RU2021118348A

RU2021118348A - CYCLIC TETRAMERIC COMPOUNDS AS PROTEIN CONVERTASE INHIBITORS SUBTILYSIN/KEXIN TYPE 9 (PCSK9) FOR THE TREATMENT OF METABOLIC DISORDERS

Info

Publication number: RU2021118348A
Application number: RU2021118348A
Authority: RU
Inventors: Карин Брайнер; Брайан Эддисон Декристофер; Алек Натансон Флайер; Андрей Александрович Голосов; Филипп Гроше; Юджин Юэцзинь Лю; Джастин Йик Чинг Мао; Лорен Джилкрист Монович; Таджешь Джейпракаш Пател; Карина Кристина Санчес; Ляньшэн Су; Лихуа Ян; Жуй Чжэн
Original assignee: Новартис Аг
Priority date: 2018-11-27
Filing date: 2019-11-26
Publication date: 2022-12-28

Claims

1. Compound of formula (I),

(I)

where

each of X ₁ and X ₂ independently represents H or (C ₁ -C ₆ )alkyl, or X ₁ and X ₂ together with the carbon atom to which they are attached, form =(O);

X ₃ is -CH ₂ - if X ₁ and X ₂ are each independently H or (C ₁ -C ₆ )alkyl, or X ₁ and X ₂ together with the carbon atom to which they are attached form =( O), or X ₃ is -O-, -NH- or -N(C ₁ -C ₆ )alkyl- if X ₁ and X ₂ together with the carbon atom to which they are attached form =(O);

R ₁ is (C ₆ -C ₁₀ )aryl or 5- or 6-membered heteroaryl containing 1-3 heteroatoms selected from N, O and S, where aryl and heteroaryl are substituted with -OR ₁₀ or -NR ₂₁ R ₁₀ and optionally substituted with one or more R ₁₁ ;

R ₂ is H, (C ₁ -C ₆ )alkyl, (C ₂ -C ₆ )alkenyl, (C ₁ -C ₆ )haloalkyl, -NR ₁₂ R ₁₃ , (C ₃ -C ₇ )carbocyclyl,

(C ₃ -C ₇ )cycloalkenyl, 5-7 membered heterocyclyl containing 1-3 heteroatoms selected from N, O and S, (C ₆ -C ₁₀ )aryl or 5- or 6-membered heteroaryl containing 1- 3 heteroatoms selected from N, O and S, where alkyl is optionally substituted with one or more R ₁₈ , and carbocyclyl, (C ₃ -C ₇ )cycloalkenyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one or more R ₁₉ ;

R ₃ is H, D, (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkoxy, (C ₁ -C ₆ )haloalkyl, (C ₁ -C ₆ )haloalkoxy, or

(C ₁ -C ₆ )hydroxyalkyl, where alkyl is optionally substituted with one or more R ₁₄ ;

R ₄ is H or (C ₁ -C ₆ )alkyl; or

R ₃ and R ₄ together with the atoms to which they are attached form a 5-7 membered heterocyclyl ring containing 1-3 heteroatoms selected from N, O and S;

each of R ₅ and R ₇ independently represents H, D, (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkoxy, (C ₁ -C ₆ )haloalkyl,

(C ₁ -C ₆ )haloalkoxy or (C ₁ -C ₆ )hydroxyalkyl, where (C ₁ -C ₆ )alkyl is optionally substituted with one or more D;

R ₆ is (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkoxy, (C ₁ -C ₆ )haloalkyl, (C ₁ -C ₆ )haloalkoxy, or

(C ₁ -C ₆ )hydroxyalkyl, wherein the alkyl is optionally substituted with one or more substituents each independently selected from (C ₁ -C ₆ )alkoxy, (C ₁ -C ₆ )haloalkoxy, -C(O)(C ₁ -C ₆ )alkyl, -C(O)OH and -C(O)O(C ₁ -C ₆ )alkyl;

