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EP-4741375-A1 - SULFONYLUREA DERIVATIVES AND THEIR USE FOR THE TREATMENT OF CANCER

EP4741375A1EP 4741375 A1EP4741375 A1EP 4741375A1EP-4741375-A1

Abstract

The present disclosure describes sulfonylurea derivatives compounds of Formula (I), and pharmaceutically acceptable salts thereof, compositions, methods, and uses thereof. Such compounds are believed to be therapeutically useful as inhibitors of KAT6A with improved selectivity particularly in the treatment and/or prevention of diseases and disorders mediated by KAT6A in a subject.

Inventors

  • El Hage, Krystel
  • NICOLAÏ, Eric

Assignees

  • Qubit Pharmaceuticals

Dates

Publication Date
20260513
Application Date
20241106

Claims (15)

  1. A compound of general formula (I) or a pharmaceutically acceptable salt thereof, wherein: A represents an aryl group, such as a phenyl group or a benzo fused cycloalkyl group, or a heteroaryl group, such as a benzo-fused heterocyclic group; wherein A is optionally substituted by one or more members selected from the group consisting of: - alkoxy groups, such as C 1 -C 4 alkoxy groups; - alkyl groups, such as C 1 -C 4 alkyl groups, optionally substituted by 1 to 3 fluorine atoms; - halogens; - unsubstituted or substituted amino groups, such as dialkylamino groups, such as a dimethylamino group (-N(CH 3 ) 2 ); - heterocyclyl groups, preferably a 4- to 6-member heterocycloalkyl group, such as azetidine, or pyrrolidine optionally substituted by one or more alkyl groups, oxo groups and/or halogens; - phenyl groups, optionally substituted by one or more alkyl groups and/or halogens; and - cycloalkyl groups optionally substituted by one or more alkyl groups and/or halogens, such as a C 3 -C 5 cycloalkyl group optionally substituted by 1 to 2 fluorine atoms; and B represents a partially saturated nitrogen containing bicyclic ring system, such as tetrahydro-isoquinoline or isoindoline, substituted by one or more members selected from the group consisting of: - halogens; - dialkylamino groups, such as a dimethylamino group (-N(CH 3 ) 2 ); - cycloalkyl groups optionally substituted by one or more alkyl groups and/or halogens, such as a C 3 -C 5 cycloalkyl group optionally substituted by 1 to 2 fluorine atoms; - alkoxy groups, such as a C 1 -C 4 alkoxy group; - 3- to 6-member cycloalkyloxy groups, such as cyclopropyloxy group, optionally substituted by one or more alkyl groups and/or halogens; - 4- to 6-member heterocycloalkyl groups, optionally substituted by one or more alkyl groups and/or halogens, which is directly bonded to the bicyclic ring system via a covalent bond or linked through a spacer, preferably chosen from a C 1 -C 4 alkylene chain, or a single oxygen atom; for example a 4- to 6-member heterocyclyl group, such as azetidine, optionally substituted by one or more alkyl groups and/or halogens; - 5- or 6-member heteroaryl groups, optionally substituted by one or more alkyl groups and/or halogens, which is directly bonded to the bicyclic ring system via a covalent bond or linked through a spacer, preferably chosen from a C 1 -C 4 alkylene chain, or a single oxygen atom; for example a 5- or 6-member heteroaryl group, such as pyrazole, isoxazole, thiazole, pyridine or oxazole, optionally substituted by one or more alkyl groups and/or halogens; and - alkyl groups, such as a C 1 -C 4 alkyl group, optionally substituted by 1 to 3 fluorine atoms.
