NZ610525B2 - Condensed imidazolylimidazoles as antiviral compounds - Google Patents

Abstract

Disclosed is the compound velpatasvir (methyl N-[(1R)-2-[(2S,4S)-2-[4-[1,11-dihydro-2-[(2S,5S)-1-[(2S)-2-[(methoxycarbonyl)amino]-3-methyl-1-oxobutyl]-5-methyl-2-pyrrolidinyl][2]benzopyrano[4',3':6,7]naphth[1,2-d]imidazol-9-yl]-1H-imidazol-2-yl]-4-(methoxymethyl)-1-pyrrolidinyl]-2-oxo-1-phenylethyl]-carbamate) as well as its derivatives and analogues. Also disclosed is a pharmaceutical composition comprising the compound for the treatment of hepatitis C virus infections. -carbamate) as well as its derivatives and analogues. Also disclosed is a pharmaceutical composition comprising the compound for the treatment of hepatitis C virus infections.

Description

CONDENSED IMIDAZOLYLIMIDAZOLES AS ANTIVIRAL COMPOUNDS CROSS REFERENCE TO RELATED APPLICATIONS This application claims the benefit under 35 U.S.C. § 119(e) of United States Provisional Application No. 61/560,654 filed on November 16, 2011, which is hereby incorporated by nce in its entirety.

BACKGROUND Hepatitis C is recognized as a c viral disease of the liver which is characterized by liver disease. Although drugs targeting the liver are in wide use and have shown effectiveness, toxicity and other side effects have limited their usefulness. Inhibitors of hepatitis C virus (HCV) are useful to limit the establishment and progression of infection by HCV as well as in diagnostic assays for HCV.

There is a need for new HCV therapeutic agents. In particular, there is a need for HCV therapeutic agents that have broad activity against HCV genotypes (e.g. pes 1a, 1b, 2a, 3a, 4a). There is also a particular need for agents that are less susceptible to viral ance. Resistance mutations to inhibitors have been described for HCV NS5A for genotypes 1a and 1b in Antimicrobial Agents and Chemotherapy, September 2010, Volume 54, p. 3641-3650.

SUMMARY In one embodiment the disclosure provides a compound of the disclosure which is a compound of formula (I): E1a-V1a –C(=O)-P1a -W1a -P1b-C(=O)-V1b-E1b (I) wherein: W1a is Y5 H N N N N H X5 and W1a is optionally tuted with one or more groups independently ed from halo, alkyl, haloalkyl, or cyano; Y5 is -O-CH2-, or -CH2-O-; X5 is H2- or -CH=CH-; E1a is -N(H)(alkoxycarbonyl), cycloalkylcarbonyl) or -N(H)(cycloalkyloxycarbonyl); or E1a-V1a taken together are R9a; E1b is -N(H)(alkoxycarbonyl), -N(H)(cycloalkylcarbonyl) or -N(H)(cycloalkyloxycarbonyl); or E1b-V1b taken together are R9b; V1a and V1b are each independently selected from: P1a is selected from: P1b is selected from: ; R9a and R9b are each ndently: N N H H O O ; or a ceutically acceptable salt or prodrug thereof.

The disclosure also es isotopically enriched compounds that are compounds of the disclosure that comprise an enriched isotope at one or more positions in the nd.

The present disclosure also provides a pharmaceutical composition comprising a compound of the disclosure or a pharmaceutically acceptable salt or prodrug thereof and at least one pharmaceutically acceptable carrier.

The present disclosure also provides a pharmaceutical composition for use in treating hepatits C (HCV). In one embodiment the composition comprises at least one additional therapeutic agent for treating HCV. In one embodiment, the therapeutic agent is selected from ribavirin, an NS3 protease inhibitor, a nucleoside or nucleotide inhibitor of HCV NS5B polymerase, an alpha-glucosidase 1 tor, a hepatoprotectant, a non-nucleoside inhibitor of HCV polymerase, or combinations thereof. In one embodiment, composition further comprises a nucleoside or nucleotide inhibitor of HCV NS5B polymerase. In one embodiment, the nucleoside or tide inhibitor of HCV NS5B polymerase is ed from ribavirin, viramidine, levovirin, a L-nucleoside, or isatoribine.

In one embodiment is provided a pharmaceutical composition comprising a compound as described herein and at least one nucleoside or nucleotide inhibitor of HCV NS5B polymerase, and at least one pharmaceutically acceptable carrier. In one embodiment, the composition further comprises an interferon, a pegylated interferon, ribavirin or combinations f. In one embodiment, the compound is the compound exemplified in Example PY. In one embodiment the the nucleoside or nucleotide inhibitor of HCV NS5B polymerase is sofosbuvir.

The present disclosure also provides a pharmaceutical composition r comprising an interferon or pegylated interferon.

The present disclosure also provides a pharmaceutical composition r comprising a side analog.

The present disclosure also provides for a ceutical composition wherein said nucleoside analogue is selected from ribavirin, viramidine, levovirin, an L-nucleoside, and isatoribine and said interferon is α-interferon or pegylated α-interferon.

The present disclosure also provides for a method of treating hepatitis C, said method comprising stering to a human patient a pharmaceutical composition which ses a therapeutically effective amount of a compound of the disclosure.

The present disclosure also provides a method of inhibiting HCV, comprising administering to a mammal afflicted with a condition associated with HCV activity, an amount of a compound of the sure, ive to inhibit HCV.

The present disclosure also provides a compound of the disclosure for use in medical y (e.g. for use in inhibiting HCV activity or treating a condition ated with HCV ty), as well as the use of a compound of the disclosure for the manufacture of a medicament useful for inhibiting HCV or the treatment of a condition associated with HCV activity in a mammal.

The present disclosure also provides synthetic processes and novel intermediates disclosed herein which are useful for preparing compounds of the disclosure. Some of the compounds of the disclosure are useful to prepare other compounds of the disclosure.

In another aspect the disclosure provides a compound of the disclosure, or a ceutically acceptable salt or prodrug thereof, for use in the prophylactic or therapeutic treatment of hepatitis C or a hepatitis C associated disorder.

In another aspect the disclosure provides a method of inhibiting HCV activity in a sample sing treating the sample with a compound of the disclosure.

Compounds of formula (I) have been found to s useful activity against HCV genotypes. Additionally certain compounds of a (I) have significant potency against resistant ts in GT1.

Accordingly, certain nds of formula (I) possess beneficial pharmacological properties that make them well suited to fulfill the current need for HCV agents with such beneficial properties.

In one embodiment the sure provides a compound having ed tory or pharmacokinetic properties, including enhanced activity t development of viral resistance, improved oral bioavailability, greater potency (for example, in inhibiting HCV ty) or extended ive half-life in vivo. Certain compounds of the disclosure may have fewer side effects, less complicated dosing schedules, or be orally active.

DETAILED DESCRIPTION Reference will now be made in detail to certain embodiments of the disclosure, examples of which are illustrated in the accompanying structures and formulas. While the disclosure will be described in conjunction with the enumerated embodiments, it will be understood that they are not intended to limit the disclosure to those embodiments. On the contrary, the disclosure is ed to cover all alternatives, modifications, and equivalents, which may be included within the scope of the present disclosure as defined by the embodiments.

Compounds The compounds of the disclosure exclude nds heretofore known. However, it is within the disclosure to use compounds that previously were not known to have ral properties for antiviral purposes (e.g. to produce an anti-viral effect in an animal). With respect to the United States, the compounds or compositions herein exclude compounds that are pated under 35 USC §102 or that are obvious under 35 USC §103.

Whenever a nd described herein is substituted with more than one of the same designated group, e.g., "R1" or "A3", then it will be understood that the groups may be the same or different, i.e., each group is independently selected.

“Absent” – Some groups are defined such that they can be absent. When a group is absent it becomes a bond connector. The two groups that would otherwise be connected to that absent group are connected to each other through a bond.

The “P” groups (e.g. P1a and P1b) defined for formula (I) herein have one bond to a -C(=O)- of formula (I) and one bond to a W1a group. It is to be understood that a nitrogen of the P group is connected to the - group of formula (I) and that a carbon of the P group is connected to the W1a group.

Y5 H N N N N H X5 In the W1a group a Y5 group is present. When that Y5 group is defined as -O-CH2-, or -CH2-O- group, those Y5 groups have a directionality. The Y5 group is connected to the W1a group in the same left to right directionality that each is drawn. So for example, when Y5 is -O-CH2-, the directly following ure is intended: For example, when Y5 is -CH2-O-, the directly following ure is intended: In the structure I, the W1a group has a o-right directionality as depicted in I and W1a as drawn.

E1a-V1a –C(=O)-P1a -W1a -P1b-C(=O)-V1b-E1b (I) wherein: W1a is Y5 H N N N N H X5 For example, the P1a group is connected to the imidazole group of W1a, and the P1b group is connected to the pentacyclic ring system of W1a.

“Alkyl” is C1-C18 hydrocarbon containing normal, secondary, tertiary or cyclic carbon atoms. es are methyl (Me, -CH3), ethyl (Et, -CH2CH3), 1-propyl (n-Pr, npropyl , -CH2CH2CH3), 2-propyl (i-Pr, i-propyl, -CH(CH3)2), 1-butyl (n-Bu, n-butyl, -CH2CH2CH2CH3), 2-methylpropyl (i-Bu, i-butyl, -CH2CH(CH3)2), 2-butyl (s-Bu, sbutyl , 3)CH2CH3), 2-methylpropyl (t-Bu, t-butyl, -C(CH3)3), 1-pentyl (n-pentyl, -CH2CH2CH2CH2CH3), 2-pentyl (-CH(CH3)CH2CH2CH3), 3-pentyl (-CH(CH2CH3)2), 2- methylbutyl (-C(CH3)2CH2CH3), 3-methylbutyl (-CH(CH3)CH(CH3)2), 3-methyl butyl (-CH2CH2CH(CH3)2), 2-methylbutyl (-CH2CH(CH3)CH2CH3), 1-hexyl (-CH2CH2CH2CH2CH2CH3), 2-hexyl (-CH(CH3)CH2CH2CH2CH3), l (-CH(CH2CH3)(CH2CH2CH3)), 2-methylpentyl 3)2CH2CH2CH3), 3-methyl pentyl (-CH(CH3)CH(CH3)CH2CH3), 4-methylpentyl H3)CH2CH(CH3)2), 3- methylpentyl (-C(CH3)(CH2CH3)2), 2-methylpentyl (-CH(CH2CH3)CH(CH3)2), 2,3- dimethylbutyl (-C(CH3)2CH(CH3)2), methylbutyl (-CH(CH3)C(CH3)3, and cyclopropylmethyl . yl” is C2-C18 hydrocarbon containing normal, secondary, tertiary or cyclic carbon atoms with at least one site of unsaturation, i.e. a carbon-carbon, sp2 double bond.

Examples include, but are not limited to, ethylene or vinyl (-CHCH2), allyl (-CH2CHCH2), cyclopentenyl (-C5H7), and 5-hexenyl (-CH2 CH2CH2CH2CHCH2).

“Alkynyl” is C2-C18 hydrocarbon containing normal, secondary, ry or cyclic carbon atoms with at least one site of unsaturation, i.e. a carbon-carbon, sp triple bond.

Examples include, but are not limited to, acetylenic (-CCH) and propargyl (-CH2CCH). ene” refers to a saturated, ed or straight chain or cyclic hydrocarbon radical of 1-18 carbon atoms, and having two monovalent radical centers derived by the removal of two hydrogen atoms from the same or two different carbon atoms of a parent alkane. Typical alkylene radicals include, but are not limited to, methylene (-CH2-) 1,2-ethyl (-CH2CH2-), 1,3- propyl (-CH2CH2CH2-), 1,4-butyl (-CH2CH2CH2CH2-), and the like.

“Alkenylene” refers to an unsaturated, branched or straight chain or cyclic hydrocarbon radical of 2-18 carbon atoms, and having two monovalent radical centers derived by the removal of two hydrogen atoms from the same or two ent carbon atoms of a parent alkene. Typical alkenylene radicals include, but are not limited to, 1,2-ethylene (-CHCH-).

“Alkynylene” refers to an unsaturated, branched or straight chain or cyclic hydrocarbon radical of 2-18 carbon atoms, and having two monovalent l centers derived by the l of two en atoms from the same or two different carbon atoms of a parent alkyne. Typical alkynylene radicals include, but are not limited to, acetylene ), gyl (-CH2CC-), and ynyl (-CH2CH2CH2CCH).

The term "alkoxy" or “alkyloxy,” as used herein, refers to an alkyl group attached to the parent molecular moiety through an oxygen atom.

The term "alkoxycarbonyl," as used herein, refers to an alkoxy group attached to the parent molecular moiety through a carbonyl group.

The term alkyl," as used herein, refers to a saturated monocyclic, hydrocarbon ring system having three to seven carbon atoms and zero heteroatoms. Representative examples of lkyl groups e, but are not limited to, cyclopropyl, cyclopentyl, and cyclohexyl. The cycloalkyl groups of the present disclosure are optionally substituted with one, two, three, four, or five tuents independently ed from alkoxy, alkyl, aryl, cyano, halo, haloalkoxy, haloalkyl, heterocyclyl, hydroxy, hydroxyalkyl, nitro, and -NRxRy wherein the aryl and the heterocyclyl are further optionally substituted with one, two, or three substituents independently selected from alkoxy, alkyl, cyano, halo, haloalkoxy, haloalkyl, hydroxy, and nitro.

The term “cycloalkylcarbonyl,” as used herein, refers to a cycloalkyl group attached to the parent molecular moiety through a carbonyl group.

The term "cycloalkyloxy," as used herein, refers to a cycloalkyl group attached to the parent molecular moiety through an oxygen atom.

The term “cycloalkyloxycarbonyl,” as used herein, refers to a cycloalkyloxy group attached to the parent molecular moiety through a carbonyl group.

“Aryl” means a monovalent aromatic hydrocarbon radical of 6-20 carbon atoms derived by the removal of one hydrogen atom from a single carbon atom of a parent aromatic ring system. Typical aryl groups include, but are not limited to, ls derived from benzene, tuted benzene, naphthalene, anthracene, biphenyl, and the like.

“Arylalkyl” refers to an acyclic alkyl radical in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or sp3 carbon atom, is replaced with an aryl radical. Typical arylalkyl groups include, but are not limited to, benzyl, 2-phenylethanyl, naphthylmethyl, 2-naphthylethanyl, naphthobenzyl, 2-naphthophenylethanyl and the like. The arylalkyl group comprises 6 to 20 carbon atoms, e.g., the alkyl moiety, including l, l or alkynyl groups, of the arylalkyl group is 1 to 6 carbon atoms and the aryl moiety is 5 to 14 carbon atoms.

“Substituted alkyl”, “substituted aryl”, and “substituted arylalkyl” mean alkyl, aryl, and arylalkyl respectively, in which one or more en atoms are each independently ed with a non-hydrogen substituent. Typical substituents include, but are not limited to: halo (e.g. F, Cl, Br, I), -R, -OR, -SR, -NR2, -CF3, -CCl3, -OCF3, -CN, -NO2, -N(R)C(=O)R, -C(=O)R, -OC(=O)R, -C(O)OR, NRR, -S(=O)R, -S(=O)2OR, -S(=O)2R, -OS(=O)2OR, -S(=O)2NRR, and each R is independently -H, alkyl, aryl, arylalkyl, or heterocycle. Alkylene, alkenylene, and lene groups may also be similarly tuted.

The term “optionally substituted” in reference to a particular moiety of the compound of formula I, (e.g., an optionally substituted aryl group) refers to a moiety having 0, 1, 2, or more substituents.

The symbol “-----“ in a ring structure means that a bond is a single or double bond. In E L E L E L D L L a miting example, can be D or D .

“Haloalkyl” as used herein includes an alkyl group substituted with one or more halogens (e.g. F, Cl, Br, or I). Representative examples of haloalkyl include trifluoromethyl, 2,2,2-trifluoroethyl, and 2,2,2-trifluoro(trifluoromethyl)ethyl.

“Heterocycle” or “heterocyclyl” as used herein includes by way of example and not limitation these heterocycles described in Paquette, Leo A.; Principles of Modern cyclic Chemistry (W.A. Benjamin, New York, 1968), particularly Chapters 1, 3, 4, 6, 7, and 9; The Chemistry of Heterocyclic Compounds, A Series of Monographs” (John Wiley & Sons, New York, 1950 to present), in particular Volumes 13, 14, 16, 19, and 28; and J.

Am. Chem. Soc. (1960) 82:5566. In one specific embodiment, “heterocycle” includes a “carbocycle” as defined herein, wherein one or more (e.g. 1, 2, 3, or 4) carbon atoms have been replaced with a heteroatom (e.g. O, N, or S). The term cycle also includes “heteroaryl” which is a heterocycle wherein at least one heterocyclic rings is aromatic.

Examples of heterocycles include by way of example and not limitation pyridyl, dihydropyridyl, tetrahydropyridyl (piperidyl), thiazolyl, tetrahydrothiophenyl, sulfur oxidized tetrahydrothiophenyl, pyrimidinyl, furanyl, thienyl, yl, pyrazolyl, imidazolyl, tetrazolyl, benzofuranyl, thianaphthalenyl, indolyl, indolenyl, quinolinyl, isoquinolinyl, idazolyl, piperidinyl, 4-piperidonyl, pyrrolidinyl, 2-pyrrolidonyl, pyrrolinyl, tetrahydrofuranyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, droisoquinolinyl, azocinyl, triazinyl, 6H-1,2,5-thiadiazinyl, 1,5,2-dithiazinyl, thienyl, thianthrenyl, pyranyl, isobenzofuranyl, chromenyl, xanthenyl, phenoxathinyl, 2H-pyrrolyl, isothiazolyl, isoxazolyl, pyrazinyl, pyridazinyl, indolizinyl, isoindolyl, 3H-indolyl, 1H-indazolyl, purinyl, 4H-quinolizinyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl, 4H-carbazolyl, carbazolyl, β-carbolinyl, phenanthridinyl, acridinyl, dinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, furazanyl, phenoxazinyl, isochromanyl, chromanyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperazinyl, indolinyl, olinyl, quinuclidinyl, morpholinyl, oxazolidinyl, benzotriazolyl, benzisoxazolyl, oxindolyl, benzoxazolinyl, isatinoyl, and bis-tetrahydrofuranyl: O .

By way of example and not limitation, carbon bonded cycles are bonded at on 2, 3, 4, 5, or 6 of a pyridine, position 3, 4, 5, or 6 of a zine, position 2, 4, 5, or 6 of a dine, position 2, 3, 5, or 6 of a pyrazine, position 2, 3, 4, or 5 of a furan, tetrahydrofuran, ran, thiophene, pyrrole or tetrahydropyrrole, position 2, 4, or 5 of an oxazole, imidazole or thiazole, position 3, 4, or 5 of an isoxazole, pyrazole, or isothiazole, position 2 or 3 of an aziridine, position 2, 3, or 4 of an azetidine, position 2, 3, 4, 5, 6, 7, or 8 of a ine or on 1, 3, 4, 5, 6, 7, or 8 of an isoquinoline. Still more typically, carbon bonded heterocycles include 2-pyridyl, 3-pyridyl, 4-pyridyl, 5-pyridyl, dyl, 3- zinyl, 4-pyridazinyl, 5-pyridazinyl, 6-pyridazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5- pyrimidinyl, 6-pyrimidinyl, 2-pyrazinyl, 3-pyrazinyl, 5-pyrazinyl, 6-pyrazinyl, zolyl, 4- thiazolyl, or 5-thiazolyl.

By way of example and not limitation, nitrogen bonded heterocycles are bonded at position 1 of an aziridine, azetidine, pyrrole, pyrrolidine, 2-pyrroline, 3-pyrroline, imidazole, imidazolidine, azoline, 3-imidazoline, pyrazole, pyrazoline, 2-pyrazoline, 3- pyrazoline, piperidine, piperazine, indole, indoline, 1H-indazole, position 2 of a isoindole, or isoindoline, position 4 of a morpholine, and position 9 of a carbazole, or β-carboline. Still more typically, nitrogen bonded heterocycles include 1-aziridyl, 1-azetedyl, 1-pyrrolyl, 1- imidazolyl, 1-pyrazolyl, and 1-piperidinyl.

“Carbocycle” refers to a saturated, unsaturated or aromatic ring having up to about 25 carbon atoms. Typically, a carbocycle has about 3 to 7 carbon atoms as a monocycle, about 7 to 12 carbon atoms as a bicycle, and up to about 25 carbon atoms as a polycycle. Monocyclic carbocycles typically have 3 to 6 ring atoms, still more typically 5 or 6 ring atoms. Bicyclic carbocycles lly have 7 to 12 ring atoms, e.g., arranged as a bicyclo [4,5], [5,5], [5,6] or [6,6] system, or 9 or 10 ring atoms ed as a bicyclo [5,6] or [6,6] system. The term carbocycle includes “cycloalkyl” which is a saturated or unsaturated carbocycle. Examples of clic ycles include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopentenyl, 1-cyclopentenyl, 1-cyclopentenyl, cyclohexyl, 1-cyclohexenyl, 1-cyclohexenyl, 1- cyclohexenyl, phenyl, spiryl and naphthyl.

The term “amino,” as used herein, refers to -NH2.

The term “chiral” refers to molecules which have the property of nonsuperimposability of the mirror image partner, while the term “achiral” refers to molecules which are superimposable on their mirror image partner.

The term “stereoisomers” refers to compounds which have cal chemical constitution, but differ with regard to the arrangement of the atoms or groups in space. ereomer” refers to a stereoisomer with two or more centers of chirality and whose molecules are not mirror images of one another. reomers have different physical properties, e.g., g points, boiling points, spectral properties, and reactivities.

Mixtures of diastereomers may te under high tion analytical procedures such as electrophoresis and chromatography.

“Enantiomers” refer to two stereoisomers of a compound which are non- superimposable mirror images of one another.

The term “treatment” or “treating,” to the extent it relates to a disease or ion includes preventing the disease or condition from ing, inhibiting the disease or condition, eliminating the e or condition, and/or relieving one or more symptoms of the disease or condition.

Stereochemical tions and conventions used herein generally follow S. P.

Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., Stereochemistry of Organic Compounds (1994) John Wiley & Sons, Inc., New York. Many organic compounds exist in optically active forms, i.e., they have the ability to rotate the plane of plane-polarized light. In bing an optically active compound, the prefixes (D and L) or (R and S) are used to denote the absolute configuration of the molecule about its chiral center(s). The prefixes d and l or (+) and (-) are employed to designate the sign of rotation of plane-polarized light by the compound, with (-) or 1 meaning that the compound is levorotatory. A nd prefixed with (+) or d is rotatory. For a given chemical structure, these stereoisomers are identical except that they are mirror images of one another. A specific stereoisomer may also be referred to as an enantiomer, and a mixture of such isomers is often called an enantiomeric mixture. A 50:50 mixture of enantiomers is ed to as a racemic mixture or a racemate, which may occur where there has been no stereoselection or stereospecificity in a chemical reaction or process. The terms “racemic mixture” and ate” refer to an equimolar mixture of two enantiomeric species, devoid of l activity. The disclosure includes all stereoisomers of the compounds bed herein.

Prodrugs The term “prodrug” as used herein refers to any compound that when administered to a biological system tes a compound of the disclosure that inhibits HCV activity (“the active inhibitory compound”). The compound may be formed from the prodrug as a result of: (i) spontaneous chemical on(s), (ii) enzyme catalyzed chemical reaction(s), (iii) photolysis, and/or (iv) metabolic chemical reaction(s).

“Prodrug moiety” refers to a labile functional group which separates from the active inhibitory nd during metabolism, systemically, inside a cell, by hydrolysis, enzymatic cleavage, or by some other process (Bundgaard, Hans, “Design and Application of Prodrugs” in A Textbook of Drug Design and Development (1991), P. Krogsgaard-Larsen and H.

Bundgaard, Eds. Harwood Academic Publishers, pp. 113-191). Enzymes which are capable of an enzymatic activation ism with the prodrug nds of the disclosure include, but are not limited to, amidases, esterases, microbial s, phospholipases, cholinesterases, and phosphases. Prodrug moieties can serve to enhance solubility, absorption and lipophilicity to optimize drug delivery, ilability and efficacy. A prodrug moiety may include an active metabolite or drug itself.

Exemplary prodrug moieties include the hydrolytically sensitive or labile acyloxymethyl esters CH2OC(=O)R99 and acyloxymethyl carbonates (=O)OR99 where R99 is C1C6 alkyl, C1C6 substituted alkyl, C6C20 aryl or C6C20 substituted aryl.

The acyloxyalkyl ester was first used as a prodrug strategy for ylic acids and then applied to phosphates and phosphonates by Farquhar et al. (1983) J. Pharm. Sci. 72: 324; also US Patent Nos. 4816570, 4968788, 5663159 and 5792756. Subsequently, the acyloxyalkyl ester was used to deliver phosphonic acids across cell nes and to enhance oral bioavailability. A close variant of the acyloxyalkyl ester, the alkoxycarbonyloxyalkyl ester (carbonate), may also enhance oral bioavailability as a prodrug moiety in the compounds of the combinations of the disclosure. An ary acyloxymethyl ester is pivaloyloxymethoxy, (POM) CH2OC(=O)C(CH3)3. An exemplary acyloxymethyl carbonate prodrug moiety is yloxymethylcarbonate (POC)  =O)OC(CH3)3.

Aryl esters of phosphorus groups, especially phenyl esters, are reported to enhance oral bioavailability (De Lombaert et al. (1994) J. Med. Chem. 37: 498). Phenyl esters containing a carboxylic ester ortho to a phosphate have also been described (Khamnei and Torrence, (1996) J. Med. Chem. 39:4109-4115). Benzyl esters are reported to generate parent phosphonic acids. In some cases, substituents at the ortho- or para- position may accelerate the hydrolysis. Benzyl analogs with an acylated phenol or an alkylated phenol may generate the phenolic compound through the action of enzymes, e.g., esterases, es, etc., which in turn undergoes cleavage at the benzylic CO bond to generate phosphoric acid and a quinone methide intermediate. Examples of this class of prodrugs are described by Mitchell et al. (1992) J. Chem. Soc. Perkin Trans. II 2345; Glazier WO 91/19721. Still other benzylic prodrugs have been described containing a carboxylic ester-containing group attached to the benzylic ene (Glazier WO 91/19721). Thio-containing prodrugs are reported to be useful for the intracellular delivery of phosphonate drugs. These proesters n an ethylthio group in which the thiol group is either esterified with an acyl group or combined with another thiol group to form a ide. rification or ion of the ide generates the free thio intermediate which subsequently breaks down to the phosphoric acid and episulfide (Puech et al. (1993) Antiviral Res., 22: 155-174; Benzaria et al. (1996) J. Med. Chem. 39: 4958).

Protecting Groups In the context of the present disclosure, protecting groups include prodrug es and al ting .

“Protecting group” refers to a moiety of a compound that masks or alters the properties of a functional group or the ties of the compound as a whole. Chemical protecting groups and gies for protection/deprotection are well known in the art. See e.g., Protective Groups in Organic Chemistry, Theodora W. Greene, John Wiley & Sons, Inc., New York, 1991. ting groups are often utilized to mask the reactivity of certain functional groups, to assist in the efficiency of desired chemical reactions, e.g., making and breaking chemical bonds in an ordered and planned fashion. Protection of functional groups of a compound alters other physical properties besides the reactivity of the protected functional group, such as the polarity, lipophilicity phobicity), and other properties which can be measured by common analytical tools. Chemically protected intermediates may themselves be biologically active or inactive.

Protected compounds may also exhibit altered, and in some cases, zed properties in vitro and in vivo, such as passage through cellular membranes and resistance to enzymatic degradation or sequestration. In this role, protected compounds with intended therapeutic effects may be referred to as prodrugs. Another function of a protecting group is to convert the parental drug into a prodrug, whereby the al drug is released upon conversion of the prodrug in vivo. Because active prodrugs may be absorbed more effectively than the parental drug, prodrugs may possess greater potency in vivo than the parental drug. ting groups are removed either in vitro, in the instance of chemical intermediates, or in vivo, in the case of prodrugs. With chemical intermediates, it is not particularly ant that the resulting ts after deprotection, e.g., ls, be physiologically acceptable, although in general it is more desirable if the products are pharmacologically innocuous.

Protecting groups are available, commonly known and used, and are optionally used to prevent side reactions with the protected group during synthetic procedures, i.e. routes or methods to prepare the compounds of the disclosure. For the most part the decision as to which groups to protect, when to do so, and the nature of the chemical protecting group “PG” will be dependent upon the chemistry of the reaction to be protected against (e.g., acidic, basic, oxidative, ive or other conditions) and the intended direction of the synthesis.

PGs do not need to be, and generally are not, the same if the compound is substituted with multiple PGs. In general, PG will be used to protect functional groups such as carboxyl, hydroxyl, thio, or amino groups and to thus prevent side reactions or to otherwise facilitate the synthetic efficiency. The order of deprotection to yield free deprotected groups is dependent upon the intended direction of the synthesis and the reaction conditions to be encountered, and may occur in any order as determined by the artisan. s functional groups of the compounds of the disclosure may be protected. For example, protecting groups for –OH groups er hydroxyl, carboxylic acid, phosphonic acid, or other functions) e “ether- or ester-forming groups”. Ether- or ester-forming groups are capable of functioning as chemical protecting groups in the tic schemes set forth herein. However, some hydroxyl and thio protecting groups are neither ether- nor esterforming , as will be understood by those skilled in the art, and are included with , discussed below.

A very large number of hydroxyl protecting groups and amide-forming groups and corresponding chemical cleavage reactions are described in Protective Groups in Organic Synthesis, Theodora W. Greene (John Wiley & Sons, Inc., New York, 1991, ISBN 0 62301-6) (“Greene”). See also Kocienski, Philip J.; Protecting Groups (Georg Thieme Verlag Stuttgart, New York, 1994), which is incorporated by reference in its ty herein.

In particular Chapter 1, Protecting Groups: An Overview, pages 1-20, Chapter 2, Hydroxyl Protecting Groups, pages 21-94, Chapter 3, Diol Protecting Groups, pages 95-117, Chapter 4, Carboxyl Protecting Groups, pages 4, Chapter 5, yl Protecting Groups, pages 155-184. For protecting groups for carboxylic acid, phosphonic acid, phosphonate, sulfonic acid and other ting groups for acids see Greene as set forth below.

By way of example and not limitation, variables described herein may recursive substituents in certain embodiments. Typically, each of these may ndently occur 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, 1, or 0, times in a given embodiment. More typically, each of these may ndently occur 12 or fewer times in a given embodiment. Whenever a compound described herein is substituted with more than one of the same designated group, e.g., “R1” or “R3”, then it will be understood that the groups may be the same or different, i.e., each group is independently selected. Wavy lines indicate the site of nt bond attachments to the adjoining groups, es, or atoms.

In one embodiment of the disclosure, the compound is in an isolated and purified form. Generally, the term ted and purified” means that the compound is substantially free from biological materials (e.g. blood, tissue, cells, etc.). In one specific embodiment of the disclosure, the term means that the nd or conjugate of the disclosure is at least about 50 wt.% free from biological materials; in another specific embodiment, the term means that the compound or conjugate of the disclosure is at least about 75 wt.% free from biological materials; in another specific embodiment, the term means that the compound or conjugate of the disclosure is at least about 90 wt.% free from biological materials; in another specific embodiment, the term means that the compound or conjugate of the disclosure is at least about 98 wt.% free from biological materials; and in another embodiment, the term means that the compound or conjugate of the disclosure is at least about 99 wt.% free from biological materials. In another specific ment, the sure provides a compound or conjugate of the disclosure that has been synthetically ed (e.g., ex vivo). isomers The compounds of the disclosure may have chiral centers, e.g., chiral carbon or phosphorus atoms. The compounds of the sure thus include racemic mixtures of all stereoisomers, including enantiomers, diastereomers, and atropisomers. In addition, the compounds of the disclosure e ed or resolved optical isomers at any or all asymmetric, chiral atoms. In other words, the chiral s apparent from the ions are provided as the chiral isomers or racemic mixtures. Both racemic and diastereomeric es, as well as the individual l isomers isolated or synthesized, substantially free of their enantiomeric or diastereomeric partners, are all within the scope of the disclosure.

The racemic mixtures are ted into their individual, substantially optically pure isomers through well-known techniques such as, for example, the separation of diastereomeric salts formed with optically active adjuncts, e.g., acids or bases followed by conversion back to the optically active nces. In most instances, the desired optical isomer is synthesized by means of stereospecific reactions, beginning with the appropriate stereoisomer of the desired starting material.

The compounds of the disclosure can also exist as tautomeric isomers in certain cases.

Although only one tautomer may be depicted, all such forms are contemplated within the scope of the disclosure. For example, ene-amine tautomers can exist for purine, pyrimidine, imidazole, guanidine, amidine, and tetrazole systems and all their possible tautomeric forms are within the scope of the disclosure.

Salts and Hydrates Examples of physiologically or pharmaceutically acceptable salts of the compounds of the disclosure include salts derived from an appropriate base, such as an alkali metal (for example, sodium), an alkaline earth metal (for example, magnesium), um and NX4+ (wherein X is C1-C4 alkyl). Physiologically acceptable salts of a hydrogen atom or an amino group include salts of organic carboxylic acids such as acetic, benzoic, lactic, fumaric, tartaric, maleic, malonic, malic, isethionic, lactobionic and ic acids; organic sulfonic acids, such as methanesulfonic, ethanesulfonic, benzenesulfonic and p-toluenesulfonic acids; and inorganic acids, such as hydrochloric, sulfuric, oric and sulfamic acids.

Physiologically acceptable salts of a compound of a hydroxy group include the anion of said compound in combination with a suitable cation such as Na+ and NX4+ (wherein X is independently selected from H or a C1C4 alkyl group).

For therapeutic use, salts of active ingredients of the nds of the sure will typically be physiologically acceptable, i.e. they will be salts d from a physiologically acceptable acid or base. However, salts of acids or bases which are not physiologically acceptable may also find use, for example, in the preparation or purification of a physiologically acceptable compound. All salts, r or not derived from a physiologically acceptable acid or base, are within the scope of the present disclosure.

Metal salts typically are prepared by reacting the metal hydroxide with a compound of this disclosure. Examples of metal salts which are prepared in this way are salts containing Li+, Na+, and K+. A less soluble metal salt can be precipitated from the solution of a more soluble salt by addition of the suitable metal compound.

In addition, salts may be formed from acid addition of certain organic and inorganic acids, e.g., HCl, HBr, H2SO4, H3PO4 or organic sulfonic acids, to basic centers, typically amines, or to acidic groups. Finally, it is to be understood that the compositions herein se compounds of the sure in their un-ionized, as well as rionic form, and combinations with stoichiometric s of water as in hydrates.

Also ed within the scope of this disclosure are the salts of the parental compounds with one or more amino acids. Any of the natural or unnatural amino acids are suitable, especially the naturally-occurring amino acids found as protein components, although the amino acid typically is one bearing a side chain with a basic or acidic group, e.g., lysine, ne or glutamic acid, or a neutral group such as glycine, serine, threonine, alanine, isoleucine, or leucine.

Methods of Inhibition of HCV Another aspect of the sure relates to methods of inhibiting the activity of HCV comprising the step of treating a sample suspected of containing HCV with a compound or composition of the disclosure.

Compounds of the disclosure may act as inhibitors of HCV, as intermediates for such inhibitors or have other utilities as described below. The inhibitors will lly bind to locations on the surface or in a cavity of the liver. Compounds binding in the liver may bind with varying degrees of reversibility. Those compounds binding substantially irreversibly are ideal candidates for use in this method of the disclosure. Once d, the substantially irreversibly binding compounds are useful as probes for the detection of HCV. Accordingly, the sure relates to methods of detecting NS3 in a sample suspected of ning HCV comprising the steps of: treating a sample suspected of containing HCV with a composition comprising a compound of the disclosure bound to a label; and observing the effect of the sample on the activity of the label. le labels are well known in the diagnostics field and include stable free radicals, phores, radioisotopes, enzymes, chemiluminescent groups and chromogens. The compounds herein are labeled in conventional n using functional groups such as hydroxyl or amino. In one ment the disclosure provides a compound of any one of formulae (I) and (A1)-(A4) that comprises or that is bound or linked to one or more detectable labels. Within the context of the disclosure samples suspected of containing HCV include natural or man-made materials such as living organisms; tissue or cell cultures; biological samples such as biological al samples (blood, serum, urine, cerebrospinal fluid, tears, sputum, saliva, tissue s, and the like); laboratory samples; food, water, or air samples; bioproduct samples such as extracts of cells, particularly recombinant cells synthesizing a desired glycoprotein; and the like. Typically the sample will be suspected of containing HCV. Samples can be contained in any medium including water and organic solvent/water es. Samples include living organisms such as humans, and man made materials such as cell cultures.

The treating step of the disclosure comprises adding the compound of the disclosure to the sample or it comprises adding a precursor of the composition to the . The addition step ses any method of administration as described above.

If desired, the activity of HCV after application of the compound can be observed by any method including direct and indirect methods of detecting HCV activity. Quantitative, qualitative, and semiquantitative methods of determining HCV activity are all contemplated.

Typically one of the screening methods described above are applied, however, any other method such as observation of the physiological properties of a living organism are also applicable.

Many sms contain HCV. The nds of this disclosure are useful in the treatment or prophylaxis of conditions associated with HCV activation in animals or in man.

However, in screening compounds capable of inhibiting HCV activity it should be kept in mind that the results of enzyme assays may not always correlate with cell culture assays. Thus, a cell based assay should typically be the primary screening tool.

Pharmaceutical Formulations The nds of this disclosure are formulated with conventional carriers and excipients, which will be selected in accord with ordinary practice. Tablets will contain excipients, glidants, fillers, binders and the like. Aqueous ations are prepared in sterile form, and when intended for delivery by other than oral administration generally will be isotonic. All formulations will optionally contain ents such as those set forth in the ok of Pharmaceutical Excipients (1986). Excipients include ascorbic acid and other antioxidants, chelating agents such as EDTA, ydrates such as dextrin, hydroxyalkylcellulose, hydroxyalkylmethylcellulose, stearic acid and the like. The pH of the ations ranges from about 3 to about 11, but is ordinarily about 7 to 10. Typically, the compound will be administered in a dose from 0.01 rams to 2 grams. In one embodiment, the dose will be from about 10 milligrams to 450 milligrams. In another embodiment, the dosage will be from about 25 to about 250 milligrams. In another embodiment, the dosage will be about 50 or 100 milligrams. In one embodiment, the dosage will be about 100 rams. It is contemplated that the compound may be administered once, twice or three times a day.

While it is possible for the active ingredients to be administered alone it may be preferable to present them as pharmaceutical formulations. The formulations, both for veterinary and for human use, of the disclosure comprise at least one active ingredient, as above defined, together with one or more acceptable carriers therefor and optionally other therapeutic ingredients. The carrier(s) must be table” in the sense of being compatible with the other ingredients of the formulation and physiologically innocuous to the recipient thereof.

The formulations include those suitable for the foregoing administration . The ations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. Techniques and formulations generally are found in Remington’s Pharmaceutical Sciences (Mack Publishing Co., Easton, PA). Such methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more accessory ingredients. In general the ations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product.

Formulations of the present disclosure suitable for oral administration may be ted as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a on or a suspension in an aqueous or non-aqueous liquid; or as an oil-in-water liquid emulsion or a in-oil liquid emulsion. The active ingredient may also be administered as a bolus, electuary or paste.

A tablet is made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable e the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a , lubricant, inert diluent, preservative, surface active or dispersing agent. Molded s may be made by molding in a suitable e a mixture of the powdered active ingredient moistened with an inert liquid t. The tablets may optionally be coated or scored and ally are ated so as to provide slow or controlled release of the active ingredient therefrom.

For administration to the eye or other external tissues e.g., mouth and skin, the formulations are preferably applied as a topical ointment or cream ning the active ingredient(s) in an amount of, for example, 0.075 to 20% w/w (including active ingredient(s) in a range between 0.1% and 20% in increments of 0.1% w/w such as 0.6% w/w, 0.7% w/w, etc.), ably 0.2 to 15% w/w and most preferably 0.5 to 10% w/w. When formulated in an ointment, the active ingredients may be employed with either a paraffinic or a watermiscible ointment base. Alternatively, the active ingredients may be formulated in a cream with an oil-in-water cream base.

If desired, the aqueous phase of the cream base may include, for example, at least % w/w of a polyhydric alcohol, i.e. an alcohol having two or more hydroxyl groups such as propylene glycol, butane 1,3-diol, mannitol, sorbitol, glycerol and polyethylene glycol (including PEG 400) and es thereof. The topical formulations may desirably include a compound which enhances absorption or penetration of the active ingredient through the skin or other affected areas. Examples of such dermal penetration enhancers include yl sulphoxide and related analogs.

The oily phase of the emulsions of this disclosure may be constituted from known ingredients in a known manner. While the phase may comprise merely an emulsifier (otherwise known as an emulgent), it desirably comprises a mixture of at least one emulsifier with a fat or an oil or with both a fat and an oil. Preferably, a hydrophilic emulsifier is included together with a lipophilic emulsifier which acts as a stabilizer. It is also preferred to include both an oil and a fat. Together, the emulsifier(s) with or without izer(s) make up the so-called emulsifying wax, and the wax together with the oil and fat make up the socalled emulsifying ointment base which forms the oily dispersed phase of the cream formulations.

Emulgents and emulsion stabilizers suitable for use in the formulation of the disclosure include Tween® 60, Span® 80, cetostearyl alcohol, benzyl alcohol, myristyl alcohol, glyceryl mono-stearate and sodium lauryl sulfate.

The choice of suitable oils or fats for the formulation is based on ing the desired cosmetic properties. The cream should preferably be a non-greasy, non-staining and washable product with suitable consistency to avoid leakage from tubes or other containers.

Straight or branched chain, mono- or dibasic alkyl esters such as di-isoadipate, isocetyl stearate, propylene glycol diester of coconut fatty acids, isopropyl myristate, decyl oleate, pyl palmitate, butyl stearate, 2-ethylhexyl palmitate or a blend of branched chain esters known as Crodamol CAP may be used, the last three being preferred esters. These may be used alone or in ation depending on the properties ed. atively, high melting point lipids such as white soft paraffin and/or liquid paraffin or other mineral oils are used.

Pharmaceutical ations according to the present disclosure comprise one or more compounds of the sure together with one or more ceutically acceptable carriers or ents and optionally other therapeutic agents. Pharmaceutical ations containing the active ingredient may be in any form suitable for the intended method of administration. When used for oral use for example, tablets, troches, lozenges, s or oil suspensions, dispersible s or granules, emulsions, hard or soft capsules, syrups or elixirs may be prepared. itions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents including sweetening agents, flavoring , coloring agents and preserving agents, in order to provide a palatable preparation. s containing the active ingredient in admixture with non-toxic pharmaceutically acceptable excipient which are suitable for manufacture of tablets are acceptable. These excipients may be, for example, inert diluents, such as calcium or sodium carbonate, lactose, lactose monohydrate, rmellose sodium, povidone, calcium or sodium phosphate; granulating and disintegrating agents, such as maize starch, or alginic acid; binding , such as cellulose, microcrystalline ose, starch, gelatin or acacia; and lubricating agents, such as magnesium stearate, c acid or talc. Tablets may be uncoated or may be coated by known techniques including microencapsulation to delay egration and adsorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as yl monostearate or glyceryl distearate alone or with a wax may be employed.

Formulations for oral use may be also ted as hard gelatin capsules where the active ingredient is mixed with an inert solid diluent, for example calcium phosphate or kaolin, or as soft gelatin es wherein the active ingredient is mixed with water or an oil medium, such as peanut oil, liquid paraffin or olive oil. s suspensions of the disclosure contain the active als in admixture with excipients suitable for the manufacture of s suspensions. Such excipients include a suspending agent, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methylcelluose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia, and dispersing or wetting agents such as a naturally occurring atide (e.g., lecithin), a condensation product of an alkylene oxide with a fatty acid (e.g., polyoxyethylene stearate), a condensation product of ethylene oxide with a long chain aliphatic alcohol (e.g., heptadecaethyleneoxycetanol), a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol anhydride (e.g., polyoxyethylene sorbitan monooleate). The aqueous suspension may also contain one or more preservatives such as ethyl or n-propyl p-hydroxy-benzoate, one or more coloring agents, one or more flavoring agents and one or more sweetening agents, such as sucrose or saccharin.

Oil suspensions may be formulated by suspending the active ingredient in a vegetable oil, such as s oil, olive oil, sesame oil or t oil, or in a mineral oil such as liquid paraffin. The oral suspensions may contain a thickening agent, such as beeswax, hard paraffin or cetyl alcohol. Sweetening agents, such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an antioxidant such as ascorbic acid.

Dispersible powders and granules of the disclosure suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or g agent, a suspending agent, and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those disclosed above.

Additional excipients, for example sweetening, ing and coloring , may also be present.

The pharmaceutical compositions of the disclosure may also be in the form of - water emulsions. The oily phase may be a vegetable oil, such as olive oil or arachis oil, a mineral oil, such as liquid paraffin, or a mixture of these. Suitable emulsifying agents include naturally-occurring gums, such as gum acacia and gum tragacanth, naturally occurring phosphatides, such as soybean lecithin, esters or partial esters derived from fatty acids and hexitol anhydrides, such as sorbitan monooleate, and condensation products of these partial esters with ethylene oxide, such as polyoxyethylene an monooleate. The emulsion may also contain sweetening and flavoring agents. Syrups and elixirs may be formulated with sweetening agents, such as glycerol, ol or sucrose. Such formulations may also contain a demulcent, a preservative, a flavoring or a coloring agent.

The pharmaceutical compositions of the disclosure may be in the form of a sterile injectable ation, such as a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated ing to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable t or solvent, such as a solution in 1,3-butane-diol or prepared as a lyophilized . Among the acceptable vehicles and solvents that may be ed are water, ’s solution and isotonic sodium chloride solution. In addition, sterile fixed oils may conventionally be employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid may likewise be used in the preparation of injectables.

The amount of active ingredient that may be combined with the carrier material to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. For e, a time-release formulation intended for oral administration to humans may contain approximately 1 to 1000 mg of active material compounded with an appropriate and ient amount of carrier material which may vary from about 5 to about 95% of the total compositions (weight:weight). The pharmaceutical composition can be prepared to provide easily measurable amounts for administration. For example, an aqueous solution intended for intravenous infusion may contain from about 3 to 500 µg of the active ingredient per milliliter of solution in order that infusion of a suitable volume at a rate of about 30 mL/hr can occur.

Formulations suitable for administration to the eye e eye drops wherein the active ient is ved or suspended in a suitable carrier, especially an aqueous solvent for the active ingredient. The active ingredient is preferably present in such formulations in a concentration of 0.5 to 20%, advantageously 0.5 to 10% ularly about 1.5% w/w.

Formulations suitable for topical administration in the mouth include lozenges comprising the active ingredient in a flavored basis, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert basis such as n and glycerin, or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.

Formulations for rectal administration may be presented as a suppository with a suitable base comprising for example cocoa butter or a salicylate.

Formulations le for intrapulmonary or nasal administration have a particle size for example in the range of 0.1 to 500 microns (including particle sizes in a range between 0.1 and 500 microns in increments such as 0.5 microns, 1 micron, 30 microns, 35 s, etc.), which is administered by rapid inhalation through the nasal passage or by inhalation through the mouth so as to reach the ar sacs. Suitable ations include aqueous or oily solutions of the active ingredient. ations suitable for aerosol or dry powder administration may be prepared according to tional methods and may be delivered with other therapeutic agents such as compounds heretofore used in the treatment or prophylaxis of conditions associated with HCV activity.

Formulations le for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations containing in addition to the active ingredient such carriers as are known in the art to be appropriate.

Formulations suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation ic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.

The ations are presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid r, for example water for injection, immediately prior to use. Extemporaneous injection solutions and suspensions are prepared from sterile s, es and tablets of the kind previously described. Preferred unit dosage formulations are those containing a daily dose or unit daily sub-dose, as herein above recited, or an appropriate fraction thereof, of the active ingredient.

It should be understood that in addition to the ingredients particularly mentioned above the formulations of this disclosure may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavoring agents.

The disclosure r provides veterinary itions comprising at least one active ingredient as above defined er with a veterinary carrier therefor.

Veterinary carriers are materials useful for the purpose of administering the composition and may be solid, liquid or gaseous materials which are otherwise inert or acceptable in the veterinary art and are compatible with the active ingredient. These veterinary compositions may be stered orally, parenterally or by any other desired route.

Compounds of the disclosure can also be formulated to provide lled e of the active ingredient to allow less frequent dosing or to improve the pharmacokinetic or toxicity profile of the active ingredient. Accordingly, the disclosure also es compositions sing one or more compounds of the disclosure formulated for ned or controlled release.

Effective dose of active ingredient depends at least on the nature of the condition being treated, toxicity, r the compound is being used prophylactically (lower doses), the method of delivery, and the pharmaceutical formulation, and will be determined by the clinician using conventional dose escalation studies.

Routes of Administration One or more compounds of the disclosure (herein referred to as the active ingredients) are administered by any route appropriate to the condition to be treated. Suitable routes include oral, rectal, nasal, topical (including buccal and sublingual), l and parenteral (including subcutaneous, intramuscular, intravenous, ermal, intrathecal and epidural), and the like. It will be iated that the preferred route may vary with for example the condition of the recipient. An advantage of the compounds of this disclosure is that they are orally bioavailable and can be dosed orally.

HCV Combination Therapy In another embodiment, non-limiting examples of suitable combinations include combinations of one or more compounds of formula (I) and (A1-A4) with one or more interferons, ribavirin or its analogs, HCV NS3 protease inhibitors, alpha-glucosidase 1 tors, hepatoprotectants, nucleoside or nucleotide inhibitors of HCV NS5B polymerase, cleoside inhibitors of HCV NS5B polymerase, HCV NS5A inhibitors, TLR-7 agonists, cyclophillin inhibitors, HCV IRES inhibitors, pharmacokinetic enhancers, and other drugs or therapeutic agents for treating HCV.

More specifically, one or more nds as described herein may be combined with one or more compounds selected from the group consisting of: 1) interferons, e.g., pegylated rIFN-alpha 2b (PEG-Intron), pegylated lpha 2a (Pegasys), rIFN-alpha 2b n A), rIFN-alpha 2a (Roferon-A), interferon alpha (MOR-22, OPC-18, Alfaferone, Alfanative, Multiferon, subalin), interferon alfacon-1 (Infergen), interferon n1 (Wellferon), interferon alpha-n3 (Alferon), interferon-beta (Avonex, DL- 8234), interferon-omega (omega DUROS, Biomed 510), albinterferon alpha-2b (Albuferon), IFN alpha-2b XL, BLX-883 (Locteron), DA-3021, glycosylated interferon alpha-2b (AVI- 005), PEG-Infergen, PEGylated interferon lambda-1 (PEGylated IL-29), and fon; 2) ribavirin and its analogs, e.g., ribavirin (Rebetol, s), and taribavirin (Viramidine); 3) HCV NS3 protease inhibitors, e.g., evir (SCH-503034, SCH-7), telaprevir (VX-950), TMC435350, BI-1335, BI-1230, MK-7009, VBY-376, VX-500, GS-9256, GS- 9451, BMS-605339, PHX-1766, AS-101, YH-5258, , YH5531, 0, ACH- 1625, 91, MK5172, MK6325, and MK2748; 4) alpha-glucosidase 1 inhibitors, e.g., celgosivir (MX-3253), Miglitol, and UT-231B; ) hepatoprotectants, e.g., emericasan 556), ME-3738, GS-9450 (LB-84451), silibilin, and MitoQ; 6) nucleoside or nucleotide inhibitors of HCV NS5B polymerase, e.g., R1626, R7128 (R4048), , IDX-102, BCX-4678, valopicitabine (NM-283), 8, sofosbuvir (GS-7977 (formerly PSI-7977)), and INX-189 (now BMS986094); 7) non-nucleoside inhibitors of HCV NS5B polymerase, e.g., PF-868554, VCH-759, VCH-916, JTK-652, 1, GS-9190, VBY-708, VCH-222, A848837, 8, GL60667, GL59728, A-63890, A-48773, A-48547, 9, 6 (nesbuvir), GSK625433, 941, XTL-2125, ABT-072, ABT-333, GS-9669, PSI-7792, and GS- 9190; 8) HCV NS5A inhibitors, e.g., AZD-2836 ), BMS-790052, ACH-3102, ACH- 2928, MK8325, MK4882, MK8742, PSI-461, IDX719, and A-689; 9) TLR-7 agonists, e.g., imiquimod, 852A, 4, ANA-773, ANA-975, AZD- 8848 (DSP-3025), and SM-360320; 10) cyclophillin inhibitors, e.g., DEBIO-025, SCY-635, and NIM811; 11) HCV IRES inhibitors, e.g., MCI-067; 12) pharmacokinetic enhancers, e.g., BAS-100, 2, PF-4194477, TMC-41629, GS-9350, GS-9585, and roxythromycin; and 13) other drugs for treating HCV, e.g., thymosin alpha 1 (Zadaxin), nitazoxanide (Alinea, NTZ), BIVN-401 (virostat), PYN-17 (altirex), KPE02003002, n (CPG-10101), GS-9525, KRN-7000, civacir, GI-5005, XTL-6865, BIT225, PTX-111, ITX2865, TT-033i, ANA 971, NOV-205, tarvacin, EHC-18, VGX-410C, EMZ-702, AVI 4065, 0032, BMS-791325, Bavituximab, MDX-1106 (ONO-4538), Oglufanide, and VX-497 (merimepodib).

More specifically, one or more nds as described herein may be combined with one or more compounds selected from the group consisting of non-nucleoside inhibitors of HCV NS5B polymerase (ABT-072 and ABT-333), HCV NS5A inhibitors (ACH-3102 and ACH-2928) and HCV NS3 protease tors(ABT-450 and ACH-1625).

In yet another ment, the present application discloses pharmaceutical compositions comprising a compound as described herein, or a pharmaceutically acceptable salt, solvate, and/or ester thereof, in combination with at least one additional therapeutic agent, and a pharmaceutically acceptable r or excipient.

According to one embodiment, the eutic agent used in combination with the compound as described herein can be any agent having a therapeutic effect when used in combination with the compound as described herein. For example, the therapeutic agent used in combination with the compound as described herein can be interferons, ribavirin analogs, NS3 protease inhibitors, NS5b polymerase inhibitors, alpha-glucosidase 1 inhibitors, hepatoprotectants, cleoside inhibitors of HCV, and other drugs for treating HCV.

In another embodiment, the present application provides pharmaceutical compositions comprising a compound of formula (I), or a pharmaceutically acceptable salt, solvate, and/or ester thereof, in combination with at least one additional therapeutic agent selected from the group consisting of pegylated rIFN-alpha 2b, pegylated rIFN-alpha 2a, rIFN-alpha 2b, IFN alpha-2b XL, rIFN-alpha 2a, consensus IFN alpha, en, rebif, locteron, AVI-005, PEG- en, pegylated IFN-beta, oral interferon alpha, feron, reaferon, intermax alpha, r-IFN- beta, infergen + actimmune, IFN-omega with DUROS, albuferon, rebetol, copegus, levovirin, VX-497, viramidine (taribavirin), A-831, A-689, NM-283, valopicitabine, R1626, PSI-6130 (R1656), HCV-796, BILB 1941, MK-0608, NM-107, R7128, VCH-759, 554, 433, XTL-2125, SCH-503034 (SCH-7), VX-950 (Telaprevir), ITMN-191, and BILN-2065, MX-3253 sivir), UT-231B, IDN-6556, ME 3738, MitoQ, and 51, benzimidazole derivatives, benzo-1,2,4-thiadiazine derivatives, and alanine derivatives, zadaxin, nitazoxanide (alinea), BIVN-401 (virostat), DEBIO-025, VGX-410C, 2, AVI 4065, bavituximab, oglufanide, PYN-17, KPE02003002, actilon (CPG- 10101), KRN-7000, civacir, GI-5005, ANA-975 (isatoribine), XTL-6865, ANA 971, NOV- 205, tarvacin, EHC-18, and NIM811 and a pharmaceutically acceptable carrier or excipient.

In yet another embodiment, the present application provides a combination pharmaceutical agent sing: a) a first pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt, solvate, or ester thereof; and b) a second pharmaceutical ition comprising at least one additional therapeutic agent selected from the group consisting of HIV protease inhibiting compounds, HIV non-nucleoside tors of reverse riptase, HIV nucleoside tors of reverse transcriptase, HIV nucleotide tors of reverse transcriptase, HIV integrase inhibitors, gp41 inhibitors, CXCR4 tors, gp120 inhibitors, CCR5 inhibitors, interferons, ribavirin analogs, NS3 protease inhibitors, alpha-glucosidase 1 inhibitors, hepatoprotectants, nonnucleoside inhibitors of HCV, and other drugs for treating HCV, and combinations f.

In another embodiment is provided a pharmaceutical composition comprising a compound of formula (I) as described herein and a nucleoside or nucleotide inhibitors of HCV NS5B polymerase and optionally an eron or ribavirin. In one embodiment, the compound is methyl {(2S)[(2S,5S)(9-{2-[(2S,4S){(2R) [(methoxycarbonyl)amino]phenylacetyl}(methoxymethyl)pyrrolidinyl]-1H- imidazolyl}-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl) methylpyrrolidinyl]methyloxobutanyl}carbamate having the formula: and the inhibitor is sofosbuvir.

Combinations of the nds of formula I and additional active therapeutic agents may be ed to treat patients ed with HCV and other conditions such as HIV infections. ingly, the compounds of formula I may be combined with one or more nds useful in treating HIV, for example HIV protease inhibiting compounds, nonnucleoside inhibitors of HIV e transcriptase, HIV nucleoside inhibitors of reverse transcriptase, HIV nucleotide inhibitors of e transcriptase, HIV integrase inhibitors, gp41 inhibitors, CXCR4 inhibitors, gp120 inhibitors, CCR5 inhibitors, interferons, ribavirin analogs, NS3 protease tors, NS5b polymerase inhibitors, alpha-glucosidase 1 inhibitors, hepatoprotectants, non-nucleoside tors of HCV, and other drugs for treating HCV.

More specifically, one or more compounds of formula (I) or (A1)-(A4) may be combined with one or more compounds selected from the group ting of 1) HIV protease inhibitors, e.g., amprenavir, atazanavir, fosamprenavir, indinavir, lopinavir, ritonavir, lopinavir + ritonavir, nelfinavir, saquinavir, tipranavir, brecanavir, darunavir, TMC- 126, TMC-114, mozenavir (DMP-450), JE-2147 (AG1776), AG1859, DG35, L-756423, RO0334649, KNI-272, DPC-681, DPC-684, and GW640385X, DG17, PPL-100, 2) a HIV non-nucleoside inhibitor of reverse transcriptase, e.g., capravirine, emivirine, delaviridine, efavirenz, nevirapine, (+) calanolide A, etravirine, GW5634, DPC-083, DPC-961, 3, 0, and TMC-120, TMC-278 (rilpivirine), efavirenz, BILR 355 BS, VRX 840773, UK-453,061, RDEA806, 3) a HIV nucleoside inhibitor of reverse riptase, e.g., zidovudine, emtricitabine, didanosine, stavudine, zalcitabine, lamivudine, abacavir, amdoxovir, elvucitabine, alovudine, MIV-210, racivir (-FTC), , emtricitabine, phosphazide, fozivudine tidoxil, fosalvudine tidoxil, apricitibine (AVX754), vir, KP- 1461, abacavir + lamivudine, abacavir + lamivudine + zidovudine, zidovudine + lamivudine, 4) a HIV nucleotide inhibitor of reverse transcriptase, e.g., tenofovir, tenofovir disoproxil fumarate + emtricitabine, vir disoproxil fumarate + emtricitabine + efavirenz, and adefovir, 5) a HIV integrase inhibitor, e.g., curcumin, derivatives of in, chicoric acid, derivatives of ic acid, 3,5-dicaffeoylquinic acid, derivatives of 3,5-dicaffeoylquinic acid, aurintricarboxylic acid, derivatives of aurintricarboxylic acid, caffeic acid phenethyl ester, derivatives of caffeic acid hyl ester, tyrphostin, derivatives of tyrphostin, tin, tives of quercetin, S-1360, zintevir 7), L-870812, and L-870810, MK-0518 (raltegravir), BMS-707035, MK-2048, , BMS-538158, GSK364735C, 6) a gp41 inhibitor, e.g., enfuvirtide, sifuvirtide, FB006M, TRI-1144, SPC3, DES6, Locus gp41, CovX, and REP 9, 7) a CXCR4 inhibitor, e.g., AMD-070, 8) an entry inhibitor, e.g., SP01A, TNX-355, 9) a gp120 inhibitor, e.g., BMS-488043 and BlockAide/CR, 10) a G6PD and NADH-oxidase inhibitor, e.g., immunitin, 11) a CCR5 inhibitor, e.g., aplaviroc, vicriviroc, INCB9471, PRO-140, INCB15050, PF-232798, CCR5mAb004, and maraviroc, 12) an interferon, e.g., pegylated rIFN-alpha 2b, pegylated rIFN-alpha 2a, rIFN-alpha 2b, IFN alpha- 2b XL, rIFN-alpha 2a, consensus IFN alpha, infergen, rebif, on, 5, PEG- infergen, pegylated IFN-beta, oral interferon alpha, feron, reaferon, intermax alpha, r-IFN- beta, infergen + actimmune, IFN-omega with DUROS, and albuferon, 13) ribavirin analogs, e.g., rebetol, copegus, levovirin, VX-497, and viramidine (taribavirin), 14) NS5a inhibitors, e.g., A-831, A-689, and BMS-790052, 15) NS5b polymerase inhibitors, e.g., NM-283, citabine, R1626, PSI-6130 (R1656), HCV-796, BILB 1941, MK-0608, NM-107, R7128, VCH-759, PF-868554, GSK625433, and XTL-2125, 16) NS3 protease inhibitors, e.g., SCH-503034 (SCH-7), VX-950 (Telaprevir), ITMN-191, and BILN-2065, 17) alphaglucosidase 1 inhibitors, e.g., 3 (celgosivir) and UT-231B, 18) hepatoprotectants, e.g., IDN-6556, ME 3738, MitoQ, and LB-84451, 19) non-nucleoside inhibitors of HCV, e.g., benzimidazole tives, benzo-1,2,4-thiadiazine derivatives, and phenylalanine derivatives, 20) other drugs for ng Hepatitis C, e.g., zadaxin, nitazoxanide (alinea), BIVN-401 (virostat), DEBIO-025, VGX-410C, EMZ-702, AVI 4065, bavituximab, oglufanide, PYN-17, 03002, n (CPG-10101), KRN-7000, civacir, GI-5005, ANA-975 (isatoribine), 65, ANA 971, NOV-205, tarvacin, EHC-18, and NIM811, ) pharmacokinetic enhancers, e.g., BAS-100 and SPI452, 21) RNAse H inhibitors, e.g., ODN-93 and ODN-112, 22) other anti-HIV agents, e.g., VGV-1, PA-457 (bevirimat), ampligen, HRG214, cytolin, polymun, VGX-410, KD247, AMZ 0026, CYT 99007, A-221 HIV, BAY 50-4798, MDX010 (iplimumab), PBS119, ALG889, and PA-1050040.