R ₈ is H, (C ₁ -C ₆ )alkyl or (C ₁ -C ₆ )haloalkyl, where alkyl is optionally substituted with one or more substituents each independently selected from (C ₃ -C ₇ )carbocyclyl, 4- 7-membered heterocyclyl containing 1-3 heteroatoms selected from N, O and S, -NR ₁₆ R ₁₇ and

-C(O)NR ₁₆ R ₁₇ ;

R ₉ is halogen, (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkoxy, (C ₁ -C ₆ )haloalkyl, (C ₁ -C ₆ )haloalkoxy, -OH, or CN;

R ₁₀ is (C ₆ -C ₁₀ )aryl or 5- or 6-membered heteroaryl containing 1-3 heteroatoms selected from N, O and S, where aryl and heteroaryl are optionally substituted with one or more R ₂₂ ;

each R ₁₁ at each occurrence is independently halogen, (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkoxy,

(C ₁ -C ₆ )haloalkyl, (C ₁ -C ₆ )haloalkoxy, -OH or CN;

each of R ₁₂ and R ₁₃ independently represents H or (C ₁ -C ₆ )alkyl;

each R ₁₄ at each occurrence is independently D, NR ₁₅ R _15' , (C ₃ -C ₇ ) carbocyclyl, or a 3-7 membered heterocyclyl containing 1-3 heteroatoms selected from N, O and S, where carbocyclyl and heterocyclyl is optionally substituted with one or more substituents each independently selected from halogen, (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkoxy, (C ₁ -C ₆ )haloalkyl, and

(C ₁ -C ₆ ) haloalkoxy;

each of R ₁₅ and R _15' independently represents H or (C ₁ -C ₆ )alkyl;

each of R ₁₆ and R ₁₇ independently represents H or (C ₁ -C ₆ )alkyl, or

R ₁₆ and R ₁₇ together with the nitrogen atom to which they are attached form a 4-7 membered heterocyclyl ring, optionally containing 1-2 additional heteroatoms selected from N, O and S;

each R ₁₈ at each occurrence is independently (C ₃ -C ₇ )carbocyclyl, 5-7 membered heterocyclyl containing 1-3 heteroatoms selected from N, O and S, (C ₆ -C ₁₀ )aryl, or 5- or 6-membered heteroaryl containing 1-3 heteroatoms selected from N, O and S, where carbocyclyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one or more R ₂₀ ;

each R ₁₉ at each occurrence is independently halogen, (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkoxy, (C ₁ -C ₆ )haloalkyl, (C ₁ -C ₆ )haloalkoxy, -OH, or CN; or

two R ₁₉ together, if they are on adjacent atoms, form (C ₆ -C ₁₀ )aryl or a 5- or 6-membered heteroaryl ring containing 1-3 heteroatoms selected from N, O and S, where aryl and heteroaryl are optional substituted with one or more substituents each independently selected from halogen, (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkoxy, (C ₁ -C ₆ )haloalkyl, (C ₁ -C ₆ )haloalkoxy, -OH and CN;

each R ₂₀ at each occurrence is independently halogen, (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkoxy,

(C ₁ -C ₆ )haloalkyl, (C ₁ -C ₆ )haloalkoxy, oxo, -OH or CN; or

if R ₁₈ is carbocyclyl or heterocyclyl, the two R _20s , when attached to the same carbon atom, together form =(O);

R ₂₁ is H or (C ₁ -C ₆ )alkyl;

each R ₂₂ at each occurrence is independently halogen, (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkoxy, (C ₁ -C ₆ )haloalkyl, (C ₁ -C ₆ )haloalkoxy, -OH, CN, (C ₆ -C ₁₀ )aryl or 5- or 6-membered heteroaryl containing 1-3 heteroatoms selected from N, O and S, where aryl and heteroaryl are optionally substituted with one or more R ₂₃ ;

each R ₂₃ at each occurrence is independently halogen, (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkoxy,

