Novel Substituted Piperidine-2,6-dione Derivatives for Treating Sickle Cell Disease and β-Thalassemia

Important Compound Classes

Title

3-(5-Methoxy-1-oxoisoindolin-2-yl)piperidine-2,6-dione Derivatives and Uses Thereof

Patent Publication Number

WO 2021/124172 A1

Publication Date

June 24, 2021

Priority Application

US 62/950,048

Priority Date

December 18, 2019

Inventors

Bonazzi, S.; Cernijenko, A.; Cobb, J. S.; Dales, N.; Kerrigan, J. R.; Lam, P.; Malik, H. A.; O’Brien, G.; Patterson, A. W.; Thomsen, N. M.; Ting, P.

Assignee Company

Novartis AG, Switzerland

Disease Area

Sickle cell disease and β-thalassemia

Biological Target

Widely Interspaced Zinc Finger Motifs (WIZ) protein

Summary

Sickle cell disease (SCD) is a group of severe inherited blood disorders that can cause red blood cells to contort into a sickle shape. These cells can cause blockages in blood flow, leading to intense pain, organ damage, and premature death. β-Thalassemias are a group of inherited blood disorders that are caused by reduced or absent synthesis of β-globin, causing anemia.

Fetal hemoglobin (HbF) induction is known to ameliorate symptoms in SCD and β-thalassemia patients, with both genetic (single nucleotide polymorphisms in the globin control locus and BCL11A) and pharmacologic (hydroxyurea) validation in the clinic. Hydroxyurea is the current standard of care for SCD and is thought to provide benefit via induction of HbF but is genotoxic, causing dose-limiting neutropenia and has a response rate of less than 40%. Other mechanisms being targeted clinically and preclinically include inhibition of HDAC1/2, LSD1, DNMT1, PDE91, and G91/GLP.

The present application describes a series of novel substituted piperidine-2,6-dione derivatives and their use in reducing widely interspaced zinc finger motif (WIZ) protein expression levels and/or inducing fetal hemoglobin (HbF) protein expression levels and are useful for treatment of sickle cell disease and β-thalassemia. Further, the application discloses compounds, their preparation, use, pharmaceutical composition, and treatment.

Definitions

Y = O, CH₂, CF₂ and CHF;

R_x1 and R_x2 = H and C₁–C₆alkyl;

R_y1 and R_y2 = H and C₁–C₆alkyl;

R_z1 and R_z2 = H; z = 0 to 2;

R₁ = H and C₁–C₆alkyl; and

R₂ = H, -C(=O)-R₃, C₃–C₈cycloalkyl, C₁–C₆haloalkyl, and C₁–C₁₀alkyl, wherein the alkyl is substituted with 0–1 substituents selected from C₆–C₁₀aryl, 5- to 10-membered heteroaryl comprising 1–4 heteroatoms selected from N, O and S, 4- to 10-membered heterocyclyl comprising 1–2 heteroatoms selected from N, O and S, C₃–C₈cycloalkyl, and -O-(R_2a),

wherein aryl, heteroaryl, heterocyclyl and cycloalkyl are substituted with 0–5 R₄.

Key Structures

Biological Assay

The quantification of WIZ protein levels in HiBit Tag Fusion Protein assay in 293T cells was performed. The compounds described in this application were tested for their ability to reduce WIZ protein. The WIZ AC₅₀ values (μM) are shown in the following table.

Biological Data

The table below shows representative compounds were tested for WIZ reduction. The biological data obtained from testing representative examples are listed in the following table.

Claims

Total claims: 101

Compound claims: 86

Pharmaceutical composition claims: 1

Method of treating claims: 6

Method of inhibiting claims: 2

Method of degrading claims: 1

Method of inducing claims: 1

Method of reactivating claims: 1

Method of increasing claims: 1

Method of reducing claims: 1

Pharmaceutical combination claims: 1

Recent Review Articles

• 1.Badawy S. M.; Beg U.; Liem R. I.; Chaudhury S.; Thompson A. A.. Blood Adv. 2021, 5, 570.
• 2.Abraham A. A.; Tisdale J.. Blood 2021, in press.
• 3.Tampaki A.; Gavriilaki E.; Varelas C.; Anagnostopoulos A.; Vlachaki E.. Blood Rev. 2021, 48, 100805.
• 4.Pace B. S.; Starlard-Davenport A.; Kutlar A.. Br. J. Hematol. 2021, 194, 240.
• 5.Ali M. A.; Ahmad A.; Chaudry H.; Aiman W.; Aamir S.; Yasir M.. Exp. Hematol. 2020, 92, 11e1.

The author declares no competing financial interest.