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1. WO2020110009 - COMPOSÉS TÉTRAMÈRES CYCLIQUES SERVANT D'INHIBITEURS DE PROPROTÉINE CONVERTASE SUBTILISINE/KEXINE DE TYPE 9 (PCSK9) POUR LE TRAITEMENT DE TROUBLES MÉTABOLIQUES

Note: Texte fondé sur des processus automatiques de reconnaissance optique de caractères. Seule la version PDF a une valeur juridique

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CLAIMS

What is claimed is:

1. A compound of Formula (I):

wherein:

X1 and X2 are each independently H or (C1-C6)alkyl, or X1 and X2 together with the carbon atom to which they are attached form =(O);

X3 is -CH2- when X1 and X2 are each independently H or (C1-C6)alkyl, or X1 and X2 together with the carbon atom to which they are attached form =(O), or X3 is–O-, -NH- or -N(C1-C6)alkyl-, when X1 and X2 together with the carbon atom to which they are attached form =(O);

R1 is (C6-C10)aryl or 5- or 6-membered heteroaryl comprising 1-3 heteroatoms selected from N, O, and S, wherein the aryl and heteroaryl are substituted with -OR10 or–NR21R10 and optionally substituted with one or more R11;

R2 is H, (C1-C6)alkyl, (C2-C6)alkenyl, (C1-C6)haloalkyl, -NR12R13, (C3-C7)carbocyclyl, (C3-C7)cycloalkenyl, 5- to 7-membered heterocyclyl comprising 1-3 heteroatoms selected from N, O, and S, (C6-C10)aryl, or 5- or 6-membered heteroaryl comprising 1-3 heteroatoms selected from N, O, and S, wherein the alkyl is optionally substituted with one or more R18, and the carbocyclyl, (C3-C7)cycloalkenyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one or more R19;

R3 is H, D, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, or

(C1-C6)hydroxyalkyl, wherein the alkyl is optionally substituted with one or more R14;

R4 is H or (C1-C6)alkyl; or

R3 and R4 together with the atoms to which they are attached form a 5- to 7-membered heterocyclyl ring comprising 1-3 heteroatoms selected from N, O, and S;

R5 and R7 are each independently H, D, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, or (C1-C6)hydroxyalkyl, wherein the (C1-C6)alkyl is optionally substituted with one or more D;

R6 is (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, or

(C1-C6)hydroxyalkyl, wherein the alkyl is optionally substituted with one or more substituents each independently selected from (C1-C6)alkoxy, (C1-C6)haloalkoxy,–C(O)(C1-C6)alkyl,– C(O)OH, and–C(O)O(C1-C6)alkyl;

R8 is H, (C1-C6)alkyl, or (C1-C6)haloalkyl, wherein the alkyl is optionally substituted with one or more substituents each independently selected from (C3-C7)carbocyclyl, 4- to 7-membered heterocyclyl comprising 1-3 heteroatoms selected from N, O, and S,–NR16R17, and –C(O)NR16R17;

R9 is halogen, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, -OH, or CN;

R10 is (C6-C10)aryl or 5- or 6-membered heteroaryl comprising 1-3 heteroatoms selected from N, O, and S, wherein the aryl and heteroaryl are optionally substituted with one or more R22;

each R11 is independently at each occurrence halogen, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, -OH, or CN;

R12 and R13 are each independently H or (C1-C6)alkyl;

each R14 is independently at each occurrence D, NR15R15', (C3-C7)carbocyclyl, or 3- to 7-membered heterocyclyl comprising 1-3 heteroatoms selected from N, O, and S, wherein the carbocyclyl and heterocyclyl are optionally substituted with one or more substituents each independently selected from halogen, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, and

(C1-C6)haloalkoxy;

R15 and R15' are each independently H or (C1-C6)alkyl;

R16 and R17 are each independently H or (C1-C6)alkyl, or

R16 and R17 together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocyclyl ring optionally comprising 1-2 additional heteroatoms selected from N, O, and S;

each R18 is independently at each occurrence (C3-C7)carbocyclyl, 5- to 7-membered heterocyclyl comprising 1-3 heteroatoms selected from N, O, and S, (C6-C10)aryl, or 5- or 6-membered heteroaryl comprising 1-3 heteroatoms selected from N, O, and S, wherein the carbocyclyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one or more R20; each R19 is independently at each occurrence halogen, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, -OH, or CN; or

two R19 together, when on adjacent atoms, form a (C6-C10)aryl or 5- or 6-membered heteroaryl ring comprising 1-3 heteroatoms selected from N, O, and S, wherein the aryl and heteroaryl are optionally substituted with one or more substituents each independently selected from halogen, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, -OH, and CN; each R20 is independently at each occurrence halogen, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, oxo, -OH, or CN; or

when R18 is a carbocyclyl or a heterocyclyl, two R20, when attached to the same carbon atom, together form =(O);

R21 is H or (C1-C6)alkyl;

each R22 is independently at each occurrence halogen, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, -OH, CN, (C6-C10)aryl, or 5- or 6-membered heteroaryl comprising 1-3 heteroatoms selected from N, O, and S, wherein the aryl and heteroaryl are optionally substituted with one or more R23;

each R23 is independently at each occurrence halogen, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, -CH2(OCH2CH2)1-3OCH2CH3, -OH, CN, or 4- to 7-membered heterocyclyl comprising 1-3 heteroatoms selected from N, O, and S, wherein the heterocyclyl is optionally substituted with one or more substituents each independently selected from halogen, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy,–OH,

-C(O)R24R25, -NR24C(O)R25, -NH2, -NH(C1-C6)alkyl, and -N((C1-C6)alkyl)2, and the alkyl is optionally substituted with -NR24R25 or a 4- to 7-membered heterocyclyl comprising 1-3 heteroatoms selected from N, O, and S optionally substituted with one or more substituents each independently selected from halogen, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy,–OH, -NH2, -NH(C1-C6)alkyl, and -N((C1-C6)alkyl)2; and

R24 and R25 are each independently H, (C1-C6)alkyl, or (C3-C7)carbocyclyl optionally substituted with one to two (C1-C6)alkyl;

or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, N-oxide, or tautomer thereof.

2. The compound according to claim 1, wherein R4 is H or (C1-C6)alkyl.

3. The compound according to claim 1 or 2, wherein R4 is H.

4. The compound according to claim 1, wherein R3 and R4 together with the atoms to which they are attached form a 5- to 7-membered heterocyclyl ring comprising 1-3 heteroatoms selected from N, O, and S.

5. The compound according to claim 4, wherein R3 and R4 together with the atoms to which they are attached form a 6-membered heterocyclyl ring comprising 1-3 heteroatoms selected from N, O, and S.

6. The compound according to any one of claims 1-5, wherein R5 is H or (C1-C6)alkyl. 7. The compound according to any one of claims 1-6, wherein R5 is (C1-C6)alkyl.

8. The compound according to any one of claims 1-7, wherein R7 is H or (C1-C6)alkyl. 9. The compound according to any one of claims 1-8, wherein R7 is (C1-C6)alkyl.

10. The compound according to any one of claims 1-9, wherein R9 is halogen.

11. The compound according to any one of claims 1-10, wherein R9 is chloro.

12. The compound according to any one of claims 1-11, wherein R8 is (C1-C6)alkyl optionally substituted with one to three substituents each independently selected from (C3-C7)carbocyclyl, 4- to 7-membered heterocyclyl comprising 1-3 heteroatoms selected from N, O, and S, –NR16R17, and–C(O)NR16R17.

13. The compound according to any one of claims 1-12, wherein R8 is (C1-C6)alkyl.

14. The compound of claim 1, having a Formula (Ia), Formula (Ib), Formula (Ic), Formula (Id), Formula (Ie), Formula (If), Formula (Ig), Formula (Ih), or Formula (Ii):

15. The compound according to any one of claims 1-14, wherein R1 is phenyl substituted with -OR10 and optionally substituted with one to three R11.

16. The compound according to any one of claims 1-14, wherein R1 is pyridinyl substituted with -OR10 and optionally substituted with one to three R11.

17. The compound of claim 1, having a Formula (Ij), Formula (Ik), Formula (Im), or Formula (Io):

wherein x is 0, 1, or 2.

18. The compound according to any one of claims 1-17, wherein R10 is phenyl substituted with one to three R22.

19. The compound according to any one of claims 1-17, wherein R10 is pyridinyl substituted with one to three R22.

20. The compound according to claim 1 selected from:

(3R,7S,10S,13R)-6-(4-chloro-2-(4-(1-methyl-2-(pyrrolidin-1-ylmethyl)-1H-imidazol-5-yl)phenoxy)benzyl)-13-(4-chlorobenzyl)-10-(hydroxymethyl)-7-methyl-3-(pyridin-2-ylmethyl)-1,6,9,12-tetraazabicyclo[11.3.1]heptadecane-2,5,8,11-tetraone;

(3S,7S,10S,13R)-6-(4-chloro-2-(4-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)benzyl)-13-(4-chlorobenzyl)-10-(methoxymethyl)-7-methyl-3-(2,2,2-trifluoroethyl)-1,6,9,12-tetraazabicyclo[11.3.1]heptadecane-2,5,8,11-tetraone;

2-(((3R,7S,10S,13R)-6-(4-chloro-2-(4-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)-6-fluorobenzyl)-13-(4-chlorobenzyl)-10-(methoxymethyl)-7,12-dimethyl-2,5,8,11-tetraoxo-1,6,9,12-tetraazabicyclo[11.3.1]heptadecan-3-yl)methyl)pyridine 1-oxide;

(3R,7S,10S,13R)-6-(4-chloro-2-(4-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)benzyl)-13-(4-chlorobenzyl)-10-(methoxymethyl)-7-methyl-3-((6-methylpyridin-2-yl)methyl)-1,6,9,12-tetraazabicyclo[11.3.1]heptadecane-2,5,8,11-tetraone;

(3S,7S,10S,13R)-6-(4-chloro-2-(4-(2-((cyclobutylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)-6-fluorobenzyl)-13-(4-chlorobenzyl)-10-(hydroxymethyl)-7-methyl-3-(2,2,2-trifluoroethyl)-1,6,9,12-tetraazabicyclo[11.3.1]heptadecane-2,5,8,11-tetraone;

(3S,7S,10S,13R)-6-(2-(4-(2-((tert-butylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)-4-chlorobenzyl)-13-(4-chlorobenzyl)-10-(methoxymethyl)-7-methyl-3-(2,2,2-trifluoroethyl)-1,6,9,12-tetraazabicyclo[11.3.1]heptadecane-2,5,8,11-tetraone;

