4-amino-4-oxobutanoyl peptide cyclic analogues, inhibitors of viral replication
The invention provides 4-amino-4-oxobutanoyl peptides and cyclic analogues thereof of Formula I and the pharmaceutically salts thereof. The variables are defined herein. Certain compounds of Formula I are useful as antiviral agents. 4-amino-4-oxobutanoyl peptide cyclic analogues as disclosed herein are potent and/or selective inhibitors of viral replication, particularly Hepatitis C virus replication. The invention also provides pharmaceutical compositions containing one or more 4-amino-4-oxobutanoyl peptide cyclic analogues and one or more pharmaceutically acceptable carriers. Such pharmaceutical compositions may contain a 4-amino-4-oxobutanoyl peptide cyclic analogue as the only active agent or may contain a combination of a 4-amino-4-oxobutanoyl peptide cyclic analogue and one or more other pharmaceutically active agents. The invention also provides methods for treating viral infections, including Hepatitis C infections, in patients.
1. A compound of the formula:
or a pharmaceutically acceptable salt thereof, where
R is —NR 1 R 2 and
R 1 and R 2 are joined to form a 4- to 7-membered heterocycloalkyl ring containing 0 to 2 additional heteroatoms independently chosen from N, O, and S which ring is optionally fused to a 5- or 6-membered heterocyclic ring, containing 1 or 2 heteroatoms independently chosen from N, O, and S, or optionally fused to a 5- or 6-membered carbocyclic ring to form a bicyclic ring system, each of which 5- to 7-membered heterocycloalkyl ring or bicyclic ring system is optionally substituted; or
R 1 and R 2 are taken together to form an optionally substituted 5- to 9-membered bridged heterocyclic ring containing 0, 1, or 2 additional N, S, or O atoms;
R 3 , R 4 , and R 8 are independently
(a) hydrogen, halogen, or amino, or
(b) C 1 -C 6 alkyl, C 2 -C 6 alkenyl, (C 3 -C 7 cycloalkyl)C 0 -C 4 alkyl, (aryl)C 0 -C 4 alkyl, (heteroaryl)C 0 -C 4 alkyl, (C 3 -C 7 cycloalkenyl)C 0 -C 4 alkyl, (heterocycloalkyl)C 0 -C 4 alkyl, C 2 -C 6 alkanoyl, or mono- or di-C 1 -C 6 alkylamino, each of which is optionally substituted;
R 6 is hydrogen, C 1 -C 6 alkyl, or (C 3 -C 7 cycloalkyl)C 0 -C 2 alkyl;
D is an alkylygr alkenyl group having 6 to 10 carbon atoms that is
(i) covalently bound to R 7 , where R 7 is a methylene or methine group or
(ii) covalently bound to an optionally substituted cycloalkyl ring formed by R 7 and R 8 being joined to form a 3- to 7-membered optionally substituted cycloalkyl ring;
T is a group of the formula:
R 9 is —NR 10 SO 2 R 11 and
R 10 and R 11 are independently at each occurrence
hydrogen or trifluoromethyl, or
C 1 -C 6 alkyl, C 2 -C 6 alkenyl, (aryl)C 0 -C 2 alkyl, (C 3 -C 7 cycloalkyl)C 0 -C 2 alkyl, (heterocycloalkyl)C 0 -C 2 alkyl, or (5- to 10-membered heteroaryl)C 0 -C 2 alkyl, each of which is optionally substituted;
Y is —O—, —O(C═O)—, or —(NR 20 )(C═O)—;
Z is (mono-, bi-, or tri-cyclic heteroaryl)C 0 -C 2 alkyl,
each of which Z is substituted with
0 or 1 or more substituents independently chosen from halogen, hydroxyl, amino, cyano, —CONH 2 , —COOH, C 1 -C 4 alkyl, C 2 -C 4 alkanoyl, C 1 -C 4 alkoxy, mono- and di-C 1 -C 4 alkylamino, C 1 -C 2 haloalkyl, and C 1 -C 2 haloalkoxy, and
0 or 1 (C 3 -C 7 cycloalkyl)C 0 C 2 alkyl, (phenyl)C 0 -C 2 alkyl, or (5- or 6-membered heteroaryl)C 0 -C 2 alkyl, each of which is substituted with 0, 1, or 2 substituents independently chosen from:
halogen, hydroxyl, amino, cyano, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, mono- and di-C 1 -C 4 alkylamino, trifluoromethyl, and trifluoromethoxy,
R 16 represents 0 to 4 substituents is independently chosen from halogen, C 1 -C 2 alkyl, and C 1 -C 2 alkoxy; and
R 20 is hydrogen, C 1 -C 2 alkyl, C 1 -C 2 haloalkyl, or C 1 -C 2 haloalkoxy, wherein the compound is not
(2R,6S,16aS,Z)-ethyl2-(7-methoxy-2-phenylquinolin-4-yloxy)-5,16-dioxo-6-(2-oxo-2-(piperidin-1-yl)ethyl)-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxylate;
(2R,6S,16aS,Z)-2-(7-methoxy-2-phenylquinolin-4-yloxy)-5,16-dioxo-6-(2-oxo-2-(piperidin-1-yl)ethyl)-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxylic acid;
(2R,6R,13aS,14aR,16aS,Z)-2-(7-methoxy-2-phenylquinolin-4-yloxy)-5,16-dioxo-6-(2-oxo-2-(piperidin-1-yl)ethyl)- 1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxylic acid;
(2R,6R,13aS,14aR,16aS,Z)-ethyl2-(7-methoxy-2 -phenylquinolin-4-yloxy)-5,16-dioxo-6-(2-oxo-2-(piperidin-1-yl)ethyl)-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxylate;
(2R,6R,13aS,14aR,16aS,Z)-ethyl6-(2-tert-butoxy-2-oxoethyl)-2-(7-methoxy-2-phenylquinolin-4-yloxy)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxylate;
(2R,6R,13aR,14aS,16aS,Z)-ethyl6-(2-tert-butoxy-2-oxoethyl)-2-(7-methoxy-2-phenylquinolin-4-yloxy)-5, 16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxylate;
(2R,6R,13aS,14aR,16aS,Z)-N-(cyclopropylsulfonyl)-2-(7-methoxy-2-phenylquinolin-4-yloxy)-5,16-dioxo-6-(2-oxo-2-(piperidin-1-yl)ethyl)-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxamide; and
(2R,6R,13aR,14aS,16aS,Z)-N-(cyclopropylsulfonyl)-2-(7-methoxy-2-phenylquinolin-4-yloxy)-5,16-dioxo-6-(2-oxo-2-(piperidin-1-yl)ethyl)-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxamide.
