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KR-20260066047-A - KAT6 inhibitor

KR20260066047AKR 20260066047 AKR20260066047 AKR 20260066047AKR-20260066047-A

Abstract

The present application provides a novel compound having KAT6 inhibitory activity, a pharmaceutical composition comprising said compound, an intermediate useful for the preparation of said compound, and a use for the preparation of a cancer treatment drug using said compound.

Inventors

  • 양 춘다오
  • 타오 웨이캉
  • 정 쉬지엔
  • 장 푸마오
  • 치엔 웬위안
  • 시 구친
  • 장 위싱
  • 구오 후지에
  • 순 웨이메이
  • 순 다칭

Assignees

  • 상하이 치루 파마슈티컬 리서치 앤 디벨롭먼트 센터 리미티드

Dates

Publication Date
20260512
Application Date
20240703
Priority Date
20230704

Claims (13)

  1. As a compound represented by formula (I) or its isomers, deuterides, or pharmaceutically acceptable salts thereof, Here, R1 and R2 are each independently selected from hydrogen, halogen, C1-4 alkyl group, C1-4 haloalkyl group, C1-4 alkoxy group, substituted or unsubstituted C3-6 cycloalkyl group, -C1-4 alkyl- OC1-4 alkyl group, hydroxyl group, -C1-4 alkylhydroxyl group, -C1-4 alkyl- SC1-4 alkyl group, amino group, and C1-4 alkylamino group; R3 is selected from hydrogen, halogen, C1-4 alkyl group, C1-4 haloalkyl group, C1-4 alkoxy group, hydroxyl group, and amino group, and R4 and R5 form a 7- to 8-membered heterocyclyl group together with carbon atoms connected thereto, wherein the heterocyclyl group may optionally be substituted with m R a , and two R a located at the same carbon atom site may form a C3-6 cycloalkyl group or a 3- to 6-membered heterocyclyl group, or two R a located at adjacent carbon atom sites may form a C3-6 cycloalkyl group or a 3- to 6-membered heterocyclyl group; or R5 is selected from hydrogen, halogen, C1-4 alkyl group, C1-4 haloalkyl group, C1-4 alkoxy group, hydroxyl group, and amino group, and R3 and R4 form a 7- to 8-membered heterocyclyl group together with carbon atoms connected thereto, wherein the heterocyclyl group may optionally be substituted with m R a , and two R a located at the same carbon atom site may form a C3-6 cycloalkyl group or a 3- to 6-membered heterocyclyl group, or two R a located at adjacent carbon atom sites may form a C3-6 cycloalkyl group or a 3- to 6-membered heterocyclyl group; R a is selected from hydrogen, halogen, C1-4 alkyl group, C1-4 haloalkyl group, C1-4 alkoxy group, hydroxyl group, and amino group; m is selected from 1, 2, 3, and 4; R6 and R7 are each independently selected from hydrogen, halogen, C1-4 alkyl group, C1-4 haloalkyl group, C1-4 alkoxy group, C1-4 haloalkoxy group, C3-6 cycloalkyl group, C3-6 cycloalkoxy group, and deuterated C1-4 alkoxy group; or R6 and R7 form a 5- to 8-membered heterocyclyl group together with carbon atoms connected thereto, wherein the heterocyclyl group may optionally be substituted with n Rb ; R b is selected from hydrogen, halogen, C1-4 alkyl group, C1-4 haloalkyl group, C1-4 alkoxy group, hydroxyl group, and amino group; n is selected from 1, 2, 3, and 4; L1 is selected from C1-4 alkylene groups, -O-, or deuterated C1-4 alkylene groups; Ring A is selected from 5- to 6-membered heteroaryls; R8 is selected from hydrogen, halogen, C1-4 alkyl group, C1-4 haloalkyl group, C1-4 alkoxy group, substituted or unsubstituted C3-6 cycloalkyl group, amino group, -C1-4 alkylamino group and hydroxyl group; P is selected from 1, 2, 3, and 4, Compounds or isomers thereof, deuterides or pharmaceutically acceptable salts thereof.
  2. In claim 1, A compound or isomer thereof, deuteride, or pharmaceutically acceptable salt thereof, characterized in that R1 is selected from CH3O- , hydrogen.
  3. In claim 1 or claim 2, The seven- to eight-membered heterocyclile group formed by R3 , R4 and carbon atoms connected thereto is, Selected from A compound or its isomer, deuterium, or pharmaceutically acceptable salt thereof characterized by
  4. In claim 1 or claim 2, The seven- to eight-membered heterocyclile group formed by R4 , R5 , and carbon atoms connected thereto is, A compound or its isomer, deuteride, or pharmaceutically acceptable salt thereof, characterized by being selected from.
  5. In any one of claims 1 to 4, A compound or isomer thereof, deuterium, or pharmaceutically acceptable salt thereof, characterized in that R a is selected from -F, -CH3 .
  6. In any one of claims 1 to 5, Structural unit Is, A compound or its isomer, deuteride, or pharmaceutically acceptable salt thereof, characterized by being selected from.
  7. In any one of claims 1 to 6, R6 and R7 are independently -F, -CH3 , CH3O- , C2H5O- , CHF2O- , , A compound or its isomer, deuteride , or pharmaceutically acceptable salt thereof, characterized by being selected from -C₂H₅ , -OCD₃ .
  8. In any one of claims 1 to 6, The 5- to 8-membered heterocyclile groups formed by R6 , R7 , and carbon atoms connected thereto , A compound or its isomer, deuterium, or pharmaceutically acceptable salt thereof, characterized by being selected from.
  9. In any one of claims 1 to 8, A compound or isomer thereof, deuterium, or pharmaceutically acceptable salt thereof, characterized by L1 being selected from -CH2- , -CD2- , -O-.
  10. In any one of claims 1 to 9, Ring A is , , A compound or its isomer, deuterium, or pharmaceutically acceptable salt thereof, characterized by being selected from.
  11. As a compound or its isomer, deuterium or pharmaceutically acceptable salt thereof, The above compound is the following compound, namely, , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , A compound or its isomer, deuterium, or pharmaceutically acceptable salt thereof, characterized by being selected from.
  12. As a pharmaceutical composition, A pharmaceutical composition comprising a compound or isomer thereof, a deuteride or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 11, and a pharmaceutically acceptable carrier.
  13. Use of a compound according to any one of claims 1 to 12, an isomer thereof, a deuteride thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 12 in the manufacture of a drug for treating a disease mediated by a KAT6 target.

