Hepatitis B antiviral agents

Patent metadata

Field	Value
Publication number	US-10538532-B2
Application number	US-201816194608-A
Country	US
Kind code	B2
Filing date	Nov 19, 2018
Priority date	Mar 7, 2016
Publication date	Jan 21, 2020
Grant date	Jan 21, 2020

Abstract

The present invention discloses compounds of Formula (I), or pharmaceutically acceptable salts, esters, or prodrugs thereof:

X-A-Y-L-R  (I)

which inhibit the protein(s) encoded by hepatitis B virus (HBV) or interfere with the function of the HBV life cycle of the hepatitis B virus and are also useful as antiviral agents. The present invention further relates to pharmaceutical compositions comprising the aforementioned compounds for administration to a subject suffering from HBV infection. The invention also relates to methods of treating an HBV infection in a subject by administering a pharmaceutical composition comprising the compounds of the present invention.

First claim

What is claimed:

1. A method of treating an HBV infection in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound represented by Formula (IIIa):

or a pharmaceutically acceptable salt thereof, wherein:
each m is independently 0, 1, 2, 3 or 4;
R 14 at each occurrence is independently selected from the group consisting of hydroxy, protected hydroxy, halogen, —CN, —NO 2 , optionally substituted amino, N 3 , optionally substituted aryl, optionally substituted heteroaryl, optionally substituted —C 1 -C 6 alkyl, optionally substituted —C 2 -C 8 alkenyl, optionally substituted —C 2 -C 8 alkynyl, optionally substituted —C 3 -C 8 cycloalkyl, optionally substituted 3- to 8-membered heterocyclic, optionally substituted —C 1 -C 6 alkoxy, —C(O) 2 —C 1 -C 6 alkyl, —C(O)NH—C 1 -C 6 alkyl, and —C(O)—C 1 -C 6 alkyl; and
R is

wherein n at each occurrence is independently selected from 0, 1, 2, or 3; v at each occurrence is independently selected from 1 and 2; T at each occurrence is independently selected from C(R 10 ) and N; E at each occurrence is independently selected from —C(R 10 ) 2 —, —N(R 10 )—, O, S, S(O), and S(O) 2 ; R 10 at each occurrence is independently selected from the group consisting of hydrogen, halo, —CN, —NO 2 , optionally substituted —C 1 -C 6 alkyl, optionally substituted —C 2 -C 8 alkenyl, optionally substituted —C 2 -C 8 alkynyl, optionally substituted —C 3 -C 8 cycloalkyl, optionally substituted 3- to 8-membered heterocyclic, optionally substituted aryl, optionally substituted heteroaryl, and -L 1 -R 1 ; wherein L 1 is —O—, —S—, —NR 1 —, —C(O)—, —C(O)O—, —OC(O)—, —C(O)N(R 1 )—, —N(R 1 )C(O)—, —OC(O)N(R 1 )—, —N(R 1 )C(O)O—, —N(R 1 )C(O)N(R 1 )—, —S(O)—, —S(O) 2 —, —S(O) 2 N(R 1 )—, —N(R 1 )S(O) 2 —; R 1 at each occurrence is independently selected from the group consisting of hydrogen, optionally substituted —C 1 -C 6 alkyl, optionally substituted —C 2 -C 8 alkenyl, optionally substituted —C 2 -C 8 alkynyl, optionally substituted —C 3 -C 8 cycloalkyl, optionally substituted 3- to 8-membered heterocyclic, optionally substituted aryl, and optionally substituted heteroaryl; alternatively, two adjacent R 10 groups are taken together with the carbon or nitrogen atoms to which they are attached to form an olefinic or iminic double-bond or a fused ring; two geminal R 10 groups together form an oxo, an optionally substituted olefin, an optionally substituted oxime, or a spiro ring; and/or two remote R 10 groups are taken together with the atoms to which they are attached to form a bridging moiety.

2. The method of claim 1 , further comprising administering to the subject at least one additional therapeutic agent selected from the group consisting of HBV polymerase inhibitors, interferon, viral entry inhibitors, viral maturation inhibitors, capsid assembly or core protein inhibitors or modulators, reverse transcriptase inhibitors, TLR-agonists, inducers of cellular viral RNA sensor, therapeutic vaccines, RNA interference (RNAi) or small interfering RNA (siRNA) and combinations thereof.

3. The method of claim 2 , wherein the compound and the at least one additional therapeutic agent are co-formulated.

4. The method of claim 2 , wherein the at least one additional therapeutic agent is administered at a lower dose and/or frequency than that which is therapeutically effective when said agent is administered alone.