  2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein: A represents an aryl group, such as a phenyl group or a benzo-fused cycloalkyl group, or a heteroaryl group, such as a benzo-fused heterocyclic group; substituted by one or more alkoxy groups, such as a C 1 -C 4 alkoxy group, and/or alkyl groups, such as a C 1 -C 4 alkyl group, optionally substituted by 1 to 3 fluorine atoms; wherein A is optionally further substituted by one or more members selected from the group consisting of: - alkoxy groups, such as a C 1 -C 4 alkoxy group; - alkyl groups, such as a C 1 -C 4 alkyl group, optionally substituted by 1 to 3 fluorine atoms; - halogens; - unsubstituted or substituted amino groups, such as dialkylamino groups, such as a dimethylamino group (-N(CH 3 ) 2 ); - heterocyclyl groups, preferably a 4- to 6-member heterocycloalkyl group, such as azetidine, or pyrrolidine optionally substituted by one or more alkyl groups, oxo groups and/or halogens; - phenyl groups, optionally substituted by one or more alkyl groups and/or halogens; and - cycloalkyl groups optionally substituted by one or more alkyl groups and/or halogens, such as a C 3 -C 5 cycloalkyl group optionally substituted by 1 to 2 fluorine atoms.
  3. The compound according to any one of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein: B represents a partially saturated nitrogen containing bicyclic ring system, such as tetrahydro-isoquinoline or isoindoline, comprising an aryl part substituted by a 5- or 6-member heteroaryl group, which is directly bonded to the aryl part of the bicyclic ring system via a covalent bond or linked through a spacer, said spacer being preferably chosen from a C 1 -C 4 alkylene chain or a single oxygen atom; wherein B is optionally further substituted by one or more members selected from the group consisting of: - halogens; - dialkylamino groups, such as a dimethylamino group (-N(CH 3 ) 2 ); - cycloalkyl groups optionally substituted by one or more alkyl groups and/or halogens, such as a C 3 -C 5 cycloalkyl group optionally substituted by 1 to 2 fluorine atoms; - alkoxy groups, such as a C 1 -C 4 alkoxy group; - 3- to 6-member cycloalkyloxy groups, such as cyclopropyloxy, optionally substituted by one or more alkyl groups and/or halogens; and - alkyl groups, such as a C 1 -C 4 alkyl group, optionally substituted by 1 to 3 fluorine atoms.
  4. The compound according to any one of claim 1 to 3, wherein the compound is of formula (II): or a pharmaceutically acceptable salt thereof, wherein: R 1 , R 2 , R 3 , R 4 , and R 5 each independently represent H; an alkyl group, such as a C 1 -C 4 alkyl group, optionally substituted by 1 to 3 fluorine atoms; a cycloalkyl group, optionally substituted by one or more alkyl groups and/or halogens; a heterocyclyl group, preferably a 4- to 6-member heterocyclyl group, optionally substituted by one or more alkyl groups, oxo groups and/or halogens; a halogen; an alkoxy group, such as a C 1 -C 4 alkoxy group; a cycloakyloxy group, optionally substituted by one or more alkyl groups and/or halogens; a phenyl group, optionally substituted by one or more alkyl groups and/or halogens; or a substituted or unsubstituted amino group, such as dialkylamino group, such as a dimethylamino group (-N(CH 3 ) 2 ); alternatively, any one pair selected from R 1 and R 3 , R 2 and R 4 , R 4 and R 5 , or R 3 and R 5 , taken together, form a 5- or 6-member heterocycloalkyl group or an heteroaromatic ring or a 5- or 6-member cycloalkyl group, optionally substituted by one or more alkyl groups and/or halogens, while the remaining R 1 , R 2 , R 3 , R 4 , and R 5 , each independently, represent H; an alkyl group, optionally substituted by 1 to 3 fluorine atoms; a cycloalkyl group, optionally substituted by one or more alkyl groups and/or halogens; a heterocyclyl group, preferably a 4- to 6-member heterocyclyl group, optionally substituted by one or more alkyl groups, oxo groups and/or halogens; a halogen; an alkoxy group, such as a C 1 -C 4 alkoxy group; a cycloakyloxy group, optionally substituted by one or more alkyl groups and/or halogens; a phenyl group, optionally substituted by one or more alkyl groups and/or halogens; or a substituted or unsubstituted amino group, such as dialkylamino groups, such as a dimethylamino group (-N(CH 3 ) 2 ).
