5-membered heteroaryl carboxamide compounds for treatment of HBV
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.
1 . A compound of Formula I
or a pharmaceutically acceptable salt thereof, wherein:
L is C 1-4 alkylene or haloC 1-4 alkylene;
L 1 is a bond, C 1-6 alkylene, O, NR c , C(O), C(O)O, C(O)NR c , S(O) t or S(O) t NR c ;
X 1 is NR x1 ;
X 3 is CR 4 R 8 ;
R a , R b and R c are independently selected for each occurrence from the group consisting of hydrogen, C 1-6 alkyl, haloC 1-6 alkyl and C 3-6 monocycloalkyl;
R d is hydrogen, OH, C 1-6 alkyl or C 1-6 alkoxy;
R x1 is hydrogen, C 1-4 alkyl, C 1-4 alkenyl, C 1-4 alkynyl, haloC 1-4 alkyl, or C 3-6 monocycloalkyl; or R x1 and R 2 together form a —CH 2 CH 2 CH 2 —, —CH 2 CH 2 CH 2 CH 2 —, —CH 2 CH 2 O—, —CH 2 OCH 2 —, —CH 2 CH 2 CH 2 O— —CH 2 CH 2 OCH 2 —, —CH 2 CH 2 —NH— —CH 2 NHCH 2 —, —CH 2 CH 2 CH 2 NH— or —CH 2 CH 2 NHCH 2 — group;
R 0a is independently selected for each occurrence from the group consisting of hydrogen, halogen, OH, CN, NO 2 , R a R b N—, C 1-4 alkyl and haloC 1-4 alkyl;
R 6a are independently hydrogen or C 1-4 alkyl;
R 0 , R 6 are independently selected for each occurrence from the group consisting of hydrogen, halogen, OH, CN, NO 2 , oxo, R d N═, hydrazino, formyl, azido, silyl, siloxy, HOC(O)—, R a R b N—, R a R b NS(O) t —, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, haloC 1-6 alkyl, hydroxyC 1-6 alkyl-, R a R b NC 1-6 alkyl-, HOC(O)C 1-6 alkyl-, R a R b NC 1-6 alkylNR c —, C 1-6 alkylNR a C 1-6 alkylNR c —, C 1-6 alkoxy, haloC 1-6 alkoxy, hydroxyC 1-6 alkoxy-, R a R b NC 1-6 alkoxy-, C 1-6 alkoxyC 1-6 alkyl-, haloC 1-6 alkoxyC 1-6 alkyl-, R a R b NC(O)—, C 1-6 alkylC(O)—, C 1-6 alkoxyC(O)—, C 1-6 alkylC(O)O—, C 1-6 alkylS(O) q —, C 1-6 alkylS(O) t NR c —, C 1-6 alkylS(O) t C 1-6 alkyl-, C 1-6 alkylS(O) t NR a C 1-6 alkyl-, C 3-6 cycloalkylS(O) t C 1-6 alkyl-, C 1-6 alkylC(O)C 1-6 alkyl-, and C 1-6 alkylC(O)OC 1-6 alkyl-;
each R 11 independently is hydrogen, OH, CN, NO 2 , C 1-6 alkyl, haloC 1-6 alkyl, HOC(O)—, HOC(O)C 1-6 alkyl, R a R b N—, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, haloC 1-6 alkoxy, or C 1-6 alkoxy;
R 1 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 R 11 groups;
R 2 is selected from the group consisting of hydrogen, halo, CN, OH, R a R b N, C 1-4 alkyl, haloC 1-4 alkyl, C 3-5 monocycloalkyl, C 1-4 alkoxy, and haloC 1-4 alkoxy;
R 8 is selected from the group consisting of hydrogen, halo, CN, OH, R a R b N, C 1-4 alkyl, haloC 1-4 alkyl, C 3-5 monocycloalkyl, C 1-6 alkoxy, and haloC 1-4 alkoxy;
R 3 is
R 4 is R 5 -L 1 -, R 6 or R 9 ;
R 5 is
R 9 is R 14 S(O) q -L-, R 14 S(O) q NH-L-, or R 14 C(O)NH-L-;
R 14 is R a R b N—, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, or R 5 -L 1 -;
q, r, t, and w are independently selected for each occurrence from 0, 1 and 2.
2 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R x1 is hydrogen or methyl.
3 . The compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein R x1 is methyl.
4 . The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein r is 0.
5 . The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 is hydrogen.
6 . The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein: R 1 is
R 11 is independently selected for each occurrence from the group consisting of halogen, CN, C 1-6 alkyl and haloC 1-6 alkyl; and z1 is 0, 1,2 or 3.
7 . The compound of claim 6 , or a pharmaceutically acceptable salt thereof, wherein for each occurrence R 11 is independently selected from the group consisting of CN, F, Cl, Br and I.
8 . The compound of claim 7 , or a pharmaceutically acceptable salt thereof, wherein R 1 is
9 . The compound of claim 7 , or a pharmaceutically acceptable salt thereof, wherein R 1 is
10 . The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3 is
11 . The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4 is R 6 .
12 . The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4 is R 5 -L 1 .
13 . The compound of claim 12 , or a pharmaceutically acceptable salt thereof, wherein L 1 is a bond.
14 . The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4 is R 9 .
15 . The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 8 is hydrogen, OH or C 1-6 alkoxy.
16 . The compound of claim 15 , or a pharmaceutically acceptable salt thereof, wherein R 8 is OH.
17 . A pharmaceutical composition comprising the compound according to claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
18 . A method of treating Hepatitis B (HBV) infection in a subject in need thereof, the method comprising: administering to the subject a therapeutically effective amount of a compound according to claim 1 , or a pharmaceutically acceptable salt thereof.
19 . A method of treating Hepatitis B (HBV) infection in a subject in need thereof, the method comprising: administering to the subject a therapeutically effective amount of pharmaceutical composition of claim 17 .
20 . 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 223
21 . A compound
or a pharmaceutically acceptable salt thereof.
22 . A compound
or a pharmaceutically acceptable salt thereof.
23 . A diastereomer of a compound
or a pharmaceutically acceptable salt thereof.
24 . A pharmaceutical composition comprising the compound according to claim 21 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
25 . A method of treating Hepatitis B (HBV) infection in a subject in need thereof, the method comprising: administering to the subject a therapeutically effective amount of a compound according to claim 21 , or a pharmaceutically acceptable salt thereof.
26 . A method of treating HBV infection in a subject in need thereof, the method comprising: administering to the subject a therapeutically effective amount of pharmaceutical composition of claim 24 .
27 . A pharmaceutical composition comprising the compound according to claim 22 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
28 . A method of treating HBV infection in a subject in need thereof, the method comprising: administering to the subject a therapeutically effective amount of a compound according to claim 22 , or a pharmaceutically acceptable salt thereof.
29 . A method of treating HBV infection in a subject in need thereof, the method comprising: administering to the subject a therapeutically effective amount of pharmaceutical composition of claim 27 .
30 . A pharmaceutical composition comprising the compound according to claim 23 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
31 . A method of treating HBV infection in a subject in need thereof, the method comprising: administering to the subject a therapeutically effective amount of a compound according to claim 23 , or a pharmaceutically acceptable salt thereof.
32 . A method of treating HBV infection in a subject in need thereof, the method comprising: administering to the subject a therapeutically effective amount of pharmaceutical composition of claim 30 .