Novel Pyrazolopyrazine Compounds as SHP2 Inhibitors for Treating Glioblastoma

Abstract

Provided herein are novel pyrazolopyrazine compounds as SHP2 inhibitors, pharmaceutical compositions, use of such compounds in treating glioblastoma, and processes for preparing such compounds.

Important Compound Classes

Title

Pyrazolopyrazine Compounds as SHP2 Inhibitors

Patent Publication Number

WO 2023/114954 A1

URL: https://patents.google.com/patent/WO2023114954A1/en

Publication Date

June 22, 2023

Priority Applications

US 63/291,012 and US 63/431,260

Priority Dates

December 17, 2021, and December 8, 2022

Inventors

Begis, G.; Bianciotto, M.; Devillers, I.; Foricher, Y.; Genevois-Borella, A.; Gill, A. L.; Karlsson, A.; Koltun, E. S.

Assignee Company

Genzyme Corporation, USA, and Revolution Medicines Inc., USA

Disease Area

Glioblastoma

Biological Target

SHP2

Summary

Src homology region 2 (SH2)-containing protein tyrosine phosphatase 2 (SHP2) is a ubiquitously expressed protein tyrosine phosphatase encoded by the PTPN11 gene that contributes to multiple cellular functions, including proliferation, differentiation, cell cycle maintenance, and migration. SHP2 is involved in signaling through the Ras-mitogen-activated protein kinase, the JAK-STAT, or the phosphoinositol-3-kinase-AKT pathways.

Mutations in the PTPN11 gene and subsequently in SHP2 have been identified in several diseases, such as Noonan syndrome, Leopard syndrome, juvenile myelomonocytic leukemias, melanoma, neuroblastoma, acute myeloid leukemia, and cancers of the breast, lung, colon, and brain, including glioblastoma. As such, SHP2 represents a highly attractive target for the development of novel therapies for the treatment of various diseases, including cancer. For treating or preventing cancers associated with the brain, an SHP2 inhibitor with brain penetration capability is particularly attractive.

The present application describes a series of novel pyrazolopyrazine compounds as SHP2 inhibitors for the treatment of glioblastoma. Further, the application discloses compounds, their preparation, use, and pharmaceutical composition, and treatment.

Definitions

Ring A = C₃–C₆ cycloalkyl, phenyl, 5- to 6-membered heterocycloalkyl, 5- to 6-membered heteroaryl, wherein heterocycloalkyl and heteroaryl contain 1–3 heteroatoms selected from N, O, and S;

R₁ = halo, cyano, -NR_2aR_2b, C₁–C₆ alkyl, oxo, hydroxy, C₁–C₆ haloalkyl, C₁–C₆ alkoxy, C₁–C₆ alkyl-OH, C₁–C₆ alkyl-CN, -C(O)NR_2aR_2b, -C(O)(C₁–C₆ alkyl), -COOH, -COO(C₁–C₆ alkyl), -Si(R_a)(R_b)(R_c), -P(O)(R_a)(R_b), -OP(O)(R_a)(R_b), C₃–C₆ cycloalkyl, 5- to 6-membered heterocycloalkyl, 5- to 6-membered heteroaryl, wherein heterocycloalkyl and heteroaryl contain 1–3 heteroatoms selected from N, O, and S; L = bond, S, O, C(O), or N(R_d);

X = CR_3aR_3b, NR_3a, or O;

R₄ = H, C₁–C₆ alkyl, C₁–C₆ alkyl-OH, C₁–C₆ haloalkyl, or -NH₂;

R₅ = halo, C₁–C₆ alkyl, C₁–C₆ haloalkyl, -(C₁–C₆ alkylene)(C₁–C₆ alkoxy), or C₁–C₆ alkyl-OH;

Ring B = fused phenyl or 5- to 6-membered heteroaryl containing 1–3 heteroatoms selected from N, O, and S;

R₇ = C₁–C₆ alkyl, halo, C₁–C₆ alkoxy, C₁–C₆ alkyl-OH, OH, CN, Si(R_a)(R_b)(R_c), -P(O)(R_a)(R_b), -OP(O)(R_a)(R_b), -NR_2aR_2b, or C₁–C₆ haloalkyl;

x = 0–5; y = 0–2; and z = 0–4.

Key Structures

Biological Assay

The SHP2 phosphatase assay was performed. The compounds described in this application were tested for their ability to inhibit SHP2. The SHP2 IC₅₀ values (nM) are shown in the table below.

Biological Data

The following table shows representative compounds that were tested for SHP2 inhibition and the biological data obtained from testing representative examples.

Claims

Total claims: 29

Compound claims: 25

Pharmaceutical composition claims: 1

Method of treatment claims: 2

Method of inhibition claims: 1

Recent Review Articles

See refs (1−6).

The author declares no competing financial interest.