Novel Pyrido-pyrimidinones and Pteridinones as Endoribonuclease Inositol Requiring Enzyme 1 (IRE1α) Inhibitors for Treating Cancer

Important Compound Classes

Title

Pyrido-pyrimidinone and Pteridinone Compounds as Inhibitors of Endoribonuclease Inositol Requiring Enzyme 1 (IRE 1 Alpha) for the Treatment of Cancer Diseases

Patent Publication Number

WO 2020/142612 A1

Publication Date

July 9, 2020

Priority Application

CN PCT/CN2019/070275 and CN PCT/CN2019/081673

Priority Date

January 3, 2019 and April 8, 2019

Inventors

Braun, M.; Castanedo, G.; Gibbons, P.; Rudolph, J.; Vernier, W.; Beveridge, R.; Wu, Y.; Wu, G.

Assignee Company

Genentech, Inc., USA

Disease Area

Cancer

Biological Target

Kinase/endoribonuclease inositol requiring enzyme 1 (IRE1α)

Summary

The kinase/endoribonuclease inositol requiring enzyme 1 (IRE1α), one of the key sensors of misfolded protein accumulation in the endoplasmic reticulum that triggers the unfolded protein response (UPR), is a potential therapeutic target for the diverse diseases including cancer for inhibitors that bind to the ATP-binding site on the kinase moiety of IRE1α and block its endoribonuclease activity. IRE1α is a transmembrane, bifunctional protein with a luminal domain that binds to misfolded proteins, a transmembrane segment, a cytoplasmic portion consisting of a kinase moiety, and a tandem endoribonuclease domain. IRE1α activity mediates certain cytoprotective and pro-survival functions of the UPR, increases viability and growth in certain tumor cell lines, and can be an effective therapeutic target for specific small molecule inhibitors that block malignant tumor growth.

Homeostatic regulation of protein folding in the endoplasmic reticulum (ER) is under the control of three key intracellular signaling pathways: IRE1α, PERK, and ATF6, which together orchestrate the UPR. An increase in demand for protein folding in the ER or certain types of cellular injury or stress lead to the accumulation of unfolded proteins in the ER—a condition called ER stress.

IRE1α is a transmembrane, bifunctional protein with cytoplasmic kinase and endoribonuclease activity. The N-terminal domain of IRE1α is proposed to sense the presence of unfolded proteins in the ER lumen, triggering activation of the cytoplasmic kinase domain, which, in turn, activates the C-terminal endoribonuclease. IRE1α transmits information across the ER lipid bilayer. The IRE1α endoribonuclease has the ability to cleave the mRNA that encodes unspliced X box protein 1 (XBP1u) as well as microRNA. Activation of the UPR has been shown to be an important survival pathway for tumors. Therefore, efforts to disrupt the UPR by blocking the IRE1α endoribonuclease cleavage and activation of XBP1 have been an active area of cancer research.

The present application describes a series of novel pyrido-pyrimidinone and pteridinone compounds as inhibitors of endoribonuclease inositol requiring enzyme 1 (IRE1α) for the treatment of cancer. Further, the application discloses compounds, their preparation, use, pharmaceutical composition, and treatment.

Definitions

X₁ = -CR_x or -N, wherein R_x is H, C₁–C₄ alkyl, cyclopropyl, or halogen;

Ring B is 5- to 7-membered aryl or 5- to 7-membered heteroaryl comprising at least one nitrogen atom;

y = 1, 2, 3, or 4;

R₁ = C₁–C₄ alkyl, C₃–C₆ cycloalkyl, or 3- to 14-membered heterocyclyl, each of which is unsubstituted or substituted with one or more substituents selected from the group consisting of -CH₂F, -CHF₂, -CF₃, halogen, C₃–C₆ cycloalkyl, hydroxyl, and -O-(C₁–C₄) alkyl, such as methoxyl;

R₂ = C₁–C₄ alkyl, C₃–C₆ cycloalkyl, or 4- to 10-membered heterocyclyl, each of which is unsubstituted or substituted with one or more R_2A;