(C ₁ -C ₆ ) haloalkyl, (C ₁ -C ₆ ) haloalkoxy, -CH ₂ (OCH ₂ CH ₂ ) _1-3 OCH ₂ CH ₃ , -OH, CN or 4-7 membered heterocyclyl containing 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, (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )alkoxy, (C ₁ - C ₆ ) haloalkyl, (C ₁ -C ₆ ) haloalkoxy, -OH,

-C(O)R ₂₄ R ₂₅ , -NR ₂₄ C(O)R ₂₅ , -NH ₂ , -NH(C ₁ -C ₆ )alkyl and -N((C ₁ -C ₆ )alkyl) ₂ , and alkyl is optionally substituted with -NR ₂₄ R ₂₅ or 4-7 membered heterocyclyl containing 1-3 heteroatoms selected from N, O and S, optionally substituted with one or more substituents each independently selected from halogen, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₆ ) haloalkyl,

(C ₁ -C ₆ )haloalkoxy, -OH, -NH ₂ , -NH(C ₁ -C ₆ )alkyl and -N((C ₁ -C ₆ )alkyl) ₂ ; and

each of R ₂₄ and R ₂₅ independently represents H, (C ₁ -C ₆ )alkyl or (C ₃ -C ₇ )carbocyclyl optionally substituted with one to two (C ₁ -C ₆ )alkyls;

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

2. A compound according to claim 1, wherein R ₄ is H or (C ₁ -C ₆ )alkyl.

3. A compound according to claim 1 or 2, where R ₄ is H.

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

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

6. The connection according to any one of paragraphs. 1-5, where R ₅ represents H or (C ₁ -C ₆ )alkyl.

7. Connection according to any one of paragraphs. 1-6, where R ₅ represents (C ₁ -C ₆ )alkyl.

8. Connection according to any one of paragraphs. 1-7, where R ₇ represents H or (C ₁ -C ₆ )alkyl.

9. Connection according to any one of paragraphs. 1-8, where R ₇ represents (C ₁ -C ₆ )alkyl.

10. Connection according to any one of paragraphs. 1-9, where R ₉ is halogen.

11. The connection according to any one of paragraphs. 1-10, where R ₉ represents chlorine.

12. Connection according to any one of paragraphs. 1-11, where R ₈ is (C ₁ -C ₆ )alkyl optionally substituted with one to three substituents, each independently selected from (C ₃ -C ₇ )carbocylyl, a 4-7 membered heterocyclyl containing 1- 3 heteroatoms selected from N, O and S,

-NR ₁₆ R ₁₇ and -C(O)NR ₁₆ R ₁₇ .

13. Connection according to any one of paragraphs. 1-12, where R ₈ represents (C ₁ -C ₆ )alkyl.

14. The compound according to claim 1, characterized by formula (Ia), formula (Ib), formula (Ic), formula (Id), formula (Ie), formula (If), formula (Ig), formula (Ih) or formula (ii):

(Ia)

(Ib),

(Ic),

(Id)

(Ie)

(If),

(Ig),

(Ih) or

(II).

15. Connection according to any one of paragraphs. 1-14, where R ₁ is phenyl substituted with -OR ₁₀ and optionally substituted with one to three R ₁₁ .

16. Connection according to any one of paragraphs. 1-14, where R ₁ is pyridinyl substituted with -OR ₁₀ and optionally substituted with one to three R ₁₁ .

17. The compound according to claim 1, characterized by formula (Ij), formula (Ik), formula (Im) or formula (Io):

(Ij), (Ik),

where x is 0, 1, or 2.

