5-membered heteroaryl carboxamide compounds for treatment of HBV
Inventors
Haydar, Simon Nicolas • Li, Leping • Bures, Mark G. • Rai, Roopa • Bannen, Lynne • Walker, Michael
Assignees
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Publication Number
US-12030869-B2
Publication Date
2024-07-09
Expiration Date
Abstract
The present disclosure provides, in part, 5-membered heteroaryl carboxamide compounds, and pharmaceutical compositions thereof, useful for disruption of HBV core protein assembly, and methods of treating Hepatitis B (HBV) infection.
Core Innovation
The invention relates to a method for synthesizing compound (VI-5) or a pharmaceutically acceptable salt thereof through a multi-step sequence that forms and transforms intermediates including (I-3), (I-5), (I-7), (II-3), (IV-3), (IV-4), and (IV-5). The method includes condensing a carboxylic acid ester or chloride (I-1) with a compound of formula (I-2), treating intermediate (I-3) with an alkylhalide (I-4), and treating intermediate (I-5) with hydrazide (I-6) to yield a 5-amino pyrazole template intermediate (I-7).
The method further includes brominating and treating intermediate (I-7) with ArNH2 to effect an ester/amide exchange to yield a bromo-pyrazole intermediate (II-3). It also includes selectively modifying diketone (IV-1) to yield boronate ester (IV-3), coupling bromo-pyrazole intermediate (II-3) with boronate ester (IV-3) to yield intermediate (IV-4), and reducing intermediate (IV-4) to yield intermediate (IV-5).
From intermediate (IV-5), the method proceeds by either converting ketone intermediate (IV-5) to epoxide (VI-1), transforming epoxide (VI-1) to sulfide (VI-3) with a nucleophile RSH, and modifying sulfide (VI-3) to yield target sulfone (VI-5), or by reacting ketone intermediate (IV-5) with a corresponding anion of sulfone, SO2R, to yield target sulfone (VI-5). The disclosed content also states that the compounds of Formula I are 5-membered heteroaryl carboxamides and relates the compounds and pharmaceutical compositions to hepatitis B treatment by disrupting HBV core protein assembly into HBV capsid/core protein (Cp).
Claims Coverage
The supplied claims center on one independent method claim for synthesizing compound (VI-5) or a pharmaceutically acceptable salt thereof, with a total of eight inventive features merged from the provided items. Dependent claims refine substituent definitions for Ar, R1, R3, and R4, and identify the specific structure of compound (VI-5).
Multi-step synthesis of compound (VI-5) or pharmaceutically acceptable salt
A method for synthesizing a compound (VI-5) or a pharmaceutically acceptable salt thereof by condensing a carboxylic acid ester or chloride (I-1) with a compound of formula (I-2) to yield intermediate (I-3), treating intermediate (I-3) with an alkylhalide (I-4) to yield intermediate (I-5), treating intermediate (I-5) with hydrazide (I-6) to yield a 5-amino pyrazole template intermediate (I-7), brominating and treating intermediate (I-7) with ArNH2 to effect an ester/amide exchange to yield a bromo-pyrazole intermediate (II-3), selectively modifying diketone (IV-1) to yield boronate ester (IV-3), coupling bromo-pyrazole intermediate (II-3) with boronate ester (IV-3) to yield intermediate (IV-4), reducing intermediate (IV-4) to yield intermediate (IV-5), and either converting ketone intermediate (IV-5) to epoxide (VI-1), transforming epoxide (VI-1) to sulfide (VI-3) with a nucleophile RSH, and modifying sulfide (VI-3) to yield target sulfone (VI-5), or reacting ketone intermediate (IV-5) with a corresponding anion of sulfone, SO2R, to yield target sulfone (VI-5).
Condensation and alkylhalide treatment to form intermediate sequence
Condensing a carboxylic acid ester or chloride (I-1) with a compound of formula (I-2) to yield intermediate (I-3), then treating intermediate (I-3) with an alkylhalide (I-4) to yield intermediate (I-5); wherein R1 is alkyl or aryl, Z is Cl or OAlkyl, R3 is alkyl, and X is halogen.
Hydrazide treatment to form a 5-amino pyrazole template
Treating intermediate (I-5) with hydrazide (I-6) to yield a 5-amino pyrazole template intermediate (I-7), wherein R4 is alkyl.
Bromination and ArNH2 ester/amide exchange to yield a bromo-pyrazole intermediate
Brominating and treating intermediate (I-7) with ArNH2 to effect an ester/amide exchange to yield a bromo-pyrazole intermediate (II-3), wherein Ar is optionally substituted phenyl and is further refined as a substituted aryl group bearing chloro and fluoro, or a phenyl group substituted with chloro and fluoro.
Selective diketone modification to boronate ester
Selectively modifying diketone (IV-1) to yield boronate ester (IV-3).
Coupling of bromo-pyrazole intermediate with boronate ester
Coupling bromo-pyrazole intermediate (II-3) with boronate ester (IV-3) to yield intermediate (IV-4), followed by reducing intermediate (IV-4) to yield intermediate (IV-5).
Epoxide-to-sulfide-to-sulfone route
Converting ketone intermediate (IV-5) to epoxide (VI-1), transforming epoxide (VI-1) to sulfide (VI-3) with a nucleophile RSH, and modifying sulfide (VI-3) to yield target sulfone (VI-5); wherein R is alkyl and is further refined as methyl.
Direct sulfone anion route
Reacting ketone intermediate (IV-5) with a corresponding anion of sulfone, SO2R, to yield target sulfone (VI-5), with the compound of formula (VI-5) identified as the specific shown compound structure.
The claims define a multi-step synthesis that builds a 5-amino pyrazole template, converts it to a bromo-pyrazole intermediate, couples it with a diketone-derived boronate ester, reduces to a ketone intermediate, and forms the target sulfone (VI-5) by either an epoxide-to-sulfide-to-sulfone sequence or a direct reaction with a sulfone anion. Dependent claims narrow substituent scope for Ar, R1, R3, and R4 and specify the target structure.
Stated Advantages
Disrupting HBV core protein assembly into HBV capsid/core protein (Cp).
Documented Applications
Hepatitis B (HBV) treatment.
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