Biphenyl bisimidazole compounds, compositions comprising the same and uses thereof

HEPATITIS C VIRUS INHIBITORS

מדכאי נגיף הפטיטיס ״c

The present disclosure is generally directed to antiviral compounds, and more specifically directed to compounds which can inhibit the function of the NS5A protein encoded by Hepatitis C virus (HCV), compositions comprising such compounds, and methods for inhibiting the function of the NS5A protein.

HCV is a major human pathogen, infecting an estimated 170 million persons worldwide ־ roughly five times the number infected by human immunodeficiency virus type 1. A substantial fraction of these HCV infected individuals develop serious progressive liver disease, including cirrhosis and hepatocellular carcinoma.

Presently, the most effective HCV therapy employs a combination of alphainterferon and ribavirin, leading to sustained efficacy in .40% of patients. Recent clinical results demonstrate that pegylated alpha-interferon is superior to unmodified alpha-interferon as monotherapy. However, even with experimental therapeutic regimens involving combinations of pegylated alpha-interferon and ribavirin, a substantial fraction of patients do not have a sustained reduction in viral load. Thus, there is a clear and long-felt need to develop effective therapeutics for treatment of HCV infection.

HCV is a positive-stranded RNA virus. Based on a comparison of the deduced amino acid sequence and the extensive similarity in the 5’ untranslated 25 region, HCV has been classified as a separate genus in the Flaviviridae family. All members of the Flaviviridae family have enveloped virions that contain a positive stranded RNA genome encoding all known virus-specific proteins via translation of a single, uninterrupted, open reading frame.

Considerable heterogeneity is found within the nucleotide and encoded amino 30 acid sequence throughout the HCV genome. At least six major genotypes have been characterized, and more than 50 subtypes have been described. The major genotypes of HCV differ in their distribution worldwide, and the clinical significance of the genetic heterogeneity of HCV remains elusive despite numerous studies of the possible effect of genotypes on pathogenesis and therapy.

The single strand HCV RNA genome is approximately 9500 nucleotides in length and has a single open reading frame (ORF) encoding a single large polyprotein of about 3000 amino acids. In infected cells, this polyprotein is cleaved at multiple sites by cellular and viral proteases to produce the structural and non-structural (NS) proteins. In the case of HCV, the generation of mature non-structural proteins (NS2, NS3, NS4A, NS4B, NS5A, and NS5B) is effected by two viral proteases. The first one is believed to be a metalloprotease and cleaves at the NS2-NS3 junction; the second one is a serine protease contained within the N-terminal region of NS3 (also referred to herein as NS3 protease) and mediates all the subsequent cleavages downstream of NS3, both in cis, at the NS3-NS4A cleavage site, and in trans, for the remaining NS4A-NS4B, NS4B-NS5A, NS5A-NS5B sites. The NS4A protein appears to serve multiple functions, acting as a cofactor for the NS3 protease and possibly assisting in the membrane localization 0fNS3 and other viral replicase components. The complex formation of the NS3 protein with NS4A seems necessary to the processing events, enhancing the proteolytic efficiency at all of the sites. The NS3 protein also exhibits nucleoside triphosphatase and RNA helicase activities. NS5B (also referred to herein as HCV polymerase) is a RNA-dependent RNA polymerase that is involved in the replication of HCV.

Compounds useful for treating HCV-infected patients are desired which selectively inhibit HCV viral replication. In particular, compounds which are effective to inhibit the function of the NS5A protein are desired. The HCV NS5A protein is described, for example, in Tan, S.-L., Katzel, M.G. Virology 2001, 284, 112; and in Park, K.-L; Choi, S.-H, J. Biological Chemistry 2003.

In a first aspect the present disclosure provides a compound of Formula (I)

<img file="IL196813A_D0001.tif" />

(I), or a pharmaceutically acceptable salt thereof, wherein m and n are independently 0,1, or 2;

q and s are independently 0, 1, 2, 3, or 4;

u and v are independently 0,1,2, or 3;

X is selected from 0, S, S(O), SO2, CH2, CHR⁵, and C(R⁵)₂;

provided that when n is 0, X is selected from CH₂, CHR⁵, and C(R⁵)₂;

Y is selected from O, S, S(O), SO₂, CH₂, CHR⁶, and CCR⁶)^ provided that when m is 0, Y is selected from CH2, CHR⁶, and C(R⁶)2;

each R¹ and R² is independently selected from alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, arylalkoxycarbonyl, carboxy, formyl, halo, haloalkyl, hydroxy, hydroxy alkyl, -NR^aR^b, (NR^aR^b)alkyl, and (NR^aR^b)carbonyl;

R³ and R⁴ are each independently selected from hydrogen, R⁹-C(O)-, and R⁹־ C(S)-;

each R⁵ and R⁶ is independently selected from alkoxy, alkyl, aryl, halo, haloalkyl, hydroxy, and -NR^aR^b, wherein the alkyl can optionally form a fused threeto six-membered ring with an adjacent carbon atom, wherein the three- to sixmembered ring is optionally substituted with one or two alkyl groups;

R⁷ and R⁸ are each independently selected from hydrogen, alkoxycarbonyl, alkyl, arylalkoxycarbonyl, carboxy, haloalkyl, (NR^aR^b)carbonyl, and trialkylsilylalkoxyalkyl; and each R⁹ is independently selected from alkoxy, alkoxyalkyl, alkoxy carbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonylalkyl, aryl, arylalkenyl, arylalkoxy, arylalkyl, aryloxyalkyl, cycloalkyl, (cycloalkyl)alkenyl, (cycloalkyl)alkyl, cycloalkyloxyalkyl, haloalkyl, heterocyclyl, heterocyclylalkenyl, heterocyclylalkoxy, heterocyclylalkyl, heterocyclyloxyalkyl, hydroxyalkyl, -NR^cR^d, (NR^cR^d)alkenyl, (NR^cR^d)alkyl, and (NR^cR^d)carbonyl.

In a first embodiment of the first aspect the present disclosure provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein m and n are each 1.

In a second embodiment of the first aspect the present disclosure provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein u and v are each independently 0,1, or 2; and each R¹ and R² is independently selected from alkoxy, alkoxyalkyl, alkyl, arylalkoxycarbonyl, carboxy, formyl, halo, haloalkyl, hydroxyalkyl, (NR^aR^b)alkyl, and (NR^aR^b)carbonyl.

In a third embodiment ofthe first aspect the present disclosure provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein u and v are each independently 0 or 1; and when present, R¹ and/or R² are halo.

In a fourth embodiment of the first aspect the present disclosure provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein u and v are each independently 0 or 1; and when present, R¹ and/or R² are halo, wherein the halo is fluoro.

In a fifth embodiment ofthe first aspect the present disclosure provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein at least one of X and Y is S.

In a sixth embodiment of the first aspect the present disclosure provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein X and Y are each S.

In a seventh embodiment of the first aspect the present disclosure provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein X is selected from CHR⁵, and C(R⁵)2; and Y is selected from CH₂, CHR⁶, and C(R⁶)2.

In an eighth embodiment of the first aspect the present disclosure provides a

ך _י compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R and R⁸ are independently selected from hydrogen, alkoxycarbonyl, alkyl, arylalkoxycarbonyl, carboxy, haloalkyl, and (NR^aR^b)carbonyl.

In a ninth embodiment of the first aspect the present dislcosure provides a

י׳ _״ compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R and R⁸ are each hydrogen.

In a tenth embodiment ofthe first aspect the present disclosure provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein q and s are independently 0,1, or 2; and each R⁵ and R⁶ is independently selected from alkyl, aryl, halo, and hydroxy, wherein the alkyl can optionally form a fused three- to six-membered ring with an adjacent carbon atom, wherein the three- to six-membered ring is optionally substituted with one or two alkyl groups.

In an eleventh embodiment of the first aspect the present dislcosure provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein q and s are independently 0 or 1; and when present, R⁵ and/or R⁶ are each halo.

In a twelfth embodiment of the first aspect the present dislcosure provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein q and s are independently 0 or 1; and when present, R⁵ and/or R⁶ are each halo, wherein the halo is fluoro.

In a thirteenth embodiment ofthe first aspect the present disclosure provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein at least one of R³ and R⁴ is hydrogen.

