Granted Patent B2

US 10,472,341 · App. 15/554,354 · Granted Nov 12, 2019

Inventors: Monika Ermann (Oxfordshire, GB); Guenther Lametschwandtner (Vienna, AT); Patricia Leonie Amouzegh (Oxfordshire, GB); Russell Stuart Craft (Groningen, NL); Thomas Hanke (Hamburg, DE); Timothy Robin James (Oxfordshire, GB); Severine Danielle Jones (Oxfordshire, GB); Hans Loibner (Vienna, AT); Pui Leng Loke (Oxfordshire, GB); Ina Sternberger (Hamburg, DE); Anton Stuetz (Altmuenster, AT); Roland Wehr (Goettingen, DE); Mark Whittaker (Oxfordshire, GB)

Assignees: APEIRON BIOLOGICS AG; EVOTEC SE

C07D285/36A61K31/554A61K45/06A61P35/00C07D417/06C07D417/10C07D417/12C07D417/14C07D513/04C12N5/0635C12N5/0636C12N5/0646C12N2501/2302C12N2501/999

Abstract

Claims (250)

1. A pharmaceutical composition comprising at least one pharmaceutically acceptable carrier and at least one compound of formula (I)

or a pharmaceutically acceptable salt thereof, wherein

X 1 is S; S(O); or S(O) 2 ;

X 2 is N; or C(R 4 );

R 1 is H; or methyl;

R 2 is phenyl; 3 to 7 membered heterocyclyl; or 7 to 11 membered heterobicyclyl, wherein R 2 is optionally substituted with one or more R 5 , which are the same or different;

R 5 is halogen; CN; C(O)OR 6 ; OR 6 ; C(O)R 6 ; C(O)N(R 6 R 6a ); S(O) 2 N(R 6 R 6a ); S(O)N(R 6 R 6a ); S(O) 2 R 6 ; S(O)R 6 ; N(R 6 )S(O) 2 N(R 6a R 6b ); SR 6 ; N(R 6 R 6a ); OC(O)R 6 ; N(R 6 )C(O)R 6a ; N(R 6 )S(O) 2 R 6a ; N(R 6 )S(O)R 6a ; N(R 6 )C(O)OR 6a ; N(R 6 )C(O)N(R 6a R 6b ); OC(O)N(R 6 R 6a ); oxo (═O), where the ring is at least partially saturated; T 1 ; C 1-6 alkyl; C 2-6 alkenyl; or C 2-6 alkynyl, wherein C 1-6 alkyl; C 2-6 alkenyl; and C 2-6 alkynyl are optionally substituted with one or more halogen, which are the same or different;

R 6 , R 6a , and R 6b are independently selected from the group consisting of H; C 1-6 alkyl, C 2-6 alkenyl; and C 2-6 alkynyl, wherein C 1-6 alkyl; C 2-6 alkenyl; and C 2-6 alkynyl are optionally substituted with one or more halogen, which are the same or different;

T 1 is phenyl; C 3-7 cycloalkyl; or 3 to 7 membered heterocyclyl, wherein T 1 is optionally substituted with one or more R 7 , which are the same or different;

R 7 is halogen; CN; C(O)OR 8 ; OR 8 ; C(O)R 8 ; C(O)N(R 8 R 8a ); S(O) 2 N(R 8 R 8a ); S(O)N(R 8 R 8a ); S(O) 2 R 8 ; S(O)R 8 ; N(R 8 )S(O) 2 N(R 8a R 8b ); SR 8 ; N(R 8 R 8a ); OC(O)R 8 ; N(R 8 )C(O)R 8a ; N(R 8 )S(O) 2 R 8a ; N(R 8 )S(O)R 8a ; N(R 8 )C(O)OR 8a ; N(R 8 )C(O)N(R 8a R 8b ); OC(O)N(R 8 R 8a ); oxo (═O), where the ring is at least partially saturated; C 1-6 alkyl; C 2-6 alkenyl; or C 2-6 alkynyl, wherein C 1-6 alkyl; C 2-6 alkenyl; and C 2-6 alkynyl are optionally substituted with one or more halogen, which are the same or different;

R 8 , R 8a , and R 8b are independently selected from the group consisting of H; C 1-6 alkyl; C 2-6 alkenyl; and C 2-6 alkynyl, wherein C 1-6 alkyl; C 2-6 alkenyl; and C 2-6 alkynyl are optionally substituted with one or more halogen, which are the same or different;

R 3 is R 3a ; OR 3a ; NHR 3a ; or NHC(O)R 3a ;

R 3a is T 2 ; C 1-12 alkyl; C 2-12 alkenyl; or C 2-12 alkynyl, wherein C 1-12 alkyl; C 2-12 alkenyl; and C 2-12 alkynyl are optionally substituted with one or more R 9 , which are the same or different;

R 9 is halogen; CN; C(O)OR 10 ; OR 10 ; C(O)R 10 ; C(O)N(R 10 R 10a ); S(O) 2 N(R 10 R 10a ); S(O)N(R 10 R 10a ); S(O) 2 R 10 ; S(O)R 10 ; N(R 10 )S(O) 2 N(R 10a R 10b ); SR 10 ; N(R 10 R 10a ); OC(O)R 10 ; N(R 10 )C(O)R 10a ; N(R 10 )S(O) 2 R 10a ; N(R 10 )S(O)R 10a ; N(R 10 )C(O)N(R 10a R 10b ); N(R 10 )C(O)OR 10a ; OC(O)N(R 10 R 10a ); T 2 ; C 1-12 alkyl; C 2-12 alkenyl; or C 2-12 alkynyl, wherein C 1-12 alkyl; C 2-12 alkenyl; and C 2-12 alkynyl are optionally substituted with one or more R 11 , which are the same or different;

R 10 , R 10a , and R 10b are independently selected from the group consisting of H; T 2 ; C 1-12 alkyl; C 2-12 alkenyl; and C 2-12 alkynyl, wherein C 1-12 alkyl; C 2-12 alkenyl; and C 2-12 alkynyl are optionally substituted with one or more R 11 , which are the same or different;

T 2 is phenyl; C 3-7 cycloalkyl; 3 to 7 membered heterocyclyl; or 7 to 11 membered heterobicyclyl, wherein T 2 is optionally substituted with one or more R 12 , which are the same or different;

R 12 is halogen; CN; C(O)OR 13 ; OR 13 ; C(O)R 13 ; C(O)N(R 13 R 13a ); S(O) 2 N(R 13 R 13a ); S(O)N(R 13 R 13a ); S(O) 2 R 13 ; S(O)R 13 ; N(R 13 )S(O) 2 N(R 13a R 13b ); SR 13 ; N(R 13 R 13a ); OC(O)R 13 ; N(R 13 )C(O)R 13a ; N(R 13 )S(O) 2 R 13a ; N(R 13 )S(O)R 13a ; N(R 13 )C(O)OR 13a ; N(R 13 )C(O)N(R 13a R 13b ); OC(O)N(R 13 R 13a ); oxo (═O), where the ring is at least partially saturated; T 3 ; C 1-6 alkyl; C 2-6 alkenyl; or C 2-6 alkynyl, wherein C 1-6 alkyl; C 2-6 alkenyl; and C 2-6 alkynyl are optionally substituted with one or more R 14 , which are the same or different;

R 13 , R 13a , and R 13b are independently selected from the group consisting of H; C 1-6 alkyl; C 2-6 alkenyl; and C 2-6 alkynyl, wherein C 1-6 alkyl; C 2-6 alkenyl; and C 2-6 alkynyl are optionally substituted with one or more R 14 , which are the same or different;