It is contemplated that the second therapeutic agent will be administered in a manner that is known in the art and the dosage may be selected by someone of skill in the art. For example, the second agent may be administered in a dose from about 0.01 milligrams to about 2 grams per day.

Metabolites of the Compounds Also falling within the scope of this disclosure are the in vivo metabolic products of the compounds described herein. Such products may result for example from the oxidation, reduction, hydrolysis, amidation, fication and the like of the administered compound, primarily due to enzymatic processes. Accordingly, the disclosure includes compounds produced by a s comprising ting a compound of this disclosure with a mammal for a period of time sufficient to yield a metabolic product thereof. Such ts typically are identified by preparing a radiolabelled (e.g., C14 or H3) compound of the disclosure, administering it parenterally in a detectable dose (e.g., greater than about 0.5 mg/kg) to an animal such as rat, mouse, guinea pig, monkey, or to man, allowing sufficient time for metabolism to occur (typically about 30 seconds to 30 hours) and isolating its conversion products from the urine, blood or other biological samples. These products are easily isolated since they are labeled (others are isolated by the use of antibodies capable of binding epitopes surviving in the metabolite). The lite structures are determined in conventional fashion, e.g., by MS or NMR analysis. In general, analysis of metabolites is done in the same way as conventional drug metabolism studies well-known to those skilled in the art. The conversion products, so long as they are not otherwise found in vivo, are useful in stic assays for therapeutic dosing of the compounds of the disclosure even if they possess no HCV –inhibitory activity of their own.

Methods for determining stability of compounds in surrogate gastrointestinal secretions are known.

Exemplary Methods of Making the nds The disclosure also relates to methods of making the compositions of the disclosure.

The compositions are ed by any of the applicable techniques of organic synthesis.

Many such ques are well known in the art. However, many of the known ques are elaborated in Compendium of Organic Synthetic Methods (John Wiley & Sons, New York), Vol. 1, Ian T. on and Shuyen Harrison, 1971; Vol. 2, Ian T. Harrison and Shuyen Harrison, 1974; Vol. 3, Louis S. Hegedus and Leroy Wade, 1977; Vol. 4, Leroy G.

Wade, Jr., 1980; Vol. 5, Leroy G. Wade, Jr., 1984; and Vol. 6, Michael B. Smith; as well as March, J., Advanced Organic Chemistry, Third Edition, (John Wiley & Sons, New York, 1985), Comprehensive c Synthesis. Selectivity, Strategy & Efficiency in Modern Organic Chemistry. In 9 Volumes, Barry M. Trost, Editor-in-Chief mon Press, New York, 1993 printing). Other methods suitable for preparing nds of the disclosure are described in International Patent Application Publication Number .

A number of exemplary s for the preparation of the compositions of the disclosure are provided in the s and examples below. These methods are intended to illustrate the nature of such preparations and are not intended to limit the scope of applicable methods. lly, the reaction conditions such as temperature, reaction time, solvents, workup procedures, and the like, will be those common in the art for the particular reaction to be performed. The cited reference material, together with material cited therein, ns detailed descriptions of such conditions. Typically the temperatures will be -100°C to 200°C, solvents will be aprotic or protic, and reaction times will be 10 seconds to 10 days. p typically consists of quenching any unreacted reagents followed by partition between a water/organic layer system (extraction) and separating the layer ning the product.

Oxidation and reduction reactions are lly carried out at temperatures near room temperature (about 20°C), although for metal hydride reductions frequently the temperature is reduced to 0°C to -100°C, solvents are typically aprotic for reductions and may be either protic or aprotic for oxidations. Reaction times are adjusted to achieve desired conversions.

Condensation reactions are typically carried out at temperatures near room temperature, although for non-equilibrating, kinetically controlled condensations reduced temperatures (0°C to -100°C) are also common. Solvents can be either protic (common in equilibrating reactions) or aprotic (common in kinetically controlled ons).

Standard synthetic techniques such as azeotropic removal of reaction by-products and use of anhydrous reaction ions (e.g., inert gas environments) are common in the art and will be applied when applicable.

The terms “treated”, “treating”, “treatment”, and the like, when used in connection with a chemical synthetic operation, mean ting, mixing, reacting, allowing to react, ng into contact, and other terms common in the art for indicating that one or more chemical entities is d in such a manner as to convert it to one or more other chemical entities. This means that “treating nd one with compound two” is synonymous with “allowing compound one to react with compound two”, cting compound one with compound two”, “reacting compound one with compound two”, and other expressions common in the art of organic synthesis for reasonably indicating that compound one was “treated”, “reacted”, “allowed to , etc., with compound two. For example, treating indicates the reasonable and usual manner in which organic chemicals are allowed to react.

Normal concentrations (0.01M to 10M, typically 0.1M to 1M), temperatures (-100°C to 250°C, typically -78°C to 150°C, more typically -78°C to 100°C, still more lly 0°C to 100°C), reaction vessels (typically glass, plastic, metal), solvents, pressures, atmospheres (typically air for oxygen and water insensitive reactions or nitrogen or argon for oxygen or water sensitive), etc., are intended unless otherwise indicated. The knowledge of similar reactions known in the art of organic synthesis is used in selecting the conditions and apparatus for “treating” in a given process. In particular, one of ordinary skill in the art of organic synthesis selects conditions and apparatus reasonably expected to successfully carry out the al ons of the described processes based on the knowledge in the art.

Modifications of each of the exemplary schemes and in the Examples (hereafter “exemplary schemes”) leads to various analogs of the specific exemplary materials produced.

The above-cited citations describing suitable methods of organic synthesis are applicable to such modifications.

In each of the exemplary schemes it may be advantageous to separate reaction products from one another and/or from starting materials. The desired products of each step or series of steps is separated and/or purified (hereinafter separated) to the desired degree of homogeneity by the techniques common in the art. Typically such tions involve multiphase extraction, crystallization from a solvent or solvent e, distillation, sublimation, or chromatography. Chromatography can involve any number of methods including, for example: e-phase and normal phase; size exclusion; ion exchange; high, medium, and low pressure liquid chromatography methods and apparatus; small scale analytical; ted moving bed (SMB) and preparative thin or thick layer chromatography, as well as techniques of small scale thin layer and flash chromatography.

Another class of tion methods involves treatment of a mixture with a reagent ed to bind to or render otherwise separable a d product, unreacted starting material, reaction by product, or the like. Such reagents e ents or ents such as activated carbon, molecular sieves, ion exchange media, or the like. Alternatively, the reagents can be acids in the case of a basic material, bases in the case of an acidic material, g reagents such as antibodies, binding proteins, selective chelators such as crown ethers, liquid/liquid ion extraction reagents (LIX), or the like.

Selection of appropriate methods of separation depends on the nature of the materials involved. For example, boiling point, and molecular weight in distillation and sublimation, presence or absence of polar functional groups in chromatography, stability of materials in acidic and basic media in multiphase extraction, and the like. One d in the art will apply techniques most likely to achieve the desired separation.

A single isomer, e.g., an enantiomer, substantially free of its isomer may be obtained by resolution of the racemic mixture using a method such as formation of diastereomers using optically active resolving agents (Stereochemistry of Carbon Compounds, (1962) by E. L. Eliel, McGraw Hill; Lochmuller, C. H., (1975) J.

Chromatogr., 113, 3) 283-302). Racemic mixtures of chiral compounds of the sure can be separated and isolated by any suitable method, including: (1) formation of ionic, diastereomeric salts with chiral compounds and separation by fractional llization or other methods, (2) formation of diastereomeric nds with chiral derivatizing reagents, separation of the diastereomers, and conversion to the pure stereoisomers, and (3) separation of the substantially pure or enriched stereoisomers directly under chiral conditions.

Under method (1), diastereomeric salts can be formed by on of enantiomerically pure chiral bases such as brucine, quinine, ephedrine, strychnine, -methyl-- phenylethylamine (amphetamine), and the like with asymmetric compounds bearing acidic functionality, such as carboxylic acid and sulfonic acid. The diastereomeric salts may be induced to separate by fractional crystallization or ionic chromatography. For separation of the optical isomers of amino compounds, addition of chiral carboxylic or sulfonic acids, such as camphorsulfonic acid, ic acid, mandelic acid, or lactic acid can result in formation of the diastereomeric salts.

Alternatively, by method (2), the substrate to be resolved is reacted with one enantiomer of a chiral compound to form a diastereomeric pair (Eliel, E. and Wilen, S. (1994) Stereochemistry of Organic nds, John Wiley & Sons, Inc., p. 322).

Diastereomeric compounds can be formed by reacting asymmetric compounds with enantiomerically pure chiral tizing reagents, such as menthyl derivatives, ed by separation of the diastereomers and hydrolysis to yield the free, enantiomerically enriched ate. A method of determining optical purity involves making chiral esters, such as a menthyl ester, e.g., (-) menthyl chloroformate in the presence of base, or Mosher ester, - methoxy--(trifluoromethyl)phenyl acetate (Jacob III. (1982) J. Org. Chem. 47:4165), of the racemic mixture, and ing the NMR spectrum for the presence of the two atropisomeric diastereomers. Stable diastereomers of atropisomeric compounds can be separated and isolated by normal- and reverse-phase chromatography following methods for separation of atropisomeric naphthyl-isoquinolines (Hoye, T., WO 96/15111). By method (3), a racemic mixture of two enantiomers can be separated by chromatography using a chiral stationary phase (Chiral Liquid Chromatography (1989) W. J. Lough, Ed. Chapman and Hall, New York; Okamoto, (1990) J. of Chromatogr. 513:375-378). Enriched or ed enantiomers can be guished by s used to distinguish other chiral molecules with asymmetric carbon atoms, such as optical on and circular dichroism.

Schemes and es General aspects of these exemplary methods are described below and in the Examples. Each of the products of the following ses is optionally separated, isolated, and/or purified prior to its use in subsequent processes.

A number of ary methods for the preparation of compounds of the disclosure are provided herein, for e, in the Examples below. These methods are intended to illustrate the nature of such preparations and are not intended to limit the scope of applicable methods. Certain compounds of the disclosure can be used as ediates for the preparation of other compounds of the disclosure. In the exemplary methods described herein, the fragment E-V- can also be written as R9-. PG represents a protecting group common for the given functional group that it is attached. The installation and removal of the protecting group can be accomplished using standard techniques, such as those described in Wuts, P. G. M., Greene, T. Protective Groups in Organic Synthesis, 4th ed.; John Wiley & Sons, Inc.: n, New Jersey, 2007.

Scheme 1. Representative synthesis of E-V-C(=O)-P-W-P-C(=O)-V-E O Cl O H2N V-C(=O)-P-W-P-C(=O)-V-E NH-V-C(=O)-P-W-P-C(=O)-V-E 1a 1b O Cl O O H2N )-P-W-P-C(=O)-V NH2 NH-V-C(=O)-P-W-P-C(=O)-V-NH O O 1c 1d Scheme 1 shows a general synthesis of an E-V-C(=O)-P-W-P-C(=O)-V-E molecule of the disclosure wherein, for illustrative purposes, E is ycarbonylamino. The treatment of either 1a or 1c with one or two equivalents respectively of methyl chloroformate under basic conditions (e.g. sodium hydroxide) provides the molecule 1b or 1d.

Scheme 2. entative synthesis of E-V-C(=O)-P-W-P-C(=O)-V-E E-V-C(=O)-P-W V-E E-V-C(=O)-P-W N O N 2a H 2b 2c H O N HO W 2 V-E N O H N 2d 2b 2e O V-E Scheme 2 shows a general synthesis of an E-V-C(=O)-P-W-P-C(=O)-V-E molecule of the disclosure wherein, for illustrative purposes, P is idine. Coupling of amine 2a with acid 2b is accomplished using a peptide coupling reagent (e.g. HATU) to afford 2c.

Alternatively, amine 2d is coupled with two equivalents of 2b under similar conditions to provide 2e.

Scheme 6. Representative synthesis of R1-V-C(=O)-P-R2 E-V-C(=O)-P-W V-NH-PG E-V-C(=O)-P-W N O N 6a H 6b 6c V-NH-PG PG-HN-V-C(=O)-P-W V-E PG-HN-V-C(=O)-P-W N O N 6d H 6e 6f PG-HN-V-C(=O)-P-W G PG-HN-V-C(=O)-P-W N O N 6d H 6b 6g V-NH-PG PG-HN-P-W V-E PG-HN-P-W N O N 6h H 6e 6i PG-HN-P-W V-NH-PG PG-HN-P-W N O N 6h H 6b 6j V-NH-PG PG-HN-W V-E PG-HN-W N O N 6k H 6e 6l PG-HN-W V-NH-PG PG-HN-W N O N 6k H 6b 6m V-NH-PG Scheme 6 shows a general synthesis of an R1-V-C(=O)-P-R2 intermediate wherein, for illustrative es, P is pyrrolidine, R1 is a generic group that is depicted as either -E or a amino protecting group, and R2 is a generic group that is depicted as -W-P-C(=O)-V-E, - W-P-C(=O)-V-NH-PG, -W-P-NH-PG, or -W-NH-PG. Coupling of amine 6a (or 6d, 6h, 6k) with acid 6b or 6e is accomplished using a e coupling reagent (e.g. HATU) to afford 6c (or 6f, 6g, 6i, 6j, 6l, 6m) respectively.

Scheme 7. Representative sis of E-V-C(=O)-R1 O Cl O H2N V-C(=O)-P-W-P-C(=O)-V-NH-PG NH-V-C(=O)-P-W-P-C(=O)-V-NH-PG 7a 7b O Cl O H2N V-C(=O)-P-W-P-PG NH-V-C(=O)-P-W-P-PG 7c 7d O Cl O H2N V-C(=O)-P-W-PG NH-V-C(=O)-P-W-PG 7e 7f O Cl O H2N V-C(=O)-P-PG NH-V-C(=O)-P-PG 7g O 7h O Cl O H2N V-C(=O)-O-PG NH-V-C(=O)-O-PG 7i 7j Scheme 7 shows a general synthesis of an E-V-C(=O)-R1 intermediate n, for illustrative purposes, E is methoxycarbonylamino and R1 is a generic group that is depicted as either -P-W-P-C(=O)-V-NH-PG, -P-W-P-PG, -P-W-PG, -P-PG, or -O-PG. Treatment of 7a (or 7c, 7e, 7g, 7i) with methyl chloroformate under basic conditions (e.g. sodium hydroxide) provides the molecule 7b (or 7d, 7f, 7h, 7j).

Scheme 9. Representative synthesis of R1-P-R2 NH2 HO P-C(=O)-V-E NH2 Br NH2 O Br NH 9b P-C(=O)-V-E 9c O N P-C(=O)-V-E Br N NH2 HO P-PG NH2 Br NH2 O Br NH 9e P-PG 9f O N P-PG Br N Scheme 9 shows a general synthesis of an R1-P-R2 intermediate wherein, for illustrative purposes, R1 is -C(=O)-V-E or a protecting group and R2 is a substituted benzimidazole. The formation of the benzimidazole is accomplished by coupling the acid 9b or 9e with an arylamine 9a, using a e coupling reagent such as HATU, to afford 9c or 9f. Cyclization of the amide in the ce of an acid (such as acetic acid) s the benzimidazole containing molecule 9d or 9g.

The formation of multiple idazoles is performed in the same manner, starting with a bis-diamine to provide the corresponding bis-benzimidazole.

Scheme 20. Representative synthesis of R1-P-W-P-R2 Scheme 20 shows a general synthesis of an R1-P-W-P-R2 intermediate of the sure wherein, for illustrative purposes, R1 and R2 are independent ting groups and W is a two aromatic ring unit constructed via a transition metal ed cyclization.

Alkylation of phenol 20b with an alkyl bromide, such as 20a, provides the ether 20c.

Cyclization of the aromatic rings in the presence of a palladium catalyst provides the compound 20d. Treatment of 20d with CuBr2 provides the α-haloketone 20e, which provides 20f upon addition of an acid under basic conditions (e.g. Et3N). Reaction of 20f with an amine or amine salt (e.g. ammonium acetate) affords the imidazole containing molecule 20g. ion of 20g, 20i, or 20l can be accomplished by heating in the presence of MnO2 to provide 20h, 20j, or 20m, respectively. Conversion of 20g or 20h with a palladium catalyst, such as Pd2dba3 and , and a boron source such as bis(pinacolato)diboron provides the c ester 20i or 20j. The boronic ester is coupled with an appropriate coupling partner (e.g. 20k) using a palladium catalyst, such as Pd(PPh3)4 or PdCl2(dppf), to afford 20l or 20m.

For each tion metal mediated cross-coupling reaction, the roles of the nucleophile and electrophile can be reversed to provide the same coupling product. Other transition metal mediated cross couplings that enable the construction of W, but employ alternative coupling partners and reagents, include, but are not limited to, the Negishi, Kumada, Stille, and Ullman ngs. For the preparation of alternate two aromatic ring containing W groups, this general scheme can be d through the appropriate choice of the starting reagents.

Scheme 21. Representative synthesis of R1-P-W-P-R2 O O O O Cl 20d O O PG-P O 21b O O Br PG-P O O 21d O O P-PG PG-P O N N P-PG N N PG-P H 21f/g Scheme 21 shows a general synthesis of an R1-P-W-P-R2 intermediate of the disclosure wherein, for illustrative purposes, R1 and R2 are independent protecting groups and W is a two ic ring unit ucted via a transition metal mediated cyclization. ent of 20d with an activated vinyl reagent (e.g. potassium rifluoroborate) in the presence of a palladium catalyst (e.g. palladium acetate and S-Phos) provides the vinyl compound 21a. Conversion to the corresponding α-halo ketone can be accomplished by bromination with N-bromosuccinimide, followed by oxidation with MnO2. Displacement of the α-halo ketone ds by the addition of an acid under basic conditions (e.g. Et3N).

Bromination of 21c proceeds upon treatment with pyridinium tribromide, and is followed by the addition of a second acid under basic conditions to provide the diester 21e. Reaction of 21e with an amine or amine salt (e.g. ammonium acetate) affords the ole containing molecule 21f. Oxidation of 21f can be accomplished in the presence of MnO2 to provide 21g.

Scheme 22. Representative synthesis of E-V-C(=O)-P-W-P-R O O E-V-C(=O)-P O 21b O O Br =O)-P O O 22b O O P-PG E-V-C(=O)-P O N N P-PG E-V-C(=O)-P N 22d/e Scheme 22 shows a general synthesis of an E-V-C(=O)-P-W-P-R intermediate of the disclosure wherein, for illustrative purposes, R is a protecting group and W is a two aromatic ring unit. Displacement of the α-halo ketone 21b proceeds by the addition of an acid under basic conditions (e.g. Et3N). Bromination of 22a proceeds upon ent with pyridinium tribromide, and is followed by the addition of a second acid under basic conditions to provide the diester 22c. Reaction of 22c with an amine or amine salt (e.g. ammonium e) affords the imidazole ning molecule 22d. Oxidation of 22d can be accomplished in the presence of MnO2 to provide 22e.

Scheme 23. entative synthesis of R-P-W-P-C(=O)-V-E Scheme 23 shows a general synthesis of an E-V-C(=O)-P-W-P-R intermediate of the disclosure wherein, for illustrative purposes, R is a protecting group and W is a two aromatic ring unit. Displacement of the α-halo ketone 21d proceeds by the addition of an acid under basic conditions (e.g. Et3N). Reaction of 23a with an amine or amine salt (e.g. ammonium acetate) affords the imidazole containing molecule 23b. Oxidation of 23b can be accomplished in the presence of MnO2 to provide 23c.

Scheme 25. Representative synthesis of E-V-C(=O)-P-W-P-C(=O)-V-E Scheme 25 shows a l synthesis of an E-V-C(=O)-P-W-P-C(=O)-V-E le of the disclosure wherein, for illustrative es, E is ethylcarbonylamino. The treatment of either 25a or 25c with one or two equivalents respectively of propionyl chloride under basic conditions (e.g. sodium hydroxide) provides the molecule 25b or 25d.

Scheme 26. Representative syntheses of E-V-C(=O)-P-R and R1-P-R Scheme 26 shows a general synthesis of an E-V-C(=O)-P-R and an R1-P-R molecule of the sure wherein, for illustrative purposes R is a haloimidazole. Treatment of the aldehyde 26a with glyoxal, in the presence of ammonium hydroxide provides the imidazole 26b. Treatment with either N-bromosuccinamide or iodine provides the corresponding haloimidazole 26c and 26d respectively. Separation from the corresponding logenated compound can be accomplished by preparative HPLC tography. The conversion of the bis-haloimidazole to the mono-haloimidazole can also be accomplished upon heating in the presence of sodium sulfite. Further onalization of the P group can be accomplished upon removal of the protecting group and coupling with an riate acid (E-V-C(=O)- OH).

Scheme 27. Representative synthesis of R1-P-W-P-R2 O O Br O 27a O Br PG-P O O 21d O O P-PG PG-P O N N P-PG PG-P N 21f/g Scheme 27 shows an alternate general synthesis of an R1-P-W-P-R2 intermediate of the invention wherein, for rative purposes, R1 and R2 are independent protecting groups and W is a two aromatic ring unit constructed via a transition metal mediated cyclization.

Bromination of 21b with a brominating agent (i.e. pyridinium tribromide) provides the dibromide 27a. Displacement of the primary bromide then ds by the addition of an acid under basic conditions (e.g. K2CO3) to provide 21d. sion to 21f or 21g can be accomplished following methods described in Scheme 21.

Scheme 28. Representative synthesis of E-V-C(=O)-P-W-P-R O O Br O 27a O Br E-V-C(=O)-P O O 22b O O P-PG E-V-C(=O)-P O N N P-PG E-V-C(=O)-P N 22d/e Scheme 28 shows an alternate general synthesis of an E-V-C(=O)-P-W-P-R intermediate of the invention wherein, for illustrative purposes, R is a protecting group and W is a two aromatic ring unit. Bromination of 21b with a brominating agent (i.e. pyridinium tribromide) provides the ide 27a. Displacement of the primary bromide then proceeds by the addition of an acid under basic ions (e.g. K2CO3) to e 22d. Conversion to 22d or 22e can be accomplished following methods described in Scheme 22.

Specific Embodiments In one embodiment the disclosure es a compound which has formula: O H N P1b-C(=O)-V1b-E1b N N E1a-V1a-C(=O)-P1a H (A1) O H N P1b-C(=O)-V1b-E1b N N E1a-V1a-C(=O)-P1a H (A2) N N P1b-C(=O)-V1b-E1b N N E1a-V1a-C(=O)-P1a H (A3) O H N N =O)-V1b-E1b N N E1a-V1a-C(=O)-P1a H (A4) wherein the imidazole ring shown in formula A1, A2, A3, and A4 is optionally substituted with one or more groups independently selected from halo, haloalkyl, cyano, or alkyl; or a pharmaceutically acceptable salt or prodrug thereof.

In one embodiment the disclosure es a compound which has formula: O H N N P1b-C(=O)-V1b-E1b N N E1a-V1a-C(=O)-P1a H (A2) or O H N P1b-C(=O)-V1b-E1b N N E1a-V1a-C(=O)-P1a H (A4) wherein the imidazole ring shown in formula A2 and A4 is optionally substituted with one or more groups independently selected from halo, haloalkyl, cyano, or alkyl; or a pharmaceutically acceptable salt or prodrug thereof.

In one embodiment at least one of E1a and E1b is -N(H)(alkoxycarbonyl).

In one ment at least one of E1a and E1b is -N(H)C(=O)OMe.

In one ment both of E1a and E1b are (=O)OMe.

In one embodiment at least one of E1a and E1b is -N(H)(cycloalkylcarbonyl) or -N(H)(cycloalkyloxycarbonyl).

In one embodiment at least one of E1a and E1b is cyclopropylcarbonylamino, cyclobutylcarbonylamino, cyclopropyloxycarbonylamino or cyclobutyloxycarbonylamino.

In one embodiment E1a and E1b are each independently ed from cyclopropylcarbonylamino, cyclobutylcarbonylamino, cyclopropyloxycarbonylamino or methoxycarbonylamino.

In one embodiment at least one of V1a and V1b is: .

In one embodiment E1a-V1a taken together are R9a or wherein E1b-V1b taken together are R9b.

In one embodiment at least one of P1a and P1b is selected from: In one embodiment P1a and P1b are each independently selected from: In one embodiment one of P1a and P1b is: and the other of P1a and P1b is: In one embodiment one of P1a and P1b is: O and the other of P1a and P1b is: In one embodiment at least one of P1a and P1b is: F O F .

In one ment at least one of P1a and P1b is: O .

In one embodiment at least one of -V1a –C(=O)-P1a – and -P1b-C(=O)-V1b- is: or O O .

In one embodiment at least one of -V1a –C(=O)-P1a – and -P1b-C(=O)-V1b- is: O O N O N N O OMe N O N or O .

In one ment both of -V1a –C(=O)-P1a – and -P1b-C(=O)-V1b- are independently selected from: O O N O N N O OMe N O N or O .

In one embodiment one of -V1a -P1a – and -P1b-C(=O)-V1b- is: O O O O N O O N N N N OMe OMe O O N N N O . and the other of -V1a –C(=O)-P1a – and -P1b-C(=O)-V1b- is: O O N O N N O OMe N O N or O .

In one embodiment the disclosure provides a nd of formula: H O O N O H N N N N N O N O O N O H O N N N N N N O N O O O H O H N O O N N N N N N O O O N H O H O H O O N N O O N N HN O N O H O N N N O O N N N O H N O O O HN H N N N O N N N H O HN O H O O N O H N N O N N N O N O O H O H N O O N N N N N N O O N H O O H O O N N N N N N O O O H O H H N O N N O N N N O H O O N O H O N N N N N N O H N O O H O O NH O N HN N N N O O H O H O O N N N N O O O O O N O H O N N N N N H O O NH O H O N N N N N N O H HN O H O H O O N N N O N N O or a pharmaceutically able salt or prodrug thereof.

In one embodiment the disclosure provides a compound of formula: O N O H N N N N N N O H N O O H or a ceutically acceptable salt or prodrug thereof.

In one embodiment the disclosure provides a compound of formula: O O H NH O N HN N N N O O O H O H N O O N N N N N N O O N H H O O O N O H O N N N N N N O H N O O H O H O H H N O N N O N N N O H N O H O H O O N N N N O O O N O H O N N N O O N N N O H N O or a pharmaceutically acceptable salt or prodrug f.

The disclosure will now be illustrated by the following non-limiting Examples. The following abbreviations are used throughout the specification, including the Examples. (aq) Aqueous (g) Gas (s) Solid °C Degree Celsius Ac Acetate ACN Acetonitrile apprx Approximate Bis- Bis(pinacolato)diboron pinB/(Bpin)2/(pinB)2 BOC/Boc tert-Butoxycarbonyl calc'd ated CC50 50% Cytotoxicity concentration COMU (Cyanoethoxy oxoethylideneaminooxy)dimethylaminomorpholino)] uronium hexafluorophosphate d Doublet dba alacetone DCM Dichloromethane dd Doublet of doublets ddd Doublet of doublet of doublets DIPEA/DIEA N,N-Diisopropylethylamine DMA methylacetamide DMAP 4-Dimethylaminopyridine DME Dimethoxyethane DMEM Eagle's minimal essential medium DMF Dimethylformamide DMSO/dmso Dimethylsulfoxide dppf 1,1'-bis( diphenylphosphanyl) ferrocene dt Doublet of triplets EC50 Half maximal effective tration ESI Electrospray ionization Et Ethyl ext. External FBS Fetal bovine serum g Gram HATU 2-(1HAzabenzotriazolyl)-1,1,3,3-tetramethyl uronium hexafluorophosphate Methanaminium HPLC High performance liquid chromatography hr/h Hour Hz Hertz J ng constant LCMS Liquid chromatography mass spectrometry M Molar m Multiplet m/z Mass to charge M+ Mass peak Me Methyl mg Milligram MHz Megahertz min Minute mL Milliliter mmol Millimole Moc Methoxycarbonyl MS Mass spectrometry MTBE Methyl tert-butyl ether N Normal NADPH Nicotinamide adenine eotide phosphate NBS N-Bromosuccinimide NMM N-Methylmorpholine NMR Nuclear magnetic resonance o/n Over night Papp nt permeability PBS Phosphate buffer system Pd/C Palladium on carbon Ph Phenyl Phg/PhGly Phenyl glycine Piv Pivalate Pro Proline pyr Pyridine q Quartet qd Quartet of doublets quant Quantitative quint Quintet rt/RT Room temperature s Singlet SPhos 2-Dicyclohexylphosphino-2',6'-dimethoxybiphenyl t t t-Bu tert-Butyl TEMPO (2,2,6,6-Tetramethyl-piperidinyl)oxyl Tf Trifluoromethanesulfonate TFA Trifluoroacetic acid THF Tetrahydrofuran Thr Threonine TLC Thin layer chromatography tol. Toluene UV Ultraviolet Val Valine w/v Weight to volume w/w Weight to weight X-Phos/XPOS/Xphos 2-Dicyclohexylphosphino-2′,4′,6′- triisopropylbiphenyl δ Chemical shift μg Microgram μL Microliter EXAMPLES Example LQ Br O O HO O K2CO3, DMF Cl Br Br rt, 18 hr. 7-hydroxytetralone 89% Cl 1-bromo(bromomethyl)- 4-chlorobenzene 7-(2-bromochlorobenzyloxy)- hydronaphthalen-1(2H)-one Pd(OPiv)2, Ph)3, t-BuCO2H, CuBr2, CHCl3, EtOAc 80 oC, 2 hr.

K2CO3, DMA, 60 oC, 24 hr.

Cl 80 - 95% 67 - 85% 3-chloro-10,11-dihydro-5H- dibenzo[c,g]chromen-8(9H)-one 1. HO O N O Boc O O H DIPEA, CH3CN, 50°C Cl N Cl N Br 2. NH4Cl, Toluene, N Boc 2-methoxyethanol, 110°C tert-butyl 2-(9-chloro-1,4,5,11- 9-bromochloro-10,11-dihydro-5H- tetrahydroisochromeno[4',3':6,7]naph dibenzo[c,g]chromen-8(9H)-one tho[1,2-d]imidazolyl)pyrrolidine carboxylate O O H B B MnO2, CH2Cl2, rt N O O Cl N N Boc Pd2dba3, KOAc, XPOS, tert-butyl hloro-1,11- dioxane, 90°C dihydroisochromeno[4',3':6,7]naphtho[1,2- d]imidazolyl)pyrrolidinecarboxylate O H O O O N N O N H B N O N Boc Pd(PPh3)4, PdCl2(dppf), K2CO3, DME/ DMF, 85°C tert-butyl 2-[9-(4,4,5,5-tetramethyl-1,3,2- dioxaborolanyl)-1,11- dihydroisochromeno[4',3':6,7]naphtho[1,2- d]imidazolyl]pyrrolidinecarboxylate O 1. HCl, EtOH, 60°C H O N H O O N N 2.

N N N Boc O H O H N O O H tert-butyl 2-[9-(2-{1-[N-(methoxycarbonyl)valyl]pyrrolidin yl}-1H-imidazolyl)-1,11- COMU, DIPEA, DMF, RT dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazol yl]pyrrolidinecarboxylate O H O N H O O N N N N N H O N O [1-(2-{5-[2-(1- hoxycarbonyl)amino](phenyl)acetyl}pyrrolidin yl)-1,11- dihydroisochromeno[4',3':6,7]naphtho[1,2- d]imidazolyl]-1H-imidazolyl}pyrrolidinyl) methyloxobutanyl]carbamic acid 7-(2-bromochlorobenzyloxy)-3,4-dihydronaphthalen-1(2H)-one To a d solution of 7-hydroxytetralone (13.9 g, 85.7 mmol) and 1-bromo (bromomethyl)chlorobenzene (25.6 g, 90.0 mmol) in dimethylformamide (850 mL) was added potassium carbonate (24 g, 172 mmol). The reaction was stirred under argon for 18 hours then diluted with ethyl acetate (1 L). The organics were washed three times with water and once with brine. The organic layer was then dried with magnesium sulfate, ed and concentrated. To the resulting oil was added methanol (500 mL) and the suspension was agitated for thirty minutes. romochlorobenzyloxy)-3,4-dihydronaphthalen-1(2H)- one (27.8 g, 89% yield) was isolated by filtration. ro-10,11-dihydro-5H-dibenzo[c,g]chromen-8(9H)-one To a 1 L flask containing ium(II) pivalate (1.18 g, 3.8 mmol), tri(4- fluorophenyl)phosphine (1.20 g, 3.8 mmol), pivalic acid (2.33 g, 22.8 mmol) and potassium carbonate (31.8 g, 228 mmol) was added a solution of 7-(2-bromochlorobenzyloxy)-3,4- dihydronaphthalen-1(2H)-one (27.8 g, 76.2 mmol) in dimethylacetamide (380 mL). The flask was evacuated and backfilled with argon 5 times and then stirred under argon at 60 oC for 24 hours. The reaction was cooled to room temperature and diluted with MTBE and water. The resulting biphasic mixture was stirred for 3 hours and filtered through Celite, rinsing with MTBE. The organic layer of the filtrate was separated and then washed twice with water and once with brine. The organics were then dried with magnesium sulfate, filtered, concentrated and purified by flash column chromatography (Hexanes/DCM) to yield 3-chloro-10,11-dihydro-5H-dibenzo[c,g]chromen-8(9H)-one (14.4 g, 67% yield) as an te solid. 9-bromochloro-10,11-dihydro-5H-dibenzo[c,g]chromen-8(9H)-one To a mixture of 3-chloro-10,11-dihydro-5H-dibenzo[c,g]chromen-8(9H)-one (14.8 g, 52 mmol) in chloroform (50 mL) and ethyl acetate (50 mL) was added copper(II) bromide (24.3 g, 104 mmol). The reaction was heated to 80 oC for 2 hours and then cooled to room temperature. The mixture was diluted with dichloromethane and washed twice with a 5:1 solution of saturated aqueous ammonium chloride and aqueous ammonium ide (~38%), and washed once with water. The organic layer was dried with magnesium sulfate, ed and concentrated to yield 9-bromochloro-10,11-dihydro-5H-dibenzo[c,g]chromen- one (18.5 g, >95% yield) with >95% purity.

Note: This reaction is not always this clean. Sometimes there is over-bromination and sometimes there is significant starting material. These impurities can be removed by flash column chromatography. tert-Butyl 2-(9-chloro-1,4,5,11-tetrahydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazol- 2-yl)pyrrolidinecarboxylate To a solution of (1R)(tert-butoxycarbonyl)cyclopentanecarboxylic acid (10.17 g, 47.25 mmol) and 9-bromochloro-10,11-dihydro-6H-naphtho[2,3-c]chromen-8(9H)-one (5.7 mg, 15.7 mmol) in acetonitrile (50 mL) was added diisopropylethylamine (11.11 mL, 64 mmol). The on was stirred at 50 oC for 4 hours and was then d with ethyl acetate.

The organics were washed with water and brine, dried (MgSO4) and concentrated. The resulting crude residue was purified by flash chromatography to yield (2S)tert-butyl 2-(3- chlorooxo-8,9,10,11-tetrahydro-5H-naphtho[c,g]chromenyl) pyrrolidine-1,2- dicarboxylate (4.52 g, 58%). To a on of (2S)tert-butyl 2-(3-chlorooxo-8,9,10,11- tetrahydro-6H-naphtho[2,3-c]chromenyl) pyrrolidine-1,2-dicarboxylate (3.27 mg, 6.56 mmol) in a mixture of toluene (11 mL) and 2-methoxyethanol (0.7 mL) was added ammonium acetate (5.06 g, 65.6 mmol). The on mixture was heated to 110 °C for 3 hours, cooled to room temperature and diluted with ethyl acetate. The organics were washed with water and brine, dried (Na2SO4), and concentrated. The crude residue was purified by flash chromatography to yield utyl 2-(9-chloro-1,4,5,11- tetrahydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl)pyrrolidinecarboxylate (1.95 g, 61%). LCMS-ESI+: calculated for C27H28ClN3O34 2: 477.98; observed [M+1]+: 478.47 tert-Butyl 2-(9-chloro-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazol yl)pyrrolidinecarboxylate To a solution of tert-butyl 2-(9-chloro-1,4,5,11- tetrahydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl)pyrrolidinecarboxylate (1.9 g, 3.96 mmol) in dichloromethane (35 mL) was added manganese(IV) oxide (17 g, 198 mmol). The reaction mixture was stirred at room temperature for 18 hours, diluted with ethyl acetate. The organics were washed with water and brine, dried (Na2SO4), and trated.

The crude residue was purified by flash chromatography to yield tert-butyl 2-(9-chloro-1,11- dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl)pyrrolidinecarboxylate (1.52 g, 81%). LCMS-ESI+: calculated for C27H26ClN3O3: 475.9; observed : 476.45. tert-Butyl 4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-1,11- dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl]pyrrolidinecarboxylate A degassed mixture of tert-butyl 2-(9-chloro-1,11- dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl)pyrrolidinecarboxylate (1.52 g, 3.17 mmol), nacolato)diboron (1.21 g, 4.75 mmol), potassium acetate (934 mg, 9.52 mmol), tris(dibenzylideneacetone)palladium (116 mg, 0.13 mmol) and 2- dicyclohexylphosphino-2’, 4’, 6’-tri-i-propyl-1, 1’-biphenyl (121 mg, 0.08 mmol) in 1,4- dioxane (16 mL) was heated to 90 oC for 1.5 hours, cooled to room temperature and diluted with ethyl acetate. The organics were washed with water and brine, dried (Na2SO4), and concentrated. The crude residue was ed by flash chromatography to yield tert-butyl 2- [9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-1,11- oisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl]pyrrolidinecarboxylate (1.7 g, 94%) tert-Butyl 2-[9-(2-{1-[N-(methoxycarbonyl)valyl]pyrrolidinyl}-1H-imidazolyl)- 1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl]pyrrolidine carboxylate To a solution of methyl (S)((S)(5-bromo-1H-imidazolyl)pyrrolidinyl) methyloxobutanylcarbamate (1.48 g, 3.97 mmol), tert-butyl 2-[9-(4,4,5,5-tetramethyl- dioxaborolanyl)-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazol yl]pyrrolidinecarboxylate (1.88 g, 1.48 mmol), tetrakis(triphenyl phosphine)palladium(0) (191 mg, 0.16 mmol) and dichloro[1,1'-bis(diphenylphosphino) ferrocene]palladium(II) (242 mg, 0.33 mmol) in a mixture of 1,2-dimethoxyethane (37.0 mL) and dimethylformamide (6 mL) was added a solution of potassium ate (2M in water, 5 mL, 9.93 mmol). The resulting mixture was degassed and then heated to 85 °C under argon for 18 hours. After cooling to room temperature, the reaction was diluted with ethyl acetate. The organics were washed with water and brine, dried (Na2SO4), and concentrated. The crude residue was purified by flash chromatography to yield tert-butyl 2-[9-(2-{1-[N- (methoxycarbonyl)valyl]pyrrolidinyl}-1H-imidazolyl)-1,11- dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl]pyrrolidinecarboxylate (1.45 mg, 59%). LCMS-ESI+: calculated for C41H47N7O6 +: 734.87. 73 733.86; observed [M+1] [1-(2-{5-[2-(1-{[(Methoxycarbonyl)amino](phenyl)acetyl}pyrrolidinyl)-1,11- dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl]-1H-imidazol yl}pyrrolidinyl)methyloxobutanyl]carbamic acid A solution of tert-butyl 2-[9-(2-{1-[N-(methoxycarbonyl)valyl]pyrrolidinyl}-1H- imidazolyl)-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl]pyrrolidine- 1-carboxylate (462 mg, 0.63 mmol), ethanol (6 mL) and concentrated HCl (2 mL) was heated to 60 °C for 1 hour. The reaction was concentrated and the crude material dissolved in DCM (6 mL). This solution was concentrated and to this material was added a solution of (R) (methoxycarbonylamino)phenylacetic acid (172 mg, 0.82 mmol) and COMU (311 mg, 0.73 mmol) in DMF (6 mL). To the resulting solution was added diisopropylethylamine (330 L, 1.89 mmol). After ng for 18 hours at room temperature, the reaction was diluted with ethyl acetate, washed with water and brine, dried (Na2SO4), trated and purified by preparative reverse phase HPLC i, 15 to 45% ACN/H2O + 0.1% TFA). The product fractions were lyophilized to give [1-(2-{5-[2-(1- {[(methoxycarbonyl)amino](phenyl)acetyl}pyrrolidinyl)-1,11- oisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl]-1H-imidazolyl}pyrrolidin yl)methyloxobutanyl]carbamic acid (231 mg, 45%). LCMS-ESI+: calculated for C46H48N8O78: 824.92; observed [M+1]+: 826.00.

Example LR CN 1) HCl, MeOH CO2Me 2) Boc2O, NaHCO3 NaOH H H MeO2C N Boc MeO2C N (2S,4S)tert-butyl 2-methyl 4-cyanopyrrolidine- 1,2-dicarboxylate (2S,4S)tert-butyl 2,4- dimethyl pyrrolidine-1,2,4- tricarboxylate CO2H 1) EtO2CCl MeI (t-Bu)2pyr 2) NaBH4 H MeO2C N Boc MeO2C N AgOTf (3S,5S)(tert-butoxycarbonyl) (2S,4S)tert-butyl 2-methyl 4- (methoxycarbonyl)pyrrolidinecarboxylic acid (hydroxymethyl)pyrrolidine-1,2- dicarboxylate O O LiOH H H MeO2C N HO2C N Boc Boc (2S,4S)tert-butyl 2-methyl (2S,4S)(tert-butoxycarbonyl) 4-(methoxymethyl)pyrrolidine- (methoxymethyl)pyrrolidine 1,2-dicarboxylate carboxylic acid )tert-butyl 2,4-dimethyl idine-1,2,4-tricarboxylate To a solution of (2S,4S)tert-butyl 2-methyl 4-cyanopyrrolidine-1,2-dicarboxylate (9.0 g, 35.4 mmol) in MeOH (196 mL) was added HCl (4M in 1,4-dioxane, 100 mL, 403 mmol). The solution was stirred at room ature for 16h and concentrated in vacuo. The crude intermediate was dissolved in EtOAc (180 mL) and basified with s onate (sat.). Di-tert-butyl dicarbonate (8.5 g, 38.9 mmol) was added and the biphasic solution was stirred at room temperature for 12h. The layers were then separated and the aqueous layer was backextracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated. The crude oil was purified by silica gel chromatography (15% to 40% to 100% EtOAc/Hexanes) to e (2S,4S)tert-butyl 2,4-dimethyl pyrrolidine-1,2,4-tricarboxylate (9.56 g, 94%). (3S,5S)(tert-butoxycarbonyl)(methoxycarbonyl)pyrrolidinecarboxylic acid To a solution of (2S,4S)tert-butyl methyl pyrrolidine-1,2,4-tricarboxylate (9.56 g, 33.3 mmol) in THF (70 mL) at 0 °C (external temperature, ice bath) was added NaOH (1N aqueous, 33 mL, 33.3 mmol) dropwise over 15 min. The solution was stirred at 0 °C for 5h before ication with HCl (1N). The solution was extracted with EtOAc (3x).

The combined c layers were dried over Na2SO4 and concentrated. The crude oil was purified by silica gel chromatography (2% to 5% to 10% H2Cl2) to provide (3S,5S)- 1-(tert-butoxycarbonyl)(methoxycarbonyl)pyrrolidinecarboxylic acid (6.38g, 70%). (2S,4S)tert-butyl 2-methyl 4-(hydroxymethyl)pyrrolidine-1,2-dicarboxylate To a on of )(tert-butoxycarbonyl)(methoxycarbonyl)pyrrolidine carboxylic acid (6.38 g, 23.3 mmol) in THF (116 mL) at 0 °C (external temperature, ice bath) was added Et3N (4.9 mL, 35.0 mmol) and ethyl chloroformate (2.7 mL, 28.0 mmol). The ing solution was stirred at 0 °C for 45 min, during which time a white precipitate forms.

The reaction e was filtered through celite and concentrated.

The crude ediate was dissolved in THF (59 mL) and cooled to 0 °C (external temperature, ice bath). NaBH4 (4.41 g, 116.7 mmol) in H2O (59 mL) was slowly added and the resulting solution was stirred at 0 °C for 2 h. The reaction mixture was diluted with EtOAc and washed with H2O. The aqueous layer was backextracted with EtOAc. The combined organic layers were dried over Na2SO4 and concentrated. The crude oil was purified by silica gel chromatography (42% to 69% to 100% EtOAc/Hexanes) to provide (2S,4S)tert-butyl 2-methyl 4-(hydroxymethyl)pyrrolidine-1,2-dicarboxylate (3.63 g, 60%). (2S,4S)tert-butyl 2-methyl 4-(methoxymethyl)pyrrolidine-1,2-dicarboxylate To a solution of (2S,4S)tert-butyl 2-methyl 4-(hydroxymethyl)pyrrolidine-1,2- dicarboxylate (2.57 g, 9.9 mmol) in CH2Cl2 (50 mL) was added AgOTf (4.07 g, 15.8 mmol) and 2,6-di-tert-butylpyridine (4.4 mL, 19.8 mmol). The reaction mixture was cooled to 0 °C (external temperature, ice bath) and MeI (0.98 mL, 15.8 mmol) was slowly added. The resulting slurry was stirred at 0 °C for 1.5 h and at room temperature for 1.5 h. The slurry was diluted with CH2Cl2 and filtered through celite. The filtrate was concentrated to dryness, dissolved in Et2O, and washed with HCl (1N) and brine. The s layers were backextracted with Et2O and the combined organic layers were dried over Na2SO4 and concentrated. The crude oil was purified by silica gel chromatography (10% to 75% to 100% EtOAc/Hexanes) to provide (2S,4S)tert-butyl 2-methyl 4-(methoxymethyl)pyrrolidine-1,2- dicarboxylate (2.11 g, 78%). 1H-NMR: 400 MHz, (CDCl 3) δ: (mixture of rotamers, major reported) 4.20 (t, 1H), 3.71 (s, 3H), 3.67 (m, 1H), 3.34 (m, 2H), 3.30 (s, 3H), 3.16 (t, 1H), 2.43 (m, 2H), 1.74 (m, 1H), 1.38 (s, 9H). (2S,4S)(tert-butoxycarbonyl)(methoxymethyl)pyrrolidinecarboxylic acid To a solution of (2S,4S)tert-butyl 2-methyl 4-(methoxymethyl)pyrrolidine-1,2- dicarboxylate (2.11 g, 7.7 mmol) in a mixture of THF (38 mL) and MeOH (15 mL) was added LiOH (2.5 M aqueous, 15 mL, 38.6 mmol). The resulting solution was stirred at room temperature for 2h, and acidified with aqueous HCl (1N). The desired product was extracted with CH2Cl2 (4x). The combined organic layers were dried over Na2SO4 and concentrated to provide (2S,4S)(tert-butoxycarbonyl)(methoxymethyl)pyrrolidinecarboxylic acid (2.0 g, 99%). 1H-NMR: 400 MHz, (CDCl 3) δ: (mixture of rotamers, major reported) 4.33 (t, 1H), 3.65 (m, 1H), 3.35 (m, 2H), 3.32 (s, 3H), 3.16 (t, 1H), 2.45 (m, 2H), 2.12 (m, 1H), 1.46 (s, 9H). e LR-1 Cl N N Boc 1. O (2S,4R)-tert-butyl hloro-4,5-dihydro- htho HO hromeno[8,9-d]imidazolyl) O N (methoxymethyl) O O Boc pyrrolidinecarboxylate Cl DIPEA, CH3CN, 50°C Br O 2. NH4OAc, Toluene, 2-methoxyethanol, O 9-bromochloro-10,11-dihydro- 110°C H 5H-dibenzo[c,g]chromen-8(9H)- N one Cl N Boc (2S,4S)-tert-butyl 2-(9-chloro-4,5-dihydro-5H- naphtho [c,g]chromeno[8,9-d]imidazolyl) (methoxymethyl) pyrrolidinecarboxylate H O O N B B MnO2, CH2Cl2, rt Cl O O N Boc (2S,4S)-tert-butyl 2-(9-chloro-5H-naphtho[ Pd2dba3, KOAc, XPOS, c,g]chromeno[8,9-d]imidazolyl) dioxane, 90°C (methoxymethyl)pyrrolidinecarboxylate (2S,4S)-tert-butyl(9-chloro-4,5-dihydro-5H-naphtho[2,3-c]chromeno[8,9-d]imidazol- 2-yl)(methoxymethyl)pyrrolidinecarboxylate: To a solution of ((S)(tert-butoxycarbonyl)(methoxymethyl)pyrrolidine carboxylic acid (5.9 g, 23.1 mmol) and 9-bromochloro-10,11-dihydro-5H- o[c,g]chromen-8(9H)-one (5.6 mg, 15.4 mmol) in acetonitrile (60 mL) was added diisopropylethylamine (5.35 mL, 30.8 mmol). The reaction was stirred at 50 oC for 18 hours and was then diluted with ethyl acetate. The organics were washed with water and brine, dried (MgSO4) and concentrated. The resulting crude residue was purified by flash chromatography to yield (2S)tert-butyl(3-chlorooxo-8,9,10,11-tetrahydro-6H- naphtho[2,3-c]chromenyl)-4(methoxymethyl) pyrrolidine-1,2-dicarboxylate (5.12 g, 61%).

To a on of (2S)tert-butyl(3-chlorooxo-8,9,10,11-tetrahydro-6H-naphtho[2,3- c]chromenyl)-4(methoxymethyl)pyrrolidine-1,2-dicarboxylate (5.11 mg, 9.42 mmol) in a mixture of toluene (94 mL) and 2-methoxyethanol (0.1 mL) was added ammonium acetate (23.5 g, 304 mmol). The reaction mixture was heated to 110 °C for 18 hours, cooled to room ature and diluted with ethyl acetate. The organics were washed with water and brine, dried (Na2SO4), and concentrated. The crude residue was purified by flash chromatography to yield (2S,4R)-tert-butyl 2-(9-chloro-4,5-dihydro-5H-naphtho[c,g]chromeno[8,9-d]imidazol- 2-yl)(methoxymethyl)pyrrolidinecarboxylate , 21%) and )-tert-butyl(9- chloro-4,5-dihydro-6H-naphtho[2,3-c]chromeno[8,9-d]imidazolyl) (methoxymethyl)pyrrolidinecarboxylate (2.0 g, 41%). LCMS-ESI+: calculated for C29H32ClN3O4 2: 522.0; observed [M+1]+: 522.2. (2S,4S)-tert-butyl(9-chloro-5H-naphtho[c,g]chromeno[8,9-d]imidazolyl) (methoxymethyl)pyrrolidinecarboxylate.

To a solution of (2S,4S)-tert-butyl(9-chloro-4,5-dihydro-5H- naphtho[c,g]chromeno[8,9-d]imidazolyl)(methoxymethyl)pyrrolidinecarboxylate (1.99 g, 3.82 mmol) in dichloromethane (30 mL) was added manganese(IV) oxide (10 g, 115 mmol). The reaction mixture was stirred at room temperature for 18 hours, diluted with ethyl acetate. The organics were washed with water and brine, dried (Na2SO4), and concentrated.

The crude residue was purified by flash chromatography to yield(2S,4S)-tert-butyl(9- chloro-6H-naphtho[2,3-c]chromeno[8,9-d]imidazolyl)methoxymethyl)pyrrolidine carboxylate (1.05g, 21%) and (2S,4S)-tert-butyl(9-chloro-4,5-dihydro-6H-naphtho[2,3- c]chromeno[8,9-d]imidazolyl)(methoxymethyl)pyrrolidinecarboxylate (1.64 g, 82%). LCMS-ESI+: calculated for C29H30ClN3O42: ; observed [M+1]+: 520.97. (2S,4S)-tert-butyl(methoxymethyl)(9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)- 5H-naphtho[c,g]chromeno[8,9-d]imidazolyl)pyrrolidinecarboxylate: A degassed mixture of (2S,4S)-tert-butyl(9-chloro-5H- naphtho[c,g]chromeno[8,9-d]imidazolyl)(methoxymethyl) idinecarboxylate (649 mg1.25 mmol), nacolato)diboron (635 mg, 2.5 mmol), potassium acetate (368 mg, 3.7 mmol), tris(dibenzylideneacetone)palladium (46 mg, 0.05 mmol) and 2- dicyclohexylphosphino-2’, 4’, 6’-tri-i-propyl-1, 1’-biphenyl (60 mg, 0.12 mmol) in 1,4- dioxane (7 mL) was heated to 90 oC for 3 hours, cooled to room temperature and diluted with ethyl acetate. The cs were washed with water and brine, dried (Na2SO4), and concentrated. The crude residue was purified by flash chromatography to yield (2S,4S)-tertbutyl 4-(methoxymethyl)(9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-5H- naphtho[c,g]chromeno[8,9-d]imidazolyl)pyrrolidinecarboxylate (467 mg, 61%) LCMSESI +: calculated for C35H42BN3O6: 611.54; observed [M+1]+: 612.96. )-tert-butyl 2-(9-(2-((S)((S)(methoxycarbonylamino) methylbutanoyl)pyrrolidinyl)-1H-imidazolyl)-5H-naphtho[c,g]chromeno[8,9- d]imidazolyl)-4(methoxymethyl)pyrrolidinecarboxylate To a solution of (2S,4S)-tert-butyl 4-(methoxymethyl)(9-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolanyl)-5H-naphtho[c,g]chromeno[8,9-d]imidazolyl)pyrrolidine carboxylate (467 mg, 0.76 mmol), methyl (S)((S)(5-bromo-1H-imidazol yl)pyrrolidinyl)methyloxobutanylcarbamate (342 mg, 0.92 mmol), tetrakis(triphenylphosphine) palladium(0) (44 mg, 0.04 mmol) and dichloro[1,1'- bis(diphenylphosphino)ferrocene]palladium(II) (56 mg, 0.07 mmol) in a mixture of 1,2- dimethoxyethane (11.0 mL) and dimethylformamide (1.9 mL) was added a solution of potassium carbonate (2M in water, 1.15 mL, 2.29 mmol). The resulting mixture was degassed and then heated to 85 °C under argon for 18 hours. After cooling to room temperature, the reaction was diluted with ethyl acetate. The organics were washed with water and brine, dried (Na2SO4), and concentrated. The crude residue was purified by flash tography to yield (2S,4S)-tert-butyl 2-((S)((S)(methoxycarbonylamino) methylbutanoyl)pyrrolidinyl)-1H-imidazolyl)-5H-naphtho[c,g] no [8,9- d]imidazolyl)(methoxymethyl)pyrrolidinecarboxylate (180 mg, 67%). LCMS-ESI+: calculated for C43H51N7O73 777.91; observed [M+1]+: . methyl {2-[2-{9-[2-(1-{2-[(methoxycarbonyl)amino]methylbutanoyl}pyrrolidinyl)- 1H-imidazolyl]-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl} (methoxymethyl)pyrrolidinyl]oxophenylethyl}carbamate A solution of (2S,4S)-tert-butyl 2-(9-(2-((S)((S)(methoxycarbonylamino) methylbutanoyl)pyrrolidinyl)-1H-imidazolyl)-5H-naphtho[c,g]chromeno[8,9- d]imidazolyl)(methoxymethyl)pyrrolidinecarboxylate (196 mg, 0.25 mmol), ethanol (3 mL) and concentrated HCl (1 mL) was heated to 60 °C for 1 hour. The reaction was concentrated and the crude material ved in DCM (6 mL). This solution was concentrated and to this material was added a solution of (R)(methoxycarbonylamino) phenylacetic acid (69 mg, 0.33 mmol) and COMU (124 mg, 029 mmol) in DMF (4 mL). To the resulting solution was added diisopropylethylamine (130 L, 0.76 mmol). After stirring for 2 hours at room temperature, the reaction was diluted with ethyl acetate, washed with water and brine, dried (Na2SO4), concentrated and purified by ative reverse phase HPLC (Gemini, 15 to 45% ACN/H2O + 0.1% TFA). The product fractions were lyophilized to give methyl {2-[2-{9-[2-(1-{2-[(methoxycarbonyl)amino]methylbutanoyl}pyrrolidin yl)-1H-imidazolyl]-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl} (methoxymethyl)pyrrolidinyl]oxophenylethyl}carbamate (84 mg, 39%). LCMSESI +: calculated for C48H52N8O8: 868.98; observed [M+1]+: 870.11 Example LS methyl {1-[2-{9-[2-(1-{2-[(methoxycarbonyl)amino]methylbutanoyl}pyrrolidinyl)- 1H-imidazolyl]-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl} (methoxymethyl)pyrrolidinyl]methyloxobutanyl}carbamate A solution of )-tert-butyl 2-(9-(2-((S)((S)(methoxycarbonylamino) butanoyl)pyrrolidinyl)-1H-imidazolyl)-5H-naphtho[c,g]chromeno[8,9- d]imidazolyl)(methoxymethyl)pyrrolidinecarboxylate (116 mg, 0.15 mmol), ethanol (5 mL) and concentrated HCl (1 mL) was heated to 60 °C for 1 hour. The reaction was concentrated and the crude al dissolved in DCM (10 mL). This solution was concentrated and to this material was added a solution of 2-methoxycarbonylamino butyric acid (38 mg, 0.22 mmol) and HATU (79 mg, 0.21 mmol) in DMF (1.4 mL).

To the resulting solution was added diisopropylethylamine (270 L, 1.5 mmol). After stirring for 18 hours at room temperature, the reaction was diluted with ethyl acetate, washed with water and brine, dried (Na2SO4), concentrated and purified by preparative reverse phase HPLC (Gemini, 15 to 45% ACN/H2O + 0.1% TFA). The product fractions were lyophilized to give methyl {1-[2-{9-[2-(1-{2-[(methoxycarbonyl)amino]methylbutanoyl}pyrrolidin yl)-1H-imidazolyl]-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl} (methoxymethyl)pyrrolidinyl]methyloxobutanyl}carbamate (58 mg, 13%).

LCMS-ESI+: calculated for C45H54N8O8: 834.96; observed [M+1]+: 835.70.

Example LT O H O O O N N N H H O N B N O N Boc Pd(PPh3)4, PdCl2(dppf), K2CO3, DME/ DMF, 85°C (2S,4S)-tert-butyl 4-(methoxymethyl)(9-(4,4,5,5- tetramethyl-1,3,2-dioxaborolanyl)-5H-naphtho [c,g]chromeno[8,9-d]imidazolyl)pyrrolidine- 1-carboxylate (2S,4S)-tert-butyl(9-(2-((S)((S)(methoxycarbonylamino) methylbutanoyl)azabicyclo[3.1.0]hexanyl)-1H-imidazolyl)-5H- naphtho[c,g]chromeno[8,9-d]imidazolyl)(methoxymethyl)pyrrolidine carboxylate To a solution of (2S,4S)-tert-butyl 4-(methoxymethyl)(9-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolanyl)-5H-naphtho[c,g]chromeno[8,9-d]imidazolyl)pyrrolidine carboxylate (557 mg, 0.91 mmol), methyl (S)((1S,3S,5S)(5-bromo-1H-imidazolyl)- 2-azabicyclo[3.1.0]hexanyl)methyloxobutanylcarbamate (350 mg, 0.91 mmol), tetrakis(triphenylphosphine) palladium(0) (53 mg, 0.04 mmol) and dichloro[1,1'- bis(diphenylphosphino)ferrocene]palladium(II) (67 mg, 0.07 mmol) in a mixture of 1,2- dimethoxyethane (11.0 mL) and dimethylformamide (1.9 mL) was added a solution of potassium carbonate (2M in water, 1.37 mL, 2.7 mmol). The resulting e was degassed and then heated to 85 °C under argon for 18 hours. After cooling to room ature, the reaction was diluted with ethyl acetate. The organics were washed with water and brine, dried 4), and concentrated. The crude residue was purified by flash chromatography to yield (2S,4S)-tert-butyl 2-(9-(2-((S)((S)(methoxycarbonylamino) methylbutanoyl)azabicyclo[3.1.0]hexanyl)-1H-imidazolyl)-5H- naphtho[c,g]chromeno[8,9-d]imidazolyl)(methoxymethyl)pyrrolidinecarboxylate (271 mg, 38%). LCMS-ESI+: calculated for C44H51N7O7. 789.92; observed : 790.76. methyl {9-[2-(2-{2-[(methoxycarbonyl)amino]methylbutanoyl} azabicyclo[3.1.0]hexyl)-1H-imidazolyl]-1,11- dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl} (methoxymethyl)pyrrolidinyl]oxophenylethyl}carbamate: A solution of (2S,4S)-tert-butyl 2-(9-(2-((S)((S)(methoxycarbonylamino) methylbutanoyl)azabicyclo[3.1.0]hexanyl)-1H-imidazolyl)-5H- naphtho[c,g]chromeno[8,9-d]imidazolyl)(methoxymethyl)pyrrolidinecarboxylate (196 mg, 0.25 mmol), ethanol (3 mL) and concentrated HCl (1 mL) was heated to 60 °C for 1 hour. The reaction was trated and the crude material dissolved in DCM (6 mL). This solution was concentrated and to this al was added a on of (R) (methoxycarbonylamino)phenylacetic acid (69 mg, 0.33 mmol) and COMU (124 mg, 0.29 mmol) in DMF (4 mL). To the resulting solution was added diisopropylethylamine (130 L, 0.76 mmol). After stirring for 2 hours at room temperature, the reaction was diluted with ethyl acetate, washed with water and brine, dried (Na2SO4), concentrated and purified by preparative reverse phase HPLC (Gemini, 15 to 45% ACN/H2O + 0.1% TFA). The product fractions were lyophilized to give methyl {2-[2-{9-[2-(2-{2-[(methoxycarbonyl)amino] methylbutanoyl}azabicyclo[3.1.0]hexyl)-1H-imidazolyl]-1,11- dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl}(methoxymethyl)pyrrolidin yl]oxophenylethyl}carbamate (84 mg, 39%). LCMS-ESI+: calculated for C49H52N8O8: 880.99; observed [M+1]+: 882.09 Example LZ O O O O NH O (Bpin)2, a)3, X-Phos, O NH O Cl B N N N N KOAc, dioxane, 90 oC O tert-butyl (2S)(9-chloro-3,7- tert-butyl (2S)[9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolandihydroisochromeno [3',4':5,6]naphtho[1,2- 2-yl)-3,7-dihydroisochromeno[3',4':5,6]naphtho[1,2- d]imidazolyl)pyrrolidinecarboxylate d]imidazolyl]pyrrolidinecarboxylate -(2-bromochlorobenzyloxy)-3,4-dihydronaphthalen-1(2H)-one To a stirred solution of 5-hydroxytetralone (2.0 g, 12.3 mmol) and 1-bromo (bromomethyl)chlorobenzene (3.6 g, 12.7 mmol) in dimethylformamide (125 mL) was added potassium carbonate (3.5 g, 25.1 mmol). The reaction was stirred under argon for 1 hour then diluted with ethyl acetate (1 L). The organics were washed three times with water and once with brine. The organic layer was then dried with magnesium sulfate, filtered and concentrated. To the resulting oil was added methanol (100 mL) and the suspension was agitated for thirty minutes. 5-(2-bromochlorobenzyloxy)-3,4-dihydronaphthalen-1(2H)- one (4.25 g, 94% yield) was isolated by filtration. 8-chloro-2,3,4,6-tetrahydro-1H-dibenzo[c,h]chromenone To a flask containing ium(II) pivalate (68 mg, 0.22 mmol), tri(4- fluorophenyl)phosphine (70 mg, 0.22 mmol), c acid (135 mg, 1.3 mmol) and potassium carbonate (1.83 g, 13.1 mmol) was added a solution of 5-(2-bromochlorobenzyloxy)-3,4- dihydronaphthalen-1(2H)-one (1.61 g, 4.4 mmol) in dimethyacetamide (23 mL). The flask was evacuated and backfilled with argon 5 times and then stirred under argon at 60 oC for 24 hours. The reaction was poured directly onto a silica gel column and purified by flash column tography (hexanes/DCM) to yield 8-chloro-2,3,4,6-tetrahydro- 1H-dibenzo[c,h]chromenone (1.22 g, 97% yield) as an ite solid. 2-bromochloro-2,3,4,6-tetrahydro-1H-dibenzo[c,h]chromenone To a e of 8-chloro-2,3,4,6-tetrahydro-1H-dibenzo[c,h]chromenone (2.58 g, 9.1 mmol) in form (9.1 mL) and ethyl e (9.1 mL) was added copper(II) bromide (4.65 g, 19.9 mmol). The reaction was heated to 80 oC for 5 hours and then cooled to room temperature. The mixture was diluted with dichloromethane and washed twice with a 5:1 solution of saturated aqueous ammonium chloride and aqueous ammonium hydroxide (~28%), and washed once with water. The organic layer was dried with magnesium sulfate, filtered and concentrated. The crude al was purified by flash column chromatography (hexanes/DCM) to yield 2-bromochloro-2,3,4,6-tetrahydro-1H-dibenzo[c,h]chromen one (2.45 g, 75% yield). (2S)tert-butyl 2-(8-chlorooxo-2,3,4,6-tetrahydro-1H-dibenzo[c,h]chromenyl) pyrrolidine-1,2-dicarboxylate To a solution of 2-bromochloro-2,3,4,6-tetrahydro-1H-dibenzo[c,h]chromenone (1.05 g, 2.9 mmol) and o-OH (1.75 g, 8.1 mmol) in acetonitrile (9.0 mL) was added diisopropylethylamine (1.5 mL, 8.7 mmol). The solution was stirred under argon at 50 oC for two hours. Extra Boc-Pro-OH (620 mg, 2.9 mmol) and diisopropylethylamine (0.5 mL, 2.9 mmol) were added and the reaction was stirred at 50 oC for 16 hours. The reaction was cooled to room temperature and d with ethyl acetate. The organics were washed with water and brine, dried with magnesium sulfate and concentrated. The crude material was purified by flash column chromatography and the product (2S)tert-butyl hloro oxo-2,3,4,6-tetrahydro-1H-dibenzo[c,h]chromenyl) pyrrolidine-1,2-dicarboxylate was isolated as a mixture of diastereomers (0.99 g, 69% yield). tert-butyl (2S)(9-chloro-3,4,5,7-tetrahydroisochromeno[3',4':5,6]naphtho[1,2- azolyl)pyrrolidinecarboxylate To a solution of (2S)tert-butyl 2-(8-chlorooxo-2,3,4,6-tetrahydro-1H- dibenzo[c,h]chromenyl) pyrrolidine-1,2-dicarboxylate (2.2 g, 4.4 mmol) in toluene (40 mL) was added um acetate (7 g, 91 mmol). The reaction mixture was vigorously refluxed for 3 hours, then cooled to room temperature and diluted with ethyl acetate. The organics were washed with water and brine, dried with magnesium sulfate and trated.

