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EP-4741389-A1 - KAT6 INHIBITOR

EP4741389A1EP 4741389 A1EP4741389 A1EP 4741389A1EP-4741389-A1

Abstract

Provided in the present application is a new compound having KAT6 imhibitory activity, a pharmaceutical composition containing the compound, a useful intermediate for preparimg the compound, and the use of the compound of the present application in the preparation of a drug for treating cancer.

Inventors

  • YANG, Chundao
  • TAO, WEIKANG
  • ZHENG, Xuejian
  • ZHANG, Fumao
  • QIAN, WENYUAN
  • SHI, Guqin
  • ZHANG, YUXING
  • GUO, HUIJIE
  • SUN, Weimei
  • SUN, DAQING

Assignees

  • Shanghai Qilu Pharmaceutical Research and Development Centre Ltd.

Dates

Publication Date
20260513
Application Date
20240703

Claims (13)

  1. A compound of formula (I), or an isomer, deuterated form, or pharmaceutically acceptable salt thereof, wherein, R 1 and R 2 are each independently selected from the group consisting of hydrogen, halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, substituted or unsubstituted C 3-6 cycloalkyl, -C 1-4 alkyl-O-C 1-4 alkyl, hydroxyl, -C 1-4 alkylhydroxy, -C 1-4 alkyl-S-C 1-4 alkyl, amino, and C 1-4 alkylamino; R 3 is selected from the group consisting of hydrogen, halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, hydroxyl, and amino; R 4 and R 5 together with carbon atoms to which they are bonded form a 7- or 8-membered heterocyclyl, the heterocyclyl is optionally substituted by m R a ; two R a located on the same carbon atom can form a C 3-6 cycloalkyl or a 3- to 6-membered heterocyclyl, or two R a located on adjacent carbon atoms can form a C 3-6 cycloalkyl or a 3- to 6-membered heterocyclyl; or R 5 is selected from the group consisting of hydrogen, halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, hydroxyl, and amino; R 3 and R 4 together with carbon atoms to which they are bonded form a 7- or 8-membered heterocyclyl, the heterocyclyl is optionally substituted by m R a ; two R a located on the same carbon atom can form a C 3-6 cycloalkyl or a 3- to 6-membered heterocyclyl, or two R a located on adjacent carbon atoms can form a C 3-6 cycloalkyl or a 3- to 6-membered heterocyclyl; R a is selected from the group consisting of hydrogen, halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, hydroxyl, and amino; m is 1, 2, 3, or 4; R 6 and R 7 are each independently selected from the group consisting of hydrogen, halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkyloxy, and deuterated C 1-4 alkoxy; or R 6 and R 7 together with carbon atoms to which they are bonded form a 5- to 8-membered heterocyclyl, the heterocyclyl is optionally substituted by n R b ; R b is selected from the group consisting of hydrogen, halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, hydroxyl, and amino; n is 1, 2, 3, or 4; L 1 is selected from the group consisting of C 1-4 alkylene, -O-, and deuterated C 1-4 alkylene; ring A is a 5- or 6-membered heteroaryl; R 8 is selected from the group consisting of hydrogen, halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, substituted or unsubstituted C 3-6 cycloalkyl, amino, -C 1-4 alkylamino, and hydroxyl; and p is 1, 2, 3, or 4.
  2. The compound according to claim 1, or an isomer, deuterated form, or pharmaceutically acceptable salt thereof, wherein R 1 is selected from the group consisting of CH 3 O- and hydrogen.
  3. The compound according to any one of claims 1 to 2, or an isomer, deuterated form, or pharmaceutically acceptable salt thereof, wherein the 7- or 8-membered heterocyclyl formed by R 3 and R 4 together with the carbon atoms to which they are bonded is selected from the group consisting of
  4. The compound according to any one of claims 1 to 2, or an isomer, deuterated form, or pharmaceutically acceptable salt thereof, wherein the 7- or 8-membered heterocyclyl formed by R 4 and R 5 together with the carbon atoms to which they are bonded is selected from the group consisting of
  5. The compound according to any one of claims 1 to 4, or an isomer, deuterated form, or pharmaceutically acceptable salt thereof, wherein R a is selected from the group consisting of -F and -CH 3 .
  6. The compound according to any one of claims 1 to 5, or an isomer, deuterated form, or pharmaceutically acceptable salt thereof, wherein is selected from the group consisting of and
  7. The compound according to any one of claims 1 to 6, or an isomer, deuterated form, or pharmaceutically acceptable salt thereof, wherein R 6 and R 7 are each independently selected from the group consisting of -F, -CH 3 , CH 3 O-, C 2 H 5 O-, CHF 2 O-, -C 2 H 5 , and -OCD 3 .
  8. The compound according to any one of claims 1 to 6, or an isomer, deuterated form, or pharmaceutically acceptable salt thereof, wherein the 5- to 8-membered heterocyclyl formed by R 6 and R 7 together with the carbon atoms to which they are bonded is selected from the group consisting of
  9. The compound according to any one of claims 1 to 8, or an isomer, deuterated form, or pharmaceutically acceptable salt thereof, wherein L 1 is selected from the group consisting of -CH 2 -, -CD 2 -, and -O-.
  10. The compound according to any one of claims 1 to 9, or an isomer, deuterated form, or pharmaceutically acceptable salt thereof, wherein ring A is selected from the group consisting of
  11. A compound, or an isomer, deuterated form, or pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of:
  12. A pharmaceutical composition comprising the compound according to any one of claims 1 to 11, or an isomer, deuterated form, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  13. Use of the compound according to any one of claims 1 to 12, or an isomer, deuterated form, or pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 12, in the manufacture of a medicament for treating a disease mediated by a KAT6 target.