2. The compound or salt of claim 1 , wherein R 1 and R 2 are joined to form a pyrrolidine, morpholine, piperidine, or piperazine ring, each of which is substituted with 0 to 2 substituents independently chosen from fluoro, amino, hydroxyl, methyl, and trifluoromethyl.
3. The compound or salt of claims 1 in which R 1 and R 2 are taken together to form a group of the formula
4. A compound or salt of claims 2 , wherein R 3 is hydrogen or methyl and R 4 is hydrogen or C 1 -C 4 alkyl.
5. A compound or salt of claim 4 , wherein R 3 and R 4 are independently hydrogen or methyl.
6. The compound or salt of claim 5 , of the formula
where
R 3 , R 4 , R 6 , and R 8 are independently hydrogen or C 1 -C 4 alkyl.
7. The compound or salt of claim 6 , of the formula
8. The compound or salt of claim 1 , having the formula
where D is an alkyl or alkenyl group having 6 to 10 carbon atoms; and
R 3 , R 4 , and R 6 are independently hydrogen or C 1 -C 4 alkyl.
9. The compound or salt according to claim 8 , of the formula
10. The compound or salt of claim 2 , wherein
R 9 is —NR 10 SO 2 R 11 ; and
R 11 is C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, phenyl, or benzyl, each of which is substituted with 0 to 2 substituents independently chosen from halogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 2 -C 4 alkenyl, and (phenyl)C 0 -C 2 alkyl.
11. The compound or salt of claim 10 wherein
R 10 is hydrogen or methyl; and R 11 is C 1 -C 4 alkyl or cyclopropyl.
12. The compound or salt of claim 2 wherein
Y is O, —O(C═O)—, or —(NR 20 )(C═O)—; and
R 20 is hydrogen or methyl.
13. The compound or salt of claim 2 wherein Z is
each of which is substituted by 0, 1, 2, or 3 substituents independently chosen from halogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, and mono- and di-C 1 -C 4 alkylamino.
14. The compound or salt of claim 2 , wherein Z is a group of the formula
wherein
X 1 , X 2 , X 3 , X 4 , and X 5 are independently N or CH and no more than two of X 1 -X 5 are N;
G 1 and G 2 are independently CH 2 , O, S, or NR 26 , G 5 is N or CH;
R 21 represents from 0 to 3 groups independently chosen from halogen, hydroxyl, amino, cyano, —CONH 2 , —COOH, C 1 -C 4 alkyl, C 2 -C 4 alkanoyl, C 1 -C 4 alkoxy, C 1 -C 4 alkylthio, mono- and di-C 1 -C 4 alkylamino, C 1 -C 2 haloalkyl, and C 1 -C 2 haloalkoxy,
R 22 is hydrogen, halogen, hydroxyl, amino, cyano, —CONH 2 , —COOH, C 1 -C 4 alkyl, C 2 -C 4 alkanoyl, C 1 -C 4 alkoxy, C 1 -C 4 alkylthio, mono- or di-C 1 -C 4 alkylamino, C 1 -C 4 alkylester, C 1 -C 2 haloalkyl, or C 1 -C 2 haloalkoxy, or
R 22 is (phenyl)C 0 -C 2 alkyl, (phenyl)C 0 -C 2 alkoxy, (pyridyl)C 0 -C 2 alkyl, or (thiazolyl)C 0 -C 2 alkyl, each of which is substituted with 0, 1, or 2 substituents independently chosen from
halogen, hydroxyl, amino, cyano, —COOH, —CONH 2 , C 1 -C 4 alkyl, C 1 -C 4 alkoxy,mono- and di-C 1 -C 4 alkylamino, trifluoromethyl, and trifluoromethoxy; and
R 23 is 0 to 2 substituents independently chosen from halogen, hydroxyl, C 1 -C 2 alkyl, and C 1 -C 2 alkoxy.