The crude material was purified by flash column chromatography to yield tert-butyl (2S) (9-chloro-3,4,5,7-tetrahydroisochromeno[3',4':5,6]naphtho[1,2-d]imidazolyl)pyrrolidine carboxylate (1.13 g, 54% yield) as well as red (2S)tert-butyl 2-(8-chlorooxo- 2,3,4,6-tetrahydro-1H-dibenzo[c,h]chromenyl) pyrrolidine-1,2-dicarboxylate (0.8 g, 36%).

). LCMS-ESI+: calculated for C27H28N3O3: 477.98; observed [M+1]+: 478.54. tert-butyl (2S)(9-chloro-3,7-dihydroisochromeno[3',4':5,6]naphtho[1,2-d]imidazol yl)pyrrolidinecarboxylate To a solution of Intermediate tert-butyl (2S)(9-chloro-3,4,5,7- tetrahydroisochromeno[3',4':5,6]naphtho[1,2-d]imidazolyl)pyrrolidinecarboxylate (1.43 g, 3.0 mmol) in dichloromethane (30 mL) was added manganese(IV) oxide (15 g, 198 mmol).

The mixture was stirred for four hours at room temperature then ed through Celite. The MnO2 was thoroughly rinsed with dichloromethane and the total filtrate was concentrated to yield tert-butyl (2S)(9-chloro-3,7-dihydroisochromeno[3',4':5,6]naphtho[1,2-d]imidazol yl)pyrrolidinecarboxylate (1.37 g, 96% yield). This material was used without further purification. tert-butyl (2S)[9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-3,7- dihydroisochromeno[3',4':5,6]naphtho[1,2-d]imidazolyl]pyrrolidinecarboxylate To a solution of tert-butyl (2S)(9-chloro-3,7- oisochromeno[3',4':5,6]naphtho[1,2-d]imidazolyl)pyrrolidinecarboxylate (1.4 g, 2.9 mmol) in dioxane (20 mL) was added bis(pinacolato)diboron (1.5 g, 5.9 mmol), ibenzylideneacetone)dipalladium(0) (110 mg, 0.12 mmol), X-Phos (145 mg, 0.30 mmol) and ium acetate (870 mg, 8.9 mmol). The mixture was degassed with a stream of argon for ten minutes. The degassed reaction was heated under argon to 90 oC for 2.5 hours then cooled to room temperature and diluted with ethyl acetate. The organics were washed with water and brine, dried with magnesium sulfate and concentrated. The crude material was purified by flash column chromatography (DCM/EtOAc) to yield tert-butyl (2S)[9- (4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-3,7-dihydroisochromeno[3',4':5,6]naphtho[1,2- d]imidazolyl]pyrrolidinecarboxylate (1.5 g, 90% yield). methyl 3-methyloxo{(2S)[9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)- 3,7-dihydroisochromeno[3',4':5,6]naphtho[1,2-d]imidazolyl]pyrrolidinyl}butan yl]carbamate A solution of tert-butyl (2S)[9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-3,7- dihydroisochromeno[3',4':5,6]naphtho[1,2-d]imidazolyl]pyrrolidinecarboxylate (0.98 g, 1.7 mmol), concentrated HCl (2 mL) and ethanol (20 mL) was heated to 60 oC for 2 hours.

The reaction was concentrated and redissolved in a minimal amount of methanol. An equal volume of dichloromethane was added and the solution was again trated.

Dichloromethane was added to the resulting e and concentrated off two more times.

The resulting crude material was dissolved in dimethylformamide (17 mL). To this on was added (S)(methoxycarbonylamino)methylbutanoic acid (455 mg, 2.6 mmol), HATU (955 mg, 2.5 mmol) and diisopropylethylamine (3 mL, 17 mmol). The reaction was stirred at room temperature for one hour then diluted with ethyl acetate. The organics were washed with water (x2) and brine, dried with magnesium sulfate and concentrated. The resulting residue was purified by flash column chromatography to yield Intermediate methyl [(2S)methyloxo{(2S)[9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-3,7- dihydroisochromeno[3',4':5,6]naphtho[1,2-d]imidazolyl]pyrrolidinyl}butan yl]carbamate (780 mg, 72% yield over 2 steps). tert-butyl (2R)[5-(2-{(2S)[N-(methoxycarbonyl)-L-valyl]pyrrolidinyl}-3,7- oisochromeno[3',4':5,6]naphtho[1,2-d]imidazolyl)-1H-imidazol yl]pyrrolidinecarboxylate A mixture of Pentacyclic ediate methyl [(2S)methyloxo{(2S)[9- (4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-3,7-dihydroisochromeno[3',4':5,6]naphtho[1,2- d]imidazolyl]pyrrolidinyl}butanyl]carbamate (780 mg, 1.3 mmol), (S)-tert-butyl 2- (5-bromo-1H-imidazolyl)pyrrolidinecarboxylate (450 mg, 1.4 mmol), tetrakis(triphenylphosphine)palladium(0) (30 mg, 0.03 mmol), PdCl2(dppf) (60 mg, 0.08 mmol), 2M aqueous potassium carbonate (1.9 mL, 3.9 mmol), dimethoxyethane (10 mL) and dimethylformamide (2 mL) was degassed with argon for 15 minutes. The reaction was then heated to 85 oC for 3 hours. Upon completion, the reaction was cooled to room temperature, diluted with ethyl e and filtered through Celite. The filtrate was washed with water and brine, dried (MgSO4) and concentrated. The resulting crude material was purified by flash column chromatography (EtOAc/MeOH) to yield Intermediate tert-butyl -[5-(2-{(2S)- 1-[N-(methoxycarbonyl)-L-valyl]pyrrolidinyl}-3,7- dihydroisochromeno[3',4':5,6]naphtho[1,2-d]imidazolyl)-1H-imidazolyl]pyrrolidine carboxylate (390 mg, 43% yield). methyl {(2S)[(2R)(5-{2-[(2S){(2S)[(methoxycarbonyl)amino] methylbutanoyl}pyrrolidinyl]-3,7-dihydroisochromeno[3',4':5,6]naphtho[1,2- d]imidazolyl}-1H-imidazolyl)pyrrolidinyl]methyloxobutanyl}carbamate A mixture of Intermediate tert-butyl -[5-(2-{(2S)[N-(methoxycarbonyl)-L- valyl]pyrrolidinyl}-3,7-dihydroisochromeno[3',4':5,6]naphtho[1,2-d]imidazolyl)-1H- imidazolyl]pyrrolidinecarboxylate (390 mg, 0.53 mmol), trated HCl (2 mL) and ethanol (10 mL) was heated to 60 oC for 2 hours. The reaction was concentrated and redissolved in a minimal amount of methanol. An equal volume of dichloromethane was added and the solution was again concentrated. Dichloromethane was added to the resulting residue and concentrated off two more times. One half of the crude material (~0.27 mmol) was dissolved in dimethylformamide (2.5 mL). To this solution was added (S) (methoxycarbonylamino)methylbutanoic acid (66 mg, 0.38 mmol), HATU (140 mg, 0.37 mmol) and diisopropylethylamine (0.48 mL, 2.7 mmol). The reaction was d at room temperature for 2 hours, and then diluted with acetonitrile (2 mL) and ol (2 mL). To this solution was added ten drops of 5M aqueous NaOH solution and stirring was continued for 30 minutes. The reaction was diluted with ethyl acetate and the organic layer was washed with water and brine. The combined s washings were extracted three times with ethyl acetate, and the combined organic layers were dried ) and concentrated. The crude al was purified by reverse phase HPLC (Gemini, 15 to 45% ACN/H2O + 0.1% TFA) to yield methyl {(2S)[(2R)(5-{2-[(2S){(2S)[(methoxycarbonyl)amino] methylbutanoyl}pyrrolidinyl]-3,7-dihydroisochromeno[3',4':5,6]naphtho[1,2-d]imidazol- 9-yl}-1H-imidazolyl)pyrrolidinyl]methyloxobutanyl}carbamate (140 mg, 67% yield over 2 steps). LCMS-ESI+: calculated for C43H50N8O7: 790.91; observed [M+1]+: e MA This compound was made in an analogous manner to methyl {(2S)[(2R)(5-{2- [(2S){(2S)[(methoxycarbonyl)amino]methylbutanoyl}pyrrolidinyl]-3,7- dihydroisochromeno[3',4':5,6]naphtho[1,2-d]imidazolyl}-1H-imidazolyl)pyrrolidin yl]methyloxobutanyl}carbamate, substituting (R)(methoxycarbonylamino) phenylacetic acid for (S)(methoxycarbonylamino)methylbutanoic acid and substituting COMU for HATU in the final amide coupling step. LCMS-ESI+: calculated for C46H48N8O7: 824.92; observed [M+1]+: 825.72.

Example MB tert-butyl (2S)[9-(2-{(2R)[N-(methoxycarbonyl)-L-valyl]pyrrolidinyl}-1H- imidazolyl)-3,7-dihydroisochromeno[3',4':5,6]naphtho[1,2-d]imidazol yl]pyrrolidinecarboxylate A mixture of utyl (2S)[9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-3,7- dihydroisochromeno[3',4':5,6]naphtho[1,2-d]imidazolyl]pyrrolidinecarboxylate (450 mg, 0.79 mmol), methyl (S)((S)(5-bromo-1H-imidazolyl)pyrrolidinyl)methyl- 1-oxobutanylcarbamate (325 mg, 0.87 mmol), tetrakis(triphenylphosphine)palladium(0) (30 mg, 0.02 mmol), PdCl2(dppf) (35 mg, 0.05 mmol), 2M aqueous potassium carbonate (1.2 mL, 2.4 mmol), dimethoxyethane (6.8 mL) and dimethylformamide (1.2 mL) was degassed with argon for 15 minutes. The reaction was then heated to 85 oC for 2.5 hours. Upon completion, the reaction was cooled to room temperature, diluted with ethyl acetate and filtered through Celite. The te was washed with water and brine, dried (MgSO4) and concentrated. The resulting crude material was purified by flash column tography (EtOAc/MeOH) to yield tert-butyl (2S)[9-(2-{(2R)[N-(methoxycarbonyl)-L- valyl]pyrrolidinyl}-1H-imidazolyl)-3,7-dihydroisochromeno[3',4':5,6]naphtho[1,2- d]imidazolyl]pyrrolidinecarboxylate (270 mg, 46% yield). methyl {(2S)[(2R)(5-{2-[(2S){(2R)[(methoxycarbonyl)amino] phenylacetyl}pyrrolidinyl]-3,7-dihydroisochromeno[3',4':5,6]naphtho[1,2-d]imidazol- 9-yl}-1H-imidazolyl)pyrrolidinyl]methyloxobutanyl}carbamate: A e of tert-butyl (2S)[9-(2-{(2R)[N-(methoxycarbonyl)-L- valyl]pyrrolidinyl}-1H-imidazolyl)-3,7-dihydroisochromeno[3',4':5,6]naphtho[1,2- d]imidazolyl]pyrrolidinecarboxylate (270 mg, 0.37 mmol), concentrated HCl (1.5 mL) and ethanol (8 mL) was heated to 60 oC for 1 hour. The reaction was concentrated and redissolved in a l amount of methanol. An equal volume of dichloromethane was added and the solution was again concentrated. Dichloromethane was added to the resulting residue and concentrated off two more times. The crude material was dissolved in 5:1 dichloromethane/dimethylformamide (3.8 mL). To this solution was added (R) (methoxycarbonylamino)phenylacetic acid (96 mg, 0.46 mmol), COMU (190 mg, 0.44 mmol) and diisopropylethylamine (0.20 mL, 1.1 mmol). The reaction was stirred at 0 oC for minutes then warmed to room temperature. Upon completion, the reaction was d with acetonitrile (2 mL) and methanol (2 mL). To this solution was added ten drops of 5M aqueous NaOH solution and stirring was continued for 30 minutes. The reaction was diluted with ethyl acetate and the organic layer was washed with water and brine. The combined s washings were extracted three times with ethyl acetate, and the ed organic layers were dried (MgSO4) and concentrated. The crude al was purified by reverse phase HPLC (Gemini, 15 to 45% ACN/H2O + 0.1% TFA) to yield methyl {(2S)[(2R) (5-{2-[(2S){(2R)[(methoxycarbonyl)amino]phenylacetyl}pyrrolidinyl]-3,7- dihydroisochromeno[3',4':5,6]naphtho[1,2-d]imidazolyl}-1H-imidazolyl)pyrrolidin methyloxobutanyl}carbamate (155 mg, 51% yield over 2 steps). LCMS-ESI+: calculated for C46H48N8O7: 824.92; observed [M+1]+: 825.67.

Example MC dimethyl (2S,2'S)-1,1'-((2S,2'S)-2,2'l-pyrrolidinyl)-5H-naphtho[c,g]chromeno[8,9- d]imidazolyl)-1H-imidazolyl)pyrrolidinyl))bis(3-methyloxobutane-2,1- icarbamate This compound was made in an analogous manner to methyl {(2S)[(2R)(5-{2- [(2S){(2S)[(methoxycarbonyl)amino]methylbutanoyl}pyrrolidinyl]-3,7- dihydroisochromeno[3',4':5,6]naphtho[1,2-d]imidazolyl}-1H-imidazolyl)pyrrolidin yl]methyloxobutanyl}carbamate, tuting 7-hydroxytetralone for 5-hydroxy- 1-tetralone in the first step of the sequence. All reactions in the synthesis gave similar product yields as in the synthesis of methyl {(2S)[(2R)(5-{2-[(2S){(2S) [(methoxycarbonyl)amino]methylbutanoyl}pyrrolidinyl]-3,7- dihydroisochromeno[3',4':5,6]naphtho[1,2-d]imidazolyl}-1H-imidazolyl)pyrrolidin yl]- 3-methyloxobutanyl}carbamate. LCMS-ESI+: calculated for C43H50N8O7: 790.91; observed [M+1]+: 791.6.

Example MD NH O O O O N NH N N N H O methyl {5-[2-(1-{[(methoxycarbonyl)amino]methyl oxobutanyl}pyrrolidinyl)-1,11- dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl]-1H- imidazolyl}pyrrolidinyl)-phenyloxoacetyl]carbamate This compound was made in an analogous manner to dimethyl (2S,2'S)-1,1'-((2S,2'S)- 2,2'l-pyrrolidinyl)-5H-naphtho[c,g]chromeno[8,9-d]imidazolyl)-1H-imidazol yl)pyrrolidinyl))bis(3-methyloxobutane-2,1-diyl)dicarbamate, tuting (R) (methoxycarbonylamino)phenylacetic acid for (S)(methoxycarbonylamino) methylbutanoic acid and substituting COMU for HATU in the final amide coupling step.

LCMS-ESI+: calculated for N8O7: 824.92; observed [M+1]+: 825.67.

Example ME yl (2S,2'S)-1,1'-((2S,2'S)-2,2'l-pyrrolidinyl)-7H-dihydro- naphtho[c,g]chromeno[8,9-d]imidazolyl)-1H-imidazolyl)pyrrolidinyl))bis(3- methyloxobutane-2,1-diyl)dicarbamate This compound was made in an analogous manner to dimethyl (2S,2'S)-1,1'-((2S,2'S)- 2,2'l-pyrrolidinyl)-5H-naphtho[c,g]chromeno[8,9-d]imidazolyl)-1H-imidazol yl)pyrrolidinyl))bis(3-methyloxobutane-2,1-diyl)dicarbamate, omitting the MnO2 oxidation of tert-butyl 2-(9-chloro-1,4,5,11-tetrahydroisochromeno[4',3':6,7]naphtho[1,2- d]imidazolyl)pyrrolidinecarboxylate. LCMS-ESI+: calculated for C43H52N8O7: 792.40; observed [M+1]+: 793.69. e MF methyl [1-(2-{5-[2-(1-{[(methoxycarbonyl)amino]methyloxobutanyl}pyrrolidin- 1,4,5,11-tetrahydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl]-1H- imidazolyl}pyrrolidinyl)-phenyloxoacetyl]carbamate This compound was made in an analogous manner to dimethyl (2S,2'S)-1,1'-((2S,2'S)- 2,2'l-pyrrolidinyl)-7H-dihydro-naphtho[c,g]chromeno[8,9-d]imidazolyl)-1H-imidazol- 2-yl)pyrrolidinyl))bis(3-methyloxobutane-2,1-diyl)dicarbamate, substituting (R) (methoxycarbonylamino)phenylacetic acid for (S)(methoxycarbonylamino) methylbutanoic acid and substituting COMU for HATU in the final amide coupling step.

LCMS-ESI+: calculated for C46H50N8O7: ; observed [M+1]+: 827.71.

Example MG O O O N O NH O Pd(PPh3)4, PdCl2(dppf), Br B N N O N N K2CO3, DME, DMF, 85 oC methyl (S)((S)(5-bromo-1H- tert-butyl (2S)[9-(4,4,5,5-tetramethylimidazolyl )pyrrolidinyl) 1,3,2-dioxaborolanyl)-3,4,5,11- oxobutanylcarbamate tetrahydroisochromeno[4',3':6,7]naphtho[ 1,2-d]imidazolyl]pyrrolidine carboxylate O O NH 1) HCl, EtOH, 60 oC O O HN O NH O N O O 2) Moc-Val-OH, COMU, N N N N DIPEA, DMF H HO tert-butyl (2S)[9-(2-{(2R)[N-(methoxycarbonyl)-L- (R)(methoxycarbonylamino)- valyl]pyrrolidinyl}-1H-imidazolyl)-3,4,5,11- 2-phenylacetic acid tetrahydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazol- 2-yl]pyrrolidinecarboxylate NH O O O O N NH N N N N [1-(2-{5-[2-(1-{[(methoxycarbonyl)amino](phenyl)acetyl}pyrrolidinyl)-1,4,5,11- tetrahydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl]-1H-imidazol yl}pyrrolidinyl)methyloxobutanyl]carbamic acid This compound was made in an ous manner to methyl {(2S)[(2R)(5-{2- [(2S){(2R)[(methoxycarbonyl)amino]phenylacetyl}pyrrolidinyl]-3,7- dihydroisochromeno[3',4':5,6]naphtho[1,2-d]imidazolyl}-1H-imidazolyl)pyrrolidin yl]methyloxobutanyl}carbamate, substituting tert-butyl (2S)[9-(2-{(2R)[N- xycarbonyl)-L-valyl]pyrrolidinyl}-1H-imidazolyl)-3,4,5,11- tetrahydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl]pyrrolidinecarboxylate for tert-butyl (2S)[9-(2-{(2R)[N-(methoxycarbonyl)-L-valyl]pyrrolidinyl}-1H-imidazol- 5-yl)-3,7-dihydroisochromeno[3',4':5,6]naphtho[1,2-d]imidazolyl]pyrrolidine ylate. LCMS-ESI+: calculated for C46H50N8O7: 826.94; observed [M+1]+: 827.64.

Example MM O 1. HCl, EtOH, 60°C O N N 2.

B O O N Boc O H N O )-tert-butyl 4-(methoxymethyl)(9-(4,4,5,5- O H tetramethyl-1,3,2-dioxaborolanyl)-1,11- HATU, DIPEA, DMF, RT dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl)pyrrolidine- 1-carboxylate O Boc N H Br O N N N B N H O N N O Pd(PPh3)4, PdCl2(dppf), H K2CO3, DME/ DMF, 85°C (2S,4S)-methyl {4-(methoxymethyl)[(9-(4,4,5,5- tetramethyl-1,3,2-dioxaborolanyl)-1,11- dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazol- 2-yl)pyrrolidin-1yl]methyloxobutanyl}carbamate H 1. HCl, EtOH, 60°C Boc N N N N N H O N O H O O H N O tert-butyl (2S)[5-(2-{(2S,4S)[N-(methoxycarbonyl)- L-valyl]methylpyrrolidinyl}-1,11-dihydroisochromeno O H [4',3':6,7]naphtho[1,2-d]imidazolyl)-1H-imidazolyl COMU, DIPEA, DMF, RT ]pyrrolidinecarboxylate H O O O H N N N N N N O methyl {(1R)[(2S)(5-{2-[(2S,4S){(2S)[(methoxycarbonyl) amino]methylbutanoyl}(methoxymethyl)pyrrolidinyl]-1,11- dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl}-1H-imidazol- 2-yl)pyrrolidinyl]oxophenylethyl}carbamate (2S,4S)-methyl {4-(methoxymethyl)[(9-(4,4,5,5-tetramethyl-1,3,2-dioxa borolanyl)- 1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl) pyrrolidin-1yl] methyloxobutanyl}carbamate A solution of (2S,4S)-tert-butyl 4-(methoxymethyl)(9-(4,4,5,5-tetramethyl-1,3,2- dioxaborolanyl)- 1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]-imidazol yl)pyrrolidinecarboxylate (424 mg, 0.69 mmol), ethanol (6 mL) and concentrated HCl (2 mL) was heated to 60 °C for 1 hour. The reaction was concentrated and the crude al dissolved in DCM (10 mL). This solution was concentrated and to this material was added a solution of 2-methoxycarbonylaminomethylbutyric acid (152 mg, 0.86 mmol) and HATU (303 mg, 0.79 mmol) in DMF (6 mL). To the resulting on was added diisopropylethylamine (360 L, 2.08 mmol). After stirring for 2 hours at room temperature, the on was diluted with ethyl acetate, washed with 5% NaHCO3 on, water and brine, dried (Na2SO4), concentrated and dried under vacuum to give (2S,4S)-methyl {4- (methoxymethyl)[(9-(4,4,5,5-tetramethyl-1,3,2-dioxaboro lanyl)-1,11- dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl)pyrrolidinyl]methyl oxobutanyl}carbamate. tert-butyl(2S)[5-(2-{(2S,4S)[N-(methoxycarbonyl)-L-valyl]methylpyrroli din yl}-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl)-1H-imidazol rolidinecarboxylate To a solution of (2S, 4S)-methyl{4-(methoxymethyl)[(9-(4,4,5,5-tetramethyl-1,3,2- dioxaborolanyl)-1,11-dihydroiso chromeno[4',3':6,7]naphtho[1,2-d]imidazol yl)pyrrolidin-1yl]methyloxobutanyl}carbamate (0.69 mmol), (S)-tert-butyl 2-(5- bromo-1H-imidazolyl)pyrrolidinecarboxylate (220 mg, 0.69 mmol), tetrakis(triphenylphosphine) palladium(0) (24 mg, 0.02 mmol) and ro[1,1'- bis(diphenylphosphino) ene]palladium(II) (31 mg, 0.04 mmol) in a mixture of 1,2- dimethoxyethane (6.0 mL) and dimethylformamide (1.0 mL) was added a solution of potassium carbonate (2M in water, 1.04 mL, 2.0 mmol). The resulting mixture was degassed and then heated to 85 °C under argon for 18 hours. After g to room temperature, the reaction was diluted with ethyl acetate. The organics were washed with water and brine, dried (Na2SO4), and concentrated. The crude residue was purified by flash chromatography to yield (tert-butyl -[5-(2-{(2S,4S)[N-(methoxycarbonyl)-L-valyl] methylpyrrolidinyl}-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl)-1H- imidazolyl]pyrrolidinecarboxylate (145 mg, 27%). methyl{(1R)[(2S)(5-{2-[(2S,4S){(2S)[(methoxycarbonyl)amino] methylbutanoyl}(methoxymethyl)pyrrolidinyl]-1,11-dihydroiso chromeno[4',3':6,7]naphtho[1,2-d]imidazolyl}-1H-imidazolyl)pyrrolidinyl] oxophenylethyl}carbamate A solution of tert-butyl (2S)[5-(2-{(2S,4S)[N-(methoxycarbonyl)-L-valyl] methylpyrrolidinyl}-1,11-dihydroisochromeno [4',3':6,7]naphtho[1,2-d]imidazolyl)-1H- imidazolyl]pyrrolidinecarboxylate (145 mg, 0.18 mmol), ethanol (3 mL) and concentrated HCl (1 mL) was heated to 60 °C for 1 hour. The reaction was concentrated and the crude material dissolved in DCM (6 mL). This solution was concentrated and to this material was added a on of (R)(methoxycarbonylamino)phenylacetic acid (51 mg, 0.24 mmol) and COMU (92 mg, 021 mmol) in DMF (3 mL). To the resulting solution was added diisopropylethylamine (100 L, 0.56 mmol). After stirring for 2 hours at room temperature, the reaction was diluted with ethyl acetate, washed with water and brine, dried (Na2SO4), concentrated and purified by preparative reverse phase HPLC (Gemini, 15 to 43% ACN/H2O + 0.1% TFA). The product fractions were lyophilized to give methyl 2- [(2S)(5-{2-[(2S,4S){(2S)[(methoxycarbonyl)amino]methylbutanoyl} (methoxymethyl)pyrrolidinyl]-1,11-dihydroisochromeno [4',3':6,7]naphtho[1,2- azolyl}-1H-imidazolyl)pyrrolidinyl]oxophenylethyl}carbamate (68 mg, 39%). MS (ESI) m/z 870 [M + H]+. 1H NMR (400 MHz, dmso) δ 8.71 (s, 1H), 8.22 (d, 1H, J = 8 Hz), 8.09 (m, 1H), 7.88 – 7.63 (m, 6H), 7.36 - 7.29 (m, 6H), 5.41 (d, 1H, J = 8.4 Hz), .30 – 5.24 (m, 2H), 5.14 – 5.10 (m, 1H), 4.13 -3.09 (m, 15H), 2.47 - 1.80 (m, 8H), 0.80 (dd, 6H, J = 6.4 Hz, J = 23 Hz). e MN tert-butyl(2S,4S)[9-(2-{(2S4S)[N-(methoxycarbonyl)-L-valyl]methyl pyrrolidin- 2-yl}-1H-imidazolyl)-3,11-dihydroisochromeno[4',3':6,7]naphtho [1,2-d]imidazol yl](methoxymethyl)pyrrolidinecarboxylate To a solution of (2S,4S)-tert-butyl 4-(methoxymethyl)(9-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolanyl)-1,11-dihydroisochromeno[4',3':6,7] naphtho [1,2-d]imidazol yl)pyrrolidinecarboxylate (438 mg, 0.72 mmol), methyl (S)((2S,4S)(5-bromo-1H- imidazolyl)methylpyrrolidinyl)methyloxobutanylcarbamate (276 mg, 0.72 mmol), tetrakis(triphenylphosphine) palladium(0) (41 mg, 0.04 mmol) and dichloro[1,1'- bis(diphenylphosphino) ferrocene]palladium(II) (52 mg, 0.07 mmol) in a mixture of 1,2- dimethoxyethane (8.6 mL) and dimethylformamide (1.5 mL) was added a solution of ium carbonate (2M in water, 1.07 mL, 2.15 mmol). The resulting mixture was degassed and then heated to 85 °C under argon for 18 hours. After g to room temperature, the reaction was diluted with ethyl acetate. The organics were washed with water and brine, dried (Na2SO4), and concentrated. The crude residue was purified by flash tography to yield tert-butyl (2S,4S)[9-(2-{(2S,4S)[N-(methoxycarbonyl)-L- valyl]methylpyrrolidinyl}-1H-imidazolyl)-3,11- dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl]- 4-(methoxymethyl)pyrrolidinecarboxylate (182 mg, 32%). methyl {(2S)[(2S,4S)(5-{2-[(2S,4S){(2R)[(methoxycarbonyl)amino] phenylacetyl}(methoxymethyl)pyrrolidinyl]-1,11-dihydroisochromeno [4',3':6,7]naphtho[1,2-d]imidazolyl}-1H-imidazolyl)methylpyrrolidinyl] methyloxobutanyl}carbamate A solution of tert-butyl )[9-(2-{(2S,4S)[N-(methoxycarbonyl)-L-valyl] methylpyrrolidinyl}-1H-imidazolyl)-3,11-dihydroisochromeno[4',3':6,7]naphtho[1,2- d]imidazolyl](methoxy )pyrrolidinecarboxylate (182 mg, 0.18 mmol), ethanol (3 mL) and concentrated HCl (1 mL) was heated to 60 °C for 1 hour. The reaction was concentrated and the crude material ved in DCM (6 mL). This solution was concentrated and to this material was added a solution of (R)(methoxycarbonylamino) phenylacetic acid (47 mg, 0.23 mmol) and COMU (85 mg, 0.2 mmol) in DMF (3 mL). To the resulting solution was added diisopropylethylamine (90 L, 0.52 mmol). After stirring for 2 hours at room temperature, the reaction was diluted with ethyl acetate, washed with water and brine, dried (Na2SO4), concentrated and purified by preparative reverse phase HPLC (Gemini, 15 to 49% ACN/H2O + 0.1% TFA). The product fractions were lyophilized to give methyl{(2S)[(2S,4S)(5-{2-[(2S,4S){(2R)[(methoxycarbonyl)amino] phenylacetyl}(methoxymethyl)pyrrolidinyl]-1,11-dihydroisochromeno [4',3':6,7]naphtho[1,2-d]imidazolyl}-1H-imidazolyl)-methylpyrrolidinyl]methyl- 1-oxobutanyl}carbamate (32 mg, 39%). MS (ESI) m/z 884 [M + H]+. 1H NMR (400 MHz, dmso) δ 8.70 (s, 1H), 8.21 (d, 1H, J = 8 Hz), 8.08 (s, 1H), 7.90 – 7.64 (m, 6H), 7.34 – 7.31 (m, 3H), 7.64 (d, 1H, J = 8.4 Hz), 5.47 (d, 1H, J = 7.6 Hz), 5.28 – .25 (m, 3H), 5.05 – 5.01 (m, 1H), 4.19 – 4.04 (m, 3H), 3.67 – 3.15 (m, 15H), 2.51 -2.46 (m, 4H), 1.95 – 1.92 (m, 2H), 1.82 – 1.76 (m, 1H), 1.10 (d, 3H, J = 6 Hz), 0.75 (dd, 6H, J = 6.8 Hz, J = 14 Hz).

Example MO methyl {(2S)[(2S,4S)(5-{2-[(2S,4S){(2S)[(methoxycarbonyl)amino] methylbutanoyl}methoxymethylpyrrolidinyl]-1,11- dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl}-1H-imidazolyl) methylpyrrolidinyl]methyloxobutanyl}carbamate To a solution of methyl {(2S)[(2S,4S)(5-{2-[(2S,4S) xymethyl)pyrrolidinyl]-1,11-dihydroisochromeno[4',3':6,7] naphtho[1,2- d]imidazolyl}-1H-imidazolyl)(methyl)pyrrolidinyl]methyloxobutan bamate (57 mg, 0.08 mmol), 2-methoxycarbonylaminomethylbutyric acid (19 mg, 0.1 mmol), HATU (303 mg, 0.79 mmol) in DMF (1 mL) was added diisopropylethylamine (43 L, 0.24 mmol). After stirring for 2 hours at room temperature, the reaction was diluted with ethyl acetate, washed with 5% NaHCO3 solution, water and brine, dried (Na2SO4), concentrated and ed by preparative reverse phase HPLC (Gemini, 15 to 43% ACN/H2O + 0.1% TFA). The product fractions were lyophilized to give methyl {(2S)[(2S,4S)(5- {2-[(2S,4S){(2S)[(methoxycarbonyl)amino]methyl butanoyl} ymethylpyrrolidinyl]-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazol- 9-yl}-1H-imidazolyl)methylpyrrolidinyl]methyl- 1-oxobutanyl}carbamate. (13 mg, 19%). MS (ESI) m/z 850 [M + H]+. 1H NMR (400 MHz, dmso) δ 8.66 (s, 1H), 8.28 – 8.13 (m, 1H), 8.12 – 7.99 (m, 1H), 7.90 – 7.75 (m, 3H), 7.73 – 7.65 (m, 1H), 7.63 – 7.57 (m, 1H), 7.34 – 7.19 (m, 2H), 5.30 – .24 (m, 2H), 5.21 – 4.95 (m, 2H), 4.33 – 3.93 (m, 6H), 3.23 -3.58 (m, 12H), 2.76 – 2.59 (m, 2H), 2.02 – 1.73 (m, 6H), 1.12 – 1.07 (m, 3H), 0.86 – 0.68 (m, 12H).

Example MP tert-butyl(2S,4S)[9-(2-{(2S,5S)[N-(methoxycarbonyl)-L-valyl]methyl idin- 2-yl}-1H-imidazolyl)-3,11-dihydroisochromeno[4',3':6,7]naphtho [1,2-d]imidazol yl](methoxymethyl)pyrrolidinecarboxylate To a solution of (2S,4S)-tert-butyl 4-(methoxymethyl)(9-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolanyl)-1,11-dihydroisochromeno[4',3':6,7] naphtho[1,2-d]imidazol yl)pyrrolidinecarboxylate (217 mg, 0.35 mmol), methyl (S)((2S,5S)(5-bromo-1H- olyl)methylpyrrolidinyl)methyloxobutanylcarbamate (170 mg, 0.39 mmol), tetrakis(triphenylphosphine) palladium(0) (21 mg, 0.02 mmol) and dichloro[1,1'- bis(diphenylphosphino) ferrocene]palladium(II) (26 mg, 0.04 mmol) in a mixture of 1,2- dimethoxyethane (4.3 mL) and dimethylformamide (0.75 mL) was added a solution of potassium carbonate (2M in water, 0.53 mL, 1.06 mmol). The resulting mixture was degassed and then heated to 85 °C under argon for 18 hours. After cooling to room temperature, the reaction was diluted with ethyl acetate. The organics were washed with water and brine, dried 4), and concentrated. The crude residue was ed by flash chromatography to yield tert-butyl (2S,4S)[9-(2-{(2S,5S)[N-(methoxycarbonyl)-L- valyl]methylpyrrolidinyl}-1H-imidazolyl)-3,11- dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl](methoxy methyl)pyrrolidine- 1-carboxylate (110 mg, 39%). methyl{(2S)[(2S,5S)(5-{2-[(2S,4S){(2S)[(methoxycarbonyl)amino] methylbutanoyl}methoxymethylpyrrolidinyl]-1,11-dihydroisochromeno [4',3':6,7]naphtho[1,2-d]imidazolyl}-1H-imidazolyl)methylpyrrolidinyl] methyloxobutanyl}carbamate A solution of tert-butyl (2S,4S)[9-(2-{(2S,5S)[N-(methoxycarbonyl)-L-valyl] methylpyrrolidinyl}-1H-imidazolyl)-3,11-dihydroisochromeno[4',3':6,7]naphtho[1,2- d]imidazolyl](methoxy methyl)pyrrolidinecarboxylate (108 mg, 0.14 mmol), ethanol (2 mL) and concentrated HCl (0.7 mL) was heated to 60 °C for 1 hour. The reaction was concentrated and the crude material dissolved in DCM (10 mL). This solution was concentrated and to this material was added a solution of 2-methoxycarbonylamino methylbutyric acid (31 mg, 0.18 mmol) and HATU (60 mg, 0.16 mmol) in DMF (2 mL). To the resulting solution was added diisopropylethylamine (70 L, 0.41 mmol). After ng for 2 hours at room ature, the on was diluted with ethyl acetate, washed with 5% NaHCO3 on, water and brine, dried (Na2SO4). After stirring for 2 hours at room temperature, the reaction was diluted with ethyl acetate, washed with 5% NaHCO3 solution, water and brine, dried (Na2SO4), concentrated and purified by preparative reverse phase HPLC (Gemini, 15 to 43% O + 0.1% TFA). The product fractions were lyophilized to give methyl {(2S)[(2S,5S)(5-{2-[(2S,4S){(2S)[(methoxycarbonyl)amino] methylbutanoyl}methoxy methylpyrrolidinyl]-1,11- dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl}-1H-imidazolyl) methylpyrrolidinyl]methyloxobutanyl}carbamate (52 mg, 45%). MS (ESI) m/z 850 [M + H]+. 1H NMR (400 MHz, dmso) δ 8.69 (s, 1H), 8.18 (d, 1H, J = 7.6 Hz), 7.99 – 7.86 (m, 4H), 7.72 (s, 1H), 7.64 (d, 1H, J = 8.8 Hz), 7.51 (d, 1H, J = 8 Hz), 7.23 (d, 1H, J = 8.4 Hz), .29 (s, 2H), 5.22 – 5.18 (m, 1H), 5.01 – 4.70 (m, 1H), 4.64 – 4.61 (m, 1H), 4.21-4.17 (m, 1H), 4.09-4.05 (m, 1H), 3.92 – 3.88 (m, 1H), 3.59 – 3.08 (m, 14H), 2.67 – 1.83 (m, 7H), 1.43 (d, 3H, J = 6.4 Hz), 0..91-0.71 (m, 12H). e MQ (2S,4R)-tert-butyl(methoxymethyl)(9-(4,4,5,5-tetramethyl-1,3,2-dioxa borolan yl)-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl) pyrrolidine carboxylate A degassed mixture of (2S,4R)-tert-butyl(9-chloro-1,11- dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl)(methoxymethyl) pyrrolidine- 1-carboxylate (335 mg, 0.64 mmol), bis(pinacolato)diboron (246 mg, 0.96 mmol), potassium acetate (190 mg, 1.9 mmol), tris(dibenzylideneacetone) ium (24 mg, 0.02 mmol) and 2- dicyclohexylphosphino-2’, 4’, 6’-tri-i-propyl-1, 1’-biphenyl (31 mg, 0.06 mmol) in 1,4- e (3.3 mL) was heated to 90 oC for 3 hours, cooled to room temperature and d with ethyl acetate. The organics were washed with water and brine, dried 4), and concentrated. The crude residue was purified by flash chromatography to yield (2S,4R)-tertbutyl 4-(methoxymethyl)(9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-1,11- dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazol yl)pyrrolidinecarboxylate (379 mg, 96%). (2S,4R)-tert-butyl(9-(2-((S)((S)(methoxycarbonylamino)methyl butanoyl)pyrrolidinyl)-1H-imidazolyl)-1,11-dihydroisochromeno[4',3':6,7] naphtho[1,2-d]imidazol -4(methoxymethyl) pyrrolidinecarboxylate.

To a solution of (2S,4R)-tert-butyl 4-(methoxymethyl)(9-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolanyl)- 1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl) pyrrolidinecarboxylate (299 mg, 0.49 mmol), methyl (S)((S)(5-bromo-1H-imidazol- 2-yl)pyrrolidinyl)methyloxobutanylcarbamate (217 mg, 0.58 mmol), tetrakis(triphenylphosphine) palladium(0) (28 mg, 0.02 mmol) and ro[1,1'- bis(diphenylphosphino)ferrocene]palladium(II) (35 mg, 0.04 mmol) in a mixture of 1,2- dimethoxyethane (4.3 mL) and dimethylformamide (0.75 mL) was added a solution of potassium carbonate (2M in water, 0.73 mL, 1.46 mmol). The resulting mixture was degassed and then heated to 85 °C under argon for 18 hours. After cooling to room temperature, the reaction was diluted with ethyl acetate. The organics were washed with water and brine, dried (Na2SO4), and concentrated. The crude residue was purified by flash chromatography to yield (2S,4R)-tert-butyl 2-((S)((S)(methoxycarbonylamino) methylbutanoyl)pyrrolidinyl)-1H-imidazolyl)-1,11- dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl)(methoxymethyl)pyrrolidine carboxylate (170 mg, 45%). methyl{(1R)[(2S,4R)(9-{2-[(2S){(2S)[(methoxycarbonyl)amino] methylbutanoyl}pyrrolidinyl)-1H-imidazolyl]-1,11-dihydroisochromeno [4',3':6,7]naphtho[1,2-d]imidazolyl}(methoxymethyl)pyrrolidinyl]oxophenylethyl }carbamate A solution of (2S,4R)-tert-butyl 2-(9-(2-((S)((S)(methoxycarbonylamino) methylbutanoyl)pyrrolidinyl)-1H-imidazolyl)-1,11- dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl)(methoxymethyl)pyrrolidine carboxy late (170 mg, 0.22 mmol), ethanol (3 mL) and concentrated HCl (1 mL) was heated to 60 °C for 1 hour. The reaction was concentrated and the crude al dissolved in DCM (6 mL). This on was concentrated and to this material was added a solution of (R) (methoxycarbonylamino)phenylacetic acid (59 mg, 0.28 mmol) and COMU (108 mg, 0.25 mmol) in DMF (3 mL). To the resulting on was added diisopropylethylamine (110 L, 0.66 mmol). After stirring for 2 hours at room temperature, the reaction was diluted with ethyl acetate, washed with water and brine, dried (Na2SO4), concentrated and purified by preparative reverse phase HPLC (Gemini, 15 to 44% ACN/H2O + 0.1% TFA). The product ons were lyophilized to give methyl {(1R)[(2S,4R)(9-{2-[(2S){(2S) [(methoxycarbonyl)amino]methylbutanoyl}pyrrolidinyl)-1H-imidazolyl]-1,11- dihydroisochromeno[4',3':6,7]-naphtho[1,2-d]imidazolyl}-(methoxymethyl) pyrrolidin yl]oxo-phenylethyl}carbamate (67 mg, 35%). MS (ESI) m/z 870 [M + H]+. 1H NMR (400 MHz, dmso) δ 8.71 (s, 1H), 8.20 (d, 1H, J = 8.4 Hz), 8.01 (m, 1H), 7.91 – 7.64 (m, 6H), 7.38 - 7.28 (m, 6H), 6.85 (s, 1H), 5.51 (d, 1H, J = 7.2 Hz), 5.39 – 5.29 (m, 3H), 5.13 – 5.09 (m, 1H), 4.11 -3.04 (m, 15H), 2.77 - 1.98 (m, 8H), 0.79 (dd, 6H, J = 6.8 Hz, J = 12.8 Hz).

Example MR O O O O O O Cl N Pd2dba3, KOAc, XPOS, N Boc e, 90°C (2S,4S)-tert-butyl 2-(9-chloro-4,5-dihydro-1,11- dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazol yl)(methoxymethyl)pyrrolidinecarboxylate O H O O O N N H H O N B N O N Boc Pd(PPh3)4, PdCl2(dppf), K2CO3, DME/ DMF, 85°C (2S,4S)-tert-butyl 4-(methoxymethyl)(9-(4,4,5,5- tetramethyl-1,3,2-dioxaborolanyl)-4,5-dihydro-1,11- dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazol yl)pyrrolidinecarboxylate H O N H O O N 1. HCl, EtOH, 60°C N N N N N Boc 2. (2S,4S)-tert-butyl 2-(9-(2-((S)((S)(methoxycarbonyl O H N O amino)methylbutanoyl)pyrrolidinyl)-1H-imidazol- -yl-4,5-dihydro-1,11-dihydroisochromeno[4',3':6,7]naphtho O H [1,2-d]imidazolyl)(methoxymethyl)pyrrolidine COMU, DIPEA, DMF, RT carboxylate H O N H O O N N N N N N O methyl 2-[(2S,4S)(9-{2-[(2S){(2S)[(methoxy carbonyl)amino]methylbutanoyl}pyrrolidinyl)-1H-imidazol- -yl]-1,11-dihydroisochromeno[4',3':6,7]-4,5-dihydro-naphtho[1,2-d] imidazolyl}(methoxymethyl)pyrrolidinyl]oxo phenylethyl}carbamate (2S,4S)-tert-butyl4-(methoxymethyl)(9-(4,4,5,5-tetramethyl-1,3,2-dioxaboro lan yl)-4,5-dihydro-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazol yl)pyrrolidinecarboxylate A degassed mixture of (2S,4S)-tert-butyl 2-(9-chloro-4,5-dihydro-1,11- dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazol (methoxymethyl)pyrrolidine- 1-carboxylate (322 mg, 0.61 mmol), bis(pinacolato) diboron (235 mg, 0.92 mmol), potassium e (182 mg, 1.9 mmol), tris(dibenzylideneacetone)palladium (23 mg, 0.02 mmol) and 2- dicyclohexylphosphino-2’, 4’, -i-propyl-1, 1’-biphenyl (29 mg, 0.06 mmol) in 1,4- e (3.3 mL) was heated to 90 oC for 3 hours, cooled to room temperature and diluted with ethyl acetate. The organics were washed with water and brine, dried (Na2SO4), and concentrated. The crude residue was ed by flash chromatography to yield (2S,4S)-tertbutyl 4-(methoxymethyl)(9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-4,5-dihydro- 1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl)pyrrolidinecarboxylate (267 mg, 70%). (2S,4S)-tert-butyl(9-(2-((S)((S)(methoxycarbonylamino)methylbutano yl)pyrrolidinyl)-1H-imidazolyl-4,5-dihydro-1,11-dihydroisochromeno [4',3':6,7]naphtho[1,2-d]imidazolyl)(methoxymethyl)pyrrolidinecarboxylate To a solution of (2S,4S)-tert-butyl 4-(methoxymethyl)(9-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolanyl)-4,5-dihydro-1,11-dihydroisochrome no[4',3':6,7]naphtho[1,2- d]imidazolyl)pyrrolidinecarboxylate (267 mg, 0.52 mmol), methyl (S)((S)(5- bromo-1H-imidazolyl)pyrrolidinyl)methyloxobutanylcarbamate (195 mg, 0.52 mmol), tetrakis (triphenylphosphine) palladium(0) (25 mg, 0.02 mmol) and dichloro[1,1'- bis(diphenylphosphino)ferrocene] palladium(II) (32 mg, 0.04 mmol) in a mixture of 1,2- dimethoxyethane (4.3 mL) and dimethylformamide (0.75 mL) was added a solution of potassium carbonate (2M in water, 0.65 mL, 1.3 mmol). The resulting mixture was degassed and then heated to 85 °C under argon for 18 hours. After cooling to room temperature, the reaction was diluted with ethyl acetate. The organics were washed with water and brine, dried (Na2SO4), and concentrated. The crude residue was purified by flash chromatography to yield )-tert-butyl 2-(9-(2-((S)((S)(methoxycarbonylamino) methylbutanoyl)pyrrolidinyl)-1H-imidazolyl-4,5-dihydro-1,11- dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl)(methoxymethyl)pyrrolidine carboxy late (75 mg, 22%). methyl{(1R)[(2S,4S)(9-{2-[(2S){(2S)[(methoxycarbonyl)amino] methylbutanoyl}pyrrolidinyl)-1H-imidazolyl]-1,11-dihydroisochromeno [4',3':6,7]- hydro-naphtho[1,2-d]imidazolyl}-(methoxymethyl)pyrrolidinyl]oxo phenylethyl}carbamate A solution of )-tert-butyl 2-(9-(2-((S)((S)(methoxy carbonylamino) methylbutanoyl)pyrrolidinyl)-1H-imidazolyl-4,5-dihydro-1,11- dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl)(methoxymethyl) pyrrolidine- 1-carboxylate (75 mg, 0.09 mmol), ethanol (2 mL) and concentrated HCl (0.6 mL) was heated to 60 °C for 1 hour. The reaction was concentrated and the crude material ved in DCM (6 mL). This on was concentrated and to this material was added a solution of (R)(methoxycarbonylamino)phenylacetic acid (26 mg, 0.13 mmol) and COMU (47 mg, 0.11 mmol) in DMF (2 mL). To the resulting solution was added diisopropylethylamine (50 L, 0.29 mmol). After stirring for 2 hours at room temperature, the reaction was diluted with ethyl acetate, washed with water and brine, dried (Na2SO4), concentrated and purified by preparative reverse phase HPLC (Gemini, 15 to 44% ACN/H2O + 0.1% TFA). The product fractions were lyophilized to give methyl {(1R)[(2S,4S)(9-{2-[(2S){(2S) [(methoxycarbonyl)amino]methylbutanoyl}pyrrolidinyl)-1H-imidazolyl]-1,11- dihydroisochromeno[4',3':6,7]-4,5-dihydro-naphtho[1,2-d]imidazolyl} (methoxymethyl)pyrrolidinyl]oxophenylethyl}carbamate (15 mg, 18%).

MS (ESI) m/z 872 [M + H]+. 1H NMR (400 MHz, dmso) δ 7.95 – 7.63 (m, 6H), 7.35 - 7.25 (m, 7H), 6.97 (s, 1H), .42 (d, 1H, J = 6.8 Hz), 5.18 (s, 2H), 5.09 (s, 2H), 4.28 -2.63 (m, 19H), 2.47 - 1.80 (m, 8H), 0.77 (dd, 6H, J = 4.8 Hz, J = 12.4 Hz).

Example MS (2S,4S)-tert-butyl(9-(2-((S)((S)(methoxycarbonylamino) methylbutanoyl)pyrrolidinyl)-1H-benzo[d]imidazolyl)- 1,11- dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl)(methoxymethyl) pyrrolidinecarboxylate To a solution of )-tert-butyl 4-(methoxymethyl)(9-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolanyl)- 1,11-dihydroisochromeno [4',3':6,7] naphtho[1,2-d]imidazol yl)pyrrolidinecarboxylate (400 mg, 0.85 mmol), methyl (S)((S)(6-bromo-1H- benzo[d]imidazolyl)pyrrolidinyl)methyloxobutanylcarbamate (360 mg, 0.85 mmol), is(triphenylphosphine) palladium(0) (38 mg, 0.03 mmol) and dichloro[1,1'- bis(diphenylphosphino) ferrocene]palladium(II) (48 mg, 0.07 mmol) in a mixture of 1,2- dimethoxyethane (8.0 mL) and dimethylformamide (1.4 mL) was added a solution of potassium carbonate (2M in water, 0.98 mL, 1.96 mmol). The resulting mixture was ed and then heated to 85 °C under argon for 18 hours. After cooling to room temperature, the reaction was diluted with ethyl acetate. The organics were washed with water and brine, dried 4), and concentrated. The crude residue was purified by flash chromatography to (2S,4S)-tert-butyl 2-(9-(2-((S)((S)(methoxycarbonylamino) methylbutanoyl)pyrrolidinyl)-1H-benzo[d]imidazolyl)-1,11- dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl)(methoxymethyl)pyrrolidine carboxylate (156 mg, 29%). methyl{(2S)[[(2S,4S){9-[2-((2S){(2S)[(methoxycarbonyl)amino] methylbutanoyl}pyrrolidinyl)-1H-benzo[d]imidazoly]-1,11-dihydroiso chromeno[4',3':6,7]naphtho[1,2-d]imidazolyl}(methoxymethyl)pyrrolidinyl] oxophenylethyl}carbamate A solution of (2S,4S)-tert-butyl 2-(9-(2-((S)((S)(methoxycarbonylamino) methylbutanoyl)pyrrolidinyl)-1H-benzo[d] imidazolyl)-1,11- dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl)(methoxymethyl)pyrrolidine carboxylate (156 mg, 0.18 mmol), l (3 mL) and concentrated HCl (1 mL) was heated to 60 °C for 1 hour. The reaction was concentrated and the crude material dissolved in DCM (6 mL). This solution was concentrated and to (90 mg, 0.12 mmol) of this material was added a solution of (methoxycarbonylamino)phenylacetic acid (34 mg, 0.16 mmol) and COMU (61 mg, 014 mmol) in DMF (2 mL). To the resulting solution was added diisopropylethylamine (60 L, 0.37 mmol). After stirring for 2 hours at room temperature, the reaction was diluted with ethyl acetate, washed with water and brine, dried (Na2SO4), concentrated and ed by preparative reverse phase HPLC (Gemini, 15 to 49% ACN/H2O + 0.1% TFA). The product fractions were lyophilized to give methyl {(2S)[[(2S,4S){9- [2-((2S){(2S)[(methoxycarbonyl)amino]methylbutanoyl}pyrrolidinyl)-1H- benzo[d]imidazoly]-1,11-dihydroisochrome no[4',3':6,7]naphtho[1,2-d]imidazolyl} (methoxymethyl)pyrrolidinyl]oxophenylethyl}carbamate (62 mg, 56%). MS (ESI) m/z 920 [M + H]+. 1H NMR (400 MHz, dmso) δ 8.73 (s, 1H), 8.17 (d, 2H, J = 8.4 Hz), 7.94 (d, 3H, J = 8.8 Hz), 7.84 – 7.67 (m, 6H), 7.37 - 7.29 (m, 6H), 5.48 (d, 1H, J = 7.6 Hz), 5.35 – 5.20 (m, 5H), 4.14 -3.12 (m, 15H), 2.52 - 1.92 (m, 8H), 0.80 (dd, 6H, J = 6.8 Hz, J = 6.4 Hz).

Example MT methyl{(2S)[(2S,4S){9-[2-((2S){(2S)[(methoxycarbonyl)amino] butanoyl}pyrrolidinyl)-1H-benzo[d]imidazoly]-1,11-dihydroiso chromeno[4',3':6,7]naphtho[1,2-d]imidazolyl}(methoxymethyl)pyrrolidinyl] methyloxobutanyl}carbamate A on of (2S,4S)-tert-butyl(9-(2-((S)((S)(methoxycarbonylamino) methylbutanoyl)pyrrolidinyl)-1H-benzo [d]imidazolyl)-1,11- dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl)(methoxymethyl)pyrrolidine carboxylate (156 mg, 0.18 mmol), ethanol (3 mL) and concentrated HCl (1 mL) was heated to 60 °C for 1 hour. The reaction was concentrated and the crude material dissolved in DCM (6 mL). This solution was concentrated and to 68 mg (0.09 mmol) of this material was added a solution of (S)(methoxycarbonylamino)methylbutanoic acid (21 mg, 0.12 mmol) and HATU (41 mg, 0.1 mmol) in DMF (1 mL). To the resulting solution was added ropylethylamine (50 L, 0.28 mmol). After stirring for 2 hours at room temperature, the reaction was diluted with ethyl e, washed with water and brine, dried (Na2SO4), concentrated and purified by preparative reverse phase HPLC (Gemini, 15 to 44% ACN/H2O + 0.1% TFA). The product fractions were lyophilized to give methyl {(2S)[(2S,4S){9- [2-((2S){(2S)[(methoxycarbonyl)amino]methylbutanoyl}pyrrolidinyl)-1H- benzo[d]imidazoly]-1,11-dihydroisochrome no[4',3':6,7]naphtho[1,2-d]imidazolyl} (methoxymethyl)pyrrolidinyl]methyloxobutanyl}carbamate (32 mg, 40%). MS (ESI) m/z 886 [M + H]+. 1H NMR (400 MHz, dmso) δ 8.71 (s, 1H), 8.15 (d, 1H, J = 8 Hz), 7.95 – 7.64 (m, 8H), 7.28 (dd, 2H, J = 8.8 Hz, J = 14.4 Hz), 5.31 (s, 2H), 5.23 – 5.19 (m, 2H), 4.09 – 3.85 (m, 5H), 3.58 -3.28 (m, 14H), 2.47 – 1.89 (m, 9H), 0.83 – 0.72 (m, 12H).

Example MU Boc N O N Br H H O N O B N O N N O 3)4, PdCl2(dppf), H K2CO3, DME/ DMF, 85°C (2S)-methyl {[(9-(4,4,5,5-tetramethyl-1,3,2- dioxaborolanyl)-1,11-dihydroisochromeno[4',3':6,7] naphtho[1,2-d]imidazolyl)pyrrolidin-1yl]methyl oxobutanyl}carbamate N N Boc N 1. HCl, EtOH, 60°C N N N H O N O H O O O H N O tert-butyl (2S,4S)[5-(2-{(2S,4S)[N-(methoxycarbonyl)- O H l]-pyrrolidinyl}-1,11-dihydroisochromeno COMU, DIPEA, DMF, RT [4',3':6,7]naphtho[1,2-d]imidazolyl)-1H-imidazolyl] (methoxymethyl)pyrrolidinecarboxylate H O N H O O N N N N N N O O O methyl {(1R)[(2S,4S)(5-{2-[(2S){(2S)[(methoxycarbonyl) amino]methylbutanoyl}-pyrrolidinyl]-1,11-dihydroisochromeno :6,7]naphtho[1,2-d]imidazolyl}-1H-imidazolyl)- 4-(methoxymethyl)pyrrolidinyl]oxophenylethyl}carbamate tert-butyl (2S,4S)[5-(2-{(2S,4S)[N-(methoxycarbonyl)-L-valyl]-pyrrolidinyl}- 1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl)-1H-imidazolyl] (methoxymethyl)pyrrolidinecarboxylate To a solution of (2S)-methyl {[(9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)- 1,11-dihydroisochromeno [4',3':6,7]naphtho[1,2-d]imidazolyl)pyrrolidinyl]methyl oxobutanyl} carbamate (460 mg, 0.74 mmol), (2S,4S)-tert-butyl 2-(5-bromo-1H-imidazol- 2-yl)(methoxymethyl)pyrrolidinecarboxylate (250 mg, 0.61 mmol), tetrakis (triphenylphosphine) palladium(0) (35 mg, 0.03 mmol) and dichloro[1,1'-bis (diphenylphosphino) ene]palladium(II) (45 mg, 0.06 mmol) in a mixture of 1,2- dimethoxyethane (9.0 mL) and ylformamide (1.5 mL) was added a solution of potassium carbonate (2M in water, 0.92 mL, 1.84 mmol). The resulting mixture was degassed and then heated to 85 °C under argon for 18 hours. After cooling to room temperature, the reaction was diluted with ethyl acetate. The organics were washed with water and brine, dried (Na2SO4), and concentrated. The crude residue was ed by flash chromatography to tert-butyl (2S,4S)[5-(2-{(2S,4S)[N-(methoxycarbonyl)-L-valyl]- pyrrolidinyl}-1,11-dihydroisochromeno[4',3':6,7] o[1,2-d]imidazolyl)-1H- imidazolyl](methoxymethyl)pyrrolidinecarboxylate (123 mg) methyl{(1R)[(2S,4S)(5-{2-[(2S){(2S)[(methoxycarbonyl)amino] methylbutanoyl}-pyrrolidinyl]-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d] imidazolyl}-1H-imidazolyl)(methoxymethyl)pyrrolidinyl]oxo phenylethyl}carbamate A solution of tert-butyl (2S,4S)[5-(2-{(2S,4S)[N-(methoxy carbonyl)-L-valyl]- pyrrolidinyl}-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d] imidazolyl)-1H- imidazolyl](methoxymethyl)pyrrolidine-carboxylate (122 mg, 0.16 mmol), ethanol (3 mL) and concentrated HCl (1 mL) was heated to 60 °C for 1 hour. The reaction was concentrated and the crude material dissolved in DCM (3 mL). This solution was concentrated and to this material was added a solution of (R)(methoxycarbonylamino) phenylacetic acid (43 mg, 0.2 mmol) and COMU (77 mg, 018 mmol) in DMF (3 mL). To the resulting solution was added ropylethylamine (80 L, 0.37 mmol). After stirring for 2 hours at room temperature, the on was diluted with ethyl acetate, washed with water and brine, dried (Na2SO4), trated and purified by preparative reverse phase HPLC (Gemini, 15 to 44% ACN/H2O + 0.1% TFA). The product fractions were lyophilized to give methyl {(1R)[(2S,4S)(5-{2-[(2S){(2S)[(methoxycarbonyl)amino] methylbutanoyl}-pyrrolidinyl]-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2- d]imidazolyl}-1H-imidazolyl)(methoxymethyl)pyrrolidinyl]oxo phenylethyl}carbamate (60 mg, 44%). MS (ESI) m/z 870 [M + H]+. 1H NMR (400 MHz, dmso) δ 8.71 (s, 1H), 8.22 (d, 1H, J = 8 Hz), 8.09 (m, 1H), 7.88 – 7.63 (m, 6H), 7.36 - 7.29 (m, 6H), 5.41 (d, 1H, J = 8.4 Hz), 5.30 – 5.24 (m, 2H), 5.14 – .10 (m, 1H), 4.13 -3.09 (m, 15H), 2.47 - 1.80 (m, 8H), 0.80 (dd, 6H, J = 6.4 Hz, J = 23 Hz).