Description

The present application claims priorities to Chinese Patent Application No. CN202310816102X, filed with the China National Intellectual Property Administration on July 04, 2023, titled "KAT6 INHIBITOR"; Chinese Patent Application No. CN2023111614487, filed with the China National Intellectual Property Administration on September 08, 2023, titled "KAT6 INHIBITOR"; Chinese Patent Application No. CN2023116187290, filed with the China National Intellectual Property Administration on November 29, 2023, titled "KAT6 INHIBITOR"; Chinese Patent Application No. CN2024100246927, filed with the China National Intellectual Property Administration on January 08, 2024, titled "KAT6 INHIBITOR"; and Chinese Patent Application No. CN2024104524832, filed with the China National Intellectual Property Administration on April 15, 2024, titled "KAT6 INHIBITOR", which are incorporated herein by reference in their entirety. TECHNICAL FIELD The present application belongs to the field of medicinal chemistry and relates to a KAT6 inhibitor, specifically to a novel compound with KAT6 inhibitory activity, a pharmaceutical composition containing the compound, a useful intermediate for preparing the compound, and a method of using the compound of the present application for treating a disease mediated by KAT6. BACKGROUND KAT6A (Lysine Acetyltransferase 6A, also known as MOZ) and KAT6B (Lysine Acetyltransferase 6B, also known as MORF) are members of the MYST family of acetyltransferases. KAT6A is involved in chromosomal translocations in acute myeloid leukemia and exhibits amplification mutations in various cancers such as lung cancer, breast cancer, ovarian cancer, endometrial carcinoma, bladder cancer, and esophageal cancer. Similarly, KAT6B is also involved in chromosomal translocation mutations in various cancer types. MOZ- and MORF-linked fusion proteins identified in acute myeloid leukemia include MOZ-CBP, MOZ-p300, MOZ-TIF2, MOZ-NcoA3, MOZ-LEUTX, and MORF-CBP. Among these, MOZ-TIF2 exhibits transforming activity in cultured cells and can induce acute myeloid leukemia in mice. In tumor cells with KAT6A and KAT6B amplification, the expression of KAT6A and KAT6B is closely related to gene copy number, indicating selective pressure to maintain their activity during tumorigenesis. Furthermore, in cell proliferation assays, tumor cells with high expression of KAT6A and KAT6B are generally more dependent on the activity of KAT6A and KAT6B. KAT6A and KAT6B typically widely acetylate histone H3 at lysine 23 (H3K23), while KAT6A can also specifically acetylate at H3K9 of its regulated genes. KAT6A interacts with transcription factors such as p53 and RUNX1, acetylates histones, and regulates the expression of downstream genes. KAT6A binds to the proximal promoter region of the Estrogen Receptor α (ERα) gene and activates ERα gene expression. In ER-positive breast cancer cells with KAT6A amplification mutations or high expression, inhibiting the acetyltransferase activity of KAT6A or knocking down KAT6A can significantly inhibit the proliferation of breast cancer cells. In addition, the acetyltransferase activity of KAT6A is crucial for promoting the expression of MEIS1 and HOXa9 genes, which are often overexpressed in some lymphoma and leukemia cells. In a MYC-induced lymphoma mouse model, deletion of one KAT6A allele significantly prolonged the median survival of the mice. In mice, mutation of the KAT6B allele leads to a significant reduction in the division and differentiation of cortical progenitor cells, severely affecting brain cortex development. KAT6B also plays an important role in maintaining the number of adult neural stem cells. KAT6B also has gene mutations in some rare types of leukemia. Although numerous research efforts have been directed toward this mechanism of action, but no KAT6 inhibitor has been approved for clinical use to date. Consequently, there is an urgent need to develop effective KAT6 inhibitors for clinical application. SUMMARY The present application provides a compound of formula (I), or an isomer, deuterated form, or pharmaceutically acceptable salt thereof, wherein, R1 and R2 are each independently selected from the group consisting of hydrogen, halogen, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, substituted or unsubstituted C3-6 cycloalkyl, -C1-4 alkyl-O-C1-4 alkyl, hydroxy, -C1-4 alkylhydroxy, -C1-4 alkyl-S-C1-4 alkyl, amino, and C1-4 alkylamino;R3 is selected from the group consisting of hydrogen, halogen, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, hydroxy, and amino; R4 and R5 together with carbon atoms to which they are bonded form a 7- or 8-membered heterocyclyl, the heterocyclyl is optionally substituted by m Ra, two Ra located on the same carbon atom can form a C3-6 cycloalkyl or a 3- to 6-membered heterocyclyl, or two Ra located on adjacent carbon atoms can form a C3-6 cycloalkyl or a 3- to 6-membered heterocyclyl;or R5 is selected from the group consisting of hydrogen, halogen, C1-4 alkyl, C1-4 haloal