15. The compound or salt according to Claim 14 , wherein Z is a group of the formula
16. The compound or salt of claim 15 , where Z is a quinoline of the formula
wherein
R 21 represents a substituent at the 7-position of the quinoline, and 0 to 2 additional substituents independently chosen from halogen, hydroxyl, amino, cyano, —CONH 2 , —COOH, C 1 -C 4 alkyl, C 2 -C 4 alkanoyl, C 1 -C 4 alkoxy, mono- and di-C 1 -C 4 alkylamino, C 1 -C 2 haloalkyl, and C 1 -C 2 haloalkoxy; and
R 22 is phenyl, pyridyl, or thiazolyl, each of which is substituted with 0, 1, or 2 substituents independently chosen from halogen, hydroxyl, amino, cyano, —COOH, —CONH 2 , C 1 -C 4 alkyl, C 1 -C 4 alkoxy, mono- and di-C 1 -C 4 alkylamino, trifluoromethyl, and trifluoromethoxy.
17. The compound or salt of claim 15 , wherein
R 21 is a methoxy or ethoxy substituent at the 7-position of the quinoline, and optionally an additional halogen substituent at the 8-position of the quinoline; and
R 22 is phenyl, pyridyl, or thiazolyl, each of which is substituted with 0, 1, or 2 substituents independently chosen from methyl, methoxy, chloro, C 1 -C 4 alkyl, C 1 -C 4 mono and di-alkyl amino.
18. A compound or salt of claim 1 of the formula
wherein
R 1 and R 2 are joined to form an azetidine, pyrrolidine, morpholine, piperidine, or piperazine ring,
each of which is substituted with 0 to 3 substituents independently chosen from fluoro, amino, hydroxyl, C 1 -C 2 alkyl, and trifluoromethyl, and
also substituted with 0 or 1 substituent chosen from methoxyimino, aminoC 1 -C 4 alkyl, C 1 -C 2 alkylsulfonyl, and pyrazinyl;
R 3 is hydrogen;
R 4 is hydrogen, C 1 -C 4 alkyl, or (C 3 -C 7 cycloalkyl)C 0 -C 2 alkyl;
R 6 and R 8 are independently hydrogen or methyl;
R 9 is —NR 10 SO 2 R 11 ;
R 10 is hydrogen or methyl; and
R 11 is C 1 -C 4 alkyl or C 3 -C 7 cycloalkyl; and R 12 is C 1 -C 4 alkyl;
R 16 is 0 to 2 substituents independently chosen from halogen, C 1 -C 2 alkyl, and C 1 -C 2 alkoxy;
Y is O,—O(C═O)—, or —(NH)(C═O)—; and
Z is a group of the formula:
each of which is substituted by 0, 1, 2, or 3 substituents independently chosen from halogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, and mono- and di-C 1 -C 4 alkylamino.
19. A pharmaceutical composition comprising a therapeutically effective amount of one or more compounds or salts of claim 18 and at least one pharmaceutically acceptable carrier.
20. A method of treating hepatitis C infection in a patient, comprising providing a therapeutically effective amount of one or more compounds of claim 1 to the patient.
21. A compound or salt of claim 18 wherein Z is a group of the formula
which is substituted by 0, 1, 2, or 3 substituents independently chosen from halogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, and mono- and di-C 1 -C 4 alkylamino.
22. A compound or salt of claim 1 , wherein the compound is
(2R,6R,16aS,Z)-14a-(cyclopropylsulfonylcarbamoyl)-5,16-dioxo-6-(2-oxo-2-(piperidin-1-yl)ethyl)-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-2-yl4-fluoroisoindoline-2-carboxylate;
(2R,6R,13aR,14aR,16a5)-N-(cyclopropylsulfonyl)-2-(7-methoxy-2-phenylquinolin-4-yloxy)-5,16-dioxo-6-(2-oxo-2-(piperidin-1-yl)ethyl)octadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxamide;
(3S,13R,17R,18aS)-N-(cyclopropylsulfonyl)-17-(7-methoxy-2-phenylquinolin-4-yloxy)-1,14-dioxo-13-(2-oxo-2-(piperidin-1-yl)ethyl)octadecahydropyrrolo[1,2-a][1,4]diazacyclohexadecine-3-carboxamide;
(3S,4S,12R,16R,17aS)-N-(cyclopropylsulfonyl)-16-(7-methoxy-2-phenylquinolin-4-yloxy)-4-methyl-1,13-dioxo-12-(2-oxo-2-(piperidin-1-yl)ethyl)hexadecahydro-1H-pyrrolo[1,2-a][1,4]diazacyclopentadecine-3-carboxamide;