18. Connection according to any one of paragraphs. 1-17, where R ₁₀ is phenyl substituted with one to three R ₂₂ .

19. Connection according to any one of paragraphs. 1-17, where R ₁₀ is pyridinyl substituted with one to three R ₂₂ .

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]heptadecan-2,5,8, 11-tetraon;

(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]heptadecan-2,5,8 ,11-tetraon;

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]heptadecan-2, 5,8,11-tetraon;

(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]heptadecan-2, 5,8,11-tetraon;

(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]heptadecan-2,5, 8,11-tetraon;

(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]heptadecan-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 )hydroxy)-6-fluorobenzyl)-13-(4-chlorobenzyl)-10-(methoxymethyl)-7-methyl-3-(2,2,2-trifluoroethyl)-1,6,9,12-tetraazabicyclo[11.3 .1]heptadecan-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]heptadecan-2,5 ,8,11-tetraon;

(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]heptadecan-2,5,8, 11-tetraon;

(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]heptadecan-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]heptadecan-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]heptadecan- 2,5,8,11-tetraon;

(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]heptadecan-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]heptadecan-2,5,8, 11-tetraon;

(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]heptadecan-2,5,8 ,11-tetraon;

(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]heptadecan-2,5,8,11 -tetraon;

(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]heptadecan-2,5 ,8,11-tetraon;

(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]heptadecan-2,5,8,11 -tetraon;

(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]heptadecan- 2,5,8,11-tetraon;

(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]heptadecan-2,5,8,11 -tetraon;

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

(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]heptadecan-2 ,5,8,11-tetraon;

(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] heptadecan-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]heptadecan-2,5 ,8,11-tetraon;

(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]heptadecan-2,5,8,11-tetraone;

(3 S ,7 S ,10 S ,13 R )-6-(4-chloro-2-((5-(2-((dimethylamino)methyl)-1-methyl-1H-imidazol-5-yl)pyridine -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]heptadecan-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]heptadecan-2, 5,8,11-tetraon;

(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]heptadecan-2,5,8 ,11-tetraon;

(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]heptadecan-2,5, 8,11-tetraon;

(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]heptadecan-2,5,8,11 -tetraon;

(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]heptadecan-2,5,8,11 -tetraon;

(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]heptadecan-2,5 ,8,11-tetraon;

(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]heptadecan- 2,5,8,11-tetraon;

(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]heptadecan-2,5,8,11- tetraon;

(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-tetraon;

(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]heptadecan-2, 5,8,11-tetraon;

(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]heptadecan-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]heptadecan-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]heptadecan-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]heptadecan-2, 5,8,11-tetraon;

(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]heptadecan-2,5,8 ,11-tetraon;

(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]heptadecan-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]heptadecan-2, 5,8,11-tetraon;

(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]heptadecan-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]heptadecan-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]heptadecan-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)pyridine -3-yl)oxy)benzyl)-13-(4-chlorobenzyl)-10-(methoxymethyl)-7-methyl-1,6,9,12-tetraazabicyclo[11.3.1]heptadecan-2,5,8, 11-tetraon;

(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]heptadecan-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]heptadecan-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-tetraon;

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

(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]heptadecan-2, 5,8,11-tetraon;

(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]heptadecan-2,5,8 ,11-tetraon;

(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]heptadecan-2,5 ,8,11-tetraon;

(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]heptadecan-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]heptadecan-2,5,8,11 -tetraon;

(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]heptadecan-2,5,8, 11-tetraon;

(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]heptadecan-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-tetraon;

(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]heptadecan-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]heptadecan-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]heptadecan-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]heptadecan-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)pyridine -3-yl)oxy)benzyl)-13-(4-chlorobenzyl)-10-(hydroxymethyl)-7,12-dimethyl-1,6,9,12-tetraazabicyclo[11.3.1]heptadecan-2,5, 8,11-tetraon;

(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]heptadecan- 2,5,8,11-tetraon;

(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]heptadecan-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]heptadecan-2,5,8,11 -tetraon;

(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]heptadecan-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]heptadecan-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]heptadecan-2,5,8,11- tetraon;

(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]heptadecan-2,5 ,8,11-tetraon;

(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]heptadecan- 2,5,8,11-tetraon;

