# US 11,026,993 B2 · Cyclic tetramer compounds as proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors for the treatment of metabolic disorders

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- Number: US 11,026,993 B2
- Document ID: US11026993B2
- Status: Granted
- Kind: B2
- Application number: 16/695,843
- Filed: 2019-11-26
- Published: 2020-05-28
- Granted: 2021-06-08
- Earliest claimed: 2018-11-27
- Assignees: Novartis AG
- Applicants: Novartis AG
- Inventors: Karin Briner; Brian Addison Dechristopher; Alec Nathanson Flyer; Andrei Alexandrovich Golosov; Philipp Grosche; Eugene Yuejin Liu; Justin Yik Ching Mao; Lauren Gilchrist Monovich; Tajesh Jayprakash Patel; Carina Cristina Sanchez; Liansheng Su; Lihua Yang; Rui Zheng
- Web page: https://patentgrep.com/patent/US11026993B2

## CPC

- A61K 38/12: Cyclic peptides {, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C (A61K38/043 - A61K38/046 take precedence)}
- C07D 471/08: Bridged systems
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 3/06: Antihyperlipidemics
- C07D 211/56: Nitrogen atoms (nitro radicals C07D211/38)
- C07D 403/12: linked by a chain containing hetero atoms as chain links
- C07D 498/08: Bridged systems
- C07K 5/126: {Tetrapeptides}
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00)

## Abstract

The disclosure relates to inhibitors of PCSK9 useful in the treatment of cholesterol lipid metabolism, and other diseases in which PCSK9 plays a role, having the Formula (I): or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, N-oxide, or tautomer thereof, wherein R1, R1, R1, R1, R1, R1, R1, R1, R1, X1, X2, and X3 are described herein.

## Claims

### Claim 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 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.

### Claim 2 (depends on 1)

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

### Claim 3 (depends on 1)

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

### Claim 4 (depends on 1)

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.

### Claim 5 (depends on 4)

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.

### Claim 6 (depends on 1)

The compound according to claim 1, wherein R5 is H or (C1-C6)alkyl.

### Claim 7 (depends on 1)

The compound according to claim 1, wherein R5 is (C1-C6)alkyl.

### Claim 8 (depends on 1)

The compound according to claim 1, wherein R7 is H or (C1-C6)alkyl.

### Claim 9 (depends on 1)

The compound according to claim 1, wherein R7 is (C1-C6)alkyl.

### Claim 10 (depends on 1)

The compound according to claim 1, wherein R9 is halogen.

### Claim 11 (depends on 1)

The compound according to claim 1, wherein R9 is chloro.

### Claim 12 (depends on 1)

The compound according to claim 1, 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.

### Claim 13 (depends on 1)

The compound according to claim 1, wherein R8 is (C1-C6)alkyl.

### Claim 14 (depends on 1)

The compound of claim 1, having a Formula (Ia), Formula (Ib), Formula (Ic), Formula (Id), Formula (Ie), Formula (If), Formula (Ig), Formula (Ih), Formula (Ii), Formula (Ij), Formula (Ik), Formula (Im), or Formula (Io):

### Claim 15 (depends on 14)

The compound according to claim 14, wherein R1 is phenyl substituted with —OR10 and optionally substituted with one to three R11 or R1 is pyridinyl substituted with —OR10 and optionally substituted with one to three R11.

### Claim 16 (depends on 14)

The compound according to claim 14, wherein R10 is phenyl substituted with one to three R22 or R10 is pyridinyl substituted with one to three R22.

### Claim 17 (depends on 1)

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-H-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-H-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-TH-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-TH-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-TH-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-H-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-H-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-H-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.

### Claim 18 (depends on 1)

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-H-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-H-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.

### Claim 19 (depends on 1)

A pharmaceutical composition comprising a therapeutically effective amount of a compound according to claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

### Claim 20 (depends on 19)

The pharmaceutical composition of claim 19 further comprising at least one additional pharmaceutical agent.

### Claim 21 (depends on 1)

A method of modulating PCSK9 comprising administering to a patient in need thereof a compound of claim 1, or a pharmaceutically acceptable salt thereof.

### Claim 22 (depends on 1)

A method of inhibiting PCSK9 comprising administering to a patient in need thereof a compound of claim 1, or a pharmaceutically acceptable salt thereof.

### Claim 23 (depends on 1)

A method of inhibiting PCSK9 activity comprising administering to a patient in need thereof a compound of claim 1, or a pharmaceutically acceptable salt thereof.

### Claim 24 (depends on 1)

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 claim 1, or a pharmaceutically acceptable salt thereof.

### Claim 25 (depends on 24)

The method of claim 24, 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.

### Claim 26 (depends on 1)

A method of reducing LDL-C in a patient in need thereof, the method comprising administering a therapeutically effective amount of a compound of claim 1, or a pharmaceutically acceptable salt thereof to the patient, thereby reducing LDL-C in the patient.

### Claim 27

A process for the manufacture of a compound of Formula (II), or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, N-oxide, or tautomer thereof,
wherein Ra1 and R5 are each independently (C1-C6 alkyl) and R9 is as defined above for Formula (I), comprising:
(a) alkylating a compound of Formula (IIa), or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, N-oxide, or tautomer thereof,
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,
(b) 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),
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;
(c) 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),
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).

### Claim 28 (depends on 27)

The process of claim 27, wherein the solvent in step (a) is DMF.

### Claim 29 (depends on 27)

The process of claim 27, wherein the temperature in step (a) is about 0° C. and the acid in step (b) is trifluoroacetic acid (TFA).

### Claim 30 (depends on 27)

The process of claim 27, wherein a metal oxide is used in step (c) and the metal oxide is silver (I) oxide (Ag2O).

### Claim 31 (depends on 27)

The process of claim 27, wherein the palladium catalyst in step (d) is tetrakis(triphenylphosphine) palladium(0).

### Claim 32

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

### Claim 33 (depends on 32)

The process of claim 32, wherein the solvent is dichloromethane and palladium catalyst is tetrakis(triphenylphosphine) palladium(0).