(3R,12R,16R,17aS)-N-(cyclopropylsulfonyl)-16-(7-methoxy-2-phenylquinolin-4-yloxy)-3-methyl-1,13-dioxo-12-(2-oxo-2-(piperidin-1-yl)ethyl)hexadecahydro-1H-pyrrolo[1,2-a][1,4]diazacyclopentadecine-3-carboxamide;
(2R,6R,13aS,14aR,16aS,Z)-N-(cyclopropylsulfonyl)-2-(7-methoxy-2-phenylquinolin-4-yloxy)-5,16-dioxo-6-(2-oxo-2-(pyrrolidin-1-yl)ethyl)-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxamide;
(3R,12R,16R,17aS,Z)-N-(cyclopropylsulfonyl)-16-(7-methoxy-2-phenylquinolin-4-yloxy)-1,13-dioxo-12-(2-oxo-2-(piperidin-1-yl)ethyl)-2,3,4,7,8,9,10,11,12,13,15,16,17,17a-tetradecahydro-1H-pyrrolo[1,2-a][1,4]diazacyclopentadecine-3-carboxamide ;
(3 S,12R,16R,17aS,Z)-N-(cyclopropylsulfonyl)-16-(7-methoxy-2-phenylquinolin-4-yloxy)-1,13-dioxo-12-(2-oxo-2-(piperidin-1-yl)ethyl)-2,3,4,7,8,9,10,11,12,13,15,16,17,17a-tetradecahydro-1H-pyrrolo[1,2-a][1,4]diazacyclopentadecine-3-carboxamide ;
tert-butyl2-((2R,6R,13aS,14aR,16aS,Z)-14a-(cyclopropylsulfonylcarbamoyl)-2-(7-methoxy-2-phenylquinolin-4-yloxy)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)acetate;
2-((2R,6R,13aS,14aR,16aS,Z)-14a-(cyclopropylsulfonylc arb amoyl)-2-(7-methoxy-2-phenylquinolin-4-yloxy)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)acetic acid;
(2R,6R,13aS,14aR,16aS,Z)-N-(cyclopropylsulfonyl)-2-(7-methoxy-2-phenylquinolin-4-yloxy)-6-(2-morpholino-2-oxoethyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxamide;
(2R,6R,13aS,14aR,16aS,Z)-N-(cyclopropylsulfonyl)-6-(2-(4,4-difluoropiperidin-1-yl)-2-oxoethyl)-2-(7-methoxy-2-phenylquinolin-4-yloxy)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo [1,2-a][1,4]diazacyclopentadecine-14a-carboxamide;
(2R,6R,13aS,14aR,16aS,Z)-N-(cyclopropylsulfonyl)-2-(7-methoxy-2-phenylquinolin-4-yloxy)-5,16-dioxo-6-(2-oxo-2-(4-(trifluoromethyl)piperidin-1-yl)ethyl)-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo [1,2-a][1,4]diazacyclopentadecine-14a-carboxamide;
(2R,6R,13aS,14aR,16aS,Z)-N-(cyclopropylsulfonyl)-6-(2-(3,3-difluoropyrrolidin-1-yl)-2-oxoethyl)-2-(7-methoxy-2-phenylquinolin-4-yloxy)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo [1,2-a][1,4]diazacyclopentadecine-14a-carboxamide;
(12R,16R,17aS,Z)-16-(7-methoxy-2-phenylquinolin-4-yloxy)-3-methyl-1,13-dioxo-12-(2-oxo-2-(piperidin-1-yl)ethyl)-2,3,4,7,8,9,10,11,12,13,15,16,17,17a-tetradecahydro-1H-pyrrolo[1,2-a][1,4]diazacyclopentadecine-3-carboxylic acid;
(3R,12R,16R,17aS,Z)-N-(cyclopropylsulfonyl)-16-(7-methoxy-2-phenylquinolin-4-yloxy)-3-methyl-1,13-dioxo-12-(2-oxo-2-(piperidin-1-yl)ethyl)-2,3,4,7,8,9,10,11,12,13,15,16,17,17a-tetradecahydro-1H-pyrrolo[1,2-a][1,4]diazacyclopentadecine-3-carboxamide;
(3S,12R,16R,17aS,Z)-N-(cyclopropylsulfonyl)-16-(7-methoxy-2-phenylquinolin-4-yloxy)-3-methyl-1,13-dioxo-12-(2-oxo-2-(piperidin-1-yl)ethyl)-2,3,4,7,8,9,10,11,12,13,15,16,17,17a-tetradecahydro-1H-pyrrolo[1,2-a][1,4]diazacyclopentadecine-3-carboxamide;
tert-butyl4-(2-((2R,6R,13aS,14aR,16aS,Z)-14a-(cyclopropylsulfonylcarbamoyl)-2-(7-methoxy-2-phenylquinolin-4-yloxy)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)acetyl)piperazine-1-carboxylate;
(2R,6R,13aS,14aR,16aS,Z)-N-(cyclopropylsulfonyl)-6-(2-(3,5-dimethylpiperidin-1-yl)-2-oxoethyl)-2-(7-methoxy-2-phenylquinolin-4-yloxy)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxamide;
(2R,6R,13aS,14aR,16aS,Z)-N-(cyclopropylsulfonyl)-6-(2-(2,6-dimethylpiperidin-1-yl)-2-oxoethyl)-2-(7-methoxy-2-phenylquinolin-4-yloxy)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxamide;
(2R,6R,13aS,14aR,16aS,Z)-N-(cyclopropylsulfonyl)-6-(2-(4-fluoropiperidin-1-yl)-2-oxoethyl)-2-(7-methoxy-2-phenylquinolin-4-yloxy)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxamide;
(2R,6R,13aS,14aR,16aS,Z)-N-(cyclopropylsulfonyl)-2-(7-methoxy-2-phenylquinolin-4-yloxy)-5,16-dioxo-6-(2-oxo-2-(3-(trifluoromethyl)piperidin-1-yl)ethyl)-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxamide;