(3S,7S,10S,13R)-6-(4-chloro-2-(4-(4-((dimethylamino)methyl)-5-methyl-1H-imidazol-1-yl)phenoxy)benzyl)-13-(4-chlorobenzyl)-3-((S)-2,3-dihydro-1H-inden-1-yl)-10-(hydroxymethyl)-7-methyl-1,6,9,12-tetraazabicyclo[11.3.1]heptadecane-2,5,8,11-tetraone;

(3S,7S,10S,13R)-6-(4-chloro-2-((6-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)pyridin-3-yl)oxy)-6-fluorobenzyl)-13-(4-chlorobenzyl)-10-(methoxymethyl)-7-methyl-3-(2,2,2-trifluoroethyl)-1,6,9,12-tetraazabicyclo[11.3.1]heptadecane-2,5,8,11-tetraone;

(3S,7S,10S,13R)-6-(4-chloro-2-(4-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)benzyl)-13-(4-chlorobenzyl)-10-(methoxymethyl)-7,12-dimethyl-3-(2,2,2-trifluoroethyl)-1,6,9,12-tetraazabicyclo[11.3.1]heptadecane-2,5,8,11-tetraone;

(3R,7S,10S,13R)-6-(4-chloro-2-fluoro-6-(4-(1-methyl-2-(pyrrolidin-1-ylmethyl)-1H-imidazol-5-yl)phenoxy)benzyl)-13-(4-chlorobenzyl)-3-(cyclopropylmethyl)-10-(hydroxymethyl)-7-methyl-1,6,9,12-tetraazabicyclo[11.3.1]heptadecane-2,5,8,11-tetraone;

(3R,7S,10S,13R)-3-benzyl-6-(4-chloro-2-(4-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)-6-fluorobenzyl)-13-(4-chlorobenzyl)-10-(hydroxymethyl)-7-methyl-1,6,9,12-tetraazabicyclo[11.3.1]heptadecane-2,5,8,11-tetraone;

(3S,7S,10S,13R)-6-(4-chloro-2-((6-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)pyridin-3-yl)oxy)benzyl)-13-(4-chlorobenzyl)-10-(methoxymethyl)-7,12-dimethyl-3-(2,2,2-trifluoroethyl)-1,6,9,12-tetraazabicyclo[11.3.1]heptadecane-2,5,8,11-tetraone;

(3R,7S,10S,13R)-6-(4-chloro-2-(4-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)-6-fluorobenzyl)-13-(4-chlorobenzyl)-10-(methoxymethyl)-7,12-dimethyl-3-((6-methylpyridin-2-yl)methyl)-1,6,9,12-tetraazabicyclo[11.3.1]heptadecane-2,5,8,11-tetraone; (3R,7S,10S,13R)-6-(4-chloro-2-fluoro-6-(4-(1-methyl-2-(pyrrolidin-1-ylmethyl)-1H-imidazol-5-yl)phenoxy)benzyl)-13-(4-chlorobenzyl)-10-(methoxymethyl)-7,12-dimethyl-3-((6-methylpyridin-2-yl)methyl)-1,6,9,12-tetraazabicyclo[11.3.1]heptadecane-2,5,8,11-tetraone;

(3S,7S,10S,13R)-6-(4-chloro-2-fluoro-6-(4-(1-methyl-2-(pyrrolidin-1-ylmethyl)-1H-imidazol-5-yl)phenoxy)benzyl)-13-(4-chlorobenzyl)-10-(hydroxymethyl)-7-methyl-3-(2,2,2-trifluoroethyl)-1,6,9,12-tetraazabicyclo[11.3.1]heptadecane-2,5,8,11-tetraone;

(3S,7S,10S,13R)-6-(4-chloro-2-(4-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)benzyl)-13-(4-chlorobenzyl)-3-((R)-6,7-dihydro-5H-cyclopenta[b]pyridin-5-yl)-10-(hydroxymethyl)-7-methyl-1,6,9,12-tetraazabicyclo[11.3.1]heptadecane-2,5,8,11-tetraone; (3R,7S,10S,13R)-3-benzyl-6-((5-chloro-3-(4-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)pyridin-2-yl)methyl)-13-(4-chlorobenzyl)-10-(methoxymethyl)-7-methyl-1,6,9,12-tetraazabicyclo[11.3.1]heptadecane-2,5,8,11-tetraone;

(3R,7S,10S,13R)-6-(4-chloro-2-(4-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)benzyl)-13-(4-chlorobenzyl)-10-(hydroxymethyl)-7,12-dimethyl-3-(pyridin-2-ylmethyl)-1,6,9,12-tetraazabicyclo[11.3.1]heptadecane-2,5,8,11-tetraone;

(3R,7S,10S,13R)-6-(4-chloro-2-(4-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)benzyl)-13-(4-chlorobenzyl)-10-(hydroxymethyl)-7-methyl-3-(pyridin-3-ylmethyl)-1,6,9,12-tetraazabicyclo[11.3.1]heptadecane-2,5,8,11-tetraone;

(3S,7S,10S,13R)-6-(4-chloro-2-(4-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)benzyl)-13-(4-chlorobenzyl)-10-(hydroxymethyl)-7,12-dimethyl-3-(2,2,2-trifluoroethyl)-1,6,9,12-tetraazabicyclo[11.3.1]heptadecane-2,5,8,11-tetraone;

(3R,7S,10S,13R)-6-(4-chloro-2-(4-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)benzyl)-13-(4-chlorobenzyl)-10-(methoxymethyl)-7-methyl-3-(pyridin-2-ylmethyl)-1,6,9,12-tetraazabicyclo[11.3.1]heptadecane-2,5,8,11-tetraone;

(3S,7S,10S,13R)-6-(4-chloro-2-(4-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)-6-fluorobenzyl)-13-(4-chlorobenzyl)-10-(methoxymethyl)-7,12-dimethyl-3-(2,2,2-trifluoroethyl)-1,6,9,12-tetraazabicyclo[11.3.1]heptadecane-2,5,8,11-tetraone;

(3R,7S,10S,13R)-6-(4-chloro-2-(4-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)benzyl)-13-(4-chlorobenzyl)-10-(methoxymethyl)-7-methyl-3-(pyridin-3-ylmethyl)-1,6,9,12-tetraazabicyclo[11.3.1]heptadecane-2,5,8,11-tetraone;

(3R,7S,10S,13R)-6-(4-chloro-2-((6-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)pyridin-3-yl)oxy)benzyl)-13-(4-chlorobenzyl)-10-(methoxymethyl)-7,12-dimethyl-3-((6-methylpyridin-2-yl)methyl)-1,6,9,12-tetraazabicyclo[11.3.1]heptadecane-2,5,8,11-tetraone; (3R,7S,10S,13R)-3-benzyl-6-(4-chloro-2-(4-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)-3-fluorobenzyl)-13-(4-chlorobenzyl)-10-(hydroxymethyl)-7-methyl-1,6,9,12-tetraazabicyclo[11.3.1]heptadecane-2,5,8,11-tetraone;

(3R,7S,10S,13R)-6-(4-chloro-2-(4-(1-methyl-2-(pyrrolidin-1-ylmethyl)-1H-imidazol-5-yl)phenoxy)benzyl)-13-(4-chlorobenzyl)-3-ethyl-10-(hydroxymethyl)-7-methyl-1,6,9,12-tetraazabicyclo[11.3.1]heptadecane-2,5,8,11-tetraone;

(3R,7S,10S,13R)-3-benzyl-6-(4-chloro-2-((6-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)pyridin-3-yl)oxy)benzyl)-13-(4-chlorobenzyl)-10-(methoxymethyl)-7,12-dimethyl-1,6,9,12-tetraazabicyclo[11.3.1]heptadecane-2,5,8,11-tetraone;

(3S,7S,10S,13R)-6-(2-(4-(2-(azetidin-1-ylmethyl)-1-methyl-1H-imidazol-5-yl)phenoxy)-4-chloro-6-fluorobenzyl)-13-(4-chlorobenzyl)-10-(hydroxymethyl)-7-methyl-3-(2,2,2-trifluoroethyl)-1,6,9,12-tetraazabicyclo[11.3.1]heptadecane-2,5,8,11-tetraone;

(3S,7S,10S,13R)-6-((5-chloro-3-(4-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)pyridin-2-yl)methyl)-13-(4-chlorobenzyl)-10-(methoxymethyl)-7-methyl-3-(2,2,2-trifluoroethyl)-1,6,9,12-tetraazabicyclo[11.3.1]heptadecane-2,5,8,11-tetraone;

(3R,7S,10S,13R)-6-(4-chloro-2-(4-(1-methyl-2-(pyrrolidin-1-ylmethyl)-1H-imidazol-5-yl)phenoxy)benzyl)-13-(4-chlorobenzyl)-10-((difluoromethoxy)methyl)-7-methyl-3-(pyridin-2-ylmethyl)-1,6,9,12-tetraazabicyclo[11.3.1]heptadecane-2,5,8,11-tetraone;

(3S,7S,10S,13R)-6-(4-chloro-2-((5-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)pyridin-2-yl)oxy)benzyl)-13-(4-chlorobenzyl)-3-((R)-2,3-dihydro-1H-inden-1-yl)-10-(hydroxymethyl)-7-methyl-1,6,9,12-tetraazabicyclo[11.3.1]heptadecane-2,5,8,11-tetraone;

(3S,7S,10S,13R)-6-(4-chloro-2-((5-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)pyridin-2-yl)oxy)benzyl)-13-(4-chlorobenzyl)-3-((S)-2,3-dihydro-1H-inden-1-yl)-10-(hydroxymethyl)-7-methyl-1,6,9,12-tetraazabicyclo[11.3.1]heptadecane-2,5,8,11-tetraone;

(3R,7S,10S,13R)-6-(4-chloro-2-(4-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)-6-fluorobenzyl)-13-(4-chlorobenzyl)-10-(hydroxymethyl)-7,12-dimethyl-3-(pyridin-2-ylmethyl)-1,6,9,12-tetraazabicyclo[11.3.1]heptadecane-2,5,8,11-tetraone;

(3S,7S,10S,13R)-6-(2-(4-(2-(azetidin-1-ylmethyl)-1-methyl-1H-imidazol-5-yl)phenoxy)-4-chlorobenzyl)-13-(4-chlorobenzyl)-10-(methoxymethyl)-7-methyl-3-(2,2,2-trifluoroethyl)-1,6,9,12-tetraazabicyclo[11.3.1]heptadecane-2,5,8,11-tetraone;

(3R,7S,10S,13R)-6-(4-chloro-2-(4-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)-6-fluorobenzyl)-13-(4-chlorobenzyl)-3-(2,6-difluorobenzyl)-10-(hydroxymethyl)-7-methyl-1,6,9,12-tetraazabicyclo[11.3.1]heptadecane-2,5,8,11-tetraone;

