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KR-20260065865-A - Exatecan hydroxylamine derivatives and their applications

KR20260065865AKR 20260065865 AKR20260065865 AKR 20260065865AKR-20260065865-A

Abstract

The present invention provides exatecan derivatives substituted with a series of hydroxylamine-containing structures, a method for preparing pharmaceutically acceptable salts thereof, and applications in the field of antitumor. These exatecan derivatives possess excellent tumor cell growth inhibitory activity while having good cell membrane permeability or peripheral cell killing effects, and can be utilized in tumor treatment as a monotherapy, combination therapy, or as a toxic component of an ADC.

Inventors

  • 미아오 전웨이
  • 황 윈성
  • 리 야오우

Assignees

  • 항저우 애드코리스 바이오파마 컴퍼니 리미티드

Dates

Publication Date
20260511
Application Date
20240914
Priority Date
20230915

Claims (11)

  1. In the compound of formula (I) or its pharmaceutically acceptable salt, stereoisomer, or prodrug, (I) In the equation, R is or Selected from among; Here, R1 is selected from C1 – C6 alkyl, dehydrogenated C1 – C6 alkyl, or C3 – C6 cycloalkyl, wherein the C1 – C6 alkyl or C3 – C6 cycloalkyl is optionally substituted with one or more halogens; Or, R1 is selected from C1 – C6 alkyl, and two hydrogen atoms of the same carbon atom on the C1 – C6 alkyl are simultaneously substituted with -( CH2 ) j- to form a C3 – C6 cycloalkyl, wherein j is 1, 2, 3, 4, or 5; R2 and R3 are each independently selected from hydrogen, C1 – C6 alkyl, deuterated C1 – C6 alkyl, halogenated C1 – C6 alkyl, or C3 – C6 cycloalkyl, and X and Y are each independently selected from or do not exist among O atoms, provided that at least one of X and Y must be O; A compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer, or prodrug thereof, characterized in that m and n are each independently selected from 0, 1, 2, or 3.
  2. In paragraph 1, R1 is selected from C1 ~ C6 alkyl or deuterated C1 ~ C6 alkyl; Preferably, R1 is selected from -CH2- , -CD2- , -( CH2 ) 2- , or -CH( CH3 )-; or, R1 is selected from C1 – C3 alkyls, and two hydrogen atoms of the same carbon atom on the C1 – C3 alkyl group are simultaneously substituted with -( CH2 ) j- to form cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; Preferably, R1 is , , , A compound characterized by being selected from among.
  3. In paragraph 1 or 2, R2 is selected from C1 ~ C6 alkyl or deuterated C1 ~ C6 alkyl; Preferably, a compound characterized in that R2 is selected from methyl, ethyl, or deuterium methyl.
  4. In any one of paragraphs 1 through 3, R3 is selected from hydrogen or C1 – C6 alkyl; m and n are each independently selected from 0, 1, or 2; Preferably, silver or A compound characterized by being selected from among.
  5. In any one of paragraphs 1 through 4, A compound characterized in that X is O and Y is non-existent, or Y is O and X is non-existent.
  6. In any one of paragraphs 1 through 5, The compound of formula (I) above is a compound represented by formula (IIa) or formula (IIb): (IIa) In formula (IIa), R1 and R2 are each defined identically to the compound of formula (I); Preferably, R1 is -CH2- , -CD2- , -( CH2 ) 2- , -CH( CH3 )- or Selected from among; Preferably, R2 is selected from methyl, ethyl, or deuterium methyl; (IIb) In formula (IIb), R1 and R2 are each defined as being the same as the compound of formula (I), and preferably, R1 is -CH2- , -CD2- , -( CH2 ) 2- , -CH( CH3 )- or Selected from among; Preferably, a compound characterized in that R2 is selected from methyl, ethyl, or deuterium methyl.
  7. In any one of paragraphs 1 through 6, A compound or a pharmaceutically acceptable salt, stereoisomer, or prodrug thereof characterized in that the compound of formula (I) above is a compound represented by formulas (D1) to (D5): .
  8. It includes a small molecule drug, a linker, and an antibody, Herein, the antibody-drug conjugate is characterized in that the small molecule drug comprises a compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt, stereoisomer, or prodrug thereof.
  9. A pharmaceutical composition characterized by comprising a compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt, stereoisomer, or prodrug thereof, a pharmaceutically acceptable adjuvant, or an antibody-drug conjugate according to claim 8.
  10. A compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt, stereoisomer, or prodrug thereof, an antibody-drug conjugate according to claim 8, or a pharmaceutical composition according to claim 9, in application in the manufacture of drugs for cancer treatment, Preferably, the application is characterized in that the cancer comprises one or more of esophageal adenocarcinoma, gastric cancer, esophageal duct cancer, lung cancer, lung squamous cell carcinoma, breast cancer, breast adenocarcinoma, and bladder cancer cells.
  11. The method comprises the step of administering to a patient in need a compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt, stereoisomer, or prodrug thereof, an antibody-drug conjugate according to claim 8, or a pharmaceutical composition according to claim 9; Preferably, a cancer treatment method characterized in that the cancer comprises one or more of esophageal adenocarcinoma, gastric cancer, esophageal duct cancer, lung cancer, lung squamous cell carcinoma, breast cancer, breast adenocarcinoma, and bladder cancer cells.