In a fourteenth embodiment of the first aspect the present disclosure provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R³and R⁴ are each R⁹-C(O)-.

In a fifteenth embodiment of the first aspect the present disclosure provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein each R⁹ is independently selected from alkoxy, alkoxyalkyl, alkyl, alkylcarbonyl alkyl, aryl, arylalkenyl, arylalkoxy, arylalkyl, aryloxy alkyl, cycloalkyl, (cycloalky !)alkyl, cycloalkyloxyalkyl, heterocyclyl, heterocyclylalkyl, hydroxyalkyl, -NR^cR^d, (NR^cR^d)alkenyl, (NR^cR^d)alkyl, and (NR^cR^d)carbonyl.

In a second aspect the present disclosure provides a compound of Formula (II)

<img file="IL196813A_D0002.tif" />

(Π), or a pharmaceutically acceptable salt thereof, wherein q and s are independently 0,1, or 2;

u and v are independently 0,1, or 2;

X is selected from S, CH2, CHR⁵, and C(R⁵)2;

Y is selected from S, CH₂, CHR⁶, and C(R⁶)₂;

each R¹ and R² is independently selected from alkoxy, alkoxyalkyl, alkyl, arylalkoxycarbonyl, carboxy, formyl, halo, haloalkyl, hydroxyalkyl, (NR^aR^b)alkyl, and (NR^aR^b)carbonyl;

R³ and R⁴ are each independently selected from hydrogen and R⁹-C(O)-;

each R⁵ and R⁶ is independently selected from alkyl, aryl, halo, and hydroxy, wherein the alkyl can optionally form a fused three- to six-membered ring with an adjacent carbon atom, wherein the three- to six-membered ring is optionally substituted with one or two alkyl groups;

R⁷ and R⁸ are each independently selected from hydrogen, alkoxycarbonyl, alkyl, arylalkoxycarbonyl, carboxy, haloalkyl, and (NR^aR^b)carbonyl; and each R⁹ is independently selected from alkoxy, alkoxyalkyl, alkyl, alkylcarbonylalkyl, aiyl, arylalkenyl, arylalkoxy, arylalkyl, aryloxyalkyl, cycloalkyl, (cycloalkyl)alkyl, cycloalkyloxyalkyl, heterocyclyl, heterocyclylalkyl, hydroxyalkyl, -NR^cR^d, (NR^cR^d)alkenyl, (NR^cR^d)alkyl, and (NR^cR^d)carbonyl.

In a third aspect the present disclosure provides a compound of Formula (ΙΠ)

<img file="IL196813A_D0003.tif" />

(ΠΙ), or a pharmaceutically acceptable salt thereof, wherein q and s are independently 0,1, or 2;

u and v are independently 0 or 1;

X is selected from CH2, CHR⁵, and C(R⁵)2;

Y is selected from CH2, CHR⁶, and C(R⁶)2;

when present, R¹ and/or R² are halo, wherein the halo is fluoro;

R³ and R⁴ are each R⁹-C(O)-;

when present, R⁵ and/or R⁶ are halo, wherein the halo is fluoro; and each R⁹ is independently selected from alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonylalkyl, aryl, arylalkenyl, arylalkoxy, arylalkyl, aryloxyalkyl, cycloalkyl, (cycloalkyl)alkenyl, (cycloalkyl)alkyl, cycloalkyloxyalkyl, haloalkyl, heterocyclyl, heterocyclylalkenyl, heterocyclylalkoxy, heterocyclylalkyl, heterocyclyloxyalkyl, hydroxyalkyl, -NR^cR^d, (NR^cR^d)alkenyl, (NR^cR^d)alkyl, and (NR^cR^d)carbonyl.

In a fourth aspect the present disclosure provides a compound selected from

ר methyl ((lS)-l-(((2S)-2-(5-(4'-(2-((2S)-l-((2S)-2-((methoxycarbonyl)amino)3־methylbutanoyl)-2-pyrrolidinyl)-lH-imidazol5־-yl)-4-biphenylyl)-lH-imidazol-2־yl)l-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate;

(lR,l'R)-2_>2'-(4,4'-biphenyldiylbis(lH-imidazole-5,2-diyl(2S)-2,lpyrrolidinediyl))bis(N,N-dimethyl-2-oxo-l־phenylethanamine);

methyl ((1 S)-2-((2S)-2-(52))-2)-'4)־S)-1 -((2R)-2־(diethylamino)-2-phenylacetyl)-2pyrrolidinyl)- lH-imidazol-5-yl)-4-biphenylyl)- lH-imidazol2־-yl)-1 -pyrrolidinyl)-1 methyl-2-oxoethyl)carbamate;

methyl ((IS)-l-(((2S)-2-(4-(4'-(2-((2S)-4,4-difluoro-l-((2S)2־((methoxycarbonyl)amino)-3-methylbutanoyl)-2-pyrrolidinyl)־lH־imidazol־4־yl)4־biphenylyl)-1 H-imidazol-2-yl)-4,4-difluoro-1 -pyrrolidinyl)carbony 1)-2methylpropyl)carbamate;

methyl ((lS)-l-(((lR,3R5_־R)-3-(5-(4'-(2-((lR,3R,5R)-2-((2S)-2((methoxycarbonyl)amino)-3־methylbutanoyl)-2-azabicyclo[3.1.0]hex-3-yl)-lHimidazol-5-yl)-4-biphenylyl)- lH-imidazol-2-yl)-2-azabicyclo[3.1.0]hex-2yl)carbonyl)-2-methylpropyl)carbamate;

methyl ((lR)-2-oxo-l-phenyl-2-((2S)-2-(5-(4'-(2-((2S)-l-((2R)-tetrahydro-2furanylcarbonyl)-2-pyrrolidinyl)-1 H-imidazol-5-yl)-4-biphenylyl)-1 H-imidazol-2yl)-1 -pyrrolidinyl)ethyl)carbamate;

methyl ((lS)-2-methyl-l-(((2S)2))-2)-'4)-5)-2־S)-l-(N-2-pyrimidinyl-D-valyl)-2pyrrolidinyl)- lH-imidazol-5-yl)-4-biphenylyl)-1 H-imidazol-2-yl)-1pyrrolidinyl)carbonyl)propyl)carbamate;

methyl ((lR)-2-((2S)-2-(5-(4'-(2-((2S)-l-((2R)-2-(dimethylamino)-2-phenylacetyl)-2pyrrolidinyl)-1 H-imidazol-5 -y l)-4-bipheny lyl)-1 H-imidazol-2-y 1)-1 -pyrrolidinyl)-2oxo-1 -phenylethy !)carbamate;

dimethyl (4,4'-biphenyldiylbis(lH-imidazole-5,2-diyl(2S)-2,1 -pyrrolidinediyl((!R)2-oxo-1 -phenyl-2,1 -ethanediy !)))biscarbamate;

(1 R)-N,N-dimethyl-2-oxo-1 -phenyl-2-((2S)-2-(5-(4'-(2-((2S)־l -((2R)־tetrahydro-2furanylcarbonyl)-2-pyrrolidinyl)-lH-imidazol-5־yl)-4-biphenylyl)-lH-imidazol-2yl)-1 -pyrrolidiny !)ethanamine;

methyl ((1 S)-2-((2S)-2-(5-(4'-(2-((2S)-1 -(N-(methoxycarbonyl)-L-alanyl)-2pyrrolidinyl)-lH-imidazol-5-yl)-4-biphenylyl)-lH-imidazol-2-yl)-l-pyrrolidinyl)-lmethyl-2-oxoethyl)carbamate; and methyl ((IS)-1 -(((2S)-2-(5-(4'-(2-((2S)-1 -((2S)-2-((methoxycarbonyl)amino)-3,3dimethylbutanoyl)-2-pyrrolidinyl)-lH-imidazol-5-yl)-4-biphenylyl)-lH-imidazol-2yl)-1 -pynolidinyl)carbonyl)-2,2-dimethylpropy !)carbamate;

or a pharmaceutically acceptable salt thereof.

In a first embodiment of the fifth aspect the pharmaceutically acceptable salt is a dihydrochloride salt.