Example MV O N O N H N O N N Br B N O N Boc O 3)4, PdCl2(dppf), (1R,3S,5R)-tert-butyl (9-(4,4,5,5-tetramethyl- K2CO3, Dioxane/ DMSO, 1,3,2-dioxaborolanyl)-1,11-dihydroisochromeno 95°C [4',3':6,7]naphtho[1,2-d]imidazolyl)azabicyclo [3.1.0]hexanecarboxylate H O O O H N N N 1. HCl, EtOH, 60°C N N N Boc H 2.

O O (1R,3S,5R)-tert-butyl 3-(9-(2-((S)((S)(methoxy O H N O carbonylamino)methylbutanoyl)methoxymethyl O H pyrrolidinyl)-1H-imidazolyl)-1,11- dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazol COMU, DIPEA, DMF, RT yl)azabicyclo[3.1.0]hexanecarboxylate H O O O H N N N N N N O O O methyl {(1R)[(1R,3S,5R)(9-{2-[(2S,5S){(2S)[(methoxy carbonyl)amino]methylbutanoyl}methoxymethylpyrrolidinyl]- 1H-imidazolyl}-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d] imidazolyl)azabicyclo[3.1.0]hexyl]oxophenylethyl}carbamate (1R,3S,5R)-tert-butyl(9-(2-((S)((S)(methoxycarbonylamino)methylbutanoyl)- oxymethylpyrrolidinyl)-1H-imidazolyl)- 1,11- dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl)azabicyclo[3.1.0] hexane- 2-carboxylate To a solution of (1R,3S,5R)-tert-butyl (9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan- 2-yl)- 1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl)azabicyclo [3.1.0]hexanecarboxylate (213 mg, 0.37 mmol), methyl (S)((2S,4S)(5-bromo-1H- imidazolyl)(methoxymethyl)pyrrolidinyl)methyloxobutanylcarbamate (142 mg, 0.31 mmol), tetrakis (triphenylphosphine) ium(0) (35 mg, 0.03 mmol) and dichloro[1,1'-bis (diphenylphosphino) ferrocene]palladium(II) (22 mg, 0.03 mmol) in a mixture of oxane (3.0 mL) and dimethylsulfoxide (3.0 mL) was added a solution of potassium carbonate (2M in water, 0.46 mL, 0.9 mmol). The resulting mixture was degassed and then heated to 95 °C under argon for 7 hours. After cooling to room temperature, the reaction was diluted with ethyl acetate. The organics were washed with water and brine, dried (Na2SO4), and concentrated. The crude residue was purified by flash chromatography to (1R,3S,5R)-tert-butyl 3-(9-(2-((S)((S)(methoxycarbonyl amino)methylbutanoyl)- 4-methoxymethylpyrrolidinyl)-1H-imidazolyl)-1,11- dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl)azabicyclo[3.1.0] hexane carboxylate (101 mg, 42%). methyl{(1R)[(1R,3S,5R)(9-{2-[(2S,5S){(2S)[(methoxycarbonyl)amino] methylbutanoyl}methoxymethylpyrrolidinyl]-1H-imidazolyl}-1,11- dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl)-azabicyclo[3.1.0]hexyl] oxophenylethyl}carbamate A solution (1R,3S,5R)-tert-butyl 3-(9-(2-((S)((S)(methoxycarbonylamino) methylbutanoyl)methoxymethylpyrrolidinyl)-1H-imidazolyl)-1,11- dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl)aza o[3.1.0]hexane carboxylate (101 mg, 0.16 mmol), ethanol (3 mL) and concentrated HCl (1 mL) was heated to 60 °C for 1 hour. The reaction was concentrated and the crude material dissolved in DCM (3 mL). This on was trated and to this material was added a solution of (R) (methoxycarbonylamino)phenylacetic acid (35 mg, 0.17 mmol) and COMU (63 mg, 015 mmol) in DMF (3 mL). To the resulting on was added diisopropylethylamine (70 L, 0.38 mmol). After stirring for 2 hours at room ature, the reaction was diluted with ethyl acetate, washed with water and brine, dried (Na2SO4), concentrated and purified by preparative reverse phase HPLC (Gemini, 15 to 44% ACN/H2O + 0.1% TFA). The product fractions were lyophilized to give methyl {(1R)[(1R,3S,5R)(9-{2-[(2S,5S){(2S) [(methoxycarbonyl)amino]methylbutanoyl}methoxymethylpyrrolidinyl]-1H- imidazol-5 yl}-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl)azabicyclo [3.1.0]hexyl]oxophenylethyl}carbamate (71 mg, 63%).

MS (ESI) m/z 882 [M + H]+. 1H NMR (400 MHz, dmso) δ 8.66 (s, 1H), 8.17 (d, 1H, J = 8.8 Hz), 8.04 (s, 1H), 7.87 – 7.59 (m, 6H), 7.39 - 7.22 (m, 6H), 5.72 (d, 1H, J = 7.6 Hz), 5.68 (s, 1H), 5.25 (s, 1H), 5 .13 – 5.01 (m, 2H), 4.12 -4.00 (m, 2H), 3.81 – 3.00 (m, 13H), 2.60 (m, 1H), 2.43 – 2.37 (m, 3H), 1.92-1.82 (m, 3H), 0.83 – 0.58 (m, 7H), 0.59 (s, 1H), 0.00 (s, 1H).

Example MW This compound was synthesized using the same conditions as example OO substituting with the respective (1R,3S,5R)((S)(methoxycarbonylamino) butanoyl)azabicyclo[3.1.0]hexanecarboxylic acid and (2S,4S)(tertbutoxycarbonyl )((difluoromethoxy)methyl)pyrrolidinecarboxylic acid as appropriate.

MS (ESI) m/z 918 [M + H]+.

Example MX H O N H O O N N N N N O O N O methyl {(1R)[(2S,4S)(9-{2-[(1R,3S,5R){(2S,3S)- 3-methoxy[(methoxycarbonyl)amino]butanoyl}azabicyclo [3.1.0]hexyl]-1H-imidazolyl}-1,11-dihydroisochromeno [4',3':6,7]naphtho[1,2-d]imidazolyl)(difluoromethoxy) methylpyrrolidinyl]oxophenylethyl}carbamate This compound was synthesized using the same conditions as example OO substituting with the respective (1R,3S,5R)((2S,3S)methoxy-2 (methoxycarbonylamino) butanoyl)azabicyclo[3.1.0]hexanecarboxylic acid and )methoxy(methoxycarbonylamino)butanoic acid as appropriate.

MS (ESI) m/z 898 [M + H]+.

Example MY O NH H nacolato)diboron O N O B N X-Phos, Pd2dba3, KOAc N + O N Boc Dioxane N 100 °C N Br H (2S,4S)-tert-butyl 4-methyl(9-(4,4,5,5-tetramethylmethyl ((S)((S)(5-bromo-1H- 1,3,2-dioxaborolanyl)- ihydroisochromeno imidazolyl)pyrrolidinyl) [4',3':6,7] naphtho[1,2-d]imidazol yl)pyrrolidine methyloxobutanyl)carbamate carboxylate O NH Pd(PPh3)4, O O Pd(dppf)2Cl2, K2CO3 1. HCl N H N N 2. COMU, DIPEA, DMF DME N N Boc 85 °C H (2S,4S)-tert-butyl 2-(9-(2-((S)((S) OH (methoxycarbonylamino)methylbutanoyl)pyrrolidin- O N 2-yl)-1H-imidazolyl)-5H-naphtho[c,g]chromeno[8,9- O d]imidazolyl)methylpyrrolidinecarboxylate (R) ((methoxycarbonyl)ami O no)phenylacetic acid O NH O O N H N N N N H O HN O methyl {2-[2-{9-[2-(1-{2-[(methoxycarbonyl)amino] O methylbutanoyl}pyrrolidinyl)-1H-imidazolyl]-1,11- dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl} methylpyrrolidinyl]oxophenylethyl}carbamate (2S,4S)tert-butyl 2-(3-chlorooxo-8,9,10,11-tetrahydro-5H-dibenzo[c,g]chromen yl) 4-methylpyrrolidine-1,2-dicarboxylate To a solution of 9-bromochloro-10,11-dihydro-5H-dibenzo[c,g]chromen-8(9H)- one (1.32 g, 3.63 mmol) in MeCN (40 mL) was added (2S,4S)(tert-butoxycarbonyl) methylpyrrolidinecarboxylic acid (1.0 g, 4.36 mmol) and DIPEA (0.7 mL, 3.99 mmol).

After stirring for 18 h, the on was diluted with EtOAc and washed successively with saturated aqueous NaHCO3 and brine. The organics were dried over MgSO4, filtered and concentrated under reduced pressure. The crude residue was purified by silica column chromatography (10% to 40% EtOAc/hexanes) to afford (2S,4S)tert-butyl 2-(3-chloro oxo-8,9,10,11-tetrahydro-5H-dibenzo[c,g]chromenyl) 4-methylpyrrolidine-1,2- dicarboxylate (1.31 g, 70%). (2S,4S)-tert-butyl 2-(9-chloro-4,5-dihydro-5H-naphtho[c,g]chromeno[8,9-d]imidazol yl)methylpyrrolidinecarboxylate (2S,4S)tert-butyl 2-(3-chlorooxo-8,9,10,11-tetrahydro-5H- o[c,g]chromenyl) 4-methylpyrrolidine-1,2-dicarboxylate (1.31 g, 2.56 mmol) was added xylenes (25 mL) and ammonium acetate (3.95 g, 51.2 mmol) and the solution was heated to 136 °C and stirred overnight. The following morning, the solution was cooled to rt and was diluted with EtOAc and washed successively with water, saturated aqueous NaHCO3 and brine. The organics were dried over MgSO4, filtered and concentrated under reduced pressure. The crude residue was purified by silica column tography (60% to 100 % EtOAc/hexanes) to afford (2S,4S)-tert-butyl 2-(9-chloro-4,5-dihydro-5H- o[c,g]chromeno[8,9-d]imidazolyl)methylpyrrolidinecarboxylate (711 mg, 56%). (2S,4S)-tert-butyl hloro-5H-naphtho[c,g]chromeno[8,9-d]imidazolyl) methylpyrrolidinecarboxylate To a solution of (2S,4S)-tert-butyl 2-(9-chloro-4,5-dihydro-5H- naphtho[c,g]chromeno[8,9-d]imidazolyl)(methyl)pyrrolidinecarboxylate (935 mg, 1.9 mmol) in CH2Cl2 (20 mL) was added MnO2 (8.25 g, 95 mmol). The on mixture was stirred for 3 h, and then filtered over celite. The filter cake was washed with copious CH2Cl2 and MeOH, and the filtrate was trated under reduced re. The crude residue was purified by silica column chromatography (0% to 10 % MeOH/EtOAc) to afford (2S,4S)-tertbutyl 2-(9-chloro-5H-naphtho[c,g]chromeno[8,9-d]imidazolyl)methylpyrrolidine carboxylate (692 mg, 74%). (2S,4S)-tert-butyl 4-methyl(9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-1,11- dihydroisochromeno :6,7] naphtho[1,2-d]imidazol yl)pyrrolidinecarboxylate (2S,4S)-tert-butyl 2-(9-chloro-5H-naphtho[c,g]chromeno[8,9-d]imidazolyl) methylpyrrolidinecarboxylate (692 mg, 1.41 mmol) in dioxane (15 mL) was added bis(pinacolato)diboron (1.07 g, 4.23 mmol), KOAc (415 mg, 4.23 mmol), X-Phos (52 mg, 0.11 mmol), and Pd2dba3 (26 mg, 0.03 mmol). The solution was degassed with N2 for 10 min, then heated to 100 °C for 16 h. The solution was cooled to rt, diluted with EtOAc, washed with saturated s NaHCO3, brine, dried with MgSO4, and concentrated.

Purified by silica gel chromatography (0% to 30 % MeOH/EtOAc) to afford (2S,4S)-tert- butyl 4-methyl(9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-1,11-dihydroisochromeno [4',3':6,7] naphtho[1,2-d]imidazol yl)pyrrolidinecarboxylate (821 mg, quant). (2S,4S)-tert-butyl 2-(9-(2-((S)((S)(methoxycarbonylamino) methylbutanoyl)pyrrolidinyl)-1H-imidazolyl)-5H-naphtho[c,g]chromeno[8,9- d]imidazolyl)-4(methyl)pyrrolidinecarboxylate To a solution of )-tert-butyl 4-methyl(9-(4,4,5,5-tetramethyl-1,3,2- dioxaborolanyl)-1,11-dihydroisochromeno [4',3':6,7] naphtho[1,2-d]imidazol yl)pyrrolidinecarboxylate (821 mg, 1.41 mmol), methyl (S)((S)(5-bromo-1H- imidazolyl)pyrrolidinyl)methyloxobutanylcarbamate (1.05 g, 2.82 mmol), tetrakis(triphenylphosphine) palladium(0) (162 mg, 0.14 mmol) and dichloro[1,1'- bis(diphenylphosphino)ferrocene]palladium(II) (102 mg, 0.14 mmol) in DME (15 mL) was added a solution of ium carbonate (2M in water, 2.32 mL, 4.65 mmol). The resulting mixture was degassed and then heated to 85 °C for 18 hours. After cooling to room temperature, the reaction was diluted with ethyl acetate. The organics were washed with saturated sodium onate and brine, dried over MgSO4 and trated. The crude residue was purified by flash chromatography to yield (2S,4S)-tert-butyl 2-(9-(2-((S)((S)- 2-(methoxycarbonylamino)methylbutanoyl)pyrrolidinyl)-1H-imidazolyl)-5H- naphtho[c,g]chromeno[8,9-d]imidazolyl)-4methylpyrrolidinecarboxylate (386 mg, 37%).

Methyl {2-[2-{9-[2-(1-{2-[(methoxycarbonyl)amino]methylbutanoyl}pyrrolidinyl)- 1H-imidazolyl]-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl} (methyl)pyrrolidinyl]oxophenylethyl}carbamate A solution of (2S,4S)-tert-butyl 2-(9-(2-((S)((S)(methoxycarbonylamino) methylbutanoyl)pyrrolidinyl)-1H-imidazolyl)-5H-naphtho[c,g]chromeno[8,9- d]imidazolyl)-4methylpyrrolidinecarboxylate (386 mg, 0.52 mmol), CH2Cl2 (8 mL), MeOH (2 mL) and HCl (4M in Dioxane, 2 mL) and was stirred overnight. The reaction was trated and the crude material dissolved in DMF (8 mL). This solution was concentrated and to this material was added a solution of (R)(methoxycarbonylamino) phenylacetic acid (108 mg, 0.52 mmol) and COMU (248 mg, 0.52 mmol). To the resulting solution was added diisopropylethylamine (0.45 mL, 2.6 mmol). After stirring for 2 hours at room temperature, the reaction was diluted with 10% MeOH/EtOAc, washed with saturated NaHCO3, water and brine, dried 4), trated and purified by HPLC to give methyl {2-[2-{9-[2-(1-{2-[(methoxycarbonyl)amino]methylbutanoyl}pyrrolidinyl)-1H- imidazolyl]-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl} methylpyrrolidinyl]oxophenylethyl}carbamate (27 mg, 6%). LCMS-ESI+: calculated for C47H50N8O7: 838.38; observed [M+1]+: 840.12 Example NB )-tert-butyl 4-methyl(9-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolanyl)-1,11-dihydroisochromeno [4',3':6,7] naphtho[1,2-d]imidazol yl)pyrrolidine carboxylate Methyl [(2S)methyl{(2S,4S)methyl[9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan- 2-yl)-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl]pyrrolidinyl} oxobutanyl]carbamate (2S,4S)-tert-butyl 4-methyl(9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-1,11- dihydroisochromeno [4',3':6,7] naphtho[1,2-d]imidazol yl)pyrrolidinecarboxylate (950 mg, 1.63 mmol) was ved in DCM (12 mL), MeOH (3 mL) and HCl (4 M in dioxane, 3 mL) was added. The reaction mixture was d for 4 h and then concentrated under reduced pressure. The crude residue was treated with (S)(methoxycarbonylamino) methylbutanoic acid (285 mg, 1.63 mmol), HATU (620 mg, 1.63 mmol) and DMF (15 mL), then DIPEA (1.42 mL, 8.15 mmol) was added dropwise. After 1 h, the mixture was diluted with EtOAc and washed successively with saturated aqueous NaHCO3 and brine. The organics were dried over MgSO4, filtered and concentrated under reduced pressure. The crude residue was ed by silica column chromatography (0% to 30% tOAc) to afford methyl [(2S)methyl{(2S,4S)methyl[9-(4,4,5,5-tetramethyl-1,3,2- dioxaborolanyl)-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazol yl]pyrrolidinyl}oxobutanyl]carbamate (596 mg, 57%).

Tert-butyl (2S)[5-(2-{(2S,4S)[N-(methoxycarbonyl)-L-valyl]methylpyrrolidin yl}-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl)-1H-imidazol yl]pyrrolidinecarboxylate Methyl [(2S)methyl{(2S,4S)methyl[9-(4,4,5,5-tetramethyl-1,3,2- dioxaborolanyl)-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazol yl]pyrrolidinyl}oxobutanyl]carbamate (298 mg, 0.47 mmol), (S)-tert-butyl 2-(5- bromo-1H-imidazolyl)pyrrolidinecarboxylate (443 mg, 1.4 mmol), Pd(PPh3)4 (54 mg, 0.05 mmol), PdCl2(dppf)2 (36 mg, 0.05 mmol), and K2CO3 (2M in H2O, 0.78 mL, 1.55 mmol) were combined in DME (5 mL). The mixture was degassed with bubbling N2 for 10 min then heated to 85 ˚C for 16 h. After cooling, the reaction mixture was diluted with EtOAc, and washed successively with ted aqueous NaHCO3 and brine. The cs were dried over MgSO4, filtered and concentrated under reduced pressure. The crude residue was purified by silica column chromatography (0% to 30% MeOH/EtOAc) to afford tert- butyl (2S)[5-(2-{(2S,4S)[N-(methoxycarbonyl)-L-valyl]methylpyrrolidinyl}- 1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl)-1H-imidazol yl]pyrrolidinecarboxylate (84 mg, 24%).

Methyl {(1R)[(2S)(5-{2-[(2S,4S){(2S)[(methoxycarbonyl)amino] methylbutanoyl}methylpyrrolidinyl]-1,11- dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl}-1H-imidazol yl)pyrrolidinyl]oxophenylethyl}carbamate Tert-butyl (2S)[5-(2-{(2S,4S)[N-(methoxycarbonyl)-L-valyl] pyrrolidinyl}-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl)-1H- imidazolyl]pyrrolidinecarboxylate (84 mg, 0.11 mmol) was dissolved in DCM (2.5 mL), MeOH (0.5 mL) and HCl (4 M in e, 0.5 mL) was added. The reaction mixture was stirred for 18 h and then concentrated under reduced pressure. The crude e was treated with (R)(methoxycarbonylamino)phenylacetic acid (23 mg, 0.11 mmol), COMU (53 mg, 0.11 mmol) and DMF (3 mL), then DIPEA (0.10 mL, 0.56 mmol) was added dropwise. After 30 min, the mixture was diluted with 10% MeOH/EtOAc and washed successively with saturated aqueous NaHCO3 and brine. The organics were dried over MgSO4, filtered and concentrated under reduced pressure. The crude residue was purified by HPLC to afford methyl {(1R)[(2S)(5-{2-[(2S,4S){(2S) [(methoxycarbonyl)amino]methylbutanoyl}methylpyrrolidinyl]-1,11- dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl}-1H-imidazolyl)pyrrolidin yl]oxophenylethyl}carbamate (41 mg, 45%). LCMS-ESI+: calculated for C47H50N8O7: 838.38; ed [M+1]+: 839.39 Example NC Methyl {(2S)[(2S,5S)(5-{2-[(2S,4S){(2S)[(methoxycarbonyl)amino] methylbutanoyl}methylpyrrolidinyl]-1,11- dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl}-1H-imidazolyl) methylpyrrolidinyl]methyloxobutanyl}carbamate Tert-butyl (2S,4S)[9-(2-{(2S,4S)[N-(methoxycarbonyl)-L-valyl] methylpyrrolidinyl}-1H-imidazolyl)-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2- d]imidazolyl]methylpyrrolidinecarboxylate (164 mg, 0.23 mmol) was dissolved in DCM (2.57 mL), MeOH (0.7 mL) and HCl (4 M in dioxane, 0.7 mL) was added. The reaction e was stirred for 16 h and then concentrated under reduced pressure. The crude e was d with (S)(methoxycarbonylamino)methylbutanoic acid (30 mg, 0.17 mmol), HATU (65 mg, 0.17 mmol) and DMF (3 mL), then DIPEA (0.15 mL, 0.85 mmol) was added dropwise. After 45 min, the mixture was diluted with 10% MeOH/EtOAc and washed successively with saturated aqueous NaHCO3 and brine. The organics were dried over MgSO4, filtered and concentrated under reduced pressure. The crude residue was purified by HPLC to afford methyl {(2S)[(2S,5S)(5-{2-[(2S,4S){(2S) [(methoxycarbonyl)amino]methylbutanoyl}methylpyrrolidinyl]-1,11- dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl}-1H-imidazolyl) methylpyrrolidinyl]methyloxobutanyl}carbamate (23 mg, 16%).

LCMS-ESI+: calculated for C45H54N8O7: 818.41; observed [M+1]+: 820.70.

Example ND Boc N O H Pd(PPh3)4, N O I + N N Pd(dppf)2Cl2, K2CO3 N B H O N Boc DME 85 °C (2S,4S)-tert-butyl 2-(5- (2S,4S)-tert-butyl 4-methyl(9-(4,4,5,5- iodo-1H-imidazolyl) tetramethyl-1,3,2-dioxaborolanyl)-1,11- methylpyrrolidine dihydroisochromeno [4',3':6,7] naphtho[1,2- ylate d]imidazol yl)pyrrolidinecarboxylate 1. HCl Boc N H 2. HATU, DIPEA, DMF N N N N Boc H OH O N tert-butyl (2S,4S)(5-{2-[(2S,4S)(tert- H butoxycarbonyl)methylpyrrolidinyl]-1,11- (S)(methoxycarbonylamino)- dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazol 3-methylbutanoic acid yl}-1H-imidazolyl)methylpyrrolidinecarboxylate O NH O O N H N N N N H O HN O methyl 1-[(2S,5S)(5-{2-[(2S,4S){(2S) O oxycarbonyl)amino]methylbutanoyl}methylpyrrolidinyl]-1,11- dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl}-1H-imidazolyl)- 4-methylpyrrolidinyl]methyloxobutanyl}carbamate Tert-butyl (2S,4S)(5-{2-[(2S,4S)(tert-butoxycarbonyl)methylpyrrolidinyl]- 1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl}-1H-imidazolyl) pyrrolidinecarboxylate (2S,4S)-tert-butyl yl(9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-1,11- dihydroisochromeno [4',3':6,7] naphtho[1,2-d]imidazol yl)pyrrolidinecarboxylate (293 mg, 0.78 mmol), (2S,4S)-tert-butyl 2-(5-iodo-1H-imidazolyl)methylpyrrolidine carboxylate (300 mg, 0.52 mmol), Pd(PPh3)4 (60 mg, 0.052 mmol), PdCl2(dppf)2 (38 mg, 0.052 mmol), and K2CO3 (2M in H2O, 0.86 mL, 1.72 mmol) were combined in DME (6 mL).

The mixture was degassed with bubbling N2 for 10 min then heated to 85 ˚C for 16 h. After cooling, the reaction mixture was diluted with EtOAc, and washed successively with saturated aqueous NaHCO3 and brine. The organics were dried over MgSO4, filtered and concentrated under reduced pressure. The crude residue was purified by silica column chromatography (100% EtOAc) to afford tert-butyl (2S,4S)(5-{2-[(2S,4S)(tertbutoxycarbonyl )methylpyrrolidinyl]-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2- d]imidazolyl}-1H-imidazolyl)methylpyrrolidinecarboxylate (183 mg, 50%).

Methyl 1-[(2S,5S)(5-{2-[(2S,4S){(2S)[(methoxycarbonyl)amino] methylbutanoyl}methylpyrrolidinyl]-1,11- dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl}-1H-imidazolyl) methylpyrrolidinyl]methyloxobutanyl}carbamate Tert-butyl (2S,4S)(5-{2-[(2S,4S)(tert-butoxycarbonyl)methylpyrrolidin yl]-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl}-1H-imidazolyl) methylpyrrolidinecarboxylate (183 mg, 0.26 mmol) was dissolved in DCM (4 mL), MeOH (1 mL) and HCl (4 M in dioxane, 1 mL) was added. The reaction mixture was stirred for 2 h and then concentrated under reduced re. The crude residue was d with (S) (methoxycarbonylamino)methylbutanoic acid (91 mg, 0.52 mmol), HATU (198 mg, 0.52 mmol) and DMF (5 mL), then DIPEA (0.45 mL, 2.6 mmol) was added se. After 1 h, the mixture was diluted with 10% MeOH/EtOAc and washed successively with saturated aqueous NaHCO3 and brine. The organics were dried over MgSO4, filtered and concentrated under reduced pressure. The crude residue was purified by HPLC to afford methyl {(2S) [(2S,5S)(5-{2-[(2S,4S){(2S)[(methoxycarbonyl)amino]methylbutanoyl} methylpyrrolidinyl]-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl}-1H- imidazolyl)methylpyrrolidinyl]methyloxobutanyl}carbamate (6 mg, 3%).

LCMS-ESI+: calculated for C45H54N8O7: 818.41; observed [M+1]+: 819.41.

Example NF O NH O H Pd(PPh3)4, O O N K2CO3 N + B N Pd(dppf)2Cl2, N O N Boc DMSO, Dioxane N I 85 °C (2S,4S)-tert-butyl 4-methyl(9-(4,4,5,5- methyl ((S)((2S,4S)(5-iodo-1H- tetramethyl-1,3,2-dioxaborolanyl)-1,11- imidazolyl)methylpyrrolidinyl)- dihydroisochromeno [4',3':6,7] naphtho[1,2- 3-methyloxobutanyl)carbamate d]imidazol yl)pyrrolidinecarboxylate 1. HCl O NH 2. COMU, DIPEA, DMF O O N H N N N N Boc O H OH O N tert-butyl (2S,4S)[9-(2-{(2S,4S)[N-(methoxycarbonyl)- O L-valyl]methylpyrrolidinyl}-1H-imidazolyl)-1,11- (R) dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl] ((methoxycarbonyl)amino) methylpyrrolidinecarboxylate phenylacetic acid O NH O O N H N N N N H O HN O methyl {(2S)[(2S,4S)(5-{2-[(2S,4S){(2R) [(methoxycarbonyl)amino]phenylacetyl}methylpyrrolidin yl]-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazol yl}-1H-imidazolyl)methylpyrrolidinyl]methyl oxobutanyl}carbamate Tert-butyl (2S,4S)[9-(2-{(2S,4S)[N-(methoxycarbonyl)-L-valyl] methylpyrrolidinyl}-1H-imidazolyl)-1,11- dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl]methylpyrrolidine carboxylate )-tert-butyl 4-methyl(9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-1,11- dihydroisochromeno [4',3':6,7] naphtho[1,2-d]imidazol yl)pyrrolidinecarboxylate (558 mg, 0.96 mmol), methyl (S)((2S,4S)(5-iodo-1H-imidazolyl)methylpyrrolidin yl)methyloxobutanylcarbamate (501 mg, 1.15 mmol), Pd(PPh3)4 (111 mg, 0.096 mmol), dppf)2 (70 mg, 0.096 mmol), and K2CO3 (2M in H2O, 1.6 mL, 3.17 mmoL) were combined in DMSO (6 mL) and dioxane (6 mL). The mixture was degassed with bubbling N2 for 10 min then heated to 95 ˚C for 14 h. After g, the reaction e was diluted with EtOAc, and washed successively with saturated aqueous NaHCO3 and brine. The organics were dried over MgSO4, ed and concentrated under reduced pressure. The crude residue was purified by silica column chromatography (0 %- 30% MeOH/EtOAc) to afford tert-butyl (2S,4S)[9-(2-{(2S,4S)[N-(methoxycarbonyl)-L-valyl] methylpyrrolidinyl}-1H-imidazolyl)-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2- d]imidazolyl]methylpyrrolidinecarboxylate (257 mg, 35%).

Methyl {(2S)[(2S,4S)(5-{2-[(2S,4S){(2R)[(methoxycarbonyl)amino] phenylacetyl}methylpyrrolidinyl]-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2- d]imidazolyl}-1H-imidazolyl)methylpyrrolidinyl]methyloxobutan yl}carbamate Tert-butyl (2S,4S)[9-(2-{(2S,4S)[N-(methoxycarbonyl)-L-valyl] pyrrolidinyl}-1H-imidazolyl)-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2- d]imidazolyl]methylpyrrolidinecarboxylate (257 mg, 0.34 mmol) was dissolved in DCM (4 mL), MeOH (1 mL) and HCl (4 M in dioxane, 1 mL) was added. The reaction mixture was stirred for 3 h and then concentrated under reduced pressure. The crude e was treated with (R)(methoxycarbonylamino)phenylacetic acid (71 mg, 0.34 mmol), COMU (161 mg, 0.34 mmol) and DMF (6 mL), then DIPEA (0.3 mL, 1.67 mmol) was added dropwise. After 15 h, the e was diluted with 10% MeOH/EtOAc and washed successively with saturated aqueous NaHCO3 and brine. The organics were dried over MgSO4, filtered and trated under reduced pressure. The crude residue was purified by HPLC to afford methyl {(2S)[(2S,4S)(5-{2-[(2S,4S){(2R) [(methoxycarbonyl)amino]phenylacetyl}methylpyrrolidinyl]-1,11- oisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl}-1H-imidazolyl) methylpyrrolidinyl]methyloxobutanyl}carbamate (152 mg, 53%). LCMS-ESI+: calculated for C48H52N8O7: ; observed [M+1]+: 854.26. 'H NMR (CD3OD): 8.677 (s, 1H), 8.232-7.837 (m, 5H), 7.695-7.673 (m, 2H), 7.496-7.426 (m, 5H), 5.499 (s, 1H), 5.445-5.401 (m, 1H), 5.337 (s, 1H), 5.253-5.208 (q, 1H, J= 7.2 Hz), 4.870 (m, 1H), 4.230 (d, 1H, J= 7.2 Hz), 3.781 (m, 1H), 3.671 (s, 3H), 3.607 (s, 3H), 3.425 (m, 3H), 2.750-2.689 (m, 2H), 2.683 (m, 2H), 2.384 (m, 1H), 1.894 (quint, 2H, J=12 Hz), 1.249-1.151 (m, 6H), 0.974- 0.890 (m, 6H).

Example NG O O O O O Boc O Et3N Br MeCN O 50 °C Boc O (2S,5S)tert-butyl 2-(2-oxo(8- 3-(2-bromoacetyl)-10,11-dihydro-5H- N oxo-8,9,10,11-tetrahydro-5H- dibenzo[c,g]chromen-8(9H)-one dibenzo[c,g]chromenyl)ethyl) 5- methylpyrrolidine-1,2-dicarboxylate (2S,5S)(tertbutoxycarbonyl ) methylpyrrolidine carboxylic acid pyridiunium O O mide Boc O Cs2CO3 N acetone CH2Cl2/MeOH O Br 40 °C (2S,5S)(2-(9-bromooxo-8,9,10,11-tetrahydro- N 5H-dibenzo[c,g]chromenyl)oxoethyl) 1-tert- O Boc butyl 5-methylpyrrolidine-1,2-dicarboxylate (2S,5S)(tertbutoxycarbonyl ) methylpyrrolidine O carboxylic acid Boc O O O N NH4OAc O O N PhMe, MeOEtOH O Boc reflux )(2-(9-((2S,5S)(tert-butoxycarbonyl) methylpyrrolidinecarbonyloxy)oxo-8,9,10,11-tetrahydro-5H- dibenzo[c,g]chromenyl)oxoethyl) 1-tert-butyl 5- methylpyrrolidine-1,2-dicarboxylate O O Boc N H Boc N H N MnO2 N N N N N N Boc CH2Cl2 N Boc H N utyl (2S,5S)(9-{2-[(2S,5S)(tert-butoxycarbonyl)- tert-butyl (2S,5S)(5-{2-[(2S,5S)(tert- -methylpyrrolidinyl]-1H-imidazolyl}-1,4,5,11- butoxycarbonyl)methylpyrrolidinyl]-1,11- tetrahydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazol dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazol yl)methylpyrrolidinecarboxylate yl}-1H-imidazolyl)methylpyrrolidinecarboxylate 1. HCl O NH O O 2. HATU, DIPEA, DMF N H O N N OH N O N O H HN O (S) O (methoxycarbonylamino) methyl {(2S)[(2S,5S)(5-{2-[(2S,5S){(2S) hylbutanoic acid [(methoxycarbonyl)amino]methylbutanoyl}methylpyrrolidin- 2-yl]-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazol- 9-yl}-1H-imidazolyl)methylpyrrolidinyl]methyl oxobutanyl}carbamate (2S,5S)tert-butyl 2-(2-oxo(8-oxo-8,9,10,11-tetrahydro-5H-dibenzo[c,g]chromen yl)ethyl) 5-methylpyrrolidine-1,2-dicarboxylate To a solution of 3-(2-bromoacetyl)-10,11-dihydro-5H-dibenzo[c,g]chromen-8(9H)- one in MeCN (30 mL) was added (2S,5S)(tert-butoxycarbonyl)methylpyrrolidine carboxylic acid (1.2 g, 3.23 mmol) and triethyl amine (0.48 mL, 3.55 mmol) and the on was heated to 50 °C. After stirring for 15 h, the solution was cooled to rt, and diluted with EtOAc and washed successively with saturated aqueous NaHCO3 and brine. The organics were dried over MgSO4, filtered and concentrated under reduced pressure. The crude residue was purified by silica column chromatography (20% to 50% EtOAc/hexanes) to afford )tert-butyl 2-(2-oxo(8-oxo-8,9,10,11-tetrahydro-5H-dibenzo[c,g]chromen yl)ethyl) 5-methylpyrrolidine-1,2-dicarboxylate (1.09 g, 65%). (2S,5S)(2-(9-bromooxo-8,9,10,11-tetrahydro-5H-dibenzo[c,g]chromenyl) oxoethyl) 1-tert-butyl 5-methylpyrrolidine-1,2-dicarboxylate (2S,5S)tert-butyl 2-(2-oxo(8-oxo-8,9,10,11-tetrahydro-5H- dibenzo[c,g]chromenyl)ethyl) 5-methylpyrrolidine-1,2-dicarboxylate (1.29 g, 2.48 mmol) was dissolved in a solution of DCM (17.5 mL) and MeOH (7 mL), then treated with pyridinium tribromide (873 mg, 2.73 mmol). After stirring at RT for 1 h, the reaction mixture was diluted with DCM and 10% HCl, and extracted with DCM. The organic phase was dried over MgSO4, ed and concentrated under reduced pressure and the crude al was carried on t further purification. (2S,5S)(2-(9-((2S,5S)(tert-butoxycarbonyl)methylpyrrolidinecarbonyloxy) oxo-8,9,10,11-tetrahydro-5H-dibenzo[c,g]chromenyl)oxoethyl) 1-tert-butyl 5- methylpyrrolidine-1,2-dicarboxylate (2S,5S)(2-(9-bromooxo-8,9,10,11-tetrahydro-5H-dibenzo[c,g]chromenyl) oxoethyl) -butyl 5-methylpyrrolidine-1,2-dicarboxylate (700 mg, 1.17 mmol) was treated with a solution of (2S,5S)(tert-butoxycarbonyl)methylpyrrolidinecarboxylic acid (375 mg, 1.64 mmol) in e (6 mL) and Cs2CO3 (267 mg, 0.82 mmol). The stirred reaction mixture was heated to 40 ˚C for 16 h, then cooled to RT and diluted with CH2Cl2 and extracted 3X. The organic phase was washed with brine, then dried over MgSO4, filtered and concentrated under d pressure. The crude residue was purified by silica column chromatography (40% to 100% EtOAc/hexanes) to afford (2S,5S)(2-(9-((2S,5S)(tertbutoxycarbonyl )methylpyrrolidinecarbonyloxy)oxo-8,9,10,11-tetrahydro-5H- dibenzo[c,g]chromenyl)oxoethyl) 1-tert-butyl 5-methylpyrrolidine-1,2-dicarboxylate (464 mg, 53%). utyl (2S,5S)(9-{2-[(2S,5S)(tert-butoxycarbonyl)methylpyrrolidinyl]- dazolyl}-1,4,5,11-tetrahydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazol yl)methylpyrrolidinecarboxylate (2S,5S)(2-(9-((2S,5S)(tert-butoxycarbonyl)methylpyrrolidine carbonyloxy)oxo-8,9,10,11-tetrahydro-5H-dibenzo[c,g]chromenyl)oxoethyl) 1-tertbutyl -methylpyrrolidine-1,2-dicarboxylate (464 mg, 0.62 mmol) and NH4OAc (8.48 g, 110.0 mmol) were ded in a solution of 10:1 PhMe/2-methoxyethanol (22 mL). The stirred reaction mixture was heated to 110 ˚C for 20 h, then cooled to RT and diluted with EtOAc. The organic phase was washed with water, saturated aqueous NaHCO3, and brine, then dried over MgSO4, filtered and concentrated under reduced pressure. The crude residue was purified by silica column chromatography (0% to 30% MeOH/EtOAc) to afford tertbutyl (2S,5S)(9-{2-[(2S,5S)(tert-butoxycarbonyl)methylpyrrolidinyl]-1H- imidazolyl}-1,4,5,11-tetrahydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl) methylpyrrolidinecarboxylate (393 mg, 90%).

Tert-butyl (2S,5S)(5-{2-[(2S,5S)(tert-butoxycarbonyl)methylpyrrolidinyl]- 1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl}-1H-imidazolyl) methylpyrrolidinecarboxylate Tert-butyl (2S,5S)(9-{2-[(2S,5S)(tert-butoxycarbonyl)methylpyrrolidin yl]-1H-imidazolyl}-1,4,5,11-tetrahydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazol methylpyrrolidinecarboxylate (393 mg, 0.55 mmol) was suspended in DCM (7 mL) and activated MnO2 (1.45 g, 16.7 mmol) was added in a single n. The reaction mixture was heated to 40 °C. After stirring for 2.5 h, the mixture was cooled to rt and the slurry was filtered over celite. The filter cake was washed with copious CH2Cl2 and MeOH and the filtrate was concentrated under reduced pressure. The crude material was taken on to the next step without further purification to afford tert-butyl (2S,5S)(5-{2-[(2S,5S)(tertbutoxycarbonyl )methylpyrrolidinyl]-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2- d]imidazolyl}-1H-imidazolyl)methylpyrrolidinecarboxylate (328 mg, 85%).

Methyl {(2S)[(2S,5S)(5-{2-[(2S,5S){(2S)[(methoxycarbonyl)amino] methylbutanoyl}methylpyrrolidinyl]-1,11- dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl}-1H-imidazolyl) methylpyrrolidinyl]methyloxobutanyl}carbamate utyl )(5-{2-[(2S,5S)(tert-butoxycarbonyl)methylpyrrolidin yl]-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl}-1H-imidazolyl) methylpyrrolidinecarboxylate (164 mg, 0.23 mmol) was dissolved in DCM (7 mL), MeOH (1.5 mL) and HCl (4 M in dioxane, 1.5 mL) was added. The reaction mixture was stirred for 16 h and then concentrated under reduced pressure. The crude residue was treated with (S) (methoxycarbonylamino)methylbutanoic acid (81 mg, 0.46 mmol), HATU (175 mg, 0.46 mmol) and DMF (5 mL), then DIPEA (0.4 mL, 2.34 mmol) was added se. After 35 min, the mixture was diluted with 10% MeOH/EtOAc and washed successively with saturated aqueous NaHCO3 and brine. The organics were dried over MgSO4, filtered and concentrated under d pressure. The crude residue was purified by HPLC to afford methyl {(2S)[(2S,5S)(5-{2-[(2S,5S){(2S)[(methoxycarbonyl)amino] methylbutanoyl}methylpyrrolidinyl]-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2- d]imidazolyl}-1H-imidazolyl)methylpyrrolidinyl]methyloxobutan yl}carbamate (132 mg, 69%). LCMS-ESI+: calculated for C45H54N8O7: 818.41; observed : 820.19. 'H NMR (CD3OD): 8.492 (m, 1H), 8.179-7.538 (m, 7H), 5.267-5.201 (m, 3H), 5.125-5.082 (m, 1H), 4.070 (m, 1H), 3.383-3.592 (m, 4 H), 3.225 (s, 3H), 2.466-2.249 (m, 5H), 1.992-1.892 (m, 3H), 1.568 (d, 3H, J=6.4 Hz), 1.490 (d, 3H, J=6.8 Hz), 1.266 (m, 2H), 1.020-0.806 (m, 14H).

Example NI Boc N H N 1. HCl N N N 2. HATU, DIPEA, DMF N Boc H OH O tert-butyl (2S,5S)(5-{2-[(2S,5S)(tert- O HN O butoxycarbonyl)methylpyrrolidinyl]-1,11- dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazol O -imidazolyl)methylpyrrolidinecarboxylate (2S,3R)methoxy (methoxycarbonylamin O noic acid O NH O O N H O N N O N N H O HN O methyl [(2S,3R)methoxy{(2S,5S)[9-(2-{(2S,5S)[N- (methoxycarbonyl)-O-methyl-L-threonyl]methylpyrrolidinyl}-1H- imidazolyl)-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazol yl]methylpyrrolidinyl}oxobutanyl]carbamate Methyl [(2S,3R)methoxy{(2S,5S)[9-(2-{(2S,5S)[N-(methoxycarbonyl)-O- methyl-L-threonyl]methylpyrrolidinyl}-1H-imidazolyl)-1,11- dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl]methylpyrrolidinyl} oxobutanyl]carbamate Tert-butyl (2S,5S)(5-{2-[(2S,5S)(tert-butoxycarbonyl)methylpyrrolidin yl]-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl}-1H-imidazolyl) methylpyrrolidinecarboxylate (164 mg, 0.23 mmol) was dissolved in DCM (7 mL), MeOH (1.5 mL) and HCl (4 M in dioxane, 1.5 mL) was added. The reaction mixture was d for 16 h and then concentrated under reduced pressure. The crude residue was treated with (2S,3R)methoxy(methoxycarbonylamino)butanoic acid (90 mg, 0.46 mmol), HATU (175 mg, 0.46 mmol) and DMF (6 mL), then DIPEA (0.4 mL, 2.34 mmol) was added dropwise. After 30 min, the e was diluted with 10% MeOH/EtOAc and washed sively with saturated s NaHCO3 and brine. The organics were dried over MgSO4, filtered and concentrated under reduced pressure. The crude residue was purified by HPLC to afford methyl [(2S,3R)methoxy{(2S,5S)[9-(2-{(2S,5S)[N- (methoxycarbonyl)-O-methyl-L-threonyl]methylpyrrolidinyl}-1H-imidazolyl)-1,11- dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl]methylpyrrolidinyl} oxobutanyl]carbamate (97 mg, 50%). LCMS-ESI+: calculated for C45H54N8O9: 850.40; observed [M+1]+: 851.58. 'H NMR (CD3OD): 8.631 (s, 1H), 8.191-7.938 (m, 7 H), 6.100 (m, 1 H), 5.925 (m, 1H), 5.303 (m, 3H), 5.179 (t, 1H, J=6.8 Hz), 4.406-4.358 (m, 2H), 3.754- 3.598 (m, 8H), 3.376 (s, 3H), 3.263 (s, 3H), 2.625-2.256 (m, 6H), 2.038-1.955 (m, 2H), 1.598 (d, 3H, J=6.4 Hz), 1.530 (d, 3H, J=6.8 Hz), 1.302-1.099 (m, 6H).

Example NJ Boc O O O Cs2CO3 O Br acetone 40 °C O (2S,5S)(2-(9-bromooxo-8,9,10,11- HO tetrahydro-5H-dibenzo[c,g]chromenyl) N oxoethyl) 1-tert-butyl 5-methylpyrrolidine-1,2- O Boc dicarboxylate (2S,4S)(tert-butoxycarbonyl) xymethyl)pyrrolidine carboxylic acid Boc O O O O N NH4OAc O O PhMe, MeOEtOH O Boc reflux (2S,5S)(2-(9-((2S,4S)(tert-butoxycarbonyl) (methoxymethyl)pyrrolidinecarbonyloxy)oxo-8,9,10,11- tetrahydro-5H-dibenzo[c,g]chromenyl)oxoethyl) 1-tertbutyl -methylpyrrolidine-1,2-dicarboxylate Boc N H N MnO2 N N N N Boc CH2Cl2 tert-butyl (2S,5S)(9-{2-[(2S,4S)(tert-butoxycarbonyl) (methoxymethyl)pyrrolidinyl]-1H-imidazolyl}-1,4,5,11- ydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl) methylpyrrolidinecarboxylate )(2-(9-((2S,4S)(tert-butoxycarbonyl)(methoxymethyl)pyrrolidine yloxy)oxo-8,9,10,11-tetrahydro-5H-dibenzo[c,g]chromenyl)oxoethyl) 1- tert-butyl 5-methylpyrrolidine-1,2-dicarboxylate (2S,5S)(2-(9-bromooxo-8,9,10,11-tetrahydro-5H-dibenzo[c,g]chromenyl) oxoethyl) 1-tert-butyl 5-methylpyrrolidine-1,2-dicarboxylate (800 mg, 1.34 mmol) was treated with a solution of (2S,4S)(tert-butoxycarbonyl)(methoxymethyl)pyrrolidine carboxylic acid (485 mg, 1.87 mmol) in acetone (6 mL) and Cs2CO3 (306 mg, 0.94 mmol).

The stirred on mixture was heated to 40 ˚C for 16 h, then cooled to RT and diluted with CH2Cl2 and extracted 3X. The organic phase was washed with brine, then dried over MgSO4, filtered and concentrated under reduced pressure. The crude residue was purified by silica column chromatography (40% to 100% EtOAc/hexanes) to afford (2S,5S)(2-(9-((2S,4S)- 1-(tert-butoxycarbonyl)(methoxymethyl)pyrrolidinecarbonyloxy)oxo-8,9,10,11- tetrahydro-5H-dibenzo[c,g]chromenyl)oxoethyl) 1-tert-butyl 5-methylpyrrolidine-1,2- dicarboxylate (680 mg, 65%). utyl )(9-{2-[(2S,4S)(tert-butoxycarbonyl) (methoxymethyl)pyrrolidinyl]-1H-imidazolyl}-1,4,5,11- tetrahydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl)methylpyrrolidine carboxylate (2S,5S)(2-(9-((2S,4S)(tert-butoxycarbonyl)(methoxymethyl)pyrrolidine carbonyloxy)oxo-8,9,10,11-tetrahydro-5H-dibenzo[c,g]chromenyl)oxoethyl) 1-tertbutyl -methylpyrrolidine-1,2-dicarboxylate (680 mg, 0.87 mmol) and NH4OAc (10.0 g, 130.0 mmol) were suspended in a solution of 10:1 PhMe/2-methoxyethanol (22 mL). The stirred reaction e was heated to 110 ˚C for 24 h, then cooled to RT and diluted with EtOAc. The organic phase was washed with water, saturated aqueous NaHCO3, and brine, then dried over MgSO4, ed and concentrated under reduced pressure. The crude residue was purified by silica column chromatography (0% to 30% MeOH/EtOAc) to afford tertbutyl (2S,5S)(9-{2-[(2S,4S)(tert-butoxycarbonyl)(methoxymethyl)pyrrolidinyl]- 1H-imidazolyl}-1,4,5,11-tetrahydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl) methylpyrrolidinecarboxylate (461 mg, 72%).

Tert-butyl (2S,5S)(5-{2-[(2S,4S)(tert-butoxycarbonyl) (methoxymethyl)pyrrolidinyl]-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2- d]imidazolyl}-1H-imidazolyl)methylpyrrolidinecarboxylate utyl (2S,5S)(9-{2-[(2S,4S)(tert-butoxycarbonyl) (methoxymethyl)pyrrolidinyl]-1H-imidazolyl}-1,4,5,11- tetrahydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl)methylpyrrolidine carboxylate (461 mg, 0.62 mmol) was suspended in DCM (7 mL) and activated MnO2 (1.6 g, 18.8 mmol) was added in a single portion. The reaction mixture was heated to 40 °C. After ng for 5.5 h, the mixture was cooled to rt and the slurry was filtered over celite. The filter cake was washed with copious CH2Cl2 and MeOH and the filtrate was concentrated under reduced pressure. The crude material was taken on to the next step without further purification to afford tert-butyl (2S,5S)(5-{2-[(2S,4S)(tert-butoxycarbonyl) (methoxymethyl)pyrrolidinyl]-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazol- 1H-imidazolyl)methylpyrrolidinecarboxylate (414 mg, 90%).

Methyl {(2S,3S)[(2S,5S)(5-{2-[(2S,4S){(2S,3S)[(methoxycarbonyl)amino] methylpentanoyl}(methoxymethyl)pyrrolidinyl]-1,11- dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl}-1H-imidazolyl) methylpyrrolidinyl]methyloxopentanyl}carbamate Tert-butyl (2S,5S)(5-{2-[(2S,4S)(tert-butoxycarbonyl) (methoxymethyl)pyrrolidinyl]-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazol- 9-yl}-1H-imidazolyl)methylpyrrolidinecarboxylate (207 mg, 0.28 mmol) was dissolved in DCM (4 mL), MeOH (1 mL) and HCl (4 M in e, 1 mL) was added. The reaction mixture was d for 1.5 h and then concentrated under reduced pressure. The crude residue was treated with (2S,3S)(methoxycarbonylamino)methylpentanoic acid (106 mg, 0.56 mmol), HATU (214 mg, 0.56 mmol) and DMF (5 mL), then DIPEA (0.49 mL, 2.8 mmol) was added dropwise. After 30 min, the mixture was diluted with 10% MeOH/EtOAc and washed successively with saturated aqueous NaHCO3 and brine. The cs were dried over MgSO4, filtered and concentrated under reduced pressure. The crude residue was purified by HPLC to afford methyl {(2S,3S)[(2S,5S)(5-{2-[(2S,4S)- 1-{(2S,3S)[(methoxycarbonyl)amino]methylpentanoyl}(methoxymethyl)pyrrolidin- 2-yl]-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl}-1H-imidazolyl) methylpyrrolidinyl]methyloxopentanyl}carbamate (132 mg, 69%). LCMS-ESI+: calculated for C45H54N8O7: 876.45; observed [M+1]+: 879.02 Example NK (2S,4S)tert-butyl 2-(2-oxo(8-oxo-8,9,10,11-tetrahydro-5H-dibenzo[c,g]chromen yl)ethyl) 4-methylpyrrolidine-1,2-dicarboxylate To a solution of 3-(2-bromoacetyl)-10,11-dihydro-5H-dibenzo[c,g]chromen-8(9H)- one (647 mg, 1.74 mmol) in MeCN (20 mL) was added ((2S,4S)(tert-butoxycarbonyl) methylpyrrolidinecarboxylic acid (559 mg, 2.44 mmol) and DIPEA (0.36 mL, 2.09 mmol) and the solution was heated to 60 °C. After stirring for 3 h, the solution was cooled to rt, and diluted with EtOAc and washed sively with saturated aqueous NaHCO3 and brine. The cs were dried over MgSO4, filtered and concentrated under reduced pressure. The crude residue was purified by silica column chromatography (20% to 50% EtOAc/hexanes) to afford (2S,4S)tert-butyl 2-(2-oxo(8-oxo-8,9,10,11-tetrahydro-5H- dibenzo[c,g]chromenyl)ethyl) 4-methylpyrrolidine-1,2-dicarboxylate (621 mg, 69%). (2S,4S)(2-(9-bromooxo-8,9,10,11-tetrahydro-5H-dibenzo[c,g]chromenyl) yl) -butyl 4-methylpyrrolidine-1,2-dicarboxylate (2S,4S)tert-butyl 2-(2-oxo(8-oxo-8,9,10,11-tetrahydro-5H- dibenzo[c,g]chromenyl)ethyl) 4-methylpyrrolidine-1,2-dicarboxylate (621 mg, 1.19 mmol) was dissolved in a solution of DCM (10 mL) and MeOH (4 mL), then treated with pyridinium tribromide (421 mg, 1.3 mmol). After stirring at RT for 1.5 h, the reaction mixture was diluted with DCM and 10% HCl, and extracted with DCM. The organic phase was dried over MgSO4, filtered and trated under reduced pressure and the crude material was carried on without further purification. (2S,4S)(2-(9-((2S,4S)(tert-butoxycarbonyl)(methoxymethyl)pyrrolidine carbonyloxy)oxo-8,9,10,11-tetrahydro-5H-dibenzo[c,g]chromenyl)oxoethyl) 1- tert-butyl 4-methylpyrrolidine-1,2-dicarboxylate (2S,4S)(2-(9-bromooxo-8,9,10,11-tetrahydro-5H-dibenzo[c,g]chromenyl) oxoethyl) 1-tert-butyl 4-methylpyrrolidine-1,2-dicarboxylate (709 mg, 1.18 mmol) was treated with a solution of (2S,4S)(tert-butoxycarbonyl)(methoxymethyl)pyrrolidine carboxylic acid (614 mg, 2.36 mmol) in Me-THF (12 mL) and Cs2CO3 (384 mg, 1.18 mmol).

The stirred reaction mixture was heated to 50 ˚C for 16 h, then cooled to RT and diluted with CH2Cl2 and extracted 3X. The organic phase was washed with brine, then dried over MgSO4, filtered and concentrated under reduced pressure. The crude e was purified by silica column chromatography (40% to 100% EtOAc/hexanes) to afford (2S,4S)(2-(9-((2S,4S)- 1-(tert-butoxycarbonyl)(methoxymethyl)pyrrolidinecarbonyloxy)oxo-8,9,10,11- tetrahydro-5H-dibenzo[c,g]chromenyl)oxoethyl) 1-tert-butyl 4-methylpyrrolidine-1,2- oxylate (651 mg, 71%). utyl (2S,4S)(9-{2-[(2S,4S)(tert-butoxycarbonyl) xymethyl)pyrrolidinyl]-1H-imidazolyl}-1,4,5,11- tetrahydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl)methylpyrrolidine carboxylate (2S,4S)(2-(9-((2S,4S)(tert-butoxycarbonyl)(methoxymethyl)pyrrolidine carbonyloxy)oxo-8,9,10,11-tetrahydro-5H-dibenzo[c,g]chromenyl)oxoethyl) butyl 4-methylpyrrolidine-1,2-dicarboxylate (651 mg, 0.84 mmol) and NH4OAc (10.0 g, 129.7 mmol) were suspended in a solution of 10:1 PhMe/2-methoxyethanol (22 mL). The stirred reaction mixture was heated to 110 ˚C for 20 h, then cooled to RT and diluted with EtOAc. The organic phase was washed with water, saturated aqueous NaHCO3, and brine, then dried over MgSO4, filtered and concentrated under reduced pressure. The crude e was purified by silica column chromatography (0% to 30% MeOH/EtOAc) to afford tertbutyl (2S,4S)(9-{2-[(2S,4S)(tert-butoxycarbonyl)(methoxymethyl)pyrrolidinyl]- 1H-imidazolyl}-1,4,5,11-tetrahydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl) methylpyrrolidinecarboxylate (382 mg, 62%).

Tert-butyl (2S,4S)[5-(2-{(2S,4S)[N-(methoxycarbonyl)-L-valyl] (methoxymethyl)pyrrolidinyl}-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2- azolyl)-1H-imidazolyl]methylpyrrolidinecarboxylate Tert-butyl (2S,4S)(9-{2-[(2S,4S)(tert-butoxycarbonyl) (methoxymethyl)pyrrolidinyl]-1H-imidazolyl}-1,4,5,11- tetrahydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl)methylpyrrolidine carboxylate (382 mg, 0.52 mmol) was suspended in DCM (8 mL) and activated MnO2 (1.35 g, 15.5 mmol) was added in a single portion. The reaction mixture was heated to 35 °C. After stirring for 15 h, the mixture was cooled to rt and the slurry was filtered over celite. The filter cake was washed with copious CH2Cl2 and MeOH and the filtrate was concentrated under reduced pressure. The crude material was taken on to the next step without further purification to afford tert-butyl (2S,4S)[5-(2-{(2S,4S)[N-(methoxycarbonyl)-L-valyl]- 4-(methoxymethyl)pyrrolidinyl}-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2- azolyl)-1H-imidazolyl]methylpyrrolidinecarboxylate (347 mg, 91%).

Methyl {(2S,3R)methoxy[(2S,4S)[9-(2-{(2S,4S)[N-(methoxycarbonyl)-O- methyl-L-threonyl]methylpyrrolidinyl}-1H-imidazolyl)-1,11- dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl] (methoxymethyl)pyrrolidinyl]oxobutanyl}carbamate Tert-butyl (2S,4S)[5-(2-{(2S,4S)[N-(methoxycarbonyl)-L-valyl] (methoxymethyl)pyrrolidinyl}-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2- azolyl)-1H-imidazolyl]methylpyrrolidinecarboxylate (174 mg, 0.24 mmol) was dissolved in DCM (4 mL), MeOH (1 mL) and HCl (4 M in dioxane, 1 mL) was added.

The reaction mixture was d for 5 h and then concentrated under reduced re. The crude residue was treated with ((2S,3R)methoxy(methoxycarbonylamino)butanoic acid (92 mg, 0.48 mmol), HATU (182 mg, 0.48 mmol) and DMF (5 mL), then DIPEA (0.31 mL, 2.4 mmol) was added dropwise. After 35 min, the mixture was diluted with 10% MeOH/EtOAc and washed successively with saturated aqueous NaHCO3 and brine. The organics were dried over MgSO4, ed and concentrated under reduced pressure. The crude residue was purified by HPLC to afford methyl {(2S,3R)methoxy[(2S,4S)[9- (2-{(2S,4S)[N-(methoxycarbonyl)-O-methyl-L-threonyl]methylpyrrolidinyl}-1H- imidazolyl)-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl] (methoxymethyl)pyrrolidinyl]oxobutanyl}carbamate (72 mg, 34%). LCMS-ESI+: calculated for N8O10: 880.41; observed [M+1]+: 882.39. 'H NMR (CD3OD): 8.558 (s, 1H), 8.123-7.572 (m, 7H), 5.436-5.391 (dd, 1H, J=7.2, 3.6 Hz), 5.252 (s, 2H), 5.220 (m, 1H), 4.493-4.444 (m, 2H), 4.287-4.206 (m, 2H), 3.756-3.256 (m, 21H), 2.834 (m, 1H), 2.717- 2.621 (m, 2H), 2.500 (m, 1H), 2.150 (m, 1H), 1.882 (m, 1H), 1.208 (d, 3H, J=6.4 Hz), 1.159- 1.099 (m, 6H). e NL O NH O O MnO2 N H N N CH2Cl2 N N Boc tert-butyl (2S,4S)[9-(2-{(2S,5S)[N-(methoxycarbonyl)-L-valyl]methylpyrrolidinyl}- 1H-imidazolyl)-1,4,5,11-tetrahydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl] methylpyrrolidinecarboxylate O NH O O 1. HCl N H N 2. HATU, DIPEA, DMF N O N Boc HO HN O tert-butyl (2S,4S)[9-(2-{(2S,5S)[N-(methoxycarbonyl)-L- methylpyrrolidinyl}-1H-imidazolyl)-1,11- O dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl] (2S,3R)methoxy methylpyrrolidinecarboxylate (methoxycarbonylami no)butanoic acid O NH O O N H N N O N N H O HN O methyl {(2S)[(2S,5S)(5-{2-[(2S,4S){(2S,3R)methoxy[(methoxycarbonyl)amino]butanoyl} methylpyrrolidinyl]-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl}-1H-imidazol yl)methylpyrrolidinyl]methyloxobutanyl}carbamate (2S,5S)oxo(8-oxo-8,9,10,11-tetrahydro-5H-dibenzo[c,g]chromenyl)ethyl 1-((S)- 2-(methoxycarbonylamino)methylbutanoyl)methylpyrrolidinecarboxylate To a solution of 3-(2-bromoacetyl)-10,11-dihydro-5H-dibenzo[c,g]chromen-8(9H)- one (750 mg, 2.02 mmol) in MeCN (20 mL) was added )((S) (methoxycarbonylamino)methylbutanoyl)methylpyrrolidinecarboxylic acid (600 mg, 2.09 mmol) and DIPEA (0.35 mL, 2.02 mmol) and the solution was heated to 60 °C. After ng for 4 h, the solution was cooled to rt, and diluted with EtOAc and washed successively with saturated s NaHCO3 and brine. The organics were dried over MgSO4, filtered and concentrated under reduced pressure. The crude residue was purified by silica column chromatography (40% to 80% EtOAc/hexanes) to afford (2S,5S)oxo(8- oxo-8,9,10,11-tetrahydro-5H-dibenzo[c,g]chromenyl)ethyl 1-((S) (methoxycarbonylamino)methylbutanoyl)methylpyrrolidinecarboxylate (1.16 g, (2S,5S)(9-bromooxo-8,9,10,11-tetrahydro-5H-dibenzo[c,g]chromenyl) oxoethyl 1-((S)(methoxycarbonylamino)methylbutanoyl)methylpyrrolidine carboxylate (2S,5S)oxo(8-oxo-8,9,10,11-tetrahydro-5H-dibenzo[c,g]chromenyl)ethyl 1- ((S)(methoxycarbonylamino)methylbutanoyl)methylpyrrolidinecarboxylate (400 mg, 0.61 mmol) was dissolved in a solution of DCM (15 mL) and MeOH (6 mL), then treated with pyridinium tribromide (409 mg, 1.28 mmol). At 2 h, an additional portion of pyridinium tribromide (40 mg) was added. After stirring at RT for another 20 min, the reaction mixture was diluted with DCM and 10% HCl, and ted with DCM. The organic phase was dried over MgSO4, filtered and concentrated under reduced pressure and the crude al was carried on without further purification. (2S,4S)tert-butyl 2-(3-(2-((2S,5S)((S)(methoxycarbonylamino) methylbutanoyl)methylpyrrolidinecarbonyloxy)acetyl)oxo-8,9,10,11- tetrahydro-5H-dibenzo[c,g]chromenyl) 4-methylpyrrolidine-1,2-dicarboxylate (2S,5S)(9-bromooxo-8,9,10,11-tetrahydro-5H-dibenzo[c,g]chromenyl) oxoethyl 1-((S)(methoxycarbonylamino)methylbutanoyl)methylpyrrolidine carboxylate ) was treated with a solution of (2S,4S)(tert-butoxycarbonyl) methylpyrrolidinecarboxylic acid (280 mg, 1.22 mmol) in Me-THF (6 mL) and Cs2CO3 (199 mg, 0.61 mmol). The stirred reaction mixture was heated to 50 ˚C for 2.5 h, then cooled to RT and diluted with CH2Cl2 and extracted 3X. The organic phase was washed with brine, then dried over MgSO4, filtered and concentrated under reduced pressure. The crude residue was purified by silica column chromatography (50% to 100% EtOAc/hexanes) to afford (2S,4S)tert-butyl 2-(3-(2-((2S,5S)((S)(methoxycarbonylamino)methylbutanoyl)- -methylpyrrolidinecarbonyloxy)acetyl)oxo-8,9,10,11-tetrahydro-5H- o[c,g]chromenyl) 4-methylpyrrolidine-1,2-dicarboxylate (441 mg, 90%).

