R C3a )(R C3b ), -N3, SF5, C 3 -C 8 cycloalkyl, -(C 1 -C 6 alkyl)-(C 3 -C 8 cycloalkyl), 3- to 10-membered heterocyclyl, -(C 1 -C 6 alkyl)-(3- to 10-membered heterocyclyl), C6-C10 aryl, -(C1- C6 alkyl)-(C6-C10 aryl), 5- to 10-membered heteroaryl, or -(C 1 -C 6 alkyl)-(5- to 10-membered heteroaryl), wherein each alkyl is substituted with 0, 1, 2, or 3 -CN, -C(O)OR C3a1 , -C(O)N(R C3a1 )(R C3a2 ), -N(R C3a1 )C(O)(R C3a2 ), -OC(O)N(R C3a1 )(R C3a2 ), -OR C3a1 , -SR C3a1 , N3, SF5, or 3- to 10-membered heterocyclyl substituted with 0, 1, 2, or 3 R C3a2 , each cycloalkyl, alkyl-cycloalkyl, heterocyclyl, alkyl-heterocyclyl, aryl, alkyl-aryl, heteroaryl, and alkyl-heteroaryl is substituted with 0, 1, 2, or 3 halo, -CN, or R C3a2 , each alkenyl is substituted with 0, 1, 2, or 3 halo, and each alkoxyalkyl and alkynyl is substituted with 0, 1, 2, or 3 C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 8 cycloalkyl substituted with 0 or 1 C 1 -C 6 haloalkyl, C6-C10 aryl, or 5- to 10-membered heteroaryl; each R C3a and R C3b is independently H, C 1 -C 10 alkyl, C 1 -C 6 haloalkyl, C6-C10 aryl, C3-C6 cycloalkyl, 3- to 6-membered heterocyclyl, or 5- to 10-membered heteroaryl, wherein each aryl and heteroaryl is substituted with 0, 1, 2, or 3 halo, -CN, or R C3a2 ; alternatively, R C3a and R C3b together with the N to which they are attached form a 3- to 8- membered heterocycle; each R C3a1 and R C3a2 is independently C1-C3 alkyl, halo, C 1 -C 6 haloalkyl, C 3 -C 8 cycloalkyl, -(C1- C 3 alkyl)-(C 3 -C 8 cycloalkyl), 3- to 10-membered heterocyclyl, -(C 1 -C 3 alkyl)-(3- to 10-membered heterocyclyl), C6-C10 aryl, -(C1-C3 alkyl)-(C6-C10 aryl), -(C2-C4 alkynyl)-(C6-C10 aryl), 5- to 10- membered heteroaryl, -(C1-C3 alkyl)-(5- to 10-membered heteroaryl), or SF5, wherein each cycloalkyl, alkyl-cycloalkyl, heterocyclyl, alkyl-heterocyclyl, aryl, alkyl-aryl, alkynyl-aryl, heteroaryl, and alkyl-heteroaryl is substituted with 0, 1, 2, or 3 halo, C1-C3 haloalkyl, C1-C3 haloalkoxy, or SF5; alternatively, R C3a1 and R C3a2 together with the N to which they are attached form a 3- to 8- membered heterocycle; R D is halo; each heterocyclyl has 1, 2, 3, or 4 heteroatoms selected from N, O, S, and Si; and each heteroaryl has 1, 2, 3, or 4 heteroatoms selected from N, O, and S. 2. A compound of Formula (I): Formula (I), or a pharmaceutically acceptable salt thereof, wherein X is N, CH, or CR x ; R x is (CH2)mCN or halo; m is 0, 1, 2 or 3; each R 3 and R 4 is independently H or C1-C3 alkyl; R A is phenyl, naphthyl, or 5- to 14-membered heteroaryl, wherein R A is substituted with 0, 1,
  2. 2,
  3. 3,
  4. 4, or 5 R A2 ; each R A2 is independently -OH, C 1 -C 10 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C 1 -C 10 alkoxy, C 1 -C 10 hydroxyalkyl, C2-C10 alkoxyalkyl, C 1 -C 6 alkyl-N(R A2a )(R A2b ), C 1 -C 10 thioalkyl, halo, C1- C6 haloalkyl, -CN, -C(O)R A2a , -C(O)OR A2a , -OC(O)R A2a , -OC(O)OR A2a , -C(O)N(R A2a )(R A2b ), - N(R A2a )C(O)(R A2b ), -OC(O)N(R A2a )(R A2b ), -N(R A2a )C(O)(OR A2b ), oxo, -OR A2a , -SR A2a , - S(O)2R A2a , -S(O)2OR A2a , -N(R A2a )(R A2b ), -(C0-C3 