In a sixth aspect the present disclosure provides a composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

In a first embodiment of the sixth aspect the composition further comprises one or two additional compounds having anti-HCV activity. In a second embodiment at least one of the additional compounds is an interferon or a ribavirin. In a third embodiment the interferon is selected from interferon alpha 2B, pegylated interferon alpha, consensus interferon, interferon alpha 2A, and lymphoblastiod interferon tau.

In a fourth embodiment of the sixth aspect the composition further comprises one or two additional compounds having anti-HCV activity wherein at least one of the additional compounds is selected from interleukin 2, interleukin 6, interleukin 12, a compound that enhances the development of a type 1 helper T cell response, interfering RNA, anti-sense RNA, Imiqimod, ribavirin, an inosine 5'-monophospate dehydrogenase inhibitor, amantadine, and rimantadine.

In a fifth embodiment of the sixth aspect the composition further comprises one or two additional compounds having anti-HCV activity wherein at least one of the additional compounds is effective to inhibit the function of a target selected from HCV metalloprotease, HCV serine protease, HCV polymerase, HCV helicase, HCV NS4B protein, HCV entry, HCV assembly, HCV egress, HCV NS5A protein, and 1MPDH for the treatment of an HCV infection.

In an seventh aspect the present disclosure provides a method of treating an HCV infection in a patient, comprising administering to the patient a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof.

In a first embodiment of the seventh aspect the method further comprises administering one or two additional compounds having anti-HCV activity prior to, after or simultaneously with the compound of formula (I), or a pharmaceutically acceptable salt thereof. In a second embodiment at least one of the additional compounds is an interferon or a ribavirin. In a third embodiment the interferon is selected from interferon alpha 2B, pegylated interferon alpha, consensus interferon, interferon alpha 2A, and lymphoblastiod interferon tau.

In a fourth embodiment the method further comprises administering one or two additional compounds having anti-HCV activity prior to, after or simultaneously with the compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein at least one of the additional compounds is selected from interleukin 2, interleukin 6, interleukin 12, a compound that enhances the development of a type 1 helper T cell response, interfering RNA, anti-sense RNA, Imiqimod, ribavirin, an inosine 5'-monophospate dehydrogenase inhibitor, amantadine, and rimantadine.

In a fifth embodiment the method further comprises administering one or two additional compounds having anti-HCV activity prior to, after or simultaneously with the compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein at least one of the additional compounds is effective to inhibit the function of a target selected from HCV metalloprotease, HCV serine protease, HCV polymerase, HCV helicase, HCV NS4B portein, HCV entry, HCV assembly, HCV egress, HCV NS5A protein, and IMPDH for the treatment of an HCV infection.

Other embodiments of the present disclosure may comprise suitable combinations of two or more of embodiments and/or aspects disclosed herein.

Yet other embodiments and aspects ofthe disclosure will be apparent according to the description provided below.

The compounds ofthe present disclosure also exist as tautomers; therefore the present disclosure also encompasses all tautomeric forms.

The description of the present disclosure herein should be construed in congruity with the laws and principals of chemical bonding. In some instances it may be necessary to remove a hydrogen atom in order accommodate a substitutent at any given location. For example, in the structure shown below

<img file="IL196813A_D0004.tif" />

R⁸

R⁸ may be attached to either the carbon atom in the imidazole ring or, alternatively,

R⁸ may take the place of the hydrogen atom on the nitrogen ring to form an Nsubstituted imidazole.

It should be understood that the compounds encompassed by the present disclosure are those that are suitably stable for use as pharmaceutical agent.

It is intended that the definition of any substituent or variable (e.g., R , R , R , R⁶, etc.) at a particular location in a molecule be independent of its definitions elsewhere in that molecule. For example, when u is 2, each of the two R¹ groups may be the same or different.

All patents, patent applications, and literature references cited in the specification are herein incorporated by reference in their entirety. In the case of inconsistencies, the present disclosure, including definitions, will prevail.

As used in the present specification, the following terms have the meanings indicated:

As used herein, the singular forms “a”, “an”, and “the” include plural reference unless the context clearly dictates otherwise.

Unless stated otherwise, all aryl, cycloalkyl, and heterocyclyl groups of the present disclosure may be substituted as described in each of their respective definitions. For example, the aryl part of an arylalkyl group may be substituted as described in the definition of the term ‘aryl’.

The term “alkenyl,” as used herein, refers to a straight or branched chain group of two to six caibon atoms containing at least one carbon-carbon double bond.

The term “alkenyloxy,” as used herein, refers to an alkenyl group attached to the parent molecular moiety through an oxygen atom.

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

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

The term “alkoxyalkyl,” as used herein, refers to an alkyl group substituted with one, two, or three alkoxy groups.

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

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

The term “alkoxycarbonylalkyl,” as used herein, refers to an alkyl group substituted with one, two, or three alkoxycarbonyl groups.

The term “alkyl,” as used herein, refers to a group derived from a straight or branched chain saturated hydrocarbon containing from one to six carbon atoms. In the compounds of the present disclosure, when m and/or n is 1 or 2; X and/or Y is CHR⁵ and/or CHR⁶, respectively, and R⁵ and/or R⁶ is alkyl, each alkyl can optionally form a fused three- to six-membered ring with an adjacent carbon atom to provide one of the structures shown below:

(R⁵⁰)w

<img file="IL196813A_D0005.tif" />

where z is 1, 2, 3, or 4, w is 0, 1, or 2, and R⁵⁰ is alkyl. When w is 2, the two R⁵⁰alkyl groups may be the same or different.

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

The term “alkylcarbonylalkyl,” as used herein, refers to an alkyl group substituted with one, two, or three alkylcarbonyl groups.

The term “alkylcarbonyloxy,” as used herein, refers to an alkylcarbonyl group attached to the parent molecular moiety through an oxygen atom.

The term “alkylsulfanyl,” as used herein, refers to an alkyl group attached to the parent molecular moiety through a sulfur atom.

The term “alkylsulfonyl,” as used herein, refers to an alkyl group attached to the parent molecular moiety through a sulfonyl group.

The term “aryl,” as used herein, refers to a phenyl group, or a bicyclic fused ring system wherein one or both of the rings is a phenyl group. Bicyclic fused ring systems consist of a phenyl group fused to a four- to six-membered aromatic or nonaromatic carbocyclic ring. The aryl groups of the present disclosure can be attached to the parent molecular moiety through any substitutable carbon atom in the group.

Representative examples of aryl groups include, but are not limited to, indanyl, indenyl, naphthyl, phenyl, and tetrahydronaphthyl. The aryl groups of the present disclosure are optionally substituted with one, two, three, four, or five substituents independently selected from alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, a second aryl group, arylalkoxy, arylalkyl, arylcarbonyl, cyano, halo, haloalkoxy, haloalkyl, heterocyclyl, heterocyclylalkyl, heterocyclylcarbonyl, hydroxy, hydroxyalkyl, nitro, -NR^xR^y, (NR^xR^y)alkyl, oxo, and -P(O)OR2, wherein each R is independently selected from hydrogen and alkyl; and wherein the alkyl part of the arylalkyl and the heterocyclylalkyl are unsubstituted and wherein the second aryl group, the aryl part of the arylalkyl, the aryl part of the arylcarbonyl, the heterocyclyl, and the heterocyclyl part of the heterocyclylalkyl and the heterocyclylcarbonyl are further optionally substituted with one, two, or three substituents independently selected from alkoxy, alkyl, cyano, halo, haloalkoxy, haloalkyl, and nitro.

The term “arylalkenyl,” as used herein, refers to an alkenyl group substituted with one, two, or three aryl groups.

The term “arylalkoxy,” as used herein, refers to an aryl group attached to the parent molecular moiety through an alkoxy group.

The term “arylalkoxyalkyl,” as used herein, refers to an alkyl group substituted with one, two, or three arylalkoxy groups.

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

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

The term “arylalkyl,” as used herein, refers to an alkyl group substituted with one, two, or three aryl groups. The alkyl part of the arylalkyl is further optionally substituted with one or two additional groups independently selected from alkoxy, alkylcarbonyloxy, halo, haloalkoxy, haloalkyl, heterocyclyl, hydroxy, and -NR^cR^d, wherein the heterocyclyl is further optionally substitued with one or two substituents independently selected from alkoxy, alkyl, unsubstituted aryl, unsubstituted arylalkoxy, unsubstituted arylalkoxycarbonyl, halo, haloalkoxy, haloalkyl, hydroxy, and -NR^xR^y.

