Benzofuran Compounds For The Treatment Of Hepatitis C Virus Infections

• US 20150080343A1
• Filed: 11/20/2014
• Published: 03/19/2015
• Est. Priority Date: 08/19/2011
• Status: Active Grant

• Current Assignee: Glaxo Group Limited (Glaxosmithkline Holdings Ltd.)
• Original Assignee: Glaxo Group Limited (Glaxosmithkline Holdings Ltd.)
• Inventors: Chong, Pek Yoke, Miller, John F., Peat, Andrew James, Shotwell, John Brad
• Granted Patent: US 9,682,999 B2
• Time in Patent Office: Days
• US Class Current: 514/64
• CPC Class Codes: A61K 31/34 having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
• CPC Class Codes: A61K 31/343 condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
• CPC Class Codes: A61K 31/69 Boron compounds
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 31/14 for RNA viruses
• CPC Class Codes: C07D 307/85 attached in position 2
• CPC Class Codes: C07F 5/025 Boronic and borinic acid compounds
• CPC Class Codes: C07F 5/027 Organoboranes and organoborohydrides
• CPC Class Codes: C07F 5/04 Esters of boric acids

Abstract

The present invention features compounds of formula (I):

and salts thereof, pharmaceutical compositions comprising said compounds, and uses of such compounds in treating or preventing viral infections, such as HCV infections, and diseases associated with such infections.

Claims

1. A compound of formula (I):

2. The compound of formula (I) according to claim 1 wherein R is halogen;

m is 1;

R¹ is —

C(O)NHR⁵ wherein R⁵ is C_1-6alkyl;

R² is C_3-6cycloalkyl;

R³ is —

S(O)₂R⁷ wherein R⁷ is C_1-6alkyl and R⁴ is C_6-10aryl substituted with B(R⁸)(R⁹) or X(R⁸)(R⁹), wherein R⁸ and R⁹ are both hydroxy, and wherein C_6-10aryl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, —

CN, —

C(H)F₂ and —

CF₃.

3. The compound of formula (I) according to claim 1 wherein R is halogen;

m is 1;

R¹ is —

C(O)NHR⁵ wherein R⁵ is C_1-6alkyl;

R² is C_3-6cycloalkyl;

R³ is —

S(O)₂R⁷ wherein R⁷ is C_1-6alkyl and R⁴ is heteroaryl substituted with B(R⁸)(R⁹) or X(R⁸)(R⁹), wherein R⁸ and R⁹ are both hydroxy, and wherein heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, —

CN, —

C(H)F₂ and —

CF₃.

4. The compound of formula (I) according to claim 1 wherein R is halogen;

m is 1;

R¹ is —

C(O)NHR⁵ wherein R⁵ is C_1-6alkyl;

R² is C_3-6cycloalkyl;

R³ is —

S(O)₂R⁷ wherein R⁷ is C_1-6alkyl, and R⁴ is Het substituted with one or more substituents independently selected from the group consisting of halogen, hydroxyl, and —

CN.

13. A pharmaceutically acceptable salt of a compound as claimed in claim 1.

14. A pharmaceutical composition comprising a compound according to claim 1 together with at least one pharmaceutically acceptable excipient.

15. A compound according to claim 1 for use in treating or preventing a viral infection or disease associated with such infection.

16. The compound according to claim 15 wherein the viral infection is HCV infection.

17. A method of treating or preventing a viral infection or disease associated with such infection in a human comprising administering to a human a therapeutically effective amount of compound as claimed in claim 1.

18. The method according to claim 17 wherein the viral infection is HCV infection.

19. A compound of formula (I) or (I)′

as claimed in claim 1 in combination with one or more active anti-viral agents.

5. A compound of formula (I)′

6. The compound of formula (I)′

according to claim 5 wherein R⁴ is heteroaryl substituted with B(R⁸)(R⁹) or X B(R⁸)(R⁹), wherein R⁸ and R⁹ are each independently hydroxy, alkoxy, or aminoalkyl; and

wherein heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, —

CN, —

C(H)F₂, and —

CF₃.

7. The compound of formula (I)′

according to claim 5 wherein R⁴ is C_6-10aryl substituted with B(R⁸)(R⁹) or X B(R⁸)(R⁹), wherein R⁸ and R⁹ are each independently hydroxy, alkoxy, or aminoalkyl; and

wherein C_6-10aryl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, —

CN, —

C(H)F₂, and —

CF₃.

