IP Library › Granted Patent US 9,657,013

Granted Patent B2

US 9,657,013 · App. 14/382,074 · Granted May 23, 2017

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

Inventors: Andrea Cuconati (Oreland, PA); Haitao Guo (Lansdale, PA); Timothy M. Block (Doylestown, PA); Ju-Tao Guo (Lansdale, PA); Xiaodong Xu (Doylestown, PA); Huagang Lu (Plainsboro, NJ); Dawei Cai (Doylestown, PA)

Assignees: Baruch S. Blumberg Institute; Drexel University

C07D471/04 A61K31/445 A61K31/4409 A61K31/4465 A61K31/505 C07C311/21 C07C317/32 C07D209/08 C07D211/26 C07D211/34 C07D211/60 C07D213/40 C07D213/56 C07D213/76 C07D235/08 C07D239/26 C07D263/56 C07D277/64 C07D295/135 C07D295/155 C07D401/12

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Quick Facts

Patent No.: US 9,657,013
App. No.: 14/382,074
Granted: May 23, 2017
Kind: B2

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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.

Claims (130)

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,

(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-trifluoromethyl-phenyl)-amino]-N-(2-methyl-benzothiazol-5-yl)-acetamide

2-[Benzenesulfonyl-(2-chloro-5-trifluoromethyl-phenyl)-amino]-N-[4-(4-methyl-piperazin-1-yl)-benzyl]-acetamide

2-[Benzenesulfonyl-(2-chloro-5-trifluoromethyl-phenyl)-amino]-N-[3-(4-methyl-piperazin-1-yl)-benzyl]-acetamide

and a pharmaceutically acceptable form thereof.

11. A pharmaceutical composition comprising at least one compound according to claim 1 and at least one pharmaceutically acceptable excipient.

12. A pharmaceutical composition comprising at least one compound according to claim 2 and at least one pharmaceutically acceptable excipient.

13. A pharmaceutical composition comprising at least one compound according to claim 3 and at least one pharmaceutically acceptable excipient.

14. A pharmaceutical composition comprising at least one compound according to claim 4 and at least one pharmaceutically acceptable excipient.

15. A pharmaceutical composition comprising at least one compound according to claim 5 and at least one pharmaceutically acceptable excipient.

16. A pharmaceutically acceptable composition comprising at least one pharmaceutically acceptable excipient and at least one compound selected from the group consisting of:

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

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) phenylsulfonamido)-N-(pyridin-4-ylmethyl) propanamide;

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

2-(N-(2-chloro-5-(trifluoromethyl)phenyl)phenyl sulfonamido)-N-(pyridin-3-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 chloride;

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-ylmethyl-propionamide;

2-[Benzenesulfonyl-(2-chloro-5-trifluoromethyl-phenyl)-amino]-N-(2-methyl-benzothiazol-5-yl)-acetamide;

2-[Benzenesulfonyl-(2-chloro-5-trifluoromethyl-phenyl)-amino]-N-benzyl-acetamide;

2-[Benzenesulfonyl-(2-chloro-5-trifluoromethyl-phenyl)-amino]-N-[4-(4-methyl-piperazin-1-yl)-benzyl]-acetamide;

2-[Benzenesulfonyl-(2-chloro-5-trifluoromethyl-phenyl)-amino]-N-[3-(4-methyl-piperazin-1-yl)-benzyl]-acetamide;

and a pharmaceutically acceptable form thereof.

17. A method of treating a disease associated with covalently closed circular DNA formation, said method comprising administering to a subject an effective amount of at least one compound according to the claim 1 to treat the disease.

18. The method of claim 17 , wherein the at least one compound is administered in a composition further comprising at least one pharmaceutically acceptable excipient.

19. A method of treating a disease associated with covalently closed circular DNA formation, said method comprising administering to a subject an effective amount of at least one compound according to the claim 2 to treat the disease.

20. The method of claim 19 , wherein the at least one compound is administered in a composition further comprising at least one pharmaceutically acceptable excipient.

21. A method of treating a disease associated with covalently closed circular DNA formation, said method comprising administering to a subject an effective amount of at least one compound according to the claim 3 to treat the disease.

22. The method of claim 21 , wherein the at least one compound is administered in a composition further comprising at least one pharmaceutically acceptable excipient.

23. A method of treating a disease associated with covalently closed circular DNA formation, said method comprising administering to a subject an effective amount of at least one compound according to the claim 4 to treat the disease.

24. The method of claim 23 , wherein the at least one compound is administered in a composition further comprising at least one pharmaceutically acceptable excipient.

25. A method of treating a disease associated with covalently closed circular DNA formation, said method comprising administering to a subject an effective amount of at least one compound according to the claim 5 to treat the disease.

26. The method of claim 25 , wherein the at least one compound is administered in a composition further comprising at least one pharmaceutically acceptable excipient.

27. A method of treating a disease associated with covalently closed circular DNA formation, said method comprising administering to a subject an effective amount of at least one compound selected from the group consisting of:

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

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) phenyl sulfonamido)-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) phenylsulfonamido)-N-(pyridin-4-ylmethyl)acetamide;

2-(N-(2-chloro-5-(trifluoromethyl)phenyl)phenyl sulfonamido)-N-(pyridin-3-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;