WO2011091446A1 - Chemical compounds - Google Patents

Abstract

Disclosed are compounds of Formula II. Also disclosed are salts of the compounds, pharmaceutical compositions comprising the compounds or salts, and methods for treating HCV infection by administration of the compounds or salts.

Description

Chemical Compounds

Field of the invention

The present disclosure relates to antiviral compounds, pharmaceutical compositions comprising the compounds, and methods for treating viral infections.

Background of the Invention

Chronic infection with HCV is a major health problem associated with liver cirrhosis, hepatocellular carcinoma and liver failure. An estimated 170 million chronic carriers worldwide are at risk of developing liver disease. See, for example, Szabo, et al, Pathol. Oncol. Res. 2003, 9:215-221, and Hoofnagle JH, Hepatology 1997, 26:15S-20S. In the United States alone 2.7 million are chronically infected with HCV, and the number of HCV-related deaths in 2000 was estimated between 8,000 and 10,000, a number that is expected to increase significantly over the next years. Infection by HCV is insidious in a high proportion of chronically infected (and infectious) carriers who may not experience clinical symptoms for many years. Liver cirrhosis can ultimately lead to liver failure. Liver failure resulting from chronic HCV infection is now recognized as a leading cause of liver transplantation.

HCV is a member of the Flaviviridae family of R A viruses that affect animals and humans. The genome is a single ~9.6-kiIobase strand of RNA, and consists of one open reading frame that encodes for a polyprotein of -3000 amino acids flanked by untranslated regions at both 5' and 3' ends (5'- and 3'-UTR). The polyprotein serves as the precursor to at least 10 separate viral proteins critical for replication and assembly of progeny viral particles. The organization of structural and non-structural proteins in the HCV polyprotein is as follows: C-El-E2-p7-NS2-NS3-NS4a-NS4b-NS5a-NS5b.

Because the replicative cycle of HCV does not involve any DNA intermediate and the virus is not integrated into the host genome, HCV infection can theoretically be cured. While the pathology of HCV infection affects mainly the liver, the virus is found in other cell types in the body including peripheral blood lymphocytes. See, for example, Thomson B J and Finch RG, Clin Microbial Infect. 2005, 11 :86-94, and Moriishi K and Matsuura Y, Antivir. Chem. Chemother. 2003, 14:285-297.

At present, the standard treatment for chronic HCV is interferon alpha (IFN- alpha) in combination with ribavirin and this requires at least six (6) months of treatment. IFN-alpha belongs to a family of naturally occurring small proteins with characteristic biological effects such as antiviral, immunoregulatory and antitumoral activities that are produced and secreted by most animal nucleated cells in response to several diseases, in particular viral infections. IFN-alpha is an important regulator of growth and

differentiation affecting cellular communication and immunological control. Treatment of HCV with interferon has frequently been associated with adverse side effects such as fatigue, fever, chills, headache, myalgias, arthralgias, mild alopecia, psychiatric effects and associated disorders, autoimmune phenomena and associated disorders and thyroid dysfunction. Ribavirin, an inhibitor of inosine 5'-monophosphate dehydrogenase

(IMPDH), enhances the efficacy of IFN-alpha in the treatment of HCV. Despite the introduction of ribavirin, more than 50% of the patients do not eliminate the virus with the current standard therapy of interferon-alpha (IFN) and ribavirin. By now, standard therapy of chronic hepatitis C has been changed to the combination of pegylated IFN- alpha plus ribavirin. However, a number of patients still have significant side effects, primarily related to ribavirin. Ribavirin causes significant hemolysis in 10-20% of patients treated at currently recommended doses, and the drug is both teratogenic and embryotoxic. Even with recent improvements, a substantial fraction of patients do not respond with a sustained reduction in viral load and there is a clear need for more effective antiviral therapy of HCV infection. See, for example, Fried, et al. N. Engl. J Medial, 347:975-982.

A number of approaches are being pursued to combat the virus. They include, for example, application of antisense oligonucleotides or ribozymes for inhibiting HCV replication. Furthermore, low-molecular weight compounds that directly inhibit HCV proteins and interfere with viral replication are considered as attractive strategies to control HCV infection. Among the viral targets, the NS3/4A protease/helicase and the NS5b RNA-dependent RNA polymerase are considered the most promising viral targets for new drugs. See, for example, Ni, Z. J. and Wagman, A. S. C rr. Opin. Drug Discov. Devel. 2004, 7, 446-459, Beaulieu, P. L. and Tsantrizos, Y. S. Curr. Opin. Investig. Drugs 2004, 5, 838-850, and Griffith, et al., Ann. Rep. Med. Chem 39, 223-237, 2004.

Besides targeting viral genes and their transcription and translation products, antiviral activity can also be achieved by targeting host cell proteins that are necessary for viral replication. For example, Watashi, et al, Molecular Cell, 19, 111-122, 2005, show how antiviral activity can be achieved by inhibiting host cell cyclophilins. Alternatively, a potent TLR7 agonist has been shown to reduce HCV plasma levels in humans. See, Horsmans, et al, Hepatology, 42, 724-731, 2005.

Compounds said to be useful for treating HCV infection are disclosed, for example, in WO 2008/064218 (Leivers et. al), WO 2008/244380 (Bachand et. al), and US 2009/0068140 (Bachand et. al). These references also disclose methods for preparing the compounds, compositions comprising the compounds, compositions comprising the compounds and additional compounds, methods of treating HCV, and etc.

Summary of the Invention

In one aspect, the present invention discloses compounds of Formula I

wherein; each Z is independently CH or N with the proviso that no more than one Z in each ring is N;

each R³ is independently H, F, or two R³ groups bound to the same carbon atom together with the carbon atom to which they are bound form a 5- or 6-membered saturated heterocyclic spiro ring containing 1 or 2 oxygen or sulphur atoms, or two R groups bound to adjacent carbon atoms together with the carbon atoms to which they are bound form a saturated 5- or 6-membered cycloalkyl group.

In another aspect, the present invention discloses compounds of Formula II

II wherein;

each Z is independently CH or N with the proviso that no more than one Z in each ring is N;

each R¹ is independently H, Ci_-6alkyl, C_3-6cycloalkyl, phenyl, or phenyl containing one F substituent,

each R² is independently H, Ci_-3alkyl, Ci_-3acyl, C_3-6cycloacyl, or C(0)OCi_-3alkyl, or two R²s bound to the same nitrogen atom may, together with the nitrogen atom to which they are bound, join together to form a 5- or 6-membered saturated heterocyclic ring;

each R³ is independently H, F, or two R³ groups bound to the same carbon atom together with the carbon atom to which they are bound form a 5- or 6-membered saturated heterocyclic spiro ring containing 1 or 2 oxygen or sulphur atoms, or two R³ groups bound to adjacent carbon atoms together with the carbon atoms to which they are bound form a saturated 5- or 6-membered cycloalkyl group. In another aspect, the present invention discloses pharmaceutically acceptable salts of the compounds of Formula I or Formula II.

In another aspect, the present invention discloses pharmaceutical compositions comprising a compound of Formula I, a compound of Formula II, or a pharmaceutically acceptable salt thereof.

In another aspect, the present invention discloses a method for treating a viral infection, for example infection with HCV, in a human, comprising administration of a compound of Formula I, a compound of Formula II or a pharmaceutically acceptable salt thereof.

Detailed Description of the Invention

Pharmaceutically acceptable salts can be prepared by methods well known in the art. Suitable salts include those described, for example, in P. Heinrich Stahl, Camille G. Wermuth (eds.), handbook of Pharmaceutical Salts properties, selection, and Use; 2002.

In one aspect of the invention, every Z is CH.

In one aspect of the invention each R³ is independently H, F, or two R³ groups bound to the same carbon atom together with the carbon atom to which they are bound form a 5-membered saturated heterocyclic spiro ring containing 2 oxygen atoms, or two R³ groups bound to adjacent carbon atoms together with the carbon atoms to which they are bound form a cyclohexyl or a cyclopentyl group.

Examples

A table of abbreviations used in this Experimental section is set forth below.

DCM - Dichloromethane

DMF N,N-dimethylformamide

HATU (O-7-azabenzotriazol- 1 -yl)-N,N,N' ,Ν' -tetramethyluronium hexafluorophosphate)

ES LC-MS Electrospray Liquid Chromatography Mass Spectrometry Tetrahydrofuran

Diisopropylethylamine

Dimethylsulfoxide

Dimethoxyethane

Triethylamine

Isopropyl alcohol

Dess-Martin periodinane

High Resolution Mass Spectroscopy

1 , 1 '-Bis(diphenylphosphino)ferrocene

4-Dimethylaminopyridine

l-Ethyl-3-(3-dimethylaminopropyl)carbodiimide

Boc anhydride

N-hydroxybenzotriazole

Ethyl acetate

Room temperature

Hour

Methanol

Reverse Phase High Performance Liquid Chromatography 1 ,2-Dimethoxyethane

The synthetic schemes below are intended to illustrate synthetic methods which can be used to prepare compounds of the present invention. When specific compounds are shown, they are meant to be illustrative of the general method and not restricted to the specific compound shown.

Scheme I

Scheme II intermediate 9)

intermediate 9B

Scheme III (intermediate 10) intermediate 9A

Scheme IV (intermediate 1 1)

Scheme V (Intermediates 18A, 18B and 18C)

 Scheme VII. S nthesis of isoquinoline analogues

Intermediate 2 (Scheme 1)

6-bromo-N-methyl-N-(methyloxy)-2-naphthalenecarboxamide:

To a solution of 6-bromo-2-naphthalenecarboxylic acid (lg, 3.98 mmol) in

dichloromethane (20 ml) under nitrogen at 0°C was added a solution of oxalyl chloride (1.74 ml, 19.91 mmol) for 5 min. Drop of DMF was added and the reaction mixture was stirred at RT for 12h. The solution become clear and solvent was concentrated in vacuo. The yellowish solid was co-evaporated twice with toluene to provide slightly reddish powder and was preceded to the next step without further purification.

6-bromo-2-naphthalenecarbonyl chloride (lg, 4.2 mmol) was dissolved in DCM/Pyrdine (lOmL, 1.T). N,<9-dirnethylhydroxylamine ( 0.25g, 4.2 mmol) was added and the reaction mixture become reddish solution and was stirred at room temperature for 12 h under a nitrogen atm. The solution was concentrated in vacuo and the residue was suspended in DCM. Aqueous HCl (0.5N) was added and the DCM layer was separated and then washed with sat. NaHC0₃. Organic layer was dried, evaporated and passed through silica plug and eluted with ethyl acetate to provide the clean amide which was subjected to next step. Yield : 51.2%. ES LC-MS m/z = 295.1 (M+H)⁺

Intermediate 3: l-(6-Bromo-2-naphthalenyl)ethanone (Scheme 1)

Methylmagnesium bromide (1.133 mL, 3.40 mmol), was added to 6-bromo-N- methyl-N-(methyloxy)-2-naphthalenecarboxamide (500mg, 1.70 mmol) in THF at 0°C. Stirring continued for 2h at 0°C and allowed to reach T and stirred for additional 12h. Aqueous 0.5 M HCl (ImL) and 0.5mL H₂0 (1 mL) was added, stirred for lOmin and the light yellow color THF layer was decanted. The solid layer was washed with ethyl acetate. After evaporation of the solvent, the material was subjected to silica gel chromatography using 50% ethyl acetate to 100% in hexane to provide pure compound. Yield : 76.0%.

'H MR (400 MHz, CHLOROFORM-d) δ ppm 8.39 - 8.47 (m, 1 H), 8.02 - 8.12 (m, 2 H), 7.79 - 7.90 (m, 2 H), 7.60 - 7.69 (m, 1 H), 2.74 (s, 3 H);

ES LC-MS m/z = 250.1 (M+H)⁺;

Intermediate 4: 2-Bromo-l-(6-bromo-2-naphthalenyl)ethanone (Scheme 1)

To the l-(6-bromo-2-naphthalenyl)ethanone (lg, 4.01 mmol) dissolved in acetic acid (5ml) was added pyridinium tribromide (1.28 g, 4.01 mmol) and stirred for lOmin. HBr (33% in acetic acid, 1.321 ml, 8.03 mmol) was added slowly and the solution was stirred for 4h. Yellow precipitation was noticed. The reaction mixture was quenched by adding cold sat NaHC0₃ solution and the precipitate formed was filtered and washed with water and dried.

Yield : 76.0%

'H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.50 (s, 1 H), 8.03 - 8.13 (m, 2 H), 7.79 - 7.91 (m, 2 H), 7.67(dd, J=8.8, 1.5 Hz, 1 H), 4.57 (s, 2 H). Intermediate 5: 2-(6-Bromo-2-naphthalenyl)-2-oxoethyl N-[(methyloxy)carbonyl]-L- valyl-L-prolinate (Scheme 1)

2-Bromo-l-(6-bromo-2-naphthalenyl)ethanone (lg, 3.05 mmol), DIEA (0.481 ml, 2.75 mmol)and N-[(methyloxy)carbonyl]-L-valyl-L-proline 9 (500 mg, 1.836 mmol) were dissolved in acetonitrile (2ml) and the reaction was stirred at RT for 12h. It became clear solution and the reaction was concentrated, impregnated on silica gel and subjected to silica gel purification to provide pure compound.

Yield : 84.0%

*H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.31 - 8.41 (m, 1 H), 8.02 - 8.12 (m, 1 H), 7.91 - 8.03 (m, 1 H), 7.84 (d, J=8.7 Hz, 2 H), 7.58 - 7.71 (m, 1 H), 5.60 - 5.72 (m, 1 H), 5.28 - 5.41 (m, 2 H), 4.60 - 4.81 (m, 1 H), 4.29 - 4.43 (m, 1 H), 3.79 - 3.90 (m, 1 H), 3.70 - 3.79 (m, 1 H), 3.64 - 3.70 (m, 3 H), 2.30 - 2.47 (m, 2 H), 2.15 - 2.29 (m, 1 H), 2.06 - 2.13 (m, 2 H),0.90 - 1.09 (m, 6 H).

ES LC-MS m/z = 520.1 (M+H)⁺;

Intermediate 6: Methyl [(15)-l-({(2,S -2-[4-(6-bromo-2-naphthalenyl)-lH-imidazol-2- yl]-l-pyrrolidinyl}carbonyl)-2-methylpropyl]carbamate (Scheme 1)

2-(6-Bromo-2-naphthalenyl)-2-oxoethyl-N-[(methyloxy)carbonyl]-L-valyl-L- prolinate (450mg, 0.90 mmol) and ammonium acetate (0.14 g, 1.84 mmol) were dissolved in 1,4-dioxane (4ml) and degassed. The reaction was micro waved at 130°C for 30min. Solvent was evaporated to dryness and water was added to precipitate out the compound. The reddish solid was use as is in the next step.

Yield : 49.0% ES LC-MS m/z = 550.4 (M+H)⁺;

^!H NMR (400 MHz, DMSO-d6) δ ppm 11.86 (br. s., 1 H), 8.21 (s, 1 H), 8.12 (d, J=1.5 Hz, 1 H), 7.94 (dd,J=8.7, 1.3 Hz, 1 H), 7.79 - 7.88 (m, 2 H), 7.64 (d, J=2.0 Hz, 1 H), 7.57 (dd, J=8.8, 2.0 Hz, 1 H), 7.32 (d, J=8.4 Hz, 1 H), 5.05 - 5.17 (m, 1 H), 3.99 - 4.15 (m, 1 H), 3.82 (br. s., 1 H), 3.28 - 3.35 (m, 4 H), 2.16 (br. s., 2 H),

1.99 (br. s., 3 H), 0.76 - 1.03 (m, 6 H)

Intermediate 6B Methyl [(15)- 1 -( { (85)-8-[4-(6-bromo-2-naphthalenyl)- 1 H-imidazol-2-yl] - 1 ,4- dioxa-7-azas iro[4.4]non-7-yl}carbonyl)-2-methylpropyl]carbamate intermediate 6B

2-bromo-l-(6-bromo-2-naphthalenyl)ethanone (Intermediate 4) (1.00 g, 3.05 mmol) and (8S)-7- {N-[(methyloxy)carbonyl]-L-valyl} - 1 ,4-dioxa-7-azaspiro[4.4]nonane- 8-carboxylic acid (Intermediate 10) (1.007 g, 3.05 mmol) in acetonitrile (30 mL) was added DIEA (0.532 mL, 3.05 mmol) and the reaction mixture was stirred at room temperature overnight. The volatiles were removed under reduced pressure. 1 ,4-Dioxane (30.0 mL) and ammonium acetate (1.175 g, 15.24 mmol) were added to the residue and the reaction mixture was refluxed overnight. The volatiles were removed under reduced pressure and the residue was purified by flash column chromatography with hexane and ethyl acetate to afford 1.02 g (60 %) of intermediate 6B. ^!H NMR (DMSO-d₆) δ: 11.97 (d, J = 16.2 Hz, 1H), 8.23 (s, 1H), 8.12 (br. s., 1H), 7.94 (d, J = 8.6 Hz, 1H), 7.84 (d, J = 8.6 Hz, 2H), 7.65 (s, 1H), 7.57 (d, J - 8.6 Hz, 1H), 7.32 (d, 1H), 5.09 (t, J = 8.1 Hz, 1H), 3.83 - 4.13 (m, 6H), 3.76 (d, J = 10.5 Hz, 1H), 3.55 (s, 3H), 3.29 - 3.41 (m, 1H), 2.44 (d, J = 8.2 Hz, 2H), 0.85 (d, J = 6.2 Hz, 3H), 0.80 (d, J = 6.2 Hz, 3H). MS (ESI): 556

Synthesis of Intermediate 9 (Scheme II)

Intermediate 9A; N-[(methyloxy)carbonyl]-L-valine

L-valine (101.09g, 863 mmol), sodium hydroxide (34.5 g, 863 mmol) and sodium carbonate (45.7 g, 431 mmol) were combined in a flask. Methyl chloroformate (100 ml, 1294 mmol) was added dropwise over 10 min. Reaction was stirred at RT for 16h. Ether (200 mL) was added and the reaction stirred for 20 min. Organics were removed and discarded. The aqueous layer pH was adjusted to ~ 1 with 1M HC1 and then extracted with DCM (2 x 400 mL). The combined organics were dried over MgS0 , filtered and concentrated to afford 90.23 g (515 mmol, 60%) of product as a white solid. 'H NMR (400 MHz, CHLOROFORM-^) δ ppm 0.84 - 1.13 (m, 6 H) 2.14 - 2.37 (m, 1 H) 3.72 (s, 3 H) 4.35 (dd, J=8. 8, 4.5 Hz, 1 H) 5.19 (d, J=8.5 Hz, 1 H).

