Granted Patent B2

US 8,927,569 · App. 12/668,987 · Granted Jan 6, 2015

Abstract

Claims (59)

1. A compound of formula (I):

or a pharmaceutically acceptable salt thereof,

wherein:

m is 0, 1, 2 or 3; n is 0;

R 1 is CO 2 R 5 , CONR 5 SO 2 R 5 , CONR 5 SO 2 N(R 5 ) 2 or tetrazolyl;

R a is C 2-6 alkylene-R 2 ;

R b is hydrogen;

or R a and R b , together with the carbon atom to which they are attached, form a C 3-6 cycloalkyl group, optionally substituted by R 2 ;

R 2 is C 1-6 alkyl, C 2-6 alkenyl or C 3-8 cycloalkyl, wherein said alkyl, alkenyl or cycloalkyl is optionally substituted with 1 to 3 halo;

R 3 is C 1-6 alkyl, (CH 2 ) 0-3 C 3-8 cycloalkyl, (CH 2 ) 0-3 aryl or (CH 2 ) 0-3 Het, optionally substituted by halo, OR 5 , SR 5 , N(R 5 ) 2 , C 1-6 alkyl, NO 2 , CN, CF 3 , NR 5 SO 2 R 5 , SO 2 N(R 5 ) 2 , NHCO 2 R 5 , NHCOR 5 , NHCONHR 5 , CO 2 R 5 , C(O)R 5 or CON(R 5 ) 2 ;

each W is independently halo, OR 5 , C 1-6 alkyl, CN, NO 2 , CF 3 , CO 2 R 5 or CON(R 5 ) 2 ;

each R 5 is independently hydrogen, C 1-6 alkyl or C 3-8 cycloalkyl;

Z is O or NR 6 ;

R 6 is hydrogen or C 1-6 alkyl;

Y is C═O, SO 2 or CR c R d ;

X is O, NR e or CR e R f ;

R c , R d , R e and R f are independently hydrogen, halo or C 1-6 alkyl;

M is C 4-12 alkylene, C 4-12 alkenylene or C 4-12 alkynylene, optionally substituted by C 1-6 alkyl, (CH 2 ) 0-3 C 3-8 cycloalkyl, (CH 2 ) 0-3 aryl, and optionally containing one O or S atom or one NH or NC 1-6 alkyl group, and optionally spiro-fused to a C 3-7 cycloalkyl group, and optionally fused to a 3- to 8-membered ring, which ring optionally contains 1 or 2 heteroatoms selected from N, O and S;

ring A is

 optionally substituted by R 4 ; and

R 4 is halo, hydroxy, C 1-6 alkyl, C 1-6 alkoxy, CN, NO 2 , oxo, C 3-8 cycloalkyl, N(R 5 ) 2 , aryl or heteroaryl, optionally substituted by 1 to 8 halo or C 1-4 alkyl.

2. The compound as claimed in claim 1 , wherein m is 0 or 1.

3. The compound as claimed in claim 1 , wherein R 1 is CONR 5 SO 2 R 5 or CONR 5 SO 2 N(R 5 ) 2 .

4. The compound as claimed in claim 1 , wherein R a is C 2-5 alkylene-R 2 , R b is hydrogen or R a and R b , together with the carbon atom to which they are attached, form a C 3-5 cycloalkyl group, optionally substituted by R 2 , where R 2 is C 1-6 alkyl or C 2-6 alkenyl.

5. The compound as claimed in claim 1 , wherein R 3 is C 1-6 alkyl, or (CH 2 ) 0-3 C 3-8 cycloalkyl, optionally substituted by halo, OR 5 or C 1-6 alkyl.

6. The compound as claimed in claim 1 , wherein M is C 4-10 alkylene, C 4-10 alkenylene or C 4-10 alkynylene, optionally substituted by C 1-6 alkyl or (CH 2 ) 0-3 C 3-8 cycloalkyl, and optionally containing one O or S group or one NH or NC 1-4 alkyl group, and optionally fused to a 3- to 8-membered carbocyclic ring.

