Inhibitors of hepatitis B virus covalently closed circular DNA formation and their method of use

Patent metadata

Field	Value
Publication number	US-9657013-B2
Application number	US-201314382074-A
Country	US
Kind code	B2
Filing date	Feb 28, 2013
Priority date	Feb 29, 2012
Publication date	May 23, 2017
Grant date	May 23, 2017

Abstract

Pharmaceutical compositions of the invention comprise covalently closed circular DNA formation inhibitors having a disease-modifying action in the treatment of diseases associated with the formation of covalently closed circular DNA that include hepatitis B infection, and any disease involving formation of covalently closed circular DNA.

First claim

What is claimed is:

1. A compound having formula (Ia):

or hydrates, solvates and pharmaceutically acceptable salts thereof, wherein:
(a) R 1 is 2-halo-5-trifluoromethyl phenyl;
R 2 is selected from the group consisting of substituted phenyl, and optionally substituted heteroaryl; and
R 3 is selected from the group consisting of optionally substituted phenyl, optionally substituted C 1 -C 6 linear alkyl, optionally substituted C 1 -C 6 branched alkyl, optionally substituted C 3 -C 7 cycloalkyl,

or
(b) R 1 is 2,5-substituted phenyl, wherein the substituents at the 2-position and 5-position of the phenyl are independently selected from the group consisting of halo and trifluoromethyl;
R 2 is phenyl; and
R 3 is selected from the group consisting of

n is 1;
L 1 is, independently, —[C(R 4a R 4b )] m —;
m is 1 or 2;
at each occurrence R 4a and R 4b are each independently selected from a group consisting of hydrogen and methyl; or R 4a and R 4b are taken together with the carbon atom to which they are bound to form a cyclopropyl ring; and
x is 1.

2. The compound of claim 1 having formula (Ie):

or hydrates, solvates and pharmaceutically acceptable salts thereof.

3. The compound of claim 1 having formula (If) in (a):

or hydrates, solvates and pharmaceutically acceptable salts thereof.

4. A compound having formula (Ig) in (a):

or hydrates, solvates and pharmaceutically acceptable salts thereof.

5. The compound of claim 1 having formula (Ih) in (b):

or hydrates, solvates and pharmaceutically acceptable salts thereof.

6. The compound of claim 1 , wherein
in (a) R 1 is selected from the group consisting of 2-chloro-5-trifluoromethyl-phenyl, 2 bromo-5-trifluoromethyl-phenyl and 2-fluoro-5-trifluoromethyl-phenyl, and
in (b) R 1 is selected from the group consisting of 2-chloro-5-trifluoromethyl-phenyl, 2-fluoro-5-chloro-phenyl, 2-bromo-5-trifluoromethyl-phenyl and 2-fluoro-5-trifluoromethyl-phenyl.

7. The compound of claim 1 , wherein in (a) R 2 is selected from the group consisting of 4-methyl-phenyl, 4-fluoro-phenyl, 4-chloro-phenyl, 4-methoxyphenyl, 4-trifluoromethyl-phenyl and 2-chloro-4-trifluoromethyl-phenyl.

8. The compound of claim 1 , wherein in (a) R 3 is selected from the group consisting of:

9. The compound of claim 1 , wherein in (b) R 3 is selected from the group consisting of:

10. A compound selected from the group consisting of:
2-[(2-Chloro-5-trifluoromethyl-phenyl)-(toluene-4-sulfonyl)-amino]-N-pyridin-4-ylmethyl-acetamide

2-[(2-Chloro-5-trifluoromethyl-phenyl)-(4-fluoro-benzenesulfonyl)-amino]-N-pyridin-4-ylmethyl-acetamide

2-(N-(2-chloro-5-(trifluoromethyl)phenyl) phenyl sulfonamido)-N-(pyridin-4-ylmethyl) propanamide

4-(N-(2-chloro-5-(trifluoromethyl)phenyl) phenyl sulfonamido)-N-(pyridin-4-ylmethyl) butanamide

2-(4-chloro-N-(2-chloro-5-(trifluoromethyl)phenyl) phenylsulfonamido)-N-(pyridin-4-ylmethyl) acetamide

2-(N-(2-chloro-5-(trifluoromethyl)phenyl)-4-methoxyphenylsulfonamido)-N-(pyridin-4-ylmethyl)acetamide

2-(N-(5-chloro-2-fluorophenyl)phenylsulfonamido)-N-(pyridin-4-ylmethyl)acetamide

2-(N-(2-chloro-5-(trifluoromethyl)phenyl)-4-(trifluoromethyl)phenylsulfonamido)-N-(pyridin-4-ylmethyl)acetamide

2-(2-chloro-N-(2-chloro-5-(trifluoromethyl)phenyl)-4-(trifluoromethyl) phenyl sulfonamido)-N-(pyridin-4-ylmethyl)acetamide

2-(N-(2-chloro-5-(trifluoromethyl)phenyl)phenyl sulfonamido)-N-(pyrimidin-5-ylmethyl) acetamide

2-(N-(2-chloro-5-(trifluoromethyl)phenyl)phenyl sulfonamido)-N-(pyrimidin-4-ylmethyl) acetamide

tert-butyl 4-((2-(N-(2-chloro-5-(trifluoromethyl)phenyl)phenylsulfonamido)acetamido) methyl) piperidine-1-carboxylate

tert-butyl (2-(2-(N-(2-chloro-5-(trifluoromethyl)phenyl)phenylsulfonamido)acetamido) ethyl)carbamate

2-(N-(2-chloro-5-(trifluoromethyl)phenyl)phenylsulfonamido)-N-(piperidin-4-ylmethyl) acetamide

N-(2-aminoethyl)-2-(N-(2-chloro-5-(trifluoromethyl)phenyl)phenylsulfonamido) acetamide

2-(N-(2-chloro-5-(trifluoromethyl)phenyl)phenylsulfonamido)-N-((1-methylpiperidin-4-yl)methyl)acetamide

4-((2-(N-(2-chloro-5-(trifluoromethyl)phenyl) phenylsulfonamido)acetamido)methyl)-1,1-dimethylpiperidin-1-ium

2-[Benzenesulfonyl-(2-bromo-5-trifluoromethyl-phenyl)-amino]-N-pyridin-4-ylmethyl-acetamide

2-[Benzenesulfonyl-(2-fluoro-5-trifluoromethyl-phenyl)-amino]-N-pyridin-4-ylmethyl-acetamide

2-[Benzenesulfonyl-(2-chloro-5-trifluoromethyl-phenyl)-amino]-N-pyridin-4-yl methyl-propionamide

2-[Benzenesulfonyl-(2-chloro-5-trifluoromethy

Assignees

• Baruch S Blumberg Inst
• Univ Drexel

Inventors

• Cuconati Andrea
• Guo Haitao
• Block Timothy M
• Guo Ju-Tao
• Xu Xiaodong
• Lu Huagang
• Cai Dawei

Classifications

• A61P31/20

  for DNA viruses · CPC title

• A61P43/00

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

• A61P1/16

  for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics · CPC title

• C07D209/08

  with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring · CPC title

• C07D401/12

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