Intermediate 9B 1,1-dimethylethyl N-[(methyloxy)carbonyl]-L-valyl-L-prolinate

1, 1-dimethylethyl L-prolinate, (2.85 g, 16.64 mmol) and N- [(methyloxy)carbonyl] -L-valine (2.92 g, 16.64 mmol) were dissolved in DCM (50 mL). DIPEA (8.72 mL, 49.9 mmol) and HOBT (2.55 g, 16.64 mmol) were added. After 5 min EDC (3.19 g, 16.64 mmol) was added. The reaction was stirred at RT for 3h.The reaction was then diluted with water (50 mL) and IN HC1 (1 mL) were added. A precipitant was removed by filtration and then theorganic/aqueous layers were filtered through a hydrophobic frit. The organics were concentrated and the residue was dissolved in dioxane (40 mL). The solution was then passed though a flash elute column, washing the column with dioxane (3 x 40 mL). The combined organics were concentrated to dryness to afford 4.37g (13.31 mmol, 80%) of the product as colorless oil. The oil crystallized upon standing. Ή NMR (400 MHz, CHLOROFORM-d) δ ppm 0.96 (d, J=6.78 Hz, 3 H) 1.06 (d, J=6.78 Hz, 3 H) 1.43 - 1.51 (m, 9 H) 1.88 - 2.13 (m, 6 H) 2.13 - 2.27 (m, 1 H) 3.64 - 3.68 (m, 3 H) 4.29 - 4.38 (m, 1 H) 4.41 (d, J=3.51 Hz, 1 H) 5.34 - 5.45 (m, 1 H).

Intermediate 9; N-[(methyloxy)carbonyl]-L-valyl-L-proline intermediate 9

l,l-dimethylethyl N-[(methyloxy)carbonyl]-L-valyl-L-prolinate (5.22 g, 15.89 mmol) was dissolved in Trifluoroacetic acid (TFA) (10 mL) and stirred for 2h. The reaction was concentrated and then the residue was taken up in EtOAc (100 mL). The organics were washed with brine ( 3 x 100 mL) and then dried over MgS0₄, filtered and concentrated to afford 4.3g (15.79 mmol, 99%) of the product as a light brown foam. Ή NMR (400 MHz, DMSO-t 6) δ ppm 0.85 - 0.96 (m, 6 H) 1.76 - 1.98 (m, 5 H) 2.09 - 2.22 (m, 1 H) 3.51 (s, 3 H) 3.54 - 3.63 (m, 1 H) 3.72 - 3.85(m, 1 H) 4.01 (t, J=8.66 Hz, 1 H) 4.24 (dd, J=8.66, 4.89 Hz, 1 H) 7.32 (d, J=8.28 Hz, 1 H).

Synthesis of Intermediate 10 (Scheme III)

Intermediate 10B: Methyl (4R)-4-hydroxy-L-prolinate (50 g, 275 mmol), N- [(methy loxy)carbony 1] -L- val ine

(50.6 g, 289 mmol) intermediate 9A and HOBT (52.7 g, 344 mmol) were suspended in Dichloromethane (DCM) (500 mL) and cooled to 0 ⁰ C. DIEA (99 mL, 564 mmol) was added and when the mixture was added EDC (66.0 g, 344 mmol), stirred at RT for 2hrs. The clear solution was extracted with water (300mL), washed with saturated sodium carbonate (3xl00mL), brine (lOOmL), dried with sodium sulfate and evaporated to give 10B (70.6g, 234 mmol, 85 % yield) as a sticky oil.

Intermediate IOC:

In a 5L 4-neck round bottom flask equipped with an overhead stirrer and a bleach bubbler trap was added dichloromethane (1300 mL) and oxalyl chloride (58.3 mL, 667 mmol). The mixture was cooled to -72°C (IPA/dry ice) and DMSO (63.1 mL, 889 mmol) added over 40 min, keeping the temp below -62°C, during which gas evolution was observed. A pale yellow solution of methyl N-[(methyloxy)carbonyl]-L-valyl-(4R)-4- hydroxy-L-prolinate 10B (134.34 g, 444 mmol) in DCM (1000 mL) was added over 1.5 h, keeping the temp below -64°C. The resulting opaque pale yellow mixture was stirred for 1 h. TEA (217 mL, 1555 mmol) was added over 40 min below -65°C, subsequently IPA/CO2 bath was removed and the mixture was allowed to warm up to 0°C. Saturated NaHC0₃ solution (500 mL) was then added and layers were separated, the organic layer was washed with a IN HC1 solution (500 mL) and a saturated NaCl solution (500 mL). After drying over a₂S0₄ overnight, the slurry was filtered and solution concentrated yielding 127.61 g of IOC.

Intermediate 10D:

A mixture of 80g (1290 mmol) of ethylene glycol, 77.46g, (258 mmol) of methyl N-[(methyloxy)carbonyl]-L-valyl-4-oxo-L-prolinate IOC and 4.91g (25.8 mmol) of TsOH in 775 mL toluene was heated to reflux in a flask fitted with a Dean Stark trap and condenser. After 1.5 hours the reaction mixture was allowed to cool down and then washed with saturated aqueous NaHC0₃. The aqueous layer was back extracted with EtOAc and the combined organic layers were washed with brine and dried with N ₂S0₄, filtered and concentrated. The crude material was dissolved in 50 mL of 1.T hexane: DCM and chromatographed on silica with 10-100% gradient if EtOAc in hexanes.

Fractions containing pure product were combined to yield 32.54g (36.6% yield) of 10D.

Intermediate 10, (8S)-7-{N-[(methyloxy)carbonyl]-L-valyl}-l,4-dioxa-7- azaspiro[4.4]nonane-8-carboxylic acid

Methyl (8S)-7-{N-[(methyloxy)carbonyl]-L-valyl}-l,4-dioxa-7- azaspiro[4.4]nonane-8-carboxylate 10D (38.41 g, 112 mmol) was dissolved in a cold solvent mixture of tetrahydrofuran (THF) (295 mL), t-butanol (73.8 mL) and water (73.8 mL). LiOH (5.62 g, 134 mmol) was added as solid and the mixture was stirred at RT for lhr. The mixture was quenched with HCI (139 mL, 139 mmol), diluted with ethyl acetate (590 mL) and brine (200mL). The organic phase was washed twice with brine (lOOmL), dried (Na₂S0₄) and evaporated to give a dark solid which was sonicated with 200 mL ether and filtered to yield (8S)-7-{N-[(methyloxy)carbonyl]-L-valyl}-l,4-dioxa-7- azaspiro[4.4]nonane-8-carboxylic acid 10 (30.004g, 91 mmol, 81 % yield)

1H NMR (400 MHz, DMSO-c/₆) δ ppm 12.56 (br. s., 1 H) 7.40 (d, J=8.4 Hz, 1 H) 4.33 (dd, J=8.8, 7.02 Hz, 1 H) 3.81 - 4.10 (m, 5 H) 3.41 - 3.66 (m, 5 H) 2.28 - 2.43 (m, 1 H) 1.94 - 2.11 (m, 1 H) 1.74 - 1.94 (m, 1 H) 0.67 - 1.05 (m, 6 H). ES LC-MS m/z =331.6 (M+H)⁺.

Intermediate 11 (Scheme IV); (25',3a5',7a5 -l-{N-[(methyloxy)carbonyl]-L- valyl}octahydro-lH-indole-2-carboxylic acid

To a solution of (25',3a5',7a₁S)-l-{[(l,l-dimethylethyl)oxy]carbonyl}octahydro- lH-indole-2-carboxylic acid (lg, 3.71 mmol) in methanol (5ml) was added thionyl chloride (0.406 ml, 5.57 mmol) at 0°C and under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 12h. Solvent was pumped off and was co- evaporated twice with toluene to provide methyl (25',3a5',7a5)-octahydro-lH-indole-2- carboxylate (0.6g, 3.27 mmol, 88 % yield), which was taken up ϊη Ν,Ν- Dimethylformamide (DMF) (5.00 ml), followed by addition of N-(3- dimethylaminopropyl)-N'-ethylcarbodiimide (0.712 g, 3.71 mmol), ΗΟΒΤ (0.569 g, 3.71 mmol), N-[(methyloxy)carbonyl]-L-valine (0.65 g, 3.71 mmol) and N,N- diisopropylethylamine (0.648 ml, 3.71 mmol). The solution was stirred at room temperature for 4h. The reaction mixture was partitioned between ethyl acetate and saturated sodium bicarbonate. The organic phase was separated and dried over sodium sulfate and evaporated in vacuo to give methyl (2S,3aS,7aS)-l-{N- [(methyloxy)carbonyl]-L-valyl}octahydro-lH-indole-2-carboxylate. To this was added tetrahydrofuran (5.00 mL) and a solution of sodium hydroxide (2.321 ml, 18.56 mmol) was added. The reaction mixture was stirred at room temperature for 12 h. The reaction mixture was concentrated and upon slow addition of concentrated hydrochloric acid; a viscous solid was obtained. The solid was filtered, washed with water and dried to provide 0.60 g (49%) of intermediate 11. 'H NMR (400 MHz, DMSO-d6) d ppm 0.86 (dd, J=14.4, 6.6 Hz, 6 H), 1.01 - 1.29 (m, 3 H), 1.21 - 1.48 (m, 2H), 1.51 - 1.73 (m, 3 H), 1.77 - 1.97 (m, 3 H), 1.99- 2.14 (m, 1 H), 2.18 - 2.30 (m, 1 H), 3.56 - 3.70 (m, 1 H),3.76 - 3.94 (m, 1 H), 3.97 - 4.11 (m, 1 H), 4.13 - 4.25 (m, 1 H), 4.24 - 4.35 (m, 1 H), 7.41 - 7.57 (m, 1 H). MS (ESI): 327 [M+H]⁺.

Intermediate 6C; Methyl ((15)-l-{[(25^,,3a5',7a₁S)-2-(5-bromo-lH-benzimidazol-2- l)octahydro-lH-indol-l-yl]carbonyl}-2-methylpropyl)carbamate

intermediate 6C

To a solution of (25',3a5',7a5)-l-{N-[(methyloxy)carbonyl]-L-valyl}octahydro- lH-indole-2-carboxylic acid (intermediate 11) (1.26 g, 6.74 mmol), 4-bromo-l,2- benzenediamine (2.00 g, 6.13 mmol) and HATU (2.56 g, 6.74 mmol) in dichloromethane (60 mL) was added N,N-Diisopropylethylamine (2.38 g, 18.38 mmol) and the reaction mixture was stirred at room temperature overnight. The volatiles were removed in vacuo and the residue was dissolved in acetic acid (50 mL) and heated at 70 °C overnight. The reaction was cooled to room temperature and poured into water. The solid was filtered, dissolved in ethyl acetate and dried over sodium sulfate. Stripped to afford a solid, which was column chromatographed with hexane and ethyl acetate to afford 1.44 g (49%) of intermediate 6C.

¾ NMR (DMSO-d₆) d: 12.22 - 12.43 (m, 1H), 7.62 - 7.77 (m, 1H), 7.37 - 7.59 (m, 2H), 7.17 - 7.33 (m, 1H), 5.06 (d, J = 6.2 Hz, 1H), 4.41 (d, J = 4.3 Hz, 1H), 3.81 (t, J = 9.0 Hz, 1H), 3.54 (s, 3H), 2.28 - 2.45 (m, 2H), 2.17 (t, J = 6.5 Hz, 1H), 1.58 - 1.96 (m, 6H), 1.42 - 1.53 (m, 1H), 1.34 (d, J = 11.9 Hz, 1H), 1.23 (br. s., 1H), 0.84 (d, J = 6.4 Hz, 3H), 0.65 (dd, J = 6.3, 4.0 Hz, 3H).

Intermediate 7B; Methyl [(15)-2-methyl-l-({(25',3a5',7aS)-2-[5-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)-lH-benzimidazol-2-yl]octahydro-lH-indol-l- 1 } carbony l)propy 1] carbamate

Intermediate 7B

Methyl ((15 -l-{[(2 ',3a»S^,,7a5)-2-(5-bromo-lH-benzimidazol-2-yl)octahydro-lH- indol-l-yl]carbonyl}-2-methylpropyl)carbamate, intermediate 6C (1.00 g, 2.10 mmol), 4,4,4',4^,,5,5,5',5'-octamethyl-2,2'-bi-l,3,2-dioxaborolane (2.13 g, 8.38 mmol), potassium acetate (0.82 g, 8.38 mmol) and PdCl₂dppf (0.23 g, 0.314 mmol) were placed in a microwave vial and sealed. It vial was placed under high vacuum and filled with N2. 1,4- Dioxane (20 mL) was added and the reaction mixture was stirred at 85°C overnight.

Concentrated onto silica and chromatographed to afford 0.84 g (76%>) of intermediate 7B, MS (ESI): 525 [M+H]⁺.

Intermediate 13 was obtained analogously to intermediate 9

intermediate 13

'H MR (CHLOROFORM-d) δ: 6.50 (br. s., 1H), 5.55 (d, J = 9.2 Hz, 1H), 4.82 (dd, J = 9.3, 5.8 Hz, 1H), 4.26 - 4.41 (m, 1H), 4.09 - 4.24 (m, 1H), 3.93 - 4.07 (m, 1H), 3.68 (s, 3H), 2.49 - 2.89 (m, 2H), 1.97 - 2.14 (m, 1H), 0.94 - 1.10 (m, 6H). ES LC-MS m/z =309.2 (M+H)⁺

Intermediate 14

Intermediate 14

At 0°C, to a stirred suspension of 6-bromo-2-carboxyquinoline (1.45g,

5.57mmol), EDCI (1.32g, 6.9mmol), DMAP (cat.) and Ν,Ο-dimethylhydroxylamine HCl (0.62g, 6.33 mmol) in DCM was added TEA (1.7g, 17 mmol). After addition, the reaction mixture became clear. Stirring was continued overnight at rt. before quenched with NaHC0₃ (ss). The layers were separated and the organic layer was washed with brine, dried over Na₂S0₄. After evaporation of the solvents, the crude product was purified by column chromatography (silica gel, 0 to 30% EtOAc in hexanes) to give 6- bromo-N-methoxy-N-methylquinoline-2-carboxamide (intermediate 14) (750mg, 44%) as an oil which was slowly solidified. Ή NMR (400MHz, CHLOROFORM-d) . 8.16 (d, J= 8.4 Hz, 1 H), 8.08 - 7.93 (m, 2 H), 7.81 (dd, J= 2.1, 9.0 Hz, 1 H), 7.74 - 7.56 (m, 1 H), 3.77 (br. s„ 3 H), 3.45 (br. s., 3 H). ES LC-MS m/z = 296.7 (M+H)⁺

Intermediate 15

Intermediate 15

At 0°C, to a stirred solution of 6-bromo-N-methyl-N-(methyloxy)-2- quinolinecarboxamide (intermediate 14) (750mg, 2.54mmol) in THF was slowly added MeMgBr ( l.OmL, 3M in ether). The reaction was stirred at this temperature for 1 hr before quenched with NH₄C1 (ss) and extracted with EtOAc. (2X). The combined organic phase was dried over Na₂S0₄. After evaporation of the solvents, the crude product was purified by column chromatography (silica gel, 0 to 30% EtOAc in hexanes) to give l-(6- bromo-2-quinolinyl)ethanone (intermediate 15) (635mg, 100%). Ή NMR (400MHz, CHLOROFORM-d) δ. 8.22 - 8.12 (m, 2 H), 8.12 - 8.00 (m, 2 H), 7.95 - 7.77 (m, 1 H), 2.86 (s, 3 H).

Intermediate 17

F intermediate 17

To a solution of 1 -(6-bromo-2-quinolinyl)ethanone (132 mg, 0.4mmol) in THF (3mL) was added phenyltrimethylarnmonium tribromide (150mg, 0.4mmol) . The resulting mixture was stirred at 65°C for one hour. LC-MS indicated the mono- bromination was completed. To this solution, N-[(methyloxy)carbonyl]-L-valyl-4,4- difluoro-L-proline (intermediate 13) (123mg, 0.4mmol) was introduced and followed by triethylamine (40 mg, 0.4mmol) . Stirring was continued for one hour at 50 °C.

