US 12,030,869 B2
5-membered heteroaryl carboxamide compounds for treatment of HBV
Simon Nicolas Haydar, South San Francisco, CA (US); Leping Li, South San Francisco, CA (US); Mark G. Bures, South San Francisco, CA (US); Roopa Rai, South San Francisco, CA (US); Lynne Bannen, South San Francisco, CA (US); and Michael Walker, South San Francisco, CA (US)
Assigned to ASSEMBLY BIOSCIENCES, INC., South San Francisco, CA (US)
Filed by Assembly Biosciences, Inc., South San Francisco, CA (US)
Filed on Nov. 17, 2022, as Appl. No. 17/989,237.
Application 17/989,237 is a continuation of application No. 17/287,681, granted, now 11,560,370, previously published as PCT/US2019/057362, filed on Oct. 22, 2019.
Claims priority of provisional application 62/858,790, filed on Jun. 7, 2019.
Claims priority of provisional application 62/748,906, filed on Oct. 22, 2018.
Prior Publication US 2024/0150324 A1, May 9, 2024
Int. Cl. C07D 231/38 (2006.01); A61P 31/20 (2006.01); C07D 401/08 (2006.01); C07D 403/04 (2006.01); C07D 403/08 (2006.01); C07D 403/10 (2006.01); C07D 403/12 (2006.01); C07D 405/04 (2006.01); C07D 413/04 (2006.01); C07D 413/08 (2006.01); C07D 417/08 (2006.01)
CPC C07D 403/08 (2013.01) [A61P 31/20 (2018.01); C07D 231/38 (2013.01); C07D 401/08 (2013.01); C07D 403/04 (2013.01); C07D 403/10 (2013.01); C07D 403/12 (2013.01); C07D 405/04 (2013.01); C07D 413/04 (2013.01); C07D 413/08 (2013.01); C07D 417/08 (2013.01)] 5 Claims
 
1. A method for synthesizing a compound (VI-5)

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or a pharmaceutically acceptable salt thereof,
wherein
Ar is optionally substituted phenyl; and
R is alkyl;
the method comprising:
a) condensing a carboxylic acid ester or chloride (I-1) with a compound of formula (I-2) to yield intermediate (I-3);

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wherein
R1 is alkyl or aryl; and
Z is Cl or OAlkyl;
b) treating intermediate (I-3) with an alkylhalide (I-4) to yield intermediate (I-5);

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wherein
R3 is alkyl; and
X is halogen;
c) treating intermediate (I-5) with hydrazide (I-6) to yield a 5-amino pyrazole template intermediate (I-7);

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wherein
R4 is alkyl;
d) brominating and treating intermediate (I-7) with ArNH2 to effect an ester/amide exchange to yield a bromo-pyrazole intermediate (II-3);

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e) selectively modifying diketone (IV-1) to yield boronate ester (IV-3);

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f) coupling bromo-pyrazole intermediate (II-3) with boronate ester (IV-3) to yield intermediate (IV-4);

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g) reducing intermediate (IV-4) to yield intermediate (IV-5);

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and
either
h) converting ketone intermediate (IV-5) to epoxide (VI-1);

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transforming epoxide (VI-1) to with a nucleophile RSH to form sulfide (VI-3);

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and
modifying sulfide (VI-3) to yield target sulfone (VI-5);

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or
i) reacting ketone intermediate (IV-5) with a corresponding anion of sulfone, —SO2R, to yield target sulfone (VI-5)

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