R 11 and R 14 are independently selected from the group consisting of halogen; CN; C(O)OR 15 ; OR 15 ; C(O)R 15 ; C(O)N(R 15 R 15a ); S(O) 2 N(R 15 R 15a ); S(O)N(R 15 R 15a ); S(O) 2 R 15 ; S(O)R 15 ; N(R 15 )S(O) 2 N(R 15a R 15b ); SR 15 ; N(R 15 R 15a ); OC(O)R 15 ; N(R 15 )C(O)R 15a ; N(R 15 )S(O) 2 R 15a ; N(R 15 )S(O)R 15a ; N(R 15 )C(O)OR 15a ; N(R 15 )C(O)N(R 15a R 15b ); OC(O)N(R 15 R 15a ); and T 3 ;

R 15 , R 15a , and R 15b are independently selected from the group consisting of H; T 3 ; C 1-6 alkyl; C 2-6 alkenyl; and C 2-6 alkynyl, wherein C 1-6 alkyl; C 2-6 alkenyl; and C 2-6 alkynyl are optionally substituted with one or more halogen, which are the same or different;

T 3 is phenyl; C 3-7 cycloalkyl; or 3 to 7 membered heterocyclyl, wherein T 3 is optionally substituted with one or more R 16 , which are the same or different;

R 16 is halogen; CN; C(O)OR 17 ; OR 17 ; C(O)R 17 ; C(O)N(R 17 R 17a ); S(O) 2 N(R 17 R 17a ); S(O)N(R 17 R 17a ); S(O) 2 R 17 ; S(O)R 17 ; N(R 17 )S(O) 2 N(R 17a R 17b ); SR 17 ; N(R 17 R 17a ); OC(O)R 17 ; N(R 17 )C(O)R 17a ; N(R 17 )S(O) 2 R 17a ; N(R 17 )S(O)R 17a ; N(R 17 )C(O)OR 17a ; N(R 17 )C(O)N(R 17a R 17b ); OC(O)N(R 17 R 17a ); oxo (═O), where the ring is at least partially saturated; C 1-6 alkyl; C 2-6 alkenyl; or C 2-6 alkynyl, wherein C 1-6 alkyl; C 2-6 alkenyl; and C 2-6 alkynyl are optionally substituted with one or more halogen, which are the same or different;

R 17 , R 17a , and R 17b are independently selected from the group consisting of H; C 1-6 alkyl; C 2-6 alkenyl; and C 2-6 alkynyl, wherein C 1-6 alkyl; C 2-6 alkenyl; and C 2-6 alkynyl are optionally substituted with one or more halogen, which are the same or different;

R 4 is H; F; Cl; or N(CH 3 ) 2 ;

R 18 is H; C 1-6 alkyl; C 2-6 alkenyl; or C 2-6 alkynyl; wherein C 1-6 alkyl, C 2-6 alkenyl; and C 2-6 alkynyl are optionally substituted with one or more R 19 , which are the same or different;

R 19 is halogen; CN; C(O)OR 20 ; OR 20 ; C(O)R 20 ; C(O)N(R 20 R 20a ); S(O) 2 N(R 20 R 20a ); S(O)N(R 20 R 20a ); S(O) 2 R 20 ; S(O)R 20 ; N(R 20 )S(O) 2 N(R 20a R 20b ); SR 20 ; N(R 20 R 20a ); NO 2 ; OC(O)R 20 ; N(R 20 )C(O)R 20a ; N(R 20 )SO 2 R 20a ; N(R 20 )S(O)R 20a ; N(R 20 )C(O)N(R 20a R 20b ); N(R 20 )C(O)OR 20a ; or OC(O)N(R 20 R 20a ); and

R 20 , R 20a , and R 20b are independently selected from the group consisting of H; and C 1-6 alkyl, wherein C 1-6 alkyl is optionally substituted with one or more halogen, which are the same or different.

2. The pharmaceutical composition of claim 1 having formula (IIa)

3. The pharmaceutical composition of claim 1 , wherein R 18 is H.

4. The pharmaceutical composition of claim 1 , wherein X 1 is S(O) 2 .

5. The pharmaceutical composition of claim 1 , wherein R 1 is H.

6. The pharmaceutical composition of claim 1 , wherein X 2 is C(R 4 ).

7. The pharmaceutical composition of claim 1 , wherein R 4 is H; F; or N(CH 3 ) 2 .

8. The pharmaceutical composition of claim 1 , wherein R 2 is phenyl, 5 to 6 membered aromatic heterocyclyl, or 9 to 11 membered aromatic heterobicyclyl; and wherein R 2 is optionally substituted with one or two R 5 , which are the same or different.

9. The pharmaceutical composition of claim 1 , wherein R 2 is substituted with one or two R 5 , which are the same or different.

10. The pharmaceutical composition of claim 1 , wherein R 5 is halogen; CN; OR 6 ; C(O)N(R 6 R 6a ); T 1 ; or C 1-6 alkyl, wherein C 1-6 alkyl is optionally substituted with one or more halogen, which are the same or different.

11. The pharmaceutical composition of claim 1 , wherein T 1 is cyclopropyl; or 3 to 7 membered heterocyclyl, wherein T 1 is unsubstituted or substituted with unsubstituted C 1-6 alkyl.

12. The pharmaceutical composition of claim 1 , wherein R 2 in formula (I) is selected to give formula (IIaa) or (IIab)

13. The pharmaceutical composition of claim 1 , wherein R 3a is T 2 ; C 1-12 alkyl; unsubstituted C 2-12 alkenyl; or unsubstituted C 2-12 alkynyl, wherein C 1-12 alkyl is optionally substituted with one, two or three R 9 , which are the same or different.

14. The pharmaceutical composition of claim 1 , wherein T 2 is phenyl; C 3-7 cycloalkyl; or 3 to 7 membered heterocyclyl, wherein T 2 is optionally substituted with one or more R 12 , which are the same or different.

15. The pharmaceutical composition of claim 1 , wherein T 2 is unsubstituted or substituted with one or two R 12 , which are the same or different.

16. The pharmaceutical composition of claim 1 , wherein R 12 is halogen; OR 13 ; unsubstituted T 3 ; T 3 which is substituted with unsubstituted C 1-6 alkyl; or unsubstituted C 1-6 alkyl.

17. The pharmaceutical composition of claim 1 , wherein in formula (I) X 1 , X 2 , R 1 , R 2 , R 3 , and R 18 are selected to give:

(3R)-3-amino-5-[(4-chlorophenyl)methyl]-N-(2,2-difluorocyclopropyl)-8-fluoro-1,1,4-trioxo-2,3,4,5-tetrahydro-1λ 6 ,5-benzothiazepine-7-carboxamide;

(3R)-3-amino-N-butyl-5-[(4-tert-butylphenyl)methyl]-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-7-carboxamide;

(3R)-3-amino-N-butyl-4-oxo-5-{[4-(trifluoromethoxy)phenyl]methyl}-2,3,4,5-tetrahydro-1,5-benzothiazepine-7-carboxamide;

(3R)-3-amino-5-[(4-tert-butylphenyl)methyl]-4-oxo-N-(propan-2-yl)-2,3,4,5-tetrahydro-1,5-benzothiazepine-7-carboxamide;

(3R)-3-amino-N-butyl-8-fluoro-4-oxo-5-{[4-(trifluoromethoxy)phenyl]methyl}-2,3,4,5-tetrahydro-1,5-benzothiazepine-7-carboxamide;

