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EP-4735439-A1 - KRAS INHIBITORS

EP4735439A1EP 4735439 A1EP4735439 A1EP 4735439A1EP-4735439-A1

Abstract

The present disclosure provides KRAS inhibitors. Methods of treating cancers using the compounds are also provided.

Inventors

  • FINK, Brian Edward
  • Panda, Manoranjan
  • PALKOWITZ, Maximilian David
  • LAKKARAJU, SIRISH KAUSHIK
  • BANERJEE, Moloy
  • SHIRUDE, PRAVIN S.
  • CHATTOPADHYAY, AMIT KUMAR
  • NANDA, Laxmi Narayan
  • BALIGAR, Vishweshwaraiah
  • SESHADRI, Balaji
  • DHAR, T.G. MURALI
  • SUN, LI-QIANG
  • ZHENG, ZHIZHEN BARBARA

Assignees

  • Bristol-Myers Squibb Company

Dates

Publication Date
20260506
Application Date
20240628

Claims (20)

  1. WHAT IS CLAIMED IS: 1. A compound of formula (I): or a pharmaceutically acceptable salt thereof, wherein: Y is O or SO 2 ; R 1 is hydrogen, halo, ethynyl or ethyl; R 1’ is hydrogen, halo, or C 1-3 alkyl; R 1’’ is selected from hydrogen, C 2-3 alkenyl, C 1-3 alkyl, C 2-3 alkynyl, halo, and hydroxy; R 2 is C 1-4 alkoxy, C 1-4 haloalkoxy, C 1-4 haloalkyl, or C 3-6 cycloalkyl; R 3 is halo; R 4 and R 5 are the same or different and each is hydrogen, C 1-4 alkyl, hydroxy, C 1-4 hydroxyalkyl, or C 1-4 haloalkyl; R 20 is selected from hydrogen and hydroxyC 1-4 alkyl; R 6 is C 1-6 alkyl optionally substituted with one or more deuterium atoms; C 3-6 cycloalkyl optionally substituted with C 1 -C 3 alkoxy, C 1 -C 3 alkoxyC 1-6 alkyl, amino, or cyanoethynyl; hydroxyC 1-6 alkyl; haloC 1-6 alkyl; hydroxy-haloC 1-6 alkyl; methylsulfonylC 1 -C 6 alkyl; or –(CH 2 ) n - A; wherein A is a cyclic moiety selected from C 3-6 cycloalkyl, C 3-10 heterocycloalkyl, aryl, heteroaryl, spiro structures of any of these rings, and bicyclic structures of any of these rings, and n is 0, 1, 2, or 3; wherein A is optionally substituted with one or more substituents selected from C 1-4 alkyl, C 1-4 alkylcarbonyl, C 3-6 cycloalkylcarbonyl, hydroxy, halo, cyano, haloC 1-6 alkyl, C 1-4 alkoxy, C 1- 4 alkoxy C 1-4 alkyl, C 1-4 alkoxycarbonyl, haloC 1-4 alkoxycarbonyl, C 1-4 alkylcarbamato, amido, C 1 - 4 alkylamido, oxo, and methylsulfonyl; and R 7 and R 8 are the same or different and each is hydrogen, hydroxy, C 1-6 alkyl, C 1-6 alkylsulfonyl, or halo.
  2. 2. A compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R 1’’ is halo and wherein the halo is fluoro.
  3. 3. A compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R 6 is –(CH 2 ) n -A.
  4. 4. A compound of claim 3, or a pharmaceutically acceptable salt thereof, wherein n is 0.
  5. 5. A compound of claim 3, or a pharmaceutically acceptable salt thereof, wherein n is 1.