(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]heptadecan-2,5,8 ,11-tetraon;

(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]heptadecan-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 ]heptadecan-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]heptadecan-2,5,8,11 -tetraon;

(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]heptadecan-2, 5,8,11-tetraon;

(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]heptadecan-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] heptadecan-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]heptadecan-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-tetraon;

(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]heptadecan-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]heptadecan-2,5,8,11-tetraone;

(3 S ,10 S ,13 R )-6-(5-chloro-2-(4-(2-((dimethylamino)methyl)-1-methyl- 1H -imidazol-5-yl)phenoxy)benzyl) -13-(4-chlorobenzyl)-3-((S)-2,3-dihydro-1 H -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]heptadecan-2 ,5,8,11-tetraon;

(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-tetraazacyclotetradecan- 3,6,11,14-tetraon;

(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-imidazole -5-yl)phenoxy)benzyl)-13-(4-chlorobenzyl)-10-(hydroxymethyl)-7-methyl-1,4,6,9,12-pentaazabicyclo[11.3.1]heptadecan-2,5, 8,11-tetraon;

(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]heptadecan-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-imidazole -5-yl)phenoxy)benzyl)-8-(4-chlorobenzyl)-5-(hydroxymethyl)-2,7,10-trimethyl-1,4,7,10-tetraazacyclotetradecane-3,6,11,14- tetraon;

(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-tetraon;

(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]heptadecan-2,5,8,11 -tetraon;

(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-tetraon;

(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-tetraon;

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

(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]heptadecan-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)pyridine -3-yl)oxy)benzyl)-13-(4-chlorobenzyl)-10-(methoxymethyl)-7-methyl-1,6,9,12-tetraazabicyclo[11.3.1]heptadecan-2,5,8, 11-tetraon;

(3 S ,10 S ,13 R )-13-(4-chlorobenzyl)-3-((S)-2,3-dihydro-1 H -inden-1-yl)-6-(4-(4- (2-((dimethylamino)methyl)-1-methyl-1 H -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-(pyrrolidine- 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-tetraazacyclotetradecan-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]heptadecan-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] heptadecan-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]heptadecan- 2,5,8,11-tetraon;

(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] heptadecan-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]heptadecan-2,5,8,11- tetraon;

(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-tetraon;

(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]heptadecan- 2,5,8,11-tetraon;

(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]heptadecan-2,5 ,8,11-tetraon;

(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]heptadecan-2,5,8,11- tetraon;

(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]heptadecan-2,5, 8,11-tetraon;

(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]heptadecan-2,5, 8,11-tetraon;

(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]heptadecan-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]heptadecan-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]heptadecan-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]heptadecan- 2,5,8,11-tetraon;

(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]heptadecan-2,5,8,11- tetraon;

(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-tetraon;

(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]heptadecan-2,5,8,11- tetraon;

(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]heptadecan-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-tetraon;

(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]heptadecan-2, 5,8,11-tetraon;

(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]heptadecan-2,5,8,11- tetraon;

(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] heptadecan-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]heptadecan-2,5, 8,11-tetraon;

(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]heptadecan-2,5,8, 11-tetraon;

(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]heptadecan-2, 5,8,11-tetraon;

(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]heptadecan-2, 5,8,11-tetraon;

(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]heptadecan- 2,5,8,11-tetraon;

(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]heptadecan-2,5,8 ,11-tetraon;

(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-methylpyridin-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 )hydroxy)-6-fluorobenzyl)-13-(4-chlorobenzyl)-3-(3,3-difluorocyclobutyl)-10-(methoxymethyl)-7,12-dimethyl-1,6,9,12-tetraazabicyclo[11.3 .1]heptadecan-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-tetraon;

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

21. The compound according to claim 1, selected from

(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-tetraon; 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-tetraon;

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

23. A pharmaceutical composition according to claim 22, further comprising at least one additional pharmaceutical agent.

24. A pharmaceutical composition according to claim 22 or 23 for use in the treatment of a disease or disorder mediated by PCSK9.

