Novel BTK Inhibitors for Treating Autoimmune Disorders and Cancer

Important Compound Classes

Title

BTK Inhibitors

Patent Publication Number

WO 2022/032019 A1

URL

https://patents.google.com/patent/WO2022032019A1/en

Publication Date

February 10, 2022

Priority Application

US 63/063,188 and US 63/189,476

Priority Date

August 7, 2020, and May 17, 2021

Inventors

Ma, B.; Hopkins, B. T.; Marx, I.; Schulz, J.; Vandeveer, G.; Prince, R.; Nevalainen, M.; Chen, T. Y.; Yousaf, Z.; Himmel-Bauer, M.; Pattaropong, V.; Jones, J. H.; Gilfillan, R.; Lin, E. Y. S.; Gonzalez Lopez de Turiso, F.

Assignee Company

Biogen MA Inc., USA

Disease Area

Autoimmune disorders and cancer

Biological Target

BTK

Summary

Protein kinases are a large multigene family consisting of more than 500 proteins which play a critical role in the development and treatment of several human diseases in oncology, neurology, and immunology. The Tec kinases are a family of non-receptor tyrosine kinases which consists of five members—Tec (tyrosine kinase expressed in hepatocellular carcinoma), BTK (Bruton’s tyrosine kinase), ITK (interleukin-2 (IL-2)-inducible T-cell kinase, also known as EMT or TSK), RLK (resting lymphocyte kinase, also known as TXK), and BMX (bone-marrow tyrosine kinase gene on chromosome X, also known as ETK)—and are primarily expressed in hematopoietic cells. BTK is a downstream mediator of B cell receptor (BCR) signaling, which is involved in regulating B cell activation, proliferation, and differentiation.

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

Definitions

A₁ and A₂ = C-R_6A or N;

Q₁, Q₂, and Q₃ = C-R₆ and N;

ring A = 4- to 8-membered monocyclic saturated or partially saturated heterocyclyl, substituted with one or more R₁₁;

R₁ = N(R_1a)₂, phenyl, 3- to 7-membered saturated or partially saturated monocyclic carbocyclyl, 3- to 7-membered saturated or partially saturated monocyclic heterocyclyl, 5- or 6-membered heteroaryl, 7- to 10-membered saturated or partially saturated bicyclic carbocyclyl, 7- to 10-membered saturated or partially saturated bicyclic heterocyclyl, 8- to 10-membered bicyclic heteroaryl, and 9- or 10-membered bicyclic aryl;

R₂ = H, C_1–6 alkyl, C_2–6 alkenyl, and C_2–6 alkynyl;

R₃ = H, halogen, C(O)N(R_3a)₂, C(O)OR_3a, C(O)R_3a, C_1–6 alkyl, C_2–6 alkenyl, and C_2–6 alkynyl;

R₄ = H, halogen, NO₂, CN, OR_4a, SR_4a, N(R_4a)₂, C(O)R_4a, C(O)OR_4a, S(O)R_4a, S(O)₂R_4a, C(O)N(R_4a)₂, SO₂N(R_4a)₂, OC(O)R_4a, N(R_4a)C(O)R_4a, N(R_4a)C(O)OR_4a, N(R_4a)SO₂R_4a, OC(O)N(R_4a)₂, C_1–6 alkyl, C_2–6 alkenyl, and C_2–6 alkynyl;

R₅ = H, NHR_5s, or NHC(O)R_5s;

R₇ and R₈ = H or C_1–6 alkyl optionally substituted with one or more substituents selected from halogen and C_1–6 alkoxy;

R₉ = H, C_1–6 alkyl or C_3–6 cycloalkyl;

m = 0 or 1, and n = 0 or 1.

Key Structures

Biological Assay

The in vitro BTK Kinase assay (BTK-PolyGAT-LS assay) was performed. The compounds described in this application were tested for their ability to inhibit BTK. The BTK IC₅₀ (nM) are shown in the table below.

Biological Data

The table below shows representative compounds tested for BTK inhibition and the biological data obtained from testing the representative examples. For IC₅₀, +++ means ≤1 nM, ++ means >1 nM to ≤10 nM, and + means >10 nM.

Claims

Total claims: 61

Compound claims: 53

Pharmaceutical composition claims: 1

Method of treatment claims: 7

The author declares no competing financial interest.