(2R,6R,13aS,14aR,16aS,Z)-N-(cyclopropylsulfonyl)-2-(7-methoxy-2-(pyridin-2-yl) quinolin-4-yloxy)-5,16-dioxo-6-(2-oxo-2-(piperidin-1-yl)ethyl)-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxamide;
(2R,6R,13aS,14aR,16aS,Z)-N-(cyclopropylsulfonyl)-2-(7-methoxy-2-phenylquinolin-4-yloxy)-6-(2-(2-methylmorpholino)-2-oxoethyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxamide;
(2R,6R,13aS,14aR,16aS,Z)-N-(cyclopropylsulfonyl)-6-(2-(2,6-dimethylmorpholino)-2-oxoethyl)-2-(7-methoxy-2-phenylquinolin-4-yloxy)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxamide;
(2R,6R,13aS,14aR,16aS,Z)-6-(2-(2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-2-oxoethyl)-N -(cyclopropylsulfonyl)-2-(7-methoxy-2-phenylquinolin-4-yloxy)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxamide;
(2R,6R,13aS,14aR,16aS,Z)-N-(cyclopropylsulfonyl)-2-(7-methoxy-2-phenylquinolin-4-yloxy)-6-(2-(3-methylpiperidin-1-yl)-2-oxoethyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo [1,2-a][1,4]diazacyclopentadecine-14a-carboxamide;
(2R,6R,13aS,14aR,16aS,Z)-N-(cyclopropylsulfonyl)-6-(2-(4,4-difluoropiperidin-1-yl)-2-oxoethyl)-5,16-dioxo-2-(2-phenylquinoline-4-carboxamido)-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxamide;
(2R,6R,13aS,14aR,16aS,Z)-N-(cyclopropylsulfonyl)-5,16-dioxo-6-(2-oxo-2-(piperidin-1-ly)ethyl)-2-(2-phenylquinoline-4-carboxamido)-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxamide;
(2R,6R,14aR,16aS,Z)-N-(cyclopropylsulfonyl)-5,16-dioxo-6-(2-oxo-2-(piperidin-1-ly)ethyl)-2-(2-phenylquinoline-4-carboxamido)-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxamide;
(2R,6R,14aR,16aS,Z)-N-(cyclopropylsulfonyl)-6-(2-(4,4-difluoropiperidin-1-yl)-2-oxoethyl)-5,16-dioxo-2-(2-(pyridin-2-yl)-8,9-dihydro furo[2,3-h]quinolin-4-yloxy)-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo [1,2-a][1,4]diazacyclopentadecine-14a-carboxamide;
(2R,6R,14aR,16aS,Z)-N-(cyclopropylsulfonyl)-5,16-dioxo-6-(2-oxo-2-(4-(trifluoromethyl)piperidin-1-yl)ethyl)-2-(2-(pyridin-2-yl)-8,9-dihydrofuro[2,3-h]quinolin-4-yloxy)-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxamide;
(2R,6R,14aR,16aS,Z)-N-(cyclopropylsulfonyl)-5,16-dioxo-6-(2-oxo-2-(piperidin-1-yl) ethyl)-2-(2-(pyridin-2-yl)-8,9-dihydro furo[2,3-h]quinolin-4-yloxy)-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo [1,2-a][1,4]diazacyclopentadecine-14a-carboxamide;
(2R,6R,14aR,16aS,Z)-N-(cyclopropylsulfonyl)-2-(7-methoxy-2-phenylquinolin-4-yloxy)-5,16-dioxo-6-(2-oxo-2-(4-(pyrrolidine-1-carbonyl)piperazin-1-yl)ethyl)-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo [1,2-a][1,4]diazacyclopentadecine-14a-carboxamide;
(2R,6R,14aR,16aS,Z)-N-(cyclopropylsulfonyl)-6-(2-(4-(ethylsulfonyl)piperazin-1-yl)-2-oxoethyl)-2-(7-methoxy-2-phenylquinolin-4-yloxy)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo [1,2-a][1,4]diazacyclopentadecine-14a-carboxamide;
(2R,6R,14aR,16aS,Z)-N-(cyclopropylsulfonyl)-2-(7-methoxy-2-phenylquinolin-4-yloxy)-5,16-dioxo-6-(2-oxo-2-(4-(pyrazin-2-yl)piperazin-1-yl)ethyl)-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a ][1,4]diazacyclopentadecine-14a-carboxamide;
tert-butyl2-((2R,6R,14aR,16aS,Z)-2-(8-chloro-7methoxy-2-(pyridin-2-yl)quinolin-4-yloxy)-14a-(cyclopropylsulfonylcarbamoyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)acetate;
2-((2R,6R,14aR,16aS,Z)-2-(8-chloro-7-methoxy-2-(pyridin-2-yl)quinolin-4-yloxy)-14a-(cyclopropylsulfonylcarbamoyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)acetic acid;
(2R,6R,14aR,16aS,Z)-2-(8-chloro-7-methoxy-2-(pyridin-2-yl)quinolin-4-yloxy)-N-(cyclopropylsulfonyl)-5,16-dioxo-6-(2-oxo-2-(piperidin-1-yl)ethyl)-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo [1,2-a][1,4]diazacyclopentadecine-14a-carboxamide;