(3R)-3-amino-N-benzyl-4-oxo-5-{[4-(trifluoromethoxy)phenyl]methyl}-2,3,4,5-tetrahydro-1,5-benzothiazepine-7-carboxamide;

(3R)-3-amino-N-[(4-methoxyphenyl)methyl]-4-oxo-5-{[4-(trifluoromethoxy)-phenyl]methyl}-2,3,4,5-tetrahydro-1,5-benzothiazepine-7-carboxamide;

(3R)-3-amino-N-(oxan-4-yl)-4-oxo-5-{[4-(trifluoromethoxy)phenyl]methyl}-2,3,4,5-tetrahydro-1,5-benzothiazepine-7-carboxamide;

(3R)-3-amino-N-butyl-4-oxo-5-{[3-(trifluoromethoxy)phenyl]methyl}-2,3,4,5-tetrahydro-1,5-benzothiazepine-7-carboxamide;

(3R)-3-amino-N-butyl-5-[(4-chlorophenyl)methyl]-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-7-carboxamide;

(3R)-3-amino-N-{[4-(morpholin-4-yl)phenyl]methyl}-4-oxo-5-{[4-(trifluoromethoxy)-phenyl]methyl}-2,3,4,5-tetrahydro-1,5-benzothiazepine-7-carboxamide;

N-(3-{[(3R)-3-amino-4-oxo-5-{[4-(trifluoromethoxy)phenyl]methyl}-2,3,4,5-tetrahydro-1,5-benzothiazepin-7-yl]formamido}propyl)-2,2-dimethylpropanamide;

(3R)-3-amino-N-butyl-5-{[4-(morpholin-4-yl)phenyl]methyl}-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-7-carboxamide;

(3R)-3-amino-8-fluoro-N-(oxan-4-yl)-4-oxo-5-{[4-(trifluoromethoxy)phenyl]methyl}-2,3,4,5-tetrahydro-1,5-benzothiazepine-7-carboxamide;

(3R)-3-amino-8-fluoro-4-oxo-N-(propan-2-yl)-5-{[4-(trifluoromethoxy)phenyl]-methyl}-2,3,4,5-tetrahydro-1,5-benzothiazepine-7-carboxamide;

(3R)-3-amino-N-benzyl-8-fluoro-4-oxo-5-{[4-(trifluoromethoxy)phenyl]methyl}-2,3,4,5-tetrahydro-1,5-benzothiazepine-7-carboxamide;

(3R)-3-amino-N-methyl-4-oxo-5-{[4-(trifluoromethoxy)phenyl]methyl}-2,3,4,5-tetrahydro-1,5-benzothiazepine-7-carboxamide;

(3R)-3-amino-N-ethyl-4-oxo-5-{[4-(trifluoromethoxy)phenyl]methyl}-2,3,4,5-tetrahydro-1,5-benzothiazepine-7-carboxamide;

(3R)-3-amino-N-({4-[(5-acetamidopentyl)oxy]phenyl}methyl)-4-oxo-5-{[4-(trifluoromethoxy)phenyl]methyl}-2,3,4,5-tetrahydro-1,5-benzothiazepine-7-carboxamide;

(3R)-3-amino-5-[(4-chlorophenyl)methyl]-N-(2-methoxyethyl)-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-7-carboxamide;

(3R)-3-amino-N-butyl-5-[(4-cyanophenyl)methyl]-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-7-carboxamide;

(3R)-3-amino-5-[(4-chlorophenyl)methyl]-4-oxo-N-(4,4,4-trifluorobutyl)-2,3,4,5-tetrahydro-1,5-benzothiazepine-7-carboxamide;

(3R)-3-amino-5-[(4-chlorophenyl)methyl]-N-(oxan-4-ylmethyl)-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-7-carboxamide;

(3R)-3-amino-N-(5-tert-butyl-1,2-oxazol-3-yl)-5-[(4-chlorophenyl)methyl]-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-7-carboxamide;

(3R)-3-amino-4-oxo-N-(pyridin-3-yl)-5-{[4-(trifluoromethoxy)phenyl]methyl}-2,3,4,5-tetrahydro-1,5-benzothiazepine-7-carboxamide;

(3R)-3-amino-5-[(4-chlorophenyl)methyl]-N-[(4-fluorophenyl)methyl]-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-7-carboxamide;

(3R)-3-amino-5-[(4-chlorophenyl)methyl]-N-[(1R)-1-(4-methoxyphenyl)ethyl]-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-7-carboxamide;

(3R)-3-amino-5-[(4-chlorophenyl)methyl]-N-(oxan-3-ylmethyl)-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-7-carboxamide;

(3R)-3-amino-4-oxo-N-(4,4,4-trifluorobutyl)-5-{[4-(trifluoromethoxy)phenyl]methyl}2,3,4,5-tetrahydro-1,5-benzothiazepine-7-carboxamide;

(3R)-3-amino-N-(oxan-4-ylmethyl)-4-oxo-5-{[4-(trifluoromethoxy)phenyl]-methyl}-2,3,4,5-tetrahydro-1,5-benzothiazepine-7-carboxamide;

(3R)-3-amino-N-[(4-fluorophenyl)methyl]-4-oxo-5-{[4-(trifluoromethoxy)phenyl]-methyl}-2,3,4,5-tetrahydro-1,5-benzothiazepine-7-carboxamide;

(3R)-3-amino-N-[(4-fluorophenyl)methyl]-4-oxo-5-{[4-(1,2,3-thiadiazol-4-yl)phenyl]-methyl}-2,3,4,5-tetrahydro-1,5-benzothiazepine-7-carboxamide;

(3R)-3-amino-5-[(4-chlorophenyl)methyl]-N-(4,4-difluorocyclohexyl)-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-7-carboxamide;

(3R)-3-amino-5-[(4-chlorophenyl)methyl]-N-[1-(4-fluorophenyl)ethyl]-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-7-carboxamide;

(3R)-3-amino-5-[(4-chlorophenyl)methyl]-N-[(1S)-1-(4-methoxyphenyl)ethyl]-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-7-carboxamide;

(3R)-3-amino-4-oxo-N-(4,4,4-trifluorobutyl)-5-{[6-(trifluoromethyl)pyridin-3-yl]methyl}-2,3,4,5-tetrahydro-1,5-benzothiazepine-7-carboxamide;

(3R)-3-amino-N-[(4-fluorophenyl)methyl]-4-oxo-5-{[6-(trifluoromethyl)pyridin-3-yl]methyl}-2,3,4,5-tetrahydro-1,5-benzothiazepine-7-carboxamide;

(3R)-3-amino-5-[(4-chlorophenyl)methyl]-N-[(1R)-1-(4-fluorophenyl)ethyl]-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-7-carboxamide;

(3R)-3-amino-5-[(4-chlorophenyl)methyl]-8-fluoro-N-[(4-fluorophenyl)methyl]-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-7-carboxamide;

(3R)-3-amino-5-[(4-chlorophenyl)methyl]-8-fluoro-4-oxo-N-(4,4,4-trifluorobutyl)-2,3,4,5-tetrahydro-1,5-benzothiazepine-7-carboxamide;

(3R)-3-amino-N-butyl-5-[(4-chlorophenyl)methyl]-8-fluoro-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-7-carboxamide;

(3R)-3-amino-5-[(4-chlorophenyl)methyl]-8-fluoro-N-(oxan-4-yl methyl)-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-7-carboxamide;

(3R)-3-amino-5-[(4-chlorophenyl)methyl]-8-fluoro-N-[(4-methoxyphenyl)methyl]-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-7-carboxamide;