Tert-butyl )[9-(2-{(2S,5S)[N-(methoxycarbonyl)-L-valyl] pyrrolidinyl}-1H-imidazolyl)-1,4,5,11- tetrahydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl]methylpyrrolidine carboxylate (2S,4S)tert-butyl 2-(3-(2-((2S,5S)((S)(methoxycarbonylamino) methylbutanoyl)methylpyrrolidinecarbonyloxy)acetyl)oxo-8,9,10,11-tetrahydro-5H- dibenzo[c,g]chromenyl) ylpyrrolidine-1,2-dicarboxylate (441 mg, 0.55 mmol) and NH4OAc (5 g, 65.0 mmol) were suspended in a solution of 10:1 PhMe/2-methoxyethanol (11 mL). The stirred reaction mixture was heated to 110 ˚C for 7 h, then cooled to RT and diluted with EtOAc. The organic phase was washed with water, saturated aqueous NaHCO3, and brine, then dried over MgSO4, ed and trated under reduced pressure. The crude e was ed by silica column tography (0% to 30% MeOH/EtOAc) to afford tert-butyl (2S,4S)[9-(2-{(2S,5S)[N-(methoxycarbonyl)-L-valyl]methylpyrrolidin -imidazolyl)-1,4,5,11-tetrahydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazol yl]methylpyrrolidinecarboxylate (266 mg, 63%).

Tert-butyl (2S,4S)[9-(2-{(2S,5S)[N-(methoxycarbonyl)-L-valyl] methylpyrrolidinyl}-1H-imidazolyl)-1,11- dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl]methylpyrrolidine carboxylate Tert-butyl (2S,4S)[9-(2-{(2S,5S)[N-(methoxycarbonyl)-L-valyl] methylpyrrolidinyl}-1H-imidazolyl)-1,4,5,11 tetrahydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl]methylpyrrolidine carboxylate (266 mg, 0.35 mmol) was suspended in DCM (7 mL) and activated MnO2 (908 mg, 10.45 mmol) was added in a single portion. The reaction mixture was stirred overnight.

After ng for 15 h, additional activated MnO2 (500 mg, 5.75 mmol) was added in a single portion.

After stirring 2 h at 35 °C, the mixture was cooled to rt and the slurry was filtered over celite. The filter cake was washed with copious CH2Cl2 and MeOH and the filtrate was concentrated under reduced pressure. The crude material was taken on to the next step without further purification to afford tert-butyl (2S,4S)[9-(2-{(2S,5S)[N- (methoxycarbonyl)-L-valyl]methylpyrrolidinyl}-1H-imidazolyl)-1,11- dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl]methylpyrrolidine carboxylate (266 mg, quant).

Methyl {(2S)[(2S,5S)(5-{2-[(2S,4S){(2S,3R)methoxy [(methoxycarbonyl)amino]butanoyl}methylpyrrolidinyl]-1,11- dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl}-1H-imidazolyl) methylpyrrolidinyl]methyloxobutanyl}carbamate Tert-butyl (2S,4S)[9-(2-{(2S,5S)[N-(methoxycarbonyl)-L-valyl] methylpyrrolidinyl}-1H-imidazolyl)-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2- d]imidazolyl]methylpyrrolidinecarboxylate (266 mg, 0.23 mmol) was dissolved in DCM (4 mL), MeOH (1mL) and HCl (4 M in dioxane, 1 mL) was added. The reaction mixture was stirred for 1.5 h and then concentrated under reduced pressure. The crude residue was treated with (2S,3R)methoxy(methoxycarbonylamino)butanoic acid (44 mg, 0.23 mmol), HATU (87 mg, 0.23 mmol) and DMF (5 mL), then DIPEA (0.3 mL, 1.75 mmol) was added dropwise. After 30 min, the mixture was diluted with 10% MeOH/EtOAc and washed successively with saturated aqueous NaHCO3 and brine. The organics were dried over MgSO4, filtered and concentrated under reduced pressure. The crude residue was purified by HPLC to afford methyl {(2S)[(2S,5S)(5-{2-[(2S,4S){(2S,3R)methoxy [(methoxycarbonyl)amino]butanoyl}methylpyrrolidinyl]-1,11- dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl}-1H-imidazolyl) methylpyrrolidinyl]methyloxobutanyl}carbamate (59 mg, 31%). LCMS-ESI+: ated for N8O8: 834.41; observed [M+1]+: 836.89. 'H NMR (CD3OD): 8.186 (s, 1H), 7.800-7.291 (m, 7H), 5.258-5.213 (dd, 1H, J=7.2, 3.6 Hz), 5.027-4.918 (m, 4H), 4.620 (t, 1H, J=6.8 Hz), 4.246 (m, 1H), 4.116 (m, 1H), 3.972 (d, 1H, J=8.8 Hz), 3.701-3.675 (m, 1H), 3.503 (s, 3H), 3.479 (s, 3H), 3.177 (s, 3H), 2.554-2.191 (m, 3H), 1.821 (m, 6H), 1.392 (d, 2H, J=6.4 Hz), 1.113-0.728 (m, 12H). e NM Tert-butyl (2S,4S)[5-(2-{(2S,4S)[N-(methoxycarbonyl)-L-valyl] methylpyrrolidinyl}-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl)- 1H-imidazolyl](methoxymethyl)pyrrolidinecarboxylate Methyl [(2S)methyl{(2S,4S)methyl[9-(4,4,5,5-tetramethyl-1,3,2- dioxaborolanyl)-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazol yl]pyrrolidinyl}oxobutanyl]carbamate (312 mg, 0.49 mmol), methyl (S)((2S,4S)- 2-(5-iodo-1H-imidazolyl)(methoxymethyl)pyrrolidinyl)methyloxobutan ylcarbamate (219 mg, 0.54 mmol), Pd(PPh3)4 (58 mg, 0.05 mmol), PdCl2(dppf)2 (36 mg, 0.05 mmol), and K2CO3 (2M in H2O, 0.8 mL, 1.6 mmoL) were ed in DMSO (5 mL) and dioxane (5 mL). The mixture was degassed with bubbling N2 for 10 min then heated to 95 ˚C for 5 h. After cooling, the reaction mixture was diluted with EtOAc, and washed successively with saturated aqueous NaHCO3 and brine. The organics were dried over MgSO4, filtered and concentrated under reduced pressure. The crude residue was purified by silica column chromatography (0 %- 30% MeOH/EtOAc) to afford tert-butyl (2S,4S)[5-(2-{(2S,4S) [N-(methoxycarbonyl)-L-valyl]methylpyrrolidinyl}-1,11- dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl)-1H-imidazolyl] (methoxymethyl)pyrrolidinecarboxylate (166 mg, 43%).

Methyl {(1R)[(2S,4S)(5-{2-[(2S,4S){(2S)[(methoxycarbonyl)amino] methylbutanoyl}methylpyrrolidinyl]-1,11- dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl}-1H-imidazolyl) (methoxymethyl)pyrrolidinyl]oxophenylethyl}carbamate Tert-butyl (2S,4S)[5-(2-{(2S,4S)[N-(methoxycarbonyl)-L-valyl] methylpyrrolidinyl}-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl)-1H- imidazolyl](methoxymethyl)pyrrolidinecarboxylate (166 mg, 0.21 mmol) was dissolved in DCM (4 mL), MeOH (1 mL) and HCl (4 M in dioxane, 1 mL) was added. The reaction mixture was stirred for 2 h and then concentrated under reduced pressure. The crude residue was treated with (R)(methoxycarbonylamino)phenylacetic acid (44 mg, 0.21 mmol), COMU (100 mg, 0.21 mmol) and DMF (5 mL), then DIPEA (0.18 mL, 1.05 mmol) was added dropwise. After 1 h, the mixture was diluted with 10% MeOH/EtOAc and washed sively with ted aqueous NaHCO3 and brine. The organics were dried over MgSO4, filtered and concentrated under reduced pressure. The crude residue was purified by HPLC to afford methyl 2-[(2S,4S)(5-{2-[(2S,4S){(2S) [(methoxycarbonyl)amino]methylbutanoyl}methylpyrrolidinyl]-1,11- oisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl}-1H-imidazolyl) (methoxymethyl)pyrrolidinyl]oxophenylethyl}carbamate (71 mg, 38%). I +: calculated for N8O8: 882.41; observed [M+1]+: 884.34. 'H NMR (CD3OD): 8.462 (s, 1H), 8.029-7.471 (m, 7H), 7.394-7.343 (m, 5H), 5.410 (d, 2H, J=6.8 Hz), 5.300 (m, 1H), 5.233 (m, 2H), 4.341 (m, 1H), 4.236 (d, 1H, J=7.2 Hz), 3.603 (s, 3H), 3.551 (s, 3H), 3.522-3.241 (m, 8H), 2.650 (m, 1H), 2.550 (m, 2H), 1.977-1.926 (m, 4H), 1.221 (d, 3H, J=3.2 Hz), 0.897-0.779 (dd, 6H, J=19.2, 6.8 Hz). e NO CH3-MgBr Boc TFA CH3 O EtO EtO NH N THF, -40 - 0 oC DCM O O Boc EtO O (S)-ethyl 5-methyl- tert-butyl 2-ethyl 5- hydro-2H- oxopyrrolidine-1,2- (S)-ethyl 2-(tertpyrrole dicarboxylate butoxycarbonylamino) oxohexanoate carboxylate (Boc)2O LiOH H2 (g) CH3 CH3 EtO EtO N H O Boc EtOH, H2O Pd/C O DIEA, DMAP (2S,5S)tert-butyl 2-ethyl (2S,5S)-ethyl 5- 5-methylpyrrolidine-1,2- methylpyrrolidine dicarboxylate carboxylate TEMPO, NaBr Borane NaClO, NaHCO3 CH3 CH3 HO CH3 H N HO N O Boc Dimethysulfide Boc Boc DCM, 0 oC O )-tert-butyl 2-formyl- (2S,5S)(tert- (2S,5S)-tert-butyl 2- butoxycarbonyl) (hydroxymethyl) 5-methylpyrrolidine methylpyrrolidine carboxylate methylpyrrolidine carboxylic acid carboxylate O Na2SO3 O CH3 I2, Na2CO3 CH3 N N N N Ammonia (aq) NH Boc NH Dioxane, H2O Dioxane / H2O MeOH, 10 oC I (2S,5S)-tert-butyl 2-(1H- (2S,5S)-tert-butyl 2-(4,5-diiodoimidazolyl ) 1H-imidazolyl) methylpyrrolidinecarboxylate methylpyrrolidinecarboxylate CH3 N N N 1. HCl / Dioxane N NH O O NH Boc 2. L-Valine MOC I HN I HATU, DIEA O (2S,5S)-tert-butyl 2-(5-iodo-1H- (2S)[(2S,5S)(5-iodo-1H-imidazolyl)- olyl)methylpyrrolidine- 5-methylpyrrolidinyl][(1- 1-carboxylate methoxyethenyl)amino]methylbutanone (S)-ethyl 2-(tert-butoxycarbonylamino)oxohexanoate A solution of ethyl N-Boc (S)-pyroglutamate (20.0 g, 77.7 mmol) was in anhydrous THF (150 mL) in a two neck round bottom under argon was cooled to -40 oC. Methylmagnesium bromide solution (3.0 M in Ether, 28.5 mL, 85.5 mmol) was added to the reaction mixture dropwise over 30 s. The reaction was stirred for 4 hrs at -40 oC then for 1 hr at 0 oC. The reaction was partitioned between ethyl acetate and saturated ammonium chloride solution and acidified with 1 N HCl. The aqueous layer was extracted two more times with ethylacetate. The organic layers were combined and dried with sodium sulfate.

The crude material was purified by column chromatography (20% - 40% EtOAc/hexanes) to yield (S)-ethyl 2-(tert-butoxycarbonylamino)oxohexanoate as a s oil and was used directly in the following step.

(S)-ethyl 5-methyl-3,4-dihydro-2H-pyrrolecarboxylate (S)-ethyl 2-(tert-butoxycarbonylamino)oxohexanoate in a 1 L flask was treated with a trifluoro acetic acid / dichloromethane solution (1:1 mixture, 100 mL). escence was observed and the mixture was allowed to stir for 4 hours at room temperature. After which time the volatiles were removed in vacuo to yield hyl 5-methyl-3,4-dihydro-2H- pyrrolecarboxylate as an oil, and used directly in the following step. (2S,5S)-ethyl 5-methylpyrrolidinecarboxylate The crude imine in a 1L flask was dissolved with l (400 mL) was ted and charged with argon three times (3x). Palladium on carbon (apprx. 750 mg, 10% w/w, dry) was added and the reaction was evacuated of gas and charged with hydrogen gas (3x).

The reaction was allowed to stir under atmospheric hydrogen for 16 hours. The mixture was filtered h a plug of celite and the filtrate was concentrated in vacuo. Diethyl ether was added to the oil and a precipitate formed. The mixture was filtered to yield (2S,5S)-ethyl 5- pyrrolidinecarboxylate, as a white solid (10.6 g, 67.4 mmol, 86.7% over three steps). 1H NMR (400 MHz, cdcl 3) δ 4.48 (dd, 1H), 4.27 (q, 2H), 3.92 – 3.80 (m, 1H), 2.52 – 2.36 (m, 1H), 2.32 – 2.13 (m, 2H), 1.75 – 1.60 (m, 1H), 1.51 (d, 3H), 1.30 (t, 3H). (2S,5S)tert-butyl 2-ethyl 5-methylpyrrolidine-1,2-dicarboxylate To a solution of (2S,5S)-ethyl 5-methylpyrrolidinecarboxylate (7.0 g, 44.5 mmol) in dichloromethane (250 mL), ditertbutylanhydride (10.7 g, 49.0 mmol), diisopropylethylamine (17.1 mL, 98.0 mmol) dropwise over 10 minutes, and dimethyl amino pyridine (0.27 g, 2.23 mmol) were added successively. Effervescence was observed and the mixture was allowed to stir for 16 hours at room temperature. The reaction was washed with HCl (250 mL, of 1N). The organic layer was then dried with sodium e. The crude material was purified by column chromatography (5% - 25% EtOAc/hexanes) to yield (2S,5S)tert-butyl 2-ethyl 5-methylpyrrolidine-1,2-dicarboxylate as an oil (6.46 g, 25.1 mmol, 56%). LCMS-ESI+: calc’d for C13H23NO4: 257.16 (M +); Found: 258.70 (M+H+). (2S,5S)(tert-butoxycarbonyl)methylpyrrolidinecarboxylic acid To a solution of (2S,5S)tert-butyl 2-ethyl 5-methylpyrrolidine-1,2-dicarboxylate (6.46 g, 25.1 mmol) in ethanol (20 mL) was added lithium ide mono hydrate (2.11 g, 50.2 mmol) and deionized water (12mL). The mixture was allowed to stir for 16 hours then ioned between cetate and a 1:1 mixture of saturated brine and 1N HCl. The s layer was extracted an additional time with ethyl acetate. The c layers were combined, dried with sodium sulfate and the solvent was removed in vacuo to yield (2S,5S)- 1-(tert-butoxycarbonyl)methylpyrrolidinecarboxylic acid as a white solid (quant.) and was used directly in the following step. (2S,5S)-tert-butyl 2-(hydroxymethyl)methylpyrrolidinecarboxylate To a solution of (2S,5S)(tert-butoxycarbonyl)methylpyrrolidinecarboxylic acid (5.91 g, 25.8 mmol) in tetrahydrofuran at 0 oC, was added borane in dimethylsulfide (1.0 M, 3.4 mL, 34 mmol) dropwise. The reaction was d for 4 hours at 0 oC then 18 hours at room temperature. The mixture was then cooled to 0 oC and methanol (70 mL) was added dropwise. The on was warmed to room temperature and the solvents were d in vacuo. The residue was taken up in dichloromethane (200 mL) and extracted with saturated sodium bicarbonate. The organic layer was dried with sodium sulfate and the t was removed in vacuo to yield (2S,5S)-tert-butyl 2-(hydroxymethyl)methylpyrrolidine carboxylate as a clear oil (5.15 g, 23.9 mmol, 93%) and was used directly in the following step. (2S,5S)-tert-butyl 2-formylmethylpyrrolidinecarboxylate To a solution of (2S,5S)-tert-butyl 2-(hydroxymethyl)methylpyrrolidine carboxylate (5.15 g, 23.9 mmol) in dichloromethane, was added TEMPO (0.075 g, 0.48 mmol), sodium bromide (0.246 g, 2.39 mmol) and sodium bicarbonate (0.442 g, 5.26 mmol).

Sodium hypochlorite (2.67 g, 35.9 mmol) of a 6% solution was added and the biphasic mixture was vigorously stirred for 2 hours at room temperature. The reaction mixture was extracted two times with dichloromethane (2x100mL). The organic layers were combined and washed with saturated sodium thiosulfate solution, dried with sodium sulfate and the solvent was removed in vacuo to yield (2S,5S)-tert-butyl 2-formylmethylpyrrolidine carboxylate (3.9 g, 18.29 mmol, 77%) as a slight colored oil and was used directly in the following step. (2S,5S)-tert-butyl 2-(1H-imidazolyl)methylpyrrolidinecarboxylate To a solution of )-tert-butyl 2-formylmethylpyrrolidinecarboxylate (3.9g, 18.30 mmol) in MeOH (15 mL) and ammonium hydroxide (15 mL, 99.9%), glyoxal (11.7 mL, 40% w/v in water, 102.40 mmol) was added dropwise. The biphasic mixture turned orange and turbid. The reaction was stirred vigorously overnight at room temperature. The solvent was removed in vacuo. The crude mixture was redissolved in ethyl acetate and washed with water. The aqueous layer was washed an additional time with ethyl e.

The organic layers were combined and washed with brine, dried with sodium sulfate and the solvent was removed in vacuo. The crude material was purified by column chromatography 85% to 100% ethyl acetate in hexanes to yield (2S,5S)-tert-butyl 2-(1H-imidazolyl) methylpyrrolidinecarboxylate as an off white solid (3.47 g, 13.8 mmol, 75%). LCMS- ESI+: calc’d for C13H21N3O2: 251.16 (M +); Found: 252.20 (M+H+). (2S,5S)-tert-butyl 2-(4,5-diiodo-1H-imidazolyl)methylpyrrolidinecarboxylate A 500 mL round bottom flask was charged with (2S,5S)-tert-butyl 2-(1H-imidazol yl)methylpyrrolidinecarboxylate (3.47 g, 13.8 mmol), iodine (7.7 g, 30.4 mmol) and sodium carbonate (4.54 g, 42.8 mmol). e (70 mL) and water (45 mL) was added to mixture and the on was stirred vigorously overnight in the dark. The reaction was then partitioned between ethyl acetate and a 10% aqueous solution of sodium thiosulfate and extracted. The aqueous layer was extracted an additional time with ethyl e. The organic layers were combined, dried with sodium sulfate and the solvent was removed in vacuo. The crude material was ed h a plug of silica with 25% ethyl acetate in hexanes to yield (2S,5S)-tert-butyl 2-(4,5-diiodo-1H-imidazolyl)methylpyrrolidinecarboxylate as a white solid (4.28 g, 8.50 mmol, 62%). LCMS-ESI+: calc’d for C13H19I2N3O2: 502.96 (M +); Found: 503.94 . (2S,5S)-tert-butyl 2-(5-iodo-1H-imidazolyl)methylpyrrolidinecarboxylate To a solution of (2S,5S)-tert-butyl 2-(4,5-diiodo-1H-imidazolyl) pyrrolidinecarboxylate (4.28 g, 8.50 mmol) in ethanol (75 mL) and water (75 mL), sodium thiosulfate (10.72 g, 85.1 mmol) was added and the reaction mixture was stirred vigorously for 1 hour at 100 oC, 16 hours at 90 oC, and 5 hours at 100 oC. The reaction mixture was partitioned between ethyl acetate and water. The aqueous layer was washed onally with ethyl acetate and the organic layers were combined. The organic layer was dried with sodium sulfate, concentrated and the crude material was ed by column chromatography to yield (2S,5S)-tert-butyl 2-(5-iodo-1H-imidazolyl)methylpyrrolidine- 1-carboxylate as a white solid (2.34 g, 6.20 mmol, 73%). 1H NMR (400 MHz, cdcl 3) δ 7.04 (s, 1H), 4.89 (dd, 1H), 3.92 (m, 1H), 2.91 (s, 1H), 2.18 – 2.06 (m, 2H), 1.78 (m, 1H), 1.52 (m, 1H), 1.48 (s, 9H), 1.13 (d, 3H). (2S)[(2S,5S)(5-iodo-1H-imidazolyl)methylpyrrolidinyl][(1- methoxyethenyl)amino]methylbutanone A round bottom flask was charged with (2S,5S)-tert-butyl 2-(5-iodo-1H-imidazol yl)methylpyrrolidinecarboxylate (1.5 g, 3.98 mmol) and treated with an excess of hydrochloric acid (100 mL of 4.0M in dioxane). The mixture was stirred vigorously for 3 hours in which time a precipitate formed and the solvent was d in vacuo. To a e of the crude intermediate, (S)(methoxycarbonylamino)methylbutanoic acid (0.836 g, 4.77 mmol), HATU (1.81 g, 4.77 mmol) in dichloromethane (25 mL), diisopropylethylamine (3.46 mL, 19.9 mmol) was then added dropwise and was stirred over night under nitrogen.

The reaction mixture was partitioned ethyl acetate and saturated sodium bicarbonate. The organic layer was dried with sodium sulfate, the solvent removed in vacuo. The crude product was purified by column chromatography to yield (2S)[(2S,5S)(5-iodo-1H- imidazolyl)methylpyrrolidinyl][(1-methoxyethenyl)amino]methylbutanone as a white solid (1.63 g, 3.75 mmol, 94%). SI+: calc’d for C15H23IN4O3: 434.08 (M +); Found: 435.51 (M+H+). e NP Methyl {(2S)[(2S,5S)(5-{2-[(2S,4S){(2R)[(methoxycarbonyl)amino] phenylacetyl}(methoxymethyl)pyrrolidinyl]-1,11 dihydroisochromeno [4',3':6,7]naphtho[1,2-d]imidazolyl}-1H-imidazolyl)methylpyrrolidinyl] methyloxobutanyl}carbamate The synthesis of this compound was prepared according to the procedure of example LR-1 with the following modification. During the Suzuki coupling, (2S)[(2S,5S)(5- iodo-1H-imidazolyl)methylpyrrolidinyl][(1-methoxyethenyl)amino] methylbutanone was used in lieu of (2S)[(2S)(5-bromo-1H-imidazolyl)pyrrolidin- 1-yl][(1-methoxyethenyl)amino]methylbutanone. The crude material was purified by preparative HPLC to provide methyl {(2S)[(2S,5S)(5-{2-[(2S,4S){(2R) [(methoxycarbonyl)amino]phenylacetyl}(methoxymethyl) pyrrolidinyl]-1,11 dihydroisochromeno [4',3':6,7]naphtho[1,2-d]imidazolyl}-1H-imidazolyl) pyrrolidinyl]methyloxobutanyl}carbamate as a white solid (17 mg, 0.019 mmol, 17%). 1H NMR (400 MHz, cd3od) δ 8.63 (s, 1H), 8.19 (d, 1H), 8.04 (m, 1H), 7.87 (m, 2H), 7.66 (m, 2H), 7.52 – 7.39 (m, 6H), 5.50 (m, 2H), 5.32 (s, 2H), 5.16 (m, 1H), 4.12 (m, 1H), 3.80 (m, 4H), 3.66 (s, 6H), 3.43 (m, 4H), 3.23 (s, 3H), 2.72-1.99 (m, 9H), 1.56 (d, 3H), 1.29 (m, 1H), 0.99 (d, 3H), 0.88 (d, 3H). e NQ O O O N N O N H B N O N Boc Pd(PPh3)4, dppf), K2CO3, DME/ DMF, 85°C tert-butyl 2-[9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan- 2-yl)-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2- d]imidazolyl]pyrrolidinecarboxylate O 1. HCl, EtOH, 60°C H O O O H N N 2.

N N N Boc O H O H N O tert-butyl (2S)[9-(2-{(2S,5S)[N-(methoxycarbonyl)-L-valyl]- O H -methylpyrrolidinyl}-1H-imidazolyl)-3,11- COMU, DIPEA, DMF, RT dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazol yl]pyrrolidinecarboxylate H O O O H N N N N N N O methyl {(2S)[(2S,5S)(5-{2-[(2S){(2R)[(methoxycarbonyl)amino] phenylacetyl}pyrrolidinyl]-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2- d]imidazolyl}-1H-imidazolyl)methylpyrrol idinyl]methyloxobutanyl}carbamate Methyl {(2S)[(2S,5S)(5-{2-[(2S){(2R)[(methoxycarbonyl)amino] phenylacetyl}pyrrolidinyl]-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2- d]imidazolyl}-1H-imidazolyl)methylpyrrolidinyl]methyloxobutan yl}carbamate The synthesis of this compound was prepared according to the procedure of example LQ with the following modification. During the Suzuki coupling, (2S)[(2S,5S)(5-iodo- 1H-imidazolyl)methylpyrrolidinyl][(1-methoxyethenyl)amino]methylbutan one was used in lieu of (2S)[(2S)(5-bromo-1H-imidazolyl)pyrrolidinyl][(1- yethenyl)amino]methylbutanone. The crude material was purified by preparative HPLC to provide methyl {(2S)[(2S,5S)(5-{2-[(2S){(2R) [(methoxycarbonyl)amino]phenylacetyl}pyrrolidinyl]-1,11- dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl}-1H-imidazolyl) methylpyrrolidinyl]methyloxobutanyl}carbamate as a white solid (110 mg, 0.131 mmol, 57 %). 1H NMR (400 MHz, cd 3od) δ 8.65 (s, 1H), 8.21 (d, 1H), 8.04 (m, 2H), 7.91 (s, 1H), 7.81 (m, 1H), 7.67 (m, 2H), 7.46 (m, 6H), 5.59 (s, 1H), 5.50 (dd, 1H), 5.33 (s, 2H), 5.22 – 5.09 (m, 1H), 4.14 (m, 2H), 3.74 (s, 1H), 3.65 (m, 6H), 3.52 – 3.37 (m, 2H), 2.60 – 1.89 (m, 11H), 1.56 (d, 3H), 1.29 (d, 1H), 0.99 (d, 3H), 0.88 (d, 3H).

Example NR H O O O H N N 1. HCl, EtOH, 60°C N N N Boc 2. tert-butyl (2S)[9-(2-{(2S,5S)[N-(methoxycarbonyl)-L- O valyl]methylpyrrolidinyl}-1H-imidazolyl)-3,11- H N O dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazol O H yl]pyrrolidinecarboxylate COMU, DIPEA, DMF, RT H O N H O O N N N HCl, Dioxane N N N H Boc methyl {(2S)[(2S,5S)(5-{2-[(2S){(2R)[(tert-butoxycarbonyl)amino]- 2-phenylacetyl}pyrrolidinyl]-3,11- dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl}-1H-imidazolyl)- -methylpyrrolidinyl]methyloxobutanyl}carbamate H O N H O O N N N N N H H methyl 1-{(2S,5S)[5-(2-{(2S)[(2R)aminophenylacetyl]pyrrolidinyl}- 1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl)-1H-imidazolyl] methylpyrrolidinyl}methyloxobutanyl]carbamate Methyl [(2S){(2S,5S)[5-(2-{(2S)[(2R)aminophenylacetyl]pyrrolidinyl}- 1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl)-1H-imidazolyl] methylpyrrolidinyl}methyloxobutanyl]carbamate The synthesis of this compound was prepared according to Example NQ with the ing modifications. During the amide coupling, (tert-butoxycarbonylamino) phenylacetic acid was used in lieu of (R)(methoxycarbonylamino)phenylacetic acid.

This was then treated with an excess of hloric acid (15 mL, 4.0 M in Dioxane) for 2 hours. The crude product was purified by HPLC to provide methyl [(2S){(2S,5S)[5-(2- {(2S)[(2R)aminophenylacetyl]pyrrolidinyl}-1,11- dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl)-1H-imidazolyl] methylpyrrolidinyl}methyloxobutanyl]carbamate as a white solid (153 mg, 0.196 mmol, 74%). 1H NMR (400 MHz, cd 3od) δ 8.63 (s, 1H), 8.20 (d, 1H), 7.99 (m, 1H), 7.93 (m, 2H), 7.80 (m, 2H), 7.72 – 7.64 (m, 2H), 7.63 – 7.52 (m, 5H), 5.52 (dd, 1H), 5.44 (m, 1H), .33 (s, 2H), 5.21 – 5.10 (m, 1H), 4.80 (m, 2H), 4.14 (m, 1H), 4.02 (m, 1H), 3.75 (s, 1H), 3.67 (s, 3H), 3.12 (dd, 1H), 2.72 – 2.13 (m, 7H), 2.00 (m, 3H), 1.56 (d, 3H), 1.30 (d, 1H), 0.98 (d, 3H), 0.88 (d, 3H).

Example OE )-Ethyl 1-((S)(methoxycarbonylamino)methylbutanoyl) methylpyrrolidinecarboxylate (2S,5S)-Ethyl 5-methylpyrrolidinecarboxylate-TFA (10.0 g, 39.3 mmol), (S) xycarbonylamino)methylbutanoic acid (6.88 g, 39.3 mmol) and HATU (14.9 g, 39.3 mmol) were combined in DMF (100 mL) and DIPEA (15.0 mL, 86.5 mmol) was added.

After stirring for 1 h at RT, the reaction mixture was diluted with EtOAc. The organic phase was washed successively with 10% HCl, saturated aqueous NaHCO3 and brine, then dried over MgSO4, filtered and concentrated under reduced pressure to afford (2S,5S)-ethyl 1-((S)- 2-(methoxycarbonylamino)methylbutanoyl)methylpyrrolidinecarboxylate. The crude material was carried on without further purification. (2S,5S)((S)(Methoxycarbonylamino)methylbutanoyl)methylpyrrolidine carboxylic acid (2S,5S)-Ethyl 1-((S)(methoxycarbonylamino)methylbutanoyl) methylpyrrolidinecarboxylate (39.3 mmol, assuming complete conversion from the us transformation) was suspended in MeOH (200 mL) and aqueous LiOH (1.0 M, 100 mL, 100 mmol) was added. The reaction mixture was stirred o/n, then concentrated under reduced pressure to remove most of the MeOH. The s solution was washed 2x with DCM before being acidified to pH~1-2 with 10% HCl. The acidic aqueous phase was then extracted 5x with EtOAc. The combined EtOAc extracts were dried over MgSO4 filtered and concentrated under reduced pressure to afford (2S,5S)((S)(Methoxycarbonylamino) butanoyl)methylpyrrolidinecarboxylic acid (6.89 g, 56% over 2 steps).

Example OF potassium O vinyltrifluoroborate, O O Pd(OAc)2, SPhos, K2CO3 O propanol (reflux) 3-chloro-10,11-dihydro-5H- 3-vinyl-10,11-dihydro-5H- dibenzo[c,g]chromen-8(9H)-one dibenzo[c,g]chromen-8(9H)-one O Boc 1. NBS HO2C N Cs2CO3 H2O/THF/DMSO O O + 2-Me-THF 2. MnO2, DCM Br 3-(2-bromoacetyl)-10,11-dihydro-5H- (2S,4S)(tert-butoxycarbonyl) o[c,g]chromen-8(9H)-one (methoxymethyl)pyrrolidine carboxylic acid MeO O pyridinium tribromide, O O O DCM/MeOH Boc O (2S,4S)tert-butyl 2-(2-oxo(8-oxo-8,9,10,11- tetrahydro-5H-dibenzo[c,g]chromenyl)ethyl) 4- (methoxymethyl)pyrrolidine-1,2-dicarboxylate NHCO2Me MeO O O O O + O N Cs2CO3 Boc O Br HO 2-MeTHF; 50 oC )(2-(9-bromooxo-8,9,10,11-tetrahydro-5H- (2S,5S)((S) dibenzo[c,g]chromenyl)oxoethyl) 1-tert-butyl 4- (methoxycarbonylamino) xymethyl)pyrrolidine-1,2-dicarboxylate methylbutanoyl)methylpyrrolidine carboxylic acid MeO2CHN H O H N N N N MnO2 N N DCM tert-butyl (2S,4S)[5-(2-{(2S,5S)[N-(methoxycarbonyl)-L- valyl]methylpyrrolidinyl}-1,4,5,11- tetrahydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl)- 1H-imidazolyl](methoxymethyl)pyrrolidinecarboxylate MeO2CHN H O H N 1. HCl/dioxane; DCM N N N N 2. HATU, DIPEA, DMF N O tert-butyl (2S,4S)[5-(2-{(2S,5S)[N-(methoxycarbonyl)-L- HO (2S,3S) (methoxycarbonylamino) valyl]methylpyrrolidinyl}-1,11- methylpentanoic acid dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl)- 1H-imidazolyl](methoxymethyl)pyrrolidinecarboxylate MeO2CHN H O H N N N N N N MeO2CHN O methyl {(2S,3S)[(2S,4S)(5-{2-[(2S,5S){(2S) [(methoxycarbonyl)amino]methylbutanoyl}methylpyrrolidinyl]-1,11- oisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl}-1H-imidazol yl)(methoxymethyl)pyrrolidinyl]methyloxopentanyl}carbamate 3-Vinyl-10,11-dihydro-5H-dibenzo[c,g]chromen-8(9H)-one A 3-neck oven-dried 500 mL round-bottom flask was cooled under Ar, then charged with 3-Chloro-10,11-dihydro-5H-dibenzo[c,g]chromen-8(9H)-one (12.0 g, 42.1 mmol), potassium vinyltrifluoroborate (8.47 g, 6.32 mmol), Pd(OAc)2 (473 mg, 2.11 mmol), SPhos (1.74 g, 4.25 mmol), K2CO3 (17.5 g, 126 mmol) and anhydrous ol (120 mL). The reaction mixture was d with Ar for 16 min, then heated to reflux for 5.5 h. Upon completion, the reaction mixture was cooled to RT and concentrated under reduced pressure.

The crude residue was suspended in DCM, then washed with H2O and brine. The organic on was dried over MgSO4, filtered and concentrated under reduced pressure. The resulting residue was further purified via silica plug, eluting with DCM to afford 3-vinyl- ,11-dihydro-5H-dibenzo[c,g]chromen-8(9H)-one (10.2 g, 87%). 3-(2-Bromoacetyl)-10,11-dihydro-5H-dibenzo[c,g]chromen-8(9H)-one 3-Vinyl-10,11-dihydro-5H-dibenzo[c,g]chromen-8(9H)-one (9.98 g, 36.1 mmol) was ved in a stirred solution of THF (70 mL), DMSO (70 mL) and H2O (35 mL). NBS (6.75 g, 37.9 mmol) was added in a single portion and the reaction mixture was stirred at RT for 33 min. Upon completion, the reaction medium was diluted with EtOAc and washed twice with H2O and once with brine. The organic phase was dried over MgSO4, filtered and concentrated under reduced pressure. The resulting crude bromohydrin was suspended in DCM (200 mL) and treated with ted MnO2 (62.7 g, 722 mmol). After stirring for 15 h at RT, the reaction mixture was filtered over celite and the filter cake was rinsed several times with DCM. The combined filtrate (~400 mL) was treated with MeOH (~100 mL) and the e was gradually concentrated under reduced pressure, causing solid material to precipitate from solution. When the liquid volume d ~200 mL, the solid was filtered off and rinsed with MeOH. The concentration/precipitation/filtration/rinsing ce was performed 2x more, resulting in the tion of 3 crops of powdered 3-(2-bromoacetyl)-10,11-dihydro-5H- dibenzo[c,g]chromen-8(9H)-one (7.49 g, 56% over 2 steps). (2S,4S)tert-Butyl 2-(2-oxo(8-oxo-8,9,10,11-tetrahydro-5H-dibenzo[c,g]chromen yl)ethyl) 4-(methoxymethyl)pyrrolidine-1,2-dicarboxylate 3-(2-Bromoacetyl)-10,11-dihydro-5H-dibenzo[c,g]chromen-8(9H)-one (7.47 g, 20.1 mmol) and (2S,4S)(tert-butoxycarbonyl)(methoxymethyl)pyrrolidinecarboxylic acid (5.22 g, 20.1 mmol) were suspended in 2-Me-THF (75 mL) and treated with Cs2CO3 (3.27 g, .1 mmol). After stirring 4 h at RT, the reaction mixture was diluted with DCM. The organic layer was washed with H2O. The aqueous layer was then back extracted 2x with DCM. The combined organics were dried over MgSO4, filtered and concentrated under reduced pressure. The crude residue was purified by silica column chromatography (10% to 50% EtOAc/DCM) to afford (2S,4S)tert-butyl 2-(2-oxo(8-oxo-8,9,10,11-tetrahydro- 5H-dibenzo[c,g]chromenyl)ethyl) 4-(methoxymethyl)pyrrolidine-1,2-dicarboxylate (7.73 g, 70%). )(2-(9-Bromooxo-8,9,10,11-tetrahydro-5H-dibenzo[c,g]chromenyl) oxoethyl) 1-tert-butyl 4-(methoxymethyl)pyrrolidine-1,2-dicarboxylate (2S,4S)tert-Butyl 2-(2-oxo(8-oxo-8,9,10,11-tetrahydro-5H- dibenzo[c,g]chromenyl)ethyl) 4-(methoxymethyl)pyrrolidine-1,2-dicarboxylate (7.66 g, 13.9 mmol) was ved in a solution of DCM (100 mL) and MeOH (40 mL), then treated with pyridinium tribromide (4.90 g, 15.3 mmol). After stirring at RT for 1.75 h, the reaction mixture was diluted with DCM and washed successively with 10% HCl, saturated aqueous NaHCO3 and brine. The organic phase was dried over MgSO4, filtered and concentrated under reduced pressure and the crude material was carried on t further purification. (2S,4S)tert-Butyl 2-(2-(9-((2S,5S)((S)(methoxycarbonylamino) methylbutanoyl)methylpyrrolidinecarbonyloxy)oxo-8,9,10,11-tetrahydro-5H- dibenzo[c,g]chromenyl)oxoethyl) 4-(methoxymethyl)pyrrolidine-1,2-dicarboxylate (2S,4S)(2-(9-Bromooxo-8,9,10,11-tetrahydro-5H-dibenzo[c,g]chromenyl) oxoethyl) 1-tert-butyl 4-(methoxymethyl)pyrrolidine-1,2-dicarboxylate (8.76 g, 13.94 mmol) was treated with a on of (2S,5S)((S)(methoxycarbonylamino)methylbutanoyl)- 5-methylpyrrolidinecarboxylic acid (6.85 g, 23.92 mmol) in 2-Me-THF (70 mL) and Cs2CO3 (3.63 g, 11.15 mmol). The stirred reaction mixture was heated to 50 ˚C for 20 h, then cooled to RT and diluted with EtOAc. The organic phase was washed with H2O and brine, then dried over MgSO4, filtered and concentrated under reduced pressure. The crude residue was ed by silica column chromatography (0% to 30% MeOH/EtOAc) to afford (2S,4S)butyl 2-(2-(9-((2S,5S)((S)(methoxycarbonylamino)methylbutanoyl) methylpyrrolidinecarbonyloxy)oxo-8,9,10,11-tetrahydro-5H-dibenzo[c,g]chromen yl)oxoethyl) 4-(methoxymethyl)pyrrolidine-1,2-dicarboxylate (10.47 g, 90%). tert-Butyl (2S,4S)[5-(2-{(2S,5S)[N-(methoxycarbonyl)-L-valyl]methylpyrrolidin- 2-yl}-1,4,5,11-tetrahydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl)-1H- olyl](methoxymethyl)pyrrolidinecarboxylate (2S,4S)tert-Butyl 2-(2-(9-((2S,5S)((S)(methoxycarbonylamino) methylbutanoyl)methylpyrrolidinecarbonyloxy)oxo-8,9,10,11-tetrahydro-5H- dibenzo[c,g]chromenyl)oxoethyl) 4-(methoxymethyl)pyrrolidine-1,2-dicarboxylate (10.47 g, 12.56 mmol) and NH4OAc (50.9 g, 660 mmol) were suspended in a solution of 10:1 -methoxyethanol (132 mL). The stirred on mixture was heated to 110 ˚C for 4.5 h, then cooled to RT and diluted with EtOAc. The organic phase was washed 3x with saturated aqueous NaHCO3, then dried over MgSO4, filtered and trated under reduced pressure. The crude residue was purified by silica column chromatography (0% to 30% MeOH/EtOAc) to afford tert-butyl (2S,4S)[5-(2-{(2S,5S)[N-(methoxycarbonyl)-L- valyl]methylpyrrolidinyl}-1,4,5,11-tetrahydroisochromeno[4',3':6,7]naphtho[1,2- d]imidazolyl)-1H-imidazolyl](methoxymethyl)pyrrolidinecarboxylate (8.33 g, 84%). tert-Butyl (2S,4S)[5-(2-{(2S,5S)[N-(methoxycarbonyl)-L-valyl]methylpyrrolidin- 2-yl}-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl)-1H-imidazol yl](methoxymethyl)pyrrolidinecarboxylate tert-Butyl (2S,4S)[5-(2-{(2S,5S)[N-(methoxycarbonyl)-L-valyl] methylpyrrolidinyl}-1,4,5,11-tetrahydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazol yl)-1H-imidazolyl](methoxymethyl)pyrrolidinecarboxylate (8.33 g, 1.049 mmol) was suspended in DCM and activated MnO2 (55.0 g, 630 mmol) was added in a single portion. After 13 h, MeOH (200 mL) was added and the slurry was ed over celite. The filter cake was washed with MeOH (600 mL) and the filtrate was concentrated under reduced pressure. The crude material was purified by silica column chromatography (0% to 45% tOAc) to afford tert-butyl )[5-(2-{(2S,5S)[N-(methoxycarbonyl)-L- valyl]methylpyrrolidinyl}-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazol- 9-yl)-1H-imidazolyl](methoxymethyl)pyrrolidinecarboxylate (4.85 g, 58%).

Methyl {(2S,3S)[(2S,4S)(5-{2-[(2S,5S){(2S)[(methoxycarbonyl)amino] methylbutanoyl}methylpyrrolidinyl]-1,11- dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl}-1H-imidazolyl) (methoxymethyl)pyrrolidinyl]methyloxopentanyl}carbamate tert-Butyl (2S,4S)[5-(2-{(2S,5S)[N-(methoxycarbonyl)-L-valyl] methylpyrrolidinyl}-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl)-1H- imidazolyl](methoxymethyl)pyrrolidinecarboxylate (179 mg, 0.226 mmol) was dissolved in DCM (4 mL) and HCl (4.0 M in dioxane, 1 mL) was added. The reaction mixture was stirred for 1 h at RT then trated under reduced pressure. The resulting residue was treated with (2S,3S)(methoxycarbonylamino)methylpentanoic acid (51 mg, 0.27 mmol), HATU (95 mg, 0.25 mmol), DMF (2 mL) and DIPEA (0.39 mL, 2.3 mmol).

After stirring for 6 min, the reaction was quenched with H2O, filtered and purified by reverse phase HPLC to afford methyl S)[(2S,4S)(5-{2-[(2S,5S){(2S) [(methoxycarbonyl)amino]methylbutanoyl}methylpyrrolidinyl]-1,11- dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl}-1H-imidazolyl) (methoxymethyl)pyrrolidinyl]methyloxopentanyl}carbamate (116 mg, 59%). MS (ESI) m/z 864 [M + H]+. 1H NMR (400 MHz, cd 3od) δ 8.57 (d, J = 14.7 Hz, 1H), 8.45 (s, 1H), 8.20 (d, J = 14.4 Hz, 1H), 8.15 – 7.98 (m, 2H), 7.91 (dd, J = 21.8, 14.1 Hz, 2H), 7.85 – 7.69 (m, 2H), 7.69 – 7.48 (m, 2H), 5.42 – 5.12 (m, 5H), 4.34 (dd, J = 22.3, 13.7 Hz, 1H), 4.30 – 4.10 (m, 2H), 3.87 – 3.73 (m, 1H), 3.73 – 3.63 (m, 7H), 3.62 – 3.48 (m, 2H), 3.48 – 3.38 (m, 4H), 3.35 (s, 3H), 2.95 – 2.70 (m, 1H), 2.70 – 2.55 (m, 2H), 2.55 – 2.20 (m, 2H), 2.20 – 1.91 (m, 3H), 1.77 (d, J = 42.0 Hz, 1H), 1.65 (d, J = 6.6 Hz, 3H), 1.43 (t, J = 24.6 Hz, 1H), 1.28 (d, J = 6.2 Hz, 1H), 1.23 – 1.01 (m, 3H), 0.98 (d, J = 6.6 Hz, 3H), 0.90 (dd, J = 13.1, 5.9 Hz, 10H).

Example OG Methyl {(2S)[(2S,5S)(9-{2-[(2S,4S)[N-(methoxycarbonyl)-L-alloisoleucyl]- 4-(methoxymethyl)pyrrolidinyl]-1H-imidazolyl}-1,11- dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl)methylpyrrolidinyl] methyloxobutanyl}carbamate was ed from tert-butyl (2S,4S)[5-(2-{(2S,5S) [N-(methoxycarbonyl)-L-valyl]methylpyrrolidinyl}-1,11- dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl)-1H-imidazolyl] (methoxymethyl)pyrrolidinecarboxylate by the same method employed in the synthesis of methyl {(2S,3S)[(2S,4S)(5-{2-[(2S,5S){(2S)[(methoxycarbonyl)amino] methylbutanoyl}methylpyrrolidinyl]-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2- d]imidazolyl}-1H-imidazolyl)(methoxymethyl)pyrrolidinyl]methyl oxopentanyl}carbamate, replacing (2S,3S)(methoxycarbonylamino)methylpentanoic acid with (2S,3R)(methoxycarbonylamino)methylpentanoic acid. MS (ESI) m/z 864 [M + H]+. 1H NMR (400 MHz, cd 3od) δ 8.62 – 8.41 (m, 1H), 8.22 (s, 1H), 8.07 (dt, J = 20.1, 10.0 Hz, 1H), 7.89 (dt, J = 35.6, 15.6 Hz, 2H), 7.77 (dd, J = 20.3, 7.0 Hz, 2H), 7.68 – 7.48 (m, 2H), 5.95 (d, J = 5.0 Hz, 1H), 5.42 – 5.13 (m, 4H), 4.47 (t, J = 5.5 Hz, 1H), 4.40 – 4.09 (m, 2H), 3.80 – 3.73 (m, 1H), 3.73 – 3.62 (m, 6H), 3.57 (dt, J = 16.1, 9.7 Hz, 2H), 3.40 (s, 3H), 3.34 (d, J = 7.5 Hz, 1H), 2.81 (dd, J = 18.4, 12.5 Hz, 1H), 2.63 (td, J = 13.3, 6.8 Hz, 2H), 2.55 – 2.18 (m, 2H), 2.16 – 1.77 (m, 4H), 1.65 (d, J = 6.6 Hz, 3H), 1.50 – 1.31 (m, 1H), 1.26 (dd, J = 15.6, 6.7 Hz, 2H), 1.17 – 1.03 (m, 2H), 0.98 (dd, J = 6.7, 4.5 Hz, 5H), 0.89 (dd, J = 15.5, 7.8 Hz, 3H), 0.86 – 0.74 (m, 3H).

Example OH MeO2CHN H H N 1. HCl/dioxane; DCM N N N Boc 2. COMU, DIPEA, DMF N N O NHCO2Me tert-butyl (2S,4S)[5-(2-{(2S,5S)[N-(methoxycarbonyl)-L- valyl]methylpyrrolidinyl}-1,4,5,11- Ph tetrahydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl)-1H- imidazolyl](methoxymethyl)pyrrolidinecarboxylate (R) (methoxycarbonylamino) phenylacetic acid MeO2CHN H H N Ph N N N N N MeO2CHN O methyl {(1R)[(2S,4S)(5-{2-[(2S,5S){(2S)[(methoxycarbonyl)amino] methylbutanoyl}methylpyrrolidinyl]-1,4,5,11-tetrahydroisochromeno[4',3':6,7]naphtho[1,2- d]imidazolyl}-1H-imidazolyl)(methoxymethyl)pyrrolidinyl]oxo phenylethyl}carbamate Methyl 2-[(2S,4S)(5-{2-[(2S,5S){(2S)[(methoxycarbonyl)amino] methylbutanoyl}methylpyrrolidinyl]-1,4,5,11- tetrahydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl}-1H-imidazolyl) (methoxymethyl)pyrrolidinyl]oxophenylethyl}carbamate tert-Butyl )[5-(2-{(2S,5S)[N-(methoxycarbonyl)-L-valyl] methylpyrrolidinyl}-1,4,5,11-tetrahydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazol yl)-1H-imidazolyl](methoxymethyl)pyrrolidinecarboxylate (102 mg, 0.128 mmol) was dissolved in DCM (4 mL) and HCl (4.0 M in dioxane, 2.0 mL, 8.0 mmol) was added.

After stirring at RT for 30 min, the solution was concentrated under reduced re. The residue was treated with (R)(methoxycarbonylamino)phenylacetic acid (29 mg, 0.141 mmol), COMU (60 mg, 0.141 mmol), DMF (3.0 mL) and DIPEA (0.223 mL, 1.28 mmol).

After stirring at RT for 20 min, the reaction mixture was diluted with EtOAc. The c solution was washed with saturated aqueous NaHCO3 and brine, then dried over MgSO4, filtered and concentrated under reduced pressure. The crude material was ed by reversephase HPLC to afford methyl {(1R)[(2S,4S)(5-{2-[(2S,5S){(2S) [(methoxycarbonyl)amino]methylbutanoyl}methylpyrrolidinyl]-1,4,5,11- tetrahydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl}-1H-imidazolyl) (methoxymethyl)pyrrolidinyl]oxophenylethyl}carbamate as the bis-TFA salt (82.4 mg, 60%). MS (ESI) m/z 866 [M + H]+. 1H NMR (400 MHz, cd 3od) δ 7.94 – 7.67 (m, 4H), 7.59 (d, J = 9.1 Hz, 1H), 7.52 (s, 1H), 7.48 – 7.33 (m, 4H), 7.11 (d, J = 18.7 Hz, 1H), 5.68 (d, J = 6.3 Hz, 1H), 5.48 – 5.33 (m, 1H), 5.23 (dd, J = 24.1, 15.7 Hz, 1H), 5.17 – 5.03 (m, 3H), 4.22 (dd, J = 17.0, 9.6 Hz, 1H), 4.16 – 4.01 (m, 1H), 3.91 (d, J = 24.1 Hz, 1H), 3.83 – 3.68 (m, 1H), 3.68 – 3.59 (m, 3H), 3.59 – 3.49 (m, 3H), 3.38 (ddd, J = 15.9, 9.6, 5.7 Hz, 2H), 3.28 – 3.14 (m, 5H), 3.10 (dd, J = 14.0, 8.2 Hz, 1H), 3.00 (dd, J = 17.8, 9.6 Hz, 1H), 2.92 (dd, J = 14.5, 6.7 Hz, 1H), 2.73 – 2.41 (m, 2H), 2.40 – 2.11 (m, 2H), 2.11 – 1.83 (m, 2H), 1.54 (t, J = 9.7 Hz, 2H), 1.24 (d, J = 6.2 Hz, 1H), 1.06 (t, J = 8.0 Hz, 1H), 0.99 (d, J = 6.8 Hz, 1H), 0.94 (d, J = 6.6 Hz, 2H), 0.85 (d, J = 6.7 Hz, 2H).

Example OI MeO O O O O Boc O Br (2S,4S)(2-(9-bromooxo-8,9,10,11- tetrahydro-5H-dibenzo[c,g]chromenyl) oxoethyl) 1-tert-butyl 4- MeO (methoxymethyl)pyrrolidine-1,2-dicarboxylate H O H BocN N N 1. HCl/dioxane; DCM N OMe N 2. HATU, DIPEA, DMF N O NHCO2Me utyl )(5-{2-[(2S,4S)(tert-butoxycarbonyl) HO (S) (methoxymethyl)pyrrolidinyl]-1,11- (methoxycarbonylamino) dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl}-1H- hylbutanoic acid imidazolyl)(methoxymethyl)pyrrolidinecarboxylate MeO2CHN H O H N N N N OMe N N MeO2CHN O methyl {(2S)[(2S,4S)(5-{2-[(2S,4S){(2S)[(methoxycarbonyl)amino]methylbutanoyl}- 4-(methoxymethyl)pyrrolidinyl]-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl}- 1H-imidazolyl)(methoxymethyl)pyrrolidinyl]methyloxobutanyl}carbamate tert-Butyl (2S,4S)(5-{2-[(2S,4S)(tert-butoxycarbonyl) (methoxymethyl)pyrrolidinyl]-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazol- 9-yl}-1H-imidazolyl)(methoxymethyl)pyrrolidinecarboxylate was prepared from (2S,4S)(2-(9-bromooxo-8,9,10,11-tetrahydro-5H-dibenzo[c,g]chromenyl) oxoethyl) 1-tert-butyl 4-(methoxymethyl)pyrrolidine-1,2-dicarboxylate by the same method employed in the synthesis of tert-butyl (2S,4S)[5-(2-{(2S,5S)[N-(methoxycarbonyl)-L- valyl]methylpyrrolidinyl}-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazol- 9-yl)-1H-imidazolyl](methoxymethyl)pyrrolidinecarboxylate, replacing (2S,5S) -(methoxycarbonylamino)methylbutanoyl)methylpyrrolidinecarboxylic acid with (2S,4S)(tert-butoxycarbonyl)(methoxymethyl)pyrrolidinecarboxylic acid.

Methyl {(2S)[(2S,4S)(5-{2-[(2S,4S){(2S)[(methoxycarbonyl)amino] methylbutanoyl}(methoxymethyl)pyrrolidinyl]-1,11- dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl}-1H-imidazolyl) (methoxymethyl)pyrrolidinyl]methyloxobutanyl}carbamate tert-Butyl (2S,4S)(5-{2-[(2S,4S)(tert-butoxycarbonyl) (methoxymethyl)pyrrolidinyl]-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazol- 9-yl}-1H-imidazolyl)(methoxymethyl)pyrrolidinecarboxylate (137 mg, 0.179 mmol) was ved in DCM (5 mL) and HCl (4.0 M in dioxane, 1 mL) was added. After stirring at RT for 1.5 h, the on mixture was concentrated under reduced pressure. The crude residue was treated with (S)(methoxycarbonylamino)methylbutanoic acid (69 mg, 0.39 mmol), HATU (149 mg, 0.393 mmol), DMF (2.0 mL) and DIPEA (0.31 mL, 1.8 mmol).

After stirring for 15 min at RT, the reaction e was quenched with water and purified by HPLC to provide methyl {(2S)[(2S,4S)(5-{2-[(2S,4S){(2S) [(methoxycarbonyl)amino]methylbutanoyl}(methoxymethyl)pyrrolidinyl]-1,11- dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl}-1H-imidazolyl) (methoxymethyl)pyrrolidinyl]methyloxobutanyl}carbamate (123 mg). MS (ESI) m/z 880 [M + H]+. 1H NMR (400 MHz, cd 3od) δ 8.48 (s, 1H), 8.05 (t, J = 11.2 Hz, 1H), 7.92 (dd, J = 19.7, 10.1 Hz, 2H), 7.74 (s, 2H), 7.59 – 7.44 (m, 2H), 5.49 (s, 1H), 5.40 (dt, J = 16.3, 8.1 Hz, 1H), 5.31 – 5.15 (m, 3H), 4.47 – 4.10 (m, 4H), 3.86 – 3.44 (m, 12H), 3.39 (dd, J = 13.2, 7.1 Hz, 6H), 2.94 – 2.57 (m, 4H), 2.25 – 1.94 (m, 4H), 1.02 – 0.82 (m, 12H).

Example OJ Methyl {(2S,3S)[(2S,4S)(5-{2-[(2S,4S){(2S,3S) [(methoxycarbonyl)amino]methylpentanoyl}(methoxymethyl)pyrrolidinyl]-1,11- dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl}-1H-imidazolyl) (methoxymethyl)pyrrolidinyl]methyloxopentanyl}carbamate was prepared from tert-Butyl (2S,4S)(5-{2-[(2S,4S)(tert-butoxycarbonyl)(methoxymethyl)pyrrolidin yl]-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl}-1H-imidazolyl) (methoxymethyl)pyrrolidinecarboxylate using the same method employed in the synthesis of methyl {(2S)[(2S,4S)(5-{2-[(2S,4S){(2S)[(methoxycarbonyl)amino] methylbutanoyl}(methoxymethyl)pyrrolidinyl]-1,11- dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl}-1H-imidazolyl) (methoxymethyl)pyrrolidinyl]methyloxobutanyl}carbamate, replacing with (S) (methoxycarbonylamino)methylbutanoic acid with (2S,3S)(methoxycarbonylamino) methylpentanoic acid. MS (ESI) m/z 908 [M + H]+.

Example OK MeO O O O O Boc O Br (2S,4S)(2-(9-bromooxo-8,9,10,11- tetrahydro-5H-dibenzo[c,g]chromenyl) oxoethyl) 1-tert-butyl 4- (methoxymethyl)pyrrolidine-1,2-dicarboxylate MeO2CHN O 1. HCl/dioxane; DCM H O H N N N N 2. COMU, DIPEA, DMF N O NHCO2Me tert-butyl )[5-(2-{(2S)[N- (methoxycarbonyl)-L-valyl]pyrrolidinyl}-1,4,5,11- Ph tetrahydroisochromeno[4',3':6,7]naphtho[1,2- (R) d]imidazolyl)-1H-imidazolyl] (methoxycarbonylamino) (methoxymethyl)pyrrolidinecarboxylate phenylacetic acid H O H N Ph N N N N N MeO2CHN O methyl {(1R)[(2S,4S)(5-{2-[(2S){(2S)[(methoxycarbonyl)amino] methylbutanoyl}pyrrolidinyl]-1,4,5,11- tetrahydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl}-1H-imidazol yl)(methoxymethyl)pyrrolidinyl]oxophenylethyl}carbamate tert-Butyl (2S,4S)[5-(2-{(2S)[N-(methoxycarbonyl)-L-valyl]pyrrolidinyl}- 1,4,5,11-tetrahydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl)-1H-imidazolyl] (methoxymethyl)pyrrolidinecarboxylate was sized from (2S,4S)(2-(9-bromo oxo-8,9,10,11-tetrahydro-5H-dibenzo[c,g]chromenyl)oxoethyl) 1-tert-butyl 4- (methoxymethyl)pyrrolidine-1,2-dicarboxylate using the same methods described for the synthesis of tert-butyl (2S,4S)[5-(2-{(2S,5S)[N-(methoxycarbonyl)-L-valyl] methylpyrrolidinyl}-1,4,5,11-tetrahydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazol yl)-1H-imidazolyl](methoxymethyl)pyrrolidinecarboxylate, substituting (S)((S)- 2-(methoxycarbonylamino)methylbutanoyl)pyrrolidinecarboxylic acid for ) ((S)(methoxycarbonylamino)methylbutanoyl)methylpyrrolidinecarboxylic acid.

Methyl {(1R)[(2S,4S)(5-{2-[(2S){(2S)[(methoxycarbonyl)amino] methylbutanoyl}pyrrolidinyl]-1,4,5,11-tetrahydroisochromeno[4',3':6,7]naphtho[1,2- d]imidazolyl}-1H-imidazolyl)(methoxymethyl)pyrrolidinyl]oxo ethyl}carbamate was synthesized from tert-butyl (2S,4S)[5-(2-{(2S)[N- (methoxycarbonyl)-L-valyl]pyrrolidinyl}-1,4,5,11- tetrahydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl)-1H-imidazolyl] (methoxymethyl)pyrrolidinecarboxylate using the same method employed for the sis of methyl {(1R)[(2S,4S)(5-{2-[(2S,5S){(2S)[(methoxycarbonyl)amino]- 3-methylbutanoyl}methylpyrrolidinyl]-1,4,5,11- tetrahydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl}-1H-imidazolyl) (methoxymethyl)pyrrolidinyl]oxophenylethyl}carbamate substituting tert-butyl (2S,4S)[5-(2-{(2S)[N-(methoxycarbonyl)-L-valyl]pyrrolidinyl}-1,4,5,11- tetrahydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl)-1H-imidazolyl] (methoxymethyl)pyrrolidinecarboxylate for tert-Butyl (2S,4S)[5-(2-{(2S,5S)[N- (methoxycarbonyl)-L-valyl]methylpyrrolidinyl}-1,4,5,11- tetrahydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl)-1H-imidazolyl] (methoxymethyl)pyrrolidinecarboxylate. MS (ESI) m/z 871 [M + H]+. 1H NMR (400 MHz, cd3od) δ 7.87 (ddd, J = 20.5, 15.3, 6.8 Hz, 4H), 7.65 (s, 1H), 7.50 – 7.38 (m, 5H), 7.17 (s, 1H), 5.41 (d, J = 24.5 Hz, 1H), 5.28 (t, J = 8.3 Hz, 1H), 5.20 (d, J = 7.3 Hz, 3H), 4.24 (d, J = 7.2 Hz, 1H), 4.12 (d, J = 10.3 Hz, 1H), 4.03 – 3.94 (m, 1H), 3.89 (dd, J = 15.4, 8.6 Hz, 1H), 3.77 (t, J = 9.6 Hz, 1H), 3.72 – 3.64 (m, 4H), 3.63 – 3.52 (m, 4H), 3.43 (qd, J = 9.5, 5.6 Hz, 3H), 3.30 (s, 3H), 3.24 – 3.08 (m, 2H), 2.97 (dd, J = 11.6, 5.4 Hz, 2H), 2.59 (dt, J = 21.1, 7.8 Hz, 3H), 2.29 (s, 1H), 2.24 – 2.14 (m, 2H), 2.11 – 1.85 (m, 2H), 0.92 (dd, J = 15.8, 6.7 Hz, 6H).

