US 12,655,130 B2Granted

5-membered heteroaryl carboxamide compounds for treatment of HBV

AssigneeAssembly Biosciences, Inc.

InventorsThilo Heckrodt, Michael Walker, Min Zhong

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Abstract

The present disclosure relates to 5-membered heteroaryl carboxamide compounds, which may disrupt Hepatitis B (HBV) core protein assembly. The present disclosure further relates to pharmaceutical compositions comprising 5-membered heteroaryl carboxamide compounds which may disrupt HBV core protein assembly. The present disclosure further relates to uses of 5-membered heteroaryl carboxamide compounds and pharmaceutical compositions thereof in methods of treating Hepatitis B (HBV) infection.

Claims32

Dependent claims

A compound of Formula I

or a pharmaceutically acceptable salt thereof, wherein:
L is C1-4alkylene or haloC1-4alkylene;
L1 is a bond, C1-6alkylene, O, NRc, C(O), C(O)O, C(O)NRc, S(O)t or S(O)tNRc;
X1 is NRx1;
X3 is CR4R8;
Ra, Rb and Rc are independently selected for each occurrence from the group consisting of hydrogen, C1-6 alkyl, haloC1-6 alkyl and C3-6 monocycloalkyl;
Rd is hydrogen, OH, C1-6 alkyl or C1-6 alkoxy;
Rx1 is hydrogen, C1-4 alkyl, C1-4 alkenyl, C1-4 alkynyl, haloC1-4 alkyl, or C3-6 monocycloalkyl;
or Rx1 and R2 together form a —CH2CH2CH2—, —CH2CH2CH2CH2—, —CH2CH2O—, —CH2OCH2—, —CH2CH2CH2O— —CH2CH2OCH2—, —CH2CH2—NH— —CH2NHCH2—, —CH2CH2CH2NH— or —CH2CH2NHCH2— group;
R0a is independently selected for each occurrence from the group consisting of hydrogen, halogen, OH, CN, NO2, RaRbN—, C1-4alkyl and haloC1-4alkyl;
R6a are independently hydrogen or C1-4 alkyl;
R0, R6 are independently selected for each occurrence from the group consisting of hydrogen, halogen, OH, CN, NO2, oxo, RdN═, hydrazino, formyl, azido, silyl, siloxy, HOC(O)—, RaRbN—, RaRbNS(O)t—, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, haloC1-6alkyl, hydroxyC1-6alkyl-, RaRbNC1-6alkyl-, HOC(O)C1-6alkyl-, RaRbNC1-6alkylNRc—, C1-6alkylNRaC1-6alkylNRc—, C1-6alkoxy, haloC1-6alkoxy, hydroxyC1-6alkoxy-, RaRbNC1-6alkoxy-, C1-6alkoxyC1-6alkyl-, haloC1-6alkoxyC1-6alkyl-, RaRbNC(O)—, C1-6alkylC(O)—, C1-6alkoxyC(O)—, C1-6alkylC(O)O—, C1-6alkylS(O)q—, C1-6alkylS(O)tNRc—, C1-6alkylS(O)tC1-6alkyl-, C1-6alkylS(O)tNRaC1-6alkyl-, C3-6cycloalkylS(O)tC1-6alkyl-, C1-6alkylC(O)C1-6alkyl-, and C1-6alkylC(O)OC1-6alkyl-;
each R11 independently is hydrogen, OH, CN, NO2, C1-6 alkyl, haloC1-6alkyl, HOC(O)—, HOC(O)C1-6alkyl, RaRbN—, C2-6alkenyl, C2-6alkynyl, C1-6alkoxy, haloC1-6alkoxy, or C1-6alkoxy;
R1 is a phenyl or 5-6 membered monocyclic heteroaryl, wherein the phenyl or 5-6 membered monocyclic heteroaryl is optionally substituted with one, two, or three independently selected R11 groups;
R2 is selected from the group consisting of hydrogen, halo, CN, OH, RaRbN, C1-4alkyl, haloC1-4alkyl, C3-5monocycloalkyl, C1-4alkoxy, and haloC1-4alkoxy;
R8 is selected from the group consisting of hydrogen, halo, CN, OH, RaRbN, C1-4alkyl, haloC1-4alkyl, C3-5monocycloalkyl, C1-6alkoxy, and haloC1-4alkoxy;
R3 is
R4 is R5-L1-, R6 or R9;
R5 is
R9 is R14S(O)q-L-, R14S(O)qNH-L-, or R14C(O)NH-L-;
R14 is RaRbN—, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkyl, C1-6haloalkoxy, or R5-L1-;
q, r, t, and w are independently selected for each occurrence from 0, 1 and 2.

19 more elements

A compound, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:

Example
No.
Name/Structure
Example 1
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Example
N-(3-Chloro-4-fluorophenyl)-4-(5-hydroxy-5-
68
(3-((1-hydroxypropan-2-yl)oxy)-1-methyl-1H-
pyrazol-5-yl)octahydropentalen-2-y1)-1-
methyl-1H-imidazole-5-carboxamide,
Example 70
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Example 220
Example 221
Example 222
Example 223

219 more elements

Dependencies are inferred from the claim text.

