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US-12624033-B2 - KRAS inhibitors

US12624033B2US 12624033 B2US12624033 B2US 12624033B2US-12624033-B2

Abstract

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

Inventors

  • Brian Edward Fink
  • Manoranjan PANDA
  • Maximilian David Palkowitz
  • Sirish Kaushik LAKKARAJU
  • Moloy BANERJEE
  • Pravin S. Shirude
  • Amit Kumar Chattopadhyay
  • Laxmi Narayan Nanda
  • Vishweshwaraiah Baligar
  • Balaji SESHADRI
  • T.G. Murali Dhar
  • Li-Qiang Sun
  • Zhizhen Barbara Zheng

Assignees

  • BRISTOL-MYERS SQUIBB COMPANY

Dates

Publication Date
20260512
Application Date
20250306

Claims (15)

  1. 1 . A compound selected from the group consisting of: or a pharmaceutically acceptable salt thereof.
  2. 2 . A compound of claim 1 which is a pharmaceutically acceptable salt.
  3. 3 . A compound of claim 1 selected from the group consisting of:
  4. 4 . The compound of claim 3 , which is:
  5. 5 . The compound of claim 3 , which is:
  6. 6 . The compound of claim 3 , which is:
  7. 7 . The compound of claim 3 , which is:
  8. 8 . The compound of claim 3 , which is:
  9. 9 . The compound of claim 3 , which is:
  10. 10 . The compound of claim 1 , which is: or a pharmaceutically acceptable salt thereof.
  11. 11 . The compound of claim 1 , which is or a pharmaceutically acceptable salt thereof.
  12. 12 . The compound of claim 1 , which is or a pharmaceutically acceptable salt thereof.
  13. 13 . The compound of claim 1 , which is or a pharmaceutically acceptable salt thereof.
  14. 14 . The compound of claim 1 , which is or a pharmaceutically acceptable salt thereof.
  15. 15 . The compound of claim 1 , which is or a pharmaceutically acceptable salt thereof.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS This application is a continuation of U.S. application Ser. No. 18/759,708, filed on Jun. 28, 2024, which claims the priority benefit of U.S. Provisional Application No. 63/511,455, filed Jun. 30, 2023; U.S. Provisional Application No. 63/588,239, filed Oct. 5, 2023; U.S. Provisional Application No. 63/551,905, filed Feb. 9, 2024; and U.S. Provisional Application No. 63/655,965, filed Jun. 4, 2024, which are each incorporated by reference herein in their entireties. FIELD The present disclosure provides KRAS inhibitors. Methods of treating cancers using the inhibitors are also provided. BACKGROUND 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 In some aspects, the present disclosure provides a compound of formula (I): or a pharmaceutically acceptable salt thereof, wherein: Y is O or SO2,R1 is hydrogen, halo, ethynyl or ethyl;R1′ is hydrogen, halo, or C1-3 alkyl;R1″ is selected from hydrogen, C2-3alkenyl, C1-3 alkyl, C2-3 alkynyl, halo, and hydroxy;R2 is hydrogen;R3 is halo;R4 and R5 are the same or different and each is hydrogen, C1-4 alkyl, hydroxy, C1-4 hydroxyalkyl, or C1-4 haloalkyl;R20 is selected from hydrogen and hydroxyC1-4alkyl;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; methylsulfonylC1-C6alkyl; or —(CH2)n-A;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;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; andR7 and R8 are the same or different and each is hydrogen, hydroxy, C1-C4hydroxyalkyl, C1-6 alkyl, C1-6 alkylsulfonyl, or halo. In some aspects the present disclosure provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein: Y is O or SO2;R1 is ethynyl or ethyl;R1′ is hydrogen, halo, or C1-3 alkyl, and R1″ is hydrogen;R2 is hydrogen;R3 is halo;R4 and R5 are the same or different and each is hydrogen, C1-4 alkyl, hydroxy, or C1-4 haloalkyl;R6 is C1-6 alkyl, C3-6 cycloalkyl, hydroxyC1-6 alkyl, haloC1-6 alkyl, hydroxy-haloC1-6 alkyl, methylsulfonylC1-C6alkyl, or —(CH2)n-A;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;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; andR7 and R8 are the same or different and each is hydrogen, hydroxy, C1-6 alkyl, C1-6 alkylsulfonyl, or halo. 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. In some aspects of formula (I), R1″ is halo. In some aspects of formula (I), R1″ is fluoro. In some aspects of formula (I), R3 is fluoro. In some aspects of formula (I), R4 and R5 are both hydrogen. In other aspects, one of R4 and R5 is hydroxy and the other is methyl. In some aspects of form