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

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

The term “aryloxy,” as used herein, refers to an aryl group attached to the parent molecular moiety through an oxygen atom.

The term “aryloxyalkyl,” as used herein, refers to an alkyl group substituted with one, two, or three aryloxy groups.

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

The term “arylsulfonyl,” as used herein, refers to an aryl group attached to the parent molecular moiety through a sulfonyl group.

The terms “Cap” and “cap” as used herein, refer to the group which is placed on the nitrogen atom of the terminal nitrogen-containing ring, i.e., the pyrrolidine rings of compound le. It should be understood that “Cap” or “cap” can refer to the reagent used to append the group to the terminal nitrogen-containing ring or to the fragment in the final product, i.e., “Cap-51” or “The Cap-51 fragment found in LS19”.

The term “carbonyl,” as used herein, refers to -C(O)-.

The term “carboxy,” as used herein, refers to -CO2H.

The term “cyano,” as used herein, refers to -CN.

The term “cycloalkyl,” as used herein, refers to a saturated monocyclic, hydrocarbon ring system having three to seven carbon atoms and zero heteroatoms. Representative examples of cycloalkyl groups include, 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 substituents independently selected from alkoxy, alkyl, aryl, cyano, halo, haloalkoxy, haloalkyl, heterocyclyl, hydroxy, hydroxyalkyl, nitro, and -NR^xR^y, wherein the aryl and the heterocyclyl are futher optionally substituted with one, two, or three substituents independently selected from alkoxy, alkyl, cyano, halo, haloalkoxy, haloalkyl, hydroxy, and nitro.

The term “(cycloalkyl)alkenyl,” as used herein, refers to an alkenyl group substituted with one, two, or three cycloalkyl groups.

The term “(cycloalkyl)alkyl,” as used herein, refers to an alkyl group substituted with one, two, or three cycloalkyl groups. The alkyl part of the (cycloalkyl)alkyl is further optionally substituted with one or two groups independently selected from hydroxy and -NR^cR^d.

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

The term “cycloalkyloxyalkyl,” as used herein, refers to an alkyl group substituted with one, two, or three cycloalkyloxy groups.

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

The term “formyl,” as used herein, refers to -CHO.

The terms “halo” and “halogen,” as used herein, refer to F, Cl, Br, or I.

The term “haloalkoxy,” as used herein, refers to a haloalkyl group attached to the parent molecular moiety through an oxygen atom.

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

The term “haloalkyl,” as used herein, refers to an alkyl group substituted by one, two, three, or four halogen atoms.

The term “heterocyclyl,” as used herein, refers to a four־, five־, six-, or sevenmembered ring containing one, two, three, or four heteroatoms independently selected from nitrogen, oxygen, and sulfur. The four-membered ring has zero double bonds, the five-membered ring has zero to two double bonds, and the six- and sevenmembered rings have zero to three double bonds. The term “heterocyclyl” also includes bicyclic groups in which the heterocyclyl ring is fused to another monocyclic heterocyclyl group, or a four- to six-membered aromatic or non-aromatic carbocyclic ring; as well as bridged bicyclic groups such as 7-azabicyclo[2.2.1]hept7-yl, 2-azabicyclo[2.2.2]oc-2-tyl, and 2-azabicyclo[2.2.2]oc-3-tyl. The heterocyclyl groups of the present disclosure can be attached to the parent molecular moiety through any carbon atom or nitrogen atom in the group. Examples of heterocyclyl groups include, but are not limited to, benzothienyl, furyl, imidazolyl, indolinyl, indolyl, isothiazolyl, isoxazolyl, morpholinyl, oxazolyl, piperazinyl, piperidinyl, pyrazolyl, pyridinyl, pyrrolidinyl, pyrrolopyridinyl, pyrrolyl, thiazolyl, thienyl, thiomorpholinyl, 7-azabicyclo[2.2.1]hept-7-yl, 2-azabicyclo[2.2.2]oc-2-tyl, and 2 azabicyclo[2.2.2]oc-3-tyl. The heterocyclyl groups of the present disclosure are optionally substituted with one, two, three, four, or five substituents independently selected from alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, aryl, arylalkyl, arylcarbonyl, cyano, halo, haloalkoxy, haloalkyl, a second heterocyclyl group, heterocyclylalkyl, heterocyclylcarbonyl, hydroxy, hydroxyalkyl, nitro, NR^xR^y, (NR^xR^y)alkyl, and oxo, wherein the alkyl part of the arylalkyl and the heterocyclylalkyl are unsubstituted and wherein the aryl, the aryl part of the arylalkyl, the aryl part of the arylcarbonyl, the second heterocyclyl group, and the heterocyclyl part of the heterocyclylalkyl and the heterocyclylcarbonyl are further optionally substituted with one, two, or three substituents independently selected from alkoxy, alkyl, cyano, halo, haloalkoxy, haloalkyl, and nitro.

The term “heterocyclylalkenyl,” as used herein, refers to an alkenyl group substituted with one, two, or three heterocyclyl groups.

The term “heterocyclylalkoxy,” as used herein, refers to a heterocyclyl group attached to the parent molecular moiety through an alkoxy group.

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

The term “heterocyclylalkyl,” as used herein, refers to an alkyl group substituted with one, two, or three heterocyclyl groups. The alkyl part of the heterocyclylalkyl is further optionally substituted with one or two additional groups independently selected from alkoxy, alkylcarbonyloxy, aryl, halo, haloalkoxy, haloalkyl, hydroxy, and -NR^cR^d, wherein the aryl is further optionally substitued with one or two substituents independently selected from alkoxy, alkyl, unsubstituted aryl, unsubstitued arylalkoxy, unsubstituted arylalkoxycarbonyl, halo, haloalkoxy, haloalkyl, hydroxy, and -NR^xR^y.

The term “heterocyclylalkylcarbonylas used herein, refers to a heterocyclylalkyl group attached to the parent molecular moiety through a carbonyl group.

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

The term “heterocyclyloxy,” as used herein, refers to a heterocyclyl group attached to the parent molecular moiety through an oxygen atom.

The term “heterocyclyloxyalkyl,” as used herein, refers to an alkyl group substituted with one, two, or three heterocyclyloxy groups.

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

The term “hydroxy,” as used herein, refers to -OH.

The term “hydroxyalkyl,” as used herein, refers to an alkyl group substituted with one, two, or three hydroxy groups.

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

The term “nitro,” as used herein, refers to -NO₂.

The term “-NR^aR^b,” as used herein, refers to two groups, R^a and R^b, which are attached to the parent molecular moiety through a nitrogen atom. R^a and R^b are independently selected from hydrogen, alkenyl, and alkyl.

The term “(NR^aR^b)alkyl,” as used herein, refers to an alkyl group substituted with one, two, or three -NR^aR^b groups.

The term “(NR^aR^b)carbonylas used herein, refers to an -NR^aR^b group attached to the parent molecular moiety through a carbonyl group.

The term “-NR^cR^d,” as used herein, refers to two groups, R^c and R , which are attached to the parent molecular moiety through a nitrogen atom. R^c and R^d are independently selected from hydrogen, alkenyloxycarbonyl, alkoxyalkylcarbonyl, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylsulfonyl, aryl, arylalkoxycarbonyl, arylalkyl, arylalkylcarbonyl, arylcarbonyl, aryloxycarbonyl, arylsulfonyl, cycloalkyl, cycloalkylsulfonyl, formyl, haloalkoxycarbonyl, heterocyclyl, heterocyclylalkoxycarbonyl, heterocyclylalkyl, heterocyclylalkylcarbonyl, heterocyclylcarbonyl, heterocyclyloxycarbonyl, hydroxyalkylcarbonyl, (NR^eR^f)alkyl, (NR'R^alkylcarbonyl, (NR^eR^f)carbonyl, (NR^eR^f)sulfonyl, -C(NCN)OR’, and C(NCN)NR^xR^y, wherein R’ is selected from alkyl and unsubstituted phenyl, and wherein the alkyl part of the arylalkyl, the arylalkylcarbonyl, the heterocyclylalkyl, and the heterocyclylalkylcarbonyl are further optionally substituted with one -NR'R group; and wherein the aryl, the aryl part of the arylalkoxycarbonyl, the arylalkyl, the arylalkylcarbonyl, the arylcarbonyl, the aryloxycarbonyl, and the arylsulfonyl, the heterocyclyl, and the heterocyclyl part of the heterocyclylalkoxycarbonyl, the heterocyclylalkyl, the heterocyclylalkylcarbonyl, the heterocyclylcarbonyl, and the heterocyclyloxycarbonyl are further optionally substituted with one, two, or three substituents independently selected from alkoxy, alkyl, cyano, halo, haloalkoxy, haloalkyl, and nitro.