  5. The compound according to any one of claim 1 or 2, wherein the compound is of formula (III): or a pharmaceutically acceptable salt thereof, wherein: R 6 , R 7 , R 8 , and R 9 each independently represent H; or an alkyl group; n and m each independently represent 0 or 1; R 10 and R 13 each independently represent H; a halogen; an alkoxy group; a 4- to 6-member heterocycloalkyl group or a 5- or 6-member heteroaryl group, optionally substituted by one or more alkyl groups and/or halogens; a cycloalkyl group, optionally substituted by one or more alkyl groups and/or halogens; or an alkyl group, optionally substituted by 1 to 3 fluorine atoms; and R 11 and R 12 each independently represent H; a halogen; a dialkylamino group, such as a dimethylamino group (-N(CH 3 ) 2 ); a cycloalkyl group, optionally substituted by one or more alkyl groups and/or halogens; a 4- to 6-member heterocycloalkyl group, optionally substituted by one or more alkyl groups and/or halogens, such as azetidine, optionally substituted by one or more alkyl groups and/or halogens; or a 4- to 6-member heteroaryl group, optionally substituted by one or more alkyl groups and/or halogens, which is directly bonded to the aryl via a covalent bond or linked through a spacer such as an alkyl chain; such as pyrazole or oxazole, optionally substituted by one or more alkyl groups and/or halogens.
  6. The compound according to any one of claim 1 or 2 or 5, wherein the compound is of formula (IIIf): or a pharmaceutically acceptable salt thereof, wherein Z represents a halogen; an alkyl group optionally substituted by 1 to 3 fluorine atoms; an alkoxy group; or a cycloalkyl group optionally substituted by one or more alkyl groups and/or halogens.
  7. The compound according to any one of claim 1 to 3, wherein the compound is of formula (IV): or a pharmaceutically acceptable salt thereof, wherein: R 1 , R 2 , R 3 , R 4 , and R 5 each independently represent H; an alkyl group, such as a C 1 -C 4 alkyl group, optionally substituted by 1 to 3 fluorine atoms; a cycloalkyl group, optionally substituted by one or more alkyl groups and/or halogens; a heterocyclyl group, preferably a 4- to 6-member heterocyclyl group, optionally substituted by one or more alkyl groups, oxo groups and/or halogens; a halogen; an alkoxy group, such as a C 1 -C 4 alkoxy group; a cycloakyloxy group, optionally substituted by one or more alkyl groups and/or halogens; a phenyl group, optionally substituted by one or more alkyl groups and/or halogens; or a substituted or unsubstituted amino group, such as dialkylamino groups, such as a dimethylamino group (-N(CH 3 ) 2 ); alternatively, any one pair selected from R 1 and R 3 , R 2 and R 4 , R 4 and R 5 , or R 3 and R 5 , taken together, form a 5- or 6-member heterocycloalkyl group or an heteroaromatic ring or a 5- or 6-member cycloalkyl group, optionally substituted by one or more alkyl groups and/or halogens, while the remaining R 1 , R 2 , R 3 , R 4 , and R 5 , each independently, represent H; an alkyl group, optionally substituted by 1 to 3 fluorine atoms; a cycloalkyl group, optionally substituted by one or more alkyl groups and/or halogens; a heterocyclyl group, preferably a 4- to 6-member heterocyclyl group, optionally substituted by one or more alkyl groups, oxo groups and/or halogens; a halogen; an alkoxy group such as a C 1 -C 4 alkoxy group; a cycloakyloxy group, optionally substituted by one or more alkyl groups and/or halogens; a phenyl group, optionally substituted by one or more alkyl groups and/or halogens; or a substituted or unsubstituted amino group, such as dialkylamino groups, such as a dimethylamino group (-N(CH 3 ) 2 ); R 6 , R 7 , R 8 , and R 9 each