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

Patent metadata

Field	Value
Publication number	US-12083118-B2
Application number	US-201916982842-A
Country	US
Kind code	B2
Filing date	Mar 29, 2019
Priority date	Mar 29, 2018
Publication date	Sep 10, 2024
Grant date	Sep 10, 2024

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

What is claimed is:

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 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, —(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 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), or —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 a 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), or —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 a 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), or —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), or —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 a 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 a 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), or —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), or —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 a 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 a 4-8 membered optionally substituted heterocyclyl;

R 4a is selected from the group consisting of H, halogen, cyano, and C 1 -C 3 alkyl; and
R 4b is selected from the group consisting of H, 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 the following applies:
(i) R 1a is identical to R 1b ,
(ii) R 2a is identical to R 2b ,
(iii) R 3a is identical to R 3b , and
(iv) R 4a is identical to R 4b .

3. The compound of claim 1 , wherein R 1b is H.

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

5. 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).

6. 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)O(C 1 -C 6 alkyl)](CH 2 ) 1-6 OH.

7. 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).

8. The compound of claim 6 , 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, and —O(CH 2 ) 0-3 C(═O)O(C 1 -C 6 alkyl).

9. 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)O(C 1 -C 6 alkyl](CH 2 ) 1-6 OH.

10. 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 ) 0-1 (optionally substituted tetrahydropyrimidinyl), —(CH 2 ) 0-1 (optionally substituted imidazolyl)

Assignees

• Arbutus Biopharma Corp

Inventors

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

Classifications

• C07D401/14

  containing three or more hetero rings · CPC title

• C07D401/12

  linked by a chain containing hetero atoms as chain links · CPC title

• C07D239/06

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

• C07D233/26

  Radicals substituted by carbon atoms having three bonds to hetero atoms · 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