Solvents were removed and the crude product was subjected to column chromatography (silica gel, 0 to 50% EtOAc in hexanes) to give 2-(6-bromoquinolin-2-yl)-2-oxoethyl N- (methoxycarbonyl)-L-valyl-4,4-difluoro-L-prolinate ( intermediate 17) (150mg, 67%). ^!H NMR (400MHz, CHLOROFORM-d) δ. 8.20 (d, J= 8.6 Hz, 1 H), 8.13 - 7.97 (m, 3 H), 7.87 (d, J= 2.0 Hz, 1 H), 5.99 (d, J= 17.8 Hz, 1 H), 5.70 (d, J- 17.8 Hz, 1 H), 5.45 - 5.31 (m, 1 H), 4.41 - 4.26 (m, 1 H), 4.26 - 4.16 (m, 1 H), 4.12 (d, J= 7.0 Hz, 2 H), 3.68 (s, 3 H), 2.98 - 2.77 (m, 2 H), 2.04 (br, 1 H), 1.09 - 0.86 (m, 6 H). ES LC-MS m/z = 556.1, 558.1 (M+H)⁺

Intermediate 18A

To a stirred solution of 2-(6-bromo-2-quinolinyl)-2-oxoethyl N- [(methyloxy)carbonyl]-L-valyl-4,4-difluoro-L-prolinate (150 mg, 0.27 mmol) in dioxane (5 mL) was added the excess of ammonium acetate. The resulting suspension was stirred in a sealed tube at 110°C overnight. After evaporation of the solvents, the crude was directly loaded to prep TLC for the purification (EtOAc/Hexane 1 : 1) to give methyl [(lS)-l-({(2S)-2-[4-(6-bromo-2-quinolinyl)-lH-imidazol-2-yl]-4,4-difluoro-l- pyrrolidinyl}carbonyl)-2-methylpropyl]carbamate intermediate 18A (50mg, 35%). ES LC-MS m/z = 536.2, 538.2 (M+H)⁺v

Intermediate 18B

Methyl [(lS)-l-({(2S)-2-[4-(6-bromo-2-quinolinyl)-lH-imidazol-2-yl]-l- pyrrolidinyl}carbonyl)-2-methylpropyl]carbamate (intermediate 18B) was prepared by similar synthetic sequence as one used in preparation of intermediate 18A. ES LC-MS m/z = 500.2, 502.2 (M+H)^+r

Intermediate 18C

Methyl [(lS)-l-({(lS,3aS,7aR)-l-[4-(6-bromo-2-quinolinyl)-lH-imidazol-2- yl]octahydro-2H-isoindol-2-yl}carbonyl)-2-methylpropyl]carbamate (18C) was prepared by using the similar synthetic sequence as illustrated in preparation of intermediate 18A. ES LC-MS m/z = 554.4, 556.5 (M+H)⁺⁷

Intermediate 19

To a stirred mixture of 4-bromo-l,2-diaminebenzene (2.83g, 15.14mmol), (8S)- 7-{N-[(methyloxy)carbonyl]-L-valyl}-l,4-dioxa-7-azaspiro[4.4]nonane-8-carboxylic acid (10) (5g, 15.14mmol) and TEA (1.53g, 15.14mmol) in DCM (60 mL) was added HATU (5.76g, 15.14mmol). The resulting mixture was stirred for 4 hrs. at rt. before quenched with NaHC0₃₍Ss). The layers were separated and the aqueous layer was extracted with DCM (2X). The combined extracts was dried over Na₂S0₄, filtered and evaporated the solvents. The crude product was purified by flash chromatography (silica gel 10 to 80% EtOAc in hexanes) to give a mixture of amidation on either amino group (7.4g, 98%). ES LC-MS m/z = 499.2, 501.2 (M+H)^+T

Intermediate 20 Intermediate 20

A mixture of intermediate 19 (7.4 g, 14. 82 mmol) was stirred in acetic acid (50 mL) at 70 °C for two hrs. Solvents were evaporated and the residue dissolved in

DCM/NaHC0₃ (ss) (lOOmL/lOOmL). The layers were separated and the aqueous layer was extracted with DCM (2X). The combined extracts were dried over Na₂S0₄. Solvents were filtered and evaporated. The crude product was purified by flash chromatograpgy (silica gel 10 to 80% EtOAc in hexanes) to give methyl ((lS)-l-{[(8S)-8-(5-bromo-lH- benzimidazol-2-yl)-l,4-dioxa-7-azaspiro[4.4]non-7-yl]carbonyl}-2- methylpropyl)carbamate (intermediate 20) (6.04g, 85%) 'H NMR (400MHZ,

CHLOROFORM-d) δ. 7.70 (br. s., 1 H), 7.46 - 7.40 (m, 1 H), 7.33 (dd, J= 1.8, 8.6 Hz, 1 H), 5.55 - 5.39 (m, 2 H), 4.36 - 4.22 (m, 1 H), 4.17 - 3.86 (m, 4 H), 3.76 - 3.67 (m,4 H), 3.67 - 3.58 (m, 1 H), 3.42 - 3.25 (m, 1 H), 2.60 - 2.41 (m, 1 H), 2.00 - 1.84 (m, 1 H), 1.11 - 0.98 (m, 1 H), 0.91 - 0.64 (m, 6 H). ES LC-MS m/z = 481.5, 483.5 (M+H)⁺

Intermediate 7A

Intermediate 7A

To a Schlenk flask were added methyl ((lS)-l-{[(8S)-8-(5-bromo-lH- benzimidazol-2-yl)-l,4-dioxa-7-azaspiro[4.4]non-7-yl]carbonyl}-2- methylpropyl)carbamate (intermediate 20) (963mg, 2mmol), 4,4,4',4',5,5,5',5'- octamethyl-2,2'-bi-l,3,2-dioxaborolane (660mg, 2.6mmol) KOAc (981mg, 10 mmol) and PdCl₂(dppf). Purged the flask with N₂ (3X) before addition of THF. The resulting suspension was further degassed (3x) before heated to 60 °C for 20 hrs. Cooled down to rt and poured the mixture into ice-water. Extracted with EtOAc (3X). The combined organic phases were dried over MgS0₄. Evaporated solvents and purified by column chromatography (silca gel 10 to 100% EtOAc in hexanes) to give methyl [(lS)-2-methyl- l-({(8S)-8-[5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-benzimidazol-2-yl]-l,4- dioxa-7-azaspiro[4.4]non-7-yl}carbonyl)propyl]carbamate), intermediate 7A (810mg, 77%). 1H NMR (400MHZ, CHLOROFORM-d) δ. 8.14 - 7.87 (m, 1 H), 7.82 - 7.55 (m, 2 H), 5.67 - 5.47 (m, 2 H), 4.30 (br. s., 1 H), 4.22 - 3.86 (m, 5 H), 3.75 - 3.58 (m, 4 H), 3.47 - 3.24 (m, 1 H), 2.58 - 2.48 (m, 1 H), 1.97 - 1.83 (m, 1 H), 1.44 - 1.29 (m, 12 H), 1.09 - 0.97 (m, 1 H), 0.92 - 0.56 (m, 6 H). ES LC-MS m/z = 530 (M+H)⁺

Intermediate 21; N-[(l£)-(5-bromo-2-iodophenyI)methylidene]-2-methyl-2- ropanamine

To a solution of 2-1, 4-Br benzaldehyde (2.0 g, 6.4 mmol) in anhydrous THF (10 mL) was added tert-butylamine (2.0 mL, 19.3 mmol) and the reaction stirred at room temperature under a nitrogen atmosphere for 4 days. The reaction was concentrated in vacuo and partitioned between dichloromethane and water. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo to afford the desired compound as a pale yellow solid in quantitative yield.

Intermediate 22; (7-bromo-3-isoquinolinyl)methanol

In a sealed tube were combined N-[(l£)-(5-bromo-2-iodophenyl)methylidene]-2- methyl-2-propanamine ( intermediate 21) (170 mg, 0.46 mmol), 2-propyn-l-ol (0.03 mL, 0.56 mmol), copper (I) iodide (18 mg, 0.09 mmol), diisopropylamine (0.1 mL, 0.7 mmol) and dichlorobis(triphenylphosphine)palladium (16 mg, 0.02 mmol) with toluene (3 mL) and the reaction was degassed with nitrogen and heated to 100 C for 4 h. The reaction was partitioned between dichloromethane and water, and the organic layer was dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography, eluting with 75-100% hexanes/ethyl acetate to afford the desired compound as a tan solid (44 mg, 44% yield). ^!H NMR (400 MHz, DMSO-i¼) δ ppm 9.24 (s, 1 H) 8.40 (d, J=l .8 Hz, 1 H) 7.93 - 8.02 (m, 1 H) 7.80 - 7.92 (m, 2 H) 5.56 (t, J=5.7 Hz, 1 H) 4.72 (d, J=5.7 Hz, 2 H). LC-MS: ESI (M+H)⁺ = 237.97.

Intermediate 23; l-(7-bromo-3-isoquinolinyl)ethanol

To a solution of (7-bromo-3-isoquinolmyl)methanol (intermediate 22) (43 mg, 0.18 mmol) in anhydrous dichloromethane (2 mL) was added Dess-Martin Periodinane (153 mg, 0.36 mmol) and the reaction stirred at room temperature under nitrogen for 1 h. To the reaction was added 10% aqueous sodium thiosulfate (2 mL) and saturated sodium bicarbonate solution (2 mL) and the reaction stirred for 10 min. The reaction was extracted with dichloromethane and the organic layer dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was dissolved in anhydrous THF (2 mL) and cooled to 0 °C. To the solution was added methylmagnesium bromide as a 3M solution in ether (0.07 mL) and the reaction stirred at 0 °C for 10 minutes. The reaction was quenched with saturated sodium bicarbonate solution and partitioned between dichloromethane and water. The aqueous layer was extracted with dichloromethane and the organic layer dried over anhydrous magnesium sulfate and concentrated in vacuo to afford the desired compound as a white solid (42 mg, 94% yield).

Intermediate 24; l-(7-bromo-3-isoquinolinyl)ethanone

To a solution of l-(7-bromo-3-isoquinolinyl)ethanol (intermediate 23) (41 mg, 0.16 mmol) in anhydrous dichloromethane (1.5 mL) was added Dess-Martin Periodinane (138 mg, 0.33 mmol) and the reaction stirred at room temperature under nitrogen for 1 h. To the reaction was added 10% aqueous sodium thiosulfate (2 mL) and saturated sodium bicarbonate solution (2 mL) and the reaction stirred for 10 min. The reaction was diluted with dichloromethane and the organic layer separated. The aqueous layer was extracted with dichloromethane and the combined organic layers were dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with 5-50% hexanes/ethyl acetate to afford the desired compound as a white solid (25 mg, 62% yield).

Intermediate 25; 2-(7-bromo-3-isoquinolinyl)-2-oxoethyl (2S,3aS,7aS)-\-{N- [(methyloxy)carbonyl]-L-valyl}octahydro-lH-indole-2-carboxylate

To a solution of l-(7-bromo-3-isoquinolinyl)ethanone (intermediate 24) (80 mg, 0.32 mmol) and pyridinium tribromide (72 mg, 0.22 mmol) in glacial acetic acid (2 mL) was added 33% HBr in acetic acid (0.04 mL) and the reaction stirred for 5 h at room temperature. The reaction was diluted with ethyl acetate, washed with water (2x) followed by saturated sodium bicarbonate (2x), brine and the organic layer dried over anhydrous magnesium sulfate. The organic layer was concentrated in vacuo and the residue suspended in anhydrous acetonitrile (2 mL). To the suspension was added (2_>S',3a₁S',7aiS - l-{N-[(methyloxy)carbonyl]-L-valyl}octahydro-lH-indole-2-carboxylic acid (intermediate 11) (1 15 mg, 0.35 mmol), prepared as described in scheme IV, followed by triethylamine (0.13 mL, 0.96 mmol) and the reaction stirred at room temperature for 18 h under a nitrogen atmosphere. The reaction was partitioned between ethyl acetate and water, the organic layer was washed with brine and dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with 20-100% hexanes/ethyl acetate to give the desired compound as a tan solid (64 mg, 35%). Ή NMR (400 MHz, DMSO-i¾) δ ppm 9.44 (s, 1 H) 8.61 (d, J=7.2 Hz, 2 H) 8.23 (d, J=8.8 Hz, 1 H) 8.07 (dd, J=8.8, 2.0 Hz, 1 H) 7.60 (d, J=8.4 Hz, 1 H) 5.44 - 5.90 (m, 2 H) 4.53 (t, J=9.1 Hz, 1 H) 4.26 - 4.45 (m, 1 H) 3.83 (t, J-9.1 Hz, 1 H) 3.53 (s, 3 H) 2.13 - 2.43 (m, 3 H) 1.82 - 2.02 (m, 2 H) 1.58 - 1.83 (m, 3 H) 1.40 - 1.59 (m, 2 H) 1.18 - 1.38 (m, 2 H) 0.66 - 0.94 (m, 6 H). LC-MS: ESI (M+H)⁺ = 574.18.

Intermediate 26; methyl [(16)-l-({(25^,,3a5^,,7a5)-2-[4-(7-bromo-3-isoquinolinyl)-lH- imidazol-2- l]octahydro-lH-indol-l-yl}carbonyl)-2-methylpropyl]carbamate

To a solution of 2-(7-bromo-3-isoquinolinyl)-2-oxoethyl (2S,3aS,7aS)-l-{N- [(methyloxy)carbonyl]-L-valyl}octahydro-lH-indole-2-carboxylate (intermediate 25) (63 mg, 0.1 1 mmol) in anhydrous dioxane (1.5 mL) was added ammonium acetate (85 mg, 1.1 mmol) and the reaction was degassed with nitrogen. The reaction was heated to 110 °C for 2.5 h in a sealed tube, cooled to room temperature and partitioned between dichloromethane and saturated sodium bicarbonate solution. The organic layer was dried over anhydrous magnesium sulfate and concentrated in vacuo to afford the desired compound as a brown solid in quantitative yield.

Example 1; Methyl [(l_iS)-2-methyl-l-({(25)-2-[4-(6-{2-[(25)-l-((25)-3-methyl-2- {[(methyloxy)carbonyl]amino}butanoyl)-2-pyrrolidinyl]-lH-benzimidazol-5-yl}-2- naphthalenyl)-lH-imidazol-2-yl]-l pyrrolidinyl}carbonyl)propyl]carbamate.

Methyl[(15)-l-({(25)-2-[4-(6-bromo-2-naphthalenyl)-lH-imidazol-2-yl]-l- pyrrolidinyl}carbonyl)-2-methylpropyl]carbamate intermediate 6 (50mg, 0.10 mmol) and methyl [(15)-2-methyl-l-({(25)-2-[5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)- lH-benzimidazol-2-yl]- 1 -pyrrolidinyl}carbonyl)propyl]carbamate intermediate 7 (obtained analogously to intermediate 7A) (47.1 mg, 0.10 mmol) were dissolved in 1,4- dioxane (2 ml). The mixture was degassed and PdCl₂(dppf)-CH₂Cl₂ (3.66 mg, 5.01 μιηοΐ) was added. The reaction mixture was microwaved at 130°C for 30 min. The solvent was evaporated, taken in DCM and subjected to prep TLC using 15% MeOH/EA as eluent (Rr=0.3).

Yield : 11.0%

'H NMR (400 MHz, DMSO-d6) δ ppm 12.29 (br. s., 1 H), 11.83 (br. s., 1 H), 8.06 - 8.30 (m, 2 H), 7.91 (br. s.,3 H), 7.74 - 7.86 (m, 2 H), 7.62 (br. s., 2 H), 7.34 (br. s., 2 H), 4.97 - 5.26 (m, 2 H), 4.09 (br. s., 2 H), 3.85 (br.s., 3 H), 3.45 - 3.65 (m, 6 H), 2.11 - 2.34 (m, 4 H), 1.98 (br. s., 5 H), 1.23 (br. s., 1 H), 0.99 - 1.08 (m, 2 H), 0.78 - 0.99 (m, 12 H).

ES LC-MS m/z = 763.8 (M+H)⁺;

Example 2; Methyl [(l,S)-2-methyl-l-({(25)-2-[4-(6-{2-[(85)-7-((25)-3-methyl-2- {[(methyloxy)carbonyl]amino}butanoyl)-l,4-dioxa-7-azaspiro[4.4]non-8-yl]-lH- benzimidazol- 5 -y 1 } -2-naphthaleny 1)- 1 H-imidazo 1-2 -y 1] - 1 - rrolidinyl}carbonyl)propyl]carbamate

Example 2 was prepared using similar procedure to one described for example 1, except that intermediate 7A was used instead of intermediate 7. Final product was dissolved in DMSO and purified by HPLC using gradient of 10-80% H₂0 containing 0.2%NH₃ and CH₃CN containing 0.2% NH₃) to afford the title compound as yellow solid.

Yield : 29.2%

'H NMR (400 MHz, DMSO-d6 ) δ ppm 12.36 (br. s., 1 H), 11.83 (br. s., 1 H), 8.13 (s, 2 H), 7.72 - 8.02 (m, 5H), 7.62 (br. s., 3 H), 7.33 (br. s., 2 H), 5.19 (s, 1 H), 5.07 - 5.14 (m, 1 H), 3.97 (br. s., 7 H), 3.82 (br. s., 3 H), 3.33 (s, 7 H), 2.33 (br. s., 1 H), 2.16 (br. s., 2 H), 1.98 (br. s., 4 H), 0.71 - 1.00 (m, 12 H).

ES LC-MS m/z = 821.5 (M+H)⁺;

Example 3; Methyl [(l,S)-2-methyl-l-({(25',3a₁S^,,7a5 -2-[4-(6-{2-[(85)-7-((25)-3-methyl- 2-{[(methyloxy)carbonyl]amino}butanoyl)-l,4-dioxa-7-azaspiro[4.4]non-8-yl]-lH- benzimidazol-5-yl}-2-naphthalenyl)-lH-imidazol-2-yl]octahydro-lH-indol-l- l}carbonyl)propyl] carbamate

Example 3 was prepared in a fashion similar to procedure described for target example 1, except that intermediate 7A and intermediate 6C were used. Final product was dissolved in DMSO and purified by HPLC using gradient of 10-80% H₂0 containing 0.2%NH₃ and CH₃CN containing 0.2% NH₃) to afford the title compound as yellow solid.

Yield : 16.6%

lH NMR (400 MHz, DMSO-d€) δ ppm 12.33 (br. s., 1 H), 11.74 (br. s., 1 H), 8.05 - 8.27 (m, 2 H), 7.78 - 8.01(m, 5 H), 7.46 - 7.67 (m, 4 H), 7.34 (d, J=8.5 Hz, 1 H), 5.20 (t, J=8.2 Hz, 1 H), 4.91 - 5.08 (m, 1 H), 4.40 (br. s., 1 H), 4.12 (d, J=10.7 Hz, 1 H), 4.00 - 4.06 (m, 2 H), 3.89 - 4.00 (m, 3 H), 3.77 - 3.89 (m, 2 H), 3.55 (s, 6 H),

2.54 (br. s., 1 H), 2.40 - 2.47 (m, 1 H), 2.34 (br. s., 1 H), 2.10 - 2.21 (m, 1 H), 2.07 (s, 1 H), 1.85 - 1.99 (m, 4H), 1.78 (br. s., 2 H), 1.59 - 1.71 (m, 1 H), 1.48 (br. s., 2 H), 1.24 (br. s., 1 H), 0.63 - 0.96 (m, 12 H);

ES LC-MS m/z = 876.5 (M+H)⁺;

Example 4; Methyl [(1,¾-2-Γη6 1-1-({(25)-2-[5-(6-{2-[(25,335,735)-1-((25 -3-Γη₆ 1- 2- { [(methyloxy)carbonyl]amino}butanoyl)octahydro-lH-indol-2-yl]- 1 H-imidazol-4-yl} - 2-na hthalenyl)-lH-benzimidazol-2-yl]-l-pyrrolidinyl}carbonyl)propyl]carbamate.