8. The compound of formula (I)′

according to claim 5, wherein R⁴ is Het optionally substituted one or more substituents independently selected from the group consisting of halogen, C_1-6alkoxy, —

C(H)F₂, —

CF₃, C_1-6alkyl, hydroxy, hydroxyalkyl, aminoalkyl, —

C(O)NH₂, —

C(O)OH, —

C(O)NHR⁵, —

S(O)₂R⁶, —

S(O)₂NH₂, —

CN, —

OCF₃, —

OR⁶, —

NR¹⁰R¹¹, —

NHC(O)R¹⁰, C_3-6cycloalkyl, and heterocyclyl;

wherein Het is a 5- to 6-membered monocyclic heterocyclic ring or 8- to 11-membered bicyclic heterocyclic ring system any ring of which is either saturated, partially saturated or unsaturated wherein each Het consists of one or more carbon atoms and one boron atom and one or more oxygen atoms;

one boron atom, one oxygen atom, and one nitrogen atom;

or one boron atom and one or more nitrogen atoms.

9. The compound of formula (I)′

according to claim 5, wherein R⁴ is Het optionally substituted one or more substituents independently selected from the group consisting of halogen, C_1-6alkoxy, —

C(H)F₂, —

CF₃, C_1-6alkyl, hydroxy, hydroxyalkyl and aminoalkyl.

10. The compound of formula (I)′

according to claim 5 wherein R⁷ is C_1-6alkyl.

11. The compound of formula (I)′

according to claim 5 wherein X is alkylene.

12. A compound selected from the group consisting of:

(2-Chloro-4-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)phenyl)boronic acid;

(2-Chloro-4-(N-(2-(4-chlorophenyl)-5-cyclopropyl-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)phenyl)boronic acid;

4-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)phenylboronic acid;

3-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)phenylboronic acid;

4-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)-2-fluorophenylboronic acid;

4-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)-3-fluorophenylboronic acid;

4-(N-(2-(4-chlorophenyl)-5-cyclopropyl-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)-2-fluorophenylboronic acid;

6-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)pyridin-3-ylboronic acid;

(4-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)-2-(difluoromethyl)phenyl)boronic acid;

(4-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)-2-(trifluoromethyl)phenyl)boronic acid;

(4-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)-2,6-difluorophenyl)boronic acid;

(2-cyano-4-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)phenyl)boronic acid;

6-(N-(4-borono-3-chlorophenyl)methylsulfonamido)-2-(4-chlorophenyl)-5-cyclopropylbenzofuran-3-carboxylic acid;

(4-(N-(3-carbamoyl-2-(4-chlorophenyl)-5-cyclopropylbenzofuran-6-yl)methylsulfonamido)-2-chlorophenyl)boronic acid;

6-(N-(7-chloro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide;

(4-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)-2-(methylsulfonyl)phenyl)boronic acid;

1-(2-Chloro-4-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)phenyl)-4-methyl-2,6,7-trioxa-1-borabicyclo[2.2.2]octan-1-uide;

((4-(N-(5-Cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)phenoxy)methyl)boronic acid;

((2-Chloro-4-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)phenoxy)methyl)boronic acid;

5-Cyclopropyl-2-(4-fluorophenyl)-6-(N-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yl)methylsulfonamido)-N-methylbenzofuran-3-carboxamide;

(4-(N-(2-(4-Chlorophenyl)-5-cyclopropyl-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)-2-cyanophenyl)boronic acid;

5-Cyclopropyl-2-(4-fluorophenyl)-N-methyl-6-(N-(3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methylsulfonamido)benzofuran-3-carboxamide;

(2-Chloro-4-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)phenethyl)boronic acid;

5-Cyclopropyl-6-(N-(7-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yl)methylsulfonamido)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide;

6-(N-(3-Chloro-4-(2-hydroxy-1,2-oxaborolan-4-yl)phenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide;

(3-(N-(5-Cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)phenethyl)boronic acid;

6-(N-(3-Chloro-4-(2-hydroxy-1,2-oxaborolan-5-yl)phenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide;

6-(N-(3-Chloro-4-(2-hydroxy-1,2-oxaborolan-5-yl)phenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide, enantiomer 1;

6-(N-(3-Chloro-4-(2-hydroxy-1,2-oxaborolan-5-yl)phenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide, enantiomer 2;

5-Cyclopropyl-2-(4-fluorophenyl)-6-(N-(1-hydroxy-3,4-dihydro-1H-benzo[c][1,2]oxaborinin-6-yl)methylsulfonamido)-N-methylbenzofuran-3-carboxamide;

and pharmaceutically acceptable salts thereof.