Description

KAT6 inhibitor [Cross-citation of related applications] The present application is a Chinese patent application filed with the Chinese Intellectual Property Office on July 4, 2023, with application number CN202310816102X and the title of the invention "KAT6 Inhibitor", filed with the Chinese Intellectual Property Office on September 8, 2023, with application number CN2023111614487 and the title of the invention "KAT6 Inhibitor", and a Chinese patent application filed with the Chinese Intellectual Property Office on November 29, 2023, with application number CN2023116187290 and the title of the invention "KAT6 Inhibitor", a Chinese patent application filed with the Chinese Intellectual Property Office on January 8, 2024, with application number CN2024100246927 and the title of the invention "KAT6 Inhibitor", and an application filed with the Chinese Intellectual Property Office on April 15, 2024, Claiming priority to the Chinese patent application CN2024104524832, titled "KAT6 inhibitor," the entire contents thereof are incorporated into the present application by reference. [Technology Field] The present application belongs to the field of medicinal chemistry and relates to KAT6 inhibitors, in particular to novel compounds having KAT6 inhibitory activity, pharmaceutical compositions comprising said compounds, useful intermediates for producing said compounds, and methods for treating KAT6-mediated related diseases using said compounds. KAT6A (Lysine Acetyltransferase 6A, also known as MOZ) and KAT6B (Lysine Acetyltransferase 6B, also known as MORF) are acetyltransferases belonging to the MYST family. Chromosomal translocations of KAT6A have been identified in acute myeloid leukemia, and amplification mutations have been identified in cancer types including lung cancer, breast cancer, ovarian cancer, endometrial cancer, bladder cancer, and esophageal cancer. Similarly, chromosomal translocation mutations of KAT6B have also been identified 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. Here, MOZ-TIF2 possesses transforming activity in cultured cells and can induce acute myeloid leukemia in mice. In tumor cells amplified with KAT6A and KAT6B, the expression of KAT6A and KAT6B is closely related to the gene copy number, suggesting the existence of selective pressure to maintain their activity during tumorigenesis. Furthermore, in cell proliferation experiments, tumor cells highly expressing KAT6A and KAT6B generally exhibit a relatively high dependence on the activity of KAT6A and KAT6B. KAT6A and KAT6B generally cause extensive acetylation modifications at the lysine 23 position (H3K23) of histone H3, and KAT6A may cause acetylation modifications only at the H3K9 position, which is its regulatory gene. KAT6A interacts with specific transcription factors such as p53 and RUNX1 to induce acetylation modifications of histones and regulate the expression of downstream genes. KAT6A binds to the proximal promoter region of the estrogen receptor ERα and activates the expression of the ERα gene. In breast cancer cells with ER+, 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. Furthermore, the acetyltransferase activity of KAT6A plays a crucial role in promoting the expression of MEIS1 and HOXa9 genes, both of which are frequently overexpressed in certain lymphoma and leukemia cells. In a mouse model of MYC-induced lymphoma, the deletion of a single KAT6A allele significantly extends the median survival of the mice. In mice, mutations in the KAT6B allele significantly reduce the division and differentiation of cortical progenitor cells, severely impacting cerebral cortex development; thus, KAT6B also plays an important role in maintaining the quantity of adult neural stem cells. Gene mutations in KAT6B have also been identified in certain rare types of leukemia. Currently, although there are many studies based on this mechanism of action, there are no commercially available drugs in the KAT6 inhibitor class; therefore, there is an urgent need to develop effective KAT6 inhibitors applicable to clinical patients. The present application provides a compound of formula (I), or an isomer thereof, a deuteride thereof, or a pharmaceutically acceptable salt thereof, Here, R1 and R2 are each independently selected from hydrogen, halogen, C1-4 alkyl group, C1-4 haloalkyl group, C1-4 alkoxy group, substituted or unsubstituted C3-6 cycloalkyl group, -C1-4 alkyl- OC1-4 alkyl group, hydroxyl group, -C1-4 alkylhydroxyl group, -C1-4 alkyl- SC1-4 alkyl group, amino group, and C1-4 alkylamino group; R3 is selected from hydrogen, halogen, C1-4 alkyl group, C1-4 haloalkyl group, C1-4 alkoxy group, hydroxyl group, and amino group, and R4 and R5 form a 7- to 8-membered heterocy