Example OL tert-Butyl (2S,4S)[5-(2-{(2S)[N-(methoxycarbonyl)-L-valyl]pyrrolidinyl}- 1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl)-1H-imidazolyl] (methoxymethyl)pyrrolidinecarboxylate was prepared according to the method described for the synthesis of tert-butyl (2S,4S)[5-(2-{(2S,5S)[N-(methoxycarbonyl)-L-valyl] methylpyrrolidinyl}-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl)-1H- imidazolyl](methoxymethyl)pyrrolidinecarboxylate, substituting tert-butyl (2S,4S)- 2-{(2S)[N-(methoxycarbonyl)-L-valyl]pyrrolidinyl}-1,11- dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl)-1H-imidazolyl] (methoxymethyl)pyrrolidinecarboxylate for tert-Butyl (2S,4S)[5-(2-{(2S,5S)[N- (methoxycarbonyl)-L-valyl]methylpyrrolidinyl}-1,4,5,11- tetrahydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl)-1H-imidazolyl] (methoxymethyl)pyrrolidinecarboxylate.

Methyl 1-[(2S)(9-{2-[(2S,4S)[(2R)aminophenylacetyl] (methoxymethyl)pyrrolidinyl]-1H-imidazolyl}-1,11- dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl)pyrrolidinyl]methyl oxobutanyl}carbamate was prepared according to the method described for the synthesis of methyl (S)((2S,4S)(2'-((2S,4S)((R)aminophenylacetyl) (methoxymethyl)pyrrolidinyl)-1H,1'H-7,7'-binaphtho[1,2-d]imidazolyl) methylpyrrolidinyl)methyloxobutanylcarbamate, substituting methyl (S) ((2S,4S)(2'-((2S,4S)((R)tert-butoxycarbonylaminophenylacetyl) (methoxymethyl)pyrrolidinyl)-1H,1'H-7,7'-binaphtho[1,2-d]imidazolyl) methylpyrrolidinyl)methyloxobutanylcarbamate with utyl (2S,4S)[5-(2-{(2S)[N-(methoxycarbonyl)-L-valyl]pyrrolidinyl}- 1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl)-1H-imidazolyl] (methoxymethyl)pyrrolidinecarboxylate. MS (ESI) m/z 811 [M + H]+.

Example OM O O 3-(2-bromoacetyl)-10,11-dihydro- 5H-dibenzo[c,g]chromen-8(9H)-one H O H N N N N OMe MnO2 N N DCM MeO2CHN O tert-butyl (2S,4S)[9-(2-{(2S,5S)[N-(methoxycarbonyl)-L-valyl] methylpyrrolidinyl}-1H-imidazolyl)-1,4,5,11- ydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl] (methoxymethyl)pyrrolidinecarboxylate H O H N N N N OMe 1. HCl/dioxane; DCM N N 2. HATU, DIPEA, DMF MeO2CHN O O NHCO2Me tert-butyl (2S,4S)[9-(2-{(2S,5S)[N-(methoxycarbonyl)- HO (2S,3R) L-valyl]methylpyrrolidinyl}-1H-imidazolyl)-1,11- O methoxy dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl]- (methoxycarbonyla 4-(methoxymethyl)pyrrolidinecarboxylate utanoic acid MeO2CHN O H O H N N N N OMe N N MeO2CHN O methyl {(2S)[(2S,4S)(5-{2-[(2S,5S){(2S,3R)methoxy [(methoxycarbonyl)amino]butanoyl}(methoxymethyl)pyrrolidinyl]- 1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl}-1H- imidazolyl)methylpyrrolidinyl]methyloxobutanyl}carbamate tert-Butyl (2S,4S)[9-(2-{(2S,5S)[N-(methoxycarbonyl)-L-valyl] pyrrolidinyl}-1H-imidazolyl)-1,4,5,11- tetrahydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl] (methoxymethyl)pyrrolidinecarboxylate was synthesized from romoacetyl)-10,11- dihydro-5H-dibenzo[c,g]chromen-8(9H)-one, by the same methods employed in the synthesis of tert-butyl (2S,4S)[5-(2-{(2S,5S)[N-(methoxycarbonyl)-L-valyl]methylpyrrolidin- 2-yl}-1,4,5,11-tetrahydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl)-1H-imidazol yl](methoxymethyl)pyrrolidinecarboxylate, substituting (2S,5S)((S) (methoxycarbonylamino)methylbutanoyl)methylpyrrolidinecarboxylic acid for (2S,4S)(tert-butoxycarbonyl)(methoxymethyl)pyrrolidinecarboxylic acid and (2S,4S)(tert-butoxycarbonyl)(methoxymethyl)pyrrolidinecarboxylic acid for (2S,5S)((S)(methoxycarbonylamino)methylbutanoyl)methylpyrrolidine carboxylic acid. tert-Butyl (2S,4S)[9-(2-{(2S,5S)[N-(methoxycarbonyl)-L-valyl] methylpyrrolidinyl}-1H-imidazolyl)-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2- d]imidazolyl](methoxymethyl)pyrrolidinecarboxylate was prepared ing to the method described for the synthesis of tert-butyl (2S,4S)[5-(2-{(2S,5S)[N- (methoxycarbonyl)-L-valyl]methylpyrrolidinyl}-1,11- oisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl)-1H-imidazolyl] (methoxymethyl)pyrrolidinecarboxylate, tuting tert-butyl (2S,4S)[9-(2-{(2S,5S)- 1-[N-(methoxycarbonyl)-L-valyl]methylpyrrolidinyl}-1H-imidazolyl)-1,4,5,11- tetrahydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl] (methoxymethyl)pyrrolidinecarboxylate for tert-butyl (2S,4S)[5-(2-{(2S,5S)[N- (methoxycarbonyl)-L-valyl]methylpyrrolidinyl}-1,4,5,11- tetrahydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl)-1H-imidazolyl] (methoxymethyl)pyrrolidinecarboxylate.

Methyl {(2S)[(2S,4S)(5-{2-[(2S,5S){(2S,3R)methoxy [(methoxycarbonyl)amino]butanoyl}(methoxymethyl)pyrrolidinyl]-1,11- dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl}-1H-imidazolyl) methylpyrrolidinyl]methyloxobutanyl}carbamate was prepared from utyl (2S,4S)[9-(2-{(2S,5S)[N-(methoxycarbonyl)-L-valyl]methylpyrrolidinyl}-1H- imidazolyl)-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl] (methoxymethyl)pyrrolidinecarboxylate according to the same method described for the synthesis of methyl (S)((2S,4S)(2'-((2S,4S)((2S,3R)methoxycarbonylamino methoxybutanoyl)(methoxymethyl)pyrrolidinyl)-1H,1'H-7,7'-binaphtho[1,2-d]imidazol- 2-yl)methylpyrrolidinyl)methyloxobutanylcarbamate, substituting (2S,4S)-tert- Butyl 2-(2'-((2S,4S)((S)(methoxycarbonylamino)methylbutanoyl) pyrrolidinyl)-1H,1'H-7,7'-binaphtho[1,2-d]imidazolyl) (methoxymethyl)pyrrolidinecarboxylate with tert-butyl (2S,4S)[9-(2-{(2S,5S)[N- (methoxycarbonyl)-L-valyl]methylpyrrolidinyl}-1H-imidazolyl)-1,11- dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl](methoxymethyl)pyrrolidine carboxylate. MS (ESI) m/z 866 [M + H]+. 1H NMR (400 MHz, cd 3od) δ 8.44 (d, J = 19.8 Hz, 1H), 8.02 (t, J = 8.6 Hz, 2H), 7.98 – 7.81 (m, 3H), 7.74 (dd, J = 22.2, 13.6 Hz, 2H), 7.63 – 7.41 (m, 2H), 5.79 (d, J = 6.0 Hz, 1H), 5.42 (dt, J = 43.3, 21.5 Hz, 2H), 5.31 – 5.10 (m, 5H), 4.85 – 4.70 (m, 1H), 4.52 (d, J = 3.8 Hz, 1H), 4.31 (t, J = 8.2 Hz, 1H), 4.17 (dd, J = 20.8, 8.8 Hz, 1H), 3.80 (dt, J = 19.0, 7.3 Hz, 2H), 3.73 – 3.63 (m, 7H), 3.63 – 3.49 (m, 3H), 3.39 (d, J = 9.7 Hz, 4H), 3.35 (s, 5H), 3.28 (d, J = 4.4 Hz, 3H), 2.84 (d, J = 8.8 Hz, 1H), 2.72 (dd, J = 12.5, 6.6 Hz, 1H), 2.59 – 2.45 (m, 1H), 2.45 – 2.11 (m, 4H), 2.11 – 1.82 (m, 2H), 1.56 (d, J = 6.6 Hz, 3H), 1.35 – 1.21 (m, 1H), 1.22 – 1.12 (m, 4H), 1.10 – 1.01 (m, 2H), 0.99 (d, J = 6.6 Hz, 3H), 0.91 (d, J = 6.7 Hz, 3H).

Example ON Methyl {(2S)[(2S,4S)(5-{2-[(2S,5S){(2S,3S)[(methoxycarbonyl)amino]- 3-methylpentanoyl}(methoxymethyl)yl]-1,11- dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl}-1H-imidazolyl) methylpyrrolidinyl]methyloxobutanyl}carbamate was prepared according to the method described for the synthesis of methyl {(2S,3S)[(2S,4S)(5-{2-[(2S,4S) {(2S,3S)[(methoxycarbonyl)amino]methylpentanoyl}(methoxymethyl)pyrrolidin 11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl}-1H-imidazolyl) (methoxymethyl)pyrrolidinyl]methyloxopentanyl}carbamate substituting tertbutyl (2S,4S)[9-(2-{(2S)[N-(methoxycarbonyl)-L-valyl]pyrrolidinyl}-1H-imidazol- 5-yl)-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl] (methoxymethyl)pyrrolidinecarboxylate for tert-Butyl )[5-(2-{(2S,5S)[N- (methoxycarbonyl)-L-valyl]methylpyrrolidinyl}-1,11- dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl)-1H-imidazolyl] (methoxymethyl)pyrrolidinecarboxylate. MS (ESI) m/z 863 [M + H]+. 1H NMR (400 MHz, cd3od) δ 8.43 (d, J = 24.6 Hz, 1H), 8.01 (dt, J = 16.1, 8.0 Hz, 1H), 7.95 – 7.78 (m, 2H), 7.77 – 7.64 (m, 2H), 7.59 – 7.41 (m, 2H), 5.79 (d, J = 5.8 Hz, 1H), 5.39 (dt, J = 46.2, 23.1 Hz, 1H), 5.27 – 5.07 (m, 3H), 4.85 – 4.72 (m, 1H), 4.42 (t, J = 8.6 Hz, 1H), 4.31 (d, J = 7.9 Hz, 1H), 4.17 (dd, J = 19.7, 8.7 Hz, 1H), 3.81 (dd, J = 23.6, 13.3 Hz, 1H), 3.69 (d, J = 10.0 Hz, 5H), 3.60 (dd, J = 14.7, 7.8 Hz, 2H), 3.42 (s, 3H), 3.17 (d, J = 6.1 Hz, 1H), 3.07 (s, 1H), 2.99 – 2.91 (m, 1H), 2.85 (s, 1H), 2.73 (dd, J = 12.5, 6.4 Hz, 1H), 2.62 – 2.48 (m, 1H), 2.45 – 2.14 (m, 3H), 2.10 – 1.91 (m, 2H), 1.83 (s, 1H), 1.57 (d, J = 6.6 Hz, 3H), 1.44 (d, J = 7.4 Hz, 1H), 1.34 – 1.23 (m, 1H), 1.20 – 0.96 (m, 5H), 0.90 (dt, J = 14.8, 6.7 Hz, 9H).

Example OO O 1. HCl/dioxane; DCM H H N N N N OMe 2. COMU, DIPEA, DMF N N O MeO2CHN O NHBoc HO (R)(tertbutoxycarbonylamino ) utyl (2S,4S)[9-(2-{(2S)[N-(methoxycarbonyl)-L- Ph phenylacetic acid valyl]pyrrolidinyl}-1H-imidazolyl)-1,11- dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl] (methoxymethyl)pyrrolidinecarboxylate BocHN H O 1. HCl/dioxane; DCM H N N N N OMe N N MeO2CHN O methyl {(2S)[(2S)(5-{2-[(2S,4S){(2R)[(tertbutoxycarbonyl )amino]phenylacetyl}(methoxymethyl)pyrrolidinyl]- 1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl}-1H- imidazolyl)pyrrolidinyl]methyloxobutanyl}carbamate H O H N N N N OMe N N MeO2CHN O methyl {(2S)[(2S)(5-{2-[(2S,4S)[(2R)aminophenylacetyl] xymethyl)pyrrolidinyl]-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2- d]imidazolyl}-1H-imidazolyl)pyrrolidinyl]methyloxobutanyl}carbamate Methyl {(2S)[(2S)(5-{2-[(2S,4S)[(2R)aminophenylacetyl] (methoxymethyl)pyrrolidinyl]-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazol- 9-yl}-1H-imidazolyl)pyrrolidinyl]methyloxobutanyl}carbamate was prepared according to the method described for the synthesis of methyl (S)((2S,4S)(2'-((2S,4S)- 1-((R)aminophenylacetyl)(methoxymethyl)pyrrolidinyl)-1H,1'H-7,7'- binaphtho[1,2-d]imidazolyl)methylpyrrolidinyl)methyloxobutan ylcarbamate, substituting utyl (2S,4S)[9-(2-{(2S)[N-(methoxycarbonyl)-L- valyl]pyrrolidinyl}-1H-imidazolyl)-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2- d]imidazolyl](methoxymethyl)pyrrolidinecarboxylate for (2S,4S)-tert-butyl 2-(2'- ((2S,4S)((S)(methoxycarbonylamino)methylbutanoyl)methylpyrrolidinyl)- 1H,1'H-7,7'-binaphtho[1,2-d]imidazolyl)(methoxymethyl)pyrrolidinecarboxylate.

MS (ESI) m/z 811 [M + H]+.

Example OP Boc 1. HCl/dioxane; DCM H O H N N 2. COMU, DIPEA, DMF N N N O O NHCO2Me NHCO2Me tert-butyl (2S,4S)[9-(2-{(2S,5S)[N-(methoxycarbonyl)- (R) L-valyl]methylpyrrolidinyl}-1H-imidazolyl)-1,4,5,11- xycarbonylamino) ydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazol phenylacetic acid yl](methoxymethyl)pyrrolidinecarboxylate MeO2CHN O Ph H O H N N N N N NHCO2Me methyl {(1R)[(2S,4S)(9-{2-[(2S,5S){(2S)[(methoxycarbonyl)amino]- 3-methylbutanoyl}methylpyrrolidinyl]-1H-imidazolyl}-1,4,5,11- tetrahydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl) (methoxymethyl)pyrrolidinyl]oxophenylethyl}carbamate Methyl {(1R)[(2S,4S)(9-{2-[(2S,5S){(2S)[(methoxycarbonyl)amino] methylbutanoyl}methylpyrrolidinyl]-1H-imidazolyl}-1,4,5,11- tetrahydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl)(methoxymethyl)pyrrolidin- 1-yl]oxophenylethyl}carbamate was synthesized according to the protocol described for the preparation of methyl {(1R)[(2S,4S)(5-{2-[(2S){(2S) oxycarbonyl)amino]methylbutanoyl}pyrrolidinyl]-1,4,5,11- tetrahydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl}-1H-imidazolyl) (methoxymethyl)pyrrolidinyl]oxophenylethyl}carbamate, substituting tert-butyl )[9-(2-{(2S,5S)[N-(methoxycarbonyl)-L-valyl]methylpyrrolidinyl}-1H- imidazolyl)-1,4,5,11-tetrahydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl] (methoxymethyl)pyrrolidinecarboxylate for tert-butyl (2S,4S)[5-(2-{(2S)[N- (methoxycarbonyl)-L-valyl]pyrrolidinyl}-1,4,5,11 ydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl)-1H-imidazolyl] (methoxymethyl)pyrrolidinecarboxylate. MS (ESI) m/z 886 [M + H]+. 1H NMR (400 MHz, cd3od) δ 8.02 – 7.85 (m, 2H), 7.85 – 7.68 (m, 2H), 7.58 (d, J = 21.5 Hz, 1H), 7.55 – 7.35 (m, 4H), 7.31 (d, J = 13.6 Hz, 1H), 5.43 (d, J = 19.1 Hz, 1H), 5.28 (t, J = 8.3 Hz, 1H), 5.25 – 5.10 (m, 3H), 4.13 (t, J = 9.5 Hz, 1H), 3.93 – 3.54 (m, 7H), 3.42 (qd, J = 9.5, 5.5 Hz, 2H), 3.34 (d, J = 7.9 Hz, 1H), 3.28 (s, 3H), 3.19 (t, J = 7.8 Hz, 2H), 3.00 (t, J = 7.8 Hz, 2H), 2.74 – 2.46 (m, 3H), 2.44 – 2.15 (m, 2H), 2.12 – 1.86 (m, 2H), 1.56 (d, J = 6.7 Hz, 2H), 1.29 (d, J = 6.3 Hz, 1H), 1.15 – 1.01 (m, 1H), 0.98 (d, J = 6.7 Hz, 2H), 0.88 (d, J = 6.8 Hz, 2H). e OQ OEt OEt H H O N Pd(dba)2 N O N N Cl B N (pinB)2 O O N O O HN O O O methyl {(2S)[(2S,4S)(9-chloro-1,11- methyl [(2S){(2S,4S)ethoxy[9-(4,4,5,5- dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl) tetramethyl-1,3,2-dioxaborolanyl)-1,11- pyrrolidinyl]methyloxobutanyl}carbamate dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazol yl]pyrrolidinyl}methyloxobutanyl]carbamate Pd(PPh3)4 N N N PdCl2(dppf) Boc N N N DME H H O utyl (2S)[5-(2-{(2S,4S)ethoxy[N-(methoxycarbonyl)-L-O pyrrolidinyl}-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2- d]imidazolyl)-1H-imidazolyl]pyrrolidinecarboxylate NH H H 1) HCl O O N N N 2) HATU N N N Moc- Val H O H O methyl {(2S)[(2S)(5-{2-[(2S,4S)ethoxy{(2S)[(methoxycarbonyl)amino] methylbutanoyl}pyrrolidinyl]-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2- d]imidazolyl}-1H-imidazolyl)pyrrolidinyl]methyloxobutanyl}carbamate (2S,4S)Tert-butyl 2-(3-chlorooxo-8,9,10,11-tetrahydro-5H-dibenzo[c,g]chromen yl) 4-ethoxypyrrolidine-1,2-dicarboxylate To a slurry of 9-bromochloro-10,11-dihydro-5H-dibenzo[c,g]chromen-8(9H)-one (2.50 g, 6.8 mmol) in MeCN (20 mL) was added )(tert-butoxycarbonyl) ethoxypyrrolidinecarboxylic acid (2.68 g, 10.3 mmol) and DIPEA (1.3 mL, 7.5 mmol).

The reaction was heated with stirring to 50 °C for 18 h. The reaction was then cooled to room temperature and diluted with EtOAc. The solution was washed with HCl (1N) and brine. The aqueous layers were backextracted with EtOAc and the resulting organic layers were combined, dried (Na2SO4) and concentrated under reduced pressure. The crude e was purified by silica column chromatography (15% to 50 % EtOAc/Hexanes) to afford (2S,4S)tert-butyl 2-(3-chlorooxo-8,9,10,11-tetrahydro-5H-dibenzo[c,g]chromenyl) 4-ethoxypyrrolidine-1,2-dicarboxylate (2.08 g, 56%).

Tert-butyl (2S,4S)(9-chloro-1,4,5,11-tetrahydroisochromeno[4',3':6,7]naphtho[1,2- d]imidazolyl)ethoxypyrrolidinecarboxylate To a solution of (2S,4S)tert-butyl 2-(3-chlorooxo-8,9,10,11-tetrahydro-5H- dibenzo[c,g]chromenyl) 4-ethoxypyrrolidine-1,2-dicarboxylate (2.08 g, 3.8 mmol) in a mixture of toluene (30 mL) and methoxyethanol (4 mL) was added ammonium acetate (2.90 g, 37.7 mmol). The solution was heated with stirring to 80 °C for 18 h. The reaction was then cooled to room temperature and diluted with EtOAc. The solution was washed with brine, and the resulting aqueous layer was backextracted with EtOAc. The resulting c layers were combined, dried (Na2SO4), and concentrated under reduced pressure. The crude residue was purified by silica column chromatography (10% to 75 % EtOAc(w/5% MeOH)/Hexanes) to afford tert-butyl (2S,4S)(9-chloro-1,4,5,11- tetrahydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl)ethoxypyrrolidine carboxylate (0.99 g, 50%).

Tert-butyl (2S,4S)(9-chloro-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2- d]imidazolyl)ethoxypyrrolidinecarboxylate To a solution of (2S,4S)(9-chloro-1,4,5,11- tetrahydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl)ethoxypyrrolidine carboxylate (0.99 g, 1.9 mmol) in CH2Cl2 (18 mL) was added MnO2 (4.52 g, 52.0 mmol).

The resulting slurry was stirred at room ature for 18 h. The reaction was ed through , washed with CH2Cl2, and concentrated under reduced pressure. The crude residue was purified by silica column chromatography (10% to 75 % EtOAc(w/5% MeOH)/Hexanes) to afford tert-butyl (2S,4S)(9-chloro-1,11- dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl)ethoxypyrrolidine carboxylate (0.71 g, 72%) Methyl {(2S)[(2S,4S)(9-chloro-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2- d]imidazolyl)ethoxypyrrolidinyl]methyloxobutanyl}carbamate To a solution of tert-butyl (2S,4S)(9-chloro-1,11- dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl)ethoxypyrrolidine carboxylate (0.46 g, 0.9 mmol) in a mixture of CH2Cl2 (9.0 mL) and MeOH (1.5 mL) was added HCl (in dioxanes, 4M, 6.5 mL, 26.0 mmol). The resulting solution was stirred at room ature for 2 h. The solution was concentrated to dryness under reduced pressure. To the crude intermediate in CH2Cl2 (10.0 mL) was added (S)(methoxycarbonylamino) methylbutanoic acid (0.17 g, 0.9 mmol), HATU (0.41 g, 1.1 mmol), and DIPEA (0.5 mL, 2.9 mmol). The resulting solution was stirred at room temperature for 48 h and diluted with . The solution was washed with aqueous HCl (1N) and brine. The aqueous layers were backextracted with CH2Cl2 (2x). The ing organic layers were combined, dried (Na2SO4), and concentrated under d pressure. The crude residue was purified by silica column chromatography (20% to 100 % EtOAc(w/5% MeOH)/Hexanes to 80% MeOH/EtOAc) to afford methyl 1-[(2S,4S)(9-chloro-1,11- dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl)ethoxypyrrolidinyl] methyloxobutanyl}carbamate (0.46 g, 90%).

Methyl [(2S){(2S,4S)ethoxy[9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)- 1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl]pyrrolidinyl} methyloxobutanyl]carbamate To a solution of methyl {(2S)[(2S,4S)(9-chloro-1,11- oisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl)ethoxypyrrolidinyl] methyloxobutanyl}carbamate (0.46 g, 0.84 mmol) in dioxane (8.5 mL) was added ,4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (0.32 g, 1.3 mmol), potassium acetate (0.25 g, 2.5 mmol), benzylideneacetone)palladium (0.032 g, 0.035 mmol), and 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (Xphos, 0.032 g, 0.067 mmol). The resulting solution was degassed with argon for 5 min and heated, with stirring, to 90 °C for 6 h. The reaction was cooled to room ature, diluted with EtOAc, and filtered through celite. The crude residue was purified by silica column chromatography (20% to 100 % EtOAc(w/5% MeOH)/Hexanes to 90% MeOH/EtOAc) to afford methyl [(2S){(2S,4S) ethoxy[9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-1,11- dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl]pyrrolidinyl}methyl oxobutanyl]carbamate (0.41 g, 73%).

Tert-butyl (2S)[5-(2-{(2S,4S)ethoxy[N-(methoxycarbonyl)-L-valyl]pyrrolidin yl}-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl)-1H-imidazol yl]pyrrolidinecarboxylate To a solution of methyl [(2S){(2S,4S)ethoxy[9-(4,4,5,5-tetramethyl-1,3,2- dioxaborolanyl)-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazol rolidinyl}methyloxobutanyl]carbamate (0.41 g, 0.61 mmol) in a mixture of DME (6.1 mL) and DMF (1.0 mL) was added (S)-tert-butyl 2-(5-bromo-1H-imidazol rolidinecarboxylate (0.39 g, 1.2 mmol), tetrakis(triphenylphosphine)palladium (0.021 g, 0.018 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (0.030 g, 0.041 mmol), and aqueous potassium carbonate (2M, 1.0 mL, 2.0 mmol). The solution was degassed with argon for 5 min and heated, with stirring, to 85 °C for 6 h. The solution was cooled to room temperature and diluted with EtOAc. The organic layer was washed with water and brine. The aqueous layers were backextracted with EtOAc (3x). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The crude residue was purified by silica column chromatography (20% to 100 % EtOAc(w/5% MeOH)/Hexanes to 80% MeOH/EtOAc) to afford tert-butyl (2S)[5-(2-{(2S,4S)ethoxy- 1-[N-(methoxycarbonyl)-L-valyl]pyrrolidinyl}-1,11- dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl)-1H-imidazolyl]pyrrolidine carboxylate (0.16 g, 33%).

Methyl 1-[(2S)(5-{2-[(2S,4S)ethoxy{(2S)[(methoxycarbonyl)amino] butanoyl}pyrrolidinyl]-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2- d]imidazolyl}-1H-imidazolyl)pyrrolidinyl]methyloxobutanyl}carbamate To a solution of tert-butyl (2S)[5-(2-{(2S,4S)ethoxy[N-(methoxycarbonyl)- L-valyl]pyrrolidinyl}-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl)- 1H-imidazolyl]pyrrolidinecarboxylate (0.048 g, 0.062 mmol) in a mixture of CH2Cl2 (1.0 mL) and MeOH (0.25 mL) was added HCl (in dioxanes, 4M, 0.47 mL, 1.9 mmol). The solution was stirred at room temperature for 3 h, and then concentrated to dryness under reduced pressure. To the crude intermediate suspended in CH2Cl2 (1.5 mL) was added (S) (methoxycarbonylamino)methylbutanoic acid (0.012 g, 0.069 mmol), HATU (0.029 g, 0.076 mmol), and DIPEA (0.050 mL, 0.28 mmol). The resulting solution was stirred at room temperature for 1.5 h. The reaction was d with DMF and aqueous LiOH (2.5 M, 4 drops) was added. The solution was concentrated to remove the CH2Cl2 and the crude residue was purified by preparative reverse phase HPLC (10% to 52 % MeCN/water with 0.1% TFA). The desired fractions were combined and concentrated under reduced re to remove volatile organics. The addition of aqueous sodium bicarbonate with stirring ed in precipitation of a white solid. The precipitate was filtered through a membrane filter and washed with water. Drying under reduced re afforded methyl {(2S)[(2S)- 2-(5-{2-[(2S,4S)ethoxy{(2S)[(methoxycarbonyl)amino] methylbutanoyl}pyrrolidinyl]-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazol- 9-yl}-1H-imidazolyl)pyrrolidinyl]methyloxobutanyl}carbamate (0.008 g, 17%). : 400 MHz, (MeOD) δ: (Mixture of rs) 8.37 (s, 1H), 7.97 (s, 2H), 7.37-7.76 (m, 5H), 5.38-5.54 (m, 1H), 5.18 (s, 2H), 5.14-5.16 (m, 1H), 4.21-4.31 (m, 4H), 3.87-4.09 (m, 1H), 3.79-3.85 (m, 2H), 3.66 (s, 3H), 3.64 (s, 3H), 3.46-3.55 (m, 2H), 2.30- 2.35 (m, 3H), 2.04-2.06 (m, 3H), 1.11 (m, 2H), 0.95 (d, 3H), 0.88 (d, 3H). MS (ESI) m/z 836.02 [M + H]+.

Example OR 1) HCl N N N N N N 2) COMU H O H O Moc- Phg tert-butyl (2S)[5-(2-{(2S,4S)ethoxy[N-(methoxycarbonyl)-L- valyl]pyrrolidinyl}-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2- d]imidazolyl)-1H-imidazolyl]pyrrolidinecarboxylate NH H H O O N N N N N N H O H O methyl {(1R)[(2S)(5-{2-[(2S,4S)ethoxy{(2S) oxycarbonyl)amino]methylbutanoyl}pyrrolidinyl]-1,11- dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl}-1H- imidazolyl)pyrrolidinyl]oxophenylethyl}carbamate Methyl {(1R)[(2S)(5-{2-[(2S,4S)ethoxy{(2S)[(methoxycarbonyl)amino] methylbutanoyl}pyrrolidinyl]-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2- azolyl}-1H-imidazolyl)pyrrolidinyl]oxophenylethyl}carbamate To a solution of tert-butyl (2S)[5-(2-{(2S,4S)ethoxy[N-(methoxycarbonyl)- L-valyl]pyrrolidinyl}-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl)- 1H-imidazolyl]pyrrolidinecarboxylate (0.11 g, 0.14 mmol) in a mixture of CH2Cl2 (2.0 mL) and MeOH (0.5 mL) was added HCl (in dioxanes, 4M, 1.0 mL, 4.0 mmol). The solution was stirred at room temperature for 3 h, and then concentrated to dryness under reduced pressure. To the crude intermediate suspended in CH2Cl2 (1.5 mL) was added (R) (methoxycarbonylamino)phenylacetic acid (0.044 g, 0.21 mmol) and DIPEA (0.075 mL, 0.43 mmol). The resulting solution was cooled to -40 °C and COMU (0.096 g, 0.22 mmol) was added. The on was allowed to slowly warm to 0 °C over 1 h. The reaction was diluted with DMF. The solution was concentrated to remove the CH2Cl2 and the crude residue was purified by preparative reverse phase HPLC (10% to 55% MeCN/water with 0.1% TFA). The desired fractions were combined and concentrated under d pressure to remove volatile organics. The addition of aqueous sodium bicarbonate with stirring resulted in precipitation of a white solid. The precipitate was filtered through a membrane filter and washed with water. Drying under reduced pressure afforded methyl {(1R)[(2S)- 2-(5-{2-[(2S,4S)ethoxy{(2S)[(methoxycarbonyl)amino] methylbutanoyl}pyrrolidinyl]-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazol- 9-yl}-1H-imidazolyl)pyrrolidinyl]oxophenylethyl}carbamate (0.022 g, 18%). 1H-NMR: 400 MHz, (MeOD) δ: re of rotamers) 8.28 (d, 1H), 7.88 (d, 1H), 7.52-7.70 (m, 3H), 7.28-7.38 (m, 5H), 6.90-6.96 (m, 2H), 5.44-5.47 (m, 1H), 5.31 (s, 1H), 5.12 (s, 2H), 4.16-4.48 (m, 3H), 3.81-3.19 (m, 1H), 3.62-3.76 (m, 2H), 3.58 (s, 3H), 2.56 (s, 3H), 2.42- 2.57 (m, 1H), 2.31 (m, 1H), 1.81-2.41 (m, 5H), 1.04 (t, 3H), 0.87 (d, 3H), 0.81 (d, 3H). MS (ESI) m/z 869.55 [M + H]+.

Example OS Boc Br 1) HCl NH N N O N H Br H 2) HATU Moc-MeThr N O H (S)-tert-butyl 2-(5-bromo-1H-imidazol yl)pyrrolidinecarboxylate methyl (2S,3R)((S)(5-bromo-1H- olyl)pyrrolidinyl)methoxy- 1-oxobutanylcarbamate Methyl (2S,3R)((S)(5-bromo-1H-imidazolyl)pyrrolidinyl)methoxy oxobutanylcarbamate To a solution of (S)-tert-butyl 2-(5-bromo-1H-imidazolyl)pyrrolidine carboxylate (1.00 g, 3.2 mmol) in a mixture of CH2Cl2 (30 mL) and MeOH (5 mL) was added HCl (in e, 4 M, 11.5 mL, 46.0 mmol). The on was stirred at 40 °C for 1h, cooled to room temperature, and concentrated to dryness under reduced re. To the crude intermediate suspended in CH2Cl2 (30 mL) was added (2S,3R)methoxy (methoxycarbonylamino)butanoic acid (0.67 g, 3.5 mmol), HATU (1.47 g, 3.8 mmol), and DIPEA (1.00 mL, 6.0 mmol). The resulting solution was stirred at room ature for 24 h. DMF (2 mL) and aqueous LiOH (2.5 M, 1 mL) were added and the reaction was concentrated to dryness under reduced pressure. The crude material was diluted with EtOAc and washed with H2O and brine. The aqueous layers were backextracted with EtOAc. The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure.

The crude residue was purified by silica column chromatography (20% to 100 % EtOAc(w/5% CH2Cl2) to afford methyl (2S,3R)((S)(5-bromo-1H-imidazol yl)pyrrolidinyl)methoxyoxobutanylcarbamate (1.2g, 100%).

Example OT Tert-butyl (2S,4S)[9-(2-{(2S)[N-(methoxycarbonyl)-O-methyl-L- threonyl]pyrrolidinyl}-1H-imidazolyl)-1,11- dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl] (methoxymethyl)pyrrolidinecarboxylate To a solution of tert-butyl 4-(methoxymethyl)[9-(4,4,5,5-tetramethyl-1,3,2- orolanyl)-1,11-dihydroisochromeno[4',3':6,7]-naphtho[1,2-d]imidazol yl]pyrrolidinecarboxylate (1.0 g, 3.2 mmol) in a mixture of DMSO (2.0 mL) and dioxanes (2.0 mL) was added methyl (2S,3R)((S)(5-bromo-1H-imidazolyl)pyrrolidinyl) methoxyoxobutanylcarbamate (0.24 g, 0.62 mmol), tetrakis(triphenylphosphine)palladium (0.050 g, 0.043 mmol), [1,1′- bis(diphenylphosphino)ferrocene]dichloropalladium (0.030 g, 0.041 mmol), and aqueous potassium carbonate (2M, 0.65 mL, 1.3 mmol). The solution was ed with argon for 5 min and heated, with stirring, to 85 °C for 6 h. The solution was cooled to room temperature and diluted with EtOAc. The c layer was washed with water and brine. The aqueous layers were backextracted with EtOAc (3x). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The crude residue was purified by silica column chromatography (20% to 100 % EtOAc(w/5% Hexanes to 60% MeOH/EtOAc) to afford tert-butyl (2S,4S)[9-(2-{(2S)[N-(methoxycarbonyl)-O-methyl- L-threonyl]pyrrolidinyl}-1H-imidazolyl)-1,11- dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl](methoxymethyl)pyrrolidine carboxylate (0.20 g, 63%).

Methyl {(1R)[(2S,4S)(9-{2-[(2S){(2S,3R)methoxy [(methoxycarbonyl)amino]butanoyl}pyrrolidinyl]-1H-imidazolyl}-1,11- oisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl) (methoxymethyl)pyrrolidinyl]oxophenylethyl}carbamate To a solution of tert-butyl )[9-(2-{(2S)[N-(methoxycarbonyl)-O-methyl- L-threonyl]pyrrolidinyl}-1H-imidazolyl)-1,11- dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl](methoxymethyl)pyrrolidine carboxylate (0.20 g, 0.26 mmol) in a mixture of CH2Cl2 (3.0 mL) and MeOH (0.5 mL) was added HCl (in dioxanes, 4M, 2.0 mL, 8.0 mmol). The solution was stirred at 40 ºC for 1 h, and then cooled to room temperature and concentrated to dryness under reduced pressure. To the crude intermediate suspended in CH2Cl2 (3.0 mL) was added (R) (methoxycarbonylamino)phenylacetic acid (0.081 g, 0.39 mmol) and DIPEA (0.150 mL, 0.86 mmol). The resulting on was cooled to -40 °C and COMU (0.180 g, 0.42 mmol) was added. The on was allowed to slowly warm to room temperature over 30 min and maintained for 1.5 h. The solution was diluted with CH2Cl2 and washed with s bicarbonate. The aqueous layer was backextracted with CH2Cl2. The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The crude residue was purified by preparative reverse phase HPLC (10% to 50% MeCN/water with 0.1% TFA).

The desired fractions were combined and concentrated under reduced pressure to remove volatile organics. The addition of aqueous sodium bicarbonate with stirring resulted in itation of a white solid. The precipitate was filtered through a membrane filter and washed with water. Drying under reduced pressure afforded methyl {(1R)[(2S,4S)(9- {2-[(2S){(2S,3R)methoxy[(methoxycarbonyl)amino]butanoyl}pyrrolidinyl]-1H- imidazolyl}-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl) (methoxymethyl)pyrrolidinyl]oxophenylethyl}carbamate (0.10 g, 46%). 1H-NMR: 400 MHz, (MeOD) δ: (Mixture of rotamers) 8.34 (s, 1H), .97 (m, 2H), 7.33-7.69 (m, 10H), 5.53 (s, 1H), 5.36-5.39 (m, 1H), 5.15-5.21 (m, 3H), 4.44 (d, 1H), 3.86-3.93 (m, 2H), 3.68-3.75 (m, 2H), 3.66 (s, 3H), 3.65 (s, 3H), 3.46-3.57 (m, 2H), 3.28 (s, 3H), 3.19 (s, 3H), 2.47-2.60 (m, 3H), 2.22-2.36 (m, 4H), 1.99-2.08 (m, 3H), 1.15 (d, 3H). MS (ESI) m/z 886.19 [M + H]+.

Example OU H H 1) HCl O N N B Boc 2) HATU O N Moc-MeThr tert-butyl 4-(methoxymethyl)[9-(4,4,5,5-tetramethyl-1,3,2- dioxaborolanyl)-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2- azolyl]pyrrolidinecarboxylate Boc I O N N O H O N O O N O O methyl (1-{4-(methoxymethyl)[9-(4,4,5,5-tetramethyl-1,3,2- dioxaborolanyl)-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2- d]imidazolyl]pyrrolidinyl}methoxyoxobutan bamate H H 1) HCl N N O Boc 2) COMU N N N O Moc- Phg H O tert-butyl (2S)(5-{2-[(2S,4S)[N-(methoxycarbonyl)-O-methyl-L-threonyl] (methoxymethyl)pyrrolidinyl]-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2- d]imidazolyl}-1H-imidazolyl)pyrrolidinecarboxylate NH H H O O N N O N N N H O H O methyl {(1R)[(2S)(5-{2-[(2S,4S){(2S)[(methoxycarbonyl)amino]methoxybutanoyl} (methoxymethyl)pyrrolidinyl]-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl}-1H- imidazolyl)pyrrolidinyl]oxophenylethyl}carbamate Methyl (1-{4-(methoxymethyl)[9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-1,11- dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl]pyrrolidinyl}methoxy- 1-oxobutanyl)carbamate To a solution of tert-butyl 4-(methoxymethyl)[9-(4,4,5,5-tetramethyl-1,3,2- dioxaborolanyl)-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazol yl]pyrrolidinecarboxylate (0.25 g, 0.41 mmol) in a mixture of CH2Cl2 (4.0 mL) and MeOH (1.0 mL) was added HCl (in dioxanes, 4M, 3.0 mL, 12.0 mmol). The resulting solution was stirred at 40 ºC for 45 min. The on was cooled to room temperature and concentrated to dryness under reduced pressure. To the crude intermediate in CH2Cl2 (4.0 mL) was added (2S,3R)methoxy(methoxycarbonylamino)butanoic acid (0.08 g, 0.42 mmol), HATU (0.17 g, 0.45 mmol), and DIPEA (0.4 mL, 2.3 mmol). The resulting solution was stirred at room ature for 48 h and diluted with CH2Cl2. The solution was washed with brine.

The aqueous layer was backextracted with CH2Cl2 (2x). The ing organic layers were combined, dried (Na2SO4), and concentrated under reduced pressure. The crude residue was purified by silica column chromatography (30% to 100 % EtOAc(w/5% MeOH)/Hexanes to 80% MeOH/EtOAc) to afford methyl (methoxymethyl)[9-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolanyl)-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazol yl]pyrrolidinyl}methoxyoxobutanyl)carbamate (0.24 g, 92%).

Tert-butyl (2S)(5-{2-[(2S,4S)[N-(methoxycarbonyl)-O-methyl-L-threonyl] (methoxymethyl)pyrrolidinyl]-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2- d]imidazolyl}-1H-imidazolyl)pyrrolidinecarboxylate To a solution of methyl (1-{4-(methoxymethyl)[9-(4,4,5,5-tetramethyl-1,3,2- dioxaborolanyl)-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazol rolidinyl}methoxyoxobutanyl)carbamate (0.15 g, 0.22 mmol) in a mixture of DMSO (2.0 mL) and dioxane (2.0 mL) was added (S)-tert-butyl 2-(5-iodo-1H-imidazol yl)pyrrolidinecarboxylate (0.15 g, 0.40 mmol), tetrakis(triphenylphosphine)palladium (0.028 g, 0.024 mmol), bis(diphenylphosphino)ferrocene]dichloropalladium (0.018 g, 0.025 mmol), and aqueous potassium carbonate (2M, 0.35 mL, 0.70 mmol). The solution was degassed with argon for 5 min and , with stirring, to 90 °C for 6 h. The solution was cooled to room temperature and diluted with EtOAc. The organic layer was washed with water and brine. The aqueous layers were backextracted with EtOAc (3x). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The crude residue was purified by preparative reverse phase HPLC (10% to 55% MeCN/water with 0.1% TFA). The d fractions were combined and concentrated under reduced pressure to remove volatile organics. The ing solution was basified with aqueous bicarbonate and extracted with CH2Cl2 (3x). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to provide tert-butyl (2S)(5-{2-[(2S,4S)[N- (methoxycarbonyl)-O-methyl-L-threonyl](methoxymethyl)pyrrolidinyl]-1,11- dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl}-1H-imidazolyl)pyrrolidine carboxylate (0.013 g, 7%).

Methyl {(1R)[(2S)(5-{2-[(2S,4S){(2S)[(methoxycarbonyl)amino] methoxybutanoyl}(methoxymethyl)pyrrolidinyl]-1,11- dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl}-1H-imidazol yl)pyrrolidinyl]oxophenylethyl}carbamate To a solution of tert-butyl (2S)(5-{2-[(2S,4S)[N-(methoxycarbonyl)-O-methyl- L-threonyl](methoxymethyl)pyrrolidinyl]-1,11- dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl}-1H-imidazolyl)pyrrolidine carboxylate (0.013 g, 0.016 mmol) in a mixture of CH2Cl2 (0.5 mL) and MeOH (0.02 mL) was added HCl (in dioxanes, 4M, 0.20 mL, 0.80 mmol). The solution was d at room temperature for 1 h, and then concentrated to dryness under reduced pressure. To the crude ediate suspended in CH2Cl2 (0.5 mL) was added (R)(methoxycarbonylamino) phenylacetic acid (0.006 g, 0.029 mmol) and DIPEA (0.05 mL, 0.28 mmol). The resulting solution was cooled to 0 °C and COMU (0.012 g, 0.028 mmol) was added. The reaction was stirred at 0 °C for 30 min. The solution was diluted with DMF and s LiOH (2.5 M, 2 drops) and concentrated under reduced pressure to remove the CH2Cl2. The crude residue was purified by preparative reverse phase HPLC (10% to 55% MeCN/water with 0.1% TFA).

The desired fractions were combined and concentrated under reduced pressure to remove volatile organics. The addition of aqueous sodium bicarbonate with stirring resulted in precipitation of a white solid. The precipitate was filtered through a membrane filter and washed with water. Drying under reduced pressure afforded methyl {(1R)[(2S)(5-{2- [(2S,4S){(2S)[(methoxycarbonyl)amino]methoxybutanoyl} (methoxymethyl)pyrrolidinyl]-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazol- 9-yl}-1H-imidazolyl)pyrrolidinyl]oxophenylethyl}carbamate (0.008 g, 61%). 1H- NMR: 400 MHz, (MeOD) δ: re of rotamers) 8.37 (m, 1H), 7.96-7.98 (m, 2H), 7.60- 7.79 (m, 3H), .52 (m, 6H), 6.98-7.03 (m, 1H), 5.52 (s, 1H), 5.26-5.39 (m, 2H), 5.20 (s, 2H), 4.44 (m, 1H), 4.27 (m, 1H), 3.64 (s, 6H), .57 (m, 3H), 3.37 (s, 3H), 3.29-3.44 (m, 3H), 3.20 (s, 3H), 2.68-2.72 (m, 2H), 2.57-2.62 (m, 2H), 1.89-2.15 (m, 6H), 1.18 (d, 3H).

MS (ESI) m/z 885.73 [M + H]+.

Example OV Boc I N N H H (2S,4S)-tert-butyl 2-(5-iodo-1H-imidazolyl) O (methoxymethyl)pyrrolidinecarboxylate N N O N Pd(PPh3)4 O O PdCl2(dppf) DME, DMF methyl [(2S){(2S,4S)[9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan- 2-yl)-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl]- 2-azabicyclo[3.1.0]hexyl}methyloxobutanyl]carbamate N N N 1) HCl N N N H O O 2) COMU H HN Moc- Phg tert-butyl (2S,4S)[5-(2-{(1S,3S,5S)[N-(methoxycarbonyl)-L-valyl] azabicyclo[3.1.0]hexyl}-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazol- 9-yl)-1H-imidazolyl](methoxymethyl)pyrrolidinecarboxylate NH H H O O N N N N N N H O H O methyl {(1R)[(2S,4S)(5-{2-[(1S,3S,5S){(2S) [(methoxycarbonyl)amino]methylbutanoyl}azabicyclo[3.1.0]hexyl]-1,11- dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl}-1H-imidazol yl)(methoxymethyl)pyrrolidinyl]oxophenylethyl}carbamate Methyl [(2S){(2S,4S)[9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-1,11- dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl]azabicyclo[3.1.0]hex yl}methyloxobutanyl]carbamate Methyl [(2S){(2S,4S)[9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-1,11- dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl]azabicyclo[3.1.0]hexyl} oxobutanyl]carbamate was ed following the procedure for methyl [(2S) {(2S,4S)ethoxy[9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-1,11- dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl]pyrrolidinyl}methyl oxobutanyl]carbamate by substitution of (1S,3S,5S)(tert-butoxycarbonyl) azabicyclo[3.1.0]hexanecarboxylic acid for (2S,4S)(tert-butoxycarbonyl) ethoxypyrrolidinecarboxylic acid. utyl (2S,4S)[5-(2-{(1S,3S,5S)[N-(methoxycarbonyl)-L-valyl] azabicyclo[3.1.0]hexyl}-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazol yl)-1H-imidazolyl](methoxymethyl)pyrrolidinecarboxylate To a solution of methyl [(2S){(2S,4S)[9-(4,4,5,5-tetramethyl-1,3,2- dioxaborolanyl)-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl] azabicyclo[3.1.0]hexyl}methyloxobutanyl]carbamate (0.19 g, 0.30 mmol) in a mixture of DMSO (2.0 mL) and dioxane (2.0 mL) was added (2S,4S)-tert-butyl 2-(5-iodo- 1H-imidazolyl)(methoxymethyl)pyrrolidinecarboxylate (0.20 g, 0.55 mmol), tetrakis(triphenylphosphine)palladium (0.035 g, 0.030 mmol), [1,1′- bis(diphenylphosphino)ferrocene]dichloropalladium (0.025 g, 0.034 mmol), and aqueous potassium carbonate (2M, 0.5 mL, 1.0 mmol). The solution was degassed with argon for 5 min and heated, with stirring, to 90 °C for 6 h. The on was cooled to room temperature, diluted with EtOAc, and filtered through celite. The te was trated under reduced pressure and purified by silica column chromatography (2% to 25 % CH2Cl2/MeOH) and preparative reverse phase HPLC (10% to 55% MeCN/water with 0.1% TFA). The desired fractions were combined and concentrated under reduced pressure to remove volatile organics. The aqueous layer was basified with aqueous sodium bicarbonate and extracted with CH2Cl2 (3x). The organic layers were combine, dried over Na2SO4, and concentrated under reduced pressure to afford tert-butyl (2S,4S)[5-(2-{(1S,3S,5S)[N- (methoxycarbonyl)-L-valyl]azabicyclo[3.1.0]hexyl}-1,11- oisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl)-1H-imidazolyl] (methoxymethyl)pyrrolidinecarboxylate (0.025 g, 11%).

Methyl 2-[(2S,4S)(5-{2-[(1S,3S,5S){(2S)[(methoxycarbonyl)amino] butanoyl}azabicyclo[3.1.0]hexyl]-1,11- dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl}-1H-imidazolyl) (methoxymethyl)pyrrolidinyl]oxophenylethyl}carbamate To a solution of tert-butyl (2S,4S)[5-(2-{(1S,3S,5S)[N-(methoxycarbonyl)-L- valyl]azabicyclo[3.1.0]hexyl}-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2- d]imidazolyl)-1H-imidazolyl](methoxymethyl)pyrrolidinecarboxylate (0.025 g, 0.032 mmol) in a mixture of CH2Cl2 (1.0 mL) and MeOH (0.25 mL) was added HCl (in dioxanes, 4M, 0.50 mL, 2.0 mmol). The solution was stirred at room temperature for 12 h, and then concentrated to dryness under reduced pressure. To the crude intermediate suspended in CH2Cl2 (0.5 mL) was added (R)(methoxycarbonylamino)phenylacetic acid (0.012 g, 0.057 mmol) and DIPEA (0.05 mL, 0.28 mmol). The resulting on was cooled to 0 °C and COMU (0.023 g, 0.054 mmol) was added. The reaction was stirred at 0 °C for 30 min. The solution was diluted with DMF and aqueous LiOH (2.5 M, 2 drops) and concentrated under reduced pressure to remove the CH2Cl2. The crude residue was purified by preparative reverse phase HPLC (10% to 55% MeCN/water with 0.1% TFA). The desired fractions were combined and concentrated under reduced pressure to remove volatile organics. The on of aqueous sodium bicarbonate with stirring resulted in itation of a white solid. The precipitate was ed through a membrane filter and washed with water. Drying under reduced pressure ed methyl 2-[(2S,4S)(5-{2- [(1S,3S,5S){(2S)[(methoxycarbonyl)amino]methylbutanoyl} azabicyclo[3.1.0]hexyl]-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl}- 1H-imidazolyl)(methoxymethyl)pyrrolidinyl]oxophenylethyl}carbamate (0.015 g, 55%). 1H-NMR: 400 MHz, (MeOD) δ: (Mixture of rotamers) 8.35 (m, 1H), 7.94- 7.96 (m, 2H), 7.54-7.78 (m, 6H), 6.93-7.00 (m, 1H), 5.72 (m, 1H), 5.46 (s, 1H), 5.19 (s, 2H), .14-5.16 (m, 1H), 3.95 (m, 1H), 3.67 (s, 3H), 3.63 (s, 3H), 3.42-3.49 (m, 2H), 3.24 (s, 3H), 2.67-2.78 (m, 2H), 2.41-2.62 (m, 3H), 2.01-2.13 (m, 2H), 1.86-1.99 (m, 3H), 0.99-1.03 (m, 2H), 0.90 (d, 3H). MS (ESI) m/z 882.23 [M + H]+.

Example OW O O N N O methyl (2S,3S)((2S,5S)(5-iodo-1H- imidazolyl)methylpyrrolidinyl) H H oxopentanylcarbamate O N N B Boc Pd(PPh3)4 O N PdCl2(dppf) DME, DMF methyl (1-{4-(methoxymethyl)[9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan- 2-yl)-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazol rolidinyl}methyloxobutanyl)carbamate O 1) HCl NH H H O O N N N 2) COMU Boc Moc- Phg N N N tert-butyl (2S,4S)[9-(2-{(2S,5S)[N-(methoxycarbonyl)-L-isoleucyl] methylpyrrolidinyl}-1H-imidazolyl)-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2- d]imidazolyl](methoxymethyl)pyrrolidinecarboxylate NH H H O O N N N N N N H O H O methyl {(1R)[(2S,4S)(9-{2-[(2S,5S){(2S,3S)[(methoxycarbonyl)amino] methylpentanoyl}methylpyrrolidinyl]-1H-imidazolyl}-1,11- dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazol yl)(methoxymethyl)pyrrolidinyl]oxophenylethyl}carbamate Tert-butyl )[9-(2-{(2S,5S)[N-(methoxycarbonyl)-L-isoleucyl] methylpyrrolidinyl}-1H-imidazolyl)-1,11- dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl] (methoxymethyl)pyrrolidinecarboxylate To a solution of methyl (1-{4-(methoxymethyl)[9-(4,4,5,5-tetramethyl-1,3,2- dioxaborolanyl)-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazol yl]pyrrolidinyl}methyloxobutanyl)carbamate (0.47 g, 0.78 mmol) in a mixture of DMSO (4.0 mL) and dioxane (4.0 mL) was added methyl (2S,3S)((2S,5S)(5-iodo-1H- imidazolyl)methylpyrrolidinyl)methyloxopentanylcarbamate (0.26 g, 0.72 mmol), tetrakis(triphenylphosphine)palladium (0.090 g, 0.078 mmol), [1,1′- bis(diphenylphosphino)ferrocene]dichloropalladium (0.061g, 0.083 mmol), and aqueous potassium carbonate (2M, 1.2 mL, 2.4 mmol). The solution was degassed with argon for 5 min and heated, with stirring, to 90 °C for 6 h. The solution was cooled to room temperature, diluted with EtOAc, and filtered through celite. The filtrate was concentrated under reduced pressure and diluted with EtOAc. The organic solution was washed with water and brine and the aqueous layers were backextracted with EtOAc. The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The crude residue was purified by silica column chromatography (10% to 100% EtOAc (5% MeOH)/CH2Cl2) to afford tertbutyl )[9-(2-{(2S,5S)[N-(methoxycarbonyl)-L-isoleucyl]methylpyrrolidin yl}-1H-imidazolyl)-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl] (methoxymethyl)pyrrolidinecarboxylate (0.25 g, 40%).

Methyl {(1R)[(2S,4S)(9-{2-[(2S,5S){(2S,3S)[(methoxycarbonyl)amino] methylpentanoyl}methylpyrrolidinyl]-1H-imidazolyl}-1,11- dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl) (methoxymethyl)pyrrolidinyl]oxophenylethyl}carbamate To a on of tert-butyl (2S,4S)[9-(2-{(2S,5S)[N-(methoxycarbonyl)-L- isoleucyl]methylpyrrolidinyl}-1H-imidazolyl)-1,11- dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl](methoxymethyl)pyrrolidine carboxylate (0.175 g, 0.21 mmol) in a mixture of CH2Cl2 (2.0 mL) and MeOH (0.5 mL) was added HCl (in dioxanes, 4M, 1.6 mL, 6.4 mmol). The solution was stirred at 40 ºC for 1 h, cooled to room ature, and then concentrated to dryness under reduced re. To the crude intermediate suspended in CH2Cl2 (3.0 mL) was added (R) (methoxycarbonylamino)phenylacetic acid (0.070 g, 0.34 mmol) and DIPEA (0.15 mL, 0.86 mmol). The ing on was cooled to -40 °C and COMU (0.15 g, 0.35 mmol) was added. The reaction was warmed to room temperature over 30 min and diluted with CH2Cl2. The solution was washed with saturated aqueous sodium bicarbonate. The aqueous layer was backextracted with , and the combined organic layers were dried over Na2SO4 and concentrated under d pressure. The crude residue was purified by preparative reverse phase HPLC (10% to 58% MeCN/water with 0.1% TFA). The desired fractions were combined and concentrated under reduced pressure to remove volatile organics. The addition of aqueous sodium onate with stirring resulted in itation of a white solid. The precipitate was filtered through a membrane filter and washed with water. Drying under reduced pressure afforded methyl {(1R)[(2S,4S)(9-{2-[(2S,5S) {(2S,3S)[(methoxycarbonyl)amino]methylpentanoyl}methylpyrrolidinyl]-1H- imidazolyl}-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl) (methoxymethyl)pyrrolidinyl]oxophenylethyl}carbamate (0.079 g, 41%). 1H-NMR: 400 MHz, (MeOD) δ: (Mixture of rotamers) 8.36 (m, 1H), 7.93-7.98 (m, 2H), 7.66-7.84 (m, 3H), 7.35-7.48 (m, 7H), 5.53 (s, 1H), 5.36-5.39 (m, 1H), 5.17 (d, 2H), 5.08 (m, 1H), 4.14- 4.35 (m, 1H), 3.74 (m, 4H), 3.64 (s, 3H), 3.62 (s, 3H), 3.46 (m, 1H), 3.19 (s, 3H), 2.76 (m, 1H), 2.46-2.60 (m, 3H), 2.24-2.35 (m, 1H), 2.08-2.18 (m, 2H), 1.91 (m, 1H), 1.61-1.87 (m, 2H), 1.48 (d, 3H), 1.13-1.21 (m, 3H), 0.80-0.97 (m, 3H). MS (ESI) m/z 898.24 [M + H]+.

Example OX NH H H 1) HCl O O N N N Boc 2) HATU N N N Moc-Val tert-butyl (2S,4S)[9-(2-{(2S,5S)[N-(methoxycarbonyl)-L-isoleucyl] pyrrolidinyl}-1H-imidazolyl)-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2- d]imidazolyl](methoxymethyl)pyrrolidinecarboxylate NH H H O O N N N N N N H O H O methyl {(2S)[(2S,4S)(9-{2-[(2S,5S){(2S,3S)[(methoxycarbonyl)amino]methylpentanoyl} pyrrolidinyl]-1H-imidazolyl}-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazol yl)(methoxymethyl)pyrrolidinyl]methyloxobutanyl}carbamate Methyl {(2S)[(2S,4S)(9-{2-[(2S,5S){(2S,3S)[(methoxycarbonyl)amino] methylpentanoyl}methylpyrrolidinyl]-1H-imidazolyl}-1,11- dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl) (methoxymethyl)pyrrolidinyl]methyloxobutanyl}carbamate To a solution of tert-butyl (2S,4S)[9-(2-{(2S,5S)[N-(methoxycarbonyl)-L- isoleucyl]methylpyrrolidinyl}-1H-imidazolyl)-1,11- dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl](methoxymethyl)pyrrolidine carboxylate (0.075 g, 0.09 mmol) in a mixture of CH2Cl2 (1.0 mL) and MeOH (0.25 mL) was added HCl (in dioxanes, 4M, 0.7 mL, 2.8 mmol). The solution was stirred at 40 ºC for 1 h, cooled to room ature, and then concentrated to dryness under reduced pressure. To the crude intermediate suspended in CH2Cl2 (3.0 mL) was added (methoxycarbonylamino)- 3-methylbutanoic acid (0.020 g, 0.14 mmol), HATU (0.043 g, 0.11 mmol) and DIPEA (0.10 mL, 0.57 mmol). The on was stirred at room temperature for 2 h. The reaction was diluted with DMF and aqueous LiOH (2.5 M, 3 drops) and the CH2Cl2 was removed under reduced re. The crude residue was ed by preparative reverse phase HPLC (10% to 58% ater with 0.1% TFA). The desired fractions were combined and concentrated under reduced re to remove volatile organics. The addition of aqueous sodium bicarbonate with stirring resulted in precipitation of a white solid. The precipitate was filtered through a membrane filter and washed with water. Drying under reduced pressure afforded methyl {(2S)[(2S,4S)(9-{2-[(2S,5S){(2S,3S) [(methoxycarbonyl)amino]methylpentanoyl}methylpyrrolidinyl]-1H-imidazolyl}- 1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl) (methoxymethyl)pyrrolidinyl]methyloxobutanyl}carbamate (0.031 g, 38%). 1H- NMR: 400 MHz, (MeOD) δ: (Mixture of rotamers) 8.34 (m, 1H), 7.91-9.97 (m, 2H), 7.50- 7.81 (m, 3H), 7.35-7.38 (m, 2H), 5.17-5.26 (m, 3H), 5.08 (m, 1H), 4.14-4.33 (m, 4H), 3.64 (s, 3H), 3.63 (s, 3H), 3.51- 3.59 (m, 3H), 3.37 (s, 3H), 2.71 (m, 1H), 2.55-2.59 (m, 1H), 2.23- 2.33 (m, 1H), 1.92-2.10 (m, 2H), 1.77-1.89 (m, 1H), 1.60 (m, 1H), 1.48 (d, 1H), 1.11-1.22 (m, 2H), 0.81-0.98 (m, 12H). MS (ESI) m/z 864.27 [M + H]+.