  6. 6. A compound of claim 3, or a pharmaceutically acceptable salt thereof, wherein A is a cyclic moiety selected from C 4-6 cycloalkyl, C 3-10 heterocycloalkyl, aryl, heteroaryl, spiro structures of any of these rings, and bicyclic structures of any of these rings.
  7. 7. A compound of formula (II): or a pharmaceutically acceptable salt thereof, wherein: R 1 is ethynyl or ethyl; R 1’ is hydrogen or halo; R 1’’ is selected from hydrogen, C 2-3 alkenyl, C 1-3 alkyl, C 2-3 alkynyl, halo, and hydroxy; R 2 is C 1-4 alkoxy; R 3 is halo; R 4 , R 5 , R 4’ , and R 5’ are the same or different and each is hydrogen, haloC 1-4 alkyl , C 1-4 alkyl, hydroxy, or hydroxyC 1-4 alkyl, or, R 4’ and R 5’ , together with the atom to which they are attached, form a five-membered heterocycloalkyl ring optionally substituted with oxo; R 6 is C 1-6 alkyl, hydroxyC 1-6 alkyl, haloC 1-6 alkyl, hydroxy-haloC 1-6 alkyl, methylsulfonylC 1 -C 6 alkyl, or –(CH 2 ) n -A; wherein A is a cyclic moiety selected from C 3-6 cycloalkyl, C 3-7 heterocycloalkyl, spiro structures of either of these rings, and bicyclic structures of either of these rings, and n is 0, 1, or 2; wherein A is optionally substituted with one or more substituents selected from C 1-4 alkyl, C 1-4 alkylcarbonyl, C 3-6 cycloalkylcarbonyl, hydroxy, halo, haloC 1-6 alkyl, C 1-4 alkoxy, C 1-4 alkoxy C 1-4 alkyl, C 1-4 alkoxycarbonyl, haloC 1-4 alkoxycarbonyl, C 1-4 alkylcarbamato, amido, C 1-4 alkylamido, oxo, and methylsulfonyl; and R 7 and R 8 are the same or different and each is hydrogen, C 1-6 alkyl, C 1-6 alkylsulfonyl, or halo.
  8. 8. A compound of claim 7, or a pharmaceutically acceptable salt thereof, wherein R 1’’ is halo and wherein the halo is fluoro.
  9. 9. A compound of claim 8, or a pharmaceutically acceptable salt thereof, wherein R 6 is – (CH 2 ) n -A.
  10. 10. A compound of claim 9, or a pharmaceutically acceptable salt thereof, wherein n is 0.
  11. 11. A compound of claim 9, or a pharmaceutically acceptable salt thereof, wherein n is 1.
  12. 12. A compound of claim 9, or a pharmaceutically acceptable salt thereof, wherein A is a cyclic moiety selected from C 4-6 cycloalkyl, C 3-10 heterocycloalkyl, aryl, heteroaryl, spiro structures of any of these rings, and bicyclic structures of any of these rings.