(2R,6R,14aR,16aS,Z)-2-(8-chloro-7-methoxy-2-(pyridin-2-yl)quinolin-4-yloxy)-N -(cyclopropylsulfonyl)-6-(2-(3,3-difluoropiperidin-1-yl)-2-oxoethyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo [1,2-a][1,4]diazacyclopentadecine-14a-carboxamide;
(2R,6R,14aR,16aS,Z)-2-(8-chloro-7-methoxy-2-(pyridin-2-yl)quinolin-4-yloxy)-N -(cyclopropylsulfonyl)-5,16-dioxo-6-(2-oxo-2-(4-(trifluoromethyl)piperidin-1-yl)ethyl)-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo [1,2-a][1,4]diazacyclopentadecine-14a-carboxamide;
(2R,6R,14aR,16aS,Z)-2-(8-chloro-7-methoxy-2-(pyridin-2-yl)quinolin-4-yloxy)-N -(cyclopropylsulfonyl)-6-(2-(4,4-difluoropiperidin-1-yl)-2-oxoethyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo [1,2-a][1,4]diazacyclopentadecine-14a-carboxamide;
(2R,6R,14aR,16aS,Z)-2-(8-chloro-7-methoxy-2-(pyridin-2-yl)quinolin-4-yloxy)-N -(cyclopropylsulfonyl)-6-(2-(3,3-difluoropyrrolidin-1-yl)-2-oxoethyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo [1,2-a][1,4]diazacyclopentadecine-14a-carboxamide;
(2R,6R,14aR,16aS,Z)-2-(8-chloro-7-methoxy-2-(pyridin-2-yl)quinolin-4-yloxy)-N -(cyclopropylsulfonyl)-5,16-dioxo-6-(2-oxo-2-(2-(trifluoromethyppyrrolidin-1-yl)ethyl)-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxamide;
(2R,6R,14aR,16aS,Z)-N-(cyclopropylsulfonyl)-2-(6-methoxy-2-(pyridin-2-yl)quinoline-4-carboxamido)-5,16-dioxo-6-(2-oxo-2-(piperidin-1-yl)ethyl)-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo [1,2-a][1,4]diazacyclopentadecine-14a-carboxamide;
(2R,6R,14aR,16aS,Z)-N-(cyclopropylsulfonyl)-6-(2-(4,4-difluoropiperidin-1-yl)-2-oxoethyl)-2-(6-methoxy-2-(pyridin-2-yl)quinoline-4-carboxamido)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo [1,2-a][1,4]diazacyclopentadecine-14a-carboxamide;
(2R,6R,14aR,16aS,Z)-N-(cyclopropylsulfonyl)-6-(2-(3,3-difluoropyrro lidin-1-yl)-2-oxoethyl)-2-(6-methoxy-2-(pyridin-2-yl)quinoline-4-carboxamido)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo [1,2-a][1,4]diazacyclopentadecine-14a-carboxamide;
(2R,6R,14aR,16aS, Z)-N-(cyclopropylsulfonyl)-6-(24(2R,6S)-2,6-dimethylpiperidin-1-yl)-2-oxoethyl)-2-(7-methoxy-2-phenylquinolin-4-yloxy)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo [1,2-a][1,4]diazacyclopentadecine-14a-carboxamide;
(2R,6R,14aR,16aS,Z)-2-(8-chloro-7-methoxy-2-(pyridin-2-yl)quinolin-4-yloxy)-N -(cyclopropylsulfonyl)-6-(2-(3-fluoropiperidin-1-yl)-2-oxoethyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo [1,2-a][1,4]diazacyclopentadecine-14a-carboxamide;
(2R,6R,14aR,16aS,Z)-2-(8-chloro-7-methoxy-2-(pyridin-2-yl)quinolin-4-yloxy)-N -(cyclopropylsulfonyl)-6-(2-(4-fluoropiperidin-1-yl)-2-oxoethyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo [1,2-a][1,4]diazacyclopentadecine-14a-carboxamide;
(2R,6R,14aR,16aS,Z)-6-(2-((S)-3-aminopyrrolidin-1-yl)-2-oxoethyl)-N -(cyclopropylsulfonyl)-2-(7-methoxy-2-phenylquinolin-4-yloxy)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo [1,2-a][1,4]diazacyclopentadecine-14a-carboxamide;
tert-butyl ((3S)-1-(2-((2R,6R,14aR,16aS,Z)-14a-(cyclopropylsulfonylcarbamoyl)-2-(7-methoxy-2-phenylquinolin-4-yloxy)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)acetyl)pyrrolidin-3-yl) methylcarbamate;
tert-butyl ((3S)-1-(2-((2R,6R,14aR,16aS,Z)-14a-(cyclopropylsulfonylcarbamoyl)-2-(7-methoxy-2-phenylquinolin-4-yloxy)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-yl)acetyl)pyrrolidin-3-yl) methylcarbamate;
(2R,6R,14aR,16aS,Z)-6-(2-((S)-3-(aminomethyl)pyrrolidin-1-yl)-2-oxoethyl)-N -(cyclopropylsulfonyl)-2-(7-methoxy-2-phenylquinolin-4-yloxy)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo [1,2-a][1,4]diazacyclopentadecine-14a-carboxamide;