Example 4 was prepared similarly to procedure described for target example 1 , except that intermediate 6C was used instead of intermediate 6. Final product was dissolved in DMSO and purified by HPLC using gradient of 10-80% H₂0 containing 0.2%NH₃ and CH₃CN containing 0.2% NH₃) to afford the title compound as yellow solid.

Yield : 45.2%

'H NMR (400 MHz, DMS0-d6) 5 ppm 12.15 - 12.54 (m, 1 H), 11.75 (br. s., 1 H), 8.13 (br. s., 2 H), 7.92 (br. s., 5 H), 7.59 (br. s., 4 H), 7.36 (br. s., 1 H), 5.21 (br. s., 1 H), 5.00 (br. s., 1 H), 4.40 (br. s., 1 H), 4.09 (br. s., 1H), 3.86 (br. s., 3 H), 3.55 (br. s., 6 H), 3.22 - 3.34 (m, 4 H), 2.25 (br. s., 3 H), 1.93 (br. s., 5 H), 1.78 (br. s., 2H), 1.13 - 1.54 (m, 3 H), 0.74 - 0.97 (m, 12 H);

ES LC-MS m/z = 818.6 (M+H)⁺ Example 5; Methyl [(15)-2-ηΐ6 1-1-({(25)-2-[4-(6-{2-[(2^33^,73,5)-1-((25)-3-ηΐ6 1-

2-{[(methyloxy)carbonyl]amino}butanoyl)octahydro-lH-indol-2-yl]-lH-benzimidazol-5- l}-2-naphthalenyl)-lH-imidazol-2-yl]-l-pyrrolidinyl}carbonyl)propyl]carbamate

Methyl [(15)-2-methyl-l-({(25,3a5,7a5)-2-[5-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)- lH-benzimidazoI-2-yl]octahydro- lH-indol- 1 - yl}carbonyl)propyl]carbamate, intermediate 7B (49.7 mg, 0.095 mmol), methyl [(15)-1- ({(2₁S)-2-[4-(6-bromo-2-naphthalenyl)-lH-imidazol-2-yl]-l-pyrrolidinyl}carbonyl)-2- methylpropyl] carbamate, intermediate 6 (43 mg, 0.086 mmol) and PdC12dppf (12.59 mg, 0.017 mmol) were place placed in a reaction vial. The vial was sealed and placed under high vacuum and filled with nitrogen. Followed by addition of Na₂C0₃ (0.129 mL, 0.258 mmol) and 1,4-Dioxane (2 mL) and the contents were microwave at 120 °C for 30 mins. The reaction mixture was filtered through a pad of silica with copious methanol washings. After concentration, the residue was purified by HPLC to afford 0.025 g (35%) of the title compound. Ή NMR (DMSO-d₆) δ: 12.24 (d, J = 18.5 Hz, 1H), 8.09 - 8.34 (m, 2H), 7.78 - 8.04 (m, 5H), 7.46 - 7.70 (m, 4H), 7.33 (d, J = 8.2 Hz, 1H), 5.11 (br. s., 1H), 4.36 - 4.55 (m, 1H), 4.09 (t, J = 8.4 Hz, 2H), 3.83 (d, J = 7.8 Hz, 2H), 3.55 (d, J = 2.3 Hz, 6H), 2.41 (br. s., 1H), 2.18 (d, J = 8.8 Hz, 3H), 1.88 - 2.10 (m, 6H), 1.73 - 1.88 (m, 5H), 1.68 (br. s., 1H), 1.49 (d, J = 10.1 Hz, 1H), 1.37 (d, J = 11.9 Hz, 1H), 1.19 - 1.31 (m, 1H), 0.95 (d, J = 6.6 Hz, 3H), 0.86 (t, J = 7.2 Hz, 6H), 0.70 (d, J = 6.2 Hz, 3H). MS (ESI): 817 [M+H]⁺.

Example 6; Methyl [(l_lS)-2-methyl-l-({(2₁S^,,3a ^*,7a5)-2-[4-(6-{2-[(25',3a₁S^,,7a_lS)-l-((25}-3- methyl-2- { [(methyloxy)carbonyl]amino } butanoyl)octahydro- 1 H-indol-2-yl] - 1H- benzimidazol-5 -y 1 } -2-naphthalenyl)- 1 H-imidazol-2-yl]octahydro- 1 H-indol- 1 - yl}carbonyl)propyl]carbamate

The tile compound was obtained from methyl [(15)-2-methyl-l-({(2_iS',3aS',7a_JS)- 2-[5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-benzimidazol-2-yl]octahydro-lH- indol-l-yl}carbonyl)propyl]carbamate, intermediate 7B, (44.8 mg, 0.085 mmol) and methyl [(15)-l-({(25,3a5',7a5)-2-[4-(6-bromo-2-naphthalenyl)-lH-imidazol-2- yl]octahydro-lH-indol-l-yl}carbonyl)-2-methylpropyl]carbamate (intermediate 6C) (43 mg, 0.078 mmol) following Suzuki coupling procedure (described in example 5) in 0.022 g (32%) yield.

'H NMR (DMSO-d₆) δ: 12.24 (d, J = 18.5 Hz, 1H), 11.83 (br. s., 1H), 8.09 - 8.34 (m, 2H), 7.78 - 8.04 (m, 5H), 7.46 - 7.70 (m, 5H), 7.33 (d, J = 8.2 Hz, 1H), 5.11 (br. s., 2H), 4.36 - 4.55 (m, 1H), 4.09 (t, J = 8.4 Hz, 1H), 3.83 (d, J = 7.8 Hz, 2H), 3.55 (d, J = 2.3 Hz, 6H), 2.41 (br. s., 2H), 2.18 (d, J = 8.8 Hz, 3H), 1.88 - 2.10 (m, 6H), 1.73 - 1.88 (m, 8H), 1.68 (br. s., 1H), 1.49 (d, J = 10.1 Hz, 1H), 1.37 (d, J = 11.9 Hz, 1H), 1.19 - 1.31 (m, 1H), 0.95 (d, J = 6.6 Hz, 3H), 0.86 (t, J = 7.2 Hz, 6H), 0.70 (d, J = 6.2 Hz, 3H). MS (ESI): 871 [M+H]⁺

Example 7; Methyl [(15 -2-methyl-l-({(25,3a5,7a5)-2-[5-(6-{2-[(8,S)-7-((25)-3-methyl- 2-{[(methyloxy)carbonyl]amino}butanoyl)-l,4-dioxa-7-azaspiro[4.4]non-8-yl]-lH- imidazol-4-yl}-2-naphthalenyl)-lH-benzimidazol-2-yl]octahydro-lH-indol-l- y 1 } carbony l)propy 1] carbamate

Synthesized from methyl [(15)-2-methyl-l-({(25,3a5',7a5 -2-[5-(4,4,5,5- tetramethyl- 1 ,3 ,2-dioxaborolan-2-yl)- 1 H-benzimidazol-2~yl]octahydro- 1 H-indol- 1 - yI}carbonyl)propyl]carbamate, intermediate 7B (0.090 g, 0.172 mmol), methyl [(15)-1- ({(85)-8-[4-(6-bromo-2-naphthalenyl)-lH-imidazol-2-yl]-l,4-dioxa-7-azaspiro[4.4]non- 7-yl}carbonyl)-2-methylpropyl]carbamate, intermediate 6B (82 mg, 0.147 mmol) following procedure from example 1, yield 0.037 g, (29%) yield. 1H NMR (DMSO-d₆) δ: 12.24 (d, J = 19.3 Hz, 1H), 11.91 (br. s., 1H), 8.22 (d, J = 4.9 Hz, 1H), 8.14 (d, J = 15.0 Hz, 1H), 7.88 - 7.99 (m, 4H), 7.78 - 7.88 (m, 2H), 7.49 - 7.70 (m, 5H), 7.32 (d, J = 8.6 Hz, 1H), 5.1 1 (d, J = 7.4 Hz, 2H), 4.44 (br. s., 1H), 3.70 - 4.14 (m, 9H), 3.55 (s, 6H), 2.45 (d, J = 7.8 Hz, 3H), 2.21 (br. s., 1H), 1.59 - 2.05 (m, 5H), 1.48 (br. s., 1H), 1.37 (d, J = 12.9 Hz, 1H), 1.23 (br. s., 1H), 0.77 - 0.91 (m, 9H), 0.70 (d, J = 5.9 Hz, 3H). MS (ESI): 876 [M+H]⁺

Example 8; Methyl [(l S)-l-({(2S)-4,4-difluoro-2-[4-(6-{2-[(8S)-7-((2S)-3-methyl-2- {[(methyloxy)carbonyl]amino}butanoyl)-l,4-dioxa-7-azaspiro[4.4]non-8-yl]-lH- benzimidazol-5-yl}-2-quinolinyl)-lH-imidazol-2-yl]-l-pyrrolidinyl}carbonyl)-2- meth lpropy 1] carbamate

To a Schlenk flask were added methyl [(l S)-2-methyl-l-({(8S)-8-[5-a(4,4,5,5- tetramethyl- 1 ,3 ,2-dioxaborolan-2-yl)- 1 H-benzimidazol-2-yl]- 1 ,4-dioxa-7- azaspiro[4.4]non-7-yl}carbonyl)propyl]carbamate (intermediate 7A) (54.2mg, 0.103 mmol), methyl [(l S)-l-({(2S)-2-[4-(6-bromo-2-quinolinyl)-lH-imidazol-2-yl]-4,4- difluoro-l-pyrrolidinyl}carbonyl)-2-methylpropyl]carbamate (intermediate 18A) (50 mg, 0.093mmol), NaHC0₃ (37.8mg, 0.45 mml) and PdCl₂(dppf) (15mg). The flask was purged with N₂ (3X) before addition of a mixture of DME/water (2.5mL/0.65mL). The resulting suspension was further degassed (3x) before heating to 80 °C for 18 hrs, then cooled down to RT and extracted with EtOAc (3X). The combined organic phases were dried over MgS0₄. Solvents were evaporated and product purified by HPLC (5 to 80 % acetonitrile/water (0.2% NH4OH) to give methyl [(lS)-l-({(2S)-4,4-difluoro-2-[4-(6-{2- [(8S)-7-((2S)-3-methyl-2-{[(methyloxy)carbonyl]amino}butanoyl)-l,4-dioxa-7- azaspiro[4.4]non-8-yl] - 1 H-benzimidazol-5 -yl } -2-quinolinyl)- 1 H-imidazol-2-yl]- 1 - pyrrolidinyl}carbonyl)-2-methylpropyl]carbamate (20mg, 24%). 1H NMR (400MHz, CHLOROFORM-d) δ. 11.02 - 10.44 (m, 1 H), 8.23 - 7.78 (m, 4 H), 7.80 - 7.30 (m, 4 H), 5.79 - 5.42 (m, 3 H), 4.53 - 4.16 (m, 3 H), 4.16 - 3.84 (m, 6 H), 3.84 - 3.63 (m, 7 H), 3.35 (dd, J= 7.7, 13.6 Hz, 1 H), 2.93 - 2.67 (m, 1 H), 2.57 (dd, J= 8.8, 13.5 Hz, 1 H), 2.31 - 1.47 (m, 5 H), 1.22 - 0.97 (m, 2 H), 0.97 - 0.70 (m, 12 H). HRMS for

C43H50F2N9O8 (M + H)⁺ calc: 858.3750, found: 850.3751.

Example 9; Methyl [(lS)-2-methyl-l-({(2S)-2-[4-(6-{2-[(8S)-7-((2S)-3-methyl-2- {[(methyloxy)carbonyl]amino}butanoyl)-l,4-dioxa-7-azaspiro[4.4]non-8-yl]-lH- benzimidazol-5-yl}-2-quinolinyl)-lH-imidazol-2-yl]-l- pyrrolidinyl } carbonyl)propyl] carbamate

Reaction of methyl [(1 S)- 1 -({(2S)-2- [4-(6-bromo-2-quinoIinyl)- 1 H-imidazol-2- yl]-l-pyrrolidinyl}carbonyl)-2-methylpropyl]carbamate, intermediate 18B (1 lOmg, 0.22 mmol) and methyl [(lS)-2-methyl-l-({(8S)-8-[5-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-lH-benzimidazol-2-yl]-l,4-dioxa-7-azaspiro[4.4]non-7- yl}carbonyl)propyl]carbamate (intermediate 7A) (116mg, 0.22mmol) was conducted as described in example 8, yielding 40mg (21%) of the title compound. ^!H NMR (400MHz, CHLOROFORM-d) δ. 11.01 - 10.59 (m, 1 H), 8.37 - 7.77 (m, 5 H), 7.77 - 7.28 (m, 4 H), 5.53 (br. s., 3 H), 5.38 (br. s., 1 H), 4.34 (br. s., 2 H), 4.26 - 3.57 (m, 12 H), 3.32 (br. s., 1 H), 2.88 (br. s., 1 H), 2.55 (dd, J= 8.7, 13.4 Hz, 1 H), 2.47 - 1.48 (m, 8 H), 1.13 - 0.66 (m, 12 H). HRMS for C43H52N908 (M + H)⁺ calc: 822.3939, found: 822.3937.

Example 10; Methyl [(lS)-2-methyl-l-({(2S,3aS,7aS)-2-[4-(6-{2-[(8S)-7-((2S)-3- methyl-2-{[(methyloxy)carbonyl]amino}butanoyl)-l,4-dioxa-7-azaspiro[4.4]non-8 lH-benzimidazol-5-yl}-2-quinolinyl)-lH-imidazol-2-yl]octahydro-lH-indol-l- yl } carbonyl)propyl] carbamate

Title compound (yield 21 mg) was obtained from methyl [(lS)-l- ({(2S,3aS,7aS)-2-[4-(6-bromo-2-quinolinyl)-lH-imidazol-2-yl]octahydro-lH-indol-l- yl}carbonyl)-2~methylpropyl]carbamate, intermediate 18C and methyl [(lS)-2-methyl- l-({(8S)-8-[5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-benzimidazol-2-yl]-l,4- dioxa-7-azaspiro[4.4]non-7-yl}carbonyl)propyl]carbamate (intermediate 7A), using procedure outlined in example 8. *H NMR (400MHz, CHLOROFORM-d) δ. 11.55 - 10.58 (m, 1 H), 8.44 - 7.66 (m, 5 H), 7.72 - 7.20 (m, 4 H), 5.71 (br. s., 2 H), 5.54 (t, J= 7.9 Hz, 1 H), 5.31 (br. s., 1 H), 4.55 - 4.13 (m, 3 H), 4.13 - 3.84 (m, 5 H), 3.88 - 3.52 (m, 7 H), 3.32 (d, J= 7.0 Hz, 1 H), 3.06 (br. s., 1 H), 2.56 (dd, J= 8.7, 13.4 Hz, 3 H), 2.36 - 1.42 (m, 10 H), 1.28 (br. s., 1 H), 1.16 - 0.50 (m, 12 H). ES LC-MS m/z =876.5 (M+H)⁺

Example 11; Methyl [(15)-2^ε Ι-1-({(85 -8-[4-(6-{2-[(85)-7-((2 )-3-_Με 1-2- {[(methyloxy)carbonyl]amino}butanoyl)-l,4-dioxa-7-azaspiro[4.4]non-8-yl]-lH- benzimidazol-5-yl}-2-naphthalenyl)-lH-imidazol-2-yl]-l,4-dioxa-7-azaspiro[4.4]non-7- y 1 } carbony l)propy 1] carbamate

The title compound was synthesized from methyl [(l<S)-l-({(85)-8-[4-(6-bromo- 2-naphthalenyl)-lH-imidazol-2-yl]-l,4-dioxa-7-azaspiro[4.4]non-7-yl}carbonyl)-2- methylpropyl]carbamate(0.088 g, 0.158 mmol) and methyl [(15)-2-methyl-l-({(8S)-8-[5- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-benzimidazol-2-yl]-l,4-dioxa-7- azaspiro[4.4]non-7-yl}carbonyl)propyl]carbamate (0.083 g, 0.158 mmol) following a procedure analogous to one described in example 5 in 0.037 g, (29%) yield. Ή NMR (DMSO-d₆) δ: 12.34 (d, J = 18.9 Hz, 1H), 11.92 (br. s., 1H), 8.23 (br. s., 1H), 8.13 (s, 1H), 7.92 (br. s., 4H), 7.82 (d, J = 9.6 Hz, 1H), 7.52 - 7.69 (m, 3H), 7.27 - 7.38 (m, 2H), 5.19 (t, J = 8.2 Hz, 1H), 5.10 (t, J - 8.2 Hz, 1H), 3.85 - 4.18 (m, 14H), 3.69 - 3.84 (m, 2H), 3.55 (s, 6H), 2.37 - 2.47 (m, 2H), 1.80 - 2.05 (m, 2H), 0.72 - 0.93 (m, 12H). MS , (ESI): 879 [M+H]⁺.