7. The compound as claimed in claim 1 , wherein R 4 is halo, hydroxy, C 1-6 alkyl, C 1-6 alkoxy, CN, C 3-8 cycloalkyl or aryl.

8. The compound as claimed in claim 1 which is selected from:

(2R,4S,7S)-7-cyclohexyl-N-((1R,2S)-1-{[(cyclopropylsulfonyl)amino]carbonyl}-2-vinylcyclopropyl)-12,12-dimethyl-6,9-dioxo-3,4,6,7,8,9,12,13,14,15-decahydro-2H,11H-16,18-(ethanediylidene)-2,5-methano[1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoline-4-carboxamide,

(2R,4S,7S,14E)-21-cyano-7-cyclopentyl-N-((1R,2S)-1-{[(cyclopropylsulfonyl)amino]carbonyl}-2-vinylcyclopropyl)-25-methoxy-12,12-dimethyl-6,9-dioxo-3,4,6,7,8,9,12,13-octahydro-2H,11H-16,18-(ethanediylidene)-2,5-methano[1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoline-4-carboxamide,

(2R,4S,7S)-21-cyano-7-cyclopentyl-N-((1R,2S)-1-{[(cyclopropylsulfonyl)amino]carbonyl}-2-vinylcyclopropyl)-25-methoxy-12,12-dimethyl-6,9-dioxo-3,4,6,7,8,9,12,13,14,15-decahydro-2H,11H-16,18-(ethanediylidene)-2,5-methano[1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoline-4-carboxamide,

(2R,4S,7S)-7-cyclopentyl-N-((1R,2S)-1-{[(cyclopropylsulfonyl)amino]carbonyl}-2-vinylcyclopropyl)-25-methoxy-12,12-dimethyl-6,9-dioxo-3,4,6,7,8,9,12,13,14,15-decahydro-2H,11H-16,18-(ethanediylidene)-2,5-methano[1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoline-4-carboxamide,

(2R,4S,7S)-7-cyclopentyl-N-((1R,2S)-1-{[(cyclopropylsulfonyl)amino]carbonyl}-2-vinylcyclopropyl)-25-methoxy-12,12,21-trimethyl-6,9-dioxo-3,4,6,7,8,9,12,13,14,15-decahydro-2H,11H-16,18-etheno-2,5-methano[1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoline-4-carboxamide,

(3 aR,7S,10S,12R,24aR)-7-cyclohexyl-N-((1R,2S)-1-{[(cyclopropylsulfonyl)amino]carbonyl}-2-vinylcyclopropyl)-25-methoxy-5,8-dioxo-1,2,3,3a,5,6,7,8,11,12,22,23,24,24a-tetradecahydro-10H-19,21-etheno-9,12-methanocyclopenta[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoline-10-carboxamide,

(3 aS,7S,10S,12R,24aS)-7-cyclohexyl-N-((1R,2S)-1-{[(cyclopropylsulfonyl)amino]carbonyl}-2-vinylcyclopropyl)-25-methoxy-5,8-dioxo-1,2,3,3a,5,6,7,8,11,12,22,23,24,24a-tetradecahydro-10H-19,21-etheno-9,12-methanocyclopenta[18,19][1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoline-10-carboxamide,

(2R,4S,7S,14E)-20-chloro-7-cyclopentyl-N-((1R,2S)-1-{[(cyclopropylsulfonyl)amino]carbonyl}-2-vinylcyclopropyl)-25-methoxy-12,12-dimethyl-6,9-dioxo-3,4,6,7,8,9,12,13-octahydro-2H,11H-16,18-etheno-2,5-methano[1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoline-4-carboxamide,

(2R,45,75)-20-chloro-7-cyclopentyl-N-((1R,2S)-1-{[(cyclopropylsulfonyl)amino]carbonyl}-2-vinylcyclopropyl)-25-methoxy-12,12-dimethyl-6,9-dioxo-3,4,6,7,8,9,12,13,14,15-decahydro-2H,11H-16,18-etheno-2,5-methano[1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoline-4-carboxamide,