Facts

Application: 17/920,544Filed 21 Apr 2021 · us provisional application
Priority: 22 Apr 2020
Published: US 2023/0183213 A115 Jun 2023
Granted: 16 Jun 2026
Term ends: Not estimatedThe source records don’t support an estimate.

Classification14 codes

A61P 31/12
Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics: antivirals
C07D 403/08
Containing two hetero rings: linked by a carbon chain containing alicyclic rings
A61P 31/20
Antivirals: for DNA viruses
C07D 233/90
With hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals,…:…

Family

Application63/014,001Us provisional application · filed 22 Apr 2020
US 2023/0183213 A1Pre-grant publication · published 15 Jun 2023
US 12,655,130 B2This patent

From the US filing history. Foreign family members aren’t listed.

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Abstract

A compound of Formula I

or a pharmaceutically acceptable salt thereof, wherein:
L is C1-4alkylene or haloC1-4alkylene;
L1 is a bond, C1-6alkylene, O, NRc, C(O), C(O)O, C(O)NRc, S(O)t or S(O)tNRc;
X1 is NRx1;
X3 is CR4R8;
Ra, Rb and Rc are independently selected for each occurrence from the group consisting of hydrogen, C1-6 alkyl, haloC1-6 alkyl and C3-6 monocycloalkyl;
Rd is hydrogen, OH, C1-6 alkyl or C1-6 alkoxy;
Rx1 is hydrogen, C1-4 alkyl, C1-4 alkenyl, C1-4 alkynyl, haloC1-4 alkyl, or C3-6 monocycloalkyl;
or Rx1 and R2 together form a —CH2CH2CH2—, —CH2CH2CH2CH2—, —CH2CH2O—, —CH2OCH2—, —CH2CH2CH2O— —CH2CH2OCH2—, —CH2CH2—NH— —CH2NHCH2—, —CH2CH2CH2NH— or —CH2CH2NHCH2— group;
R0a is independently selected for each occurrence from the group consisting of hydrogen, halogen, OH, CN, NO2, RaRbN—, C1-4alkyl and haloC1-4alkyl;
R6a are independently hydrogen or C1-4 alkyl;
R0, R6 are independently selected for each occurrence from the group consisting of hydrogen, halogen, OH, CN, NO2, oxo, RdN═, hydrazino, formyl, azido, silyl, siloxy, HOC(O)—, RaRbN—, RaRbNS(O)t—, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, haloC1-6alkyl, hydroxyC1-6alkyl-, RaRbNC1-6alkyl-, HOC(O)C1-6alkyl-, RaRbNC1-6alkylNRc—, C1-6alkylNRaC1-6alkylNRc—, C1-6alkoxy, haloC1-6alkoxy, hydroxyC1-6alkoxy-, RaRbNC1-6alkoxy-, C1-6alkoxyC1-6alkyl-, haloC1-6alkoxyC1-6alkyl-, RaRbNC(O)—, C1-6alkylC(O)—, C1-6alkoxyC(O)—, C1-6alkylC(O)O—, C1-6alkylS(O)q—, C1-6alkylS(O)tNRc—, C1-6alkylS(O)tC1-6alkyl-, C1-6alkylS(O)tNRaC1-6alkyl-, C3-6cycloalkylS(O)tC1-6alkyl-, C1-6alkylC(O)C1-6alkyl-, and C1-6alkylC(O)OC1-6alkyl-;
each R11 independently is hydrogen, OH, CN, NO2, C1-6 alkyl, haloC1-6alkyl, HOC(O)—, HOC(O)C1-6alkyl, RaRbN—, C2-6alkenyl, C2-6alkynyl, C1-6alkoxy, haloC1-6alkoxy, or C1-6alkoxy;
R1 is a phenyl or 5-6 membered monocyclic heteroaryl, wherein the phenyl or 5-6 membered monocyclic heteroaryl is optionally substituted with one, two, or three independently selected R11 groups;
R2 is selected from the group consisting of hydrogen, halo, CN, OH, RaRbN, C1-4alkyl, haloC1-4alkyl, C3-5monocycloalkyl, C1-4alkoxy, and haloC1-4alkoxy;
R8 is selected from the group consisting of hydrogen, halo, CN, OH, RaRbN, C1-4alkyl, haloC1-4alkyl, C3-5monocycloalkyl, C1-6alkoxy, and haloC1-4alkoxy;
R3 is
R4 is R5-L1-, R6 or R9;
R5 is
R9 is R14S(O)q-L-, R14S(O)qNH-L-, or R14C(O)NH-L-;
R14 is RaRbN—, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkyl, C1-6haloalkoxy, or R5-L1-;
q, r, t, and w are independently selected for each occurrence from 0, 1 and 2.

19 more elements

Facts

Application

17/920,544Filed 21 Apr 2021 · us provisional application

Priority

22 Apr 2020

Published

US 2023/0183213 A115 Jun 2023

Granted

16 Jun 2026

Term ends

Not estimatedThe source records don’t support an estimate.

Classification14 codes

A61P 31/12
Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics: antivirals
C07D 403/08
Containing two hetero rings: linked by a carbon chain containing alicyclic rings
A61P 31/20
Antivirals: for DNA viruses
C07D 233/90
With hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals,…:…