5. The method of claim 1 , wherein the compound is represented by Formula (IVb), (IVc), (IVd), or (IVe) or a pharmaceutically acceptable salt thereof:

wherein m, n, R 14 , R 10 , E and T are as defined in claim 1 .

6. The method of claim 1 , wherein the compound is represented by Formula (Vb), (Vc), (Vd), or (Ve), or a pharmaceutically acceptable salt thereof:

wherein m1 is 1, 2, or 3; m2 is 1 or 2; m3 is 0, 1, 2, or 3; R 21 at each occurrence is independently selected from the group consisting of halogen, CN, optionally substituted —C 1 -C 6 alkyl, optionally substituted —C 1 -C 6 alkoxy, an optionally substituted C 3 -C 8 cycloalkyl; R 22 at each occurrence is independently selected from the group consisting of halogen, CN, optionally substituted —C 1 -C 6 alkyl, and optionally substituted —C 1 -C 6 alkoxy; and n, E, and R 10 are as defined in claim 1 .

7. The method of claim 6 , wherein the compound is represented by Formula (VIIb), (VIIc), (VIId), or (VIIe), or a pharmaceutically acceptable salt thereof:

wherein m1, m 3 , n, R 10 , R 21 , R 22 and E are as defined in claim 6 .

8. The method of claim 7 , wherein the compound is represented by Formula (VIIb-1), (VIIc-1), (VIId-1), or (VIIe-1), or a pharmaceutically acceptable salt thereof:

wherein R 23 is selected from the group consisting of hydrogen, halogen, CN, optionally substituted —C 1 -C 6 alkyl, optionally substituted —C 1 -C 6 alkoxy, and optionally substituted C 3 -C 8 cycloalkyl; and
n, m 3 , R 10 , R 21 , R 22 and E are as defined in claim 7 .

9. A method of treating an HBV infection in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound represented by Formula (VIIIa), (VIIIb), (VIIIc), or (VIIId), or a pharmaceutically acceptable salt thereof:

wherein R 11 at each occurrence is independently selected from a group consisting of hydrogen, halogen, hydroxy, protected hydroxy, —CN, amino, protected amino, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted —C 1 -C 6 alkyl, optionally substituted —C 2 -C 8 alkenyl, optionally substituted —C 2 -C 8 alkynyl, optionally substituted —C 3 -C 8 cycloalkyl, optionally substituted 3- to 8-membered heterocyclic, optionally substituted —C 1 -C 6 alkoxy, optionally substituted —NH—C 1 -C 6 alkyl, optionally substituted —N(C 1 -C 6 alkyl) 2 , —CO 2 H, optionally substituted —C(O) 2 —C 1 -C 6 alkyl, optionally substituted —C(O)NH—C 1 -C 6 alkyl, and optionally substituted —C(O)—C 1 -C 6 alkyl; each m is independently 0, 1, 2, 3 or 4; R 14 at each occurrence is independently selected from the group consisting of hydroxy, protected hydroxy, halogen, —CN, —NO 2 , optionally substituted amino, N 3 , optionally substituted aryl, optionally substituted heteroaryl, optionally substituted —C 1 -C 6 alkyl, optionally substituted —C 2 -C 8 alkenyl, optionally substituted —C 2 -C 8 alkynyl, optionally substituted —C 3 -C 8 cycloalkyl, optionally substituted 3- to 8-membered heterocyclic, optionally substituted —C 1 -C 6 alkoxy, —C(O) 2 —C 1 -C 6 alkyl, —C(O)NH—C 1 -C 6 alkyl, and —C(O)—C 1 -C 6 alkyland; n at each occurrence is independently selected from 0, 1, 2, and 3; v at each occurrence is independently selected from 1 and 2; T at each occurrence is independently selected from C(R 10 ) and N; E at each occurrence is independently selected from —C(R 10 ) 2 —, —N(R 10 )—, O, S, S(O), and S(O) 2 ; and R 10 at each occurrence is independently s

Assignees

• Enanta Pharm Inc

Inventors

• Qiu Yao-Ling
• Gao Xuri
• Li Wei
• Cao Hui
• Jin Meizhong
• Kass Jorden
• Peng Xiaowen
• Or Yat Sun

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P31/20

  for DNA viruses · CPC title

• A61K31/44

  Non condensed pyridines; Hydrogenated derivatives thereof · CPC title

• A61K31/18

  Sulfonamides (compounds containing a para-N-benzene-sulfonyl-N- group A61K31/63) · CPC title

• C07B2200/07

  Optical isomers · CPC title