Heterobicyclic Carboxamides for ROCK and JAK Kinase Modulation

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Solution Overview

Problem

There is a need for small molecule ligands that can effectively inhibit or modulate the activity of kinases, particularly ROCK and JAK kinases, to address various disease states including inflammatory diseases, glaucoma, retinal diseases, cardiovascular diseases, and cancers, as existing treatments face challenges with receptor desensitization and inadequate control of disease conditions.

Innovation Solution

Development of heterobicyclic cyclopropanecarboxamide compounds that target kinases, specifically ROCK and JAK kinases, to modulate their activity and provide therapeutic benefits.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If existing kinase inhibitors are used to treat diseases, then disease symptoms can be addressed, but receptor desensitization occurs leading to inadequate control of disease conditions

Engineering Contradiction:

Improvedisease control effectivenessVSAvoidreceptor responsiveness duration

Core Design Contradiction:

ReliabilityVSDuration of action of moving object

Solution Approach 1:

The patent modifies the chemical structure of kinase inhibitors by introducing specific heterobicyclic rings and substituents (R1-R9 groups) to change the binding parameters and pharmacological properties, thereby improving efficacy while reducing desensitization effects

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The invention creates composite molecular structures combining heterobicyclic rings with cyclopropanecarboxamide groups, forming novel compounds that simultaneously target multiple kinase pathways (ROCK and JAK) to achieve better disease control without rapid receptor desensitization

Inventive Principle:

Principle #40Composite materials

2Adaptability or versatility

If small molecule ligands are developed to target multiple kinases, then broader disease coverage is achieved, but compound complexity increases

Engineering Contradiction:

Improvekinase targeting coverageVSAvoidmolecular structure complexity

Core Design Contradiction:

Adaptability or versatilityVSDevice complexity

Solution Approach 1:

The patent designs heterobicyclic cyclopropanecarboxamide compounds that can simultaneously inhibit multiple kinase families (ROCK1, ROCK2, JAK1, JAK2, JAK3, TYK2), allowing a single compound to address multiple disease conditions including inflammatory diseases, glaucoma, retinal diseases, cardiovascular diseases, and cancers

Inventive Principle:

Principle #6Universality (Multi-functionality)

Solution Approach 2:

The molecular structure is segmented into distinct functional modules: the heterobicyclic ring system (providing kinase binding), the cyclopropanecarboxamide group (providing additional interactions), and variable substituents (R1-R9) that can be optimized for specific kinase targets, allowing systematic design of multi-functional inhibitors

Inventive Principle:

Principle #1Segmentation

Data Source

PatentUS12459956B2Heterobicyclic carboxamides and uses thereof

Publication Date: 2025.11.04 ALCON INC

AI summary

Provided herein are heterobicyclic cyclopropanecarboxamide and heterobicyclic carboxamide compounds. In particular, provided herein are compounds that affect the function of kinases in a cell, and that are useful as therapeutic agents or with therapeutic agents. The compounds provided herein are useful in the treatment of a variety of diseases and conditions including eye diseases such as glaucoma, cardiovascular diseases, inflammatory diseases, and diseases characterized by abnormal growth, such as cancers. Also provided herein are compositions comprising heterobicyclic cyclopropanecarboxamide or heterobicyclic carboxamide compounds.