(3R,7S,10S,13R)-6-(4-chloro-2-(4-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)benzyl)-13-(4-chlorobenzyl)-10-(methoxymethyl)-7-methyl-3-(oxazol-2-ylmethyl)-1,6,9,12-tetraazabicyclo[11.3.1]heptadecane-2,5,8,11-tetraone;

(7S,10S,13R)-6-(4-chloro-2-(4-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)-6-(2,2,2-trifluoroethoxy)benzyl)-13-(4-chlorobenzyl)-10-(hydroxymethyl)-7-methyl-1,6,9,12-tetraazabicyclo[11.3.1]heptadecane-2,5,8,11-tetraone;

(3R,7S,10S,13R)-6-(4-chloro-2-(4-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)benzyl)-13-(4-chlorobenzyl)-10-(hydroxymethyl)-7,12-dimethyl-3-(2,4,6-trifluorobenzyl)-1,6,9,12-tetraazabicyclo[11.3.1]heptadecane-2,5,8,11-tetraone;

(3R,7S,10S,13R)-6-(4-chloro-2-(4-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)benzyl)-13-(4-chlorobenzyl)-10-(methoxymethyl)-7,12-dimethyl-3-((6-methylpyridin-2-yl)methyl)-1,6,9,12-tetraazabicyclo[11.3.1]heptadecane-2,5,8,11-tetraone;

(3R,7S,10S,13R)-3-benzyl-6-(4-chloro-2-fluoro-6-(4-(5-methyl-4-(pyrrolidin-1-ylmethyl)-1H-imidazol-1-yl)phenoxy)benzyl)-13-(4-chlorobenzyl)-10-(methoxymethyl)-7-methyl-1,6,9,12-tetraazabicyclo[11.3.1]heptadecane-2,5,8,11-tetraone;

(3R,7S,10S,13R)-3-((E)-but-2-en-1-yl)-6-(4-chloro-2-(4-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)benzyl)-13-(4-chlorobenzyl)-10-(hydroxymethyl)-7-methyl-1,6,9,12-tetraazabicyclo[11.3.1]heptadecane-2,5,8,11-tetraone;

(3R,7S,10S,13R)-6-(4-chloro-2-(4-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)benzyl)-13-(4-chlorobenzyl)-10-(hydroxymethyl)-7-methyl-3-((6-methylpyridin-2-yl)methyl)-1,6,9,12-tetraazabicyclo[11.3.1]heptadecane-2,5,8,11-tetraone;

(3R,7S,10S,13R)-6-(4-chloro-2-(4-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)benzyl)-13-(4-chlorobenzyl)-3-(cyclopropylmethyl)-10-(hydroxymethyl)-7-methyl-1,6,9,12-tetraazabicyclo[11.3.1]heptadecane-2,5,8,11-tetraone;

(3R,7S,10S,13R)-3-benzyl-6-(4-chloro-2-(4-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)-3-fluorophenoxy)benzyl)-13-(4-chlorobenzyl)-10-(hydroxymethyl)-7-methyl-1,6,9,12-tetraazabicyclo[11.3.1]heptadecane-2,5,8,11-tetraone;

(3R,7S,10S,13R)-6-(4-chloro-2-(4-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)benzyl)-13-(4-chlorobenzyl)-10-(methoxymethyl)-7-methyl-3-((1-methyl-6-oxo-1,6-dihydropyridin-2-yl)methyl)-1,6,9,12-tetraazabicyclo[11.3.1]heptadecane-2,5,8,11-tetraone; (3S,7S,10S,13R)-6-(4-chloro-2-(4-(2-((cyclobutylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)-6-fluorobenzyl)-13-(4-chlorobenzyl)-10-(methoxymethyl)-7-methyl-3-(2,2,2-trifluoroethyl)-1,6,9,12-tetraazabicyclo[11.3.1]heptadecane-2,5,8,11-tetraone;

(3R,7S,10S,13R)-6-(4-chloro-2-(4-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)benzyl)-13-(4-chlorobenzyl)-10-(hydroxymethyl)-7-methyl-3-(2,4,6-trifluorobenzyl)-1,6,9,12-tetraazabicyclo[11.3.1]heptadecane-2,5,8,11-tetraone;

(3R,7S,10S,13R)-6-(4-chloro-2-(4-(1-methyl-2-(morpholinomethyl)-1H-imidazol-5-yl)phenoxy)benzyl)-13-(4-chlorobenzyl)-10-(hydroxymethyl)-7-methyl-3-(pyridin-3-ylmethyl)-1,6,9,12-tetraazabicyclo[11.3.1]heptadecane-2,5,8,11-tetraone;

(3R,7S,10S,13R)-6-(4-chloro-2-(4-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)-6-fluorobenzyl)-13-(4-chlorobenzyl)-10-(hydroxymethyl)-7-methyl-3-(2,3,4-trifluorobenzyl)-1,6,9,12-tetraazabicyclo[11.3.1]heptadecane-2,5,8,11-tetraone;

(3S,7S,10S,13R)-6-(4-chloro-2-(4-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)-6-fluorobenzyl)-13-(4-chlorobenzyl)-3-((S)-2,3-dihydro-1H-inden-1-yl)-10-(hydroxymethyl)-7-methyl-1,6,9,12-tetraazabicyclo[11.3.1]heptadecane-2,5,8,11-tetraone;

(3R,7S,10S,13R)-3-benzyl-6-(4-chloro-2-(4-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)benzyl)-13-(4-chlorobenzyl)-10-(hydroxymethyl)-7-methyl-1,6,9,12-tetraazabicyclo[11.3.1]heptadecane-2,5,8,11-tetraone;

(3R,7S,10S,13R)-6-(4-chloro-2-(4-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)-6-fluorobenzyl)-13-(4-chlorobenzyl)-10-(hydroxymethyl)-7-methyl-3-propyl-1,6,9,12-tetraazabicyclo[11.3.1]heptadecane-2,5,8,11-tetraone;

(3R,7S,10S,13R)-3-benzyl-6-(4-chloro-2-((6-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)pyridin-3-yl)oxy)benzyl)-13-(4-chlorobenzyl)-10-(methoxymethyl)-7-methyl-1,6,9,12-tetraazabicyclo[11.3.1]heptadecane-2,5,8,11-tetraone;

(3R,7S,10S,13R)-3-benzyl-6-(4-chloro-2-(4-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)benzyl)-13-(4-chlorobenzyl)-10-(hydroxymethyl)-7,12-dimethyl-1,6,9,12-tetraazabicyclo[11.3.1]heptadecane-2,5,8,11-tetraone;

(3R,7S,10S,13R)-3-benzyl-6-(4-chloro-2-(4-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)-5-fluorobenzyl)-13-(4-chlorobenzyl)-10-(hydroxymethyl)-7-methyl-1,6,9,12-tetraazabicyclo[11.3.1]heptadecane-2,5,8,11-tetraone;

(3S,7S,10S,13R)-13-(4-chlorobenzyl)-3-((S)-2,3-dihydro-1H-inden-1-yl)-6-(2-(4-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)benzyl)-10-(hydroxymethyl)-7-methyl-1,6,9,12-tetraazabicyclo[11.3.1]heptadecane-2,5,8,11-tetraone;

(3R,7S,10S,13R)-3-benzyl-6-(4-chloro-2-(4-(5-((dimethylamino)methyl)-4-methyl-4H-1,2,4-triazol-3-yl)phenoxy)benzyl)-13-(4-chlorobenzyl)-10-(hydroxymethyl)-7-methyl-1,6,9,12-tetraazabicyclo[11.3.1]heptadecane-2,5,8,11-tetraone;

(3R,7S,10S,13R)-6-(4-chloro-2-(4-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)-6-fluorobenzyl)-13-(4-chlorobenzyl)-10-(methoxymethyl)-7,12-dimethyl-3-(pyridin-2-ylmethyl)-1,6,9,12-tetraazabicyclo[11.3.1]heptadecane-2,5,8,11-tetraone;

(3S,7S,10S,13R)-6-(4-chloro-2-(4-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)benzyl)-13-(4-chlorobenzyl)-3-(2,2-difluoroethyl)-10-(hydroxymethyl)-7-methyl-1,4,6,9,12-pentaazabicyclo[11.3.1]heptadecane-2,5,8,11-tetraone;

(3R,7S,10S,13R)-3-benzyl-6-(4-chloro-2-(4-(2-(((S)-3-hydroxypyrrolidin-1-yl)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)benzyl)-13-(4-chlorobenzyl)-10-(methoxymethyl)-7-methyl-1,6,9,12-tetraazabicyclo[11.3.1]heptadecane-2,5,8,11-tetraone;

(3S,7S,10S,13R)-3-benzyl-6-(4-chloro-2-(4-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)benzyl)-13-(4-chlorobenzyl)-10-(hydroxymethyl)-7-methyl-1,4,6,9,12-pentaazabicyclo[11.3.1]heptadecane-2,5,8,11-tetraone;

(3R,7S,10S,13R)-3-benzyl-6-(4-chloro-2-(4-(2-((4-hydroxypiperidin-1-yl)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)benzyl)-13-(4-chlorobenzyl)-10-(methoxymethyl)-7-methyl-1,6,9,12-tetraazabicyclo[11.3.1]heptadecane-2,5,8,11-tetraone;

(3R,7S,10S,13R)-6-(4-chloro-2-(4-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)benzyl)-13-(4-chlorobenzyl)-10-(hydroxymethyl)-7-methyl-3-(4-(trifluoromethyl)benzyl)-1,6,9,12-tetraazabicyclo[11.3.1]heptadecane-2,5,8,11-tetraone;

(3R,7S,10S,13R)-6-(4-chloro-2-(4-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)-6-fluorobenzyl)-13-(4-chlorobenzyl)-3-ethyl-10-(methoxymethyl)-7-methyl-1,6,9,12-tetraazabicyclo[11.3.1]heptadecane-2,5,8,11-tetraone;

(3S,7S,10S,13R)-6-(4-chloro-2-(4-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)benzyl)-13-(4-chlorobenzyl)-10-((S)-1-hydroxyethyl)-7-methyl-3-(2,2,2-trifluoroethyl)-1,6,9,12-tetraazabicyclo[11.3.1]heptadecane-2,5,8,11-tetraone;

(3R,7S,10S,13R)-3-benzyl-6-(4-chloro-2-(4-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)benzyl)-13-(4-chlorobenzyl)-10-(methoxymethyl)-7,12-dimethyl-1,6,9,12-tetraazabicyclo[11.3.1]heptadecane-2,5,8,11-tetraone;