(2R,6R,14aR,16aS,Z)-6-(2-((R)-3-aminopyrrolidin-1-yl)-2-oxoethyl)-N -(cyclopropylsulfonyl)-2-(7-methoxy-2-phenylquinolin-4-yloxy)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo [1,2-a][1,4]diazacyclopentadecine-14a-carboxamide;
(2R,6R,14aR,16aS,Z)-6-(2-((R)-3-(2-aminoprop an-2-yl)pyrro lidin-1-yl)-2-oxoethyl)-N -(cyclopropylsulfonyl)-2-(7-methoxy-2-phenylquinolin-4-yloxy)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo [1,2-a][1,4]diazacyclopentadecine-14a-carboxamide;
(2R,6R,14aR,16aS,Z)-N-(cyclopropylsulfonyl)-6-(24(S)-3-hydroxypyrrolidin-1-yl)-2-oxoethyl)-2-(7-methoxy-2-phenylquinolin-4-yloxy)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo [1,2-a][1,4]diazacyclopentadecine-14a-carboxamide;
(2R,6R,14aR,16aS,Z)-6-(24(Z)-3-(aminomethyl)-4-(methoxyimino)-3-methylpyrrolidin-1-yl)-2-oxoethyl)-N-(cyclopropylsulfonyl)-2-(7-methoxy-2-phenylquinolin-4-yloxy)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo [1,2-a][1,4]diazacyclopentadecine-14a-carboxamide;
(2R,6R,14aR,16aS,Z)-6-(2-((S)-3-(2-aminopropan-2-yl)pyrro lidin-1-yl)-2-oxoethyl)-N -(cyclopropylsulfonyl)-2-(7-methoxy-2-phenylquinolin-4-yloxy)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxamide;
(2R,6R,14aR,16aS,Z)-14a-(cyclopropylsulfonylcarbamoyl)-5,16-dioxo-6-(2-oxo-2-(piperidin-1-yl)ethyl)-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-2-yl3,4-dihydroisoquinoline-2(1H)-carboxylate;
(2R,6R,14aR,16aS,Z)-14a-(cyclopropylsulfonylcarbamoyl)-6-(2-(3,3-difluoropiperidin-1-yl)-2-oxoethyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-2-yl3,4-dihydroisoquinoline-2(1H)-carboxylate;
(2R,6R,14aR,16aS,Z)-14a-(cyclopropylsulfonylcarbamoyl)-6-(2-(3,3-difluoropyrrolidin-1-yl)-2-oxoethyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-2-yl3,4-dihydroisoquinoline-2(1H)-carboxylate;
(2R,6R,14aR,16aS,Z)-14a-(cyclopropylsulfonylcarbamoyl)-5,16-dioxo-6-(2-oxo-2-(4-(trifluoromethyppiperidin-1-yl)ethyl)-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-2-yl3,4-dihydroisoquinoline-2(1H)-carboxylate;
(2R,6R,14aR,16aS,Z)-N-(cyclopropylsulfonyl)-2-(7-methoxy-8-methyl-2-(pyridin-2-yl) quinolin-4-yloxy)-5,16-dioxo-6-(2-oxo-2-(piperidin-1-yl)ethyl)-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo [1,2-a][1,4]diazacyclopentadecine-14a-carboxamide;
(2R,6R,14aR,16aS,Z)-N-(cyclopropylsulfonyl)-2-(7-methoxy-8-methyl-2-(pyridin-2-yl) quinolin-4-yloxy)-5,16-dioxo-6-(2-oxo-2-(4-(trifluoromethyl)piperidin-1-yl)ethyl)-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo [1,2-a][1,4]diazacyclopentadecine-14a-carboxamide;
(2R,6R,14aR,16aS,Z)-N-(cyclopropylsulfonyl)-2-(2-(4-isopropylthiazol-2-yl)-7-methoxyquinolin-4-yloxy)-5,16-dioxo-6-(2-oxo-2-(piperidin-1-yl)ethyl)-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo [1,2-a][1,4]diazacyclopentadecine-14a-carboxamide;
(2R,6R,14aR,16aS,Z)-N-(cyclopropylsulfonyl)-2-(2-(4-isopropylthiazol-2-yl)-7-methoxyquinolin-4-yloxy)-5,16-dioxo-6-(2-oxo-2-(4-(trifluoromethyl)piperidin-1-yl)ethyl)-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo [1,2-a][1,4]diazacyclopentadecine-14a-carboxamide;
(2R,6R,14aR,16aS,Z)-N-(cyclopropylsulfonyl)-2-(6-methoxy-3-phenylnaphthalen-1-yloxy)-5,16-dioxo-6-(2-oxo-2-(piperidin-1-yl)ethyl)-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxamide;
(2R,6R,13aS,16aS,Z)-N-(cyclopropylsulfonyl)-2-(2-(2-(isopropylamino)thiazol-4-yl)-7-methoxy-8-methylquinolin-4-yloxy)-5,16-dioxo-6-(2-oxo-2-(4-(trifluoromethyl)piperidin-1-yl) ethyl)-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxamide;
(2R,6R,13aS,16aS,Z)-2-(5-chloro-6-methoxyisoquinolin-1-yloxy)-N -(cyclopropylsulfonyl)-5,16-dioxo-6-(2-oxo-2-(piperidin-1-yl)ethyl)-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo [1,2-a][1,4]diazacyclopentadecine-14a-carboxamide;
(2R,6R,13aS,16aS,Z)-2-(5-chloro-6-methoxyisoquinolin-1-yloxy)-N -(cyclopropylsulfonyl)-6-(2-(3,3-difluoropiperidin- 1-yl)-2-oxoethyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo [1,2-a][1,4]diazacyclopentadecine-14a-carboxamide;