(3R)-3-amino-5-{[4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl]methyl}-N-(oxan-4-ylmethyl)-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-7-carboxamide;

(3R)-3-amino-5-[(4-fluorophenyl)methyl]-N-(oxan-4-ylmethyl)-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-7-carboxamide;

(3R)-3-amino-N-butyl-4-oxo-5-{[4-(1H-1,2,4-triazol-1-yl)phenyl]methyl}-2,3,4,5-tetrahydro-1,5-benzothiazepine-7-carboxamide;

(3R)-3-amino-N-butyl-5-[(4-carbamoyl phenyl)methyl]-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-7-carboxamide;

(3R)-3-amino-5-[(4-chlorophenyl)methyl]-N-(2-hydroxy-2-methylpropyl)-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-7-carboxamide;

(3R)-3-amino-5-[(4-chlorophenyl)methyl]-N-[(1S)-1-(4-fluorophenyl)ethyl]-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-7-carboxamide;

(3R)-3-amino-5-[(4-chlorophenyl)methyl]-8-fluoro-N-(2-hydroxy-2-methylpropyl)-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-7-carboxamide;

(3R)-3-amino-5-[(4-chlorophenyl)methyl]-4-oxo-N-(4,4,4-trifluorobutyl)-2,3,4,5-tetrahydro-1,5-benzothiazepine-7-carboxamide;

(3R)-3-amino-5-[(4-chlorophenyl)methyl]-8-fluoro-N′-(4-fluorophenyl)-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-7-carbohydrazide;

(3R)-3-amino-N-butanoyl-5-[(4-chlorophenyl)methyl]-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-7-carbohydrazide;

(3R)-3-amino-N-butyl-5-[(4-chloro-2-fluorophenyl)methyl]-8-fluoro-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-7-carboxamide;

(3R)-3-amino-5-[(4-chloro-2-fluorophenyl)methyl]-8-fluoro-N-(oxan-4-ylmethyl)-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-7-carboxamide;

(3R)-3-amino-5-[(4-chloro-3-fluorophenyl)methyl]-8-fluoro-N-(oxan-4-ylmethyl)-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-7-carboxamide;

(3R)-3-amino-N-butyl-5-[(4-chloro-3-fluorophenyl)methyl]-8-fluoro-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-7-carboxamide;

(3R)-3-amino-5-[(4-chlorophenyl)methyl]-8-fluoro-4-oxo-N-propoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine-7-carboxamide;

(3R)-3-amino-5-[(4-chlorophenyl)methyl]-8-fluoro-N-(2-methyl propoxy)-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-7-carboxamide;

(3R)-3-amino-5-[(4-chlorophenyl)methyl]-8-fluoro-N′-(2-methyl propyl)-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-7-carbohydrazide;

(3R)-3-amino-5-[(4-chlorophenyl)methyl]-4-oxo-N-(propan-2-yl)-2,3,4,5-tetrahydro-1,5-benzothiazepine-7-carboxamide;

(3R)-3-amino-5-[(4-chlorophenyl)methyl]-N-(2-methylpropoxy)-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-7-carboxamide;

(3R)-3-amino-5-[(4-chlorophenyl)methyl]-N-(3-methyl butan-2-yl)-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-7-carboxamide;

(3R)-3-amino-N-(but-3-en-1-yl)-5-[(4-chlorophenyl)methyl]-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-7-carboxamide;

(3R)-3-amino-5-[(4-chlorophenyl)methyl]-N′-(2-methylpropyl)-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-7-carbohydrazide;

(3R)-3-amino-N-butyl-5-[(4-chlorophenyl)methyl]-1,4-dioxo-2,3,4,5-tetrahydro-1λ 4 ,5-benzothiazepine-7-carboxamide;

(3R)-3-amino-N-butyl-1,1,4-trioxo-5-{[4-(trifluoromethoxy)phenyl]methyl}-2,3,4,5-tetrahydro-1λ 6 ,5-benzothiazepine-7-carboxamide;

(3R)-3-amino-5-[(4-chlorophenyl)methyl]-8-fluoro-N-[(4-fluorophenyl)methyl]-1,1,4-trioxo-2,3,4,5-tetrahydro-1λ 6 ,5-benzothiazepine-7-carboxamide;

(3R)-3-amino-N-butyl-5-[(4-chlorophenyl)methyl]-8-fluoro-1,1,4-trioxo-2,3,4,5-tetrahydro-1λ 6 ,5-benzothiazepine-7-carboxamide;

(3R)-3-amino-5-[(4-chlorophenyl)methyl]-8-fluoro-1,1,4-trioxo-N-(4,4,4-trifluoro-butyl)-2,3,4,5-tetrahydro-1λ 6 ,5-benzothiazepine-7-carboxamide;

(3R)-3-amino-5-[(4-chlorophenyl)methyl]-8-fluoro-N-(oxan-4-ylmethyl)-1,1,4-trioxo-2,3,4,5-tetrahydro-1λ 6 ,5-benzothiazepine-7-carboxamide;

(3R)-3-amino-8-fluoro-N-(oxan-4-yl methyl)-1,1,4-trioxo-5-{[4-(trifluoromethoxy)-phenyl]methyl}-2,3,4,5-tetrahydro-1λ 6 ,5-benzothiazepine-7-carboxamide;

(3R)-3-amino-8-fluoro-1,1,4-trioxo-N-(4,4,4-trifluorobutyl)-5-{[4-(trifluoromethoxy)-phenyl]methyl}-2,3,4,5-tetrahydro-1λ 6 ,5-benzothiazepine-7-carboxamide;

(3R)-3-amino-8-fluoro-1,1,4-trioxo-N-phenoxy-5-{[4-(trifluoromethoxy)phenyl]methyl}-2,3,4,5-tetrahydro-1λ 6 ,5-benzothiazepine-7-carboxamide;

(3R)-3-amino-5-[(4-chlorophenyl)methyl]-8-fluoro-N-(2-methylpropoxy)-1,1,4-trioxo-2,3,4,5-tetrahydro-1λ 6 ,5-benzothiazepine-7-carboxamide;

(3R)-3-amino-5-[(4-chlorophenyl)methyl]-8-fluoro-1,1,4-trioxo-N-phenoxy-2,3,4,5-tetrahydro-1λ 6 ,5-benzothiazepine-7-carboxamide;

(3R)-3-amino-5-[(4-chlorophenyl)methyl]-8-fluoro-1,1,4-trioxo-N-(propan-2-yl)-2,3,4,5-tetrahydro-1λ 6 ,5-benzothiazepine-7-carboxamide;

(3R)-3-amino-5-[(4-chlorophenyl)methyl]-N-({4-[(5-acetamidopentyl)oxy]phenyl}-methyl)-1,1,4-trioxo-2,3,4,5-tetrahydro-1λ 6 ,5-benzothiazepine-7-carboxamide;

(3R)-3-amino-5-[(4-chlorophenyl)methyl]-1,1,4-trioxo-N-(propan-2-yl)-2,3,4,5-tetrahydro-1λ 6 ,5-benzothiazepine-7-carboxamide;

(3R)-3-amino-5-[(4-chlorophenyl)methyl]-1,1,4-trioxo-N-(4,4,4-trifluorobutyl)-2,3,4,5-tetrahydro-1λ 6 ,5-benzothiazepine-7-carboxamide;

(3R)-3-amino-5-[(4-chlorophenyl)methyl]-N-(2-methylpropoxy)-1,1,4-trioxo-2,3,4,5-tetrahydro-1λ 6 ,5-benzothiazepine-7-carboxamide;