Example 12; methyl [(15)-2-methyl-l-({(25,3a5^*,7a5)-2-[4-(7-{2-[(8₁S)-7-((2 )-3-methyl- 2-{[(methyloxy)carbonyl]amino}butanoyl)-l,4-dioxa-7-azaspiro[4.4Jnon-8-yl]-lH- benzimidazol-5-yl}-3-isoquinolinyl)-lH-imidazol-2-yl]octahydro-lH-indol-l- 1 } carbony l)propy 1] carbamate

A mixture of methyl [(l₁S)-l-({(2,S',3a5',7a5)-2-[4-(7-bromo-3-isoquinolinyl)-lH- imidazol-2-yl]octahydro-lH-indol-l-yl}carbonyl)-2-methylpropyl]carbamate

(intermediate 26) (60 mg, 0.11 mmol), methyl [(15)-2-methyl-l-({(85)-8-[5-(4,4,5,5- tetramethyl- 1 ,3,2-dioxaborolan-2-yl)- lH-benzimidazol-2-yl]- 1 ,4-dioxa-7- azaspiro[4.4]non-7-yl}carbonyl)propyl]carbamate (intermediate 7A), (60 mg, 0.11 mmol), prepared as described in scheme I, sodium acetate (44 mg, 0.54 mmol) and [1,1 '- Bis(diphenyphosphino)ferrocene]-dichloropalladium (dichloromethane adduct) (9 mg, 0.01 mmol) was suspended in 1 ,2-dimethoxyethane (0.8 mL) and water (0.2 mL) and the mixture degassed with nitrogen and heated to 80 °C in a sealed tube for 18 h. The reaction was partitioned between ethyl acetate and water, the aqueous layer extracted with ethyl acetate and the combined organic layers dried over anhydrous magnesium sulfate and concentrated in vacuo, whereupon it was determined that the reaction was incomplete. To the crude residue was added additional sodium acetate (44 mg, 0.54 mmol) and [l,l '-Bis(diphenyphosphino)ferrocene]-dichloropalladium (dichloromethane adduct) (36 mg, 0.04 mmol) and the reaction resubjected under the same conditions. After 18 h, the reaction was cooled to room temperature and partitioned between dichloromethane and water. The aqueous layer was extracted with dichloromethane and the combined organic layers were dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by C_\$ reverse-phase HPLC, eluting with 10-90% water/acetonitrile/0.1% formic acid. Additional purification was then carried out by Ci₈ reverse phase HPLC on a 20 x 150 mm column eluting with 40% water/acetonitrile/0.2%) NH OH to afford the title compound as an off-white solid (10 mg, 10% yield). Ή NMR (400 MHz, DMSO-i¾) δ ppm 12.19 - 12.53 (m, 2 H) 11.75 (br. s., 1 H) 9.09 - 9.50 (m, 1 H) 8.25 - 8.49 (m, 1 H) 7.78 - 8.23 (m, 3 H) 7.16 - 7.74 (m, 4 H) 4.93 - 5.29 (m, 2 H) 4.40 (br. s., 1 H) 3.70 - 4.22 (m, 7 H) 3.55 (s, 6 H) 2.25 - 2.42 (m, 2 H) 2.16 (br. s., 1 H) 1.79 - 2.04 (m, 5 H) 1.56 - 1.82 (m, 4 H) 1.14 - 1.58 (m, 5 H) 0.61 - 0.97 (m, 12 H) LC-MS: ESI 876.36 (M+H)⁺.

Scheme VIII

(S)-2-(2-f6-bromonaphthalen-2-yl -2-oxoethyQ 1-tert-butyl pyrrolidine- 1 ,2-dicarboxylate

2-Bromo-l-(6-bromo-2-naphthalenyl)ethanone (lg, 3.05 mmol), DIEA (0.8 ml,4.57 mmol)and N-[(methyloxy)carbonyl]-L-valyl-L-proline (787 mg, 3.66 mmol) were dissolved in acetonitrile (10 ml) and the reaction was stirred at RT for 12h, afterwards solution was concentrated and product purified on silica to provide pure title compound. Yield : 85%; ES LC-MS m/z = 463 (M+H)⁺;

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.40 (s, 1 H), 8.08 (br. s., 1 H), 7.99 (dd, J=8.6, 3.0 Hz, 1 H), 7.85 (d, J=8.8 Hz, 2 H), 7.61 - 7.77 (m, 1 H), 5.29 - 5.73 (m, 2 H), 4.41 - 4.55 (m, 1 H), 3.55 - 3.68 (m, 1 H),3.37 - 3.54 (m, 1 H), 2.30 - 2.38 (m, 2 H), 2.05 - 2.17 (m, 1 H), 1.87 - 2.01 (m, 1 H), 1.47 (d, J=6.4 Hz, 9 H).

(S)-tert-butyl 2-(^'5-(6-bromonaphthalen-2-yl)-lH-imidazol-2-yl)pyrrolidine-l-carboxylate (77-2

(S)-2-(2-(6-bromonaphthalen-2-yl)-2-oxoethyl) 1 -tert-butyl pyrrolidine- 1 ,2- dicarboxylate 77-1 (1.2g, 2.6 mmol) and ammonium acetate (2.3 g, 30.5 mmol) were dissolved in 1,4-dioxane (4ml) and degassed. The reaction was microwaved at 145°C for 30min.The solvent was evaporated to dryness and water was added to precipitate out the compound used as is in the next step.Yield : 44.5%; ES LC-MS m/z = 443 (M+H)⁺; fSVtert-butyl-2-(5-(6-f2-ff2SJaS aSVl-f(SV2-f(methoxycarbonvnaminoV

methylbutanovnoctahvdro-lH-indol-2-ylVlH-benzord1imidazol-6-yl¼aphthalen-2-v lH-imidazol-2-yl)pyrrolidine-l -carboxylate (36-77-1), Scheme VIII

(S)-tert-butyl 2-(5-(6-bromonaphthalen-2-yl)-lH-imidazol-2-yl)pyrrolidine-l- carboxylate 77-2 (750mg, 1.695 mmol), methyl ((R)-3-methyl-l-oxo-l-((2S,3aS,7aS)-2- (6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-benzo[d]imidazol-2-yl)octahydro- lH-indol-l-yl)butan-2-yl)carbamate (1.3g, 2.54 mmol) and Na₂C0₃ (3.39 ml, 3.39 mmol) were dissolved in 1,4-dioxane (15 ml). The mixture was degassed and PdCl₂(dppf)- CH₂CI₂ (124 mg, 0.170 mmol) was added and heated at 135°C for 12h. The product was purified on silica. Yield : 38.8%; ES LC-MS m/z = 760 (M+H)⁺;

^!H NMR (400 MHz, DMSO-d6) S ppm 11.71 - 12.36 (m, 1 H), 8.08 - 8.34 (m, 2 H), 7.95 (d, J=9.9 Hz, 4 H),7.64 (br. s., 3 H), 7.29 (br. s., 1 H), 6.90 (br. s., 1 H), 5.11 (br. s., 1 H), 4.81 (br. s., 1 H), 4.44 (br. s., 1 H), 3.72- 4.07 (m, 2 H), 3.48 - 3.63 (m, 3 H), 3.37 (br. s., 1 H), 3.19 - 3.30 (m, 1 H), 2.69 (s, 4 H), 2.37 - 2.47 (m, 1 H),2.21 (br. s., 2 H), 1.94 (br. s, 5 H), 1.76 (d, J=7.7 Hz, 5 H), 1.27 - 1.49 (m, 9 H), 0.60 - 0.96 (m, 5 H).

Methyl ((SV3-methyl-l-oxo-l-rC2SJaS,7aS)-2-r6-(6-r2-^S)-pyrrolidin-2-yl)-lH- imidazol-5-yl)naphthalen-2-yl)-lH-benzo d1imidazol-2-yl)octahydro-lH-indol-l- yl butan-2-vncarbamate f 36-77-2^{^})

To 36-77-1 (500 mg, 0.658 mmol) in tetrahydrofuran (THF) (15.00 ml) was slowly added concentrated HCl (8.48 ml, 33.9 mmol).The solution was stirred for 6h at rt and solvents were evaporated yielding title compound 36-77-2 in 31.3% yield; ES LC- MS m/z = 660 (M+H)⁺;

Example 13; Methyl ((S)-l-((2S,3aS,7aS)-2-(6-(6-(2-((S)-l-((R)-2-(dimethylamino)-2- phenylacetyl)pyrrolidin-2-yl)-lH-imidazol-5-yl)naphthalen-2-yl)-lH-benzo[d]imidazol- 2-yl)octahydro- lH-indol- 1 -yl)-3-methyl- 1 -oxobutan-2-yl)carbamate

To crude methyl ((R)-3-methyl-l-oxo-l-((2S,3aS,7aS)-2-(6-(4,4,5,5-tetramethyl- 1 ,3 ,2-dioxaborolan-2-yl)- 1 H-benzo[d] imidazol-2-yl)octahydro- 1 H-indol- 1 -yl)butan-2- yl)carbamate 36-77-2 (100 mg, 0.152 mmol) in Ν,Ν-Dimethylformamide (DMF) (1 mL) was added (R)-2-(dimethylamino)-2-phenylacetic acid (27.2 mg, 0.152 mmol), EDC (29.1 mg, 0.152 mmol), HOBT (23.21 mg, 0.152 mmol) and DIEA (0.026 mL, 0.152 mmol). The reaction mixture was stirred at rt for 4h. The reaction was partitioned between 50 mL of ethyl acetate and 20 mL of aqueous saturated NaHC0₃. The organic phase was separated and dried over sodium sulphate and evaporated in vacuo to give the crude product, which was further purified on a RP HPLC using 10-80% H₂0 (containing 0.2% H₃/ & CH₃CN containing 0.2% NH₃ as gradient) to afford the title compound as a light yellow solid in 24.1% yield. ES LC-MS m/z = 822 (M+H)⁺;

Ή NMR (400 MHz, DMSO-d6) δ ppm 12.27 (br. s., 1 H), 11.80 - 12.06 (m, 1 H), 8.20 (s, 3 H), 7.94 (br. s., 4H), 7.80 - 7.88 (m, 1 H), 7.56 - 7.67 (m, 3 H), 7.53 (d, J=8.2 Hz, 1 H), 7.46 (d, J=6.9 Hz, 2 H), 7.30 - 7.40 (m,2 H), 6.83 - 7.10 (m, 1 H), 5.07 - 5.16 (m, 1 H), 5.04 (t, J=5.3 Hz, 1 H), 4.44 (br. s., 1 H), 4.06 - 4.27 (m, 1 H),3.97 - 4.05 (m, 1 H), 3.85 (t, J=9.0 Hz, 1 H), 3.59 - 3.73 (m, 1 H), 3.55 (s, 3 H), 2.34 - 2.44 (m, 2 H), 2.23 (br.s., 1 H), 2.14 (d, J=4.3 Hz, 6 H), 2.02 (br. s., 4 H), 1.77 (br. s., 4 H), 1.56 - 1.74 (m, 1 H), 1.48 (br. s., 1 H),1.33 - 1.44 (m, 1 H), 1.26 (br. s., 1 H), 0.85 (d, J=6.5 Hz, 3 H), 0.70 (d, J=6.5 Hz, 3 H).

Example 14; Methyl ((S)-3-methyl-l-oxo-l-((2S,3aS,7aS)-2-(6-(6-(2-((S)-l-((R)-2- phenyl-2-(pyrrolidin- 1 -yl)acetyl)pyrrolidin-2-yl)- 1 H-imidazol-5 -yl)naphthalen-2-yl)- 1 H- benzo [d] imidazol-2-yl)octahydro- 1 H-indol- 1 -yl)butan-2-y l)carbamate

The title compound was prepared in a manner similar to one described in example 13, except that (R)-2-phenyl-2-(pyrrolidin-l-yl)acetic acid was used. Yield: 23.4%; ES LC-MS m/z = 848 (M+H)⁺

'H NMR (400 MHz, DMSO-d6) $ ppm 12.27 (br. s., 1 H), 11.78 - 12.03 (m, 1 H), 8.24 (s, 3 H), 7.94 (br. s., 5H), 7.45 - 7.70 (m, 6 H), 7.25 - 7.41 (m, 3 H), 6.81 - 7.11 (m, 1 H), 5.02 (s, 2 H), 4.44 (br. s., 1 H), 4.29 (s, 1H), 4.03 (br. s., 1 H), 3.81 - 3.94 (m, 1 H), 3.55 (s, 3 H), 2.53 - 2.69 (m, 1 H), 2.33 - 2.47 (m, 5 H), 2.21 (br. s.,1 H), 2.04 (br. s, 4 H), 1.78 (br. s., 4 H), 1.62 (br. s., 5 H), 1.48 (br. s., 1 H), 1.26 (br. s., 2 H), 0.64 - 0.97 (m,6 H).

Scheme IX

(2S,3aS,7aS -2-(6-bromonaphthalen-2-ylV2-oxoethyl l-(^'(^'S^N)-2-((methQxycarbonvnamino^')-3- methylbutanoynoctahvdro-lH-indole-2-carboxylate 69-1 was prepared in a manner similar to the procedure described for 77-1. Yield : 92%; ES LC-MS m/z = 574 (M+H)⁺;

Ή NMR (400 MHz, CHLOROFORM-d) δ ppm 8.38 (s, 1 H), 8.06 (d, J=1.3 Hz, 1 H), 7.98 (dd, J=8.7, 1.5 Hz,l H), 7.83 (d, J=8.5 Hz, 2 H), 7.65 (dd, J=8.7, 1.8 Hz, 1 H), 5.66 (d, J-16.3 Hz, 1 H), 5.35 (d, J=16.3 Hz, 1H), 4.64 (t, J=9.1 Hz, 1 H), 4.26 (dt, J=l 1.6, 6.0 Hz, 1 H), 4.14 (t, J=9.1 Hz, 1 H), 3.68 - 3.77 (m, 1 H), 3.67(s, 2 H), 3.10 - 3.19 (m, 1 H), 2.40 - 2.52 (m, 1 H), 2.29 - 2.38 (m, 1 H), 1.91 - 2.08 (m, 2 H), 1.54 - 1.62 (m, 3H), 1.47 (d, J=6.7 Hz, 3 H), 1.20 - 1.38 (m, 2 H), 0.98 (dd, J=6.6, 4.1 Hz, 6 H).

Methyl ((S )- 1 -(T2S .3 aS.7aS >2-(5-(6-bromonaphthalen-2-yl 1 H-imidazol-2-vnoctahydro- 1 H-indol- 1 - yl)-3-methyl- 1 -oxobutan-2-yl)carbamate 69-2 was prepared in a manner similar to 77-2. Yield :

35.6%; ES LC-MS m/z = 554 (M+H)⁺

Ή NMR (400 MHz, CHLOROFORM-d) δ ppm 7.99 (br. s., 1 H), 7.68 - 7.89 (m, 3 H), 7.52 - 7.64 (m, 1 H),5.29 (br. s., 2 H), 4.23 - 4.41 (m, 1 H), 4.10 - 4.22 (m, 1 H), 3.61 - 3.76 (m, 3 H), 3.41 (br. s., 1 H), 2.46 (br. s.,2 H), 1.95 (br. s., 2 H), 1.77 (br. s., 3 H), 1.58 (br. s., 4 H), 1.17 - 1.37 (m, 2 H), 1.07 (d, J=6.6 Hz, 1 H), 0.75 -1.00 (m, 6 H)

Meth^yl (^,rSVl-((2S.3aSJaSV2-r5-(6-r3.4-diaminophenvnnar)hthalen-2-ylVlH-imidazol-2- vDoctahydro- 1 H-indol- 1 -yl)-3-methyl- 1 -oxobutan-2-yl carbamate 83-1 was prepared in a manner similar to 36-77-1. Yield: 82%; ES LC-MS m/z = 582 (M+H)⁺ iSVtert-butyl 2- 6-(6-r2-rr2S.3aS.7aS)-l-rrSV2-^methoxycarbonvnaminoV3- methylbutanoyDoctahydro-lH-indol^-yD-lH-imidazol-S-yDnaphthalen^-yD-lH-benzoldlimidazol- 2-vDpyrrolidine- 1 -carboxylate 85-1 was prepared by stirring methyl ((S)-l-((2S,3aS,7aS)-2-(5-(6- (3,4-diaminophenyl)naphthalen-2-yl)-lH-imidazol-2-yl)octahydro-lH-indol-l-yl)-3-methyl-l- oxobutan-2-yl)carbamate (3 g, 5.17 mmol), (S)-l-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid (1.112 g, 5.17 mmol), HATU (1.964 g, 5.17 mmol) and DIEA (0.902 ml, 5.17 mmol) dissolved in Ν,Ν-Dimethylformamide (DMF) (10 ml) at RT for 12h. The solvent was evaporated to dryness and the crude was taken in acetic acid and heated to 70°C for 4h. The acetic acid was then evaporated and purified on a silica plug.

Yield : 53.5%; ES LC-MS m/z = 761 (M+H)⁺

'H MR (400 MHz, DMSO-d6) ppm 12.40 (br. s., 1 H), 11.73 (br. s., 1 H), 8.09 - 8.27 (m, 2 H), 7.89 - 8.02(m, 3 H), 7.75 - 7.86 (m, 2 H), 7.42 - 7.68 (m, 4 H), 4.83 - 5.14 (m, 2 H), 4.39 (br. s., 1 H), 3.85 (t, J=8.9 Hz, 1H), 3.55 (s, 4 H), 3.43 (d, J=9.9 Hz, 1 H), 2.34 (br. s., 3 H), 2.10 - 2.20 (m, 1 H), 1.92 (br. s., 6 H), 1.77 (br. s.,3 H), 1.40 (s, 6 H), 1.23 (br. s., 1 H), 1.10 (s, 5 H), 0.74 - 0.92 (m, 6 H)

Methyl ((S S-methyl-l-o o-l-^SJaS aS^^-rS-re- -rCSVpyrrolidin^-yl lH-benzordlimidazol-e- yl)naphthalen-2-yl^')-lH-imidazol-2-yl)octahvdro-lH-indol-l-yl butan-2-yl)carbamate 85-2 was prepared by similar procedure to one described for 36-77-2. Yield: 38.1%; ES LC-MS m/z = 661 (M+H)⁺

Example 15; methyl ((S)-l-((2S,3aS,7aS)-2-(5-(6-(2-((S)-l-((R)-2-(dimethylamino)-2- phenylacetyl)pyrrolidin-2-yl)-lH-benzo[d]imidazol-6-yl)naphthalen-2-yl)-lH-imidazol-2- yl)octahydro-lH-indol-l-yl)-3-methyl-l-oxobutan-2-yl)carbamate

. Example 15 (91-1) was prepared in a fashion similar to one described for 82-1 (Scheme

VIII) in a 25% yield. ES LC-MS m/z = 822 (M+H)⁺;

'H NMR (400 MHz, DMSO-d6) S ppm 12 A3 (br. s., 1 H), 11.75 (br. s., 1 H), 8.10 - 8.28 (m, 3 H), 7.93 (d,J=8.3 Hz, 5 H), 7.61 (br. s., 2 H), 7.52 (d, J=7.9 Hz, 1 H), 7.41 - 7.49 (m, 2 H), 7.26 - 7.41 (m, 2 H), 6.67 -6.87 (m, 1 H), 5.13 (dd, J=7.6, 3.1 Hz, 1 H), 5.00 (t, J=8.6 Hz, 1 H), 4.40 (br. s., 1 H), 4.03 (s, 2 H), 3.85 (br.s., 2 H), 3.44 - 3.64 (m, 6 H), 3.37 (d, J=17.8 Hz, 5 H), 2.34 (d, J=12.2 Hz, 2 H), 1.91 (br. s., 3 H), 1.78 (d,J=4.6 Hz, 4 H), 1.09 - 1.56 (m, 4 H), 0.88 (d, J=6.2 Hz, 7 H) Example 16; Methyl ((S)-3-methyl-l-oxo-l-((2S,3aS,7aS)-2-(5-(6-(2-((S)-l-((R)-2-phenyl-2-

( yrrolidin-l-yl)acetyl)pyrrolidin~2-yl)-lH-te

yl)octahydro- 1 H-indol- 1 -yl)butan-2-yl)carbamate

Example 16 (91-2, Scheme IX) was prepared according to procedure for 82-1 (Scheme VIII) in 25% yield. ES LC-MS m/z = 848 (M+H)⁺;

'H NMR (400 MHz, DMSO-d€) S ppm 11.59 - 12.58 (m, 1 H), 8.10 - 8.25 (m, 3 H), 7.93 (d, J=8.4 Hz, 3 H),7.82 (d, J-7.9 Hz, 1 H), 7.55 - 7.66 (m, 2 H), 7.47 - 7.55 (m, 2 H), 7.32 - 7.41 (m, 2 H), 7.19 - 7.32 (m, 1 H),6.61 - 6.84 (m, 1 H), 5.09 - 5.19 (m, 1 H), 4.91 - 5.06 (m, 1 H), 4.41 (br. s., 2 H), 4.04 (br. s., 1 H), 3.85 (br. s.,2 H), 3.55 (s, 6 H), 3.36 (br. s., 3 H), 2.26 - 2.44 (m, 3 H), 2.01 - 2.23 (m, 4 H), 1.92 (br. s., 4 H), 1.77 (br. s., 2H), 1.61 (br. s., 4 H), 1.48 (br. s., 2 H), 1.23 (br. s., 1 H), 0.88 (d, J=6.1 Hz, 6 H)

Scheme X

(S)-2-(6-bromonaphthalen-2-yl)-2-oxoethyl l-((S)-2-((methoxycarbonyl)amino)-3- methylbutanoyl)pyrrolidine-2-carboxylate 62-1, Scheme X was prepared analogously to 77-1 (Scheme VIII) in 84% yield. ES LC-MS m/z = 520 (M+H)⁺

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.90 - 1.09 (m, 6 H), 2.06 - 2.13 (m, 2 H), 2.15 - 2.29 (m, 1 H), 2.30 - 2.47 (m, 2 H), 3.64 - 3.70 (m, 3 H), 3.70 - 3.79 (m, 1 H), 3.79 - 3.90 (m, 1 H), 4.29 - 4.43 (m, 1 H), 4.60 - 4.81 (m, 1 H), 5.28 - 5.41 (m, 2 H), 5.60 - 5.72 (m, 1 H), 7.58 - 7.71 (m, 1 H), 7.84 (d, J=8.7 Hz, 2 H), 7.91 - 8.03 (m, 1 H), 8.02 - 8.12 (m, 1 H), 8.31 - 8.41 (m, 1 H).