alkyl)-SF5, -OP(O)(OR A2a )(OR A2b ), C 3 -C 8 cycloalkyl, -(C 1 -C 6 alkyl)-(C 3 -C 8 cycloalkyl), 3- to 14-membered heterocyclyl, -(C 1 -C 6 alkyl)-(3- to 14-membered heterocyclyl), C6-C14 aryl, -(C 1 -C 6 alkyl)-(C6-C14 aryl), 5- to 14-membered heteroaryl, or -(C 1 -C 6 alkyl)-(5- to 14-membered heteroaryl), wherein each alkyl, alkenyl, alkynyl, alkoxy, hydroxyalkyl, and haloalkyl is substituted with 0, 1, 2, or 3 R A3 , and wherein each cycloalkyl, alkyl-cycloalkyl, heterocyclyl, alkyl-heterocyclyl, aryl, alkyl-aryl, heteroaryl, and alkyl-heteroaryl is substituted with 0, 1, 2, or 3 R A4 ; each R A2a and R A2b is independently H, C 1 -C 10 alkyl, C 1 -C 6 haloalkyl, or C 3 -C 8 cycloalkyl; each R A3 is independently halo, -CN, -OR A3a , -SR A3a , -N(R A3a )(R A3b ), C 3 -C 8 cycloalkyl, or 5- to 14-membered heteroaryl; each R A3a and R A3b is independently H, C 1 -C 10 alkyl, C 1 -C 6 haloalkyl, or C 3 -C 8 cycloalkyl; each R A4 is independently C 1 -C 6 alkoxy, C 1 -C 6 hydroxyalkyl, C2-C6 alkoxyalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, C 1 -C 6 haloalkylthio, C 3 -C 8 cycloalkyl, -(C 1 -C 6 alkyl)-(C6-C10 aryl), halo, -CN, -OH, or -N(R A4a )(R A4b ); each R A4a and R A4b is independently H or C 1 -C 6 alkyl; alternatively, two R A2 can combine to form a C3-C10 cycloalkyl, C6-C10 aryl, a 3- to 10-membered heterocyclyl, or 5- to 14-membered heteroaryl on two adjacent atoms on R A , wherein each cycloalkyl, aryl, heterocyclyl, and heteroaryl is substituted with 0, 1, 2, or 3 R A5 ; each R A5 is independently C 1 -C 10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, halo, C 1 -C 6 haloalkyl, - CN, or C 3 -C 8 cycloalkyl; R B is H; L C is a bond or ; Y is C or Si; n is 0, 1, 2, or 3; q is 0, 1, 2, or 3; R Y1 is H or C1-C3 alkyl; R Y2 is H or C1-C3 alkyl; alternatively, R Y1 and R Y2 combine to form a C3-C10 cycloalkyl or a 3- to 10-membered heterocyclyl; R C is H, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 hydroxyalkyl, C2-C6 alkoxyalkyl, C 1 -C 6 haloalkyl, C1- C6 haloalkoxy, -NH2, -NHR C1 , -N(R C1 )2, C 3 -C 8 cycloalkyl, 3- to 14-membered heterocyclyl, C6- C14 aryl, or 5- to 14-membered heteroaryl, wherein each C 3 -C 8 cycloalkyl, 3- to 14-membered heterocyclyl, C6-C14 aryl, and 5- to 14-membered heteroaryl is substituted with 0, 1, 2, 3, or 4 R C3 ; each R C1 is independently selected from C 1 -C 6 alkyl; each R C3 is independently C 1 -C 6 alkyl, C2-C6 alkenyl, C2-C8 alkynyl, C 1 -C 6 alkoxyalkyl, C 1 -C 6 hydroxyalkyl, halo, C 1 -C 6 haloalkyl, C 1 -C 6 heteroalkyl, -(C 1 -C 6 alkyl)-N(R C3a )(R C3b ), -CN, - C(O)R C3a , -C(O)OR C3a , -C(O)N(R C3a )(R C3b ), -N(R C3a )C(O)(R C3b ), -OC(O)N(R C3a )(R C3b ), -N(R C3a )C(O)(OR C3b ), =CH2, =CF2, oxo, -OR C3a , - SR C3a , -N(R C3a )(R C3b ), -N3, SF5, C 3 -C 8 cycloalkyl, -(C 1 -C 6 alkyl)-(C 3 -C 8 cycloalkyl), 3- to 10- membered heterocyclyl, -(C 1 -C 6 alkyl)-(3- to 10-membered heterocyclyl), C6-C10 aryl, -(C 1 -C 6 alkyl)-(C6-C10 aryl), 5- to 10-membered heteroaryl, or -(C 1 -C 6 alkyl)-(5- to 10-membered heteroaryl), wherein each alkyl is substituted with 0, 1, 2, or 3 -CN, -C(O)OR C3a1 , -C(O)N(R C3a1 )(R C3a2 ), -N(R C3a1 )C(O)(R C3a2 ), -OC(O)N(R C3a1 )(R C3a2 ), -OR C3a1 , -SR C3a1 , N3, SF5, or 3- to 10-membered heterocyclyl substituted with 0, 1, 2, or 3 R C3a2 , each cycloalkyl, alkyl-cycloalkyl, heterocyclyl, alkyl-heterocyclyl, aryl, alkyl-aryl, heteroaryl, and alkyl-heteroaryl is substituted with 0, 1, 2, or 3 halo, -CN, or R C3a2 , each alkenyl is substituted with 0, 1, 2, or 3 halo, and each alkoxyalkyl and alkynyl is substituted with 0, 1, 2, or 3 C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 8 cycloalkyl substituted with 0 or 1 C 1 -C 6 haloalkyl, C6-C10 aryl, or 5- to 10-membered heteroaryl; each R C3a and R C3b is independently H, C 1 -C 10 alkyl, C 1 -C 6 haloalkyl, C6-C10 aryl, C3-C6 cycloalkyl, 3- to 6-membered heterocyclyl, or 5- to 10-membered heteroaryl, wherein each aryl and heteroaryl is substituted with 0, 1, 2, or 3 halo, -CN, or R C3a2 ; alternatively, R C3a and R C3b together with the N to which they are attached form a 3- to 8- membered heterocycle; each R C3a1 and R C3a2 is independently C1-C3 alkyl, halo, C 1 -C 6 haloalkyl, C 3 -C 8 cycloalkyl, -(C1- C3 alkyl)-(C 3 -C 8 cycloalkyl), 3- to 10-membered heterocyclyl, -(C1-C3 alkyl)-(3- to 10-membered heterocyclyl), C6-C10 aryl, -(C1-C3 alkyl)-(C6-C10 aryl), -(C2-C4 alkynyl)-(C6-C10 aryl),
  5. 5- to 10- membered heteroaryl, -(C1-C3 alkyl)-(5- to 10-membered heteroaryl), or SF5, wherein each cycloalkyl, alkyl-cycloalkyl, heterocyclyl, alkyl-heterocyclyl, aryl, alkyl-aryl, alkynyl-aryl, heteroaryl, and alkyl-heteroaryl is substituted with 0, 1, 2, or 3 halo, C1-C3 haloalkyl, C1-C3 haloalkoxy, or SF5; alternatively, R C3a1 and R C3a2 together with the N to which they are attached form a 3- to 8- membered heterocycle; R D is halo; each heterocyclyl has 1, 2, 3, or 4 heteroatoms selected from N, O, S, and Si; and each heteroaryl has 1, 2, 3, or 4 heteroatoms selected from N, O, and S. 3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R 3 and R 4 are each H. 4. The compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, having the structure of Formula (I-1): 5. The compound of any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein X is N.
  6. 6. The compound of any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein X is CH.
  7. 7. The compound of any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein X is C-F.
  8. 8. The compound of any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein X is C-Cl.
  9. 9. The compound of any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein R A is phenyl substituted with 0, 1, or 2 R A2 .
  10. 10. The compound of any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein R A is naphthyl substituted with 0, 1, 2, 3, 4, or 5 R A2 .
  11. 11. The compound of any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein R A is 5- to 14-membered heteroaryl, wherein R A is substituted with 0, 1, 2, 3, 4, or 5 R A2 .
  12. 12. The compound of any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein R A is 5- to 6-membered heteroaryl, wherein R A is substituted with 0, 1, or 2 R A2 .