(3R)-3-amino-5-[(4-chlorophenyl)methyl]-1,1,4-trioxo-N-propoxy-2,3,4,5-tetrahydro-1λ 6 ,5-benzothiazepine-7-carboxamide;

(3R)-3-amino-5-[(4-chlorophenyl)methyl]-N-(3-methylbutan-2-yl)-1,1,4-trioxo-2,3,4,5-tetrahydro-1λ 6 ,5-benzothiazepine-7-carboxamide;

(3R)-3-amino-N-(but-3-en-1-yl)-5-[(4-chlorophenyl)methyl]-1,1,4-trioxo-2,3,4,5-tetrahydro-1λ 6 ,5-benzothiazepine-7-carboxamide;

(3R)-3-amino-5-[(4-chlorophenyl)methyl]-N-cyclopropyl-8-fluoro-1,1,4-trioxo-2,3,4,5-tetrahydro-1λ 6 ,5benzothiazepine-7-carboxamide;

(3R)-3-amino-5-[(4-chlorophenyl)methyl]-N-cyclobutyl-8-fluoro-1,1,4-trioxo-2,3,4,5-tetrahydro-1λ 6 ,5-benzothiazepine-7-carboxamide;

(3R)-3-amino-5-[(4-chloro-2-fluorophenyl)methyl]-8-fluoro-1,1,4-trioxo-N-(propan-2-yl)-2,3,4,5-tetrahydro-1λ 6 ,5-benzothiazepine-7-carboxamide;

(3R)-3-amino-5-[(3,4-dichlorophenyl)methyl]-1,1,4-trioxo-N-(propan-2-yl)-2,3,4,5-tetrahydro-1λ 6 ,5-benzothiazepine-7-carboxamide;

(3R)-3-amino-5-[(4-chloro-3-fluorophenyl)methyl]-1,1,4-trioxo-N-(propan-2-yl)-2,3,4,5-tetrahydro-1λ 6 ,5-benzothiazepine-7-carboxamide;

(3R)-3-amino-5-[(4-chlorophenyl)methyl]-N-(cyclohexyloxy)-1,1,4-trioxo-2,3,4,5-tetrahydro-1λ 6 ,5-benzothiazepine-7-carboxamide;

(3R)-3-amino-5-[(4-chlorophenyl)methyl]-N-(cyclohexylmethoxy)-1,1,4-trioxo-2,3,4,5-tetrahydro-1λ 6 ,5-benzothiazepine-7-carboxamide;

(3R)-3-amino-5-[(4-chlorophenyl)methyl]-8-fluoro-1,1,4-trioxo-N-(2,2,2-trifluoro-ethyl)-2,3,4,5-tetrahydro-1λ 6 ,5-benzothiazepine-7-carboxamide;

(3R)-3-amino-5-[(4-chlorophenyl)methyl]-8-fluoro-1,1,4-trioxo-N-(3,3,3-trifluoro-propyl)-2,3,4,5-tetrahydro-1λ 6 ,5-benzothiazepine-7-carboxamide;

(3R)-3-amino-5-[(4-chlorophenyl)methyl]-8-fluoro-1,1,4-trioxo-N-[(2S)-1,1,1-trifluoropropan-2-yl]-2,3,4,5-tetrahydro-1λ 6 ,5-benzothiazepine-7-carboxamide;

(3R)-3-amino-N-(butan-2-yl)-5-[(4-chlorophenyl)methyl]-8-fluoro-1,1,4-trioxo-2,3,4,5-tetrahydro-1λ 6 ,5-benzothiazepine-7-carboxamide;

(3R)-3-amino-N-tert-butyl-5-[(4-chlorophenyl)methyl]-8-fluoro-1,1,4-trioxo-2,3,4,5-tetrahydro-1λ 6 ,5-benzothiazepine-7-carboxamide;

(3R)-3-amino-N-(tert-butoxy)-5-[(4-chlorophenyl)methyl]-1,1,4-trioxo-2,3,4,5-tetrahydro-1λ 6 ,5-benzothiazepine-7-carboxamide;

(3R)-3-amino-5-[(4-chlorophenyl)methyl]-8-fluoro-1,1,4-trioxo-N-[(1S,2R)-2-phenylcyclopropyl]-2,3,4,5-tetrahydro-1λ 6 ,5-benzothiazepine-7-carboxamide;

(3R)-3-amino-5-[(4-chlorophenyl)methyl]-8-fluoro-N-(1-methylcyclopropyl)-1,1,4-trioxo-2,3,4,5-tetrahydro-1λ 6 ,5-benzothiazepine-7-carboxamide;

(3R)-3-amino-5-[(4-chlorophenyl)methyl]-8-fluoro-N-(1-methylcyclobutyl)-1,1,4-trioxo-2,3,4,5-tetrahydro-1λ 6 ,5-benzothiazepine-7-carboxamide;

(3R)-3-amino-5-[(4-chlorophenyl)methyl]-N-(2,2-dimethylcyclopropyl)-8-fluoro-1,1,4-trioxo-2,3,4,5-tetrahydro-1λ 6 ,5-benzothiazepine-7-carboxamide;

(3R)-3-amino-5-[(4-chlorophenyl)methyl]-N-(3,3-difluorocyclobutyl)-8-fluoro-1,1,4-trioxo-2,3,4,5-tetrahydro-1λ 6 ,5-benzothiazepine-7-carboxamide;

(3R)-3-amino-N-benzyl-5-[(4-chlorophenyl)methyl]-8-fluoro-1,1,4-trioxo-2,3,4,5-tetrahydro-1λ 6 ,5-benzothiazepine-7-carboxamide;

(3R)-3-amino-5-[(4-chlorophenyl)methyl]-8-fluoro-N-heptyl-1,1,4-trioxo-2,3,4,5-tetrahydro-1λ 6 ,5-benzothiazepine-7-carboxamide;

(3R)-3-amino-5-[(4-chlorophenyl)methyl]-N-(3,3-difluorocyclopentyl)-8-fluoro-1,1,4-trioxo-2,3,4,5-tetrahydro-1λ 6 ,5-benzothiazepine-7-carboxamide;

(3R)-3-amino-5-[(4-chlorophenyl)methyl]-N-[(1R)-2,2-difluorocyclopropyl]-8-fluoro-1,1,4-trioxo-2,3,4,5-tetrahydro-1λ 6 ,5-benzothiazepine-7-carboxamide;

(3R)-3-amino-5-[(4-chlorophenyl)methyl]-N-[(1S)-2,2-difluorocyclopropyl]-8-fluoro-1,1,4-trioxo-2,3,4,5-tetrahydro-1λ 6 ,5-benzothiazepine-7-carboxamide;

(2R,3R)-3-amino-5-[(4-chlorophenyl)methyl]-N-(2,2-difluorocyclopropyl)-2-methyl-1,1,4-trioxo-2,3,4,5-tetrahydro-1λ 6 ,5-benzothiazepine-7-carboxamide;

(3R)-3-amino-5-[(4-chlorophenyl)methyl]-8-fluoro-N-hexadecyl-1,1,4-trioxo-2,3,4,5-tetrahydro-1λ 6 ,5-benzothiazepine-7-carboxamide;

(3R)-3-amino-5-[(4-chlorophenyl)methyl]-N-(cyclopropylmethyl)-8-fluoro-1,1,4-trioxo-2,3,4,5-tetrahydro-1λ 6 ,5-benzothiazepine-7-carboxamide;

(2R,3R)-3-amino-5-[(4-chlorophenyl)methyl]-2-methyl-1,1,4-trioxo-N-(4,4,4-trifluorobutyl)-2,3,4,5-tetrahydro-1λ 6 ,5-benzothiazepine-7-carboxamide;