2-(((3R,7S,10S,13R)-6-(4-chloro-2-(4-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)benzyl)-13-(4-chlorobenzyl)-10-(hydroxymethyl)-7-methyl-2,5,8,11-tetraoxo-1,6,9,12-tetraazabicyclo[11.3.1]heptadecan-3-yl)methyl)pyridine 1-oxide;

(3S,7S,10S,13R)-6-(4-chloro-2-(4-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)benzyl)-13-(4-chlorobenzyl)-10-(hydroxymethyl)-3-isopropyl-7-methyl-1,4,6,9,12-pentaazabicyclo[11.3.1]heptadecane-2,5,8,11-tetraone;

(3S,7S,10S,13R)-6-(4-chloro-2-(4-(1-methyl-2-(pyrrolidin-1-ylmethyl)-1H-imidazol-5-yl)phenoxy)benzyl)-13-(4-chlorobenzyl)-3-((R)-2,3-dihydro-1H-inden-1-yl)-10-(hydroxymethyl)-7-methyl-1,6,9,12-tetraazabicyclo[11.3.1]heptadecane-2,5,8,11-tetraone;

(3S,7S,10S,13R)-6-(4-chloro-2-(4-(1-methyl-2-(1-methylazetidin-3-yl)-1H-imidazol-5-yl)phenoxy)benzyl)-13-(4-chlorobenzyl)-3-((S)-2,3-dihydro-1H-inden-1-yl)-10-(hydroxymethyl)-7-methyl-1,6,9,12-tetraazabicyclo[11.3.1]heptadecane-2,5,8,11-tetraone;

(3S,7S,10S,13R)-6-(4-chloro-2-(4-(2-((R)-1-(dimethylamino)ethyl)-1-methyl-1H-imidazol-5-yl)phenoxy)benzyl)-13-(4-chlorobenzyl)-3-((S)-2,3-dihydro-1H-inden-1-yl)-10-(hydroxymethyl)-7-methyl-1,6,9,12-tetraazabicyclo[11.3.1]heptadecane-2,5,8,11-tetraone;

(3R,7S,10S,13R)-3-benzyl-6-(4-chloro-2-((6-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)pyridin-3-yl)oxy)benzyl)-13-(4-chlorobenzyl)-10-(hydroxymethyl)-7,12-dimethyl-1,6,9,12-tetraazabicyclo[11.3.1]heptadecane-2,5,8,11-tetraone;

(3R,7S,10S,13R)-3-benzyl-6-(4-chloro-2-(4-(2-(((S)-3-(dimethylamino)pyrrolidin-1-yl)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)benzyl)-13-(4-chlorobenzyl)-10-(methoxymethyl)-7-methyl-1,6,9,12-tetraazabicyclo[11.3.1]heptadecane-2,5,8,11-tetraone;

(3S,7S,10S,13R)-13-(4-chlorobenzyl)-3-((S)-2,3-dihydro-1H-inden-1-yl)-6-(2-(4-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)-4-fluorobenzyl)-10-(hydroxymethyl)-7-methyl-1,6,9,12-tetraazabicyclo[11.3.1]heptadecane-2,5,8,11-tetraone; (3S,7S,10S,13R)-13-(4-chlorobenzyl)-3-((S)-2,3-dihydro-1H-inden-1-yl)-6-(2-(4-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)-5-fluorobenzyl)-10-(hydroxymethyl)-7-methyl-1,6,9,12-tetraazabicyclo[11.3.1]heptadecane-2,5,8,11-tetraone; (3S,7S,10S,13R)-6-(4-chloro-2-(4-(1-methyl-2-(pyrrolidin-1-ylmethyl)-1H-imidazol-5-yl)phenoxy)benzyl)-13-(4-chlorobenzyl)-3-((S)-2,3-dihydro-1H-inden-1-yl)-10-(hydroxymethyl)-7-methyl-1,6,9,12-tetraazabicyclo[11.3.1]heptadecane-2,5,8,11-tetraone;

(3R,7S,10S,13R)-3-benzyl-13-(4-chlorobenzyl)-6-(2,4-difluoro-6-(4-(1-methyl-2-(pyrrolidin-1-ylmethyl)-1H-imidazol-5-yl)phenoxy)benzyl)-10-(hydroxymethyl)-7-methyl-1,6,9,12-tetraazabicyclo[11.3.1]heptadecane-2,5,8,11-tetraone;

(3R,7S,10S,13R)-3-benzyl-6-(4-chloro-2-(4-(1-methyl-2-((4-methylpiperazin-1-yl)methyl)-1H-imidazol-5-yl)phenoxy)benzyl)-13-(4-chlorobenzyl)-10-(methoxymethyl)-7-methyl-1,6,9,12-tetraazabicyclo[11.3.1]heptadecane-2,5,8,11-tetraone;

(3S,7S,10S,13R)-6-(4-chloro-2-(4-(1-methyl-2-(1-methyl-2,5-dihydro-1H-pyrrol-3-yl)-1H-imidazol-5-yl)phenoxy)benzyl)-13-(4-chlorobenzyl)-3-((S)-2,3-dihydro-1H-inden-1-yl)-10-(hydroxymethyl)-7-methyl-1,6,9,12-tetraazabicyclo[11.3.1]heptadecane-2,5,8,11-tetraone;

(3S,7S,10S,13R)-3-benzyl-6-(4-chloro-2-(4-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)benzyl)-13-(4-chlorobenzyl)-10-(hydroxymethyl)-7-methyl-4-oxa-1,6,9,12-tetraazabicyclo[11.3.1]heptadecane-2,5,8,11-tetraone;

(3R,7S,10S,13R)-3-benzyl-6-(4-chloro-2-(4-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)-6-fluorobenzyl)-13-(4-chlorobenzyl)-10-(hydroxymethyl)-7,12-dimethyl-1,6,9,12-tetraazabicyclo[11.3.1]heptadecane-2,5,8,11-tetraone;

(3R,7S,10S,13R)-6-(4-chloro-2-(4-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)-6-fluorobenzyl)-13-(4-chlorobenzyl)-10-(hydroxymethyl)-7-methyl-3-(3-(trifluoromethyl)benzyl)-1,6,9,12-tetraazabicyclo[11.3.1]heptadecane-2,5,8,11-tetraone;

(2S,5S,8R,12S)-1-(4-chloro-2-(4-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)benzyl)-8-(4-chlorobenzyl)-5-(hydroxymethyl)-2,7,10-trimethyl-12-((1R,3S)-3-methyl-2,3-dihydro-1H-inden-1-yl)-1,4,7,10-tetraazacyclotetradecane-3,6,11,14-tetraone;

(3S,7S,10S,13R)-6-(4-chloro-2-(4-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)-6-fluorobenzyl)-13-(4-chlorobenzyl)-10-(hydroxymethyl)-7,12-dimethyl-3-(2,2,2-trifluoroethyl)-1,6,9,12-tetraazabicyclo[11.3.1]heptadecane-2,5,8,11-tetraone;

(3S,7S,10S,13R)-6-(4-chloro-2-(4-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)benzyl)-13-(4-chlorobenzyl)-10-(hydroxymethyl)-7-methyl-3-(2,2,2-trifluoroethyl)-1,6,9,12-tetraazabicyclo[11.3.1]heptadecane-2,5,8,11-tetraone;

(3S,7S,10S,13R)-6-(4-chloro-2-(4-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)benzyl)-13-(4-chlorobenzyl)-3-((S)-2,3-dihydro-1H-inden-1-yl)-10-(hydroxymethyl)-7-methyl-1,6,9,12-tetraazabicyclo[11.3.1]heptadecane-2,5,8,11-tetraone;

(3R,7S,10S,13R)-3-benzyl-6-((5-chloro-3-((6-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)pyridin-3-yl)oxy)pyridin-2-yl)methyl)-13-(4-chlorobenzyl)-10-(methoxymethyl)-7,12-dimethyl-1,6,9,12-tetraazabicyclo[11.3.1]heptadecane-2,5,8,11-tetraone;

(2S,5S,8R,12S)-1-(4-chloro-2-(4-(1-methyl-2-(pyrrolidin-1-ylmethyl)-1H-imidazol-5-yl)phenoxy)benzyl)-8-(4-chlorobenzyl)-12-((R)-2,3-dihydro-1H-inden-1-yl)-5-(hydroxymethyl)-2,7,10-trimethyl-1,4,7,10-tetraazacyclotetradecane-3,6,11,14-tetraone;

(3R,7S,10S,13R)-3-benzyl-6-(4-chloro-2-(4-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)-2-fluorophenoxy)-6-fluorobenzyl)-13-(4-chlorobenzyl)-10-(hydroxymethyl)-7-methyl-1,6,9,12-tetraazabicyclo[11.3.1]heptadecane-2,5,8,11-tetraone;

(3S,7S,10S,13R)-6-(4-chloro-2-(4-(2-((dimethylamino)methyl)-1-ethyl-1H-imidazol-5-yl)phenoxy)-6-fluorobenzyl)-13-(4-chlorobenzyl)-10-(hydroxymethyl)-7-methyl-3-(2,2,2-trifluoroethyl)-1,6,9,12-tetraazabicyclo[11.3.1]heptadecane-2,5,8,11-tetraone;

(2S,5S,8R,12R)-12-benzyl-1-(4-chloro-2-(4-(1-methyl-2-(pyrrolidin-1-ylmethyl)-1H-imidazol-5-yl)phenoxy)benzyl)-8-(4-chlorobenzyl)-5-(hydroxymethyl)-2,7-dimethyl-1,4,7,10-tetraazacyclotetradecane-3,6,11,14-tetraone;

(3S,7S,10S,13R)-13-(4-chlorobenzyl)-3-((S)-2,3-dihydro-1H-inden-1-yl)-6-(2-(4-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)-4-(trifluoromethyl)benzyl)-10-(hydroxymethyl)-7-methyl-1,6,9,12-tetraazabicyclo[11.3.1]heptadecane-2,5,8,11-tetraone;

(2S,5S,8R,12S)-1-(4-chloro-2-(4-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)benzyl)-8-(4-chlorobenzyl)-12-((R)-2,3-dihydro-1H-inden-1-yl)-5-(hydroxymethyl)-2,7,10-trimethyl-1,4,7,10-tetraazacyclotetradecane-3,6,11,14-tetraone;

(2S,5S,8R,12R)-12-benzyl-1-(4-chloro-2-(4-(1-methyl-2-(pyrrolidin-1-ylmethyl)-1H-imidazol-5-yl)phenoxy)benzyl)-8-(4-chlorobenzyl)-5-(methoxymethyl)-2,7-dimethyl-1,4,7,10-tetraazacyclotetradecane-3,6,11,14-tetraone;

