Substituted 1,1'-biphenyl compounds, analogues thereof, and methods using same

Patent metadata

Field	Value
Publication number	US-2021052585-A1
Application number	US-201916982842-A
Country	US
Kind code	A1
Filing date	Mar 29, 2019
Priority date	Mar 29, 2018
Publication date	Feb 25, 2021
Grant date	—

Abstract

The present invention includes substituted 3,3′bis(phenoxymethyl)-1,1′-biphenyl compounds, analogues thereof, and compositions comprising the same, that can be used to treat or prevent hepatitis B virus (HBV) and/or hepatitis D virus (HDV) infections in a patient.

First claim

1 . A compound of formula (I):

wherein:
X 1 is selected from the group consisting of CH and N;
X 2 is selected from the group consisting —OCH 2 —**, —CH 2 O—**, —C(═O)NH—**, and —NHC(═O)—**, wherein the bond marked with ** is to the phenyl ring carbon marked with *;
R 1a is selected from the group consisting of H, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, cyano, halogen, and C 1 -C 3 haloalkyl;
R 1b is selected from the group consisting of H, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, cyano, halogen, and C 1 -C 3 haloalkyl;
R 1c is selected from the group consisting of H, C 1 -C 6 alkyl, —OH, C 1 -C 6 alkoxy optionally substituted with at least one selected from the group consisting of OH, C 1 -C 6 alkoxy, phenyl, and optionally substituted heterocyclyl,

X 3 is selected from the group consisting of CH and N;
R 2a is selected from the group consisting of C 1 -C 6 alkyl, C 1 -C 6 alkoxy, —(CH 2 ) 1-3 (optionally substituted phenyl), —(CH 2 ) 1-3 (optionally substituted heteroaryl), —O(CH 2 ) 1-3 (optionally substituted phenyl), —O(CH 2 ) 1-3 (optionally substituted heteroaryl), —(CH 2 ) 1-3 C(═O)OR I , —(CH 2 ) 1-3 C(═O)NR I R I , —O(CH 2 ) 1-3 C(═O)OR I , and —O(CH 2 ) 1-3 C(═O)NR I R I ,
wherein each occurrence of R I is independently H or C1-C6 alkyl optionally substituted with halogen, —OH, C 1 -C 6 alkoxy, —NH 2 , —NH(C 1 -C 6 alkyl), and —N(C 1 -C 6 alkyl)(C 1 -C 6 alkyl,
or two R I can combine with the N atom to which they are bound to form 3-8 membered optionally substituted heterocyclyl;

R 2b is selected from the group consisting of C 1 -C 6 alkyl, C 1 -C 6 alkoxy, —(CH 2 ) 1-3 (optionally substituted phenyl), —(CH 2 ) 1-3 (optionally substituted heteroaryl), —O(CH 2 ) 1-3 (optionally substituted phenyl), —O(CH 2 ) 1-3 (optionally substituted heteroaryl), —(CH 2 ) 1-3 C(═O)OR II , —(CH 2 ) 1-3 C(═O)NR II R II , —O(CH 2 ) 1-3 C(═O)OR II , and —O(CH 2 ) 1-3 C(═O)NR II R II ,
wherein each occurrence of R II is independently H or C 1 -C 6 alkyl optionally substituted with halogen, —OH, C 1 -C 6 alkoxy, —NH 2 , —NH(C 1 -C 6 alkyl), and —N(C 1 -C 6 alkyl)(C 1 -C 6 alkyl),
or two R II can combine with the N atom to which they are bound to form 3-8 membered optionally substituted heterocyclyl,

R 3a is selected from the group consisting of —CHO, —C(O)OR III , —C(═O)NR III R III , —C(═NR 5 )NR III R III , optionally substituted heterocyclyl, —(CH 2 ) 1-3 (optionally substituted heterocyclyl), optionally substituted C 1 -C 6 alkoxy, optionally substituted C 1 -C 6 aminoalkyl, and optionally substituted C 1 -C 6 hydroxyalkyl,
wherein each occurrence of R III is independently H or C 1 -C 6 alkyl optionally substituted with halogen, —OH, C 1 -C 6 alkoxy, —NH 2 , —NH(C 1 -C 6 alkyl), and —N(C 1 -C 6 alkyl)(C 1 -C 6 alkyl),
wherein each occurrence of R 5 is independently H or C 1 -C 6 alkyl optionally substituted with halogen, —OH, C 1 -C 6 alkoxy, —NH 2 , —NH(C 1 -C 6 alkyl), and —N(C 1 -C 6 alkyl)(C 1 -C 6 alkyl),
or two R III can combine with the N atom to which they are bound to form 3-8 membered optionally substituted heterocyclyl,
or, if R 3a is —C(═NR 5 )NR III R III , then R 5 and one R III can combine to form 4-8 membered optionally substituted heterocyclyl;

R 3b is selected from the group consisting of —CHO, —C(O)OR IV , —C(═O)NR IV R IV , —C(═NR 5 )NR IV R IV optionally substituted heterocyclyl, —(CH 2 ) 1-3 (optionally substituted heterocyclyl), optionally substituted C 1 -C 6 alkoxy, optionally substituted C 1 -C 6 aminoalkyl, and optionally substituted C 1 -C 6 hydroxyalkyl,
wherein each occurrence of R IV is independently H or C 1 -C 6 alkyl optionally substituted with halogen, —OH, C 1 -C 6 alkoxy, —NH 2 , —NH(C 1 -C 6 alkyl), and —N(C 1 -C 6 alkyl)(C 1 -C 6 alkyl),
wherein each occurrence of R 5 is independently H or C 1 -C 6 alkyl optionally substituted with halogen, —OH, C 1 -C 6 alkoxy, —NH 2 , —NH(C 1 -C 6 alkyl), and —N(C 1 -C 6 alkyl)(C 1 -C 6 alkyl),
or two R IV can combine with the N atom to which they are bound to form 3-8 membered optionally substituted heterocyclyl,
or, if R 3b is —C(═NR 5 )NR IV R IV then R 5 and one R IV can combine to form 4-8 membered optionally substituted heterocyclyl;

R 4a is selected from the group consisting of halogen, cyano, and C 1 -C 3 alkyl; and
R 4b is selected from the group consisting of halogen, cyano, and C 1 -C 3 alkyl;

or a salt, solvate, geometric isomer, stereoisomer, tautomer and any mixtures thereof.