(3R)-3-amino-N-butyl-8-fluoro-4-oxo-5-(quinolin-2-ylmethyl)-2,3,4,5-tetrahydro-1,5-benzothiazepine-7-carboxamide;

(3R)-3-amino-5-[(5-cyclopropyl-1,3,4-thiadiazol-2-yl)methyl]-8-fluoro-N-[(4-fluorophenyl)methyl]-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-7-carboxamide;

(3R)-3-amino-N-butyl-5-[(4-chlorophenyl)methyl]-8-(dimethylamino)-1,1,4-trioxo-2,3,4,5-tetrahydro-1λ 6 ,5-benzothiazepine-7-carboxamide;

tert-butyl N-(5-{[(3R)-5-[(4-chlorophenyl)methyl]-8-fluoro-7-{[(4-methoxyphenyl)methyl]carbamoyl}-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepin-3-yl]amino}pentyl)carbamate;

(3R)-3-amino-N-butyl-1-[(4-chlorophenyl)methyl]-2,5,5-trioxo-1H,2H,3H,4H-5λ 6 -pyrido[3,4-b][1,4]thiazepine-8-carboxamide;

(3R)-3-amino-N-benzyl-5-[(4-chlorophenyl)methyl]-8-(dimethylamino)-1,1,4-trioxo-2,3,4,5-tetrahydro-1λ 6 , 5-benzothiazepine-7-carboxamide;

(3R)-3-amino-N-(2,2-difluorocyclopropyl)-8-fluoro-5-{[4-methoxy-3-(trifluoromethyl)phenyl]methyl}-1,1,4-trioxo-2,3,4,5-tetrahydro-1λ 6 ,5-benzothiazepine-7-carboxamide;

(2R,3R)-3-amino-5-[(4-chlorophenyl)methyl]-8-fluoro-2-methyl-1,1,4-trioxo-N-(4,4,4-trifluorobutyl)-2,3,4,5-tetrahydro-1λ 6 ,5-benzothiazepine-7-carboxamide;

(3R)-3-amino-5-{[4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl]methyl}-1,1,4-trioxo-N-(4,4,4-trifluorobutyl)-2,3,4,5-tetrahydro-1λ 6 ,5-benzothiazepine-7-carboxamide;

(3R)-3-amino-5-[(4-chlorophenyl)methyl]-8-fluoro-N-(2-methoxyethyl)-1,1,4-trioxo-2,3,4,5-tetrahydro-1λ 6 ,5-benzothiazepine-7-carboxamide;

(3R)-3-amino-N-(2,2-difluorocyclopropyl)-5-{[4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl]methyl}-1,1,4-trioxo-2,3,4,5-tetrahydro-1λ 6 ,5-benzothiazepine-7-carboxamide;

(1S,3R)-3-amino-5-[(4-chlorophenyl)methyl]-8-fluoro-4-oxo-7-[(4,4,4-trifluorobutyl)carbamoyl]-2,3,4,5-tetrahydro-1H-1,5-benzothiazepin-1-ium-1-olate;

(1R,3R)-3-amino-5-[(4-chlorophenyl)methyl]-8-fluoro-4-oxo-7-[(4,4,4-trifluorobutyl)carbamoyl]-2,3,4,5-tetrahydro-1H-1,5-benzothiazepin-1-ium-1-olate;

(3R)-3-amino-5-[(4-cyanophenyl)methyl]-N-(2,2-difluorocyclopropyl)-8-fluoro-1,1,4-trioxo-2,3,4,5-tetrahydro-1λ 6 ,5-benzothiazepine-7-carboxamide;

(3R)-3-amino-5-[(4-cyanophenyl)methyl]-8-fluoro-1,1,4-trioxo-N-(4,4,4-trifluorobutyl)-2,3,4,5-tetrahydro-1λ 6 ,5-benzothiazepine-7-carboxamide;

(3R)-3-amino-5-[(4-chlorophenyl)methyl]-N-(4,4-difluorocyclohexyl-8-fluoro-1,1,4-trioxo-2,3,4,5-tetrahydro-1λ 6 ,5-benzothiazepine-7-carboxamide;

(3R)-3-amino-5-[(4-chlorophenyl)methyl]-8-fluoro-1,1,4-trioxo-N-[2-(trifluoromethyl)cyclopropyl]-2,3,4,5-tetrahydro-1λ 6 ,5-benzothiazepine-7-carboxamide;

(3R)-3-amino-5-[(4-chlorophenyl)methyl]-N-(3,3-difluorocyclobutyl)-8-fluoro-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-7-carboxamide;

(3R)-3-amino-8-fluoro-5-[(4-fluorophenyl)methyl]-1,1,4-trioxo-N-(4,4,4-trifluorobutyl)-2,3,4,5-tetrahydro-1λ 6 ,5-benzothiazepine-7-carboxamide;

(3R)-3-amino-N-(2,2-difluorocyclopropyl)-8-fluoro-5-[(4-fluorophenyl)methyl]-1,1,4-trioxo-2,3,4,5-tetrahydro-1λ 6 ,5-benzothiazepine-7-carboxamide;

(3R)-3-amino-N-butyl-8-fluoro-5-[(4-fluorophenyl)methyl]-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-7-carboxamide;

(3R)-3-amino-N-benzyl-8-fluoro-5-[(4-fluorophenyl)methyl]-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-7-carboxamide;

(3R)-3-amino-N-butyl-8-fluoro-5-[(4-fluorophenyl)methyl]-1,1,4-trioxo-2,3,4,5-tetrahydro-1λ 6 ,5-benzothiazepine-7-carboxamide;

(3R)-3-amino-N-benzyl-8-fluoro-5-[(4-fluorophenyl)methyl]-1,1,4-trioxo-2,3,4,5-tetrahydro-1λ 6 ,5-benzothiazepine-7-carboxamide;

(3R)-3-amino-5-[(4-chlorophenyl)methyl]-8-fluoro-N-[2-(oxan-4-yl)ethyl]-1,1,4-trioxo-2,3,4,5-tetrahydro-1λ 6 ,5-benzothiazepine-7-carboxamide;

(3R)-3-amino-5-benzyl-8-fluoro-1,1,4-trioxo-N-(4,4,4-trifluorobutyl)-2,3,4,5-tetrahydro-1λ 6 ,5-benzothiazepine-7-carboxamide;

(3R)-3-amino-5-[(4-chlorophenyl)methyl]-8-fluoro-N-[(4-methoxyphenyl)methyl]-1,1,4-trioxo-2,3,4,5-tetrahydro-1λ 6 ,5-benzothiazepine-7-carboxamide;

(3R)-3-amino-5-[(5-cyclopropyl-1,3,4-thiadiazol-2-yl)methyl]-8-fluoro-N-[(4-fluorophenyl)methyl]-1,1,4-trioxo-2,3,4,5-tetrahydro-1λ 6 ,5-benzothiazepine-7-carboxamide;

(3R)-3-amino-8-fluoro-5-[(4-fluorophenyl)methyl]-N-[(oxan-4-yl)methyl]-1,1,4-trioxo-2,3,4,5-tetrahydro-1λ 6 ,5-benzothiazepine-7-carboxamide;

(3R)-3-amino-N-(3,3-difluorocyclobutyl-8-fluoro-5-[(4-fluorophenyl)methyl]-1,1,4-trioxo-2,3,4,5-tetrahydro-1λ 6 ,5-benzothiazepine-7-carboxamide;