(2S,5S,8R,12S)-1-(4-chloro-2-(4-(1-methyl-2-(pyrrolidin-1-ylmethyl)-1H-imidazol-5-yl)phenoxy)benzyl)-8-(4-chlorobenzyl)-5-(hydroxymethyl)-2,7,10-trimethyl-12-((1R,3S)-3-methyl-2,3-dihydro-1H-inden-1-yl)-1,4,7,10-tetraazacyclotetradecane-3,6,11,14-tetraone;

(3R,7S,10S,13R)-6-(4-chloro-2-((6-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)pyridin-3-yl)oxy)benzyl)-13-(4-chlorobenzyl)-10-(methoxymethyl)-7,12-dimethyl-3-(pyridin-2-ylmethyl)-1,6,9,12-tetraazabicyclo[11.3.1]heptadecane-2,5,8,11-tetraone;

(3S,7S,10S,13R)-6-(4-chloro-2-(4-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)benzyl)-13-(4-chlorobenzyl)-3-((S)-2,3-dihydro-1H-inden-1-yl)-10-(methoxymethyl)-7-methyl-1,6,9,12-tetraazabicyclo[11.3.1]heptadecane-2,5,8,11-tetraone;

(3S,7S,10S,13R)-6-(4-chloro-2-(4-(1-methyl-2-(pyrrolidin-1-ylmethyl)-1H-imidazol-5-yl)phenoxy)benzyl)-13-(4-chlorobenzyl)-3-((R)-2,3-dihydro-1H-inden-1-yl)-10-(methoxymethyl)-7-methyl-1,6,9,12-tetraazabicyclo[11.3.1]heptadecane-2,5,8,11-tetraone;

(3S,7S,10S,13R)-6-(4-chloro-2-(4-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)benzyl)-13-(4-chlorobenzyl)-10-((R)-1-hydroxyethyl)-7-methyl-3-(2,2,2-trifluoroethyl)-1,6,9,12-tetraazabicyclo[11.3.1]heptadecane-2,5,8,11-tetraone;

(3R,7S,10S,13R)-3-benzyl-13-(4-chlorobenzyl)-6-(2,4-dichloro-6-(4-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)benzyl)-10-(hydroxymethyl)-7-methyl-1,6,9,12-tetraazabicyclo[11.3.1]heptadecane-2,5,8,11-tetraone;

(3R,7S,10S,13R)-6-(4-chloro-2-(4-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)-6-fluorobenzyl)-13-(4-chlorobenzyl)-10-(hydroxymethyl)-3,7,12-trimethyl-1,6,9,12-tetraazabicyclo[11.3.1]heptadecane-2,5,8,11-tetraone;

(3S,10S,13R)-6-(5-chloro-2-(4-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)benzyl)-13-(4-chlorobenzyl)-3-((S)-2,3-dihydro-1H-inden-1-yl)-10-(hydroxymethyl)-1,6,9,12-tetraazabicyclo[11.3.1]heptadecane-2,5,8,11-tetraone;

(3S,10S,13R)-6-(4-chloro-2-(4-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)benzyl)-13-(4-chlorobenzyl)-3-((S)-2,3-dihydro-1H-inden-1-yl)-10-(hydroxymethyl)-1,6,9,12-tetraazabicyclo[11.3.1]heptadecane-2,5,8,11-tetraone;

(2S,5S,8R,12S)-1-(4-chloro-2-(4-(1-methyl-2-(pyrrolidin-1-ylmethyl)-1H-imidazol-5-yl)phenoxy)benzyl)-8-(4-chlorobenzyl)-12-((R)-2,3-dihydro-1H-inden-1-yl)-5-(methoxymethyl)-2,7,10-trimethyl-1,4,7,10-tetraazacyclotetradecane-3,6,11,14-tetraone;

(2S,5S,8R,12S)-1-(4-chloro-2-(4-(1-methyl-2-(pyrrolidin-1-ylmethyl)-1H-imidazol-5-yl)phenoxy)benzyl)-8-(4-chlorobenzyl)-12-((R)-2,3-dihydrobenzofuran-3-yl)-5-(hydroxymethyl)-2,7,10-trimethyl-1,4,7,10-tetraazacyclotetradecane-3,6,11,14-tetraone;

(2S,5S,8R,12S)-1-(4-chloro-2-(4-(1-methyl-2-(pyrrolidin-1-ylmethyl)-1H-imidazol-5-yl)phenoxy)benzyl)-8-(4-chlorobenzyl)-5-(hydroxymethyl)-12-((R)-7-methoxy-2,3-dihydrobenzofuran-3-yl)-2,7,10-trimethyl-1,4,7,10-tetraazacyclotetradecane-3,6,11,14-tetraone; (3S,7S,10S,13R)-3-benzyl-6-(4-chloro-2-(4-(2-((2-(2-ethoxyethoxy)ethoxy)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)benzyl)-13-(4-chlorobenzyl)-10-(hydroxymethyl)-7-methyl-1,4,6,9,12-pentaazabicyclo[11.3.1]heptadecane-2,5,8,11-tetraone;

(3R,7S,10S,13R)-3-benzyl-6-(4-chloro-2-(4-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)benzyl)-13-(4-chlorobenzyl)-7-(2-fluoroethyl)-10-(methoxymethyl)-1,6,9,12-tetraazabicyclo[11.3.1]heptadecane-2,5,8,11-tetraone;

(2S,5S,8R,12R)-12-benzyl-1-(4-chloro-2-(3,5-difluoro-4-(1-methyl-2-(pyrrolidin-1-ylmethyl)-1H-imidazol-5-yl)phenoxy)benzyl)-8-(4-chlorobenzyl)-5-(hydroxymethyl)-2,7,10-trimethyl-1,4,7,10-tetraazacyclotetradecane-3,6,11,14-tetraone;

(2S,5S,8R,12S)-1-(4-chloro-2-(4-(1-methyl-2-(pyrrolidin-1-ylmethyl)-1H-imidazol-5-yl)phenoxy)benzyl)-8-(4-chlorobenzyl)-5-(hydroxymethyl)-2,7,10-trimethyl-12-((R)-1-phenylethyl)-1,4,7,10-tetraazacyclotetradecane-3,6,11,14-tetraone;

(2S,5S,8R,12R)-12-benzyl-1-(4-chloro-2-(4-(1-methyl-2-(pyrrolidin-1-ylmethyl)-1H-imidazol-5-yl)phenoxy)benzyl)-8-(4-chlorobenzyl)-5-(hydroxymethyl)-2,7,10-trimethyl-1,4,7,10-tetraazacyclotetradecane-3,6,11,14-tetraone;

(3R,7S,10S,13R)-3-benzyl-6-(4-chloro-2-(4-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)benzyl)-13-(4-chlorobenzyl)-10-((S)-1-hydroxyethyl)-7-methyl-1,6,9,12-tetraazabicyclo[11.3.1]heptadecane-2,5,8,11-tetraone;

(2S,5S,8R,12S)-1-(4-chloro-2-(4-(1-methyl-2-(pyrrolidin-1-ylmethyl)-1H-imidazol-5-yl)phenoxy)benzyl)-8-(4-chlorobenzyl)-12-((R)-7-methoxy-2,3-dihydrobenzofuran-3-yl)-5-(methoxymethyl)-2,7,10-trimethyl-1,4,7,10-tetraazacyclotetradecane-3,6,11,14-tetraone;

(2S,5S,8R,12S)-1-(4-chloro-2-(4-(1-methyl-2-(pyrrolidin-1-ylmethyl)-1H-imidazol-5-yl)phenoxy)benzyl)-8-(4-chlorobenzyl)-12-((R)-3,3-dimethyl-2,3-dihydro-1H-inden-1-yl)-5-(methoxymethyl)-2,7,10-trimethyl-1,4,7,10-tetraazacyclotetradecane-3,6,11,14-tetraone;

(2S,5S,8R,12R)-1-(4-chloro-2-(4-(1-methyl-2-(pyrrolidin-1-ylmethyl)-1H-imidazol-5-yl)phenoxy)-6-(2,2,2-trifluoroethoxy)benzyl)-8-(4-chlorobenzyl)-12-ethyl-5-(hydroxymethyl)-2,7-dimethyl-1,4,7,10-tetraazacyclotetradecane-3,6,11,14-tetraone;

(2S,5S,8R,12S)-1-(4-chloro-2-(4-(1-methyl-2-(pyrrolidin-1-ylmethyl)-1H-imidazol-5-yl)phenoxy)benzyl)-8-(4-chlorobenzyl)-10-(3,3-difluoropropyl)-12-((R)-2,3-dihydro-1H-inden-1-yl)-5-(methoxymethyl)-2,7-dimethyl-1,4,7,10-tetraazacyclotetradecane-3,6,11,14-tetraone; (2S,5S,8R,12R)-12-benzyl-1-(4-chloro-2-(4-(1-methyl-2-(pyrrolidin-1-ylmethyl)-1H-imidazol-5-yl)phenoxy)benzyl)-8-(4-chlorobenzyl)-5-(methoxymethyl)-2,7,10-trimethyl-1,4,7,10-tetraazacyclotetradecane-3,6,11,14-tetraone;

(2S,5S,8R,12S)-1-(4-chloro-2-(4-(1-methyl-2-(pyrrolidin-1-ylmethyl)-1H-imidazol-5-yl)phenoxy)benzyl)-8-(4-chlorobenzyl)-12-((R)-2,3-dihydro-1H-inden-1-yl)-5-(methoxymethyl)-2,7-dimethyl-10-((1-methylcyclopropyl)methyl)-1,4,7,10-tetraazacyclotetradecane-3,6,11,14-tetraone;

(2S,5S,8R,12R)-12-benzyl-1-(4-chloro-2-(4-(1-methyl-2-(pyrrolidin-1-ylmethyl)-1H-imidazol-5-yl)phenoxy)benzyl)-8-(4-chlorobenzyl)-10-(3-(dimethylamino)propyl)-5-(methoxymethyl)-2,7-dimethyl-1,4,7,10-tetraazacyclotetradecane-3,6,11,14-tetraone;

(2S,5S,8R,12R)-12-benzyl-1-(4-chloro-2-(3,5-difluoro-4-(1-methyl-2-(pyrrolidin-1-ylmethyl)-1H-imidazol-5-yl)phenoxy)benzyl)-8-(4-chlorobenzyl)-5-(methoxymethyl)-2,7,10-trimethyl-1,4,7,10-tetraazacyclotetradecane-3,6,11,14-tetraone;

(2S,5S,8S,12S)-8-(4-chlorobenzyl)-12-((S)-2,3-dihydro-1H-inden-1-yl)-1-(2-(4-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)-4-ethylbenzyl)-5-(hydroxymethyl)-2,7,10-trimethyl-1,4,7,10-tetraazacyclotetradecane-3,6,11,14-tetraone;