independently represent H; or an alkyl group; n and m each independently represent 0 or 1; R 10 and R 13 each independently represent H; a halogen; an alkoxy group; a 4- to 6-member heterocycloalkyl group or a 5- or 6-member heteroaryl group, optionally substituted by one or more alkyl groups and/or halogens; a cycloalkyl group, optionally substituted by one or more alkyl groups and/or halogens; an alkyl group, optionally substituted by 1 to 3 fluorine atoms; and R 11 and R 12 each independently represent H; a halogen; a dialkylamino group, such as a dimethylamino group (-N(CH 3 ) 2 ); a cycloalkyl group, optionally substituted by one or more alkyl groups and/or halogens; a 4- to 6-member heterocycloalkyl group, optionally substituted by one or more alkyl groups and/or halogens, such as azetidine, optionally substituted by one or more alkyl groups and/or halogens; or a 4- to 6-member heteroaryl group, optionally substituted by one or more alkyl groups and/or halogens, which is directly bonded to the aryl via a covalent bond or linked through a spacer such as an alkyl chain; such as pyrazole or oxazole, optionally substituted by one or more alkyl groups and/or halogens.
  8. A compound of general formula (I) or a pharmaceutically acceptable salt thereof according to any of claims 1 to 4, wherein B is a tetrahydro-isoquinoline substituted on its aryl part of the bicyclic ring system by a 5- or 6-member heteroaryl group, which is directly bonded to the aryl part via a covalent bond or linked through a spacer such as an alkyl chain; wherein B is optionally further substituted by one or more members selected from the group consisting of: - halogens; - dialkylamino groups, such as a dimethylamino group (-N(CH 3 ) 2 ); - cycloalkyl groups optionally substituted by one or more alkyl groups and/or halogens, such as a C 3 -C 5 cycloalkyl group optionally substituted by 1 to 2 fluorine atoms; - alkoxy groups, such as a C 1 -C 4 alkoxy group; - 3- to 6-member cycloalkyloxy groups, such as cyclopropyloxy, optionally substituted by one or more alkyl groups and/or halogens; and - alkyl groups, such as a C 1 -C 4 alkyl group, optionally substituted by 1 to 3 fluorine atoms.
  9. A compound of general formula (I) or a pharmaceutically acceptable salt thereof according to any of claims 1 to 8, which is selected from: or
  10. A compound of general formula (I) or a pharmaceutically acceptable salt thereof according to any of claims 1 to 8, which is selected from: or
  11. A pharmaceutical composition comprising a compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.
  12. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 10, or the pharmaceutical composition according to claim 11, for use in the treatment or prophylaxis of a disease, preferably wherein the disease is a hyperproliferative disorder.
  13. The compound, the pharmaceutically acceptable salt or the pharmaceutical composition for use according to claim 12, wherein it is for use in combination with a selective estrogen receptor degrader (SERD) inhibitor; an immune checkpoint inhibitor targeting PD1, PDL1, or CTLA4; and/or a cyclin-dependent kinase (CDK) inhibitor.
  14. A method for treating or prophylaxis of a disease, preferably wherein the disease is a hyperproliferative disorder, comprising administering to a patient in need thereof a compound of general formula (I), or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 10, or a pharmaceutically acceptable composition according to claim 11.
  15. A method for treating or prophylaxis of a disease according to claim 14, wherein it further comprises administering to the patient in need thereof a Selective Estrogen Receptor Degrader (SERD) inhibitor; an immune checkpoint inhibitor targeting PD1, PDL1, or CTLA4; and/or a Cyclin-Dependent Kinase (CDK) inhibitor.