  13. 13. A compound of formula (III): or a pharmaceutically acceptable salt thereof, wherein: R 1 is ethynyl or ethyl; R 1’ is hydrogen or halo; R 1’’ is selected from hydrogen, C 2-3 alkenyl, C 1-3 alkyl, C 2-3 alkynyl, halo, and hydroxy; R 2 is C 1-4 haloalkoxy or C 1-4 alkoxy; R 3 is halo; R 6 is C 1-6 alkyl, hydroxyC 1-6 alkyl, haloC 1-6 alkyl, hydroxy-haloC 1-6 alkyl, methylsulfonylC 1 -C 6 alkyl, or –(CH 2 ) n -A; wherein A is a cyclic moiety selected from C 3-6 cycloalkyl, C 3-7 heterocycloalkyl, spiro structures of either of these rings, and bicyclic structures of either of these rings, and n is 0, 1, or 2; wherein A is optionally substituted with one or more substituents selected from C 1-4 alkyl, C 1-4 alkylcarbonyl, C 3-6 cycloalkylcarbonyl, hydroxy, halo, hydroxyC 1-6 alkyl, haloC 1-6 alkyl, C 1-4 alkoxy, C 1-4 alkoxy C 1-4 alkyl, C 1-4 alkoxycarbonyl, haloC 1-4 alkoxycarbonyl, C 1-4 alkylcarbamato, amido, C 1-4 alkylamido, oxo, and methylsulfonyl; and R 7 and R 8 are the same or different and each is hydrogen, C 1-6 alkyl, C 1-6 alkylsulfonyl, or halo.
  14. 14. A compound of claim 13, or a pharmaceutically acceptable salt thereof, wherein R 1’’ is halo and wherein the halo is fluoro.
  15. 15. A compound of claim 14, or a pharmaceutically acceptable salt thereof, wherein R 6 is –(CH 2 ) n -A.
  16. 16. A compound of claim 15, or a pharmaceutically acceptable salt thereof, wherein n is 0.
  17. 17. A compound of claim 15, or a pharmaceutically acceptable salt thereof, wherein n is 1.
  18. 18. A compound of claim 15, wherein A is a cyclic moiety selected from C 4-6 cycloalkyl, C 3 - 10 heterocycloalkyl, aryl, heteroaryl, spiro structures of any of these rings, and bicyclic structures of any of these rings.
  19. 19. A compound of formula (IV): or a pharmaceutically acceptable salt thereof, wherein: R 1 is ethynyl or ethyl; R 1’ is hydrogen or halo; R 1’’ is selected from hydrogen, C 2-3 alkenyl, C 1-3 alkyl, C 2-3 alkynyl, halo, and hydroxy; R 2 is C 1-4 alkoxy; R 3 is halo; R 6 is C 1-6 alkyl, hydroxyC 1-6 alkyl, haloC 1-6 alkyl, hydroxy-haloC 1-6 alkyl, methylsulfonylC 1 -C 6 alkyl, or –(CH 2 ) n -A; wherein A is a cyclic moiety selected from C 3-6 cycloalkyl, C 3-7 heterocycloalkyl, spiro structures of either of these rings, and bicyclic structures of either of these rings, and n is 0, 1, or 2; wherein A is optionally substituted with one or more substituents selected from C 1-4 alkyl, C 1-4 alkylcarbonyl, C 3-6 cycloalkylcarbonyl, hydroxy, halo, haloC 1-6 alkyl, C 1-4 alkoxy, C 1-4 alkoxy C 1-4 alkyl, C 1-4 alkoxycarbonyl, haloC 1-4 alkoxycarbonyl, C 1-4 alkylcarbamato, amido, C 1-4 alkylamido, oxo, and methylsulfonyl; and R 7 and R 8 are the same or different and each is hydrogen, C 1-6 alkyl, C 1-6 alkylsulfonyl, or halo.
  20. 20. A compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R 1’’ is halo and wherein the halo is fluoro.