Example PF O O N N N H H Moc-Val-OH, HATU, O N B N DIPEA, DMF O N N O 3)4, PdCl2(dppf), H K2CO3, DME/ DMF, 85°C methyl [(2S){(2S,4S)ethoxy[9-(4,4,5,5-tetramethyl-1,3,2- dioxaborolanyl)-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2- d]imidazolyl]pyrrolidinyl}methyloxobutanyl]carbamate H O O O H N N N N N N O methyl {1-[2-{9-[2-(1-{[(methoxycarbonyl)amino](phenyl)acetyl}methylpyrrolidin- 2-yl)-1H-imidazolyl]-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazol- 4-(methoxymethyl)pyrrolidiny ethyloxobutanyl}carbamate utyl (2S,4S)(methoxymethyl)[9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)- 1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl]pyrrolidine carboxylate The title compound was obtained as in example LQ but using (2S,4S)(tertbutoxycarbonyl )(methoxymethyl)pyrrolidinecarboxylic acid in place of (S)(tertbutoxycarbonyl )pyrrolidinecarboxylic acid. methoxymethyl)pyrrolidinyl](4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)- 1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazole Tert-butyl (2S,4S)(methoxymethyl)[9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan- 2-yl)-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl]pyrrolidine carboxylate ( 310mg, 0.507mmol) was treated with 2mL 1.25N HCl in ethanol and stirred at room temperature for 2h then at 500C for 2h. The reaction mixture was concentrated under reduced pressure to give a dark yellow solid that was directly in the next step. methyl [(2S){(2S,4S)ethoxy[9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-1,11- dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl]pyrrolidinyl}methyl oxobutanyl]carbamate A mixture of (S)(methoxycarbonylamino)methylbutanoic acid (107mg, 0.608mmol), HATU (231mg, 0.608mmol) and 6mL 10% DIPEA in DMF was pre-activated for 5 minutes, then it was added to the amine salt from the step above and allowed to stir overnight. The reaction mixture was ioned between ethyl acetate and saturated sodium bicarbonate. The organic phase was concentrated and purified by silica gel chromatography. (103mg) tert-butyl 2-[5-(2-{1-[N-(methoxycarbonyl)valyl](methoxymethyl)pyrrolidinyl}- 1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl)-1H-imidazolyl] methylpyrrolidinecarboxylate The title compound was obtained as in example LQ but using methyl [(2S) {(2S,4S)ethoxy[9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-1,11- dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl]pyrrolidinyl}methyl oxobutanyl]carbamate , 0.154mmol) in place of utyl 2-[9-(4,4,5,5- tetramethyl-1,3,2-dioxaborolanyl)-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2- d]imidazolyl]pyrrolidinecarboxylate and methyl (S)((2S,4S)(5-iodo-1H- imidazolyl)methylpyrrolidinyl)methyloxobutanylcarbamate (58mg, 0.154mmol)in place of methyl (S)((S)(5-bromo-1H-imidazolyl)pyrrolidinyl) methyloxobutanylcarbamate. (50.0mg) methyl {1-[4-(methoxymethyl){9-[2-(4-methylpyrrolidinyl)-1H-imidazolyl]-1,11- dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl}pyrrolidinyl]methyl oxobutanyl}carbamate tert-butyl 2-[5-(2-{1-[N-(methoxycarbonyl)valyl](methoxymethyl)pyrrolidin yl}-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl)-1H-imidazolyl] methylpyrrolidinecarboxylate (50mg, mol) was treated with 2mL 1.25N HCl in ethanol and heated at 600C for 2h, then it was concentrated under d pressure and pumped dry under high vacuum and used directly in the next step. methyl {1-[2-{9-[2-(1-{[(methoxycarbonyl)amino](phenyl)acetyl}methylpyrrolidin yl)-1H-imidazolyl]-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl}- 4-(methoxymethyl)pyrrolidinyl]methyloxobutanyl}carbamate A mixture of (R)(methoxycarbonylamino)phenylacetic acid (13mg, 0.063mmol), COMU (30mg, 0.069mmol) in 0.500mL DMF and DIPEA (0.033mL, 0.189mmol) was allowed to preactivate for 15 minutes before it was added to the solid crude amine salt from the previous step and stirred ght. The product was purified by reverse phase HPLC. The product was converted to the free base by dissolution in 2mL 1:1 acetonitrile:methanol and passage through a ked cartridge of r supported carbonate. Concentration and drying gave an off white powder. (23.3mg).

MS (ESI) m/z 883.8 [M + H]+ 'H NMR (CD3CN) 8.176 (s, 1H), 7.778 (m, 1H), 7.596-7.521 (m, 4H), 7.455-7.347 (m, 6H), 7.218 (s, 1H), 5.482 (s, 1H), 5.310 (m, 1H), 5.192 (m, 1H), 4.999 (q, 2H, J= 14 Hz), 4.372 (d, 1H, J= 6.4 Hz), 4.279 (m, 1H), 3.800-3.697 (m, 2H), 3.632 (s, 3H) 3.597-3.445 (m, 7H), 3.355 (s, 3H), 2.876 (m, 2H), 2.761 (m, 1H), 2.583 (m, 2H), 2.220 (m, 2H), 1.764 (m, 1H), 1.070 (d, 3H, J = 6.4 Hz), 1.020 (d, 3H, J = 6.4 Hz), 0.898 (d, 3H, J = 6.4 Hz).

Example PG O N N N H H O N B N O N O 3)4, PdCl2(dppf), N O H K2CO3, DME/ DMF, 85°C methyl [(2S)methyl{(2S,4S)methyl[9-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolanyl)-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2- d]imidazolyl]pyrrolidinyl}oxobutanyl]carbamate H O N H O O N N N N N N O methyl {(1R)[(2S,4S)(5-{2-[(2S,4S){(2S)[(methoxycarbonyl)amino]- 3-methylbutanoyl}methylpyrrolidinyl]-1,11- dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl}-1H-imidazolyl)- 4-methylpyrrolidinyl]oxophenylethyl}carbamate tert-butyl (2S,4S)[5-(2-{(2S,4S)[N-(methoxycarbonyl)-L-valyl]methylpyrrolidin- 2-yl}-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl)-1H-imidazol yl]methylpyrrolidinecarboxylate The title compound was obtained as in example LQ but using methyl [(2S)methyl- 1-{(2S,4S)methyl[9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-1,11- dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl]pyrrolidinyl}oxobutan yl]carbamate (307mg, mol) in place of tert-butyl 2-[9-(4,4,5,5-tetramethyl-1,3,2- dioxaborolanyl)-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazol yl]pyrrolidinecarboxylate and methyl (S)((2S,4S)(5-iodo-1H-imidazolyl) pyrrolidinyl)methyloxobutanylcarbamate , 0.481mmol)in place of methyl (S)((S)(5-bromo-1H-imidazolyl)pyrrolidinyl)methyloxobutan ylcarbamate. (200.8mg) methyl {(2S)methyl[(2S,4S)methyl(9-{2-[(2S,4S)methylpyrrolidinyl]- 1H-imidazolyl}-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazol yl)pyrrolidinyl]oxobutanyl}carbamate Tert-butyl (2S,4S)[5-(2-{(2S,4S)[N-(methoxycarbonyl)-L-valyl] methylpyrrolidinyl}-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl)-1H- imidazolyl]methylpyrrolidinecarboxylate (200mg, 0.262mmol) was treated with 2mL 1.25N HCl in ethanol and heated at 600C for 2h, then it was trated under reduced pressure and pumped dry under high vacuum and used directly in the next step. methyl {(1R)[(2S,4S)(5-{2-[(2S,4S){(2S)[(methoxycarbonyl)amino] methylbutanoyl}methylpyrrolidinyl]-1,11- dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl}-1H-imidazolyl) methylpyrrolidinyl]oxophenylethyl}carbamate A mixture of (R)(methoxycarbonylamino)phenylacetic acid (13mg, 0.063mmol), COMU (30mg, 0.069mmol) in 1.5mL DMF was allowed to preactivate for 5 minutes before it was added to a solution of the amine from the previous salt in 1.5mL DMF and DIPEA (0.137mL, 0.786mmol) and stirred ght. The product was purified by reverse phase HPLC. The product was converted to the free base by ution in 2mL 1:1 acetonitrile:methanol and passage through a prepacked dge of polymer supported carbonate. Concentration and drying gave an off white powder. (25.8mg).

MS (ESI) m/z 853.8 [M + H]+.

'H NMR (CD3CN) 8.164 (s, 1H), 7.781 (m, 1H), 7.609 (m, 2H), 7.535 (m, 2H), 7.433- 7.305 (m, 6H), 7.229 (s, 1H), 5.482 (s, 1H), 5.290 (m, 1H), 5.191 (m, 1H), 4.997 (m, 2H), 4.372 (d, 1H, J= 6.4 Hz), 4.267 (m, 1H), 3.735-3.445 (m, 10H), 2.573 (m, 4H), 2.197 (m, 2H), 2.017 (m, 1H), 1.760 (m, 1H), 1.204 (d, 3H, J= 6.4 Hz), 1.068 (d, 3H, J = 6.4 Hz), 1.010 (d, 3H, J = 6.8 Hz), 0.887 (d, 3H, J = 6.8 Hz).

Example PH tert-butyl (2S,4S)[5-(2-{(2S)[(benzyloxy)carbonyl]pyrrolidinyl}-1,11- dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl)-1H-imidazolyl] xymethyl)pyrrolidinecarboxylate The title compound was obtained as in example OF (compound tert-butyl (2S,4S) [5-(2-{(2S,5S)[N-(methoxycarbonyl)-L-valyl]methylpyrrolidinyl}-1,4,5,11- tetrahydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl)-1H-imidazolyl] (methoxymethyl)pyrrolidinecarboxylate) but using (benzyloxycarbonyl)pyrrolidine- 2-carboxylic acid in place of (2S,5S)((S)(methoxycarbonylamino)methylbutanoyl)- -methylpyrrolidinecarboxylic acid in step 6. tert-butyl (2S,4S)(methoxymethyl)(5-{2-[(2S)-pyrrolidinyl]-1,11- dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl}-1H-imidazol yl)pyrrolidinecarboxylate A mixture of tert-butyl (2S,4S)[5-(2-{(2S)[(benzyloxy)carbonyl]pyrrolidin yl}-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl)-1H-imidazolyl] (methoxymethyl)pyrrolidinecarboxylate (724mg, 0.96mmol) and 70mg 10%Pd/C in 20mL ethanol was hydrogenated at 1atm overnight. Additional 10%Pd/C (300mg) and a portion of solid NaHCO3 was added and hydrogenation continued for 4 hours. Filtration h celite and concentration of the filtrate under reduced pressure gave the product as a dark brown solid, 454mg. Purification by reverse phase HPLC gave 65mg purified product. methyl {(1R)[(2S)(9-{2-[(2S,4S)(methoxymethyl)pyrrolidinyl]-1H-imidazol yl}-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl)pyrrolidinyl] oxophenylethyl}carbamate A mixture of (methoxycarbonylamino)phenylacetic acid (22mg, 0.105mmol), COMU (45mg, 0.069mmol), and tert-butyl (2S,4S)(methoxymethyl)(5- {2-[(2S)-pyrrolidinyl]-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl}- 1H-imidazolyl)pyrrolidinecarboxylate (65mg, 0.105mmol) in 1.5mL 10% DIPEA in DMF was d for 1.5h. The reaction e was partitioned between ethyl acetate and saturated sodium bicarbonate. The organic phase was dried over sodium sulphate, ed and concentrated under reduced pressure. The crude intermediate was treated with 8mL 1.25N HCl in ethanol at 500C for 4h. Added saturated sodium bicarbonate and extracted the free base into dichloromethane. (106mg). methyl {(2S)[(2S,4S)(5-{2-[(2S){(2R)[(methoxycarbonyl)amino] phenylacetyl}pyrrolidinyl]-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2- d]imidazolyl}-1H-imidazolyl)(methoxymethyl)pyrrolidinyl]methyl oxobutanyl}carbamate A mixture of methyl {(1R)[(2S)(9-{2-[(2S,4S)(methoxymethyl)pyrrolidin yl]-1H-imidazolyl}-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazol yl)pyrrolidinyl]oxophenylethyl}carbamate (55mg, 0.077mmol), (S) xycarbonylamino)methylbutanoic acid (14mg, 0.077mmol), HATU (32mg, 0.085mmol) and 0.4mL 10% DIPEA in DMF was stirred at room temperature for 1 hour.

The product was ed by reverse phase HPLC. The product was converted to the free base by dissolution in 2mL 1:1 acetonitrile:methanol and passage through a prepacked cartridge of polymer supported ate. The eluent was concentrated, the taken up in 1%TFA in 1:1 acetonitrile:water, , and lyophilized to give the product as a trifluoroacetate salt. (30.7mg) MS (ESI) m/z 869.9 [M + H]+. methyl {(1R)[(2S)(9-{2-[(2S,4S)[N-(methoxycarbonyl)-O-methyl-L-threonyl] (methoxymethyl)pyrrolidinyl]-1H-imidazolyl}-1,11- dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl)pyrrolidinyl]oxo phenylethyl}carbamate A mixture of methyl {(1R)[(2S)(9-{2-[(2S,4S)(methoxymethyl)pyrrolidin yl]-1H-imidazolyl}-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazol yl)pyrrolidinyl]oxophenylethyl}carbamate (51mg, 0.072mmol), (2S,3R) y(methoxycarbonylamino)butanoic acid (14mg, 0.072mmol), HATU (30mg, 0.079mmol) and 0.4mL 10% DIPEA in DMF was stirred at room temperature for 1 hour.

The product was purified by reverse phase HPLC. The product was ted to the free base by dissolution in 2mL 1:1 acetonitrile:methanol and passage through a prepacked cartridge of polymer ted carbonate. The eluent was concentrated, the taken up in 1%TFA in 1:1 acetonitrile:water, frozen, and lyophilized to give the product as a trifluoroacetate salt. (24mg) MS (ESI) m/z 885.8 [M + H]+; 'H NMR (CD3CN) 7.635 (s, 1H), 7.434 (m, 3H), 7.330 (m, 4H), 7.233 (m, 1H), 7.164 (m, 1H), 6.983 (m, 1H), 6.747 (m, 2H), 6.127 (m, 1H), 5.584 (d, 1H, J = 6.4 Hz), 5.431 (m, 1H), 5.145 (m, 1H), 4.729 (s, 2H), 4.442 (m, 1H), 4.029 (m, 2H), 3.838 (m, 1H), 3.662-3.534 (m, 2H), 3.572 (s, 3H) 3.552 (s, 3H), 3.444-3.310 (m, 3H), 3.240 (s, 3H), 3.225 (s, 3H), 2.618 (m, 1H), 2.464 (m, 1H), 2.304 (m, 1H), 2.129 (m, 1H), 2.041 (m, 1H), 1.899 (m, 2H), 1.107 (d, 3H, J = 6.4 Hz).

Example PI O H H N N N 10% Pd/C, H2 Boc N N Boc N N N N N H N N O H H O EtOH tert-butyl )[5-(2-{(2S,5S) [(benzyloxy)carbonyl]methylpyrrolidinyl}-1,11- tert-butyl )(methoxymethyl)(5-{2-[(2S,5S) dihydroisochromeno[4',3':6,7]naphtho[1,2- methylpyrrolidinyl]-1,11- d]imidazolyl)-1H-imidazolyl] dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazol (methoxymethyl)pyrrolidinecarboxylate yl}-1H-imidazolyl)pyrrolidinecarboxylate O O ) methoxy O OH (methoxycarbonyla mino)butanoic acid O H 1) HATU, DIPEA, DMF N N H N O 2) HCl in Ethanol N N N H O N O methyl {(2S,3R)methoxy[(2S,5S)(9-{2-[(2S,4S) (methoxymethyl)pyrrolidinyl]-1H-imidazolyl}-1,11- dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl)- -methylpyrrolidinyl]oxobutanyl}carbamate NH H Moc-Val-OH, HATU, O O N N DIPEA, DMF N O N N N H O N O methyl {(2S)[(2S,4S)(5-{2-[(2S,5S){(2S,3R)methoxy [(methoxycarbonyl)amino]butanoyl}methylpyrrolidinyl]-1,11- dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl}-1H- imidazol yl)(methoxymethyl)pyrrolidinyl]methyloxobutan yl}carbamate tert-butyl (2S,4S)[5-(2-{(2S,5S)[(benzyloxy)carbonyl]methylpyrrolidinyl}- 1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl)-1H-imidazolyl] (methoxymethyl)pyrrolidinecarboxylate The title nd was obtained as in example OF (compound tert-butyl (2S,4S) [5-(2-{(2S,5S)[N-(methoxycarbonyl)-L-valyl]methylpyrrolidinyl}-1,4,5,11- tetrahydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl)-1H-imidazolyl] (methoxymethyl)pyrrolidinecarboxylate) but using (2S,5S)(benzyloxycarbonyl) methylpyrrolidinecarboxylic acid in place of (2S,5S)((S)(methoxycarbonylamino) methylbutanoyl)methylpyrrolidinecarboxylic acid. tert-butyl (2S,4S)(methoxymethyl)(5-{2-[(2S,5S)methylpyrrolidinyl]-1,11- dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl}-1H-imidazol yl)pyrrolidinecarboxylate A mixture of tert-butyl (2S,4S)[5-(2-{(2S,5S)[(benzyloxy)carbonyl] methylpyrrolidinyl}-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl)-1H- imidazolyl](methoxymethyl)pyrrolidinecarboxylate (830mg, 1.08mmol) and 100mg %Pd/C in 20mL ethanol was hydrogenated at 1atm overnight. Additional 10%Pd/C (300mg) and a portion of solid NaHCO3 was added and hydrogenation continued for 4 hours.

Filtration through celite and concentration of the filtrate under reduced pressure gave the product as a dark brown solid, 722mg. Purification by reverse phase HPLC gave 100mg purified product. methyl R)methoxy[(2S,5S)(9-{2-[(2S,4S)(methoxymethyl)pyrrolidin yl]-1H-imidazolyl}-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl)- ylpyrrolidinyl]oxobutanyl}carbamate A e of tert-butyl (2S,4S)(methoxymethyl)(5-{2-[(2S,5S) methylpyrrolidinyl]-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl}-1H- imidazolyl)pyrrolidinecarboxylate (101mg, 0.159mmol), (2S,3R)methoxy (methoxycarbonylamino)butanoic acid (30mg, 0.159mmol), HATU (61mg, 0.159mmol) and 2mL 10% DIPEA in DMF was stirred at room ature for 1.5 hours. Saturated sodium bicarbonate was added and the t was extracted into dichloromethane, dried over sodium sulphate, filtered and concentrated under reduced pressure. This crude product was treated with 5mL 1.25N HCl in ethanol at 500C for 4h and then it was concentrated under reduced pressure. Saturated sodium bicarbonate was added and the product was extracted into dichloromethane, dried over sodium te, filtered and concentrated under reduced pressure. (74.6mg) methyl 1-[(2S,4S)(5-{2-[(2S,5S){(2S,3R)methoxy [(methoxycarbonyl)amino]butanoyl}methylpyrrolidinyl]-1,11- oisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl}-1H-imidazolyl) (methoxymethyl)pyrrolidinyl]methyloxobutanyl}carbamate A mixture of methyl {(2S,3R)methoxy[(2S,5S)(9-{2-[(2S,4S) (methoxymethyl)pyrrolidinyl]-1H-imidazolyl}-1,11- dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl)methylpyrrolidinyl] oxobutanyl}carbamate (74.6mg, 0.105mmol), (S)(methoxycarbonylamino) methylbutanoic acid (18.5mg, mol), HATU (44mg, 0.116mmol) and 0.6mL 10% DIPEA in DMF was stirred at room ature for 1 hour. The product was purified by reverse phase HPLC. (48.1mg) MS (ESI) m/z 866.1 [M + H]+.

Example PJ tert-butyl (2S,4S)(9-{2-[(2S,4S)[N-(methoxycarbonyl)-L-valyl] (trifluoromethyl)pyrrolidinyl]-1H-imidazolyl}-1,11- dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl) (methoxymethyl)pyrrolidinecarboxylate The title compound was prepared as in e OF for compound tert-butyl (2S,4S)- 2-[5-(2-{(2S,5S)[N-(methoxycarbonyl)-L-valyl]methylpyrrolidinyl}-1,11- dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl)-1H-imidazolyl] (methoxymethyl)pyrrolidinecarboxylate, by using (2S,4S)((S) (methoxycarbonylamino)methylbutanoyl)(trifluoromethyl)pyrrolidinecarboxylic acid in place of (2S,4S)(tert-butoxycarbonyl)(methoxymethyl)pyrrolidinecarboxylic acid and (2S,4S)(tert-butoxycarbonyl)(methoxymethyl)pyrrolidinecarboxylic acid in place of (2S,5S)((S)(methoxycarbonylamino)methylbutanoyl)methylpyrrolidine- 2-carboxylic acid. methyl {(1R)[(2S,4S)(9-{2-[(2S,4S){(2S)[(methoxycarbonyl)amino] butanoyl}(trifluoromethyl)pyrrolidinyl]-1H-imidazolyl}-1,11- dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl) (methoxymethyl)pyrrolidinyl]oxophenylethyl}carbamate utyl (2S,4S)(9-{2-[(2S,4S)[N-(methoxycarbonyl)-L-valyl] (trifluoromethyl)pyrrolidinyl]-1H-imidazolyl}-1,11- dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl)(methoxymethyl)pyrrolidine carboxylate (<0.412mmol, crude from previous step) was treated with 6mL 4N HCl in dioxane at room temperature overnight and then at 50OC for 1 hour. Diethyl ether (20mL) was added and the precipitate of hydrochloride salt was collected by vacuum filtration. , 0.16mmol). This material was combined with (methoxycarbonylamino) phenylacetic acid (34mg, 0.16mmol), COMU (70mg, 0.16mmol), and 1.6mL of 10% DIPEA in DMF. After 1 hour at room temperature, the mixture was added dropwise into 25mL saturated sodium bicarbonate, with stirring and the resulting precipitate was collected by vacuum filtration and washed with 2mL water. The product was purified, then re-purified by reverse phase HPLC. (3.5mg).

MS (ESI) m/z 938.1 [M + H]+.

Example PK (2S,4S)-tert-butyl 2-formylmethylpyrrolidinecarboxylate: A mixture of (2S,4S)(tert-butoxycarbonyl)methylpyrrolidinecarboxylic acid (5.2g, 22.7 mmol), O,N-dimethylhydroxylamine hloride (2.4g, 24.9mmol), HATU (10.4g, 27.2mmol) and DIPEA (9.5mL, 54.5mmol) in 114mL DMF was stirred at room temperature overnight. The mixture was extracted into ethyl e and washed with saturated bicarbonate and water, dried over sodium te, filtered, and concentrated. It was then dissolved in diethyl ether ) and washed with water to remove residual DMF, dried, filtered, and concentrated to a pale yellow oil (5.30g, 19.5mmol) of )-tert-butyl 2-(methoxy(methyl)carbamoyl)methylpyrrolidinecarboxylate. (2S,4S)-tert-butyl 2-(methoxy(methyl)carbamoyl)methylpyrrolidinecarboxylate (5.30g, 19.5mmol) was dissolved in 120mL THF, cooled to -78OC and treated with lithium aluminum hydride (1M in THF, 19.5mL, ol) se via on funnel. After 1 hour, the mixture was brought to 0OC and kept at that temperature for 2 hours. It was quenched by dropwise addition of a 50mL solution of 3.0g KHSO4 in water, removed from the ice bath, and stirred 15 minutes at room temperature. The product was extracted with three 75mL portions of ethyl acetate and washed with brine. The organic phase was dried over sodium sulphate, filtered, and concentrated to give crude (2S,4S)-tert-butyl 2-formyl methylpyrrolidinecarboxylate. (4.89g) (2S,4S)-tert-butyl 2-(1H-imidazolyl)methylpyrrolidinecarboxylate: To a solution of )-tert-butyl 2-formylmethylpyrrolidinecarboxylate (4.89g, 22.9mmol), ammonium ide (17mL) and water (17mL) was added, dropwise, glyoxal (40% in water, 14.6mL, 128mmol) and the resulting mixture was stirred at room temperature overnight. Saturated sodium bicarbonate (100mL) was added and the mixture was extracted with four 75mL portions of dichloromethane. The organic phase was washed with water, dried over sodium sulphate, filtered and concentrated, and then purified by silica gel chromatography to give a total of 3.76g product. (2S,4S)-tert-butyl 2-(5-iodo-1H-imidazolyl)methylpyrrolidinecarboxylate: A mixture of (2S,4S)-tert-butyl 2-(1H-imidazolyl)methylpyrrolidine carboxylate (1.0g, 3.97mmol), iodine (2.22g, 8.75mmol) and sodium carbonate (1.3g, mol) in 20mL dioxane and 13.25mL water was covered in foil and stirred at room temperature overnight. The mixture was diluted with ethyl acetate and treated with 10% sodium thiosulfate (5mL) and stirred for 10 minutes. The organic phase was washed with brine, and then the aqueous phase was back ted with ethyl acetate. The combined organic phases were dried over sodium te, filtered and concentrated to e crude (2S,4S)-tert-butyl 2-(4,5-diiodo-1H-imidazolyl)methylpyrrolidinecarboxylate (2.25g) as a pale yellow solid.

A solution of )-tert-butyl 2-(4,5-diiodo-1H-imidazolyl)methylpyrrolidine- 1-carboxylate , 4.4mmol) in 18mL ethanol and 18mL water was treated with sodium sulfite (5.59g, 44.4 mmol) and heated at 90 OC overnight. The mixture was partitioned between ethyl acetate and water. The aqueous phase was extracted with more ethyl acetate and the combined organic phase was washed with brine, dried over sodium sulphate, filtered, concentrated, and purified by silica gel chromatography to give 766mg (2S,4S)-tert-butyl 2- (5-iodo-1H-imidazolyl)methylpyrrolidinecarboxylate.

Example PL (2S,3aS,6aS)(tert-butoxycarbonyl)octahydrocyclopenta[b]pyrrolecarboxylic acid To a on of commercially available (2S,3aS,6aS)-benzyl octahydrocyclopenta[b]pyrrolecarboxylate hydrochloride (4.70 g, 16.68 mmol) in methylene chloride (42 mL) was added Di-tert-butyl dicarbonate (7.28 g, 33.36 mmol), N,N- diisopropylethylamine (5.82 mL, 33.36 mmol) and 4-(Dimethylamino)pyridine (0.20 g, 1.67 mmol). The solution was stirred under air for 16 hours. Upon completion, the reaction was concentrated in vacuo, diluted in ethyl acetate, and washed with 1N HCl. The aqueous layers were backextracted twice with ethyl acetate and the combined organic layers were dried over sodium sulfate, filtered and concentrated. The resulting residue was purified by silica gel chromatography (5-40% ethyl acetate in s) to afford S,6aS)(tert- butoxycarbonyl)octahydrocyclopenta[b]pyrrolecarboxylic acid which was used t further purification. MS (ESI) m/z 368.47 [M + Na]+. (2S,3aS,6aS)(tert-butoxycarbonyl)octahydrocyclopenta[b]pyrrolecarboxylic acid To a 250mL round bottom flask charged with a stir bar and (2S,3aS,6aS)benzyl 1- tert-butyl hexahydrocyclopenta[b]pyrrole-1,2(2H)-dicarboxylate (5.76 g, 16.68 mmol) was added 10% Palladium on carbon (1.77g). Ethanol was poured over the mixture and the reaction mixture was evacuated and flushed with en gas three times. The suspension was stirred at room temperature under an atmosphere of en for 24 hours. Upon completion, the reaction mixture was filtered through celite and concentrated to give (2S,3aS,6aS)(tert-butoxycarbonyl)octahydrocyclopenta[b]pyrrolecarboxylic acid (4.45g, >99%). MS (ESI) m/z 256.21 [M + H]+.

Example PM O H H H 1) HCl N N Cl N Cl N N Boc 2) HATU O HN O MocVal tert-butyl (3aS,6aS)(9-chloro-1,12- methyl {(2S)[(2S,3aS,6aS)(9-chlorodihydrochromeno [4',3':6,7]naphtho[1,2-d]imidazol- 1,11- 2-yl)hexahydrocyclopenta[b]pyrrole-1(2H)- oisochromeno[4',3':6,7]naphtho[1,2- ylate d]imidazol yl)hexahydrocyclopenta[b]pyrrol-1(2H)-yl] methyloxobutanyl}carbamate O H H N Boc Br O N N N N Pd2dba3 O N H HN O tert-butyl 2-(5-bromo-1HBis-PinB imidazolyl)pyrrolidine XPhos O methyl {(2S)methyloxo carboxylate [(2S,3aS,6aS)[9-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolanyl)-1,11- dihydroisochromeno[4',3':6,7]naphtho[1,2- Pd(PPh3)4 d]imidazol PdCl(dppf) yl]hexahydrocyclopenta[b]pyrrol-1(2H)- yl]butanyl}carbamate O H H N N Boc N N N N H O HN O tert-butyl 2-[5-(2-{(2S,3aS,6aS)[N- (methoxycarbonyl)-L- valyl]octahydrocyclopenta[b]pyrrolyl}-1,11- dihydroisochromeno[4',3':6,7]naphtho[1,2- d]imidazolyl)-1H-imidazolyl]pyrrolidine carboxylate tert-butyl 2-[5-(2-{(2S,3aS,6aS)[N-(methoxycarbonyl)-L- valyl]octahydrocyclopenta[b]pyrrolyl}-1,11- dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl)-1H-imidazol yl]pyrrolidinecarboxylate This compound was made in an analogous manner to tert-butyl (2R)[5-(2-{(2S) thoxycarbonyl)-L-valyl]pyrrolidinyl}-3,11- dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl)-1H-imidazolyl]pyrrolidine carboxylate substituting (2S,3aS,6aS)(tert-butoxycarbonyl)octahydrocyclopenta[b]pyrrole- 2-carboxylic acid for the initial alkylation of 9-bromochloro-10,11-dihydro-6H- o[2,3-c]chromen-8(9H)-one. Reactions in the synthesis of tert-butyl 2-[5-(2- {(2S,3aS,6aS)[N-(methoxycarbonyl)-L-valyl]octahydrocyclopenta[b]pyrrolyl}-1,11- dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl)-1H-imidazolyl]pyrrolidine carboxylate gave similar product yields as in the synthesis of utyl (2R)[5-(2-{(2S) [N-(methoxycarbonyl)-L-valyl]pyrrolidinyl}-3,11- oisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl)-1H-imidazolyl]pyrrolidine carboxylate. MS (ESI) m/z 774.1 [M + H]+.

Example PN O H H N N N Boc 1) HCl N N N H O HN O 2) COMU, R-MocPhg tert-butyl 2-[5-(2-{(2S,3aS,6aS)[N- (methoxycarbonyl)-L- valyl]octahydrocyclopenta[b]pyrrolyl}-1,11- dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazol yl)-1H-imidazolyl]pyrrolidinecarboxylate HN O H H N N N N N N H O HN O methyl {(1R)[2-(5-{2-[(2S,3aS,6aS){(2S)[(methoxycarbonyl)amino]- 3-methylbutanoyl}octahydrocyclopenta[b]pyrrolyl]-1,11- dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl}-1H-imidazol- 2-yl)pyrrolidinyl]oxophenylethyl}carbamate methyl {(1R)[2-(5-{2-[(2S,3aS,6aS){(2S)[(methoxycarbonyl)amino] methylbutanoyl}octahydrocyclopenta[b]pyrrolyl]-1,11- dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl}-1H-imidazol yl)pyrrolidinyl]oxophenylethyl}carbamate To a solution of utyl 2-[5-(2-{(2S,3aS,6aS)[N-(methoxycarbonyl)-L- valyl]octahydrocyclopenta[b]pyrrolyl}-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2- d]imidazolyl)-1H-imidazolyl]pyrrolidinecarboxylate (0.128 g, 0.165 mmol) in a mixture of CH2Cl2 (1.6 mL) and MeOH (0.33 mL) was added HCl (4M in 1,4-dioxane, 1.24 mL, 4.9 mmol). The solution was stirred at room temperature for 1.5 h and concentrated to dryness.

The ediate was dissolved in CH2Cl2 (1.6 mL). (R)(methoxycarbonylamino)- 2-phenylacetic acid (0.052 g, 0.25 mmol) and DIPEA (0.087 mL, 0.496 mmol) were then added to the solution. The reaction mixture was cooled to -40 °C (external temperature, O2(s) bath). COMU (0.113 g, 0.265 mmol) was then added and solution was allowed to warm to 0 °C over 1.5 h. Upon completion by LCMS, the solution was diluted with DMF and concentrated. The crude product was ed by preparative HPLC (Gemini column, 10-47% MeCN/H2O with 0.1% TFA) and the desired fractions were combined. The solution was concentrated until the aqueous layer remained and aqueous bicarbonate (sat.) was slowly added until the solution was basic. The resulting slurry was stirred at room temperature for 2h and filtered. The ing solid was dried in vacuo to e methyl {(1R)[2-(5-{2-[(2S,3aS,6aS){(2S)[(methoxycarbonyl)amino] methylbutanoyl}octahydrocyclopenta[b]pyrrolyl]-1,11- dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl}-1H-imidazolyl)pyrrolidin yl]oxophenylethyl}carbamate (0.068 g, 48%).

MS (ESI) m/z 865.7 [M + H]+. 1H NMR (400 MHz, cd 3od) δ 8.44 – 8.30 (m, 1H), 8.02 – 7.82 (m, 2H), 7.81 – 7.58 (m, 4H), 7.50 – 7.11 (m, 6H), 7.09 – 6.83 (m, 2H), 5.72 – .45 (m, 2H), 5.41 (s, 1H), 5.34 – 5.28 (m, 1H), 5.22 (s, 3H), 4.69 – 4.64 (m, 1H), 4.26 – 4.19 (m, 1H), 4.03 – 3.98 (m, 1H), 3.96 – 3.91 (m, 1H), 3.66 (d, 4H), 2.98 – 2.91 (m, 1H), 2.88 – 2.83 (m, 1H), 2.58 – 2.48 (m, 1H), 2.27 – 2.12 (m, 4H), 2.11 – 2.00 (m, 3H), 2.00 – 1.89 (m, 2H), 1.77 – 1.72 (m, 1H), 1.31 – 1.04 (m, 3H), 0.93 (d, 6H). e PO O H H N N N 1) HCl N N N H O O 2) HATU, HN S-MocVal tert-butyl 2-[5-(2-{(2S,3aS,6aS)[N- xycarbonyl)-L- valyl]octahydrocyclopenta[b]pyrrolyl}-1,11- dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazol yl)-1H-imidazolyl]pyrrolidinecarboxylate HN O H H N N N N N N H O HN O methyl {(2S)[2-(5-{2-[(2S,3aS,6aS){(2S)[(methoxycarbonyl)amino] methylbutanoyl}octahydrocyclopenta[b]pyrrolyl]-1,11- dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl}-1H-imidazol- 2-yl)pyrrolidinyl]methyloxobutanyl}carbamate methyl {(2S)[2-(5-{2-[(2S,3aS,6aS){(2S)[(methoxycarbonyl)amino] butanoyl}octahydrocyclopenta[b]pyrrolyl]-1,11- dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl}-1H-imidazol yl)pyrrolidinyl]methyloxobutanyl}carbamate To a solution of utyl 2-[5-(2-{(2S,3aS,6aS)[N-(methoxycarbonyl)-L- valyl]octahydrocyclopenta[b]pyrrolyl}-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2- d]imidazolyl)-1H-imidazolyl]pyrrolidinecarboxylate (0.030 g, 0.039 mmol) in a mixture of CH2Cl2 (0.39 mL) and MeOH (0.078 mL) was added HCl (4M in 1,4-dioxane, 0.29 mL, 1.16 mmol). The solution was stirred at room temperature for 1.5 h and concentrated to dryness.

The intermediate was dissolved in CH2Cl2 (0.39 mL). (S)(methoxycarbonylamino)- 3-methylbutanoic acid (0.007 g, 0.043 mmol) and DIPEA (0.020 mL, 0.116 mmol) were then added to the solution. HATU (0.018 g, 0.047 mmol) was added and solution was allowed to stir at room temp. Upon completion, the solution was diluted with DMF and concentrated.

The crude product was purified by preparative HPLC (Gemini column, 10-47% MeCN/H2O with 0.1% TFA) and the desired fractions were combined and lyophilized to provide methyl {(2S)[2-(5-{2-[(2S,3aS,6aS){(2S)[(methoxycarbonyl)amino] methylbutanoyl}octahydrocyclopenta[b]pyrrolyl]-1,11- dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl}-1H-imidazolyl)pyrrolidin yl]methyloxobutanyl}carbamate (0.010g, 31%). MS (ESI) m/z 832.2 [M + H]+.

Example PP methyl [(1S)[2-(5-{2-[(2S,3aS,6aS){(2S)[(methoxycarbonyl)amino] methylbutanoyl}octahydrocyclopenta[b]pyrrolyl]-1,11- oisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl}-1H-imidazol yl)pyrrolidinyl]oxo(tetrahydro-2H-pyranyl)ethyl]carbamate This compound was made in an analogous manner to methyl {(2S)[2-(5-{2- [(2S,3aS,6aS){(2S)[(methoxycarbonyl)amino] methylbutanoyl}octahydrocyclopenta[b]pyrrolyl]-1,11- dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl}-1H-imidazolyl)pyrrolidin yl]methyloxobutanyl}carbamate, substituting (S)(methoxycarbonylamino) (tetrahydro-2H-pyranyl)acetic acid for (methoxycarbonylamino)methylbutanoic acid to give methyl [(1S)[2-(5-{2-[(2S,3aS,6aS){(2S)[(methoxycarbonyl)amino] methylbutanoyl}octahydrocyclopenta[b]pyrrolyl]-1,11- dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl}-1H-imidazolyl)pyrrolidin yl]oxo(tetrahydro-2H-pyranyl)ethyl]carbamate (0.039 g, 56%). MS (ESI) m/z 874.34 [M + H]+. 1H NMR (400 MHz, cd 3od) δ 8.58 (s, 2H), 8.26 – 8.08 (m, 2H), 7.96 – 7.75 (m, 4H), 7.65 – 7.54 (m, 5H), 5.36 – 5.11 (m, 4H), 4.34 – 4.04 (m, 4H), 3.97 – 3.79 (m, 4H), 3.65 (s, 4H), 3.53 – 3.44 (m, 2H), 2.68 – 2.47 (m, 4H), 2.32 – 2.02 (m, 7H), 1.95 – 1.82 (m, 3H), 1.77 – 1.54 (m, 4H), 1.49 – 1.24 (m, 5H), 1.10 – 0.99 (m, 3H), 0.92 – 0.85 (m, 4H).

Example PQ O H H F 1) HCl N N N N N N 2) COMU, H O O MocPhg tert-butyl 2-[5-(2-{(2S,4S)[(difluoromethoxy)methyl]- 1-[N-(methoxycarbonyl)-L-valyl]pyrrolidinyl}-1,11- oisochromeno[4',3':6,7]naphtho[1,2-d]imidazol yl)-1H-imidazolyl]pyrrolidinecarboxylate O O HN O H H F O N N N N N N H O HN O methyl 2-[2-(5-{2-[(2S,4S)[(difluoromethoxy)methyl]{(2S)- 2-[(methoxycarbonyl)amino]methylbutanoyl}pyrrolidinyl]-1,11- dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl}-1H-imid azolyl)pyrrolidinyl]oxophenylethyl}carbamate tert-butyl 2-[5-(2-{(2S,4S)[(difluoromethoxy)methyl][N-(methoxycarbonyl)-L- valyl]pyrrolidinyl}-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl)- 1H-imidazolyl]pyrrolidinecarboxylate This compound was made in an analogous manner to tert-butyl 2-[5-(2- {(2S,3aS,6aS)[N-(methoxycarbonyl)-L-valyl]octahydrocyclopenta[b]pyrrolyl}-1,11- dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl)-1H-imidazolyl]pyrrolidine carboxylate substituting (2S,4S)(tert-butoxycarbonyl) ((difluoromethoxy)methyl)pyrrolidinecarboxylic acid for the initial alkylation of 9-bromo- ro-10,11-dihydro-6H-naphtho[2,3-c]chromen-8(9H)-one. Reactions in the synthesis of tert-butyl 2-[5-(2-{(2S,4S)[(difluoromethoxy)methyl][N-(methoxycarbonyl)-L- valyl]pyrrolidinyl}-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl)-1H- imidazolyl]pyrrolidinecarboxylate gave similar t yields as in the synthesis of tert-butyl 2-[5-(2-{(2S,3aS,6aS)[N-(methoxycarbonyl)-L- valyl]octahydrocyclopenta[b]pyrrolyl}-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2- d]imidazolyl)-1H-imidazolyl]pyrrolidinecarboxylate. MS (ESI) m/z 815.04 [M + H]+. 1H NMR (400 MHz, cd 3od) δ 8.58 (s, 1H), 8.18 (d, 1H), 7.96 – 7.85 (m, 3H), 7.70 (s, 1H), 7.60 (d, 1H), 7.50 – 7.38 (m, 4H), 7.10 (s, 1H), 6.46 (t, 1H), 5.51 (s, 1H), 5.39 – 5.36 (m, 1H), 5.31 – 5.28 (m, 2H), 4.43 – 4.36 (m, 1H), 4.24 (d, 1H), 4.13 – 4.02 (m, 3H), 3.75 – 3.62 (m, 7H), 3.51 – 3.47 (m, 1H), 3.18 – 3.11 (m, 2H), 2.93 – 2.83 (m, 2H), 2.75 – 2.69 (m, 1H), 2.47 – 2.36 (m, 2H), 2.23 – 2.09 (m, 3H), 2.01 – 1.94 (m, 2H), 0.87 (dd, 6H).

Example PR HO N O (1R,5R)(tert- O butoxycarbonyl) Cl Cl azabicyclo[3.1.0]hexane O N Br carboxylic acid Boc 9-bromochloro-10,11-dihydro-5H- (1R,5R)tert-butyl 3-(3-chlorooxodibenzo [c,g]chromen-8(9H)-one 8,9,10,11-tetrahydro-5H- dibenzo[c,g]chromenyl) 2- yclo[3.1.0]hexane-2,3- dicarboxylate O H NH4OAc O H H MnO2 N N N Cl N Cl Boc N Boc tert-butyl (1R,5R)(9-chloro-1,12- tert-butyl (1R,3S,5R)(9-chloro- dihydrochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl)- 1,4,5,11- 2-azabicyclo[3.1.0]hexanecarboxylate tetrahydroisochromeno[4',3':6,7]naphtho[ 1,2-d]imidazolyl) azabicyclo[3.1.0]hexanecarboxylate O H H 1) HCl N Cl N Pd2dba3 2) HATU O HN O Bis-PinB MocVal XPhos methyl 1-[(1R,3S,5R)(9-chloro-1,11- dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl) azabicyclo[3.1.0]hexyl]methyloxobutan yl}carbamate tert-butyl (2S,4S)[5-(2-{(1R,3S,5R)[N-(methoxycarbonyl)-L-valyl] azabicyclo[3.1.0]hexyl}-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazol yl)-1H-imidazolyl](methoxymethyl)pyrrolidinecarboxylate This compound was made in an analogous manner to tert-butyl (2R)[5-(2-{(2S) thoxycarbonyl)-L-valyl]pyrrolidinyl}-3,11- dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl)-1H-imidazolyl]pyrrolidine carboxylate substituting (1R,5R)(tert-butoxycarbonyl)azabicyclo[3.1.0]hexane carboxylic acid for the initial alkylation of 9-bromochloro-10,11-dihydro-5H- dibenzo[c,g]chromen-8(9H)-one, and substituting (2S,4S)-tert-butyl 2-(5-iodo-1H-imidazol- 2-yl)(methoxymethyl)pyrrolidinecarboxylate for the Suzuki-Miyara coupling.

Reactions in the synthesis of utyl (2S,4S)[5-(2-{(1R,3S,5R)[N- (methoxycarbonyl)-L-valyl]azabicyclo[3.1.0]hexyl}-1,11- dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl)-1H-imidazolyl] (methoxymethyl)pyrrolidinecarboxylategave similar product yields as in the sis of tert-butyl (2R)[5-(2-{(2S)[N-(methoxycarbonyl)-L-valyl]pyrrolidinyl}-3,11- dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl)-1H-imidazolyl]pyrrolidine carboxylate. MS (ESI) m/z 791.0 [M + H]+. methyl {(1R)[(2S,4S)(5-{2-[(1R,3S,5R){(2S)[(methoxycarbonyl)amino] methylbutanoyl}azabicyclo[3.1.0]hexyl]-1,11- dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl}-1H-imidazolyl) (methoxymethyl)pyrrolidinyl]oxophenylethyl}carbamate To a solution of tert-butyl (2S,4S)[5-(2-{(1R,3S,5R)[N-(methoxycarbonyl)-L- valyl]azabicyclo[3.1.0]hexyl}-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2- d]imidazolyl)-1H-imidazolyl](methoxymethyl)pyrrolidinecarboxylate (0.060 g, 0.076 mmol) in a mixture of CH2Cl2 (0.76 mL) and MeOH (0.15 mL) was added HCl (4M in 1,4-dioxane, 0.570 mL, 2.28 mmol). The solution was stirred at room ature for 2 h and concentrated to dryness.

The intermediate was dissolved in CH2Cl2 (0.76 mL). (R) (methoxycarbonylamino)phenylacetic acid (0.024 g, 0.114 mmol) and DIPEA (0.040 mL, 0.228 mmol) were then added to the solution. The reaction mixture was cooled to -40 °C (external temperature, MeCN/CO2(s) bath). COMU (0.052 g, 0.122 mmol) was then added and solution was allowed to warm to 0 °C over 1.5 h. Upon tion by LCMS, the on was diluted with DMF and concentrated. The crude product was purified by preparative HPLC (Gemini , 10-45% MeCN/H2O with 0.1% TFA) and lyophilized to provide methyl {(1R)[(2S,4S)(5-{2-[(1R,3S,5R){(2S)[(methoxycarbonyl)amino]- 3-methylbutanoyl}azabicyclo[3.1.0]hexyl]-1,11- dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl}-1H-imidazolyl) (methoxymethyl)pyrrolidinyl]oxophenylethyl}carbamate (0.028 g, 42%). MS (ESI) m/z 881.8 [M + H]+. 1H NMR (400 MHz, cd 3od) δ 8.45 – 8.33 (m, 1H), 8.02 – 7.94 (m, 1H), 7.91 – 7.75 (m, 2H), 7.72 – 7.67 (m, 1H), 7.61 (s, 1H), 7.59 – 7.34 (m, 6H), 7.09 – 6.91 (m, 2H), 5.62 – 5.38 (m, 2H), 5.29 (t, 1H), 5.24 – 5.09 (m, 3H), 4.61 (d, 1H), 4.37 – 4.26 (m, 1H), 3.83 – 3.73 (m, 1H), 3.69 – 3.56 (m, 6H), 3.50 – 3.40 (m, 1H), 3.20 – 3.11 (m, 1H), 2.99 (s, 1H), 2.83 (d, 1H), 2.63 – 2.50 (m, 2H), 2.47 – 2.34 (m, 2H), 2.29 – 2.13 (m, 2H), 2.10 – 1.95 (m, 2H), 1.37 – 1.23 (m, 3H), 1.19 – 1.10 (m, 1H), 1.03 – 0.78 (m, 7H).

Example PS O H H F 1) HCl/dioxane N N Boc N N N N Boc 2) MocVal, HATU H H DIPEA, DMF tert-butyl (2S,4S)(9-{2-[(2S,5S)(tertbutoxycarbonyl )methylpyrrolidinyl]-1H- imidazolyl}-1,11- dihydroisochromeno[4',3':6,7]naphtho[1,2- d]imidazolyl)[(difluoromethoxy)methyl]pyrroli -carboxylate O O HN O H H O N N N N N N H H O O NH methyl {(2S)[(2S,5S)(5-{2-[(2S,4S) [(difluoromethoxy)methyl]{(2S)[(methoxycarbonyl)amino] methylbutanoyl}pyrrolidinyl]-1,11- dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl} -1H-imidazolyl)methylpyrrolidinyl]methyloxobutan- 2-yl}carbamate tert-butyl (2S,4S)(9-{2-[(2S,5S)(tert-butoxycarbonyl)methylpyrrolidinyl]-1H- olyl}-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl) [(difluoromethoxy)methyl]pyrrolidinecarboxylate This compound was made in an analogous manner to tert-butyl (2S,4S)[5-(2- {(2S,5S)[N-(methoxycarbonyl)-L-valyl]methylpyrrolidinyl}-1,11- dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl)-1H-imidazolyl] (methoxymethyl)pyrrolidinecarboxylate tuting (2S,5S)(tert-butoxycarbonyl) methylpyrrolidinecarboxylic acid for the initial alkylation of 3-(2-bromoacetyl)-10,11- dihydro-5H-dibenzo[c,g]chromen-8(9H)-one, and substituting (2S,4S)(tertbutoxycarbonyl )((difluoromethoxy)methyl)pyrrolidinecarboxylic acid for the other alkylation in the sequence. ons in the synthesis of tert-butyl (2S,4S)(9-{2-[(2S,5S)- 1-(tert-butoxycarbonyl)methylpyrrolidinyl]-1H-imidazolyl}-1,11- dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl) [(difluoromethoxy)methyl]pyrrolidinecarboxylategave similar product yields as in the synthesis of tert-butyl (2S,4S)[5-(2-{(2S,5S)[N-(methoxycarbonyl)-L-valyl] methylpyrrolidinyl}-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl)-1H- imidazolyl](methoxymethyl)pyrrolidinecarboxylate. MS (ESI) m/z 772.03 [M + H]+. methyl 1-[(2S,5S)(5-{2-[(2S,4S)[(difluoromethoxy)methyl]{(2S) [(methoxycarbonyl)amino]methylbutanoyl}pyrrolidinyl]-1,11- oisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl}-1H-imidazolyl) methylpyrrolidinyl]methyloxobutanyl}carbamate To a solution of tert-butyl (2S,4S)(9-{2-[(2S,5S)(tert-butoxycarbonyl) methylpyrrolidinyl]-1H-imidazolyl}-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2- d]imidazolyl)[(difluoromethoxy)methyl]pyrrolidinecarboxylate (0.081 g, 0.105 mmol) in a mixture of CH2Cl2 (1.05 mL) and MeOH (0.210 mL) was added HCl (4M in 1,4- dioxane, 0.788 mL, 3.15 mmol). The solution was stirred at room temperature for 2 h and concentrated to dryness.

The intermediate was dissolved in CH2Cl2 (1.05 mL). (S)(methoxycarbonylamino)- 3-methylbutanoic acid (0.040 g, 0.231 mmol) and DIPEA (0.055 mL, 0.315 mmol) were then added to the solution. HATU (0.176 g, 0.462 mmol) was added and solution was allowed to stir at room temp. Upon completion, the solution was diluted with DMF and concentrated.

The crude product was purified by preparative HPLC (Gemini column, 10-45% MeCN/H2O with 0.1% TFA) and the d ons were combined. The solution was concentrated until the aqueous layer remained and aqueous bicarbonate (sat.) was slowly added until the solution was basic. The resulting slurry was stirred at room temperature for 2h and filtered.

The resulting solid was dried in vacuo to provide methyl {(2S)[(2S,5S)(5-{2-[(2S,4S)- fluoromethoxy)methyl]{(2S)[(methoxycarbonyl)amino] methylbutanoyl}pyrrolidinyl]-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazol- 9-yl}-1H-imidazolyl)methylpyrrolidinyl]methyloxobutanyl}carbamate (0.025 g, 27%). MS (ESI) m/z 886.1 [M + H]+. 1H NMR (400 MHz, cd 3od) δ 8.49 – 8.25 (m, 2H), 8.08 – 7.82 (m, 2H), 7.79 – 7.27 (m, 5H), 6.45 (t, 1H), 5.36 – 5.26 (m, 1H), 5.22 – .07 (m, 3H), 4.78 – 4.49 (m, 2H), 4.45 – 4.19 (m, 3H), 4.16 – 4.05 (m, 2H), 3.99 – 3.92 (m, 1H), 3.85 – 3.71 (m, 2H), 3.66 (s, 3H), 2.88 – 2.70 (m, 2H), 2.69 – 2.49 (m, 2H), 2.42 – 2.26 (m, 2H), 2.23 – 2.10 (m, 2H), 2.07 – 1.87 (m, 3H), 1.51 (d, 2H), 1.34 – 1.20 (m, 2H), 1.17 – 0.76 (m, 12H). e PT O H H N N Boc N 1) HCl/dioxane N N N Boc F H H F 2) , HATU O DIPEA, DMF tert-butyl (2S,4S)(5-{2-[(2S,5S)(tert-butoxycarbonyl)- -methylpyrrolidinyl]-1,11- dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl}- 1H-imidazolyl)[(difluoromethoxy)methyl]pyrroli dinecarboxylate HN O H H O N N N N N N F H H O O NH O O methyl {(2S)[(2S,4S)[(difluoromethoxy)methyl](5-{2-[(2S,5S) {(2S)[(methoxycarbonyl)amino]methylbutanoyl} methylpyrrolidinyl]-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2- d]imida zolyl}-1H-imidazolyl)pyrrolidinyl]methyloxobutan yl}carbamate methyl {(2S)[(2S,4S)[(difluoromethoxy)methyl](5-{2-[(2S,5S){(2S) [(methoxycarbonyl)amino]methylbutanoyl}methylpyrrolidinyl]-1,11- dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl}-1H-imidazol yl)pyrrolidinyl]methyloxobutanyl}carbamate This compound was made in an analogous manner to tert-butyl (2S,4S)[5-(2- {(2S,5S)[N-(methoxycarbonyl)-L-valyl]methylpyrrolidinyl}-1,11- dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl)-1H-imidazolyl] (methoxymethyl)pyrrolidinecarboxylate tuting (2S,4S)(tert-butoxycarbonyl) ((difluoromethoxy)methyl)pyrrolidinecarboxylic acid for the initial alkylation of 3-(2- bromoacetyl)-10,11-dihydro-5H-dibenzo[c,g]chromen-8(9H)-one, and substituting (2S,5S) (tert-butoxycarbonyl)methylpyrrolidinecarboxylic acid for the other alkylation in the sequence. Reactions in the synthesis of tert-butyl (2S,4S)(5-{2-[(2S,5S)(tert- butoxycarbonyl)methylpyrrolidinyl]-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2- d]imidazolyl}-1H-imidazolyl)[(difluoromethoxy)methyl]pyrrolidine carboxylategave similar product yields as in the synthesis of utyl )[5-(2- {(2S,5S)[N-(methoxycarbonyl)-L-valyl]methylpyrrolidinyl}-1,11- oisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl)-1H-imidazolyl] (methoxymethyl)pyrrolidinecarboxylate. MS (ESI) m/z 772.31 [M + H]+. methyl {(2S)[(2S,4S)[(difluoromethoxy)methyl](5-{2-[(2S,5S){(2S) [(methoxycarbonyl)amino]methylbutanoyl}methylpyrrolidinyl]-1,11- oisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl}-1H-imidazol yl)pyrrolidinyl]methyloxobutanyl}carbamate To tert-butyl (2S,4S)(5-{2-[(2S,5S)(tert-butoxycarbonyl)methylpyrrolidin yl]-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl}-1H-imidazolyl) [(difluoromethoxy)methyl]pyrrolidinecarboxylate (0.057 g, 0.074 mmol) in a mixture of CH2Cl2 (0.739 mL) and MeOH (0.148 mL) was added HCl (4M in 1,4-dioxane, 0.555 mL, 2.218 mmol). The solution was stirred at room temperature for 2 h and concentrated to dryness.

The intermediate was dissolved in CH2Cl2 (0.739 mL). (S) (methoxycarbonylamino)methylbutanoic acid (0.028 g, 0.163 mmol) and DIPEA (0.039 mL, 0.222 mmol) were then added to the solution. HATU (0.124 g, 0.325 mmol) was added and solution was allowed to stir at room temp. Upon completion, the on was diluted with DMF and concentrated. The crude product was purified by preparative HPLC (Gemini column, 10-46% MeCN/H2O with 0.1% TFA) and the desired fractions were combined and lyophilized to provide methyl 1-[(2S,4S)[(difluoromethoxy)methyl](5-{2- [(2S,5S){(2S)[(methoxycarbonyl)amino]methylbutanoyl}methylpyrrolidinyl]- 1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl}-1H-imidazol yl)pyrrolidinyl]methyloxobutanyl}carbamate (0.011 g, 17%). MS (ESI) m/z 886.1 [M + H]+. 1H NMR (400 MHz, cd 3od) δ 8.67 – 8.51 (m, 1H), 8.26 – 8.11 (m, 1H), 8.04 – 7.75 (m, 3H), 7.69 – 7.58 (m, 2H), 6.43 (t, 1H), 5.41 – 5.15 (m, 4H), 4.48 – 3.90 (m, 6H), 3.82 (s, 1H), 3.71 – 3.57 (m, 5H), 3.53 – 3.43 (m, 1H), 3.20 – 3.01 (m, 2H), 2.92 – 2.63 (m, 3H), 2.60 – 2.25 (m, 4H), 2.15 – 1.86 (m, 4H), 1.57 (d, 3H), 1.24 (d, 2H), 1.07 (dd, 2H), 0.98 – 0.77 (m, 9H).

Example PU tert-butyl (2S,4S)[5-(2-{(2S,4S)(tert-butoxycarbonyl) [(difluoromethoxy)methyl]pyrrolidinyl}-1,11- dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl)-1H-imidazolyl] xymethyl)pyrrolidinecarboxylate This compound was made in an analogous manner to tert-butyl (2S,4S)[5-(2- {(2S,5S)[N-(methoxycarbonyl)-L-valyl]methylpyrrolidinyl}-1,11- dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl)-1H-imidazolyl] (methoxymethyl)pyrrolidinecarboxylate substituting (2S,4S)(tert-butoxycarbonyl) (methoxymethyl)pyrrolidinecarboxylic acid for the initial alkylation of 3-(2-bromoacetyl)- ,11-dihydro-5H-dibenzo[c,g]chromen-8(9H)-one, and substituting )(tertbutoxycarbonyl )((difluoromethoxy)methyl)pyrrolidinecarboxylic acid for the other alkylation in the sequence. ons in the synthesis of tert-butyl (2S,4S)[5-(2-{(2S,4S)- 1-(tert-butoxycarbonyl)[(difluoromethoxy)methyl]pyrrolidinyl}-1,11- dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl)-1H-imidazolyl] (methoxymethyl)pyrrolidinecarboxylate gave similar product yields as in the synthesis of tert-butyl (2S,4S)[5-(2-{(2S,5S)[N-(methoxycarbonyl)-L-valyl]methylpyrrolidin yl}-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl)-1H-imidazolyl] (methoxymethyl)pyrrolidinecarboxylate. MS (ESI) m/z 801.1 [M + H]+. methyl {(2S)[(2S,4S)(5-{2-[(2S,4S)[(difluoromethoxy)methyl]{(2S) [(methoxycarbonyl)amino]methylbutanoyl}pyrrolidinyl]-1,11- dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl}-1H-imidazolyl) (methoxymethyl)pyrrolidinyl]methyloxobutanyl}carbamate To tert-butyl (2S,4S)[5-(2-{(2S,4S)(tert-butoxycarbonyl) uoromethoxy)methyl]pyrrolidinyl}-1,11 oisochromeno[4',3':6,7]naphtho[1,2- azolyl)-1H-imidazolyl](methoxymethyl)pyrrolidinecarboxylate (0.092 g, 0.115 mmol) in a mixture of CH2Cl2 (1.15 mL) and MeOH (0.230 mL) was added HCl (4M in 1,4-dioxane, 0.862 mL, 3.446 mmol). The solution was stirred at room temperature for 2 h and concentrated to dryness.

The intermediate was dissolved in CH2Cl2 (1.149 mL). (S) (methoxycarbonylamino)methylbutanoic acid (0.044 g, 0.253 mmol) and DIPEA (0.060 mL, 0.345 mmol) were then added to the solution. HATU (0.192 g, 0.505 mmol) was added and solution was allowed to stir at room temp. Upon completion, the solution was diluted with DMF and concentrated. The crude product was ed by preparative HPLC (Gemini column, 10-45% MeCN/H2O with 0.1% TFA) and the desired fractions were combined. The solution was concentrated until the aqueous layer remained and aqueous bicarbonate (sat.) was slowly added until the solution was basic. The resulting slurry was stirred at room ature for 2h and filtered. The resulting solid was dried in vacuo to provide methyl {(2S)[(2S,4S)(5-{2-[(2S,4S)[(difluoromethoxy)methyl]{(2S) [(methoxycarbonyl)amino]methylbutanoyl}pyrrolidinyl]-1,11- dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl}-1H-imidazolyl) (methoxymethyl)pyrrolidinyl]methyloxobutanyl}carbamate (0.042 g, 40%). MS (ESI) m/z 916.30 [M + H]+. 1H NMR (400 MHz, cd 3od) δ 8.55 – 8.25 (m, 1H), 8.15 – 7.85 (m, 2H), 7.83 – 7.26 (m, 5H), 6.44 (t, 1H), 5.37 – 5.02 (m, 4H), 4.47 – 4.35 (m, 1H), 4.33 – 4.18 (m, 3H), 4.15 – 3.90 (m, 3H), 3.81 – 3.45 (m, 11H), 3.39 (s, 3H), 2.90 – 2.27 (m, 5H), 2.22 – 1.92 (m, 4H), 1.12 – 0.73 (m, 13H).

Example PX (2S,4S)tert-butyl 2-methyl fluoromethoxy)methyl)pyrrolidine-1,2-dicarboxylate A 100 mL round-bottom flask was charged with (2S,4S)tert-butyl yl 4- (hydroxymethyl)pyrrolidine-1,2-dicarboxylate (3.33 g, 12.84 mmol), CuI (0.489 g, 2.56 mmol), and anhydrous itrile (57.1 mL). The reaction was heated to 45 °C (ext. oil bath). fluoro(fluorosulfonyl)acetic acid (2.655 mL, 25.68 mmol) was added at 45 °C over 30 minutes via syringe pump. The reaction was heated for 30 minutes. Upon completion as monitored by TLC, the reaction mixture was cooled to room temperature and trated in vacuo. The crude residue was diluted in EtOAc and washed with sodium bicarbonate (aq). The bicarbonate layer was back extracted with ethyl acetate twice.

Combined organic layers were washed with brine, dried over sodium sulphate, filtered and concentrated. The resulting residue was further purified via silica gel chromatography (10 to 40 % EtOAc/Hexanes) to afford (2S,4S)tert-butyl 2-methyl 4- ((difluoromethoxy)methyl)pyrrolidine-1,2-dicarboxylate (2.41 g, 61%). MS (ESI) m/z 210.21 [M + H - Boc]+. (2S,4S)(tert-butoxycarbonyl)((difluoromethoxy)methyl)pyrrolidinecarboxylic acid To a solution of (2S,4S)tert-butyl 2-methyl 4- ((difluoromethoxy)methyl)pyrrolidine-1,2-dicarboxylate (2.41 g, 7.79 mmol) in a mixture of THF (39 mL) and MeOH (15.6 mL) was added LiOH (2.5 M aqueous, 15.6 mL, 38.9 mmol).

The resulting solution was stirred at room temperature for 1h. Upon completion by TLC the reaction mixture was acidified with aqueous HCl (1N). The desired product was ted with CH2Cl2 (3x). The combined organic layers were dried over Na2SO4 and concentrated to provide )(tert-butoxycarbonyl)((difluoromethoxy)methyl)pyrrolidine carboxylic acid (2.4 g, 99%). MS (ESI) m/z 294.96 [M - H]-. : 400 MHz, (acetoned6 ) δ (mixture of rotamers): 6.50 (t, 1H), 4.36-4.17 (m, 1H), 3.93 (d, 2H), 3.77-3.67 (m, 1H), 3.63-3.59 (m, 1H), 3.26-3.12 (m, 1H), 2.72-2.41 (m, 2H), 1.89-1.73 (m, 2H), 1.41 (s, 9H).

