Novel Heteroaromatic Carboxamide Derivatives as Plasma Kallikrein Inhibitors for Treating Diabetic Complications, Ocular Diseases and Edema-Associated Diseases

Important Compound Classes

Title

Heteroaromatic Carboxamide Derivatives as Plasma Kallikrein Inhibitors

Patent Publication Number

WO 2021/160718 A1

Publication Date

August 19, 2021

Priority Application

EP 20157259.1

Priority Date

February 13, 2020

Inventors

Eckhardt, M.; Giroud, M.; Langkopf, E.; Mayer, C.; Wagner, H.; Wiedenmayer, D.

Assignee Company

Boehringer Ingelheim International GmbH, Germany

Disease Area

Diabetic complications, ocular diseases, and edema-associated diseases

Biological Target

Plasma kallikrein

Summary

Plasma kallikrein (PKK) is a trypsin-like serine protease secreted by hepatocytes in the liver as an inactive plasma prekallikrein that circulates in plasma either as a free zymogen or as a heterodimer complex bound to higher molecular weight kininogen, which is activated to give the active PKK that can liberate kinins from kininogens in addition to processing other substrates. Kinins are potent mediators of inflammation that act through G-protein-coupled receptors such as bradykinin receptors.

PKK is thought to play a role in a number of inflammatory disorders and may have numerous implications in disorders such as hereditary angioedema (HAE), retinopathy or diabetic retinopathy, proliferative and nonproliferative retinopathy, diabetic macular edema (DME), clinically significant macular edema (CSME), cystoid macular edema (CME), retinal edema, hypertensive retinopathy, retinal trauma, dry and wet age-related macular degeneration (AMD), focal cerebral ischemia, global cerebral ischemia, glioma-associated edema, spinal cord injury, pain, ischemia, focal brain ischemia, stroke, myocardial infarction, high altitude cerebral edema, cytotoxic cerebral edema, and osmotic cerebral edema.

The present application describes a series of novel heteroaromatic carboxamide derivatives as plasma kallikrein inhibitors for the treatment of diabetic complications, ocular diseases, and edema-associated diseases, in particular, diabetic macular edema, age-related macular degeneration, choroidal neovascularization, hereditary angioedema, and brain edema after stroke. Further, the application discloses compounds, their preparation, use, pharmaceutical composition, and treatment.

Definitions

Y is selected from the group Y-G1 consisting of , , , , and , each of which is substituted with one or two independent substituents R₁;

R is selected from the group R-G1 consisting of saturated 6- to 12-membered bicyclic ring system containing 1 to 2 N atoms as ring members and optionally 1 ring member selected from the group consisting of C=O, O, S, S=O, and SO₂, wherein the ring systems are optionally substituted with 1 to 6 F and optionally substituted with 1 to 3 substituents selected from the group consisting of C_1–3-alkyl, CN, HO-C_1–3-alkylene, OH and C_1–3-alkyl-O; and

Ar is selected from the group Ar-G1 consisting of 5-membered heteroaryls, containing 1 to 4 N atoms or containing 1 O or S atom or containing 1 to 2 N atoms and 1 O or S atom, and 9-membered heteroaryls, consisting of a 5-membered ring fused to a 6-membered ring and containing 1 to 4 N atoms, wherein the said heteroaryls are attached to the carbonyl group via a C atom of the 5-membered ring and to the CH₂ group via a nonadjacent C or N atom of the 5-membered ring, and wherein the said heteroaryls are optionally substituted with 1 substituent R₃.

Key Structures

Biological Assay

The plasma kallikrein (PKK) end point assay was performed. The compounds described in this application were tested for their ability to inhibit PKK. The PKK IC₅₀ (nM) are shown in the following table.

Biological Data

The table below shows representative compounds were tested for PKK inhibition. The biological data obtained from testing representative examples are listed in the following table.

Claims

Total claims: 15

Compound claims: 11

Composition claims: 3

Method of treating claims: 1

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The author declares no competing financial interest.