Novel CDK2 Inhibitors for Treating Cancer

Important Compound Classes

Title

CDK2 Inhibitors

Patent Publication Number

WO 2020/157652 A2

Publication Date

August 6, 2020

Priority Application

US 62/799,455 and US 62/959,042

Priority Date

January 31, 2019 and January 9, 2020

Inventors

Behenna, D. C.; Freeman-Cook, K. D.; Hoffman, R. L.; Nagata, A.; Ninkovic, S.; Sutton, S. C.

Assignee Company

Pfizer Inc., USA

Disease Area

Cancer

Biological Target

CDK2

Summary

Cyclin-dependent kinases (CDKs) and related serine/threonine protein kinases are important cellular enzymes that perform essential functions in regulating cell division and proliferation. CDKs 1–4, 6, 10, and 11 have been reported to play a direct role in cell cycle progression, while CDKs 3, 5, and 7–9 may play an indirect role. The CDK catalytic units are activated by binding to regulatory subunits, known as cyclins, followed by phosphorylation. Cyclins can be divided into four general classes (G₁, G₁/S, S, and M cyclins) whose expression levels vary at different points in the cell cycle.

Overexpression of CDK2 is associated with abnormal regulation of the cell-cycle. Cyclin E, the regulatory cyclin for CDK2, is frequently overexpressed in cancer. Cyclin E amplification or overexpression has long been associated with poor outcomes in breast cancer. Amplification or overexpression of cyclin E1 (CCNE1) is associated with poor outcomes in ovarian, gastric, endometrial, and other cancers.

The small molecule inhibitor dinaciclib inhibits CDK1, CDK2, CDK5, and CDK9 and is currently in clinical development for breast and hematological cancers. Seliciclib, which inhibits CDK2, CDK7, and CDK9 was studied in nasopharyngeal cancer. CYCO65, which inhibits CDK2 and CDK9, is in early clinical development. Despite significant efforts, there are no approved agents selectively targeting CDK2 to date. The present application describes a series of novel CDK2 inhibitors that are useful for treatment of cancer. Further, the application discloses compounds, their preparation, use, pharmaceutical composition, and treatment.

Definitions

R₁ = -L₁-(5–10 membered heteroaryl) or -L₁-(C₆–C₁₂ aryl), where 5–10 membered heteroaryl or C₆–C₁₂ aryl is optionally substituted by one or more R₄;

R₂ and R₃ are independently H, C₁–C₆ alkyl, C₁–C₆ fluoroalkyl, -L₂-(C₃–C₇ cycloalkyl) or -L₂-(4–7 membered heterocyclyl), where each C₁–C₆ alkyl and C₁–C₆ fluoroalkyl is optionally substituted by one or more R₅ and C₃–C₇ cycloalkyl and 4–7 membered heterocyclyl is optionally substituted by one or more R₆; or

R₂ and R₃ are taken together with the N atom to which they are attached to form a 4–6 membered heterocyclyl optionally containing an additional heteroatom selected from O, N(R₇), and S(O)_q as a ring member, where 4–6 membered heterocyclyl is optionally substituted by one or more R₈;

L₁ and L₂ is independently a bond or a C₁–C₂ alkylene optionally substituted by one or more R₉;

R₄ = F, Cl, OH, CN, NR₁₀R₁₁, C₁–C₄ alkyl, C₁–C₄ fluoroalkyl, C₁–C₄ alkoxy, C₁–C₄ fluoroalkoxy, C₃–C₈ cycloalkyl, C(O)NR₁₀R₁₁, SO₂R₁₂, SO(=NH)R₁₂ or SO₂NR₁₀R₁₁, where each C₁–C₄ alkyl and C₁–C₄ fluoroalkyl is optionally substituted by one or more R₁₃;

R₅ = OH, C₁–C₄ alkoxy or NR₁₀R₁₁;

R₆ = F, OH, C₁–C₄ alkyl, C₁–C₄ fluoroalkyl, C₁–C₄ alkoxy, C₁–C₄ fluoroalkoxy or NR₁₀R₁₁ where each C₁–C₄ alkyl, C₁–C₄ fluoroalkyl is optionally substituted by one or more R₁₃;

R₇ = H, C₁–C₄ alkyl or C(O)-C₁–C₄ alkyl;

R₈ = F, OH, C₁–C₄ alkyl, C₁–C₄ alkoxy or CN;

R₉ = F, OH, or C₁–C₂ alkyl;

R₁₀ and R₁₁ are independently H, or C₁–C₂ alkyl;

R₁₂ = C₁–C₄ alkyl or C₃–C₆ cycloalkyl;

R₁₃ = OH, C₁–C₄ alkoxy or NR₁₄R₁₅;

R₁₄ and R₁₅ are independently H, or C₁–C₂ alkyl; and

q = 0, 1 or 2.

Key Structures

Biological Assay

The CDK2/cyclin E1 and GSK3β assays were performed. The compounds described in this application were tested using a fluorescence-based microfluidic mobility shift assays to test the ability of the compounds to inhibit CDK2/cyclin E1 and GSK3β. The CDK2/cyclin E1 K_i (nM) and GSK3β K_i (nM) inhibition are shown in the following Table.

Biological Data

The Table below shows representative compounds were tested for CDK2/cyclin E1 and GSK3β inhibition. The biological data obtained from testing representative examples are listed in the following table.

Claims

Total claims: 20

Compound claims: 18

Pharmaceutical composition claims: 1

Method of treatment claims: 1

Recent Review Articles

• 1.Tadesse S.; Anshabo A. T.; Portman L.; Lim E.; Tilley W.; Caldon C. E.; Wang S.. Drug Discovery Today 2020, 25, 406.
• 2.Liu Q.; Gao J.; Zhao C.; Guo Y.; Wang S.; Shen F.; Xing X.; Luo Y.. DNA Repair 2020, 85, 102702.
• 3.Marak B. N.; Dowarah J.; Khiangte L.; Singh V. P.. Eur. J. Med. Chem. 2020, 203, 112571.
• 4.Leal-Esteban L. C.; Fajas L.. Biochim. Biophys. Acta, Mol. Basis Dis. 2020, 1866, 165715.

The author declares no competing financial interest.