The term “(NR^cR^d)alkenyl,” as used herein, refers to an alkenyl group substituted with one, two, or three -NR^cR^d groups.

The term “(NR^cR^d)alkyl,” as used herein, refers to an alkyl group substituted with one, two, or three -NR^cR^d groups. The alkyl part of the (NR^cR^d)alkyl is further optionally substituted with one or two additional groups selected from alkoxy, alkoxyalkylcarbonyl, alkoxycarbonyl, alkylsulfanyl, arylalkoxyalkylcarbonyl, carboxy, heterocyclyl, heterocyclylcarbonyl, hydroxy, and (NR^eR^f)carbonyl; wherein the heterocyclyl is further optionally substituted with one, two, three, four, or five substituents independently selected from alkoxy, alkyl, cyano, halo, haloalkoxy, haloalkyl, and nitro.

The term “(NR^cR^d)carbonyl,” as used herein, refers to an -NR^cR^d group attached to the parent molecular moiety through a carbonyl group.

The term “-NR'rV’ as used herein, refers to two groups, R^e and R^f, which are attached to the parent molecular moiety through a nitrogen atom. R^e and R^f are independently selected from hydrogen, alkyl, unsubstituted aryl, unsubstituted arylalkyl, unsubstituted cycloalkyl, unsubstituted (cyclolalkyl)alkyl, unsubstituted heterocyclyl, unsubstituted heterocyclylalkyl, (NR^xR^y)alkyl, and (NR^xR^y)carbonyl.

The term “(NR^alkyl,” as used herein, refers to an alkyl group substituted with one, two, or three -NR^eR^f groups.

The term “(NR^eR^f)alkylcarbonyl,” as used herein, refers to an (NR^eR^f)alkyl group attached to the parent molecular moiety through a carbonyl group.

The term “(NR^eR^f)carbonyl,” as used herein, refers to an -NR^eR^f group attached to the parent molecular moiety through a carbonyl group.

The term “(NR^sulfonyl,” as used herein, refers to an -NR^eR^f group attached to the parent molecular moiety through a sulfonyl group.

The term “-NR^xR^y,” as used herein, refers to two groups, R^x and R^y, which are attached to the parent molecular moiety through a nitrogen atom. R^x and R^y are independently selected from hydrogen, alkoxycarbonyl, alkyl, alkylcarbonyl, unsubstituted aryl, unsubstituted arylalkoxycarbonyl, unsubstituted arylalkyl, unsubstituted cycloalkyl, unsubstituted heterocyclyl, and (NR^X R^y )carbonyl, wherein

R^x and R^y’ are independently selected from hydrogen and alkyl.

The term “(NR^xR^y)alkyl,” as used herein, refers to an alkyl group substituted with one, two, or three -NR^xR^y groups.

The term “oxo,” as used herein, refers to =0.

The term “sulfonyl,” as used herein, refers to -SO2-.

The term “trialkylsilyl,” as used herein, refers to -SiR3, wherein R is alkyl. The R groups may be the same or different.

The term “trialkylsilylalkyl,” as used herein, refers to an alkyl group substituted with one, two, or three trialkylsilyl groups.

The term “trialkylsilylalkoxy,” as used herein, refers to a trialkylsilylalkyl group attached to the parent molecular moiety through an oxygen atom.

The term “trialkylsilylalkoxyalkyl,” as used herein, refers to an alkyl group substituted with one, two, or three trialkylsilylalkoxy groups.

Asymmetric centers exist in the compounds of the present disclosure. These centers are designated by the symbols “R” or “S”, depending on the configuration of substituents around the chiral carbon atom. It should be understood that the disclosure encompasses all stereochemical isomeric forms, or mixtures thereof, which possess the ability to inhibit NS5A. Individual stereoisomers of compounds can be prepared synthetically from commercially available starting materials which contain chiral centers or by preparation of mixtures of enantiomeric products followed by separation such as conversion to a mixture of diastereomers followed by separation or recrystallization, chromatographic techniques, or direct separation of enantiomers on chiral chromatographic columns. Starting compounds of particular stereochemistry are either commercially available or can be made and resolved by techniques known in the art.

Certain compounds of the present disclosure may also exist in different stable conformational forms which may be separable. Torsional asymmetry due to restricted rotation about an asymmetric single bond, for example because of steric hindrance or ring strain, may permit separation of different conformers. The present disclosure includes each conformational isomer of these compounds and mixtures thereof.

The term compounds of the present disclosure, and equivalent expressions, are meant to embrace compounds of Formula (I), and pharmaceutically acceptable enantiomers, diastereomers, and salts thereof. Similarly, references to intermediates are meant to embrace their salts where the context so permits.

The compounds of the present disclosure can exist as pharmaceutically acceptable salts. The term “pharmaceutically acceptable salt,” as used herein, represents salts or zwitterionic forms of the compounds of the present disclosure which are water or oil-soluble or dispersible, which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of patients without excessive toxicity, irritation, allergic response, or other problem or complication commensurate with a reasonable benefit/risk ratio, and are effective for their intended use The salts can be prepared during the final isolation and purification of the compounds or separately by reacting a suitable nitrogen atom with a suitable acid. Representative acid addition salts include acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate; digluconate, dihydrobromide, diydrochloride, dihydroiodide, glycerophosphate, hemisulfate, heptanoate, hexanoate, formate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, mesitylenesulfonate, methanesulfonate, naphthylenesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, palmoate, pectinate, persulfate, 3-phenylproprionate, picrate, pivalate, propionate, succinate, tartrate, trichloroacetate, trifluoroacetate, phosphate, glutamate, bicarbonate, para-toluenesulfonate, and undecanoate. Examples of acids which can be employed to form pharmaceutically acceptable addition salts include inorganic acids such as hydrochloric, hydrobromic, sulfuric, and phosphoric, and organic acids such as oxalic, maleic, succinic, and citric.

Basic addition salts can be prepared during the final isolation and purification of the compounds by reacting a carboxy group with a suitable base such as the hydroxide, carbonate, or bicarbonate of a metal cation or with ammonia or an organic primary, secondary, or tertiary amine. The cations of pharmaceutically acceptable salts include lithium, sodium, potassium, calcium, magnesium, and aluminum, as well as nontoxic quaternary amine cations such as ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, diethylamine, ethylamine, tributylamine, pyridine, Ν,Ν-dimethylaniline, N-methylpiperidine, N-methylmorpholine, dicyclohexylamine, procaine, dibenzylamine, Ν,Ν-dibenzylphenethylamine, and N,Ν’dibenzylethylenediamine. Other representative organic amines useful for the formation of base addition salts include ethylenediamine, ethanolamine, diethanolamine, piperidine, and piperazine.

When it is possible that, for use in therapy, therapeutically effective amounts of a compound of formula (I), as well as pharmaceutically acceptable salts thereof, may be administered as the raw chemical, it is possible to present the active ingredient as a pharmaceutical composition. Accordingly, the disclosure further provides pharmaceutical compositions, which include therapeutically effective amounts of compounds of formula (I) or pharmaceutically acceptable salts thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients. The term “therapeutically effective amount,” as used herein, refers to the total amount of each active component that is sufficient to show a meaningful patient benefit, e.g., a reduction in viral load. When applied to an individual active ingredient, administered alone, the term refers to that ingredient alone. When applied to a combination, the term refers to combined amounts of the active ingredients that result in the therapeutic effect, whether administered in combination, serially, or simultaneously. The compounds of formula (I) and pharmaceutically acceptable salts thereof, are as described above. The carriers), diluent(s), or excipient(s) must be acceptable in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. In accordance with another aspect of the present disclosure there is also provided a process for the preparation of a pharmaceutical formulation including admixing a compound of formula (I), or a pharmaceutically acceptable salt thereof, with one or more pharmaceutically acceptable carriers, diluents, or excipients. The term “pharmaceutically acceptable,” as used herein, refers to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of patients without excessive toxicity, irritation, allergic response, or other problem or complication commensurate with a reasonable benefit/risk ratio, and are effective for their intended use.