  13. 13. The compound of any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein R A is pyridyl, wherein R A is substituted with 0, 1, or 2 R A2 .
  14. 14. The compound of any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, wherein each R A2 is independently C 1 -C 6 alkyl, -OH, C2-C6 alkenyl, C2-C6 alkynyl, halo, C 1 -C 6 haloalkyl, -CN, oxo, -OR A2a , -SR A2a , -N(R A2a )(R A2b ), or -(C 1 -C 6 alkyl)-(C 3 -C 8 cycloalkyl), wherein each alkenyl is substituted with 0, 1, 2, or 3 R A3 ; each R A2a is independently C 1 -C 6 haloalkyl, or C 3 -C 8 cycloalkyl; and each R A3 is independently halo.
  15. 15. The compound of any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, wherein each R A2 is independently Me, Et, -OH, -CH=CHMe, -C(Cl)=CH2, -CH=CHF2, - &Ł&+^^)^^&O^^-CF3, -CH2CF3, oxo, -OCF3, CN, -O-cyclopropyl, -SCF3, -NH2, or –CH2- cyclopropyl.
  16. 16. The compound of any one of claims 1 to 15, wherein each R A2 is independently -OH, F, CN, or -NH2.
  17. 17. The compound of any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, wherein R A is , , .
  18. 18. The compound of any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, wherein R A is , , , ,
  19. 19. The compound of any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, wherein R A is .
  20. 20. The compound of any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, wherein R A is .

Description

KRAS MODULATING COMPOUNDS CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This application claims the benefit under 35 U.S.C. § 119(e) of U.S. Provisional Application No. 63/511,484, filed on June 30, 2023, and U.S. Provisional Application No. 63/551,426, filed on February 8, 2024, each of which is incorporated herein by reference in its entirety for all purposes. BACKGROUND [0002] The KRAS protein, Kirsten Rat Sarcoma 2 Viral Oncogene Homolog (“KRAS”), is a GTPase. KRAS gene mutations have been observed in a number of conditions including, for instance, pancreatic cancer, endometrial cancer, lung adenocarcinoma, colorectal cancer, rectal carcinoma, gall bladder cancer, thyroid cancer, bile duct cancer, small cell lung cancer, and non- small cell lung cancer (NSCLC). Accordingly, there is a need for compounds, pharmaceutical compositions, and methods for inhibiting KRAS (e.g., wild type, KRAS G12C, KRAS G12D, and/or KRAS G12V) and treating associated cancers. SUMMARY [0003] In one embodiment, the present disclosure provides a compound of Formula I: Formula I, or a pharmaceutically acceptable salt thereof, wherein X is N, CH, or CRx; Rx is (CH2)mCN or halo; m is 0, 1, 2 or 3; each R3 and R4 is independently H or C1-C3 alkyl; RA is phenyl, naphthyl, or 5- to 14-membered heteroaryl, wherein RA is substituted with 0, 1, 2, 3, 4, or 5 RA2; each RA2 is independently -OH, C1-C10 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C10 alkoxy, C1-C10 hydroxyalkyl, C2-C10 alkoxyalkyl, C1-C6 alkyl-N(RA2a)(RA2b), C1-C10 thioalkyl, halo, C1- C6 haloalkyl, -CN, -C(O)RA2a, -C(O)ORA2a, -OC(O)RA2a, -OC(O)ORA2a, -C(O)N(RA2a)(RA2b), - N(RA2a)C(O)(RA2b), -OC(O)N(RA2a)(RA2b), -N(RA2a)C(O)(ORA2b), oxo, -ORA2a, -SRA2a, - S(O)2RA2a, -S(O)2ORA2a, -N(RA2a)(RA2b), -(C0-C3 alkyl)-SF5, -OP(O)(ORA2a)(ORA2b), C3-C8 