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

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

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

28. A method of treating a disease or disorder mediated by PCSK9, comprising the step of administering to a patient in need thereof a therapeutically effective amount of a compound according to any one of paragraphs. 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 providing a reduction in the level of LDL-C in a patient in need thereof, wherein the method includes administering a therapeutically effective amount of a compound according to any one of paragraphs. 1-21 or a pharmaceutically acceptable salt thereof to a patient, thereby providing a reduction in LDL-C levels in the patient.

31. The method according to any one of paragraphs. 25-30, where the administration is carried out orally, parenterally, subcutaneously, by injection or by infusion.

32. Connection according to any one of paragraphs. 1-21 or a pharmaceutically acceptable salt thereof for use in the treatment of a disease or disorder mediated by PCSK9.

33. Connection according to any one of paragraphs. 1-21 or a pharmaceutically acceptable salt thereof for use in the treatment of a disease or disorder mediated by PCSK9 which is selected from hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, sitosterolemia, atherosclerosis, arteriosclerosis, coronary heart disease, peripheral vascular disease, vascular inflammation, and xanthoma.

34. The use of a compound according to any one of paragraphs. 1-21 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of a disease or disorder mediated by PCSK9.

35. Use according to 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. Connection according to any one of paragraphs. 1-21 or a pharmaceutically acceptable salt thereof for use in the manufacture of a medicament for the treatment of a disease associated with inhibition of PCSK9 activity.

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

38. Use according to claim 37, wherein said disease associated with 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 method for the manufacture of a compound of formula (II) or its pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, N-oxide or tautomer,

(II)

where each of R _a1 and R ₅ independently represents (C ₁ -C ₆ alkyl), and R ₉ is as defined above for formula (I), including:

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

(IIa),

where R ₅ is H and R ₉ is as defined above for formula (I),

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

(IIb),

where R ₅ is (C ₁ -C ₆ alkyl) and R ₉ is as defined above for formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, N-oxide or tautomer thereof,

(h) reacting a compound of formula (IIb) or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, N-oxide or tautomer thereof with an acid in a solvent, then with Boc ₂ O and a base to form a compound of formula (IIc),

(IIc),

where R ₅ is (C ₁ -C ₆ alkyl) and R ₉ is as defined above for formula (I), a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, N-oxide or tautomer thereof;

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

(IId),

where each of R _a1 and R ₅ independently represents (C ₁ -C ₆ alkyl), and R ₉ is as defined above for formula (I), or its pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, N-oxide or a tautomer; and

(d) deallylation of a compound of formula (IId) with a palladium catalyst and N,N -dimethyltrimethylsilylamine in a solvent to give a compound of formula (II).

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

41. The method according to p. 39 or 40, where the temperature in stage (a) is approximately 0°C.

42. The method according to any one of paragraphs. 39-41, where the acid in step (b) is trifluoroacetic acid (TFA).

43. The method according to any one of paragraphs. 39-42 where a metal oxide is used in step (c).

44. The method of claim 43 wherein the metal oxide is silver(I) oxide (Ag ₂ O).

45. The method according to any one of paragraphs. 39-44, wherein the palladium catalyst in step (d) is tetrakis(triphenylphosphine)palladium(0).

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

(II)

where R _a1 is H, R ₅ is (C ₁ -C ₆ alkyl) and R ₉ is as defined above for formula (I), comprising reacting a compound of formula (IIb),

(IIb),

where R ₅ is (C ₁ -C ₆ alkyl) and R ₉ is as defined above for formula (I), with a palladium catalyst and N,N -dimethyltrimethylsilylamine in a solvent to give a compound of formula (II).

47. The method of claim 46 wherein the solvent is dichloromethane.

48. The process of claim 46 or 47 wherein the palladium catalyst is tetrakis(triphenylphosphine)palladium(0).