Cardiac sarcomere inhibitors

Inventors

Chuang, Chihyuan • Morgan, Bradley P. • VANDERWAL, Mark • Ashcraft, Luke W. • Lau, Kevin

Assignees

Cytokinetics Inc

Abstract

Provided are compounds of Formula (I): or a pharmaceutically acceptable salt thereof, wherein R1, R2A, R2B, R3, R4, and R5 are as defined herein. Also provided is a pharmaceutically acceptable composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof. Also provided are methods of using a compound of Formula (I), or a pharmaceutically acceptable salt thereof.

Core Innovation

The invention concerns a method of preparing a compound of formula (1b-10) or a salt thereof by reacting a compound of formula (1b-1) or a salt thereof with a compound of formula (1b-2) or a salt thereof to form a compound of formula (1b-3) or a salt thereof, and converting the compound of formula (1b-3) or salt thereof to the compound of formula (1b-10) or salt thereof. The compounds are characterized by variable substituent groups R1, R2a, R3, R4, R5, n, and Alk1, with R1 selected from substituted or unsubstituted phenyl or substituted or unsubstituted pyridyl and R2a selected from substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted aminoacyl, substituted or unsubstituted aminothionyl, substituted or unsubstituted acyl, substituted or unsubstituted aminosulfonyl, substituted or unsubstituted aminocarbonylamino, substituted or unsubstituted alkyl, substituted or unsubstituted pyridin-one-yl, substituted or unsubstituted pyridazin-one-yl, substituted or unsubstituted 9-membered bicyclic heterocyclyl, and hydroxyl.

The disclosed subject matter concerns substituted spirocyclic and piperazine-2,5-dione derivatives and related structures, including triazaspiro, diazaspiro[3.5]nonane, diazaspiro[4.5]decane, and triazaspiro[3.5]nonane-6,9-dione scaffolds. The compounds are presented with stereochemical variants and with substituents such as 5-chloro-3-fluoropyridin-2-yl, 5-chloro-3-methylpyridin-2-yl, 4-chlorobenzyl, 4-methylbenzyl, 4-fluorobenzyl, 4-(trifluoromethyl)benzyl, 4-(difluoromethyl)benzyl, benzonitrile, oxadiazolyl, pyridazinyl, pyrimidinyl, pyrazolyl, thiazolyl, morpholine-4-carbonyl, azetidine-1-carbonyl, oxetanyl, cyclobutyl, and hydroxyethyl groups. The disclosure also includes enumerated compound examples and structure images for multiple numbered compounds and intermediates.

The disclosed preparation approach is a two-stage method in which a compound of formula (1b-1) is reacted with a compound of formula (1b-2) to form an intermediate of formula (1b-3), followed by conversion of the intermediate to a compound of formula (1b-10). Dependent refinements mention additional intermediates and conversion sequences, including acid-mediated conversion via formula (1b-8), named reagents such as sodium triacetoxyborohydride and TFA, and process constraints such as a temperature threshold of 80°C or higher. The description also references multiple synthetic schemes, enantiomer separation, and characterization data such as LRMS and 1H NMR.

Claims Coverage

The consolidated claim coverage includes one independent method claim for preparing compounds of formula (1b-10) via formula (1b-3), and two independent compound claims for formulas (1b-7) and (1b-8). Overall, the inventive scope centers on a two-stage preparation sequence and structural limitations on R1, R2a, R3, R4, R5, n, and Alk1, with five inventive feature groups.

The claims collectively define a method that forms an intermediate of formula (1b-3) from formula (1b-1) and formula (1b-2) and converts it to formula (1b-10), together with compound classes for formulas (1b-7) and (1b-8) limited by enumerated substituent sets for R1, R2a, R3, R4, R5, n, and Alk1. Dependent refinements further mention specific reagents, an acid-mediated conversion via formula (1b-8), and a temperature threshold.

Stated Advantages

Documented Applications