Aryl Sultam Derivatives as RORγ Modulators

Solution Overview

Problem

Current treatments for autoimmune diseases such as rheumatoid arthritis, psoriasis, and irritable bowel disease lack effective modulation of RORγ, a key transcription factor for Th17 cell differentiation, leading to inadequate therapeutic outcomes.

Innovation Solution

Development of compounds with specific heteroaryl or heterocyclyl substituents that selectively target RORγ, improving selectivity over other receptor subtypes and enhancing therapeutic properties.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If current treatments for autoimmune diseases are used, then general symptom management is achieved, but effective modulation of RORγ and Th17 cell differentiation is not achieved

Engineering Contradiction:

Improvetherapeutic efficacyVSAvoidselectivity for RORγ

Core Design Contradiction:

ReliabilityVSAdaptability or versatility

Solution Approach 1:

The patent introduces specific heteroaryl or heterocyclyl substituents at the Z position of the sultam core structure to create localized chemical features that selectively interact with RORγ. This local modification enhances binding selectivity for RORγ over other receptor subtypes while maintaining the overall therapeutic function of modulating Th17 cell differentiation

Inventive Principle:

Principle #3Local quality

Solution Approach 2:

The patent systematically varies chemical parameters including the type of heteroaryl/heterocyclyl group, the length and composition of linker A, and the substitution patterns on the sultam core to optimize both binding affinity for RORγ and selectivity over other receptors, thereby achieving improved therapeutic efficacy with specific molecular characteristics

Inventive Principle:

Principle #35Parameter changes

2Device complexity

If compounds without heteroaryl or heterocyclyl substituent at group Z are used, then simpler structure is achieved, but selectivity for RORγ over other receptor subtypes is reduced

Engineering Contradiction:

Improvemolecular structure complexityVSAvoidselectivity for RORγ

Core Design Contradiction:

Device complexityVSReliability

Solution Approach 1:

The patent introduces specific heteroaryl or heterocyclyl substituents at the Z position of the sultam core structure to create localized chemical features that selectively interact with RORγ. This local modification enhances binding selectivity for RORγ over other receptor subtypes while maintaining the overall therapeutic function of modulating Th17 cell differentiation

Inventive Principle:

Principle #3Local quality

Solution Approach 2:

The patent creates composite molecular structures by combining the sultam core with heteroaryl or heterocyclyl moieties through linker A, forming a hybrid structure that integrates the pharmacophore elements necessary for RORγ selectivity and affinity, thereby achieving enhanced therapeutic properties through structural composition

Inventive Principle:

Principle #40Composite materials

Data Source

PatentEP3319962B1Aryl sultam derivatives as rorc modulators

Publication Date: 2020.05.13 F HOFFMANN LA ROCHE & CO AG

AI summary

Compounds of the formula I, or pharmaceutically acceptable salts thereof, wherein m, n, p, q, r, X1, X2, X3, X4, Y, Z, A, Het, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12 and R13 are as defined herein.. Also disclosed are methods of making the compounds and using the compounds for treatment of inflammatory diseases such as arthritis, muscular sclerosis and psoriasis.