cycloalkyl, -(C1-C6 alkyl)-(C3-C8 cycloalkyl), 3- to 14-membered heterocyclyl, -(C1-C6 alkyl)-(3- to 14-membered heterocyclyl), C6-C14 aryl, -(C1-C6 alkyl)-(C6-C14 aryl), 5- to 14-membered heteroaryl, or -(C1-C6 alkyl)-(5- to 14-membered heteroaryl), wherein each alkyl, alkenyl, alkynyl, alkoxy, hydroxyalkyl, and haloalkyl is substituted with 0, 1, 2, or 3 RA3, and wherein each cycloalkyl, alkyl-cycloalkyl, heterocyclyl, alkyl-heterocyclyl, aryl, alkyl-aryl, heteroaryl, and alkyl-heteroaryl is substituted with 0, 1, 2, or 3 RA4; each RA2a and RA2b is independently H, C1-C10 alkyl, C1-C6 haloalkyl, or C3-C8 cycloalkyl; each RA3 is independently halo, -CN, -ORA3a, -SRA3a, -N(RA3a)(RA3b), C3-C8 cycloalkyl, or 5- to 14-membered heteroaryl; each RA3a and RA3b is independently H, C1-C10 alkyl, C1-C6 haloalkyl, or C3-C8 cycloalkyl; each RA4 is independently C1-C6 alkoxy, C1-C6 hydroxyalkyl, C2-C6 alkoxyalkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 haloalkylthio, C3-C8 cycloalkyl, -(C1-C6 alkyl)-(C6-C10 aryl), halo, -CN, -OH, or -N(RA4a)(RA4b); each RA4a and RA4b is independently H or C1-C6 alkyl; alternatively, two RA2 can combine to form a C3-C10 cycloalkyl, C6-C10 aryl, a 3- to 10-membered heterocyclyl, or 5- to 14-membered heteroaryl on two adjacent atoms on RA, wherein each cycloalkyl, aryl, heterocyclyl, and heteroaryl is substituted with 0, 1, 2, or 3 RA5; each RA5 is independently C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, halo, C1-C6 haloalkyl, - CN, or C3-C8 cycloalkyl; RB is H; LC is a bond or ; Y is C or Si; n is 0, 1, 2, or 3; q is 0, 1, 2, or 3; RY1 is H or C1-C3 alkyl; RY2 is H or C1-C3 alkyl; alternatively, RY1 and RY2 combine to form a C3-C10 cycloalkyl or a 3- to 10-membered heterocyclyl; RC is H, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C2-C6 alkoxyalkyl, C1-C6 haloalkyl, C1- C6 haloalkoxy, -NH2, -NHRC1, -N(RC1)2, C3-C8 cycloalkyl, 3- to 14-membered heterocyclyl, C6- C14 aryl, or 5- to 14-membered heteroaryl, wherein each C3-C8 cycloalkyl, 3- to 14-membered heterocyclyl, C6-C14 aryl, and 5- to 14-membered heteroaryl is substituted with 0, 1, 2, 3, or 4 RC3; each RC1 is independently selected from C1-C6 alkyl; each RC3 is independently C1-C6 alkyl, C2-C6 alkenyl, C2-C8 alkynyl, C1-C6 alkoxyalkyl, C1-C6 hydroxyalkyl, halo, C1-C6 haloalkyl, C1-C6 heteroalkyl, -(C1-C6 alkyl)-N(RC3a)(RC3b), -CN, - C(O)RC3a, -C(O)ORC3a, -C(O)N(RC3a)(RC3b), -N(RC3a)C(O)(RC3b), -OC(O)N(RC3a)(RC3b), -N(RC3a)C(O)(ORC3b), =CH2, =CHF, =CF2, oxo, - ORC3a, -SRC3a, -N(RC3a)(RC3b), -N3, SF5, C3-C8 cycloalkyl, -(C1-C6 alkyl)-(C3-C8 cycloalkyl), 3- to 10-membered heterocyclyl, -(C1-C6 alkyl)-(3- to 10-membered heterocyclyl), C6-C10 aryl, -(C1- C6 alkyl)-(C6-C10 aryl), 5- to 10-membered heteroaryl, or -(C1-C6 alkyl)-(5- to 10-membered heteroaryl), wherein each alkyl is substituted with 0, 1, 2, or 3 -CN, -C(O)ORC3a1, -C(O)N(RC3a1)(RC3a2), -N(RC3a1)C(O)(RC3a2), -OC(O)N(RC3a1)(RC3a2), -ORC3a1, -SRC3a1, N3, SF5, or 3- to 10-membered heterocyclyl substituted with 0, 1, 2, or 3 RC3a2, each cycloalkyl, alkyl-cycloalkyl, heterocyclyl, alkyl-heterocyclyl, aryl, alkyl-aryl, heteroaryl, and alkyl-heteroaryl is substituted with 0, 1, 2, or 3 halo, -CN,