(2S,5S,8R,12S)-8-(4-chlorobenzyl)-12-((S)-2,3-dihydro-1H-inden-1-yl)-1-(2-(4-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)-4-ethylbenzyl)-5-(hydroxymethyl)-2,7,10-trimethyl-1,4,7,10-tetraazacyclotetradecane-3,6,11,14-tetraone;

(3R,7S,10S,13R)-3-benzyl-6-(4-chloro-2-(4-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)benzyl)-13-(4-chlorobenzyl)-10-(methoxymethyl)-7-methyl-1,6,9,12-tetraazabicyclo[11.3.1]heptadecane-2,8,11-trione;

(2S,5R,8R,12S)-8-(4-chlorobenzyl)-12-((S)-2,3-dihydro-1H-inden-1-yl)-1-(2-(4-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)-4-ethylbenzyl)-5-(hydroxymethyl)-2,7,10-trimethyl-1,4,7,10-tetraazacyclotetradecane-3,6,11,14-tetraone;

(3R,7S,10R,13R)-3-benzyl-6-(4-chloro-2-((6-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)pyridin-3-yl)oxy)benzyl)-13-(4-chlorobenzyl)-10-(methoxymethyl)-7-methyl-1,6,9,12-tetraazabicyclo[11.3.1]heptadecane-2,5,8,11-tetraone;

(3S,10S,13R)-13-(4-chlorobenzyl)-3-((S)-2,3-dihydro-1H-inden-1-yl)-6-(4-(4-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)-2-fluorobenzyl)-10-(hydroxymethyl)-1,6,9,12-tetraazabicyclo[11.3.1]heptadecane-2,5,8,11-tetraone;

(3S,7S,10S,13R)-13-(4-chlorobenzyl)-3-((S)-2,3-dihydro-1H-inden-1-yl)-6-(4-(4-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)-2-fluorobenzyl)-10-(hydroxymethyl)-7-methyl-1,6,9,12-tetraazabicyclo[11.3.1]heptadecane-2,5,8,11-tetraone; (2S,5S,8R,12R)-1-(4-chloro-2-(4-(1-methyl-2-(pyrrolidin-1-ylmethyl)-1H-imidazol-5-yl)phenoxy)benzyl)-8-(4-chlorobenzyl)-12-ethyl-5-(hydroxymethyl)-2,7-dimethyl-1,4,7,10-tetraazacyclotetradecane-3,6,11,14-tetraone;

(2S,5S,8R,12S)-1-(4-chloro-2-(4-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)benzyl)-8-(4-chlorobenzyl)-12-((R)-2,3-dihydro-1H-inden-1-yl)-5-(methoxymethyl)-7,10-dimethyl-2-(2-morpholinoethyl)-1,4,7,10-tetraazacyclotetradecane-3,6,11,14-tetraone; (2S)-N-((3R,8S,11R)-3-benzyl-11-(4-chlorobenzyl)-10-methyl-2,5,9-trioxo-6-oxa-1,10-diazabicyclo[9.3.1]pentadecan-8-yl)-2-((4-chloro-2-(4-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)benzyl)amino)propanamide;

(2S,5S,8R,12S)-1-(4-chloro-2-(4-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)benzyl)-8-(4-chlorobenzyl)-12-((R)-2,3-dihydro-1H-inden-1-yl)-5-(methoxymethyl)-7,10-dimethyl-2-(3-morpholinopropyl)-1,4,7,10-tetraazacyclotetradecane-3,6,11,14-tetraone; (2S,5S,8R,12R)-1-(4-chloro-2-(4-(1-methyl-2-(pyrrolidin-1-ylmethyl)-1H-imidazol-5-yl)phenoxy)benzyl)-8-(4-chlorobenzyl)-12-ethyl-5-(hydroxymethyl)-2,7,10-trimethyl-1,4,7,10-tetraazacyclotetradecane-3,6,11,14-tetraone;

(2S,5S,8R,12R)-12-benzyl-1-(4-chloro-2-(4-(1-methyl-2-(pyrrolidin-1-ylmethyl)-1H-imidazol-5-yl)phenoxy)benzyl)-8-(4-chlorobenzyl)-2,7,10-trimethyl-5-(2-oxopropyl)-1,4,7,10-tetraazacyclotetradecane-3,6,11,14-tetraone;

(2S)-N-((3S,8R,11R)-8-benzyl-11-(4-chlorobenzyl)-10-methyl-2,6,9-trioxo-5-oxa-1,10-diazabicyclo[9.3.1]pentadecan-3-yl)-2-((4-chloro-2-(4-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)benzyl)amino)propanamide;

(2S,5S,8R,12S)-1-(4-chloro-2-(4-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)benzyl)-8-(4-chlorobenzyl)-12-((R)-2,3-dihydro-1H-inden-1-yl)-5-(methoxymethyl)-7,10-dimethyl-2-(4-morpholinobutyl)-1,4,7,10-tetraazacyclotetradecane-3,6,11,14-tetraone; (2S,5S,8R,12S)-2-(3-(azetidin-1-yl)-3-oxopropyl)-1-(4-chloro-2-(4-(1-methyl-2-(pyrrolidin-1-ylmethyl)-1H-imidazol-5-yl)phenoxy)benzyl)-8-(4-chlorobenzyl)-12-((R)-3,3-dimethyl-2,3-dihydro-1H-inden-1-yl)-5-(methoxymethyl)-7,10-dimethyl-1,4,7,10-tetraazacyclotetradecane-3,6,11,14-tetraone;

(3R,7S,10S,13R)-6-(4-chloro-2-(4-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)benzyl)-13-(4-chlorobenzyl)-10-(hydroxymethyl)-3-isopropyl-7-methyl-1,6,9,12-tetraazabicyclo[11.3.1]heptadecane-2,5,8,11-tetraone;

(2S,5S,8R,12R)-1-(4-chloro-2-(4-(1-methyl-2-(pyrrolidin-1-ylmethyl)-1H-imidazol-5-yl)phenoxy)benzyl)-8-(4-chlorobenzyl)-12-(dimethylamino)-5-(methoxymethyl)-2,7,10-trimethyl-1,4,7,10-tetraazacyclotetradecane-3,6,11,14-tetraone;

2-((2S,5S,8R,12R)-12-benzyl-1-(4-chloro-2-(4-(1-methyl-2-(pyrrolidin-1-ylmethyl)-1H-imidazol-5-yl)phenoxy)benzyl)-8-(4-chlorobenzyl)-2,7,10-trimethyl-3,6,11,14-tetraoxo-1,4,7,10-tetraazacyclotetradecan-5-yl)acetic acid;

(3S,7S,10S,13R)-6-(2-(4-(2-((tert-butylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)-4-chloro-6-fluorobenzyl)-13-(4-chlorobenzyl)-10-(methoxymethyl)-7,12-dimethyl-3-(2,2,2-trifluoroethyl)-1,6,9,12-tetraazabicyclo[11.3.1]heptadecane-2,5,8,11-tetraone;

(3S,7S,10S,13R)-6-(2-(4-(2-((tert-butyl(methyl)amino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)-4-chloro-6-fluorobenzyl)-13-(4-chlorobenzyl)-10-(methoxymethyl)-7-methyl-3-(2,2,2-trifluoroethyl)-1,6,9,12-tetraazabicyclo[11.3.1]heptadecane-2,5,8,11-tetraone;

(3S,7S,10S,13R)-6-(2-(4-(2-((tert-butylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)-4-chloro-6-fluorobenzyl)-13-(4-chlorobenzyl)-10-(methoxymethyl)-7-methyl-3-(2,2,2-trifluoroethyl)-1,6,9,12-tetraazabicyclo[11.3.1]heptadecane-2,5,8,11-tetraone;

(3S,7S,10S,13R)-6-(4-chloro-2-(4-(2-((cyclobutyl(methyl)amino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)-6-fluorobenzyl)-13-(4-chlorobenzyl)-10-(hydroxymethyl)-7-methyl-3-(2,2,2-trifluoroethyl)-1,6,9,12-tetraazabicyclo[11.3.1]heptadecane-2,5,8,11-tetraone;

(3S,7S,10S,13R)-6-(4-chloro-2-(4-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)-6-fluorobenzyl)-13-(4-chlorobenzyl)-3-cyclobutyl-10-(methoxymethyl)-7,12-dimethyl-1,6,9,12-tetraazabicyclo[11.3.1]heptadecane-2,5,8,11-tetraone;

(3S,7S,10S,13R)-6-(2-(4-(2-((tert-butyl(methyl)amino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)-4-chloro-6-fluorobenzyl)-13-(4-chlorobenzyl)-10-(methoxymethyl)-7,12-dimethyl-3-(2,2,2-trifluoroethyl)-1,6,9,12-tetraazabicyclo[11.3.1]heptadecane-2,5,8,11-tetraone;

(3R,7S,10S,13R)-6-(2-(4-(2-((tert-butylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)-4-chloro-6-fluorobenzyl)-13-(4-chlorobenzyl)-3-(cyclopropylmethyl)-10-(methoxymethyl)-7-methyl-1,6,9,12-tetraazabicyclo[11.3.1]heptadecane-2,5,8,11-tetraone;

(3S,7S,10S,13R)-6-(2-(4-(2-((tert-butyl(methyl)amino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)-4-chlorobenzyl)-13-(4-chlorobenzyl)-10-(hydroxymethyl)-7-methyl-3-(2,2,2-trifluoroethyl)-1,6,9,12-tetraazabicyclo[11.3.1]heptadecane-2,5,8,11-tetraone;

(3R,7S,10S,13R)-6-(4-chloro-2-(4-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)-6-fluorobenzyl)-13-(4-chlorobenzyl)-10-(hydroxymethyl)-7-methyl-3-((1-methylcyclopropyl)methyl)-1,6,9,12-tetraazabicyclo[11.3.1]heptadecane-2,5,8,11-tetraone; (3R,7S,10S,13R)-6-(4-chloro-2-(4-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)-6-fluorobenzyl)-13-(4-chlorobenzyl)-3-(cyclopropylmethyl)-10-(hydroxymethyl)-7-methyl-1,6,9,12-tetraazabicyclo[11.3.1]heptadecane-2,5,8,11-tetraone;

(3S,7S,10S,13R)-6-(4-chloro-2-(4-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)-6-fluorobenzyl)-13-(4-chlorobenzyl)-3-(2,2-difluoropropyl)-10-(hydroxymethyl)-7-methyl-1,6,9,12-tetraazabicyclo[11.3.1]heptadecane-2,5,8,11-tetraone;

(3S,7S,10S,13R)-6-(2-(4-(2-((tert-butylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)-4-chlorobenzyl)-13-(4-chlorobenzyl)-10-(hydroxymethyl)-7-methyl-3-(2,2,2-trifluoroethyl)-1,6,9,12-tetraazabicyclo[11.3.1]heptadecane-2,5,8,11-tetraone;