Pharmaceutical formulations may be presented in unit dose forms containing a predetermined amount of active ingredient per unit dose. Dosage levels of between about 0.01 and about 250 milligram per kilogram (mg/kg) body weight per day, preferably between about 0.05 and about 100 mg/kg body weight per day of the compounds of the present disclosure are typical in a monotherapy for the prevention and treatment of HCV mediated disease. Typically, the pharmaceutical compositions of this disclosure will be administered from about 1 to about 5 times per day or alternatively, as a continuous infusion. Such administration can be used as a chronic or acute therapy. The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending on the condition being treated, the severity of the condition, the time of administration, the route of administration, the rate of excretion of the compound employed, the duration of treatment, and the age, gender, weight, and condition of the patient. Prefened unit dosage formulations are those containing a daily dose or sub-dose, as herein above recited, or an appropriate fraction thereof, of an active ingredient. Treatment may be initiated with small dosages substantially less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect under the circumstances is reached. In general, the compound is most desirably administered at a concentration level that will generally afford antivirally effective results without causing any harmfill or deleterious side effects.

When the compositions of this disclosure comprise a combination of a compound of the present disclosure and one or more additional therapeutic or prophylactic agent, both the compound and the additional agent are usually present at dosage levels of between about 10 to 150%, and more preferably between about 10 and 80% of the dosage normally administered in a monotherapy regimen.

Pharmaceutical formulations may be adapted for administration by any appropriate route, for example by the oral (including buccal or sublingual), rectal, nasal, topical (including buccal, sublingual, or transdermal), vaginal, or parenteral (including subcutaneous, intracutaneous, intramuscular, intra-articular, intrasynovial, intrastemal, intrathecal, intralesional, intravenous, or intradermal injections or infusions) route. Such formulations may be prepared by any method known in the art of pharmacy, for example by bringing into association the active ingredient with the carrier(s) or excipient(s). Oral administration or administration by injection are preferred.

Pharmaceutical formulations adapted for oral administration may be presented as discrete units such as capsules or tablets; powders or granules; solutions or suspensions in aqueous or non-aqueous liquids; edible foams or whips; or oil-inwater liquid emulsions or water-in-oil emulsions.

For instance, for oral administration in the form of a tablet or capsule, the active drug component can be combined with an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, and the like. Powders are prepared by comminuting the compound to a suitable fine size and mixing with a similarly comminuted pharmaceutical carrier such as an edible carbohydrate, as, for example, starch or mannitol. Flavoring, preservative, dispersing, and coloring agent can also be present.

Capsules are made by preparing a powder mixture, as described above, and filling formed gelatin sheaths. Glidants and lubricants such as colloidal silica, talc, magnesium stearate, calcium stearate, or solid polyethylene glycol can be added to the powder mixture before the filling operation. A disintegrating or solubilizing agent such as agar-agar, calcium carbonate, or sodium carbonate can also be added to improve the availability of the medicament when the capsule is ingested.

Moreover, when desired or necessary, suitable binders, lubricants, disintegrating agents, and coloring agents can also be incorporated into the mixture. Suitable binders include starch, gelatin, natural sugars such as glucose or betalactose, com sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycol, and the like. Lubricants used in these dosage forms include sodium oleate, sodium chloride, and the like. Disintegrators include, without limitation, starch, methyl cellulose, agar, betonite, xanthan gum, and the like. Tablets are formulated, for example, by preparing a powder mixture, granulating or slugging, adding a lubricant and disintegrant, and pressing into tablets. A powder mixture is prepared by mixing the compound, suitable comminuted, with a diluent or base as described above, and optionally, with a binder such as carboxymethylcellulose, an aliginate, gelating, or polyvinyl pyrrolidone, a solution retardant such as paraffin, a resorption accelerator such as a quaternary salt and/or and absorption agent such as betonite, kaolin, or dicalcium phosphate. The powder mixture can be granulated by wetting with a binder such as syrup, starch paste, acadia mucilage, or solutions of cellulosic or polymeric materials and forcing through a screen. As an alternative to granulating, the powder mixture can be run through the tablet machine and the result is imperfectly formed slugs broken into granules. The granules can be lubricated to prevent sticking to the tablet forming dies by means of the addition of stearic acid, a stearate salt, talc, or mineral oil. The lubricated mixture is then compressed into tablets. The compounds of the present disclosure can also be combined with a free flowing inert carrier and compressed into tablets directly without going through the granulating or slugging steps. A clear or opaque protective coating consisting of a sealing coat of shellac, a coating of sugar or polymeric material, and a polish coating of wax can be provided. Dyestuffs can be added to these coatings to distinguish different unit dosages.

Oral fluids such as solution, syrups, and elixirs can be prepared in dosage unit form so that a given quantity contains a predetermined amount of the compound. Syrups can be prepared by dissolving the compound in a suitably flavored aqueous solution, while elixirs are prepared through the use of a non-toxic vehicle. Solubilizers and emulsifiers such as ethoxylated isostearyl alcohols and polyoxyethylene sorbitol ethers, preservatives, flavor additive such as peppermint oil or natural sweeteners, or saccharin or other artificial sweeteners, and the like can also be added.

Where appropriate, dosage unit formulations for oral administration can be microencapsulated. The formulation can also be prepared to prolong or sustain the release as for example by coating or embedding particulate material in polymers, wax, or the like.

The compounds of formula (I), and pharmaceutically acceptable salts thereof, can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles. Liposomes can be formed from a variety of phopholipids, such as cholesterol, stearylamine, or phophatidylcholines.

The compounds of formula (I) and pharmaceutically acceptable salts thereof may also be delivered by the use of monoclonal antibodies as individual carriers to which the compound molecules are coupled. The compounds may also be coupled with soluble polymers as targetable drug carriers. Such polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamidephenol, polyhydroxyethylaspartamidephenol, or polyethyleneoxidepolylysine substituted with palitoyl residues. Furthermore, the compounds may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates, and cross-linked or amphipathic block copolymers of hydrogels.

Pharmaceutical formulations adapted for transdermal administration may be presented as discrete patches intended to remain in intimate contact with the epidermis ofthe recipient for a prolonged period of time. For example, the active ingredient may be delivered from the patch by iontophoresis as generally described in Pharmaceutical Research 1986,3(6), 318.

Pharmaceutical formulations adapted for topical administration may be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols, or oils.

Pharmaceutical formulations adapted for rectal administration may be presented as suppositories or as enemas.

Pharmaceutical formulations adapted for nasal administration wherein the carrier is a solid include a course powder having a particle size for example in the range 20 to 500 microns which is administered in the manner in which snuff is taken, i.e., by rapid inhalation through the nasal passage from a container of the powder held close up to the nose. Suitable formulations wherein the carrier is a liquid, for administration as a nasal spray or nasal drops, include aqueous or oil solutions of the active ingredient.

Pharmaceutical formulations adapted for administration by inhalation include fine particle dusts or mists, which may be generated by means of various types of metered, dose pressurized aerosols, nebulizers, or insufflators.

Pharmaceutical formulations adapted for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams, or spray formulations.

Pharmaceutical formulations adapted for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats, and soutes which render the formulation isotonic with the blood ofthe intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. The formulations may be 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 carrier, for example water for injections, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules, and tablets.

It should be understood that in addition to the ingredients particularly mentioned above, the formulations 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 term patient includes both human and other mammals.

The term treating refers to: (i) preventing a disease, disorder or condition from occurring in a patient that may be predisposed to the disease, disorder, and/or condition but has not yet been diagnosed as having it; (ii) inhibiting the disease, disorder, or condition, i.e., arresting its development; and (iii) relieving the disease, disorder, or condition, i.e., causing regression of the disease, disorder, and/or condition.

