Sulfonylamide Compounds as CDK2 Inhibitors for Treating Cancer

Important Compound Classes

Title

Sulfonylamide Compounds as CDK2 Inhibitors

Patent Publication Number

WO 2020/205560 A1

Publication Date

October 8, 2020

Priority Application

US 62/826,477

Priority Date

March 29, 2019

Inventors

Ye, M.; Chen, Y.; Favata, M.; Lo, Y.; Sokolsky, A.; Winterton, S.; Wu, L.; Yao, W.

Assignee Company

Incyte Corporation, USA

Disease Area

Cancer

Biological Target

Cyclic-dependent kinase 2 (CDK2)

Summary

Cyclic-dependent kinases (CDKs) are a family of serine/threonine kinases. Heterodimerized with regulatory subunits known as cyclins, CDKs become fully activated and regulate key cellular processes including cell cycle progression and cell division. Uncontrolled proliferation is a hallmark of cancer cells. The deregulation of the CDK activity is associated with abnormal regulation of the cell cycle and is detected in virtually all forms of human cancers.

CDK2 is of particular interest because the deregulation of CDK2 activity frequently occurs in a variety of human cancers. CDK2 plays a crucial role in promoting G1/S transition and S phase progression. CDK2 pathways influence tumorigenesis mainly through the amplification or overexpression of CCNE1 and mutations that inactivate CDK2 endogenous inhibitors, respectively. Various approaches targeting CDK2 have been shown to induce cell-cycle arrest and tumor growth inhibition.

The present application describes a series of sulfonylamide compounds as CDK2 inhibitors for the treatment of cancer. Furthermore, the application discloses compounds and their preparation, use, pharmaceutical composition, and treatment.

Definitions

X = N or CR₉;

Y = N or CR₁₀;

R₁ = C_1–6 alkyl, C_2–6 alkenyl, C_2–6 alkynyl, C_1–6 haloalkyl, C_3–10 cycloalkyl, 6- to 10-membered aryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, C_3–10 cycloalkyl–C_1–4 alkyl, 6- to 10-membered aryl–C_1–4 alkyl, 4- to 10-membered heterocycloalkyl–C_1–4 alkyl, and 5- to 10-membered heteroaryl–C_1–4 alkyl, wherein said C_1–6 alkyl, C_2–6 alkenyl, C_2–6 alkynyl, C_1–6 haloalkyl, C_3–10 cycloalkyl, 6- to 10-membered aryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, C_3–10 cycloalkyl–C_1–4 alkyl, 6- to 10-membered aryl–C_1–4 alkyl, 4- to 10-membered heterocycloalkyl–C_1–4 alkyl, and 5- to 10-membered heteroaryl–C_1–4 alkyl are each optionally substituted by 1, 2, 3, 4, 5, or 6 independently selected R₄ substituents;

R₂ and R₃ = C_1–6 alkyl, C_1–6 haloalkyl, C_2–6 alkenyl, C_2–6 alkynyl, C_3–10 cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, and 5- to 6-membered heteroaryl, wherein said C_1–6 alkyl, C_1–6 haloalkyl, C_2–6 alkenyl, C_2–6 alkynyl, C_3–10 cycloalkyl, phenyl, 4- to 7-membered heterocycloalkyl, and 5- to 6-membered heteroaryl are each optionally substituted by 1, 2, 3, or 4 independently selected R_G substituents;

R₅ = H, C_1–6 alkyl, C_2–6 alkenyl, C_2–6 alkynyl, C_1–6 haloalkyl, C_3–10 cycloalkyl, 6- to 10-membered aryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, C_3–10 cycloalkyl–C_1–4 alkyl, 6- to 10-membered aryl–C_1–4 alkyl, 4- to 10-membered heterocycloalkyl–C_1–4 alkyl, and 5- to 10-membered heteroaryl–C_1–4 alkyl, wherein said C_1–6 alkyl, C_2–6 alkenyl, C_2–6 alkynyl, C_1–6 haloalkyl, C_3–10 cycloalkyl, 6- to 10-membered aryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, C_3–10 cycloalkyl–C_1–4 alkyl, 6- to 10-membered aryl–C_1–4 alkyl, 4- to 10-membered heterocycloalkyl–C_1–4 alkyl, and 5- to 10-membered heteroaryl–C_1–4 alkyl are each optionally substituted by 1, 2, 3, or 4 independently selected R_5A substituents;

R₆ = H, C_1–4 alkyl, C_1–4 haloalkyl, and C_3–4 cycloalkyl; and

R₇ and R₈ = H, D, OH, NO₂, CN, halo, C_1–6 alkyl, C_2–6 alkenyl, C_2–6 alkynyl, C_1–6 haloalkyl, cyano-C_1–6 alkyl, HO–C_1–6 alkyl, C_1–6 alkoxy–C_1–6 alkyl, C_3–4 cycloalkyl, C_1–6 alkoxy, C_1–6 haloalkoxy, amino, C_1–6 alkylamino, and di(C_1–6 alkyl)amino.

Key Structures

Biological Assay

The CDK2/Cyclin E1 HTRF enzyme activity assay was performed. The compounds described in this application were tested for their ability to inhibit CDK2. The CDK2 IC₅₀ (nM) are shown in the following Table.

Biological Data

The Table below shows representative compounds that were tested for CDK2 inhibition. The biological data obtained from testing representative examples are listed.

For CDK2 IC₅₀: “+” refers to ≤50 nM; “++” refers to >50–200 nM; “+++” refers to >200–500 nM; “++++” refers to >500–1000 nM.

Claims

Total claims: 35

Compound claims: 25

Pharmaceutical composition claims: 1

Method of treating claims: 5

Method of inhibiting claims: 2

Method of evaluating claims: 2

Recent Review Articles

• 1.Bitencourt-Ferreira G.; Duarte da Silva A.; Filgueira de Azevedo W. Jr.. Curr. Med. Chem. 2021, 28, 253.
• 2.Asati V.; Anant A.; Patel P.; Kaur K.; Gupta G. D.. Eur. J. Med. Chem. 2021, 225, 113781.
• 3.Rathi A.; Kumar D.; Hasan G. M.; Haque M. M.; Hassan M. I.. Biochim. Biophys. Acta, Gen. Sub. 2021, 1865, 129995.
• 4.Marak B. N.; Dowarah J.; Khiangte L.; Singh V. P.. Eur. J. Med. Chem. 2020, 203, 112571.
• 5.Sanchez-Martinez C.; Lallena M. J.; Sanfeliciano S. G.; de Dios A.. Bioorg. Med. Chem. Lett. 2019, 29, 126637.
• 6.Qiao Y.; Chen T.; Yang H.; Chen Y.; Lin H.; Qu W.; Feng F.; Liu W.; Guo Q.; Liu Z.; Sun H.. Eur. J. Med. Chem. 2019, 181, 111581.

The author declares no competing financial interest.