N-(hetero)aryl-pyrrolidine JAK1 Inhibitors

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Solution Overview

Problem

Current treatments for inflammatory and autoimmune diseases, as well as cancer, lack effective Janus Kinase (JAK) inhibitors, necessitating the development of new compounds that can selectively inhibit JAK1 to provide therapeutic benefits.

Innovation Solution

Development of N-(hetero)aryl-pyrrolidine derivatives that act as selective JAK1 inhibitors, capable of modulating JAK1 activity and treating associated diseases by administering a therapeutically effective amount of these compounds.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If current treatments are used for inflammatory and autoimmune diseases, then existing therapy options are available, but effective JAK inhibition is lacking

Engineering Contradiction:

Improvetherapeutic effectivenessVSAvoidJAK inhibition capability

Core Design Contradiction:

ReliabilityVSAdaptability or versatility

Solution Approach 1:

The patent modifies molecular parameters by developing compounds with specific chemical structures (Formula I) that contain pyrrolidine derivatives linked to heteroaryl groups. These structural parameter changes enable selective binding to JAK1 kinase, providing effective JAK inhibition that was lacking in current treatments.

Inventive Principle:

Principle #35Parameter changes

2Adaptability or versatility

If selective JAK1 inhibitors are developed, then therapeutic benefits for autoimmune diseases are provided, but new compound development is required

Engineering Contradiction:

Improveselective JAK1 inhibitionVSAvoidcompound development complexity

Core Design Contradiction:

Adaptability or versatilityVSEase of manufacture

Solution Approach 1:

The patent segments the JAK inhibitor development into specific modular components: a pyrrolidine core structure (Formula I) with variable substituents R1-R6. This segmentation allows systematic optimization of selectivity while maintaining a manageable development framework, reducing overall complexity.

Inventive Principle:

Principle #1Segmentation

Solution Approach 2:

The patent applies local quality by introducing specific functional groups at defined positions on the pyrrolidine ring (R1-R6 substituents). Each substituent position can be independently optimized to enhance JAK1 selectivity, allowing precise control over binding properties without redesigning the entire molecule.

Inventive Principle:

Principle #3Local quality

3Reliability

If JAK1 activity is modulated to treat diseases, then therapeutic benefits are achieved, but effective inhibitors must be identified

Engineering Contradiction:

Improvedisease treatment efficacyVSAvoidinhibitor identification process

Core Design Contradiction:

ReliabilityVSDevice complexity

Solution Approach 1:

The patent performs preliminary action by pre-designing compounds with Formula I structure that incorporates pharmacophore elements known to interact with JAK1 kinase. This preliminary structural design based on kinase binding principles reduces the complexity of identifying effective inhibitors, as the core binding framework is established beforehand.

Inventive Principle:

Principle #10Preliminary action

Data Source

PatentUS9334274B2N-(hetero)aryl-pyrrolidine derivatives of pyrazol-4-yl-pyrrolo[2,3-d]pyrimidines and pyrrol-3-yl-pyrrolo[2,3-d]pyrimidines as janus kinase inhibitors

Publication Date: 2016.05.10 INCYTE HLDG & INCYTE

AI summary

The present invention relates to N-(hetero)aryl-pyrrolidine derivatives of Formula I:which are JAK inhibitors, such as selective JAK1 inhibitors, useful in the treatment of JAK-associated diseases including, for example, inflammatory and autoimmune disorders, as well as cancer.