(3R)-3-amino-8-fluoro-5-[(4-methoxyphenyl)methyl]-1,1,4-trioxo-N-(4,4,4-trifluorobutyl)-2,3,4,5-tetrahydro-1λ 6 ,5-benzothiazepine-7-carboxamide;

(3R)-3-amino-8-fluoro-5-[(4-methoxyphenyl)methyl]-N-[(oxan-4-yl)methyl]-1,1,4-trioxo-2,3,4,5-tetrahydro-1λ 6 ,5-benzothiazepine-7-carboxamide;

(3R)-3-amino-N-(2,2-difluorocyclopropyl)-8-fluoro-5-[(4-methoxyphenyl)methyl]-1,1,4-trioxo-2,3,4,5-tetrahydro-1λ 6 ,5-benzothiazepine-7-carboxamide;

(3R)-3-amino-5-[(4-chlorophenyl)methyl]-8-fluoro-N-(oxan-4-yl)-1,1,4-trioxo-2,3,4,5-tetrahydro-1λ 6 ,5-benzothiazepine-7-carboxamide;

(3R)-3-amino-5-[(4-chlorophenyl)methyl]-N-(3,3-difluorocyclobutyl)-1,1,4-trioxo-2,3,4,5-tetrahydro-1λ 6 ,5-benzothiazepine-7-carboxamide;

(3R)-3-amino-5-[(4-chlorophenyl)methyl]-N-[(1S)-3,3-difluorocyclopentyl]-8-fluoro-1,1,4-trioxo-2,3,4,5-tetrahydro-1λ 6 ,5-benzothiazepine-7-carboxamide;

(3R)-3-amino-5-[(4-chlorophenyl)methyl]-N-[(1R,2S)-2-fluorocyclopropyl]-1,1,4-trioxo-2,3,4,5-tetrahydro-1λ 6 ,5-benzothiazepine-7-carboxamide;

(3R)-3-amino-N-(3,3-difluorocyclobutyl)-5-[(2-fluorophenyl)methyl]-1,1,4-trioxo-2,3,4,5-tetrahydro-1λ 6 ,5-benzothiazepine-7-carboxamide;

(3R)-3-amino-N-(3,3-difluorocyclobutyl)-5-[(3-methoxyphenyl)methyl]-1,1,4-trioxo-2,3,4,5-tetrahydro-1λ 6 ,5-benzothiazepine-7-carboxamide;

(3R)-3-amino-5-[(4-methoxyphenyl)methyl]-1,1,4-trioxo-N-(4,4,4-trifluorobutyl)-2,3,4,5-tetrahydro-1λ 6 ,5-benzothiazepine-7-carboxamide;

(3R)-3-amino-N,5-bis[(4-methoxyphenyl)methyl]-1,1,4-trioxo-2,3,4,5-tetrahydro-1λ 6 ,5-benzothiazepine-7-carboxamide;

(3R)-3-amino-5-benzyl-N-[(4-methoxyphenyl)methyl]-1,1,4-trioxo-2,3,4,5-tetrahydro-1λ 6 ,5-benzothiazepine-7-carboxamide;

(3R)-3-amino-5-[(4-chlorophenyl)methyl]-N-[(4-methoxyphenyl)methyl]-1,1,4-trioxo-2,3,4,5-tetrahydro-1λ 6 ,5-benzothiazepine-7-carboxamide;

(3R)-3-amino-N-(4,4-difluorocyclohexyl)-5-[(4-methoxyphenyl)methyl]-1,1,4-trioxo-2,3,4,5-tetrahydro-1λ 6 , 5-benzothiazepine-7-carboxamide;

(3R)-3-amino-5-[(4-chlorophenyl)methyl]-1,1,4-trioxo-N-(3,3,3-trifluoropropyl)-2,3,4,5-tetrahydro-1λ 6 ,5-benzothiazepine-7-carboxamide;

(3R)-3-amino-5-[(4-chlorophenyl)methyl]-1,1,4-trioxo-N-[(3R)-oxolan-3-yl]-2,3,4,5-tetrahydro-1λ 6 ,5-benzothiazepine-7-carboxamide;

(3R)-3-amino-5-[(4-chlorophenyl)methyl]-1,1,4-trioxo-N-[(oxolan-3-yl)methyl]-2,3,4,5-tetrahydro-1λ 6 ,5-benzothiazepine-7-carboxamide;

(3R)-3-amino-5-[(4-chlorophenyl)methyl]-N-[(1R)-2,2-difluorocyclopropyl]-1,1,4-trioxo-2,3,4,5-tetrahydro-1λ 6 ,5-benzothiazepine-7-carboxamide;

(3R)-3-amino-5-[(4-cyclopropylphenyl)methyl]-N-[(1R)-2,2-difluorocyclopropyl]-1,1,4-trioxo-2,3,4,5-tetrahydro-1λ 6 ,5-benzothiazepine-7-carboxamide;

(3R)-3-amino-N-[(1R)-2,2-difluorocyclopropyl]-5-{[4-(difluoromethoxy)phenyl]methyl}-1,1,4-trioxo-2,3,4,5-tetrahydro-1λ 6 ,5-benzothiazepine-7-carboxamide;

(3R)-3-amino-N-[(1R)-2,2-difluorocyclopropyl]-5-[(4-methoxyphenyl)methyl]-1,1,4-trioxo-2,3,4,5-tetrahydro-1λ 6 ,5-benzothiazepine-7-carboxamide;

(3R)-3-amino-5-benzyl-1,1,4-trioxo-N-(4,4,4-trifluorobutyl)-2,3,4,5-tetrahydro-1λ 6 ,5-benzothiazepine-7-carboxamide;

(3R)-3-amino-8-chloro-5-[(4-chlorophenyl)methyl]-1,1,4-trioxo-N-(4,4,4-trifluorobutyl)-2,3,4,5-tetrahydro-1λ 6 ,5-benzothiazepine-7-carboxamide;

(3R)-3-amino-5-{[4-(difluoromethoxy)phenyl]methyl}-N-[(oxan-4-yl)methyl]-1,1,4-trioxo-2,3,4,5-tetrahydro-1λ 6 ,5-benzothiazepine-7-carboxamide;

(3R)-3-amino-5-[(4-chlorophenyl)methyl]-N-[(4-fluorooxan-4-yl)methyl]-1,1,4-trioxo-2,3,4,5-tetrahydro-1λ 6 ,5-benzothiazepine-7-carboxamide;

(3R)-3-amino-5-[(4-chlorophenyl)methyl]-N-[(1R)-1-(oxan-4-yl)ethyl]-1,1,4-trioxo-2,3,4,5-tetrahydro-1λ 6 ,5-benzothiazepine-7-carboxamide;

(3R)-3-amino-5-benzyl-N-[(1R)-2,2-difluorocyclopropyl]-1,1,4-trioxo-2,3,4,5-tetrahydro-1λ 6 ,5-benzothiazepine-7-carboxamide;

(3R)-3-amino-5-[(4-chlorophenyl)methyl]-N-[(6-methylpyridin-3-yl)methyl]-1,1,4-trioxo-2,3,4,5-tetrahydro-1λ 6 ,5-benzothiazepine-7-carboxamide;

(3R)-3-amino-5-[(4-chlorophenyl)methyl]-N-[(1R)-3,3-difluorocyclopentyl]-1,1,4-trioxo-2,3,4,5-tetrahydro-1λ 6 ,5-benzothiazepine-7-carboxamide;

(3R)-3-amino-5-[(4-cyanophenyl)methyl]-8-fluoro-N-[(4-fluorophenyl)methyl]-1,1,4-trioxo-2,3,4,5-tetrahydro-1λ 6 ,5-benzothiazepine-7-carboxamide;