(3R,7S,10S,13R)-6-(2-(4-(2-((tert-butylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)-4-chlorobenzyl)-13-(4-chlorobenzyl)-3-(cyclopropylmethyl)-10-(hydroxymethyl)-7-methyl-1,6,9,12-tetraazabicyclo[11.3.1]heptadecane-2,5,8,11-tetraone;

(3R,7S,10S,13R)-3-benzyl-6-(2-(4-(2-((tert-butylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)-4-chlorobenzyl)-13-(4-chlorobenzyl)-10-(methoxymethyl)-7-methyl-1,6,9,12-tetraazabicyclo[11.3.1]heptadecane-2,5,8,11-tetraone;

(3R,7S,10S,13R)-3-benzyl-6-(4-chloro-2-(4-(1-methyl-2-((methylamino)methyl)-1H-imidazol-5-yl)phenoxy)benzyl)-13-(4-chlorobenzyl)-10-(hydroxymethyl)-7-methyl-1,6,9,12-tetraazabicyclo[11.3.1]heptadecane-2,5,8,11-tetraone;

(3R,7S,10S,13R)-6-(4-chloro-2-(4-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)-6-fluorobenzyl)-13-(4-chlorobenzyl)-10-(hydroxymethyl)-7,12-dimethyl-3-(2,2,2-trifluoroethyl)-1,6,9,12-tetraazabicyclo[11.3.1]heptadecane-2,5,8,11-tetraone;

(3S,7S,10S,13R)-6-(4-chloro-2-(4-(2-((ethyl(1-methylcyclopropyl)amino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)-6-fluorobenzyl)-13-(4-chlorobenzyl)-10-(hydroxymethyl)-7-methyl-3-(2,2,2-trifluoroethyl)-1,6,9,12-tetraazabicyclo[11.3.1]heptadecane-2,5,8,11-tetraone;

(3R,7S,10S,13R)-6-(4-chloro-2-(4-(2-((cyclobutylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)-6-fluorobenzyl)-13-(4-chlorobenzyl)-3-(cyclopropylmethyl)-10-(hydroxymethyl)-7-methyl-1,6,9,12-tetraazabicyclo[11.3.1]heptadecane-2,5,8,11-tetraone;

(3R,7S,10S,13R)-6-(2-(4-(2-((tert-butylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)-4-chloro-6-fluorobenzyl)-13-(4-chlorobenzyl)-3-(cyclopropylmethyl)-10-(hydroxymethyl)-7-methyl-1,6,9,12-tetraazabicyclo[11.3.1]heptadecane-2,5,8,11-tetraone;

(3R,7S,10S,13R)-6-(4-chloro-2-(4-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)-6-fluorobenzyl)-13-(4-chlorobenzyl)-3-(cyclobutylmethyl)-10-(hydroxymethyl)-7-methyl-1,6,9,12-tetraazabicyclo[11.3.1]heptadecane-2,5,8,11-tetraone;

(3S,7S,10S,13R)-3-benzyl-6-(4-chloro-2-(4-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)benzyl)-13-(4-chlorobenzyl)-10-(methoxymethyl)-7-methyl-4-oxa-1,6,9,12-tetraazabicyclo[11.3.1]heptadecane-2,5,8,11-tetraone;

(3S,7S,10S,13R)-6-(2-(4-(2-(azetidin-1-ylmethyl)-1-methyl-1H-imidazol-5-yl)phenoxy)-4-chloro-6-fluorobenzyl)-13-(4-chlorobenzyl)-10-(methoxymethyl)-7,12-dimethyl-3-(2,2,2-trifluoroethyl)-1,6,9,12-tetraazabicyclo[11.3.1]heptadecane-2,5,8,11-tetraone;

(3S,7S,10S,13R)-6-(4-chloro-2-(4-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)-6-fluorobenzyl)-13-(4-chlorobenzyl)-3-(2,2-difluoropropyl)-10-(methoxymethyl)-7,12-dimethyl-1,6,9,12-tetraazabicyclo[11.3.1]heptadecane-2,5,8,11-tetraone;

(3R,7S,10S,13R)-3-benzyl-6-(4-chloro-2-(4-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)-6-fluorobenzyl)-13-(4-chlorobenzyl)-10-(methoxymethyl)-7,12-dimethyl-1,6,9,12-tetraazabicyclo[11.3.1]heptadecane-2,5,8,11-tetraone;

(3S,7S,10S,13R)-6-(4-chloro-2-(4-(2-((cyclobutyl(methyl)amino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)-6-fluorobenzyl)-13-(4-chlorobenzyl)-10-(methoxymethyl)-7-methyl-3-(2,2,2-trifluoroethyl)-1,6,9,12-tetraazabicyclo[11.3.1]heptadecane-2,5,8,11-tetraone;

(3S,7S,10S,13R)-6-(4-chloro-2-(4-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)-6-fluorobenzyl)-13-(4-chlorobenzyl)-3-(3,3-difluorocyclobutyl)-10-(hydroxymethyl)-7-methyl-1,6,9,12-tetraazabicyclo[11.3.1]heptadecane-2,5,8,11-tetraone;

(3R,7S,10S,13R)-6-(2-(4-(2-((tert-butyl(methyl)amino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)-4-chlorobenzyl)-13-(4-chlorobenzyl)-3-(cyclopropylmethyl)-10-(hydroxymethyl)-7-methyl-1,6,9,12-tetraazabicyclo[11.3.1]heptadecane-2,5,8,11-tetraone;

(3R,7S,10S,13R)-6-(2-(4-(2-((tert-butyl(methyl)amino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)-4-chloro-6-fluorobenzyl)-13-(4-chlorobenzyl)-3-(cyclopropylmethyl)-10-(hydroxymethyl)-7-methyl-1,6,9,12-tetraazabicyclo[11.3.1]heptadecane-2,5,8,11-tetraone;

(3S,7S,10S,13R)-6-(4-chloro-2-(4-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)-6-fluorobenzyl)-13-(4-chlorobenzyl)-3-(3,3-difluorocyclobutyl)-10-(hydroxymethyl)-7,12-dimethyl-1,6,9,12-tetraazabicyclo[11.3.1]heptadecane-2,5,8,11-tetraone;

(3S,7S,10S,13R)-6-(2-(4-(2-((tert-butylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)-4-chloro-6-fluorobenzyl)-13-(4-chlorobenzyl)-3-(3,3-difluorocyclobutyl)-10-(methoxymethyl)-7,12-dimethyl-1,6,9,12-tetraazabicyclo[11.3.1]heptadecane-2,5,8,11-tetraone;

(3S,7S,10S,13R)-6-(2-(4-(2-(aminomethyl)-1-methyl-1H-imidazol-5-yl)phenoxy)-4-chloro-6-fluorobenzyl)-13-(4-chlorobenzyl)-3-(3,3-difluorocyclobutyl)-10-(methoxymethyl)-7,12-dimethyl-1,6,9,12-tetraazabicyclo[11.3.1]heptadecane-2,5,8,11-tetraone;

(3R,7S,10S,13R)-6-(4-chloro-2-fluoro-6-(4-(1-methyl-2-((methylamino)methyl)-1H-imidazol-5-yl)phenoxy)benzyl)-13-(4-chlorobenzyl)-10-(methoxymethyl)-7,12-dimethyl-3-((6-methylpyridin-2-yl)methyl)-1,6,9,12-tetraazabicyclo[11.3.1]heptadecane-2,5,8,11-tetraone;

2-(((3R,7S,10S,13R)-6-(4-chloro-2-(4-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)-6-fluorobenzyl)-13-(4-chlorobenzyl)-10-(methoxymethyl)-7,12-dimethyl-2,5,8,11-tetraoxo-1,6,9,12-tetraazabicyclo[11.3.1]heptadecan-3-yl)methyl)-6-methylpyridine 1-oxide; (3S,7S,10S,13R)-6-(2-(4-(2-((tert-butyl(methyl)amino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)-4-chloro-6-fluorobenzyl)-13-(4-chlorobenzyl)-3-(3,3-difluorocyclobutyl)-10-(methoxymethyl)-7,12-dimethyl-1,6,9,12-tetraazabicyclo[11.3.1]heptadecane-2,5,8,11-tetraone; (3R,7S,10S,13R)-6-(4-chloro-2-(4-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)-6-fluorobenzyl)-13-(4-chlorobenzyl)-10-(hydroxymethyl)-7,12-dimethyl-3-((6-methylpyridin-2-yl)methyl)-1,6,9,12-tetraazabicyclo[11.3.1]heptadecane-2,5,8,11-tetraone; (3S,7S,10S,13R)-6-(4-chloro-2-((6-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)pyridin-3-yl)oxy)-6-fluorobenzyl)-13-(4-chlorobenzyl)-3-(3,3-difluorocyclobutyl)-10-(methoxymethyl)-7,12-dimethyl-1,6,9,12-tetraazabicyclo[11.3.1]heptadecane-2,5,8,11-tetraone; (3S,7S,10S,13R)-6-(4-chloro-2-fluoro-6-(4-(1-methyl-2-((methylamino)methyl)-1H-imidazol-5-yl)phenoxy)benzyl)-13-(4-chlorobenzyl)-10-(methoxymethyl)-7,12-dimethyl-3-(2,2,2-trifluoroethyl)-1,6,9,12-tetraazabicyclo[11.3.1]heptadecane-2,5,8,11-tetraone;

(3S,7S,10S,13R)-6-(4-chloro-2-((6-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)pyridin-3-yl)oxy)-6-fluorobenzyl)-13-(4-chlorobenzyl)-10-(methoxymethyl)-7,12-dimethyl-3-(2,2,2-trifluoroethyl)-1,6,9,12-tetraazabicyclo[11.3.1]heptadecane-2,5,8,11-tetraone;

(3S,7S,10S,13R)-6-(4-chloro-2-(4-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)-6-fluorobenzyl)-13-(4-chlorobenzyl)-10-(methoxymethyl)-7,12-dimethyl-3-(tetrahydro-2H-pyran-4-yl)-1,6,9,12-tetraazabicyclo[11.3.1]heptadecane-2,5,8,11-tetraone; (3S,7S,10S,13R)-6-(4-chloro-2-(4-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)-6-fluorobenzyl)-13-(4-chlorobenzyl)-10-((difluoromethoxy)methyl)-7,12-dimethyl-3-(2,2,2-trifluoroethyl)-1,6,9,12-tetraazabicyclo[11.3.1]heptadecane-2,5,8,11-tetraone;

(3S,7R,10S,13R)-6-(4-chloro-2-((6-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)pyridin-3-yl)oxy)-6-fluorobenzyl)-13-(4-chlorobenzyl)-10-(methoxymethyl)-7,12-dimethyl-3-(2,2,2-trifluoroethyl)-1,6,9,12-tetraazabicyclo[11.3.1]heptadecane-2,5,8,11-tetraone;

(3S,7S,10S,13R)-6-(4-chloro-2-fluoro-6-(4-(1-methyl-2-((methylamino)methyl)-1H-imidazol-5-yl)phenoxy)benzyl)-13-(4-chlorobenzyl)-10-(hydroxymethyl)-7,12-dimethyl-3-(2,2,2-trifluoroethyl)-1,6,9,12-tetraazabicyclo[11.3.1]heptadecane-2,5,8,11-tetraone; and

(3R,7S,10S,13R)-7-(2-aminoethyl)-3-benzyl-6-(4-chloro-2-(4-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)benzyl)-13-(4-chlorobenzyl)-10-(hydroxymethyl)-1,6,9,12-tetraazabicyclo[11.3.1]heptadecane-2,5,8,11-tetraone;

or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, N-oxide, or tautomer thereof.