(2R,6R,13aS,16aS,Z)-2-(5-chloro-6-methoxyisoquinolin-1-yloxy)-N -(cyclopropylsulfonyl)-5,16-dioxo-6-(2-oxo-2-(4-(trifluoromethyl)piperidin-1-yl)ethyl)-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo [1,2-a][1,4]diazacyclopentadecine-14a-carboxamide;
(2R,6R,13aS,16aS,Z)-N-(cyclopropylsulfonyl)-5,16-dioxo-6-(2-oxo-2-(4-(trifluoromethyl)piperidin-1-yl)ethyl)-2-(2-(pyridin-2-yl)-8,9-dihydro-7H-cyclop enta [h]quinolin-4-yloxy)-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxamide;
(2R,6R,14aR,16aS,Z)-N-(cyclopropylsulfonyl)-2-(2-(4-isopropylthiazol-2-yl)-7-methoxy-8-methylquinolin-4-yloxy)-5,16-dioxo-6-(2-oxo-2-(4-(trifluoromethyl)piperidin-1-yl) ethyl)-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo [1,2-a][1,4]diazacyclopentadecine-14a-carboxamide;
(2R,6R,13aS,16aS,Z)-N-(cyclopropylsulfonyl)-6-(2-(3,3-difluoropiperidin-1-yl)-2-oxoethyl)-5,16-dioxo-2-(2-(pyridin-2-yl)-8,9-dihydro-7H-cyclopenta[h]quinolin-4-yloxy)-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo [1,2-a][1,4]diazacyclopentadecine-14a-carboxamide;
(2R,6R,14aR,16aS,Z)-N-(cyclopropylsulfonyl)-6-(2-(3,3-difluoropiperidin-1-yl)-2-oxoethyl)-2-(2-(4-isopropylthiazol-2-yl)-7-methoxy-8-methylquinolin-4-yloxy)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo [1,2-a][1,4]diazacyclopentadecine-14a-carboxamide;
(2R,6R,14aR,16aS,Z)-N-(cyclopropylsulfonyl)-6-(2-(3,3-difluoropiperidin-1-yl)-2-oxoethyl)-2-(7-methoxy-8-methyl-2-(pyridin-3-yl)quinolin-4-yloxy)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo [1,2-a][1,4]diazacyclopentadecine-14a-carboxamide;
(2R,6R,14aR,16aS,Z)-2-(5-chloro-6-methoxy-3-(pyridin-2-yl)isoquinolin-1-yloxy)-N-(cyclopropylsulfonyl)-6-(2-(3,3-difluoropiperidin-1-yl)-2-oxoethyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo [1,2-a][1,4]diazacyclopentadecine-14a-carboxamide;
(2R,6R,14aR,16aS,Z)-N-(cyclopropylsulfonyl)-2-(7-methoxy-8-methyl-2-(pyridin-3-yl) quinolin-4-yloxy)-5,16-dioxo-6-(2-oxo-2-(4-(trifluoromethyl)piperidin-1-yl)ethyl)-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo [1,2-a][1,4]diazacyclopentadecine-14a-carboxamide;
(2R,6R,14aR,16aS,Z)-2-(5-chloro-6-methoxy-3-(pyridin-2-yl)isoquinolin-1-yloxy)-N-(cyclopropylsulfonyl)-5,16-dioxo-6-(2-oxo-2-(4-(trifluoromethyl)piperidin-1-yl)ethyl)-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo [1,2-a][1,4]diazacyclopentadecine-14a-carboxamide;
(2R,6R,14aR,16aS,Z)-N-(cyclopropylsulfonyl)-6-(2-(3,3-difluoropiperidin-1-yl)-2-oxoethyl)-2-(2-(2-isopropylthiazol-4-yl)-7-methoxy-8-methylquinolin-4-yloxy)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo [1,2-a][1,4]diazacyclopentadecine-14a-carboxamide;
(2R,6R,14aR,16aS,Z)-N-(cyclopropylsulfonyl)-6-(2-(3,3-difluorocyclohexyl)-2-oxoethyl)-2-(2-(2-(isopropylamino)thiazol-4-yl)-7-methoxy-8-methylquinolin-4-yloxy)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxamide;
(2R,6R,14aR,16aS,Z)-N-(cyclopropylsulfonyl)-2-(2-(4-isopropylthiazol-2-yl)-7-methoxy-8-methylquinolin-4-yloxy)-5,16-dioxo-6-(2-oxo-2-(piperidin-1-yl)ethyl)-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo [1,2-a][1,4]diazacyclopentadecine-14a-carboxamide; or
(2R,6R,13aS,16aS,Z)-N-(cyclopropylsulfonyl)-6-(2-(3-fluoropiperidin-1-yl)-2-oxoethyl)-2-(2-(4-isopropylthiazol-2-yl)-7-methoxy-8-methylquinolin-4-yloxy)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo [1,2-a][1,4]diazacyclopentadecine-14a-carboxamide.
23. A compound or salt thereof of claim 1 , wherein the compound is
24. A compound or salt thereof of claim 1 , wherein the compound is
25. A compound or salt thereof of claim 1 , wherein the compound is
26. A compound or salt thereof of claim 1 , wherein the compound is