(2R,4S,7S)-7-cyclopentyl-N-((1R,2S)-1-{[(cyclopropylsulfonyl)amino]carbonyl}-2-vinylcyclopropyl)-21-fluoro-25-methoxy-12,12-dimethyl-6,9-dioxo-3,4,6,7,8,9,12,13,14,15-decahydro-2H,11H-16,18-(ethanediylidene)-2,5-methano[1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoline-4-carboxamide,

(2R,4S,7S,14E)-7-cyclopentyl-N-((1R,25)-1-{[(cyclopropylsulfonyl)amino]carbonyl}-2-vinylcyclopropyl)-21,25-dimethoxy-12,12-dimethyl-6,9-dioxo-3,4,6,7,8,9,12,13-octahydro-2H,11H-16,18-(ethanediylidene)-2,5-methano[1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoline-4-carboxamide, and

(2R,4S,7S)-7-cyclopentyl-N-((1R,2S)-1-{[(cyclopropylsulfonyl)amino]carbonyl}-2-vinylcyclopropyl)-21,25-dimethoxy-12,12-dimethyl-6,9-dioxo-3,4,6,7,8,9,12,13,14,15-decahydro-2H,11H-16,18-(ethanediylidene)-2,5-methano[1,10,3,6]dioxadiazacyclononadecino[11,12-b]quinoline-4-carboxamide,

or pharmaceutically acceptable salts thereof.

9. A compound as claimed in claim 1 , wherein:

m is 0 or 1;

R 1 is CONR 5 SO 2 R 5 or CONR 5 SO 2 N(R 5 ) 2 ;

R a is C 2-5 alkylene-R 2 where R 2 is as defined in claim 1 , R b is hydrogen or R a and R b , together with the carbon atom to which they are attached, form a C 3-5 cycloalkyl group, optionally substituted by R 2 , where R 2 is C 1-6 alkyl or C 2-6 alkenyl;

R 3 is C 1-6 alkyl, or (CH 2 ) 0-3 C 3-8 cycloalkyl, optionally substituted by halo, OR 5 or C 1-6 alkyl;

Z is O, Y is C═O and X is O or NR e ;

M is C 4-10 alkylene, C 4-10 alkenylene or C 4-10 alkynylene, optionally substituted by C 1-6 alkyl or (CH 2 ) 0-3 C 3-8 cycloalkyl, and optionally containing one O or S group or one NH or NC 1-4 alkyl group, and optionally fused to a 3- to 8-membered carbocyclic ring;

A is

 and which ring is optionally substituted by R 4 ; and

R 4 is halo, hydroxy, C 1-6 alkyl, C 1-6 alkoxy, CN, C 3-8 cycloalkyl or aryl.

10. A pharmaceutical composition comprising a compound as claimed in claim 1 , or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable carrier.

11. The pharmaceutical composition as claimed in claim 10 , further comprising one or more other agents for the treatment of viral infections or an immunomodulatory agent.

12. The pharmaceutical composition as claimed in claim 11 , wherein said one or more other agents for the treatment of viral infections is an antiviral agent.

13. The pharmaceutical composition as claimed in claim 11 , wherein said immunomodulatory agent is an α-, β- or γ-interferon.

14. A method of treating infection by hepatitis C virus in a human or animal, comprising administering a compound as claimed in claim 1 or a pharmaceutically acceptable salt thereof.

15. A method of inhibiting hepatitis C virus protease and/or of treating an illness due to hepatitis C virus, the method involving administering to a human or animal subject suffering from the condition a therapeutically effective amount of the pharmaceutical composition claimed in claim 10 .

16. A method of inhibiting hepatitis C virus protease and/or of treating an illness due to hepatitis C virus, the method involving administering to a human or animal subject suffering from the condition a therapeutically effective amount of a compound as claimed in claim 1 , or a pharmaceutically acceptable salt thereof.

17. A method for manufacturing a medicament for treatment of infection by heptatitis C virus in a human or animal, said method comprising providing a therapeutically effective amount of a compound as claimed in claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

Assignments (8)