Novel PARP1 Inhibitors for Treating Cancer

Abstract

Provided herein are novel PARP1 inhibitors, their pharmaceutical compositions, the use of such compounds in treating cancer, and processes for preparing such compounds.

Important Compound Classes

Title

PARP1 Inhibitors and Uses Thereof

Patent Publication Number

WO 2023/146957 A1

URL: https://patents.google.com/patent/WO2023146957A1/en

Publication Date

August 3, 2023

Priority Applications

US 63/303,866, US 63/343,425, and US 63/413,466

Priority Dates

January 27, 2022, May 18, 2022, and October 5, 2022

Inventors

Hoffman, R. L.; Va, P. J.; Pinchman, J. R.; Trzoss, L.; Dong, Q.; Kaldor, S. W.

Assignee Company

Xinthera Inc., USA

Disease Area

Cancer

Biological Target

PARP1

Summary

The poly(adenosine diphosphate-ribose) polymerase (PARP) family of 17 known enzymes regulate fundamental cellular processes, including gene expression, protein degradation, multiple cellular stress responses, replication, recombination, chromatin remodeling, DNA repair, and regulation of immune response. These actions make PARP inhibitors targets for a broad spectrum of disorders. PARP inhibitors have shown benefits in several models of degenerative diseases, including diabetes and Parkinson’s disease. PARP inhibitors have also been shown to potentiate radiation and chemotherapy by increasing cell death of cancer cells, limiting tumor growth, decreasing metastasis, and prolonging the survival of tumor-bearing animals.

PARP1 and PARP2 are the most extensively studied PARPs for their role in DNA damage repair. Inhibition of PARP family enzymes has been exploited as a strategy to selectively kill cancer cells by inactivating complementary DNA repair pathways.

The present application describes a series of novel PARP1 inhibitors for the treatment of cancer. Further, the application discloses compounds, their preparation, use, and pharmaceutical composition, and treatment.

Definitions

R₁ = H, D, halogen, CN, OR_a, NR_cR_d, C₁–C₆alkyl, C₁–C₆haloalkyl, C₁–C₆deuteroalkyl, C₁–C₆hydroxyalkyl, C₁–C₆aminoalkyl, C₁–C₆heteroalkyl, C₂–C₆alkenyl, C₂–C₆alkynyl, cycloalkyl or heterocycloalkyl, wherein alkyl, alkenyl, alkynyl, cycloalkyl and heterocycloalkyl is optionally substituted with one or more R;

R₂ = H, D, halogen, CN, OR_a, NR_cR_d, C₁–C₆alkyl, C₁–C₆haloalkyl, or C₁–C₆deuteroalkyl;

R₄ = H, D, halogen, CN, OR_a, NR_cR_d, C₁–C₆alkyl, C₁–C₆haloalkyl, or C₁–C₆deuteroalkyl;

R₅ = H, D, halogen, CN, OR_a, NR_cR_d, C₁–C₆alkyl, C₁–C₆haloalkyl, or C₁–C₆deuteroalkyl;

R₆ = H, D, halogen, C₁–C₆alkyl, C₁–C₆haloalkyl, C₁–C₆deuteroalkyl, C₁–C₆hydroxyalkyl, C₁–C₆aminoalkyl, C₁–C₆heteroalkyl, cycloalkyl or heterocycloalkyl, wherein alkyl, cycloalkyl and heterocycloalkyl is optionally substituted with one or more R;

R₇ = D, halogen, CN, OR_a, NR_cR_d, C₁–C₆alkyl, C₁–C₆haloalkyl, C₁–C₆deuteroalkyl, C₁–C₆hydroxyalkyl, C₁–C₆aminoalkyl, C₁–C₆heteroalkyl, C₂–C₆alkenyl, C₂–C₆alkynyl;

R₁₀ = H, D, halogen, CN, OR_a, NR_cR_d, C₁–C₆alkyl, C₁–C₆haloalkyl, C₁–C₆deuteroalkyl, C₁–C₆hydroxyalkyl, C₁–C₆aminoalkyl, C₁–C₆heteroalkyl, C₂–C₆alkenyl, C₂–C₆alkynyl, cycloalkyl or heterocycloalkyl;

R₁₁ = H, D, halogen, CN, OH, OR_a, NR_cR_d, C₁–C₆alkyl, C₁–C₆haloalkyl, C₁–C₆deuteroalkyl, C₁–C₆hydroxyalkyl, C₁–C₆aminoalkyl, C₁–C₆heteroalkyl, C₂–C₆alkenyl, C₂–C₆alkynyl, cycloalkyl or heterocycloalkyl;

R₁₂ = H, C₁–C₆alkyl, C₁–C₆haloalkyl, C₁–C₆deuteroalkyl, C₁–C₆hydroxyalkyl, C₁–C₆aminoalkyl, C₁–C₆heteroalkyl, C₂–C₆alkenyl, C₂–C₆alkynyl, cycloalkyl or heterocycloalkyl;

X = N or CR₃; T = N or CR₈; U = N or CR₉; and

n = 0–4.

Key Structures

Biological Assay

The PARP1 biochemical fluorescence polarization (FP) assay was performed. The compounds described in this application were tested for their ability to inhibit PARP1. The PARP1 IC₅₀ values (μM) are shown in the following table.

Biological Data

The table below shows representative compounds that were tested for PARP1 inhibition and the biological data obtained from testing representative examples.

Claims

Total claims: 69

Compound claims: 58

Pharmaceutical composition claims: 1

Method of treatment claims: 10

Recent Review Articles

See refs (1−6).

The author declares no competing financial interest.