Methyl (( S 1 - f (S V2-(5-f 6-bromonaphthalen-2-vD - 1 H-imidazol-2-y Opyrrolidin- 1 -ylV3-methyl- l-oxobutan-2-vDcarbamate 62-2, Scheme X was prepared similarly to 77-2 (Scheme VIII) in 49.1% yield. ES LC-MS m/z = 500 (M+H)⁺

'H MR (400 MHz, DMSO-d6 ) ( ppm 11.86 (br. s., 1 H), 8.21 (s, 1 H), 8.12 (d, J=1.5 Hz, 1 H), 7.94 (dd,J=8.7, 1.3 Hz, 1 H), 7.79 - 7.88 (m, 2 H), 7.64 (d, J=2.0 Hz, 1 H), 7.57 (dd, J=8.8, 2.0 Hz, 1 H), 7.32 (d, J=8.4 Hz, 1 H), 5.05 - 5.17 (m, 1 H), 3.99 - 4.15 (m, 1 H), 3.82 (br. s., 1 H), 3.28 - 3.35 (m, 4 H), 2.16 (br. s., 2 H), 1.99 (br. s., 3 H), 0.76 - 1.03 (m, 6 H). Methyl ((S)-\-(( S)-2-( 5-( 6-i3.4-diaminophenyl naphthalen-2-yl)- 1 H-imidazol-2-vnDyrrolidin- 1 - v0-3-methyl-l-oxobutan-2-v0carbamate 11-1, Scheme X was prepared similarly to 36-77-1 (Scheme VIII) in 47.4% yield. ES LC-MS /z = 527 (M+H)⁺

Ή NMR (400 MHz, DMSO-d6) S ppm 11.80 (br. s., 1 H), 8.15 (s, 2 H), 7.76 - 7.93 (m, 3 H), 7.58 (d, J-l .4 Hz,3 H), 7.32 (br. s., 1 H), 6.99 (d, J=l .7 Hz, 1 H), 6.86 (br. s., 1 H), 6.61 (d, J=8.0 Hz, 1 H), 5.11 (br. s., 1 H),4.65 (br. s., 2 H), 3.96 - 4.13 (m, 2 H), 3.83 (br. s., 1 H), 3.54 (s, 3 H), 2.16 (br. s., 3 H), 1.14 - 1.20 (m, 2 H),1.07 (s, 1 H), 0.82 - 1.01 (m, 6 H)

(2S,3aS.7aS)-tert-butyl 2-(6-(6-(2-rrSVl-(^'(SV2-(rmethoxycarbonvnaminoV3- methylbutanoy0pyrrolidin-2-yl^')-lH-imidazol-5-vnnaphthalen-2-yl^')-lH-benzord]imidazol-2- vDoctahydro- lH-indole- 1 -carboxylate X-1 was prepared analogously to 85-1 (Scheme IX).

Methyl ((S)-3-methyl-l-(rS)-2-(5-(^,6-f2-(^'r2S.3aS_<7aS)-octahvdro-lH-indol-2-yl -lH- benzord1imidazol-6-yl)naphthalen-2-yl)-lH-imidazol-2-yl pyrrolidin-l-yl)-l-oxobutan-2- vDcarbamate X-2 was prepared from X-1, analogously to procedure provided for 85-2 (Scheme IX).

Example 17; Methyl ((S)-l-((S)-2-(5-(6-(2-((2S,3aS,7aS)-l-((R)-2-(3-fluorophenyl)-2- (pyrrolidin-l-yl)acetyl)octahydro-lH-indol-2-yl)-lH-benzo[d]imidazol-6-yl)naphthalen- 2- - 1 H-imidazol-2-y l)pyrrolidin- 1 -y l)-3-methy 1- 1 -oxobutan-2-y l)carbamate

Example 17 was prepared in a manner similar to example 13 (Scheme VIII) in

15.2% yield. ES LC-MS m/z = 865(M+H)^{+ !}H NMR (400 MHz, DMSO-d6) δ ppm 11.67 - 12.42 (m, 2 H), 8.09 - 8.26 (m, 2 H), 7.75 - 8.04 (m, 5 H), 7.54 -7.71 (m, 3 H), 7.33 - 7.44 (m, 3 H), 7.08 - 7.22 (m, 1 H), 5.12 (dd, J=7.0, 3.2 Hz, 1 H), 5.02 (t, J=8.7 Hz, 1 H),4.23 (s, 1 H), 4.02 - 4.15 (m, 2 H), 3.84 (br. s., 2 H), 3.55 (s, 3 H), 2.30 (br. s., 4 H), 1.89 - 2.24 (m, 8 H), 1.44- 1.77 (m, 8 H), 1.21 - 1.44 (m, 3 H), 0.80 - 1.04 (m, 8 H)

Example 18; Methyl((S)-l-((S)-2-(5-(6-(2-((2S,3aS,7aS)-l-((R)-2-(diethylamino)-2- phenylacetyl)octahydro-lH-indol-2-yl)-lH-benzo[d]imidazol-6-yl)naphthalen-2-yl)-lH- imidazol-2-yl)pyrrolidin- 1 -yl)-3-methyl- 1 -oxobutan-2-yl)carbamate

Example 18 was prepared in a manner similar to example 13 in 16% yield. ES LC-MS m/z = 850 (M+H)⁺

^!H NMR (400 MHz, DMSO-d6) δ ppm 11.77 - 12.42 (m, 2 H), 8.07 - 8.30 (m, 2 H), 7.77 - 8.03 (m, 5 H), 7.53 -7.72 (m, 3 H), 7.41 - 7.53 (m, 2 H), 7.23 - 7.41 (m, 4 H), 5.12 (br. s., 2 H), 4.65 (s, 1 H), 4.09 (t, J=8.3 Hz, 1H), 3.84 (br. s., 3 H), 3.55 (s, 3 H), 3.39 - 3.44 (m, 1 H), 2.54 - 2.62 (m, 1 H), 2.45 (d, J=5.8 Hz, 2 H), 2.17 (br.s., 3 H), 1.99 (d, J=6.4 Hz, 5 H), 1.71 (br. s., 2 H), 1.43 (br. s., 2 H), 1.23 (br. s., 2 H), 0.68 - 1.01 (m, 14 H)s

Example 19; Methyl((S)-l-((S)-2-(5-(6-(2-((2S,3aS,7aS)-l-((R)-2-(diethylamino)-2-(2- methoxyphenyl)acetyl)octahydro-lH-indol-2-yl)-lH-benzo[d]imidazol-6-yl)naphthalen- 2-yl)- 1 H-imidazol-2-yl)pyrrolidin- 1 -yl)-3-methyl- 1 -oxobutan-2-yl)carbamate carbamate

Example 19 was prepared in a manner similar to example 13 in 8.26% yield. ES LC-MS m/z = 880 (M+H)⁺

¾ NMR (400 MHz, DMSO-dG) δ ppm 11.73 - 12.39 (m, 2 H), 8.22 (br. s., 2 H), 7.92 (br, s., 5 H), 7.63 (br. s.,3 H), 7.42 - 7.50 (m, 1 H), 7.24 - 7.37 (m, 2 H), 7.07 (d, J=8.3 Hz, 1 H), 6.95 (t, J=7.5 Hz, 1 H), 5.12 (d, J=3.6Hz, 1 H), 4.89 - 5.06 (m, 2 H), 4.09 (t, J=8.2 Hz, 1 H), 3.87 (s, 5 H), 3.54 (s, 3 H), 2.54 (s, 2 H), 2.40 (dt,J=13.6, 7.0 Hz, 2 H), 2.07 - 2.23 (m, 3 H), 1.92 - 2.07 (m, 5 H), 1.69 (br. s., 3 H), 1.41 - 1.58 (m, 2 H), 1.27 -1.40 (m, 1 H), 1.19 (br. s., 1 H), 0.83 - 1.01 (m, 8 H), 0.78 (t, J=7.0 Hz, 6 H).

Scheme XI

lJ-dimethylethvK2S.4SV2-r4-r6-bromo-2-naplithalenvn-lH-imidazol-2-yll-4-methyl-l- pyrrolidinecarboxylate 21-A1

To 2-bromo-l-(6-bromo-2-naphthalenyl)ethanone (1.6 g, 4.88 mmol) in dry acetonitrile (30 mL) was added DIPEA (0.852 mL, 4.88 mmol) and (4S)-1-{[(1,1- dimethylethyl)oxy]carbonyl}-4-methyl-L-proline (1.118 g, 4.88 mmol). The reaction was stirred at room temp overnight, solvents removed. The residue was dissolved in 1,4- dioxane (40 mL), added to a sealed reaction vessel containing ammonium acetate (3.76 g, 48.8 mmol) and stirred at 110 °C overnight. The solvent was removed and product purified on silica, eluted with 40-100% ethyl acetate in cyclohexane to furnish product as an off white foam/pale yellow gum in 35% yield. ES LC-MS m/z = 456/458 (M+H)⁺ l.l-dimethylethvK2S.4SV2-(4-r6-r3.4-diaminophenylV2-naphthalenvn-lH-imidazol-2- yl }-4-methyl- 1 -pyrrolidinecarboxylate 25-A1

To l,l-dimethylethyl (2S,4S)-2-[4-(6-bromo-2-naphthalenyl)-lH-imidazol-2-yl]- 4-methyl-l -pyrrolidinecarboxylate 21-A1 (0.81 g, 1.775 mmol) was added dry 1,4- dioxane (16 mL), 1M potassium carbonate (5.32 mL, 5.32 mmol), PdC12(dppf)-CH2C12 adduct (0.145 g, 0.177 mmol) and [2-amino-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)phenyl] amine (0.436 g, 1.864 mmol). The reaction was stirred under nitrogen at 100 °C for 1.5 hrs, then cooled and partitioned between DCM and water. The combined organics were purified on silica eluted with 0-20% 2M ammonia in MeOH in DCM to furnish product 25-A1 as a brown/yellow foam/solid in 74.6% yield. ES LC-MS m/z = 484 (M+H)⁺ U-dimethylethyl f2S,4SV4-meth^

[(methyloxy)carbonyll-L-valyl>-2-pyrrolidinylVlH-benzimidazol-5-yl1-2-naphthalenyl|- lH-imidazol-2-vP)- 1 -pyrrolidinecarboxylate 43-Al

To N-[(methyloxy)carbonyl]-L-valyl-(4S)-4-methyl-L-proline (1.628 g, 5.69 mmol) was added dry N,N-Dimethylformamide (DMF) (20 mL), DIPEA (2.98 mL, 17.06 mmol) and HATU (2.162 g, 5.69 mmol). The reaction was stirred for 5 mins then 1,1- dimethylethyl (2S,4S)-2-{4-[6-(3,4-diaminophenyl)-2-naphthalenyl]-lH-imidazol-2-yl}- 4-methyl-l -pyrrolidinecarboxylate 25-A1 (2.75 g, 5.69 mmol) in dry DMF (15ml) was added and the reaction stirred for 2 hours. Acetic Acid (40 mL) was added the reaction stirred at 80°C for 2 hrs. The solvent was removed and the material was purified on silica, eluted with 0-15% MeOH in DCM to give product 43-Al in 63% yield. ES LC- MS m/z = 735 (M+H)⁺

Methyl rri S)-2-methyl-l-q(2S.4SV4-methyl-2-r5-r6-(2-r(2S.4SV4-methyl-2- pyrrolidinyll-lH-imidazol-4-yll-2-naphthalenyl)-lH-benzimidazol-2-yll-l- pyrrolidinv carbonvDpropyllcarbamate 45-A1

To 1 , 1 -dimethylethyl (2S,4S)-4-methyl-2-(4-{6-[2-((2S,4S)-4-methyl-l-{N- [(methyloxy)carbonyl]-L-valyl}-2-pyrrolidinyl)-lH-benzimidazol-5-yl]-2-naphthalenyl}- lH-imidazol-2-yl)-l -pyrrolidinecarboxylate 43-Al (3.75 g, 5.11 mmol) was added 1,4- dioxane (40 mL) and 4M HCl in dioxane (40 mL, 5.11 mmol). The reaction was stirred for 1.5 hours then the solvent removed to furnish the product dihydrochloride as a pale orange solid in 74% yield. ES LC-MS m/z = 635 (M+H)⁺

Example 20; Methyl {(lS)-l-[((2S,4S)-2-{5-[6-(2-{(2S,4S)-l-[(2R)-2-(dimethylamino)-

2-phenylacetyl]-4-methyl-2-pyrrolidinyl}-lH-imidazol-4-yl)-2-naphthalenyl]-lH- benzimidazol-2-yl}-4-methyl-l-pyrrolidinyl)carbonyl]-2-methylpropyl}carbamate

To methyl [(1 S)-2-methyl-l-({(2S,4S)-4-methyl-2-[5-(6-{2-[(2S,4S)-4-methyl-2- pyrrolidinyl] - 1 H-imidazol-4-yl } -2-naphthalenyl)- lH-benzimidazol-2-yl]- 1 - pyrrolidinyl}carbonyl)propyl]carbamate 45-A1 (200 mg, 0.283 mmol) was added (2R)- (dimethylamino)(phenyl)ethanoic acid (53.3 mg, 0.297 mmol), dry N,N- Dimethylformamide (DMF) (4 mL), DIPEA (0.247 mL, 1.415 mmol) and then HATU (113 mg, 0.297 mmol). The reaction was then stirred at room temp overnight, followed by purification on RP HPLC, eluted with 30-85% MeCN (0.2% NH4OH) in water (0.2%

NH4OH), to furnish an off-white product in a 30.5% yield. ES LC-MS m/z = 795 (M+H)⁺

'H NMR (400 MHz, MeOD-d4) ( ppm 8.14 (br, 1 H), 8.08 (d, 1H), 7.92 (2, 3H), 7.82 (m, 3H), 7.64 (br, 2H), 7.52 (d, 2H), 7.40 (m, 4H), 6.93 (br, 1H), 5.16 (dd, 1H), 4.98 (dd, 1H), 4.30 (br t, 1H), 4.24 (d, 1H), 4.06 (br s, 1H), 4.80 (t, 1H), 3.64 (s, 3H), 3.46 (m, 2H), 3.34 (s, 3H), 3.15 (br m, 1H), 2.60 (m, 1H), 2.44 (m, 2H), 2.30 (m, 0.5H), 2.11-1.65 (m, 2.5H), 1.22 (d, 3H), 1.18-1.07 (m, 4H), 1.04-0.87 (m, 4H), 0.84 (d, 3H).

Example 21; methyl {(lS)-2-methyl-l-[((2S,4S)-4-methyl-2-{5-[6-(2-{(2S,4S)-4- methyl-l-[(2R)-2-phenyl-2-(l-pyrrolidinyl)acetyl]-2-pyrrolidinyl}-lH-imidazol-4-yl)-2- naphthalenyl]-lH-benzimidazol-2-yl}-l-pyrrolidinyl)carbonyl]propyl}carbamate

To methyl [(lS)-2-methyl-l-({(2S,4S)-4-methyl-2-[5-(6-{2-[(2S,4S)-4-methyl-2- pyrrolidinyl] - 1 H-imidazol-4-yl} -2-naphthalenyl)- 1 H-benzimidazol-2-yl]- 1 - pyrrolidinyl}carbonyl)propyl]carbamate 45-A1 (200 mg, 0.283 mmol) was added (2R)~ phenyl(l-pyrrolidinyl)ethanoic acid (61.0 mg, 0.297 mmol), dry N,N-dimethylformamide (DMF) (4 mL), DIPEA (0.247 mL, 1.415 mmol) and then HATU (113 mg, 0.297 mmol). The reaction was then stirred at room temp overnight, followed by purification on RP HPLC, eluted with 30-85% MeCN (0.2% NH4OH) in water (0.2% NH4OH), to furnish an off-white product in 13.6% yield. ES LC-MS m/z = 822 (M+H)⁺

'H NMR (400 MHz, MeOD-dA) ppm 8.14 (br, IH), 8.07 (d, IH), 7.91 (m, 3H), 7.81 (m, 3H), 7.63 (br, 2H), 7.54 (d, 2H), 7.43 (s, IH), 7.36, (m, 3H), 6.95 (s, IH), 5.17 (dd, IH), 4.97 (dd, IH), 4.30 (m, IH), 4.24 (d, IH), 4.11 (br, IH), 3.83 (t, IH), 3.46 (m, 2H), 3.17 (m, IH), 2.56 (m, 3H), 2.41 (m, 5H), 2.00-1.78 (m, 2H), 1.77- 1.65 (br m, 5H), 1.22 (d, 3H), 1.19-1.07 (m, 4H), 1.00-0.88 (m, 4H), 0.84 (d, 3H).