(3R)-3-amino-5-[(4-chlorophenyl)methyl]-N-[(3,3-difluorocyclobutyl)methyl]-1,1,4-trioxo-2,3,4,5-tetrahydro-1λ 6 ,5-benzothiazepine-7-carboxamide;

(3R)-3-amino-5-[(4-chlorophenyl)methyl]-8-fluoro-N-[2-(2-methoxyethoxy)ethyl]-1,1,4-trioxo-2,3,4,5-tetrahydro-1λ 6 ,5-benzothiazepine-7-carboxamide;

(3R)-3-amino-N-(but-3-yn-1-yl)-5-[(4-chlorophenyl)methyl]-8-fluoro-1,1,4-trioxo-2,3,4,5-tetrahydro-1λ 6 ,5-benzothiazepine-7-carboxamide;

(3R)-3-amino-5-[(4-chlorophenyl)methyl]-8-fluoro-1,1,4-trioxo-N-(pent-4-yn-1-yl)-2,3,4,5-tetrahydro-1λ 6 , 5-benzothiazepine-7-carboxamide;

(3R)-3-amino-8-chloro-5-[(4-chlorophenyl)methyl]-N-[(1R)-2,2-difluorocyclopropyl]-1,1,4-trioxo-2,3,4,5-tetrahydro-1λ 6 ,5-benzothiazepine-7-carboxamide;

(3R)-3-amino-5-[(4-chlorophenyl)methyl]-N-[2-(morpholin-4-yl)ethyl]-1,1,4-trioxo-2,3,4,5-tetrahydro-1λ 6 ,5-benzothiazepine-7-carboxamide;

(3R)-3-amino-5-[(4-chlorophenyl)methyl]-N-[(6-methoxypyridin-3-yl)methyl]-1,1,4-trioxo-2,3,4,5-tetrahydro-1λ 6 ,5-benzothiazepine-7-carboxamide;

(3R)-3-amino-5-[(4-chlorophenyl)methyl]-8-fluoro-1,1,4-trioxo-N-{[4-(prop-2-yn-1-yloxy)phenyl]methyl}-2,3,4,5-tetrahydro-1λ 6 ,5-benzothiazepine-7-carboxamide;

(3R)-3-amino-N-[(1R)-2,2-difluorocyclopropyl]-1,1,4-trioxo-5-{[4-(trifluoromethyl)phenyl]methyl}-2,3,4,5-tetrahydro-1λ 6 ,5-benzothiazepine-7-carboxamide;

(3R)-3-amino-5-[(4-bromophenyl)methyl]-N-(2,2-difluorocyclopropyl)-1,1,4-trioxo-2,3,4,5-tetrahydro-1λ 6 ,5-benzothiazepine-7-carboxamide;

(3R)-3-amino-5-[(4-chlorophenyl)methyl]-N-{2-oxaspiro[3.3]heptan-6-yl}-, 1,4-trioxo-2,3,4,5-tetrahydro-1λ 6 ,5-benzothiazepine-7-carboxamide; or

(3R)-5-[(4-chlorophenyl)methyl]-3-(ethylamino)-8-fluoro-1,1,4-trioxo-N-(4,4,4-trifluorobutyl)-2,3,4,5-tetrahydro-1λ 6 ,5-benzothiazepine-7-carboxamide.

18. A compound or a pharmaceutically acceptable salt thereof as defined claim 1 .

19. The compound or pharmaceutically acceptable salt thereof of claim 18 , wherein the following compound or a pharmaceutically acceptable salt thereof is excluded:

20. The compound or pharmaceutically acceptable salt thereof claim 18 , wherein the following compounds or pharmaceutically acceptable salts thereof are excluded:

wherein X 1 is S; S(O); or S(O) 2 ;

R 2 is phenyl; 3-chlorophenyl; 4-fluorophenyl; 4-methoxyphenyl; 3,5-dimethyl-1,2-oxazol-4-yl; 2-chlorothiophen-5-yl; pyridin-4-yl; 1,3-benzodioxol-5-yl; 5-phenyl-1,2,4-oxadiazol-3-yl; 3-(4-tert butylphenyl)-1,2,4-oxadiazol-5-yl; biphen-4-yl; or 3,4,5-trimethoxyphenyl; and

R 3 is n-butyl; 2-hydroxy-1-hydroxycarbonyl-ethyl; 2-hydroxycarbonylethyl; phenyl; or benzyl.

21. The compound or pharmaceutically acceptable salt thereof of claim 18 , wherein the following compounds or pharmaceutically acceptable salts thereof are excluded:

wherein X 1 is S; S(O); or S(O) 2 ;

R 2 is phenyl; 3 to 7 membered heterocyclyl; or 7 to 11 membered heterobicyclyl, wherein R 2 is optionally substituted with one or more R 5 , which are the same or different; and

R 3 is n-butyl; 2-hydroxy-1-hydroxycarbonyl-ethyl; 2-hydroxycarbonylethyl; phenyl; or benzyl.

22. The pharmaceutical composition of claim 7 , wherein R 4 is H or F.

23. The pharmaceutical composition of claim 8 , wherein R 2 is phenyl, pyridyl, thiadiazolyl, or quinolinyl; and wherein R 2 is optionally substituted with one or two R 5 , which are the same or different.

24. The pharmaceutical composition of claim 8 , wherein R 2 is phenyl or pyridyl; and wherein R 2 is optionally substituted with one or two R 5 , which are the same or different.

25. The pharmaceutical composition of claim 8 , wherein R 2 is phenyl; and wherein R 2 is optionally substituted with one or two R 5 , which are the same or different.

26. The pharmaceutical composition of claim 10 , wherein R 5 is F; Cl; Br; CN; OCH 3 ; OCHF 2 ; OCF 3 ; C(O)NH 2 ; 1H-1,2,4-triazol-1yl; cyclopropyl; 5-methyl-1,2,4-oxadiazol-3-yl; 1,2,3thiadiazol-4yl; morpholin-4-yl; tert-butyl; or CF 3 .

27. The pharmaceutical composition of claim 10 , wherein R 5 is F; Cl; CN; OCF 3 ; C(O)NH 2 ; 1H-1,2,4-triazol-1-yl; cyclopropyl; 5-methyl-1,2,4-oxadiazol-3-yl; 1,2,3-thiadiazol-4-yl; morpholin-4-yl; tert-butyl; or CF 3 .

28. The pharmaceutical composition of claim 13 , wherein R 3a is T 2 ; C 1-12 alkyl; or C 2-12 alkenyl, wherein C 1-12 alkyl is optionally substituted with one, two or three R 9 , which are the same or different.

29. The pharmaceutical composition of claim 13 , wherein R 3a is T 2 ; CH 2 T 2 ; CH 2 CH 2 T 2 ; C(CH 3 )T 2 ; unsubstituted C 1-12 alkyl; unsubstituted C 2-12 alkenyl; C 1-12 alkyl which is substituted with OR 10 ; N(R 10 )C(O)R 10a ; C 1-12 alkyl; or CF 3 .

30. An in vitro or ex vivo method for the production of activated immune cells comprising the steps of:

(i) providing immune cells;

(ii) contacting the cells of step (i) with:

(a) at least one compound or pharmaceutically acceptable salt thereof as defined in claim 1 , and optionally

(b) one or more further stimulating agents activating said immune cells; and

(iii) cultivating the cells of step (ii) under conditions suitable for maintaining the viability of said cells.

Assignments (9)

Priority Claims (1)

Continuity (1)