Processes and intermediates for the preparation of soluble guanylate cyclase stimulators

Inventors

Wallace, Debra Jane • Zhou, Fenger • Wang, Yuguang • Nakai, Takashi • Karnati, Vishnu Vardhan Reddy • Schairer, Wayne C. • Kissel, William • Xue, Song • Hashash, Ahmad

Assignees

Cyclerion Therapeutics Inc

Abstract

The present disclosure relates to novel processes for the preparation of compounds of Formula I. Some of these compounds are useful as stimulators of soluble guanylate cyclase (sGC). Others are useful intermediates towards the preparation of said stimulators. These processes are amenable to large scale preparation and produce stable 3-(2-pyrimidinyl) pyrazoles of Formula I in high purity and yields. The present invention has the additional advantage of facile reaction conditions, amenable to scale up for large scale manufacturing. The disclosure also provides novel intermediates useful in the preparation of said compounds.

Core Innovation

The invention relates to compounds of formula (3) or (4), including alternative labeled structural formulas (3′) or (4′), wherein R1 is phenyl or a 5 to 6-membered heteroaryl ring optionally substituted with up to three instances independently selected from halogen or methyl. The 5 or 6-membered heteroaryl ring contains up to 3 ring atoms selected from N, S or O. The document also provides explicit chemical structures for intermediates and formula definitions used to define the resulting compounds.

A multi-step transformation is described in which an amide of formula (1′) is coupled with a pyrimidine of formula (2) to yield intermediate (3′), and the intermediate is converted at pH>5 to intermediate (4′). The conversion may involve N,O-dimethylhydroxylamine salt. Intermediate (4′) is further processed by condensation with hydrazine to form a compound that proceeds through formation of Formula V and demethylation to give an alcohol (9′).

The sequence continues with chlorination to produce Formula VI, where leaving group variants are indicated as X = halogen/sulfonate. Multiple explicit chemical structures are shown for intermediates (3′, 4′), Formula V, alcohol (9′), and Formula VI, including the structural options relevant to the demethylation and chlorination stages.

Claims Coverage

The independent claim defines compounds of formula (3) or (4) with R1 as phenyl or an optionally substituted 5 to 6-membered heteroaryl ring, and dependent claims further narrow this scope to specific five-membered heteroaryl embodiments and alternative labeled structural representations. A total of four inventive features are identified across the consolidated claims coverage.

Overall claim coverage centers on compounds defined by formula (3) or (4), with R1 limited to phenyl or a constrained heteroaryl ring with bounded halogen or methyl substitution and bounded ring heteroatoms. Additional coverage is provided by dependent refinements to a five-membered heteroaryl, an unsubstituted five-membered heteroaryl with up to two N/O ring heteroatoms, and alternative representations using formulas (3′) or (4′).

Stated Advantages

Documented Applications