2 . The compound of claim 1 , wherein at least one of:
(i) R 1a is identical to R 1b , (ii) R 2a is identical to R 2b , (iii) R 3a is identical to R 3b , or (iv) R 4a is identical to R 4b .

3 . The compound of claim 1 , wherein at least one of R 1b and R 1c is H.

4 . (canceled)

5 . The compound of claim 1 , wherein R 1a is methyl and R 1b is methyl.

6 . (canceled)

7 . The compound of claim 1 , wherein at least one of R 2a and R 2b is selected from the group consisting of C 1 -C 6 alkoxy, —CH 2 (optionally substituted pyridinyl), —O(CH 2 ) 1-3 C(═O)OH, and —O(CH 2 ) 1-3 C(═O)O(C 1 -C 6 alkyl).

8 - 9 . (canceled)

10 . The compound of claim 1 , wherein R 3a is selected from the group consisting of —CHO, —CH 2 OH, —C(═NH)NH 2 , —(CH 2 ) 0-1 (optionally substituted piperidinyl), —(CH 2 ) 0-1 (optionally substituted tetrahydropyrimidinyl), —(CH 2 ) 0-1 (optionally substituted imidazolyl), —(CH 2 ) 0-1 (optionally substituted dihydroimidazolyl), —C(═O)NH(C 1 -C 6 hydroxyalkyl), CH 2 NH(C 1 -C 6 haloalkyl), —CH 2 NH(C 1 -C 6 hydroxyalkyl), —CH 2 N(C 1 -C 6 hydroalkyl)(C 1 -C 6 hydroalkyl), —CH 2 NH(C 1 -C 6 aminoalkyl), —CH 2 NH(C 1 -C 6 acetamidoalkyl), —CH 2 NH—CH[C(═O)OH](CH 2 ) 1-6 OH, and —CH 2 NH—CH[C(═O)OC 1 -C 6 alkyl](CH 2 ) 1-6 OH.

11 . The compound of claim 1 , wherein R 3a is selected from the group consisting of —C(═NH)NH 2 , —(CH 2 ) 0-1 (optionally substituted piperidinyl), —(CH 2 ) 0-1 (optionally substituted tetrahydropyrimidinyl), —(CH 2 ) 0-1 (optionally substituted imidazolyl), and —(CH 2 ) 0-1 (optionally substituted dihydroimidazolyl).

12 . The compound of claim 10 , wherein in R 3a the —C(═NH)NH 2 , piperidinyl, tetrahydropyrimidinyl, imidazolyl, or dihydroimidazolyl is optionally substituted with at least one selected from the group consisting of C 1 -C 6 alkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 N-acylaminoalkyl, —(CH 2 ) 0-3 C(═O)OH, —(CH 2 ) 0-3 C(═O)O(C 1 -C 6 alkyl), —OH, C 1 -C 6 alkoxy, —O(CH 2 ) 0-3 C(═O)OH, or —O(CH 2 ) 0-3 C(═O)O(C 1 -C 6 alkyl).

13 . The compound of claim 1 , wherein R 3b is selected from the group consisting of —CHO, —CH 2 OH, —C(═NH)NH 2 , —(CH 2 ) 0-1 (optionally substituted piperidinyl), —(CH 2 ) 0-1 (optionally substituted tetrahydropyrimidinyl), —(CH 2 ) 0-1 (optionally substituted imidazolyl), —(CH 2 ) 0-1 (optionally substituted dihydroimidazolyl), —C(═O)NH(C 1 -C 6 hydroxyalkyl), —CH 2 NH(C 1 -C 6 haloalkyl), —CH 2 NH(C 1 -C 6 hydroxyalkyl), —CH 2 N(C 1 -C 6 hydroalkyl)(C 1 -C 6 hydroalkyl), —CH 2 NH(C 1 -C 6 aminoalkyl), —CH 2 NH(C 1 -C 6 acetamidoalkyl), —CH 2 NH—CH[C(═O)OH](CH 2 ) 1-6 OH, and —CH 2 NH—CH[C(═O)OC 1 -C 6 alkyl](CH 2 ) 1-6 OH.

14 . The compound of claim 1 , wherein R 3b is selected from the group consisting of —C(═NH)NH 2 , —(CH 2 ) 0-1 (optionally substituted piperidinyl), —(CH 2 )

Assignees

• Arbutus Biopharma Corp

Inventors

• Bi Yingzhi
• Dorsey Bruce D
• Fan Yi
• Moore Christopher Brooks
• Nguyen Duyan

Classifications

• C07C217/58 Primary

  with amino groups and the six-membered aromatic ring, or the condensed ring system containing that ring, bound to the same carbon atom of the carbon chain · CPC title

• A61P31/20

  for DNA viruses · CPC title

• C07D239/06

  having one double bond between ring members or between a ring member and a non-ring member · CPC title

• C07D211/60

  Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals · CPC title

• A61K31/277

  having a ring, e.g. verapamil · CPC title