Scheme XII

lJ-dimethylethvK2S,4SV4-methyl-2-(4-{6-r2-(^'(^,2S,3aS,6aSVl-{N- [(methyloxy carbonyll-L-valylioctahydrocvclopenta[blpyrrol-2-ylVlH-benzimidazol-5- -2-naphthalenvU - lH-imidazol-2-ylV 1 -pyrrolidinecarboxylate 26-B1

To (2S,3aS,6aS)-l-{N-[(methyloxy)carbonyl]-L- valyl}octahydrocyclopenta[b]pyrrole-2-carboxylic acid (0.465 g, 1.489 mmol) was added dry Ν,Ν-Dimethylformamide (DMF) (10 mL), DIPEA (0.867 mL, 4.96 mmol) and HATU (0.566 g, 1.489 mmol). The reaction was stirred for 5 mins then 1,1- dimethylethyI (2S,4S)-2-{4-[6-(3,4-diaminophenyl)-2-naphthalenyl]-lH-imidazol-2-yl}- 4-methyl-l-pyrrolidinecarboxylate 25-A1 (0.80g, 1.654 mmol) in dry DMF (5ml) was added and the reaction stirred for 2 hours. Acetic Acid (15 mL) was added and the reaction stirred at 80°C for 3 hrs. The solvent was removed and the material purified on silica, eluted with 0-20% MeOH in DCM to give 26-B1 in 65% yield. ES LC-MS m/z = 760 (M+H)⁺;

Methyl (^,(lS)-2-methyl-l-(rr2S.3aS,6aS)-2-r5-r6-{2-rr2S,4SV4-methyl-2-pyrrolidinyll-

1 H-imidazol-4-yl } -2-naphthalenvD- 1 H-benzimidazol-2- yllhexahydrocyclopentaiblpyrrol- 1 (^FD-yllcarbonyl IpropyPcarbamate 33-A1

To l,l-dimethylethyl (2S,4S)-4-methyl-2-(4-{6-[2-((2S,3aS,6aS)-l-{N- [(methyloxy)carbonyl]-L-valyl}octahydrocyclopenta[b]pyrrol-2-yl)-lH-benzimidazol-5- yl]-2-naphthalenyl}-lH-imidazol-2-yl)-l-pyrrolidinecarboxylate 26-B1 (1.1 g, 1.447 mmol) was added 1,4-dioxane (10 mL) and 4M HC1 in 1,4-dioxane (10 ml, 40.0 mmol) and stirred for 2 hrs. Solvents were then removed to give the dihydrochloride product 33- Al as a pale orange solid in 65% yield. ES LC-MS m/z = 660 (M+H)⁺;

Example 22; Methyl ((lS)-2-methyl-l-{[(2S,3aS,6aS)-2-{5-[6-(2-{(2S,4S)-4-methyl-l- [(2R)-2-phenyl-2-(l -pyrrolidinyl)acetyl]-2-pyrrolidinyl} - lH-imidazol-4-yl)-2- naphthalenyl]-lH-benzimidazol-2-yl}hexahydrocyclopenta[b]pyrrol-l(2H)- y 1] carbony 1 } propyl)carbamate

To (2R)-phenyl(l-pyrrolidinyl)ethanoic acid (29.4 mg, 0.143 mmol) was added dry Ν,Ν-dimethylformamide (DMF) (1.5 mL), DIPEA (0.095 mL, 0.546 mmol) and HATU (54.5 mg, 0.143 mmol). The reaction was stirred for 2 minutes then methyl ((1S)- 2-methyl-l-{[(2S,3aS,6aS)-2-[5-(6-{2-[(2S,4S)-4-methyl-2-pyrrolidinyl]-lH-imidazol-4- yl } -2-naphthalenyl)- 1 H-benzimidazol-2-yl]hexahydrocyclopenta[b]pyrrol- 1 (2H)- yl]carbonyl}propyl)carbamate 33-A1 (100 mg, 0.136 mmol) in dry N,N- dimethylformamide (DMF) (1 mL) was added and the reaction stirred overnight. RP HPLC purification (30-80% MeCN (0.2% NH4OH) in water (0.2% NH4OH)) furnished the product as an off-white solid in 13.4% yield. ES LC-MS m/z = 847 (M+H)⁺

'H NMR (400 MHz, d4-MeOD) < ppm 8.23-8.15 (br, 2H), 7.93 (br, 3H), 7.82 (br, 3H), 7.66 (br, 2H), 7.54 (d, 2H), 7.43 (s, 1H), 7.36 (br, 3H), 6.96 (s, 1H), 5.23 (t, 1H), 4.98 (dd, 1H), 4.62 (m, 1H), 4.22 (d, 1H), 4.18 (br d, 1H), 4.12 (s, 1H), 3.82 (t, 1H), 3.47 (t, 1H), 3.14 (br m, 1H), 2.94 (m, 1H), 2.83 (m, 1H), 2.69 (m, 1H), 2.55 (br m, 3H), 2.47- 2.31 (br m, 4H), 2.29-2.01(br, m, 4H), 1.99-1.65, (br m, 9H), 1.10 (m, 3H), 1.02 (d, 2H), 0.91 (t, 3H).

Scheme XIII

Example 24 Example 25

Methyl r(lS)-l-ri(2S,4SV2-r4-(^,7-bromo-2-naphthalenylVlH-imidazol-2-yll-4-methyl-l- pyrrolidinyll carbonyl)-2-methylpropyl^"|carbamate XIII-1

2-Bromo-l-(7-bromo-2-naphthalenyl)ethanone (1.4396 g, 4.39 mmol) and N- [(methyloxy)carbonyl]-L-valyl-(4S)-4-methyi-L-proline (1.257 g, 4.39 mmol) were combined in acetonitrile (20 mL). Hunig's base (0.843 mL, 4.83 mmol) was added and the reaction stirred at RT for 4h. The reaction was concentrated to dryness. The residue was taken up in 1, 4-Dioxane (20.00 mL) and ammonium acetate (6.77 g, 88 mmol) was added, heated to 130 °C and stirred overnight, concentrated to dryness and purified silica (0-100% EtOAc in Hex over 20 min) to afford 2 g of product XIII-1 as a light yellow foam. ^!H NMR (400 MHz, METHANOL-i/4) δ ppm 0.80 - 0.93 (m, 6 H) 1.20 (d, J=6.25 Hz, 3 H) 2.32 - 2.56 (m, 2 H) 3.36 - 3.48 (m, 1 H) 3.60 - 3.69 (m, 3 H) 4.16 - 4.31 (m, 2 H) 5.03 - 5.13 (m, 1 H) 6.89 - 7.00 (m, 1 H) 7.45 (s, 1 H) 7.56 (d, J=1.95 Hz, 1 H) 7.71 - 7.87 (m, 4 H) 8.01 (d, J=1.56 Hz, 1 H) 8.12 (s, 1 H).

Methyl i(lS)-l-r((2S,4S -2-{4-r6-(3.4-diaminophenvn-2-naphthalenyll-lH-imidazol-2- yll -4-methyl- 1 -pyrrolidinvDcarbonyll -2-methylpropyl) carbamate XIII-2

Methyl [(l S)-l-({(2S,4S)-2-[4-(7-bromo-2-naphthalenyl)-lH-imidazol-2-yl]-4- methyl-l-pyrrolidinyl}carbonyl)-2-methylpropyI]carbamate XIII-1 (2 g, 3.90 mmol) and 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l,2-benzenediamine (0.958 g, 4.09 mmol) were combined in 1,4-Dioxane (100 mL). 1M Sodium carbonate (11.69 mL, 11.69 mmol) and PdC12(dppf)-CH2C12 adduct (0.318 g, 0.390 mmol) were added. The reaction was heated to 100 °C for 2h, diluted with water (500 mL) and extracted with DCM (3 x 250 mL). Organics were purified on silica (0-100% 2M NH3 in MeOH/DCM) to give 1.563 g of product XIII-2 as light tan foam. Ή NMR (400 MHz, METHANOL-c4) δ ppm 0.82 - 0.99 (m, 6 H) 1.83 - 2.10 (m, 2 H) 2.31 - 2.62 (m, 2 H) 3.65 (s, 3 H) 4.14 - 4.34 (m, 2 H) 5.01 - 5.15 (m, 1 H) 6.73 - 6.87 (m, 1 H) 7.00 - 7.08 (m, 1 H) 7.12 - 7.22 (m,l H) 7.32 - 7.47 (m, 1 H) 7.64 - 7.81 (m, 3 H) 7.81 - 7.89 (m, 2 H) 7.90 - 7.98 (m, 1 H).

1 , 1 -dimethylethyl (2S,4SV4-methyl-2-( 5 - i 6-r2-(i2S .4SV4-methyl- 1 - (N-

(Y methyloxy)carbonyll-D-valyi } -2-pyrrolidinvD- 1 H-imidazol-4-yl1-2-naphthalenyl}- 1H- benzimidazol-2-vD- 1 -pyrrolidinecarboxylate XIII-3

Methyl {(lS)-l-[((2S,4S)-2-{4-[6-(3,4-diaminophenyl)-2-naphthalenyl]-lH- imidazol-2-yl}-4-methyl-l-pyrrolidinyl)carbonyl]-2-methylpropyl}carbamate XIII-2 (0.743 g, 1.374 mmol) and (4S)-l-{[(l,l-dimethylethyl)oxy]carbonyl}-4-methyl-L- proline (0.315 g, 1.374 mmol) were combined in dichloromethane (DCM) (20 mL).

DIEA (0.720 mL, 4.12 mmol) and HATU (0.523 g, 1.374 mmol) were added. The reaction was stirred for 2h and then concentrated to dryness. The residue was taken up in Acetic Acid (20 mL) and heated to 80 °C. The reaction was stirred for 2h and then concentrated to dryness. Purified on silica (0-100% of 20% 2M NH3 in MeOH in DCM) to afford 0.9734g of product XIII-3 as a light brown solid. Ή NMR (400 MHz,

METHANOL-^) δ ppm 0.81 - 0.97 (m, 6 H) 1.05 - 1.27 (m, 6 H) 1.37 (d, J=5.28 Hz, 10 H) 1.72 - 2.07 (m, 3 H) 2.31 - 2.48 (m, 2 H) 2.49 - 2.68 (m, 2 H) 3.17 - 3.27 (m, 2 H) 3.37 - 3.50 (m, 1 H) 3.65 (s, 3 H) 3.68 - 3.77 (m, 1 H) 4.17 - 4.36 (m, 2 H) 4.93 - 5.06 (m, 1 H) 5.06 - 5.17 (m, 1 H) 6.86 - 7.11 (m, 1 H), 7.44 - 7.55 (m, 1 H) 7.58 - 7.75 (m, 2 H) 7.77 - 7.93 (m, 3 H) 7.92 - 8.01 (m, 2 H) 8.06 - 8.20 (m, 2 H).

Methyl rfl SV2-methyl-l-ri(2S.4S)-4-methyl-2-r4-r6-i2-r(2S.4SV4-methyl-2- pyrrolidinyl -lH-benzimidazol-5-yll-2-naphthalenvn-lH-imidazol-2-yl1-l- pyrrolidinyDcarbonyDpropyllcarbamate XIII-4

1 , 1 -Dimethylethyl (2S,4S)-4-methyl-2-(5- {6-[2-((2S,4S)-4-methyl- 1 -{N- [(methyloxy)carbonyl]-D-valyl}-2-pyrrolidinyl)-lH-imidazol-4-yl]-2-naphthalenyl}-lH- benzimidazol-2-yl)-l-pyrrolidinecarboxylate XIII-3 (0.9734 g, 1.326 mmol) was suspended in 4M HC1 in 1,4-Dioxane (10 mL). Methanol (1 mL) was added to aid in dissolution. Stirred for lh then concentrated to dryness to afford 0.9355g of product as light brown foam XIII-4. Ή NMR (400 MHz, METHANOL-^) δ ppm 0.81 - 0.95 (m, 6 H) 1.20 - 1.30 (m, 6 H) 1.73 - 1.91 (m, 1 H) 1.93 - 2.07 (m, 1 H) 2.07 - 2.23 (m, 1 H) 2.44 - 2.60 (m, 1 H) 2.60 - 2.74 (m, 2 H) 2.77 - 2.89 (m, 1 H) 3.63 (s, 9 H) 4.15 - 4.23 (in, 1 H) 4.26 - 4.40 (m, 1 H) 5.13 - 5.28 (m, 2 H) 7.76 - 7.88 (m, 2 H) 7.88 - 8.02 (m, 3 H) 8.02 - 8.16 (m, 3 H) 8.21 - 8.29 (m, 2 H).

LC-MS m/z = 634 (M+H)⁺ Example 23; Methyl {(lS)-2-methyl-l-[((2S,4S)-4-methyl-2-{4-[6-(2-{(2S,4S)-4- methyl-l-[(2R)-2-phenyl-2-(l-pyrrolidinyl)acetyl]-2-pyrrolidinyl}-lH-benzimidazol-5- -2-naphthalenyl]-lH-imidazol-2-yl}-l-pyrrolidinyl)carbonyl]propyl}carbamate

Methyl [(lS)-2-methyl-l-({(2S,4S)-4-methyl-2-[4-(6-{2-[(2S,4S)-4-methyl-2- pyrrolidinyl]-lH-benzimidazol-5-yl}-2-naphthalenyl)-lH-imidazol-2-yl]-l- pyrrolidinyl}carbonyl)propyl]carbamate Xni-4 (0.121 g, 0.191 mmol) and (2R)- phenyl(l-pyrrolidinyl)ethanoic acid (0.039 g, 0.191 mmol) were suspended in dichloromethane (DCM) (5 mL). DIEA (0.100 mL, 0.573 mmol), followed by addition of HATU (0.073 g, 0.191 mmol) and stirring for lh at rt. Purification on RP HPLC (0-50% QH^CN/Water with 0.1% Formic Acid) gave 30 mg of product as an off white solid. ^!H

NMR (400 MHz, METHANOL-^) δ ppm 0.84 - 0.99 (m, 6 H) 1.07 - 1.25 (m, 4H) 1.71 - 1.85 (m, 5 H) 1.94 - 2.09 (m, 5 H) 2.32 - 2.73 (m, 7 H) 3.44 - 3.51 (m, 4 H) 3.65 (s, 3 H) 4.17 - 4.28 (m, 2 H) 4.99 - 5.18 (m, 2 H) 7.37 - 7.49 (m, 3 H) 7.51 - 7.61 (m, 2 H) 7.60 - 7.70 (m, 2 H) 7.75 - 7.98 (m, 5 H) 8.05 - 8.29 (m, 2 H).

LC-MS m/z = 821 (M+H)⁺;

Example 24; Methyl {(lS)-l-[((2S,4S)-2-{4-[6-(2-{(2S,4S)-l-[(2R)-2-(dimethylamino)-

2-phenylacetyl]-4-methyl-2-pyrrolidinyl}-lH-benzimidazol-5-yl)-2-naphthalenyl]-lH- imidazol-2-yl}-4-methyl-l-pyrrolidinyl)carbonyl]-2-methylpropyl}carbamate

Methyl [(l S)-2-methyl-l-({(2S,4S)-4-methyl-2-[4-(6-{2-[(2S,4S)-4-methyl-2- pyrrolidinyl]-lH-benzimidazol-5-yl}-2-naphthalenyl)-lH-imidazol-2-yl]-l- pyrrolidinyl}carbonyl)propyl]carbamate XIII-4 (0.109 g, 0.172 mmol) and (2R)- (dimethylamino)(phenyl)ethanoic acid (0.03 Ig, 0.172 mmol) were suspended in dichloromethane (DCM) (5 mL). DIEA (0.090 mL, 0.516 mmol), followed by addition of HATU (0.065 g, 0.172 mmol) and stirred for lh at rt. Purification on RP HPLC (0-50% Q fjCN/Water with 0.1% Formic Acid) gave 23 mg of product as a white solid. Ή

NMR (400 MHz, METHANOL-^) δ ppm 0.82 - 0.99 (m, 6 H) 1.08 - 1.17 (m, 4 H) 1.18

- 1.26 (m, 4 H) 1.88 - 2.09 (m, 2 H) 2.23 - 2.32 (m, 6 H) 2.33 - 2.47 (m, 2 H) 2.49 - 2.60 (m, 2 H) 3.66 (s, 9 H) 4.18 - 4.31 (m, 2 H) 5.04 - 5.15 (m, 2 H) 7.41 - 7.46 (m, 3 H) 7.52

- 7.58 (m, 2 H) 7.61 - 7.71 (m, 3 H) 7.79 - 7.89 (m, 3 H) 7.90 - 7.98 (m, 2 H) 8.07 - 8.12 (m, 1 H) 8.13 - 8.20 (m, 1 H). LC-MS m/z = 795 (M+H)⁺

Scheme XIV

Example 25

U-Dimethylethyl (2S3aS.6aSV2-(^'5-i6-r2-((2S,4S)-4-methyl-l-{N- [(methyloxy)carbonyll-D-valyll-2-pyrrolidinyl)-lH-imidazol-4-yll-2-naphthalenyl|-lH- benz idazol-2-yl)hexahvdrocvclopentarblpyrrole-l(2H)-carboxylate XIV-1

Methyl {(lS)-l-[((2S,4S)-2-{4-[6-(3,4-diaminophenyl)-2-naphthalenyl]-lH- imidazol-2-yl}-4-methyl-l-pyrrolidinyl)carbonyl]-2-methylpropyl}carbamate XIII-2 (0.783 g, 1.448 mmol) and (2S,3aS,6aS)-l-{[(l,l- dtmethylethyl)oxy]carbonyI}octahydrocycIopenta[b]pyrroIe-2-carboxylic acid (0.370 g, 1.448 mmol) were combined in Dichloromethane (DCM) (20 mL). DIEA (0.759 mL, 4.34 mmol) and HATU (0.551 g, 1.448 mmol) were added and the reaction carried on for 2h and then concentrated to dryness. The residue was dissolved in acetic acid (20 mL) and carried on at 80 °C for 2h, concentrated to dryness and purified on silica (0-100% of 20% 2M NH3 in MeOH in DCM) to afford 1.102g of product XIV-1 as a light brown solid. 1H NMR (400 MHz, METHANOL-^) δ ppm 0.82 - 0.98 (m, 8 H) 1.16 - 1.25 (m, 9 H) 1.32 - 1.41 (m, 6 H)1.67 - 1.81 (m, 2 H) 1.83 - 2.18 (m, 6 H) 2.33 - 2.67 (m, 3 H) 3.38 - 3.51 (m, 1 H) 3.65 (s, 3 H) 3.67 - 3.78 (m, 1 H) 4.18 - 4.36 (m, 3 H) 5.00 - 5.18 (m, 1 H) 7.46 (s, 1 H) 7.65 (s, 2 H) 7.77 - 7.87 (m, 2 H) 7.87 - 7.98 (m, 3 H) 8.05 - 8.20 (m, 2

H).