R_2A is selected from the group consisting of H, R_2C-substituted or -unsubstituted C₁–C₄ alkyl, C₁–C₄ fluoroalkyl, halogen, -OH, -(CH₂)_q-N(R_2B)₂, wherein q is 1 or 0, -CH₂F, -CHF₂, and -CF₃; or

wherein two R_2A together with the carbon to which each is attached form a substituted or unsubstituted aziridinyl, azetidinyl, pyrrolidinyl, imidazolyl, piperidinyl, piperizinyl, morpholino;

R_2B = H, R_2C-substituted or -unsubstituted C₁–C₃ alkyl, unsubstituted C₃–C₆ cycloalkyl, or unsubstituted C₃–C₆ heterocyclyl; or

wherein two R_2B together form a substituted or unsubstituted heterocyclyl, wherein the heterocyclyl can be spiro, an unsubstituted aziridinyl, azetidinyl, pyrrolidinyl, imidazolyl, piperidinyl, piperizinyl, morpholino;

R_2C = halogen, -OCH₃, or C₃–C₅ heterocyclyl;

R₃ = H, halogen, -CN, C₁–C₆ alkyl, C₁–C₆ haloalkyl, C₃–C₆ cycloalkyl, O(C₁–C₆ alkyl), or -O(C₁–C₆ haloalkyl);

R₄ and R₅ are independently H, halogen, -CN, -NO₂, C₁–C₆ alkyl, C₂–C₆ alkenyl, C₂–C₆ alkynyl, C₃–C₁₂ cycloalkyl, C₆–C₂₀ aryl, or 3- to 14-membered heterocyclyl, 5- to 14-membered heteroaryl, -OR₆, -NR_8AR₉, -NR₈C(O)R₉, -NR₈C(O)OR₆, -NR₈C(O)NR_68AR_8B, -NR₈SO₂R₉, -NR₈SO₂R_8AR_8B, -NR₈S(O)(=NR_8C)R₉, -C(O)N(R₈)SO₂R₉, -C(O)NR₈R₉, -C(O)R₇, -C(O)OR₆, -SO₂R₉, -NR₈S(O)(=NR_8C)R₉, or -SO₂NR₈R₉; wherein C₁–C₆ alkyl, C₃–C₁₂ cycloalkyl, C₆–C₂₀ aryl, or 3- to 14-membered heterocyclyl, 5- to 14-membered heteroaryl of R₄ and R₅ are optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R₁₀.

Key Structures

Biological Assay

The kinase domain of IRE1α binding assay was performed using time-resolved fluorescence resonance energy transfer (TR-FRET). The compounds described in this application were tested for their ability to inhibit kinase/endoribonuclease IRE1α. The IRE1α HTRF IC₅₀ (μM) are shown in the following table.

Biological Data

The table below shows representative compounds were tested for kinase/endoribonuclease inositol requiring enzyme 1 (IRE1α) inhibition. The biological data obtained from testing representative examples are listed in the following table.

Claims

Total claims: 104

Compound claims: 78

Pharmaceutical composition claims: 1

Use of compound claims: 6

Method of treatment claims: 14

Method of inhibition claims: 3

Method of modulation claims: 1

Kit claims: 1

Recent Review Articles

• 1.Raymundo D. P.; Doultsinos D.; Guillory X.; Carlesso A.; Eriksson L. A.; Chevet E.. Trends Cancer 2020, in press.
• 2.Rodriguez-Hernandez M. A.; de la Cruz-Ojeda P.; Lopez-Grueso M. J.; Navarro-Villaran E.; Requejo-Aguilar R.; Castejon-Vega B.; Negrete M.; Gallego P.; Vega-Ochoa A.; Victor V. A.; Cordero M. D.; Del Campo J. A.; Barcena J. A.; Padilla C. A.; Muntane J.. Redox Biol. 2020, 36, 101510.
• 3.da Silva D. C.; Valentao P.; Andrade P. B.; Pereira D. M.. Pharmacol. Res. 2020, 155, 104702.
• 4.Lin Y.; Jiang M.; Chen W.; Zhao T.; Wei Y.. Biomed. Pharmacother. 2019, 118, 109249.

The author declares no competing financial interest.