Heteroaromatic macrocyclic ether chemotherapeutic agents

Inventors

Horan, Joshua Courtney • Tang, Xinxing • MENTE, SCOT RICHARD • Pelish, Henry Efrem • Shair, Matthew D. • Tangpeerachaikul, Anupong

Assignees

Pharmaresources Co Ltd • Nuvalent Inc

Abstract

Disclosed are heterocyclic heteroaromatic macrocyclic ether compounds of Formula (I): pharmaceutically acceptable salts of the compounds and pharmaceutical compositions thereof. The disclosure further relates to methods of treating or preventing cancer using the heterocyclic heteroaromatic macrocyclic ether compounds, pharmaceutically acceptable salts of the compounds and pharmaceutical compositions thereof.

Core Innovation

The invention relates to compounds of Formula (I) and Formula (I-B), including pharmaceutically acceptable salts, enantiomers, and tautomers. The compounds are defined by a fixed core scaffold in which Q is CH, Z is CR5, and R5 is H or F, together with X and Y defined by connection points to the —CH2— groups. The substituent framework is constrained by enumerated options for R1, each R2, R3, and R4, thereby defining a restricted chemical series with controlled substitution.

The disclosure further describes substituted heteroaryl and halogenated intermediates and example compounds within the claimed chemical space. The examples include pyrazole, triazole, isoxazole, pyridine, and other heteroaromatic motifs, with halogen substituents such as F, Cl, Br, and I, and with representative compound characterization by LC/MS (ESI) m/z values, yields, and other analytical data. Specific embodiments also include chiral, deuterated, and fused polycyclic heteroaromatic structures.

The provided content additionally presents advanced intermediates and exemplified structures that support the claimed Formula (I)/(I-B) scope. These disclosed members include substituted heteroaryl methanols, aldehydes, acetamides, azidomethyl analogs, chloromethyl derivatives, and other heteroaryl-linked scaffolds, as well as polycyclic heteroaromatic examples with varying ring heteroatoms and substituent patterns. The overall disclosure combines structurally defined compound families with concrete example compounds and analytical characterization.

Claims Coverage

The independent claims are directed to compounds of Formula (I) and Formula (I-B). Together, they define two structurally constrained compound families built around the same core variable definitions and enumerate the allowed substituents for X, Y, and R1 through R5; Formula (I) also includes enantiomers and tautomers, while both include pharmaceutically acceptable salts. The independent claims collectively present two main inventive features for each formula: the core scaffold definition and the substituted-variable definition.

The claims define a tightly constrained chemical series by fixing Q as CH and Z as CR5 with R5 limited to H or F, specifying the X/Y connection pattern through —CH2— groups, and enumerating the allowable substituents for R1, R2, R3, and R4. Formula (I) additionally covers enantiomers and tautomers, while both formulas cover pharmaceutically acceptable salts.

Stated Advantages

Documented Applications