Methyl rfl SV2-methyl-l-f((2S.4SV4-methyl-2-r4-(6-f2-rf2S,3aS,6aS)- octahvdrocvclopenta[blpyrrol-2-yll-lH-benzimidazol-5-y -2-naphthalenyl -lH- imidazol-2-yl1-l-pyiTolidinyl|carbonyl)propyl]carbamate XIV-2

l,l-Dimethylethyl (2S,3aS,6aS)-2-(5-{6-[2-((2S,4S)-4-methyl-l-{N- [(methyloxy)carbonyl]-D-valyl}-2-pyrrolidinyl)-lH-imidazol-4-yl]-2-naphthalenyl}-lH- benzimidazol-2-yl)hexahydrocyclopenta[b]pyrrole-l(2H)-carboxylate XIV-1 (1.102g, 1.45 mmol) was suspended in 4M HC1 in 1,4-dioxane (10 mL). Methanol (1 mL) was added to aid in dissolution. Stirred for lh then concentrated to dryness to afford 1.022 g of product XIV-2 as light brown foam. LC-MS m/z = 660 (M+H)⁺. Example 25; Methyl {(lS)-2-methyl-l-[((2S,4S)-4-methyl-2-{4-[6-(2-{(2S,3aS,6aS)-l- [(2R)-2-phenyl-2-(l-pyrrolidinyl)acetyl]octahydrocyclopenta[b]pyrrol-2-yl}-lH- benzimidazol-5-yl)-2-naphthalenyl]-lH~imidazol-2-yl}-l- pyrrolidinyl)carbonyl]propyl}carbamate

Methyl [(lS)-2-methyl-l-({(2S,4S)-4-methyl-2-[4-(6-{2-[(2S,3aS,6aS)- octahydrocyclopenta[b]pyrrol-2-yl]-lH-benzimidazol-5-yl}-2-naphthalenyl)-lH- imidazol-2-yl]-l-pyrrolidinyl}carbonyl)propyl]carbamate XIV-2 (0.1 195 g, 0.181 mmol) and (2R)-phenyl(l-pyrrolidinyl)ethanoic acid (0.037 g, 0.181 mmol) were suspended in dichloromethane (DCM) (5 mL). DIEA (0.095 niL, 0.543 mmol) and added HATU (0.069 g, 0.181 mmol), stirred for lh at RT and then purified on RP HPLC (0-50% CH₃CN/Water with 0.2% NH4OH) to give 45 mg of product. ^!H NMR (400 MHz,

METHANOL-^) δ ppm 0.83 - 0.99 (m, 6 H) 1.18 - 1.26 (m, 4 H) 1.82 - 2.07 (m, 5 H) 2.11 - 2.28 (m, 3 H) 2.34 - 2.59 (m, 8 H) 2.58 - 2.74 (m, 3 H) 3.60 - 3.70 (m, 5 H) 4.18 - 4.39 (m, 4 H) 5.02 - 5.17 (m, 1 H) 5.17 - 5.27 (m, 1 H) 7.35 - 7.46 (m, 3 H) 7.53 - 7.59 (m, 2 H) 7.63 - 7.70 (m, 2 H) 7.78 - 7.99 (m, 6 H) 8.05 - 8.15 (m, 2 H). LC-MS m/z = 847 (M+H)⁺.

Scheme XV

( SVtert-butyl 2-(5-(6-(3 ,4-diaminophenyl)naphthalen-2-yl)- 1 H-imidazol-2- vDpyrrolidine-l-carboxylate XV-1 (Scheme XV).

To 1 , 1 -dimethy lethy 1 (2S)-2-[4-(6-bromo-2-naphthalenyl)- lH-imidazol-2-y 1] - 1 - pyrrolidinecarboxylate (6.7 g, 15.15 mmol) was added [2-amino-4-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)phenyl]amine (3.72 g, 15.90 mmol), PdC12(dppf)-CH2C12 adduct (1.237 g, 1.515 mmol), 1,4-Dioxane (120 niL) and potassium carbonate (45.4 mL, 45.4 mmol). The reaction was stirred at 100 °C under nitrogen for 2 hrs. The reaction was partitioned between DCM and water. The phases were separated, combined organics were purified on silica eluted with 0-20% 2M ammonia in Methanol in DCM to furnish product as a brown gum/oil. i2S,3aS.7aS)-tert-butyl 2-(5-(6-r2-((S)-l-rtert-butoxycarbonyl)pyrrolidin-2-yl)-lH- imidazol-5-yl)naphthalen-2-yl)- lH-benzo[^" d]imidazol-2-yl)octahydro- 1 H-indole- 1 - carboxylate XV-2 (Scheme XV).

To (S)-tert-buty 1 2-(5 -(6-(3 ,4-diaminophenyl)naphthalen-2-yl)- 1 H-imidazol-2- yl)pyrrolidine-l-carboxylate XV-1 (3 g, 6.39 mmol) and (2S,3aS,7aS)-l-{[(l,l- dimethylethyl)oxy]carbonyl}octahydro-lH-indole-2-carboxylic acid (1.807 g, 6.71 mmol) was added Ν,Ν-Dimethylformamide (DMF) (45 mL), HATU (2.55 g, 6.71 mmol) and DIEA (3.35 mL, 19.17 mmol). The reaction was stirred for 3 hours st room temp then the solvent removed and replaced with acetic acid (45.0 mL). The reaction was then stirred at 80 °C for 1 hour, solvent removed and the residue purified on silica eluted with 40-100% ethyl acetate in cyclohexane to give XV-2.

2-rr2S.3aS.7aSVoctahvdro-lH-indol-2-vn-5-(^'6-(^'2-r(SVpyrrolidin-2-yl)-lH-imidazol-5- yl)naphthalen-2-ylV lH-benzordlimidazole XV-3 (Scheme XV).

To (2S,3aS,7aS)-tert-butyl 2-(5-(6-(2-((S)-l-(tert-butoxycarbonyl)pyrrolidin-2- yl)- 1 H-imidazol-5-yl)naphthalen-2-yl)- 1 H-benzo [d] imidazol-2-yl)octahydro- 1 H-indole-

1- carboxylate XV-2 (0.6 g, 0.854 mmol) in dry 1,4-Dioxane (6 mL) was added 4M HC1 in 1,4-dioxane (6 ml, 24.00 mmol) and a little methanol to aid solubility. The reaction was stirred for 2 hrs then the solvent removed to furnish the product as a pale yellow solid XV-3.

Example 26; (R)-2-phenyl-l-((S)-2-(5-(6-(2-((2S,3aS,7aS)-l-((R)-2-phenyl-2- (pyrrolidin-l-yl)acetyl)octahydro-lH-indol-2-yl)-lH-benzo[d]imidazol-5-yl)naphthalen-

2- yl)- 1 H-imidazol-2-yl)pyrrolidin- 1 -yl)-2-(pyrrolidin- 1 -yl)ethanone

To dipyrrolidine XV-3 (150 mg, 0.261 mmol) in dichloromethane (DCM) (5 mL) and Ν,Ν-dimethylformamide (DMF) (1.000 mL) was added premixed (5 min) mixture of (2R)-phenyl(l-pyrrolidinyl)ethanoic acid (107 mg, 0.521 mmol), HATU (198 mg, 0.521 mmol) and DIEA (0.364 mL, 2.085 mmol) in dichloromethane (DCM) (5 mL) and reaction carried on for lh at room temperature. The crude product was purified on RP HPLC to homogeneity resulting in 19.1 mg (8.1% yield) of compound in example 26. High resolution mass spectroscopy: Mass Found=877.4916, M+l calculated=877.4917 for C56 H61 N8 02.

*H NMR (400 MHz, METHANOL-^) δ ppm 8.50 (s, 2H), 8.15 (m, 1H), 8.05 (m, 2H), 7.90 (m, 4H), 7.80 (m, 1H), 7.60 (m, 2H), 7.55 (m, 3H), 7.40 (m, 4H), 7.00 (m, 2H), 5.19 (m, IH), 5.17 (m, IH), 4.80 (m, IH), 4.50 (m, IH), 4.03 (m, IH), 3.88 (m, IH), 3.22 (m, IH), 3.01 (m, 4H), 2.79 (m, 4H), 2.57 (m, IH), 2.53 (m, IH), 2.22 (m, IH) 2.18 (m, IH), 2.17 (m, IH), 2.11 (m, IH), 2.04 (m, IH), 1.91 (m, 4H), 1.88 (m, IH), 1.87 (m, IH), 1.83 (m, 4H), 1.50 (m, 4H), 1.25 (m, 2H).

Example 27; Methyl((S)-l-((2S,3aS,7aS)-2-(6-(6-(2-((S)-l-((R)-2-(diethylamino)-2-(2- methoxyphenyl)acetyl)pyrrolidin-2-yl)- 1 H-im^

yl)octahydro-lH-indol-l-yl)-3-methyl-l-oxobutan-2-yl)carbamate.

Example 27 was prepared similarly to target example 13, except that (R)-2- (diethylamino)-2-(2-methoxyphenyl)acetic acid was used, resulting in desired product in 8.3% yield. ES LC-MS mJz = 880 (M+H)⁺

Ή NMR (400 MHz, DMSO-d6) δ ppm 1 1.80 - 12.34 (m, 2 H), 8.10 - 8.29 (m, 2 H), 7.93 (br. s., 5 H), 7.63 (br.s., 3 H), 7.51 (d, J=8.2 Hz, 1 H), 7.37 - 7.48 (m, 1 H), 7.17 - 7.35 (m, 1 H), 7.02 (d, J-8.1 Hz, 1 H), 6.94 (t,J=7.4 Hz, 1 H), 5.06 - 5.17 (m, 2 H), 4.94 - 5.06 (m, 1 H), 4.44 (br. s., 1 H), 3.83 (s, 5 H), 3.55 (s, 3 H), 2.56 -2.73 (m, 2 H), 2.33 - 2.46 (m, 2 H), 2.21 (br. s., 2 H), 1.74 - 2.06 (m, 8 H), 1.57 - 1.71 (m, 1 H), 1.49 (d, J=9.1Hz, 1 H), 1.32 - 1.42 (m, 1 H), 1.23 (br. s., 2 H), 0.97 (t, J=7.0 Hz, 2 H), 0.81 - 0.93 (m, 9 H), 0.71 (d, J=6.6Hz, 3 H)

Protocol for testing and data analysis of compounds in the HCV replicon assay

Compounds were assayed for activity against HCV using the genotype la and lb subgenomic replicon model systems. Stable cell lines bearing the genotype la and lb replicons were used for screening of compounds. Both replicons are bicistronic and contain the firefly luciferase gene. The ET cell line is stably transfected with R A transcripts harboring a I₃89luc-ubi-neo/NS3-37ET replicon with firefly luciferase- ubiquitin-neomycin phosphotransferase fusion protein and EMCV-IRES driven NS3-5B polyprotein containing the cell culture adaptive mutations (E1202G; T1280I; K1846T) (Krieger at al, 2001 and unpublished). The genotype la replicon is a stable cell line licensed from Apath LLC, modified to contain the firefly luciferase gene. The cells were grown in DMEM, supplemented with 10% fetal calf serum, 2 mM Glutamine, Penicillin (100 IU/mL)/Streptomycin (100 μg/mL), lx nonessential amino acids, and 250-500 μg/mL G418 ("Geneticin"). They were all available through Life Technologies

(Bethesda, Md.). The cells were plated at 0.5 x 10⁴ cells/well in 384 well plates containing compounds. The final concentration of compounds ranged between 0.03 pM to 50 μιη and the final DMSO concentration of 0.5-1%.

Luciferase activity was measured 48 hours later by adding a Steady glo

(Promega, Madison, Wis.). Percent inhibition of replication data was plotted relative to no compound control. Under the same condition, cytotoxicity of the compounds was determined using cell titer glo (Promega, Madison, Wis). EC50s were determined from a 10 point dose response curve using 3-4-fold serial dilution for each compound, which spans a concentration range > 1000 fold. BioAssay determines the level of inhibition for each compound by normalizing cross-talk corrected plate values against the negative (low or background, cells with no compound present) and positive (high DMSO, no cells) controls to determine Percent Inhibition:

100 * (1 -(Cross-talk corrected value - Compound Positive Control Mean))

DMSO Negative Control Mean - Compound Positive Control Mean

These normalized values are exported to EC50 where they are plotted against the molar compound concentrations using the standard four parameter logistic equation:

Where:

A = minimum y D= slope factor B = maximum y x = logio compound concentration [M]

C = log_IOEC₅o pEC₅₀ = -C

As shown below, the tested compounds tested were found to inhibit the activity of the replicon.

i j REPLICON 1A pEC₅₀ REPLICON 1B pEC₅₀

1 Example 1 j 10.20 11.32

j Example 2 I 10.90 11.57

J Example 3 j 11.20 11.70

j Example 4 I 10.90 11.60

j Example 5 I 10.90 11.51

j Example 6 j 11.00 11.30

j Example 7 ] 10.50 11.20

I Example 8 j 9.20

j Example 9 j 9.40 11.00

i Example 10 ί 10.10 10.60

( Example 11 10.40 11.10

Example 12 9.80 11.30

Example 13 j 10.80 1.20

Example 14 10.70 11.10

Example 15 1 10.30 .30

Example 16 10.40 11.00

Example 17 J 10.50 j 1.00

Example 18 10.70 1 1.20

Example 19 ' 10.60 11.00

Example 20 10.80 j 11.10

Example 21 10.70 ^"j 11.00

Example 22 10.70 1.00 j

Example 23 10.40 i 10.60

Example 24 10.20 0.90

Example 25 10.50 I 11.00

Example 26 9.80 ! 10.20

Example 27 10.60 10.90 I

Claims

What is claimed is:

Claim 1. A compound of Formula I

wherein;

each Z is independently CH or N with the proviso that no more than one Z in each ring is N;

each R³ is independently H, F, or two R³ groups bound to the same carbon atom together with the carbon atom to which they are bound form a 5- or 6-membered saturated heterocyclic spiro ring containing 1 or 2 oxygen or sulphur atoms, or two R³ groups bound to adjacent carbon atoms together with the carbon atoms to which they are bound form a saturated 5- or 6-membered cycloalkyl group.

Claim 2. A compound according to Claim 1 wherein every Z is CH.

Claim 3. A compound according to Claim 1 or Claim 2 wherein each R is independently H, F, or two R³ groups bound to the same carbon atom together with the carbon atom to which they are bound form a 5-membered saturated heterocyclic spiro ring containing 2 oxygen atoms, or two R groups bound to adjacent carbon atoms together with the carbon atoms to which they are bound form a cyclohexyl group.

Claim 4. A compound according to Claim 3 wherein the two oxygen atoms in said spiro ring are each adjacent to the quaternary spiro carbon atom.

Claim 5. The com ound

Claim 6. The compound of Claim 5 wherein said compound is entantiomerically enriched with the followin enantiomer

Claim 7. A compound of Formula II

wherein; each Z is independently CH or N with the proviso that no more than one Z in each ring is N;

each R¹ is independently H, Ci_-6alkyl, C_3-6cycloalkyl, phenyl, or phenyl containing one F substituent,

each R² is independently H, Ci_-3alkyl, C_1-3acyl, C₃-₆cycloacyl, or C(0)OCi_-3alkyl, or two R²s bound to the same nitrogen atom may, together with the nitrogen atom to which they are bound, join together to form a 5- or 6-membered saturated heterocyclic ring;

each R is independently H, F, or two R groups bound to the same carbon atom together with the carbon atom to which they are bound form a 5- or 6-membered saturated heterocyclic spiro ring containing 1 or 2 oxygen or sulphur atoms, or two R groups bound to adjacent carbon atoms together with the carbon atoms to which they are bound form a saturated 5- or 6-membered cycloalkyi group.

Claim 8. A compound according to Claim 7 wherein every Z is CH.

Claim 9. A compound according to Claim 7 or Claim 8 wherein each R³ is independently H, F, or two R³ groups bound to the same carbon atom together with the carbon atom to which they are bound form a 5-membered saturated heterocyclic spiro ring containing 2 oxygen atoms, or two R³ groups bound to adjacent carbon atoms together with the carbon atoms to which they are bound form a cyclohexyl group.

Claim 10. A compound according to Claim 9 wherein the two oxygen atoms in said spiro ring are each adjacent to the quaternary spiro carbon atom.

Claim 11. A pharmaceutically acceptable salt of a compound according to any preceding claim.

Claim 12. A pharmaceutical composition comprising a compound or salt according to any preceding claim.

Claim 13. A method for treating a viral infection in a human comprising administration of a pharmaceutical composition according to Claim 12.

Claim 14. The method of Claim 13 wherein said viral infection is an HCV infection.

Claim 15. A compound or salt as defined in any of claims 1-11 for use in the treatment of a viral infection in a human.

Claim 16. The use of a compound or salt as defined in any of claims 1-11 in the manufacture of a medicament for use in the treatment of a viral infection in a human.