The compounds of the present disclosure can also be administered with a cyclosporin, for example, cyclosporin A. Cyclosporin A has been shown to be active against HCV in clinical trials (Hepatology 2003, 38, 1282; Biochem. Biophys. Res. Commun. 2004, 313,42; J. Gastroenterol. 2003, 38, 567).

Table 1 below lists some illustrative examples of compounds that can be administered with the compounds of this disclosure. The compounds of the disclosure can be administered with other anti-HCV activity compounds in combination therapy, either jointly or separately, or by combining the compounds into a composition.

Table 1

<td> Brand Name</td><td> Physiological Class</td><td> Type of Inhibitor or Target</td><td> Source Company</td>

<td> NIM811</td><td></td><td> Cyclophilin Inhibitor</td><td> Novartis</td>

<td> Zadaxin</td><td></td><td> Immunomodulator</td><td> Sciclone</td>

<td> Suvus</td><td></td><td> Methylene blue</td><td> Bioenvision</td>

<td> Actilon (CPG10101)</td><td></td><td> TLR9 agonist</td><td> Coley</td>

<td> Batabulin (T67)</td><td> Anticancer</td><td> β-tubulin inhibitor</td><td> Tularik Inc., South San Francisco, CA</td>

<td> Brand Name</td><td> Physiological Class</td><td> Type of Inhibitor or Target</td><td> Source Company</td>

<td> ISIS 14803</td><td> Antiviral</td><td> antisense</td><td> ISIS Pharmaceutica Is Inc, Carlsbad, CA/Elan Phamaceutical sine., New York, NY</td>

<td> Summetrel</td><td> Antiviral</td><td> antiviral</td><td> Endo Pharmaceutica Is Holdings Inc., Chadds Ford, PA</td>

<td> GS-9132 (ACH-806)</td><td> Antiviral</td><td> HCV Inhibitor</td><td> Achillion / Gilead________</td>

<td> Pyrazolopyrimidine compounds and salts From WO2005047288 26 May 2005</td><td> Antiviral</td><td> HCV Inhibitors</td><td> Arrow Therapeutics Ltd.</td>

<td> Levovirin</td><td> Antiviral</td><td> IMPDH inhibitor</td><td> Ribapharm Inc., Costa Mesa, CA</td>

<td> Merimepodib (VX-497)</td><td> Antiviral</td><td> IMPDH inhibitor</td><td> Vertex Pharmaceutica Is Inc., Cambridge, MA_____</td>

<td> XTL-6865 (XTL-002)</td><td> Antiviral</td><td> monoclonal antibody</td><td> XTL Biopharmaceu ticals Ltd., Rehovot, Isreal</td>

<td> Telaprevir (VX-950, LY-570310)</td><td> Antiviral</td><td> NS3 serine protease inhibitor</td><td> Vertex Pharmaceutica Is Inc., Cambridge, MA/ Eli Lilly and Co. Inc., Indianapolis, IN</td>

<td> HCV-796</td><td> Antiviral</td><td> NS5B Replicase Inhibitor</td><td> Wyeth / Viropharma</td>

<td> NM-283</td><td> Antiviral</td><td> NS5B Replicase Inhibitor</td><td> Idenix / Novartis</td>

<td> GL-59728</td><td> Antiviral</td><td> NS5B Replicase Inhibitor</td><td> Gene Labs / Novartis</td>

<td> GL-60667</td><td> Antiviral</td><td> NS5B Replicase Inhibitor</td><td> Gene Labs / Novartis</td>

<td> 2’C MeA</td><td> Antiviral</td><td> NS5B Replicase Inhibitor</td><td> Gilead</td>

<td> Brand Name</td><td> Physiological Class</td><td> Type of Inhibitor or Target</td><td> Source Company</td>

<td> PSI 6130</td><td> Antiviral</td><td> NS5B Replicase Inhibitor</td><td> Roche</td>

<td> R1626</td><td> Antiviral</td><td> NS5B Replicase Inhibitor</td><td> Roche</td>

<td> 2’C Methyl adenosine</td><td> Antiviral</td><td> NS5B Replicase Inhibitor</td><td> Merck</td>

<td> JTK-003</td><td> Antiviral</td><td> RdRp inhibitor</td><td> Japan Tobacco Inc., Tokyo,Japan</td>

<td> Levovirin</td><td> Antiviral</td><td> ribavirin</td><td> ICN Pharmaceutica Is, Costa Mesa, CA</td>

<td> Ribavirin</td><td> Antiviral</td><td> ribavirin</td><td> ScheringPlough Corporation, Kenilworth, NJ_________</td>

<td> Viramidine</td><td> Antiviral</td><td> Ribavirin Prodrug</td><td> Ribapharm Inc., Costa Mesa, CA</td>

<td> Heptazyme</td><td> Antiviral</td><td> ribozyme</td><td> Ribozyme Pharmaceutica Is Inc., Boulder, CO</td>

<td> BILN-2061</td><td> Antiviral</td><td> serine protease inhibitor</td><td> Boehringer Ingelheim Pharma KG, Ingelheim, Germany</td>

<td> SCH 503034</td><td> Antiviral</td><td> serine protease inhibitor</td><td> Schering Plough</td>

<td> Zadazim</td><td> Immune modulator</td><td> Immune modulator</td><td> SciClone Pharmaceutica Is Inc., San Mateo, CA</td>

<td> Ceplene</td><td> Immunomodulator</td><td> immune modulator</td><td> Maxim Pharmaceutica Is Inc., San Diego, CA</td>

<td> CellCept</td><td> Immunosuppressa nt</td><td> HCV IgG immunosuppressant</td><td> F. HoffmannLa Roche LTD, Basel, Switzerland</td>

<td> Civacir</td><td> Immunosuppressa nt</td><td> HCV IgG immunosuppressant</td><td> Nabi Biopharmaceu ticals Inc., Boca Raton, FL</td>

<td> Brand Name</td><td> Physiological Class</td><td> Type of Inhibitor or Target</td><td> Source Company</td>

<td> Albuferon - a</td><td> Interferon</td><td> albumin IFN-a2b</td><td> Human Genome Sciences Inc., Rockville, MD_____</td>

<td> Infergen A</td><td> Interferon</td><td> IFN alfacon-1</td><td> InterMune Pharmaceutica Is Inc., Brisbane, CA</td>

<td> Omega IFN</td><td> Interferon</td><td> IFN-ω</td><td> Intarcia Therapeutics</td>

<td> IFN-β andEMZ701</td><td> Interferon</td><td> IFN-β and EMZ701</td><td> Transition Therapeutics Inc., Ontario, Canada</td>

<td> Rebif</td><td> Interferon</td><td> IFN-β la</td><td> Serono, Geneva, Switzerland</td>

<td> Roferon A</td><td> Interferon</td><td> IFN-a2a</td><td> F. HoffmannLa Roche LTD, Basel, Switzerland</td>

<td> Intron A</td><td> Interferon</td><td> IFN-a2b</td><td> ScheringPlough Corporation, Kenilworth, NJ_________</td>

<td> Intron A and Zadaxin</td><td> Interferon</td><td> IFN-a2b/althymosin</td><td> RegeneRx Biopharmiceu ticals Inc., Bethesda, MD/ SciClone Pharmaceutica Is Inc, San Mateo, CA</td>

<td> Rebetron</td><td> Interferon</td><td> IFN-a2b/ribavirin</td><td> ScheringPlough Corporation, Kenilworth, NJ</td>

<td> Actinnnune</td><td> Interferon</td><td> INF-γ</td><td> InterMune Inc., Brisbane, CA</td>

<td> Interferon-β___________</td><td> Interferon</td><td> Interferon-β-la</td><td> Serono</td>

<td> Multiferon</td><td> Interferon</td><td> Long lasting IFN</td><td> Viragen/Valen tis</td>

<td> Wellferon</td><td> Interferon</td><td> lymphoblastoid IFN-anl</td><td> GlaxoSmithKl ine pic, Uxbridge, UK</td>

<td> Brand Name</td><td> Physiological Class</td><td> Type of Inhibitor or Target</td><td> Source Company</td>

<td> Omniferon</td><td> Interferon</td><td> natural IFN-a</td><td> Viragen Inc., Plantation, FL</td>

<td> Pegasys</td><td> Interferon</td><td> PEGylated IFN-a2a</td><td> F. HoffmannLa Roche LTD, Basel, Switzerland</td>