Description

Exatecan hydroxylamine derivatives and their applications The present application claims priority to Chinese patent application number 2023111927049, with a filing date of September 15, 2023, and the present application incorporates the full text of the said Chinese patent application. The present invention relates to the field of biopharmaceuticals, specifically to exatecan hydroxylamine derivatives and their applications. DNA topoisomerase is an essential enzyme widely present in living organisms that influences the topological structure of DNA by regulating supercoiling, linking, unlinking, and nucleic acid dissociation; it is primarily divided into topoisomerase 1 (Top1) and topoisomerase 2 (Top2). Compared to Top2 inhibitors, Top1 inhibitors exhibit higher therapeutic efficacy and a broader antitumor spectrum, making them important target enzymes for the design of new antitumor drugs. Furthermore, Top1 levels are significantly higher in various tumor cells, such as those of colon, cervical, and ovarian cancers, than in normal tissues, and activity increases substantially in S-phase tumor cells; thus, Top1 inhibitors possess excellent selectivity as they can selectively inhibit DNA replication in proliferative tumor cells. Camtothecin possesses Top1 inhibitory activity, exhibiting particularly strong inhibitory activity against complexes formed by Top1-DNA. Topoisomerase 1 (Top1) is the primary target of camtothecin (CPT) and its derivatives. Therefore, camtothecin is a broad-spectrum antitumor drug that demonstrates excellent therapeutic effects against various solid tumors, including gastric cancer, pharyngeal cancer, lung cancer, and bladder cancer. Among these, irinotecan, topotecan, and belotecan have been approved in several countries for the treatment of various cancers. Additionally, DX-8951 and SN38 have been successfully utilized as payloads for antibody-drug conjugates (ADCs), respectively, and are attracting attention for their significant therapeutic effects in the targeted therapy of various solid tumors. Currently, exatecan is characterized by strong toxic side effects, poor cell permeability, and low stability within the blood system. I. Definition Unless otherwise specified, scientific and technical terms used in this document have the meanings commonly understood by a person skilled in the art. Furthermore, related terms and laboratory operation steps used in this document refer to terms and general steps widely used in the relevant field. In addition, to better understand the invention, definitions and interpretations of related terms are provided as follows. Unless otherwise noted, the terms used in this document, such as “include,” “include,” “have,” “contain,” and their equivalent grammatical forms, should be understood in an open and non-restrictive sense, and, for example, other unlisted elements or steps are not excluded. The compounds of the present invention may be asymmetric and may have, for example, one or more stereoisomers. Unless otherwise noted, all stereoisomers include, for example, both symmetry isomers and asymmetric isomers. The above stereoisomers include geometric isomers (e.g., cis, trans structures) and optical isomers (e.g., symmetry isomers), and refer to therapeutic agents composed of monomers, racemic mixtures, racemate mixtures, and pharmaceutically acceptable salts thereof. The compounds containing asymmetric carbon atoms of the present invention may be isolated in an optically active pure form or in a racemate form. The optically active pure form may be isolated from a racemate mixture or synthesized using chiral raw materials or chiral reagents. Racemates, asymmetric isomers, and symmetry isomers are all included within the scope of the present invention. The compound of the present invention further comprises a tautomeric form. The tautomeric form results from an exchange and proton transfer between a single bond and an adjacent double bond. In this document, “pharmaceuticalally acceptable salts” means salts formed with the relevant amine compounds and inorganic or organic acids, or salts formed with the relevant carboxylic acid compounds and alkali metals or alkaline earth metals, or salts formed with organic amines. Herein, inorganic acids include, but are not limited to, hydrochloric acid, hydrobromide, hydroiodide, sulfuric acid, phosphoric acid, etc.; organic acids include, but are not limited to, acetic acid, propionic acid, butyric acid, benzoic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, oxalic acid, succinic acid, lactic acid, citric acid, succinic acid, gluconic acid, maleic acid, fumaric acid, tartaric acid, etc.; alkali metal and alkaline earth metal salts include, but are not limited to, sodium, potassium, calcium, magnesium salts, etc. Organic amine salts include, but are not limited to, salts composed of ammonia, methylamine, ethylamine, propylamine, isopropylamine, dimethylamine, diethylamine, trimethylamin