Example PY Methyl 1-[(2S,5S)(9-{2-[(2S,4S){(2R)[(methoxycarbonyl)amino] phenylacetyl}(methoxymethyl)pyrrolidinyl]-1H-imidazolyl}-1,11- dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl)methylpyrrolidinyl] methyloxobutanyl}carbamate A solution of tert-butyl (2S,4S)[5-(2-{(2S,5S)[N-(methoxycarbonyl)-L-valyl] methylpyrrolidinyl}-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl)-1H- imidazolyl](methoxymethyl)pyrrolidinecarboxylate (150 mg, 0.19 mmol) in 1.25 N HCl in EtOH (3 mL) was stirred overnight then heated to 50 °C for 3h. The reaction was concentrated and the crude material dissolved in DMF (2 mL). To this solution was added a on of (R)(methoxycarbonylamino)phenylacetic acid (52 mg, 0.25 mmol) and COMU (90 mg, 0.21 mmol). To the resulting solution was added diisopropylethylamine (0.099 mL, 0.57 mmol). After stirring for 2h at room ature, the reaction was quenched with 1N HCl (0.200 mL) and purified by HPLC. After lyophilizati on, the TFA salt was ved in EtOAc and washed with saturated NaHCO3. The organic phase was dried over Na2SO4 and concentrated. The free base was then dissolved in MeCN/H2O and lyophilized to afford methyl {(2S)[(2S,5S)(9-{2-[(2S,4S){(2R)[(methoxycarbonyl)amino] acetyl}(methoxymethyl)pyrrolidinyl]-1H-imidazolyl}-1,11- dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl)methylpyrrolidinyl] methyloxobutanyl}carbamate (65 mg, 39%). LCMS-ESI+: ated for C49H54N8O8: 882.4; observed [M+1]+: 884.1. Diagnostic peaks in NMR 'H NMR (CD3OD): 8.28 (s, 1H), 8.21 (s, 1H), 8.04 (s, 1H), 7.91-7.01 (m, 10H), 3.62 (s, 3H), 3.34 (s, 3H), 3.23 (s, 3H), 1.56 (d, 3H), 1.03 (d, 3H), 0.94 (d, 3H).

Example PY-1 9-bromo(2-bromoacetyl)-10,11-dihydro-5H-dibenzo[c,g]chromen-8(9H)-one To 3-(2-bromohydroxyethyl)-10,11-dihydro-5H-dibenzo[c,g]chromen-8(9H)-one (20.3g, 54.4 mmol) in DCM (365 mL) was added MeOH (22 mL) and pyridinium tribromide (18.24 g, 57.0 mmol). After 2h, water was added (100mL) and after briefly agitating the layers split and the bottom organic layer was collected. The organic layer was then washed with 1M HCl (100 mL) and the bottom organic layer containing 9-bromo(2-bromo hydroxyethyl)-10,11-dihydro-5H-dibenzo[c,g]chromen-8(9H)-one was collected. 400 MHz 1H NMR (CDCl 3) 7.75 (d, J = 8.1 Hz, 1H), 7.68 (s, 1H), 7.61 (s, 1H), 7.42 (d, J = 7.5 Hz, 1H), 7.24 (s, 1H), 5.13 (s, 2H), 4.99-4.96 (m, 1H), 4.73 (dd, J = 4.1, 4.1 Hz, 1H), 3.69-3.66 (m, 1H), 3.58-3.53 (m, 1H), 3.35-3.27 (m, 1H), 2.96-2.90 (m, 1H), 2.58-2.44 (m, 2H), C-OH not observed.

To 9-bromo(2-bromohydroxyethyl)-10,11-dihydro-5H-dibenzo[c,g]chromen- 8(9H)-one (approx. 54.4 mmol) in DCM ) was added sodium bicarbonate (5.45 g), sodium bromide (6.14 g), TEMPO (16.55 mg) and water (60 mL). The solution was cooled between 0-5 °C and 6% bleach (91.5 mL) was added. After 1h isopropyl alcohol (20 mL) was added and the reaction mixture was warmed to room temperature. Agitation was d, the layers ted and the lower organic layer was collected and concentrated removing approximately 345 g of solvent. The slurry was filtered and the cake washed with 50 mL water and then 50 mL DCM (pre-cooled to 5 °C). The solids were collected and dried under vacuum to obtain 9-bromo(2-bromoacetyl)-10,11-dihydro-5H-dibenzo[c,g]chromen- 8(9H)-one (18.6 g, 76% yield). 400 MHz 1H NMR (CDCl 3) δ 8.03-8.01 (m, 1H), 7.85 (d, J = 8.2 Hz, 1H), 7.82 (s, 1H), 7.71 (s, 1H), 7.67 (s, 1H), 5.19 (s, 2H), 4.74 (dd, J = 4.1, 4.1 Hz, 1H), 4.45 (s, 2H), 3.37-3.29 (m, 1H), 2.99-2.92 (m,1H), 2.59-2.46 (m, 2H); 100 MHz 13C NMR (CDCl3) δ 190.4, 189.6, 154.2, 136.6, 134.1, 133.9, 132.9, 131.8, 129.3, 127.2, 125.6, 124.2, 123.3, 117.0, 68.1, 49.9, 31.8, 30.4, 25.5.

Example PY-2 o(2-bromoacetyl)-10,11-dihydro-5H-dibenzo[c,g]chromen-8(9H)-one A mixture of 3-(2-bromoacetyl)-10,11-dihydro-5H-dibenzo[c,g]chromen-8(9H)-one (2.58 g, 6.95 mmol), pyridinium tribromide (2.56 g, 8.0 mmol), romethane (22mL) and methanol (2.5mL) was stirred at about 20°C for 3 hours to obtain a slurry. The precipitated product was filtered , washed with dichloromethane (10mL) and dried in a vacuum oven at 40°C to give 9-bromo(2-bromoacetyl)-10,11-dihydro-5H-dibenzo[c,g]chromen-8(9H)-one (2.62 g, 84% yield). 400 MHz 1H NMR (CDCl 3) δ 8.03-8.01 (m, 1H), 7.85 (d, J = 8.2 Hz, 1H), 7.82 (s, 1H), 7.71 (s, 1H), 7.67 (s, 1H), 5.19 (s, 2H), 4.74 (dd, J = 4.1, 4.1 Hz, 1H), 4.45 (s, 2H), 3.37-3.29 (m, 1H), 2.99-2.92 (m,1H), 2.59-2.46 (m, 2H). e PY-3 O O O TMS H O TFA, H2O Cl TMS PdCl2(MeCN)2, X-Phos 65 °C K3PO4, MeCN, 65 °C 3-chloro-10,11-dihydro- 3-((trimethylsilyl)ethynyl)- 5H- 10,11-dihydro-5H- dibenzo[c,g]chromen- dibenzo[c,g]chromen-8(9H)- 8(9H)-one one O O O O PyHBr3 O O Me DCM, MeOH Br Br °C 3-acetyl-10,11-dihydro- 9-bromo(2-bromoacetyl)-10,11- 5H- dihydro-5H-dibenzo[c,g]chromendibenzo [c,g]chromen- 8(9H)-one 8(9H)-one 3-((trimethylsilyl)ethynyl)-10,11-dihydro-5H-dibenzo[c,g]chromen-8(9H)-one A 300 mL flask equipped with an overhead stirrer and a reflux condenser under an atmosphere of nitrogen was charged with 3-chloro-10,11-dihydro-5H-dibenzo[c,g]chromen- 8(9H)-one (10.0g, 35.12 mmol), powdered anhydrous tripotassium phosphate (22.4 g, 105.4 mmol), XPhos (1.34 g, 2.81 mmol), and PdCl2(MeCN)2 (364 mg, 1.40 mmol). Acetonitrile (140 mL) was added followed by TMSacetylene (18 mL, 141 mmol). The mixture was heated to 65 °C. After 6h, the reaction was judged complete, and the mixture was cooled to 20 °C. The mixture was filtered h a fritted funnel, and the filtercake was washed with acetonitrile. The filtrate was concentrated to about 150 mL under reduced pressure and extracted with heptane (50 mL, 3×100 mL). N-Acetyl cysteine (15 g) was added to the acetonitrile phase, and the mixture was agitated for 5 h at 45 °C. The mixture was cooled to t ature, filtered h a fritted funnel, and the filtercake was washed with acetonitrile. The filtrate was concentrated to about 120 mL under d pressure. Water (120 mL) was added and the mixture was agitated for 40 minutes at 45 °C and then cooled to ambient temperature. After 30 minutes the e was filtered h a fritted funnel to provide 3-((trimethylsilyl)ethynyl)-10,11-dihydro-5H-dibenzo[c,g]chromen-8(9H)-one (4.07 g, 33.4% yield ) as a yellow solid: 400 MHz 1H NMR (CDCl 3) δ 7.65 (d, J = 8.1 Hz, 1H), 7.60 (s, 1H), 7.55 (s, 1H), 7.47 (dd, J = 8.1, 1.4 Hz, 1H), 7.27 (s, 1H), 5.06 (s, 2H), 2.95 (t, J = 6.1 Hz, 2H), 2.67 – 2.59 (m, 2H), 2.18 – 2.08 (m, 2H), 0.26 (s, 9H). 3-acetyl-10,11-dihydro-5H-dibenzo[c,g]chromen-8(9H)-one A 20 mL vial with stir bar was charged with 3-((trimethylsilyl)ethynyl)-10,11- dihydro-5H-dibenzo[c,g]chromen-8(9H)-one (850 mg, 2.44 mmol) and TFA (9.8 mL). The solution was heated to 65 °C. After 3 h, the reaction was judged complete. The mixture was concentrated under reduced pressure; the resulting residue was taken up in CH2Cl2 and loaded onto a prepacked 25g silica gel dge. The t was purified by chromatography on a prepacked 80g silica gel column eluting with a solvent gradient from 5% to 85% EtOAc/hexanes. The product containing fractions were combined and concentrated to provide 3-acetyl-10,11-dihydro-5H-dibenzo[c,g]chromen-8(9H)-one (616 mg, 86%): 400 MHz 1H NMR (CDCl 3) δ 8.00 – 7.94 (m, 1H), 7.81 (d, J = 8.2 Hz, 1H), 7.77 (s, 1H), 7.64 (s, 2H), 5.16 (s, 2H), 2.98 (t, J = 6.1 Hz, 2H), 2.69 – 2.64 (m, 2H), 2.63 (s, 3H), 2.21 – 2.09 (m, 2H). 9-bromo(2-bromoacetyl)-10,11-dihydro-5H-dibenzo[c,g]chromen-8(9H)-one A 20 mL vial with a stir bar was charged with 3-acetyl-10,11-dihydro-5H- dibenzo[c,g]chromen-8(9H)-one (100 mg, 0.366 mmol), 9:1 CH2Cl2/MeOH (3.4 mL) and pyridinium tribromide (246 mg, 0.769 mmol). The solution was heated to 35 °C. After 30 minutes, the reaction was judged complete. The mixture was cooled to ambient temperature, d with EtOAc (50 mL) and sequentially washed with saturated s Na2S2O3 (20 mL), 2% aqueous NaHCO3 (20 mL), water (20 mL), and brine (10 mL). The organic phase was dried over MgSO4, ed and concentrated under reduced pressure resulting in 9- bromo(2-bromoacetyl)-10,11-dihydro-5H-dibenzo[c,g]chromen-8(9H)-one (68 mg, 41%): 400 MHz 1H NMR (CDCl 3) δ 8.03 - 8.01 (m, 1H), 7.85 (d, J = 8.2 Hz, 1H), 7.82 (s, 1H), 7.71 (s, 1H), 7.67 (s, 1H), 5.19 (s, 2H), 4.74 (dd, J = 4.1, 4.1 Hz, 1H), 4.45 (s, 2H), 3.37-3.29 (m, 1H), 2.99 - 2.92 (m,1H), 2.59 - 2.46 (m, 2H).

Example PY-4 (2S, 5S)(2-(9-bromooxo-8,9,10,11-tetrahydro-5H-dibenzo[c,g]chromenyl) oxoethyl) 1-tert-butyl 5-methylpyrrolidine-1,2-dicarboxylate 9-bromo(2-bromoacetyl)-10,11-dihydro-5H-dibenzo[c,g]chromen-8(9H)-one (1.43 g, 3.17 mmol) was treated with a solution of (2S,5S)(tert-butoxycarbonyl) methylpyrrolidinecarboxylic acid (800 mg, 3.49 mmol) in dichloromethane (14 mL) and K2CO3 (658 mg, 1.18 mmol). The stirred reaction mixture was stirred at RT and diluted with CH2Cl2 and extracted 3X. The organic phase was washed with brine, then dried over MgSO4, filtered and concentrated under reduced pressure to afford ((2S,5S)(2-(9-bromooxo- 8,9,10,11-tetrahydro-5H-dibenzo[c,g]chromenyl)oxoethyl) 1-tert-butyl 5- pyrrolidine-1,2-dicarboxylate (1.61 g, 84%).

This synthesis may be used to make a variety of compounds described , including the compound exemplified in PY.

Example PZ Methyl {(2S)[(2S,5S)(9-{2-[(2S,4S){(2S)[(methoxycarbonyl)amino] methylbutanoyl}(methoxymethyl)pyrrolidinyl]-1H-imidazolyl}-1,11- dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl)methylpyrrolidinyl] methyloxobutanyl}carbamate Tert-butyl (2S,4S)[5-(2-{(2S,5S)[N-(methoxycarbonyl)-L-valyl] methylpyrrolidinyl}-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl)-1H- imidazolyl](methoxymethyl)pyrrolidinecarboxylate (100 mg, 0.13 mmol) in 1.25 N HCl in EtOH (3 mL) was heated to 50 °C for 3h and then concentrated under reduced pressure. The crude residue was treated with (S)(methoxycarbonylamino) methylbutanoic acid (34 mg, 0.20 mmol), HATU (54 mg, 0.14 mmol) and DMF (1.3 mL), then N-methylmorpholine (0.043 mL, 0.39 mmol) was added se. After 3h, the mixture was quenched with 1N HCl (0.100 mL) and then purified by HPLC to afford methyl 1- [(2S,5S)(9-{2-[(2S,4S){(2S)[(methoxycarbonyl)amino]methylbutanoyl} (methoxymethyl)pyrrolidinyl]-1H-imidazolyl}-1,11- dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl)methylpyrrolidinyl] methyloxobutanyl}carbamate ( 91 mg, 82%).

LCMS-ESI+: calculated for C46H56N8O8: 848.4; observed [M+1]+: 850.2.

Example QA 1. HCl O H 2. HATU, NMM, DMF Boc N N N N N N O O O H HO N N O O H O H tert-butyl (2S,4S)[5-(2-{(2S,5S)[N-(methoxycarbonyl)-L-valyl] (2S,3R)methoxy methylpyrrolidinyl}-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2- (methoxycarbonylamino) d]imidazolyl)-1H-imidazolyl](methoxymethyl)pyrrolidine ic acid carboxylate O N O H N N N O N N N O N H O methyl {(2S)[(2S,5S)(9-{2-[(2S,4S){(2S,3S)methoxy [(methoxycarbonyl)amino]butanoyl}(methoxymethyl)pyrrolidin yl]-1H-imidazolyl}-1,11- dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl) methylpyrrolidinyl]methyloxobutanyl}carbamate Methyl {(2S)[(2S,5S)(9-{2-[(2S,4S){(2S,3S)methoxy [(methoxycarbonyl)amino]butanoyl}(methoxymethyl)pyrrolidinyl]-1H-imidazol yl}-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl)methylpyrrolidin- 1-yl]methyloxobutanyl}carbamate Tert-butyl )[5-(2-{(2S,5S)[N-(methoxycarbonyl)-L-valyl] methylpyrrolidinyl}-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl)-1H- imidazolyl](methoxymethyl)pyrrolidinecarboxylate (119 mg, 0.15 mmol) in 1.25 N HCl in EtOH (3 mL) was heated to 50 °C for 3h and then concentrated under reduced pressure. The crude e was treated with (2S,3R)methoxy (methoxycarbonylamino)butanoic acid (43 mg, 0.23 mmol), HATU (63 mg, 0.17 mmol) and DMF (2 mL), then N-methylmorpholine (0.050 mL, 0.45 mmol) was added dropwise. After 3 hr, the mixture was quenched with 1N HCl (0.100 mL) and then purified by HPLC to afford methyl {(2S)[(2S,5S)(9-{2-[(2S,4S){(2S,3S)methoxy [(methoxycarbonyl)amino]butanoyl}(methoxymethyl)pyrrolidinyl]-1H-imidazolyl}- 1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl)methylpyrrolidinyl] oxobutanyl}carbamate ( 76 mg, 59%).

LCMS-ESI+: calculated for C46H56N8O9: 864.4; observed [M+1]+: 866.1.

Example QB 1. HCl Boc N 2. HATU, DIPEA N Br O H HO N O (2S,4S)-tert-butyl 2-(5-bromo-1H- (2S,3S) imidazolyl)methylpyrrolidine (methoxycarbonylamino) carboxylate methylpentanoic acid O NH O H O O N N N N + N O N Br Boc (2S,4S)-tert-butyl 4-(methoxymethyl)(9-(4,4,5,5- tetramethyl-1,3,2-dioxaborolanyl)- 1,11- methyl (2S,3S)((2S,4S)(5-bromo-1H- dihydroisochromeno[4',3':6,7]naphtho[1,2- imidazolyl)methylpyrrolidinyl) azolyl)pyrrolidinecarboxylate methyloxopentanylcarbamate Methyl (2S,3S)((2S,4S)(5-bromo-1H-imidazolyl)methylpyrrolidinyl) methyloxopentanylcarbamate (2S,4S)-tert-butyl 2-(5-bromo-1H-imidazolyl)methylpyrrolidinecarboxylate (100 mg, 0.13 mmol) in 1.25 N HCl in EtOH (15 mL) was heated to 50 °C for 3h and then concentrated under reduced pressure. The crude residue was treated with (2S,3S) (methoxycarbonylamino)methylpentanoic acid (625 mg, 3.30 mmol), HATU (1.05 g, 2.77 mmol) and DMF (10 mL), then DIPEA (1.33 mL, 7.62 mmol) was added dropwise. After 2h, the mixture was poured into saturated aqueous NaHCO3 and then extracted with EtOAc. The organic phase was washed successively with 5% aqueous LiCl and Brine. The organics were dried over Na2SO4, filtered and concentrated under reduced re. The crude residue was purified by silica column chromatography (30 to 90% of 10%MeOH/EtoAc to Hexanes) afforded methyl (2S,3S)((2S,4S)(5-bromo-1H-imidazolyl)methylpyrrolidinyl)- 3-methyloxopentanylcarbamate ( 932 mg, 81%).

Tert-butyl (2S,4S)[9-(2-{(2S,4S)[N-(methoxycarbonyl)-L-alloisoleucyl] methylpyrrolidinyl}-1H-imidazolyl)-1,11- oisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl] xymethyl)pyrrolidinecarboxylate (2S,4S)-Tert-butyl 4-(methoxymethyl)(9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan- 2-yl)- 1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl)pyrrolidine carboxylate (856 mg, 1.4 mmol), methyl (2S,3S)((2S,4S)(5-bromo-1H-imidazolyl)- 4-methylpyrrolidinyl)methyloxopentanylcarbamate (932 mg, 2.1 mmol), Pd(PPh3)4 (162 mg, 0.14 mmol), PdCl2(dppf)2 (102 mg, 0.14 mmol), and K2CO3 (2M in H2O, 2.31 mL, 4.62 mmol) were combined in DMSO (8 mL) and dioxanes (8 mL). The mixture was degassed with bubbling Argon for 10 min then heated to 95 ˚C for 1h. After cooling, the reaction e was diluted with EtOAc, and washed successively with saturated aqueous NaHCO3 and brine. The organics were dried over , filtered and concentrated under reduced pressure. The crude e was purified by silica column chromatography (1% to % MeOH/EtOAc) to afford tert-butyl )[9-(2-{(2S,4S)[N-(methoxycarbonyl)- L-alloisoleucyl]methylpyrrolidinyl}-1H-imidazolyl)-1,11- dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl](methoxymethyl)pyrrolidine carboxylate (701 mg, 62%).

Methyl 2-[(2S,4S)(9-{2-[(2S,4S){(2S,3R)[(methoxycarbonyl)amino] methylpentanoyl}methylpyrrolidinyl]-1H-imidazolyl}-1,11- oisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl) (methoxymethyl)pyrrolidinyl]oxophenylethyl}carbamate A solution of tert-butyl (2S,4S)[9-(2-{(2S,4S)[N-(methoxycarbonyl)-L- alloisoleucyl]methylpyrrolidinyl}-1H-imidazolyl)-1,11- dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl](methoxymethyl)pyrrolidine carboxylate (218 mg, 0.27 mmol) in 1.25 N HCl in EtOH (3 mL) was heated to 50 °C for 3h.

The reaction was concentrated and the crude material dissolved in DMF (3 mL). To this on was added a solution of (R)(methoxycarbonylamino)phenylacetic acid (73 mg, 0.35 mmol) and COMU (127 mg, 0.30 mmol). To the resulting solution was added diisopropylethylamine (0.141 mL, 0.81 mmol). After stirring for 2h at room temperature, the reaction was quenched with 1N HCl (0.200 mL) and purified by HPLC. After lyophilization, the TFA salt was dissolved in EtOAc and washed with saturated NaHCO3. The organic phase was dried over Na2SO4 and concentrated. The free base was then dissolved in MeCN/H2O and lized to afford methyl {(1R)[(2S,4S)(9-{2-[(2S,4S){(2S,3R)- 2-[(methoxycarbonyl)amino]methylpentanoyl}methylpyrrolidinyl]-1H-imidazol yl}-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl) (methoxymethyl)pyrrolidinyl]oxophenylethyl}carbamate (121 mg, 50%). LCMS-ESI+: calculated for C50H56N8O8: 896.4; observed [M+1]+: 897.5. e QC H O O N O H O N N 1. HCl N N 2. HATU, NMM N Boc H O N O tert-butyl (2S,4S)[9-(2-{(2S,4S)[N-(methoxycarbonyl)-L- O alloisoleucyl]methylpyrrolidinyl}-1H-imidazolyl)-1,11- dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl] (S) (methoxymethyl)pyrrolidinecarboxylate (methoxycarbonylamino) methylbutanoic acid H O O N O H N N N N N N H O methyl {(2S)[(2S,4S)(9-{2-[(2S,4S){(2S,3R) [(methoxycarbonyl)amino]methylpentanoyl}methylpyrrolidinyl]- 1H-imidazolyl}-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2- d]imidazolyl)(methoxymethyl)pyrrolidinyl]methyl oxobutanyl}carbamate Methyl {(2S)[(2S,4S)(9-{2-[(2S,4S){(2S,3R)[(methoxycarbonyl)amino] methylpentanoyl}methylpyrrolidinyl]-1H-imidazolyl}-1,11- dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl) (methoxymethyl)pyrrolidinyl]methyloxobutanyl}carbamate tert-butyl )[9-(2-{(2S,4S)[N-(methoxycarbonyl)-L-alloisoleucyl] methylpyrrolidinyl}-1H-imidazolyl)-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2- d]imidazolyl](methoxymethyl)pyrrolidinecarboxylate (105 mg, 0.13 mmol) in 1.25 N HCl in EtOH (3 mL) was heated to 50 °C for 3h and then concentrated under reduced pressure. The crude residue was treated with (methoxycarbonylamino) methylbutanoic acid (32 mg, 0.18 mmol), HATU (59 mg, 0.16 mmol) and DMF (1.3 mL), then N-methylmorpholine (0.043 mL, 0.39 mmol) was added dropwise. After 3h, the mixture was quenched with 1N HCl (0.100 mL) and then purified by HPLC to afford methyl {(2S) [(2S,4S)(9-{2-[(2S,4S){(2S,3R)[(methoxycarbonyl)amino]methylpentanoyl} methylpyrrolidinyl]-1H-imidazolyl}-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2- d]imidazolyl)(methoxymethyl)pyrrolidinyl]methyloxobutanyl}carbamate ( 80 mg, 71%).

LCMS-ESI+: calculated for C47H58N8O8: 862.4; observed : 864.2.

Example QD Methyl {(2S,3R)[(2S,4S)(5-{2-[(2S,4S)[N-(methoxycarbonyl)-O-methyl-L- allothreonyl](methoxymethyl)pyrrolidinyl]-1,11- dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl}-1H-imidazolyl) methylpyrrolidinyl]methyloxopentanyl}carbamate tert-butyl (2S,4S)[9-(2-{(2S,4S)[N-(methoxycarbonyl)-L-alloisoleucyl] methylpyrrolidinyl}-1H-imidazolyl)-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2- d]imidazolyl](methoxymethyl)pyrrolidinecarboxylate (105 mg, 0.13 mmol) in 1.25 N HCl in EtOH (3 mL) was heated to 50 °C for 3h and then concentrated under reduced pressure. The crude e was treated with (2S,3R)methoxy (methoxycarbonylamino)butanoic acid (35 mg, 0.18 mmol), HATU (59 mg, 0.16 mmol) and DMF (1.3 mL), then N-methylmorpholine (0.043 mL, 0.39 mmol) was added dropwise. After 3 hr, the mixture was quenched with 1N HCl (0.100 mL) and then purified by HPLC to afford methyl {(2S,3R)[(2S,4S)(5-{2-[(2S,4S)[N-(methoxycarbonyl)-O-methyl-L- allothreonyl](methoxymethyl)pyrrolidinyl]-1,11- dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl}-1H-imidazolyl) methylpyrrolidinyl]methyloxopentanyl}carbamate ( 92 mg, 81%).

LCMS-ESI+: calculated for C47H58N8O9: 878.4; observed : 879.3.

Example QE Methyl {(3R)[(2S,4S)(9-{2-[(2S,4S){(2S,3R)[(methoxycarbonyl)amino] methylpentanoyl}methylpyrrolidinyl]-1H-imidazolyl}-1,11- dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl) (methoxymethyl)pyrrolidinyl]methyloxopentanyl}carbamate tert-butyl (2S,4S)[9-(2-{(2S,4S)[N-(methoxycarbonyl)-L-alloisoleucyl] methylpyrrolidinyl}-1H-imidazolyl)-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2- d]imidazolyl](methoxymethyl)pyrrolidinecarboxylate (105 mg, 0.13 mmol) in 1.25 N HCl in EtOH (3 mL) was heated to 50 °C for 3h and then concentrated under reduced re. The crude residue was treated with (2S,3S)(methoxycarbonylamino) methylpentanoic acid (34 mg, 0.18 mmol), HATU (59 mg, 0.16 mmol) and DMF (1.3 mL), then N-methylmorpholine (0.043 mL, 0.39 mmol) was added dropwise. After 3h, the mixture was quenched with 1N HCl (0.100 mL) and then purified by HPLC to afford methyl 1- [(2S,4S)(9-{2-[(2S,4S){(2S,3R)[(methoxycarbonyl)amino]methylpentanoyl} methylpyrrolidinyl]-1H-imidazolyl}-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2- azolyl)(methoxymethyl)pyrrolidinyl]methyloxopentanyl}carbamate ( 98 mg, 86%).

LCMS-ESI+: calculated for C48H60N8O8: 876.5; observed [M+1]+: 878.2.

Example QF O H Pd(PPh3)4, O N N O O Pd(dppf)2Cl2, K2CO3 B N O N N Br DME O + N 85 °C H N O O (2S,4S)-tert-butyl 2-(5-bromo-1H- methyl [(2S)methyl{(2S,5S)methyl[9- imidazolyl)methylpyrrolidine (4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)- carboxylate 1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2- azolyl]pyrrolidinyl}oxobutan yl]carbamate O N O H N N N N N N H N O methyl {(2S)[(2S,5S)(9-{2-[(2S,4S){(2R) [(methoxycarbonyl)amino]phenylacetyl} methylpyrrolidinyl]-1H-imidazolyl}-1,11- oisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl)- -methylpyrrolidinyl]methyloxobutan yl}carbamate )tert-butyl 2-(3-chlorooxo-8,9,10,11-tetrahydro-5H-dibenzo[c,g]chromen yl) 5-methylpyrrolidine-1,2-dicarboxylate To a solution of 9-bromochloro-10,11-dihydro-5H-dibenzo[c,g]chromen-8(9H)- one (1.41 g, 3.88 mmol) in MeCN (17 mL) was added (2S,5S)(tert-butoxycarbonyl) methylpyrrolidinecarboxylic acid (980 mg, 4.27 mmol) and DIPEA (1.49 mL, 8.54 mmol).

After stirring for 18 h at 50 °C, the on was diluted with EtOAc and washed successively with 1N HCl, saturated aqueous NaHCO3 and brine. The organics were dried over Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified by silica column chromatography (10% to 30% EtOAc/hexanes) to afford (2S,5S)tert-butyl 2-(3- chlorooxo-8,9,10,11-tetrahydro-5H-dibenzo[c,g]chromenyl) 5-methylpyrrolidine-1,2- dicarboxylate (1.63 g, 81%). (2S,5S)-tert-butyl 2-(9-chloro-4,5-dihydro-5H-naphtho[c,g]chromeno[8,9-d]imidazol yl)(methyl)pyrrolidinecarboxylate (2S,5S)tert-butyl 2-(3-chlorooxo-8,9,10,11-tetrahydro-5H- dibenzo[c,g]chromenyl) 5-methylpyrrolidine-1,2-dicarboxylate (1.63 g, 3.18 mmol) was added toluene (30 mL), 2-methoxyethanol (3 mL), and um acetate (3.68 g, 77.1 mmol) and the solution was heated to reflux overnight. The following g, the solution was cooled to rt and was diluted with EtOAc and washed successively with water, ted aqueous NaHCO3 and brine. The organics were dried over Na2SO4, filtered and trated under reduced pressure. The crude residue was purified by silica column chromatography (40% to 80 % EtOAc/hexanes) to afford (2S,5S)-tert-butyl 2-(9-chloro-4,5-dihydro-5H- naphtho[c,g]chromeno[8,9-d]imidazolyl)methylpyrrolidinecarboxylate (1.13 g, 72%). ((2S,5S)-tert-butyl 2-(9-chloro-5H-naphtho[c,g]chromeno[8,9-d]imidazolyl) methylpyrrolidinecarboxylate To a on of (2S,5S)-tert-butyl 2-(9-chloro-4,5-dihydro-5H- naphtho[c,g]chromeno[8,9-d]imidazolyl)(methyl)pyrrolidinecarboxylate (1.13 g, 2.3 mmol) in CH2Cl2 (25 mL) was added MnO2 (9.98 g, 115 mmol). The reaction mixture was stirred ght then filtered over celite. The filter cake was washed with copious CH2Cl2 and MeOH, and the filtrate was concentrated under reduced pressure to afford the crude product (2S,5S)-tert-butyl 2-(9-chloro-5H-naphtho[c,g]chromeno[8,9-d]imidazolyl) methylpyrrolidinecarboxylate (931 mg, 83%).

Methyl {(2S)[(2S,5S)(9-chloro-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2- d]imidazolyl)methylpyrrolidinyl]methyloxobutanyl}carbamate (2S,5S)-tert-butyl 2-(9-chloro-5H-naphtho[c,g]chromeno[8,9-d]imidazolyl) methylpyrrolidinecarboxylate (931 mg, 1.9 mmol) in 1.25 N HCl in EtOH (8 mL) was heated to 50 °C for 3h and then concentrated under reduced pressure. The crude residue was treated with (S)(methoxycarbonylamino)methylbutanoic acid (499 mg, 2.9 mmol), HATU (795 mg, 2.1 mmol) and DMF (10 mL), then N-methylmorpholine (0.627 mL, 5.7 mmol) was added dropwise. After stirring for 1 h, the reaction was diluted with EtOAc and washed successively with saturated s NaHCO3, 5% LiCl, and brine. The organics were dried over Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified by silica column tography (50% to 100% EtOAc/hexanes) to afford methyl {(2S)[(2S,5S)(9-chloro-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazol yl)methylpyrrolidinyl]methyloxobutanyl}carbamate (950 mg, 91%).

Methyl 3-methyl{(2S,5S)methyl[9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan- 2-yl)-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl]pyrrolidinyl} oxobutanyl]carbamate To methyl {(2S)[(2S,5S)(9-chloro-1,11- dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl)methylpyrrolidinyl] methyloxobutanyl}carbamate (950 mg, 1.74 mmol) in dioxane (17 mL) was added bis(pinacolato)diboron (662 mg, 2.61 mmol), KOAc (512 mg, 5.22 mmol), X-Phos (25 mg, 0.05 mmol), and Pd2dba3 (80 mg, 0.08 mmol). The solution was degassed with N2 for 10 min, then heated to 90 °C for 16 h. The solution was cooled to rt, diluted with EtOAc, washed with saturated aqueous NaHCO3, brine, dried with , and concentrated.

Purification by silica gel chromatography (30% to 75 % gradient using 5%MeOH/EtOAc to Hexanes) to afford methyl [(2S)methyl{(2S,5S)methyl[9-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolanyl)-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazol yl]pyrrolidinyl}oxobutanyl]carbamate (800 mg, 72%). utyl (2S,4S)[5-(2-{(2S,5S)[N-(methoxycarbonyl)-L-valyl]methylpyrrolidin- 2-yl}-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl)-1H-imidazol yl]methylpyrrolidinecarboxylate To a solution of [(2S)methyl{(2S,5S)methyl[9-(4,4,5,5-tetramethyl-1,3,2- orolanyl)-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazol yl]pyrrolidinyl}oxobutanyl]carbamate (269 mg, 0.42 mmol), (2S,4S)-tert-butyl 2-(5- bromo-1H-imidazolyl)methylpyrrolidinecarboxylate (206 mg, 0.54 mmol), tetrakis(triphenylphosphine) palladium(0) (49 mg, 0.042 mmol) and dichloro[1,1'- bis(diphenylphosphino)ferrocene]palladium(II) (31 mg, 0.042 mmol) in DMSO (3 mL) and dioxanes (3 mL) was added a solution of potassium carbonate (2M in water, 0.69 mL, 1.39 mmol). The resulting mixture was degassed and then heated to 95 °C for 2h. After g to room temperature, the reaction was diluted with ethyl acetate. The organics were washed with saturated sodium bicarbonate and brine, dried over Na2SO4 and concentrated. The crude residue was purified by flash tography (1 to 20% MeOH/EtOAc) to yield tert-butyl )[5-(2-{(2S,5S)[N-(methoxycarbonyl)-L-valyl]methylpyrrolidinyl}-1,11- dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl)-1H-imidazolyl] methylpyrrolidinecarboxylate (202 mg, 63%).

Methyl {(2S)[(2S,5S)(9-{2-[(2S,4S){(2R)[(methoxycarbonyl)amino] acetyl}methylpyrrolidinyl]-1H-imidazolyl}-1,11- dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl)methylpyrrolidinyl] methyloxobutanyl}carbamate A solution of tert-butyl (2S,4S)[5-(2-{(2S,5S)[N-(methoxycarbonyl)-L-valyl] methylpyrrolidinyl}-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl)-1H- imidazolyl]methylpyrrolidinecarboxylate (80 mg, 0.11 mmol) in 1.25 N HCl in EtOH (2 mL) was heated to 50 °C for 3h. The reaction was concentrated and the crude material dissolved in DMF (1.5 mL). To this on was added a solution of (R) (methoxycarbonylamino)phenylacetic acid (29 mg, 0.14 mmol) and COMU (52 mg, 0.12 mmol). To the resulting solution was added diisopropylethylamine (0.057 mL, 0.33 mmol).

After stirring for 2h at room temperature, the reaction was quenched with 1N HCl (0.200 mL) and purified by HPLC. After lyophilization, the TFA salt was dissolved in EtOAc and washed with saturated NaHCO3. The organic phase was dried over Na2SO4 and trated. The free base was then dissolved in MeCN/H2O and lyophilized to afford methyl {(2S)[(2S,5S)(9-{2-[(2S,4S){(2R)[(methoxycarbonyl)amino] phenylacetyl}methylpyrrolidinyl]-1H-imidazolyl}-1,11- dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl)methylpyrrolidinyl] oxobutanyl}carbamate: (42 mg, 45%). LCMS-ESI+: calculated for C48H52N8O7: 852.4; observed [M+1]+: 854.2.

Example QG O H Boc 1. HCl N N N N N N 2. HATU, O NMM H O H N O HO N O O O H (S) tert-butyl (2S,4S)[5-(2-{(2S,5S)[N- (methoxycarbonylamino) (methoxycarbonyl)-L-valyl]methylpyrrolidinyl}-1,11- butanoic acid oisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl)- 1H-imidazolyl]methylpyrrolidinecarboxylate O N O H N N N N N N H N O methyl {(2S)[(2S,5S)(9-{2-[(2S,4S){(2S) [(methoxycarbonyl)amino]methylbutanoyl} methylpyrrolidinyl]-1H-imidazolyl}-1,11- dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazol yl)methylpyrrolidinyl]methyloxobutan yl}carbamate Methyl {(2S)[(2S,5S)(9-{2-[(2S,4S){(2S)[(methoxycarbonyl)amino] methylbutanoyl}methylpyrrolidinyl]-1H-imidazolyl}-1,11- dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl)methylpyrrolidinyl] methyloxobutanyl}carbamate tert-butyl (2S,4S)[5-(2-{(2S,5S)[N-(methoxycarbonyl)-L-valyl] methylpyrrolidinyl}-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl)-1H- imidazolyl]methylpyrrolidinecarboxylate (60 mg, 0.079 mmol) in 1.25 N HCl in EtOH (2 mL) was heated to 50 °C for 3h and then concentrated under reduced pressure. The crude residue was treated with (S)(methoxycarbonylamino)methylbutanoic acid (21 mg, 0.12 mmol), HATU (36 mg, 0.095 mmol) and DMF (1.5 mL), then N-methylmorpholine (0.027 mL, 0.24 mmol) was added se. After 3h, the mixture was quenched with 1N HCl (0.100 mL) and then purified by HPLC to afford methyl 1-[(2S,5S)(9-{2- [(2S,4S){(2S)[(methoxycarbonyl)amino]methylbutanoyl}methylpyrrolidinyl]- 1H-imidazolyl}-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl) methylpyrrolidinyl]methyloxobutanyl}carbamate ( 33 mg, 51%).

LCMS-ESI+: calculated for C45H54N8O7: 818.4; observed [M+1]+: 820.2.

Example QH O H 1. HCl BocN N N 2. HATU, NMM, DMF N N N (2S,3R)methoxy H (methoxycarbonylamino)butanoic acid H O tert-butyl )[5-(2-{(2S,5S)[N-(methoxycarbonyl)-L- valyl]methylpyrrolidinyl}-1,11- dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl)-1H- imidazolyl]methylpyrrolidinecarboxylate O N O H N N N O N N N H O methyl {(2S)[(2S,5S)(9-{2-[(2S,4S){(2S,3R) methoxy[(methoxycarbonyl)amino]butanoyl} methylpyrrolidinyl]-1H-imidazolyl}-1,11- oisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl) methylpyrrolidinyl]methyloxobutanyl}carbamate Methyl {(2S)[(2S,5S)(9-{2-[(2S,4S){(2S,3R)methoxy [(methoxycarbonyl)amino]butanoyl}methylpyrrolidinyl]-1H-imidazolyl}-1,11- dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl)methylpyrrolidinyl] methyloxobutanyl}carbamate tert-butyl (2S,4S)[5-(2-{(2S,5S)[N-(methoxycarbonyl)-L-valyl] methylpyrrolidinyl}-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2-d]imidazolyl)-1H- olyl]methylpyrrolidinecarboxylate (20 mg, 0.079 mmol) in 1.25 N HCl in EtOH (2 mL) was heated to 50 °C for 3h and then concentrated under reduced pressure. The crude residue was treated with (2S,3R)methoxy(methoxycarbonylamino)butanoic acid (8 mg, 0.04 mmol), HATU (12 mg, 0.03 mmol) and DMF (0.5 mL), then N- methylmorpholine (0.009 mL, 0.078 mmol) was added se. After 3h, the mixture was quenched with 1N HCl (0.100 mL) and then purified by HPLC to afford methyl {(2S) [(2S,5S)(9-{2-[(2S,4S){(2S)[(methoxycarbonyl)amino]methylbutanoyl} methylpyrrolidinyl]-1H-imidazolyl}-1,11-dihydroisochromeno[4',3':6,7]naphtho[1,2- d]imidazolyl)methylpyrrolidinyl]methyloxobutanyl}carbamate ( 7.5 mg, %).

LCMS-ESI+: calculated for C45H54N8O8: 834.4; observed [M+1]+: 835.7.

Compounds 478-647 Using procedures similar to those bed herein, the following compounds of the disclosure were prepared.

# Compound LCMS (observed (M+H)+) 478 879.4 493 838.2 494 837.3 495 835.73 498 835.34 499 823.35 503 837.35 507 865.32 510 880.0 516 836.04 518 803.2 526 806.11 536 838.29 588 842.10 602 847.99 603 822.02 617 854.19 626 885.80 643 878.15 O H O H H 646 N O N N O N O 881.66 N N O O H O BIOLOGICAL ASSAYS Effect of serum proteins on replicon potency: Replicon assays are conducted in normal cell culture medium (DMEM + ) supplemented with physiologic concentrations of human serum albumin (40 mg/mL) or α-acid glycoprotein (1 mg/mL).

EC50s in the presence of human serum proteins are compared to the EC50 in normal medium to determine the fold shift in potency.

MT-4 Cell Cytotoxicity: MT4 cells are treated with serial dilutions of compounds for a five day period. Cell viability is measured at the end of the treatment period using the Promega CellTiter-Glo assay and non-linear regression is performed to calculate CC50.

Compound Concentration Associated with Cells at EC50: Huh-luc cultures are incubated with compound at concentrations equal to EC50. At multiple time points (0 – 72 hours), cells are washed 2X with cold medium and extracted with 85% acetonitrile; a sample of the media at each time-point will also be extracted. Cell and media extracts are analyzed by MS to determine the Molar concentration of nds in each fraction.

Representative compounds of the sure have shown activity.

Solubility and Stability: lity is determined by taking an aliquot of 10 mM DMSO stock solution and preparing the nd at a final concentration of 100 µM in the test media ons (PBS, pH 7.4 and 0.1 N HCl, pH 1.5) with a total DMSO tration of 1%. The test media solutions are incubated at room temperature with shaking for 1 hr.

The solutions will then be centrifuged and the recovered supernatants are assayed on the HPLC/UV. Solubility will be calculated by comparing the amount of compound detected in the defined test on compared to the amount detected in DMSO at the same concentration. Stability of compounds after an 1 hour incubation with PBS at 37°C will also be determined. ity in Cryopreserved Human, Dog, and Rat Hepatocytes: Each compound is incubated for up to 1 hour in hepatocyte suspensions (100 µl, °Cells per well) at 37°C. Cryopreserved hepatocytes are reconstituted in the serum-free incubation medium.

The suspension is transferred into 96-well plates (50 µL/well). The compounds are diluted to 2 µM in incubation medium and then are added to hepatocyte suspensions to start the incubation. Samples are taken at 0, 10, 30 and 60 minutes after the start of incubation and reaction will be quenched with a e consisting of 0.3% formic acid in 90% itrile/10% water. The concentration of the compound in each sample is analyzed using LC/MS/MS. The disappearance half-life of the compound in hepatocyte suspension is determined by fitting the concentration-time data with a monophasic exponential equation.

The data will also be scaled up to represent intrinsic hepatic clearance and/or total hepatic clearance.

Stability in Hepatic S9 Fraction from Human, Dog, and Rat: Each compound is incubated for up to 1 hour in S9 suspension (500 µl, 3 mg protein/mL) at 37°C (n = 3). The compounds are added to the S9 suspension to start the incubation. Samples are taken at 0, 10, , and 60 minutes after the start of incubation. The concentration of the nd in each sample is analyzed using LC/MS/MS. The disappearance ife of the compound in S9 suspension is determined by fitting the concentration-time data with a monophasic exponential equation.

Caco-2 bility: Compounds are assayed via a contract service (Absorption Systems, Exton, PA). Compounds are provided to the contractor in a blinded manner. Both forward (A-to-B) and reverse (B-to-A) permeability will be measured. Caco-2 monolayers are grown to confluence on collagen-coated, microporous, rbonate nes in 12- well Costar TRANSWELL® plates. The nds are dosed on the apical side for forward permeability (A-to-B), and are dosed on the basolateral side for reverse permeability (B-to- A). The cells are incubated at 37°C with 5% CO2 in a fied incubator. At the beginning of incubation and at 1 hr and 2 hr after incubation, a 200-µL t is taken from the er chamber and replaced with fresh assay buffer. The concentration of the compound in each sample is determined with LC/MS/MS. The apparent permeability, Papp, is calculated.

Plasma Protein Binding: Plasma protein binding is ed by equilibrium dialysis. Each compound is spiked into blank plasma at a final concentration of 2 µM. The spiked plasma and phosphate buffer is placed into opposite sides of the assembled dialysis cells, which will then be rotated slowly in a 37°C water bath. At the end of the incubation, the tration of the compound in plasma and phosphate buffer is determined. The percent unbound is calculated using the following equation:  C  % Unbound = 100  f  Cb  C Where Cf and Cb are free and bound concentrations determined as the post-dialysis buffer and plasma concentrations, respectively.

CYP450 Profiling: Each compound is incubated with each of 5 recombinant human CYP450 enzymes, including CYP1A2, CYP2C9, CYP3A4, CYP2D6 and 9 in the presence and absence of NADPH. Serial samples will be taken from the incubation mixture at the beginning of the incubation and at 5, 15, 30, 45 and 60 s after the start of the incubation. The concentration of the compound in the incubation mixture is determined by LC/MS/MS. The tage of the compound remaining after incubation at each time point is calculated by comparing with the sampling at the start of incubation.

Stability in Rat, Dog, Monkey and Human Plasma: Compounds will be incubated for up to 2 hours in plasma (rat, dog, monkey, or human) at 37°C. Compounds are added to the plasma at final concentrations of 1 and 10 µg/mL. ts are taken at 0, 5, 15, 30, 60, and 120 minutes after adding the nd. Concentration of compounds and major metabolites at each time point are measured by LC/MS/MS.

Evaluation of cell-based anti-HCV activity: Antiviral potency (EC50) was determined using a Renilla luciferase -based HCV replicon reporter assay. To m the assay for genotype 1 and 2a JFH-1, stable HCV 1a RLuc replicon cells (harboring a dicistronic genotype 1a H77 replicon that encodes a RLuc reporter), stable HCV 1b RLuc replicon cells ring a dicistronic genotype 1b Con1 replicon that encodes a RLuc reporter), or stable HCV 2a JFH-1 Rluc replicon cells (harboring a dicistronic genotype 2a JFH-1 replicon that encodes a RLuc reporter; with L31 present in NS5A) were dispensed into 384-well plates for EC50 assays. To perform the assay for genotype 2a (with M31 present in NS5A) or 2b, NS5A chimeric genotype 2a JFH-1 ons that encodes a eo er and either genotype 2a J6 strain NS5A gene or genotype 2b MD2b-1 strain NS5A gene (both with M31 present) respectively, were either transiently transfected (t) into Huh- Lunet cells or were established as stably replicating replicon cells (s) is ed. Either cells were dispensed into 384-well plates for EC50 assays. To perform the assay for genotype 3 and 4, NS5A chimeric genotype 1b Con1 replicons that encodes a Pi-RLuc reporter and either genotype 3a S52 strain NS5A gene or genotype 4a ED43 strain NS5A gene respectively, were transiently transfected (t) into net cells, which were subsequently dispensed into 384-well plates. Compounds were dissolved in DMSO at a concentration of 10 mM and diluted in DMSO either manually or using an ted ng instrument. Serially 3-fold diluted compounds were either manually mixed with cell culture media and added to the seeded cells or directly added to the cells using an automated instrument. DMSO was used as a negative (solvent; no inhibition) control, and the protease tor ITMN-191 was included at a concentration > 100 x EC50 as a positive control. 72 hours later, cells were lysed and Renilla luciferase activity quantified as recommended by the manufacturer (Promega- Madison, WI). Non-linear regression was performed to calculate EC50 values.

To ine the antiviral y (EC50) against ance mutants, resistance mutations, including M28T, Q30R, Q30H, L31M, and Y93C in genotype 1a NS5A and Y93H in genotype 1b NS5A, were uced individually into either 1a Pi-Rluc or 1b Pi- Rluc replicons by site directed mutagenesis. Replicon RNA of each resistant mutant was transiently transfected into derived cured-51 cells and antiviral potency was determined on these ected cells as described above.

The EC50 ranges for genotype 1a, 1a Q30R, and 2a JFH are as follows: A ≥ 44 nM, B = 1 nM to 43.99 nM, C < 1 nM. The EC50 ranges for genotype 2a J6, 2b, 3a, and 4a are as follows: A ≥ 5 nM, B = 1 nM to 4.99 nM, C < 1 nM. The EC50 ranges for genotype 2a J6, 2b, and 4a correspond to the assay of transiently transfected cells (t). If this data is unavailable, the EC50 range for the stably ating cells (s) is provided.

IV and PO Single Dose Pharmacokinetic Studies in SD Rats: The pharmacokinetics of selected compounds was characterized in male Sprague-Dawley (SD) rats (250-300g). In this study, two groups of naïve purebred SD rats (N=3 per group, fasted over night) received the selected compound either as an intravenous (IV) infusion (1 mg/kg over 30 minutes) via the jugular vein or by oral gavage (2 mg/kg). The intravenous (IV) dosing vehicle was 5% ethanol, 35% polyethylene glycol 400 (PEG 400) and 60% water pH 2.0. The oral dosing vehicle was 5% ethanol, 55% PEG 400 and 40% citrate buffer pH 2.2.

Serial blood samples ximately 0.3 mL each) were collected from jugular vein or other suitable vein at specified time points. For the IV infusion group, the blood samples were collected predose and at 0.25, 0.48, 0.58, 0.75, 1.5, 3, 6, 8, 12 and 24 hours after the start of infusion. For the oral group, the blood samples were collected predose and at 0.25, 0.50, 1, 2, 4, 6, 8, 12 and 24 hours after dosing. The blood samples were ted into Vacutainer tubes containing EDTA-K3 as the anti-coagulant and were centrifuged at approximately 4ºC to obtain plasma. The plasma samples were stored at -20ºC until analysis by LC/MS/MS.

A bioanalytical method utilizing high performance liquid tography coupled to tandem mass spectrometry (LC/MS/MS) was ped for analysis of the selected compound in rat plasma. Detection was med using selected reaction monitoring (SRM); Ions representing the precursor (M+H)+ species was selected in quadrupole 1 (Q1) and ed with argon gas in the collision cell (Q2) to generate specific product ion, which was subsequently monitored by quadrupole 3 (Q3). rd curve and quality control samples were prepared in male rat plasma and processed in the same way as the test samples to generate quantitative data.

Pharmacokinetic parameters were generated using mpartmental pharmacokinetic analysis (Phoenix WinNonlin, version 6.3). Values below the lower limit of quantification (LLOQ) were assigned a value of zero if predose and treated as missing thereafter. Area under the curve (AUC) was calculated using the linear trapezoidal rule. The oral bioavailability (%F) was determined by comparison of the area under the curve (AUC) of the compound and/or a metabolite generated in plasma following oral stration to that generated following intravenous administration. # e 1b 1a 1a 2a 2a 2b 3a 4a 1a 1a 2a 2a J6 2a J6 2b (t) 2b (s) 3a 4a (t) 4a (s) Rat %F No. (nM) Q30R JFH J6 (nM) Q30R JFH (t) (s) (nM) (nM) (nM) (nM) (nM) (nM) (nM) (nM) (nM) 422 MC 0.017 C C C B C C C 0.016 0.990 0.004 1.155 3.523 0.162 0.375 0.004 0.008 0.028 423 LQ 0.020 C C C C C C C 0.022 0.135 0.004 0.134 0.543 0.012 0.035 0.005 0.008 0.02 426 MD 0.033 C C C C C C C 0.035 0.192 0.006 0.073 0.439 0.016 0.038 0.006 0.011 0.035 427 ME 0.049 C B C B C C C 0.033 2.514 0.012 3.428 16.075 0.198 0.701 0.015 0.016 0.029 434 MG 0.055 C C C C C C C 0.054 0.663 0.012 0.337 2.288 0.070 0.010 0.024 0.08 435 MF 0.058 C C C C C C C 0.059 0.768 0.012 0.476 2.136 0.083 0.011 0.025 478 478 0.048 C C B C C C 0.045 0.011 3.654 0.820 0.065 0.023 0.019 493 493 0.030 C C A C C C 0.036 0.008 5.036 0.650 0.050 0.013 0.018 494 494 0.021 C C C C C C C 0.037 0.118 0.005 0.098 0.017 0.005 0.017 0.031 495 495 0.026 C C C C C C C 0.021 0.201 0.008 0.280 1.016 0.135 0.541 0.024 0.014 0.014 498 498 0.016 C C C C C C C 0.030 0.040 0.004 0.012 0.039 0.010 0.013 0.005 0.011 0.004 499 499 0.032 C C C C C C 0.057 0.008 0.206 0.040 0.010 0.021 0.005 503 503 0.041 C C C C C C 0.062 0.012 0.155 0.037 0.016 0.028 0.025 507 507 1.503 B C A B C C 3.698 0.297 20.096 1.561 0.382 0.594 0.025 510 510 0.050 C C C C C C 0.021 0.009 0.007 0.018 0.017 0.020 0.008 0.016 0.072 516 516 0.024 C C C C C C 0.015 0.009 0.043 0.013 0.005 0.010 0.025 518 518 0.010 C C B C C C 0.005 0.006 2.493 0.643 0.005 0.004 0.011 526 526 0.018 C C C C C C C 0.011 0.095 0.007 0.443 1.639 0.132 0.404 0.018 0.011 0.011 536 536 0.013 C C C C C C C 0.008 0.048 0.004 0.040 0.154 0.011 0.037 0.009 0.005 0.01 538 LR-1 0.016 C C C C C C C 0.011 0.015 0.005 0.018 0.048 0.010 0.024 0.013 0.010 0.012 539 LT 0.016 C C C C C C C 0.009 0.010 0.004 0.010 0.047 0.009 0.039 0.012 0.015 0.009 543 MY 0.015 C C C C C C C 0.016 0.024 0.005 0.047 0.165 0.016 0.047 0.010 0.008 0.02 544 MM 0.026 C C C C C C C 0.022 0.044 0.007 0.018 0.064 0.015 0.042 0.020 0.017 0.016 551 OQ 0.018 C C C C C C C 0.015 0.102 0.007 0.378 1.492 0.265 0.982 0.048 0.020 0.016 552 OR 0.033 C C C C C C C 0.030 0.059 0.011 0.068 0.160 0.037 0.109 0.031 0.036 0.006 555 MN 0.021 C C C C C C C 0.014 0.018 0.008 0.017 0.071 0.013 0.040 0.034 0.024 0.007 1.5 556 MS 0.008 C C A A C 0.008 0.005 15.564 9.562 0.014 0.02 558 PQ 0.014 C C C C C C 0.014 0.106 0.005 0.025 0.155 0.032 0.057 0.015 0.017 561 MP 0.010 C C C C C C C 0.006 0.031 0.004 0.039 0.336 0.032 0.184 0.015 0.015 0.013 24.2 562 MO 0.019 C C C C C C C 0.013 0.052 0.007 0.089 0.471 0.137 0.427 0.051 0.022 0.018 7.46 563 MT 0.007 C C A A B C 0.003 0.021 44.444 44.444 1.092 0.015 0.025 565 NB 0.017 C C C C C C C 0.010 0.034 0.004 0.020 0.138 0.007 0.039 0.011 0.023 0.025 566 NC 0.009 C C C C C C C 0.007 0.060 0.005 0.089 0.762 0.068 0.191 0.014 0.011 0.026 569 ND 0.024 C C C C C C C 0.020 0.057 0.014 0.314 2.338 0.270 1.319 0.035 0.031 0.044 571 OO 0.114 C C C C C C C 0.072 0.139 0.015 0.028 0.259 0.020 0.076 0.028 0.086 0.018 572 PF 0.044 C C C C C C C 0.032 0.034 0.014 0.025 0.127 0.023 0.117 0.072 0.050 0.018 4.3 573 PG 0.030 C C C C C C C 0.033 0.043 0.018 0.045 0.335 0.027 0.119 0.050 0.063 0.008 574 PN 0.016 C C C C C C C 0.015 0.030 0.009 0.027 0.277 0.014 0.035 0.016 0.014 0.02 575 PP 0.029 C C C C C C C 0.014 0.043 0.011 0.061 0.403 0.038 0.110 0.019 0.027 0.011 576 PO 0.014 C C B C C C 0.013 0.011 3.135 0.470 0.012 0.013 0.013 579 OI 0.034 C C C C C C C 0.024 0.086 0.010 0.061 0.326 0.178 0.629 0.206 0.036 0.007 580 OJ 0.017 C C C C C C 0.018 0.013 0.502 0.813 0.259 0.026 0.017 582 NF 0.010 C C C C C C C 0.011 0.017 0.006 0.031 0.218 0.018 0.064 0.017 0.009 0.012 585 NG 0.009 C C C C C C C 0.006 0.243 0.010 0.370 1.672 0.063 0.135 0.020 0.008 587 MR 0.041 C C C C C C C 0.028 0.128 0.017 0.079 0.176 0.039 0.053 0.078 0.045 588 588 0.017 C C C C C C C 0.012 0.087 0.004 0.038 0.140 0.012 0.017 0.027 0.019 589 MQ 0.011 C C C C C C C 0.008 0.023 0.004 0.017 0.095 0.009 0.023 0.016 0.011 590 MU 0.014 C C C C C C C 0.008 0.023 0.004 0.013 0.046 0.009 0.025 0.017 0.011 592 NI 0.015 C C C C C C C 0.015 0.059 0.007 0.026 0.169 0.019 0.054 0.022 0.020 24.1 594 NP 0.013 C C C C C C C 0.014 0.032 0.007 0.010 0.096 0.011 0.043 0.020 0.028 26.1 597 NJ 0.005 C C C C C C C 0.007 0.025 0.007 0.099 0.939 0.094 0.416 0.019 0.017 599 PY 0.009 C C C C C C C 0.012 0.013 0.006 0.009 0.098 0.007 0.030 0.017 0.018 27.7 600 PZ 0.007 C C C C C C 0.009 0.057 0.005 0.175 1.712 0.071 0.386 0.025 601 MV 0.014 C C C C C C C 0.010 0.012 0.004 0.047 0.034 0.041 0.011 0.011 602 602 0.025 C C C C C 0.025 0.010 0.053 0.036 0.036 0.013 603 603 0.015 C C C C C C C 0.009 0.146 0.007 0.194 0.067 0.088 0.015 0.022 604 NR 0.020 C C C C C 0.026 0.006 0.118 0.017 0.017 0.007 605 NQ 0.015 C C C C C C 0.017 0.039 0.006 0.064 0.013 0.012 0.013 606 OK 0.034 C C C C C C 0.026 0.039 0.011 0.076 0.036 0.045 0.028 607 OL 0.067 C C C C 0.047 0.012 0.070 0.052 0.052 608 OH 0.017 C C C C C C 0.016 0.031 0.007 0.054 0.023 0.022 0.026 22.7 609 QF 0.005 C C C C C C 0.008 0.032 0.004 0.053 0.015 0.011 0.020 610 QA 0.013 C C C C C C 0.012 0.045 0.007 0.094 0.052 0.040 0.038 7.46 612 QH 0.005 C C C C C C 0.007 0.051 0.005 0.182 0.051 0.049 0.020 613 QG 0.005 C C C C C C 0.005 0.071 0.004 0.551 0.065 0.043 0.016 614 OP 0.013 C C C C C C 0.013 0.026 0.008 0.018 0.011 0.007 0.027 15.1 615 OM 0.019 C C C C C C 0.014 0.035 0.009 0.045 0.053 0.054 0.035 12.2 617 617 0.005 C C C C C C 0.009 0.024 0.004 0.032 0.013 0.011 0.019 14.4 618 OT 0.020 C C C C C C 0.011 0.041 0.005 0.013 0.012 0.024 619 OF 0.007 C C C C 0.010 0.008 0.445 0.196 620 NK 0.081 C C C C 0.049 0.018 0.056 0.154 621 NL 0.013 C C C C 0.011 0.007 0.043 0.034 622 NM 0.016 C C C C C C 0.011 0.028 0.006 0.012 0.013 0.024 6.93 623 ON 0.006 C C C C 0.005 0.004 0.068 0.086 625 PH 0.031 C C C C C C 0.024 0.051 0.014 0.055 0.042 0.029 626 626 0.030 C C C C C C 0.021 0.041 0.009 0.021 0.021 0.027 627 PI 0.039 C C C C C C 0.031 0.094 0.020 0.129 0.090 0.065 8.7 628 OG 0.009 C C C C 0.009 0.008 0.601 0.437 631 PS 0.006 C C C C A 0.005 0.004 0.077 0.113 44.444 632 PT 0.008 C C C C 0.007 0.007 0.383 0.182 633 PR 0.020 C C C C C C 0.013 0.045 0.007 0.022 0.028 0.018 634 PU 0.015 C C C C 0.012 0.006 0.068 0.442 635 OU 0.041 C C C C 0.047 0.016 0.040 0.035 636 OV 0.011 C C C C C C 0.010 0.031 0.007 0.113 0.046 0.013 637 OW 0.009 C C C C C C 0.009 0.019 0.006 0.009 0.008 0.013 13.3 638 OX 0.009 C C C C 0.007 0.006 0.113 0.107 639 QB 0.011 C C C C C C 0.011 0.029 0.008 0.021 0.022 0.028 9.56 640 QE 0.015 C C C C 0.013 0.011 0.291 0.563 641 QD 0.030 C C C C 0.025 0.013 0.103 0.193 642 QC 0.014 C C C C 0.012 0.008 0.157 0.317 643 643 0.015 C C C C 0.015 0.013 0.206 0.607 644 MW 0.026 C C C C C 0.012 0.012 0.020 0.043 0.123 0.011 645 MX 0.076 C C C C C 0.036 0.024 0.035 0.070 0.139 0.033 646 646 0.109 C C C C C 0.058 0.030 0.042 0.112 0.262 0.034 648 PJ 0.088 C C C C C 0.068 0.058 0.136 0.335 0.854 0.056 1001691089

Claims (12)

Claims

1.

A compound of a: O N O H N N N N N N O H N O O H or a pharmaceutically acceptable salt thereof. 5 2. A compound of formula: O N O H N N N N N N O H N O O H O .

3. A pharmaceutical composition comprising the compound or pharmaceutically acceptable salt thereof ing to claim 1 and at least one pharmaceutically acceptable carrier.

4. The pharmaceutical composition ing to claim 3, further comprising a nucleoside or 10 nucleotide inhibitor of NS5B polymerase.

5. Use of a compound or pharmaceutically acceptable salt thereof according to claim 1 in the manufacture of a medicament for the treatment of hepatitis C.

6. Use of the nd or pharmaceutically acceptable salt thereof according to claim 5, in combination with a side or nucleotide inhibitor of HCV NS5B polymerase. 15

7. A pharmaceutical composition comprising the compound according to claim 2 and at least one pharmaceutically acceptable carrier. 1001691089

8. The pharmaceutical composition ing to claim 7, further comprising a nucleoside or nucleotide inhibitor of NS5B polymerase.

9. Use of a compound according to claim 2 in the manufacture of a medicament for the treatment of hepatitis C. 5

10. Use of the compound according to claim 9, in ation with a nucleoside or nucleotide inhibitor of HCV NS5B polymerase.

11. Use of a ceutical composition according to claim 3 or claim 4, in the manufacture of a medicament for the treatment of hepatitis C.

12. Use of a pharmaceutical composition according to claim 7 or claim 8, in the manufacture 10 of a medicament for the treatment of hepatitis C.