Novel 4-Heteroarylcarbonyl-N-(phenyl or heteroaryl) Piperidine-1-carboxamides as Tankyrase Inhibitors

Important Compound Classes

Title

4-Heteroarylcarbonyl-N-(phenyl or heteroaryl) Piperidine-1-carboxamides as Inhibitors of Tankyrases

Patent Publication Number

WO 2020/114892 A1

Publication Date

June 11, 2020

Priority Application

EP 18209726.1

Priority Date

December 3, 2018

Inventors

Buchstaller, H.; Rohdich, F.

Assignee Company

Merck Patent GmbH, Germany

Disease Area

Cancer, multiple sclerosis, cardiovascular diseases, central nervous system injury, and different forms of inflammation

Biological Target

Tankyrases (TANKs)

Summary

Tankyrases are multifunctional poly(ADP-ribose) polymerases enzymes that regulate a variety of celluloar processes, including Wnt signaling, telomere maintenance, and mitosis regulation. Tankyrases interact with target proteins and regulate their interactions and stability through poly(ADP-ribosyl)ation. In addition to their roles in telomere regulation and regulation of mitosis, tankyrase proteins regulate tumor suppressors, including AXIN, phosphatase, tensin homologue, and angiomotin. Therefore, tankyrases may be effective targets for cancer treatment. Tankyrase inhibitors could affect a variety of carcinogenic pathways that promote uncontrolled proliferation, including Wnt, AKT, yes-associated protein, mitosis regulation, and telomere maintenance.

The two tankyrase enzymes, tankyrase 1 (TANK 1, also known as PARP5A and ARTD5) and tankyrase 2 (TANK 2, also known as PARP5B and ARTD6), belong to the PARP family. Tankyrase inhibition have therapeutic potential in several diseases including cancers such as colorectal carcinoma and lung cancer as well as in fibrotic diseases and herpes simplex virus (HSV) infections. By inhibition of tankyrase Axin 2 is stabilized and increases remyelination after multiple sclerosis lesions.

The present application describes a series of novel 4-heteroarylcarbonyl-N-(phenyl or heteroaryl) piperidine-1-carboxamides as inhibitors of tankyrases and are useful for treatment cancer, multiple sclerosis, cardiovascular diseases, central nervous system injury, and different forms of inflammation. Further, the application discloses compounds, their preparation, use, pharmaceutical composition, and treatment.

Definitions

R₁ = A;

R₂ = Ar or Het₁;

R₃ = Het₂;

Ar = phenyl, which is unsubstituted or mono-, di-, or trisubstituted by Hal, CN, A, OR₄, (CH₂)_mN(R₄)₂, SO₂N(R₄)₂, COOR₄, and/or CON(R₄)₂;

Het₁ = pyridyl, pyrimidyl, pyrazinyl, each of which is unsubstituted or mono- or disubstituted by Hal, CN, A, NO₂, (CH₂)_mOR₄, (CH₂)_mN(R₄)₂, S(O)_mR₄, SO₂N(R₄)₂, (CH₂)_mCOOR₄, and/or (CH₂)_mCON(R₄)₂;

Het₂ = benzimidazolyl, benzotriazolyl, indazolyl, or indolyl, each of which is unsubstituted or mono- or disubstituted by Hal, CN, A, NO₂, (CH₂)_mOR₄, (CH₂)_mN(R₄)₂, S(O)_mR₄, SO₂N(R₄)₂, (CH₂)_mCOOR₄, and/or (CH₂)_mCON(R₄)₂;

A = unbranched or branched alkyl with 1, 2, 3, 4, 5, 6, 7, or 8 C atoms, wherein one or two nonadjacent CH- and/or CH₂- groups may be replaced by N- or O atoms and wherein 1–7 H atoms may be replaced by F, Cl, and/or OH;

R₄ = unbranched or branched alkyl with 1, 2, 3, or 4 C atoms;

Hal = F, Cl, Br, or I;

m = 0, 1, or 2.

Key Structures

Biological Assay

The human tankyrase 1 (TNKS1) ELISA and tankyrase 2 (TNKS2) ELISA assay was performed. The compounds described in this application were tested for their ability to inhibit tankyrase 1 (TNKS1) and tankyrase 2 (TNKS2). The TNKS1 ELISA IC₅₀ (μM) and TNKS2 ELISA IC₅₀ (μM) are shown in the following table.

Biological Data

The table below shows representative compounds were tested for tankyrase 1 (TNKS1) and tankyrase 2 (TNKS2) inhibition. The biological data obtained from testing representative examples are listed in the following table.

Explanation: 5.00 E-10 means 5 × 10^–10

Claims

Total claims: 13

Compound claims: 7

Use of compound claims: 2

Process for preparing compound claims: 1

Medicament claims: 2

Kit claims: 1

Recent Review Articles

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The author declares no competing financial interest.