Description

FIELD OF THE INVENTION The present invention relates to the field of pharmaceuticals and concerns compounds capable of modulating KAT6 activity and/or KAT6-signaling, including their synthesis methods and therapeutic applications. In addition, the invention relates to incorporation of these compounds into a pharmaceutical formulation, and its application as a KAT6 inhibitor in the development of therapeutic agents for the treatment and/or prevention of cancer. BACKGROUND OF THE INVENTION KAT6A, also designated as MYST3 or MOZ, is a member of the MYST family of histone acetyltransferases (HATs) that play a role in the regulation of gene expression and chromatin modification. KAT6A functions as an epigenetic regulator by acetylating histone H3 at lysine 9 (H3K9) and lysine 14 (H3K14), post-translational modifications associated with transcriptionally active chromatin. Through these modifications, KAT6A modulates chromatin structure and accessibility, thereby influencing the transcription of genes involved in key cellular processes such as differentiation, proliferation, and survival (Lv, D. et al., 2017). Beyond its role in normal cellular function, KAT6A has been implicated in oncogenesis. Alterations in KAT6A activity, including mutations, chromosomal translocations, and aberrant expression, are associated with the initiation and progression of various cancers. Notably, chromosomal translocations involving KAT6A, such as t(8;16)(p11 ;p13), result in fusion proteins like KAT6A-CREBBP, which are linked to acute myeloid leukemia (AML) (Coenen, E. A. et al., 2013). Additionally, overexpression of KAT6A has been observed in solid tumors, including breast and colon cancers, where it contributes to increased cellular proliferation and survival (Hu, Z. et al., 2019). The oncogenic potential of KAT6A is mediated through its capacity to modify the transcriptional landscape in a manner that supports tumor progression. KAT6A, as a histone acetyltransferase, acetylates histone H3 at lysine residues K9, K14, and K23, thereby facilitating the expression of genes involved in cellular proliferation and survival while repressing those associated with differentiation and apoptosis. Additionally, KAT6A seems to interact with other epigenetic regulators, including the NuA4 complex and the p300/CBP coactivator, to modulate the expression of oncogenes and tumor suppressor genes. These interactions collectively contribute to the establishment of a transcriptional environment that promotes oncogenic processes. Thus, targeting KAT6A presents a viable therapeutic strategy for cancers characterized by KAT6A dysregulation. Inhibition of KAT6A's acetyltransferase activity has the potential to disrupt the transcriptional programs that drive cancer progression (Weber, L. M. et al., 2023). Cancers driven by KAT6A dysregulation, including AML, breast cancer, and colon cancer, frequently present aggressive phenotypes and exhibit resistance to conventional treatments like chemotherapy and radiation. Compounds such as WM-1119 demonstrate moderate efficacy in vitro but lack sufficient potency in vivo to achieve robust therapeutic outcomes due to issues such as low bioavailability, or poor pharmacokinetic properties (Sharma S. et al., 2023). A primary challenge in developing KAT6A inhibitors is achieving selectivity due to structural homology with other MYST family members, including KAT6B (MORF), KAT5 (Tip60), and KAT7 (HBO1). This similarity, particularly within the acetyl-CoA binding pocket, complicates the design of inhibitors that specifically target KAT6A without affecting other HATs, which are essential for normal cellular functions. Indeed, non-selective inhibition may lead to off-target effects and toxicity, thereby narrowing the therapeutic window. The development of novel KAT6A inhibitors with enhanced selectivity and potency could provide new therapeutic options for these cancers, particularly those resistant to existing treatments. Additionally, such inhibitors could be integrated into combination therapies to improve treatment efficacy and mitigate drug resistance. Recent advancements include the discovery of CTx-648 (PF-9363), a highly potent, and orally bioavailable inhibitor of KAT6A/B histone acetyltransferases. CTx-648 has demonstrated antitumor activity in breast cancer models with high KAT6A expression and estrogen receptor positivity (ER+). By specifically inhibiting KAT6A/B, CTx-648 reduces the acetylation of histone H3 at lysine 23 (H3K23Ac), thereby suppressing tumor growth. The efficacy of CTx-648 in preclinical trials highlights the potential of targeted KAT6A inhibition as a therapeutic approach for cancers with KAT6A dysregulation. However, in the phase 1 clinical trial of PF-07248144 for ER+HER2- metastatic breast cancer, neutropenia and anemia were among the most frequently reported treatment-related adverse events. These occurred in 59.8% and 48.6% of patients, respectively, with 35.5% and 13.1 % experiencing grad