Description

KRAS INHIBITORS CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This application claims the priority benefit of U.S. Provisional Application No. 63/511,455, filed June 30, 2023; U.S. Provisional Application No. 63/588,239, filed October 5, 2023; U.S. Provisional Application No.63/551,905, filed February 9, 2024; and U.S. Provisional Application No.63/655,965, filed June 4, 2024, which are each incorporated by reference herein in their entireties. FIELD [0002] The present disclosure provides KRAS inhibitors. Methods of treating cancers using the inhibitors are also provided. BACKGROUND [0003] The KRAS oncogene is a member of the RAS family of GTPases that are involved in numerous cellular signaling processes. KRAS mutations are gain-of-function mutations that are present in up to 30% of all tumors, including as many as 90% of pancreatic cancers. Single nucleotide substitutions that result in missense mutations at codons 12 and 13 of the KRAS primary amino acid sequence comprise approximately 40% of KRAS driver mutations in lung adenocarcinoma, with a G12C transversion being the most common activating mutation. KRAS G12C mutations occur in about 13% of lung adenocarcinomas and about 3% of colorectal adenocarcinomas and are also present in cancers of the breast, bladder, cervix, ovaries, pancreas and uterus. KRAS G12D mutations occur in 28% of all pancreatic ductal adenocarcinoma patients, 13% of all colorectal carcinoma patients, 4% of all non-small cell lung carcinoma patients and 3% of all gastric carcinoma patients. See, for example, https://www.mycancergenome.org/content/alteration/kras-g12d/. Due to the clinical significance of this protein, many attempts have been made to develop RAS inhibitors, but such attempts have been mostly unsuccessful. Accordingly, agents that inhibit mutant KRAS are desired. SUMMARY [0004] In some aspects, the present disclosure provides a compound of formula (I): or a pharmaceutically acceptable salt thereof, wherein: [0005] Y is O or SO2, [0006] R1 is hydrogen, halo, ethynyl or ethyl; [0007] R1’ is hydrogen, halo, or C1-3 alkyl; [0008] R1’’ is selected from hydrogen, C2-3alkenyl, C1-3 alkyl, C2-3 alkynyl, halo, and hydroxy; [0009] R2 is C1-4 alkoxy, C1-4 haloalkoxy, C1-4 haloalkyl, or C3-6 cycloalkyl; [0010] R3 is halo; [0011] R4 and R5 are the same or different and each is hydrogen, C1-4 alkyl, hydroxy, C1-4 hydroxyalkyl, or C1-4 haloalkyl; [0012] R20 is selected from hydrogen and hydroxyC1-4alkyl; [0013] R6 is C1-6 alkyl optionally substituted with one or more deuterium atoms; C3-6 cycloalkyl optionally substituted with C1-C3alkoxy, C1-C3alkoxyC1-6 alkyl, amino, or cyanoethynyl; hydroxyC1-6 alkyl; haloC1-6 alkyl; hydroxy-haloC1-6 alkyl;, methylsulfonyl C1- C6alkyl; or–(CH2)n-A; [0014] wherein A is a cyclic moiety selected from C3-6 cycloalkyl, C3-7 heterocycloalkyl, aryl, heteroaryl, spiro structures of any of these rings, and bicyclic structures of any of these rings, and n is 0, 1, 2, or 3; [0015] wherein A is optionally substituted with one or more substituents selected from C1-4 alkyl, C1-4 alkylcarbonyl, C3-6 cycloalkylcarbonyl, hydroxy, halo, cyano, haloC1-6 alkyl, C1-4 alkoxy, C1-4 alkoxy C1-4alkyl, C1-4 alkoxycarbonyl, haloC1-4 alkoxycarbonyl, hydroxyC1-C4alkyl, C1-4 alkylcarbamato, amido, C1-4 alkylamido, oxo, cyclopropylsulfonyl, ethylsulfonyl, and methylsulfonyl; and [0016] R7 and R8 are the same or different and each is hydrogen, hydroxy, C1- C4hydroxyalkyl, C1-6 alkyl, C1-6 alkylsulfonyl, or halo. [0017] In some aspects the present disclosure provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein: [0018] Y is O or SO2; [0019] R1 is ethynyl or ethyl; [0020] R1’ is hydrogen, halo, or C1-3 alkyl, and R1’’ is hydrogen; [0021] R2 is C1-4 alkoxy, C1-4 haloalkyl, or C3-6 cycloalkyl; [0022] R3 is halo; [0023] R4 and R5 are the same or different and each is hydrogen, C1-4 alkyl, hydroxy, or C1-4 haloalkyl; [0024] R6 is C1-6 alkyl, C3-6 cycloalkyl, hydroxyC1-6 alkyl, haloC1-6 alkyl, hydroxy- haloC1-6 alkyl, methylsulfonylC1-C6alkyl, or –(CH2)n-A; [0025] wherein A is a cyclic moiety selected from C3-6 cycloalkyl, C3-7 heterocycloalkyl, aryl, heteroaryl, spiro structures of any of these rings, and bicyclic structures of any of these rings, and n is 0, 1, 2, or 3; [0026] wherein A is optionally substituted with one or more substituents selected from C1-4 alkyl, C1-4 alkylcarbonyl, C3-6 cycloalkylcarbonyl, hydroxy, halo, cyano, haloC1-6 alkyl, C1-4 alkoxy, C1-4 alkoxy C1-4alkyl, C1-4 alkoxycarbonyl, haloC1-4 alkoxycarbonyl, C1-4 alkylcarbamato, amido, C1-4 alkylamido, oxo, and methylsulfonyl; and [0027] R7 and R8 are the same or different and each is hydrogen, hydroxy, C1-6 alkyl, C1-6 alkylsulfonyl, or halo. [0028] In some aspects of formula (I), R1 is ethynyl. In some aspects of formula (I), R1 is ethyl. In some aspects of formula (I), R1 is hydrogen. In some aspects of formula (I), R1 is halo. [0029] In some aspects of formula (I),