21. The compound according to claim 1 selected from:

(3R,7S,10S,13R)-6-(4-chloro-2-(4-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)benzyl)-13-(4-chlorobenzyl)-10-(hydroxymethyl)-7,12-dimethyl-3-(pyridin-2-ylmethyl)-1,6,9,12-tetraazabicyclo[11.3.1]heptadecane-2,5,8,11-tetraone;

(3R,7S,10S,13R)-6-(4-chloro-2-(4-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)-6-fluorobenzyl)-13-(4-chlorobenzyl)-10-(hydroxymethyl)-7,12-dimethyl-3-(pyridin-2-ylmethyl)-1,6,9,12-tetraazabicyclo[11.3.1]heptadecane-2,5,8,11-tetraone;

(3R,7S,10S,13R)-3-benzyl-6-(4-chloro-2-(4-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)benzyl)-13-(4-chlorobenzyl)-10-(hydroxymethyl)-7-methyl-1,6,9,12-tetraazabicyclo[11.3.1]heptadecane-2,5,8,11-tetraone;

(3S,7S,10S,13R)-6-(4-chloro-2-(4-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)-6-fluorobenzyl)-13-(4-chlorobenzyl)-3-((S)-2,3-dihydro-1H-inden-1-yl)-10-(hydroxymethyl)-7-methyl-1,6,9,12-tetraazabicyclo[11.3.1]heptadecane-2,5,8,11-tetraone; (3R,7S,10S,13R)-3-benzyl-6-(4-chloro-2-(4-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)benzyl)-13-(4-chlorobenzyl)-10-(hydroxymethyl)-7,12-dimethyl-1,6,9,12-tetraazabicyclo[11.3.1]heptadecane-2,5,8,11-tetraone;

(3R,7S,10S,13R)-3-benzyl-6-(4-chloro-2-(4-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)-6-fluorobenzyl)-13-(4-chlorobenzyl)-10-(hydroxymethyl)-7-methyl-1,6,9,12-tetraazabicyclo[11.3.1]heptadecane-2,5,8,11-tetraone;

(3R,7S,10S,13R)-3-benzyl-6-(4-chloro-2-(4-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)-6-fluorobenzyl)-13-(4-chlorobenzyl)-10-(hydroxymethyl)-7,12-dimethyl-1,6,9,12-tetraazabicyclo[11.3.1]heptadecane-2,5,8,11-tetraone;

(3S,7S,10S,13R)-6-(4-chloro-2-(4-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)-6-fluorobenzyl)-13-(4-chlorobenzyl)-10-(methoxymethyl)-7,12-dimethyl-3-(2,2,2-trifluoroethyl)-1,6,9,12-tetraazabicyclo[11.3.1]heptadecane-2,5,8,11-tetraone;

(3S,7S,10S,13R)-6-(4-chloro-2-(4-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)phenoxy)-6-fluorobenzyl)-13-(4-chlorobenzyl)-10-(hydroxymethyl)-7,12-dimethyl-3-(2,2,2-trifluoroethyl)-1,6,9,12-tetraazabicyclo[11.3.1]heptadecane-2,5,8,11-tetraone;

(3S,7S,10S,13R)-6-(4-chloro-2-fluoro-6-(4-(1-methyl-2-((methylamino)methyl)-1H-imidazol-5-yl)phenoxy)benzyl)-13-(4-chlorobenzyl)-10-(methoxymethyl)-7,12-dimethyl-3-(2,2,2-trifluoroethyl)-1,6,9,12-tetraazabicyclo[11.3.1]heptadecane-2,5,8,11-tetraone; and

(3S,7S,10S,13R)-6-(4-chloro-2-fluoro-6-(4-(1-methyl-2-((methylamino)methyl)-1H-imidazol-5-yl)phenoxy)benzyl)-13-(4-chlorobenzyl)-10-(hydroxymethyl)-7,12-dimethyl-3-(2,2,2-trifluoroethyl)-1,6,9,12-tetraazabicyclo[11.3.1]heptadecane-2,5,8,11-tetraone;

or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, N-oxide, or tautomer thereof.

22. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of the claims 1-21, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

23. The pharmaceutical composition of claim 22 further comprising at least one additional pharmaceutical agent.

24. The pharmaceutical composition of claim 22 or claim 23 for use in the treatment of a PCSK9-mediated disease or disorder.

25. A method of modulating PCSK9 comprising administering to a patient in need thereof a compound of any one of claims 1-21 or a pharmaceutically acceptable salt thereof.

26. A method of inhibiting PCSK9 comprising administering to a patient in need thereof a compound of any one of claims 1-21 or a pharmaceutically acceptable salt thereof.

27. A method of inhibiting PCSK9 activity comprising administering to a patient in need thereof a compound of any one of claims 1-21 or a pharmaceutically acceptable salt thereof.

28. A method for treating a PCSK9-mediated disease or disorder comprising the step of administering to a patient in need thereof a therapeutically effective amount of a compound according to any one of the claims 1-21, or a pharmaceutically acceptable salt thereof.

29. The method of claim 28, wherein said PCSK9-mediated disease or disorder is selected from hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, sitosterolemia,

atherosclerosis, arteriosclerosis, coronary heart disease, peripheral vascular disease, vascular inflammation, and xanthoma.

30. A method of reducing LDL-C in a patient in need thereof, the method comprising administering a therapeutically effective amount of a compound of any one of claims 1-21 or a pharmaceutically acceptable salt thereof to the patient, thereby reducing LDL-C in the patient. 31. The method of claims anyone of 25-30, wherein administering is performed orally, parentally, subcutaneously, by injection, or by infusion.

32. A compound according to any one of the claims 1-21, or a pharmaceutically acceptable salt thereof, for use in the treatment of a PCSK9-mediated disease or disorder.

33. A compound according to any one of the claims 1-21, or a pharmaceutically acceptable salt thereof, for use in the treatment of a PCSK9-mediated disease or disorder which is selected from hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, sitosterolemia,

atherosclerosis, arteriosclerosis, coronary heart disease, peripheral vascular disease, vascular inflammation, and xanthoma.

34. Use of a compound according to any one of claims 1-21, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a PCSK9-mediated disease or disorder.

35. The use of claim 34, wherein said PCSK9-mediated disease or disorder is selected from hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, sitosterolemia, atherosclerosis, arteriosclerosis, coronary heart disease, peripheral vascular disease, vascular inflammation, and xanthoma.

36. A compound according to any one of the claims 1-21, or a pharmaceutically acceptable salt thereof, for use in the manufacture of a medicament for treating a disease associated with inhibiting PCSK9 activity.

37. Use of a compound according to any one of claims 1-21, or a pharmaceutically acceptable salt thereof, in the treatment of a disease associated with the inhibition of PCSK9 activity.

38. The use of claim 37, wherein said disease associated with the inhibition of PCSK9 activity is selected from hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, sitosterolemia, atherosclerosis, arteriosclerosis, coronary heart disease, peripheral vascular disease, vascular inflammation, and xanthoma.

39. A process for the manufacture of a compound of Formula (II), or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, N-oxide, or tautomer thereof,

(II),

wherein Ra1 and R5 are each independently (C1-C6 alkyl) and R9 is as defined above for Formula (I), comprising:

(g) alkylating a compound of Formula (IIa), or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, N-oxide, or tautomer thereof,


(IIa),

wherein R5 is H and R9 is as defined above for Formula (I),

with an alkyl halide and a base in a solvent, and at low temperature to provide a compound of formula (IIb),

wherein R5 is (C1-C6 alkyl) and R9 is as defined above for Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, N-oxide, or tautomer thereof, (h) reacting the compound of Formula (IIb), or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, N-oxide, or tautomer thereof, with an acid in a solvent, followed by Boc2O and a base to form a compound of formula (IIc),

(IIc),

wherein R5 is (C1-C6 alkyl) and R9 is as defined above for Formula (I), a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, N-oxide, or tautomer thereof;

(i) alkylating the compound of Formula (IIc), or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, N-oxide, or tautomer thereof, with a alkylating agent, in a solvent,and optionally a metal oxide to provide a compound of Formula (IId),

(IId),

wherein Ra1 and R5 are each independently (C1-C6 alkyl) and R9 is as defined above for Formula (I),or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, N-oxide, or tautomer thereof; and

(d), deallylating the compound of Formula (IId), with a palladium catalyst and N,N-dimethyltrimethylsilylamine in a solvent to provide the compound of Formula (II).

40. The process of claim 39, wherein the solvent in step (a) is DMF.

41. The process of claim 39 or 40, wherein the temperature in step (a) is about 0 oC.

42. The process of any one of claims 39-41, wherein the acid in step (b) is trifluoroacetic acid (TFA).

43. The process of any one of claims 39-42, wherein a metal oxide is used in step (c).

44. The process of claim 43, wherein the metal oxide is silver (I) oxide (Ag2O).

45. The process of any one of claims 39-44, wherein the palladium catalyst in step (d) is tetrakis(triphenylphosphine) palladium(0).

46. A process for the manufacture of a compound of Formula (II), or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, N-oxide, or tautomer thereof,

(II),

wherein Ra1 is H, R5 is (C1-C6 alkyl), and R9 is as defined above for Formula (I), comprising reacting a compound of Formula (IIb):

(IIb),

wherein R5 is (C1-C6 alkyl) and R9 is as defined above for Formula (I), with a palladium catalyst and N,N-dimethyltrimethylsilylamine in a solvent to provide the compound of Formula (II).

47. The process of claim 46, wherein the solvent in dichloromethane.

48. The process of claim 46 or 47, wherein the palladium catalyst is

tetrakis(triphenylphosphine) palladium(0).