<td> Pegasys and Ceplene</td><td> Interferon</td><td> PEGylated IFNa2a/ immune modulator</td><td> Maxim Pharmaceutica Is Inc., San Diego, CA</td>

<td> Pegasys and Ribavirin</td><td> Interferon</td><td> PEGylated IFNa2a/ribavirin</td><td> F. HoffmannLa Roche LTD, Basel, Switzerland</td>

<td> PEG-Intron</td><td> Interferon</td><td> PEGylated IFN-a2b</td><td> ScheringPlough Corporation, Kenilworth, NJ</td>

<td> PEG-Intron 1 Ribavirin</td><td> Interferon</td><td> PEGylated IFNa2b/ribavirin</td><td> ScheringPlough Corporation, Kenilworth, NJ</td>

<td> IP-501</td><td> Liver protection</td><td> antifibrotic</td><td> Indevus Pharmaceutica Is Inc., Lexington, MA</td>

<td> IDN-6556</td><td> Liver protection</td><td> caspase inhibitor</td><td> Idun Pharmaceutica Is Inc., San Diego, CA</td>

<td> ITMN-191 (R-7227)</td><td> Antiviral</td><td> serine protease inhibitor</td><td> InterMune Pharmaceutica Is Inc., Brisbane, CA</td>

<td> GL-59728</td><td> Antiviral</td><td> NS5B Replicase Inhibitor</td><td> Genelabs</td>

<td> ANA-971</td><td> Antiviral</td><td> TLR-7 agonist</td><td> Anadys</td>

The compounds of the present disclosure may also be used as laboratory reagents. Compounds may be instrumental in providing research tools for designing of viral replication assays, validation of animal assay systems and structural biology studies to further enhance knowledge of the HCV disease mechanisms. Further, the compounds of the present disclosure are useful in establishing or determining the binding site of other antiviral compounds, for example, by competitive inhibition.

The compounds of this disclosure may also be used to treat or prevent viral contamination of materials and therefore reduce the risk of viral infection of laboratory or medical personnel or patients who come in contact with such materials,

e.g., blood, tissue, surgical instruments and garments, laboratory instruments and garments, and blood collection or transfusion apparatuses and materials.

This disclosure is intended to encompass compounds having formula (I) when prepared by synthetic processes or by metabolic processes including those occurring in the human or animal body (in vivo) or processes occurring in vitro.

The abbreviations used in the present application, including particularly in the illustrative schemes and examples which follow, are well-known to those skilled in the art. Some of the abbreviations used are as follows: HATU for 0-(7azabenzotriazol-l-yl)-N,N,N’,N’-tetramethyluronium hexafluorophosphate; Boc or BOC for tert-butoxycarbonyl; NBS for N-bromosuccinimide; tBu or t-Bu for tertbutyl; SEM for -(trimethylsilyl)ethoxymethyl; DMSO for dimethylsulfoxide; MeOH for methanol; TFA for trifluoroacetic acid; RT for room temperature or retention time (context will dictate); tR for retention time; EDCI for l-(3-dimethylaminopropyl)-3ethylcarbodiimide hydrochloride; DMAP for 4-dimethylaminopyridine; THF for tetrahydrofuran; DBU for l,8-diazabicyclo[5.4.0]undec-7-ene; ί-Bu; DEA for diethylamine; HMDS for hexamethyldisilazide; DMF for N,N-dimethylformamide; Bzl for benzyl; EtOH for ethanol; iPrOH or i-PrOH for isopropanol; Me₂S for dimethylsulfide; Et₃N or TEA for triethylamine; Ph for phenyl; OAc for acetate; EtOAc for ethyl acetate; dppf for l,l'-bis(diphenylphosphino)ferrocene; iPr₂EtN or DIPEA for diisopropylethylamine; Cbz for carbobenzyloxy; n-BuLi for nbutyUithium; ACN for acetonitrile; h or hr for hours; m or min for minutes; s for seconds; LiHMDS for lithium hexamethyldisilazide; DIBAL for diisobutyl aluminum hydride; TBDMSC1 for tert-butyldimethylsilyl chloride; Me for methyl; ca. for about; OAc for acetate; iPr for isopropyl; Et for ethyl; Bn for benzyl; and HO AT for 1hydroxy-7-azabenzotri azole.

The abbreviations used in the present application, including particularly in the illustrative schemes and examples which follow, are well-known to those skilled in the art. Some of the abbreviations used are as follows:

The compounds and processes of the present disclosure will be better understood in connection with the following synthetic schemes which illustrate the methods by which the compounds of the present disclosure may be prepared. Starting materials can be obtained from commercial sources or prepared by wellestablished literature methods known to those of ordinary skill in the art. It will be readily apparent to one of ordinary skill in the art that the compounds defined above can be synthesized by substitution of the appropriate reactants and agents in the syntheses shown below. It will also be readily apparent to one skilled in the art that the selective protection and deprotection steps, as well as the order of the steps themselves, can be carried out in varying order, depending on the nature of the variables to successfully complete the syntheses below. The variables are as defined above unless otherwise noted below.

Scheme 1: Symmetric or Asymmetric Biphenyls

Aryl halide 1 and boronic ester 2 can be coupled to produce biaryl 3 using standard Suzuki-Miayura coupling conditions (Angew Chem. Int. Ed. Engl 2001, 40,4544). It should be noted that the boronic acid analog of 2 may be used in place of the ester. Mono-deprotection of the pyrrolidine moiety may be accomplished when R¹² and R¹³ are different. When R¹² = benzyl, and R¹³ = t-butyl treatment to hydrogenolytic conditions produces 4. For example, Pd/C catalyst in the presence of a base such as potassium carbonate can be used. Acylation of 4 can be accomplished under standard acylation conditions. A coupling reagent such as HATU in combination with an amine base such as Hunig’s base can be used in this regard. Alternatively, 4 may be reacted with an isocyanate or carbamoyl chloride to provide compounds of formula 5 where R⁹ is an amine. Further deprotection of 5 can be accomplished by treatment with strong acid such as HCI or trifluoroacetic acid. Standard conditions analogous to those used to convert 4 to 5 can be used to prepare 7 from 6. In another embodiment where R¹² = R¹³ = t-Bu, direct conversion to 8 can be accomplished by treatment of 3 with strong acid such as HCI or trifluoroacetic acid. Conversion of 8 to 7 is accomplished in analogous fashion to the methods used to prepare 5 from 4 or 7 from 6. In this instance however, the caps in 7 will be identical.

<img file="IL196813A_D0006.tif" />

<img file="IL196813A_D0007.tif" />

Scheme 2: Asymmetrically Capped Biphenyls

Conversion of 6 (from Scheme 1) to 10 can be done using standard amide coupling conditions such as HATU with an amine base, such as Hunig s base.

Deprotection can be accomplished with strong acid such as HCI or trifluoroacetic acid affording 11. Compound 11 can then be converted to 12,13, or 14 using an acid chloride, an isocyanate or carbamoyl chloride, or a chloroformate respectively.

(R⁵).

<img file="IL196813A_D0008.tif" />

Scheme 3: Symmetric Cap Elaborated Biphenyls

Compound 75 (75 = 7 (Scheme 1) wherein each R⁹ is -CH(NHBoc)R¹⁸)can be converted to 76 via treatment with strong acid such as HCI or trifluoroacetic acid.

Compounds 7 7, 7 8, and 7 9 can be prepared from 7 6 by treating 7 6 with an appropriate chloroformate, isocyanate or carbamoyl chloride, or an acid chloride respectively.

<img file="IL196813A_D0009.tif" />

Scheme 4: Symmetric Biphenyls

Symmetrical biphenyl analogs (compounds of formula 7 where both halves of the molecule are equivalent) can be synthesized starting from bromoketone 20.

Amination by displacement with a nucleophile such as azide, phthalimide or preferably sodium diformylamide (Yinglin and Hongwen, Synthesis 1990, 122) followed by deprotection affords 21. Condensation under standard amination conditions such as HATU and Hunig’s base with an appropriately protected amino acid provides 22. Heating with ammonium acetate under thermal or microwave conditions results in the formation of 3 which can be deprotected with strong acid such as HCI or trifluoroacetic acid (R¹² = R¹³ = t-Bu) or by hydrogenolysis with hydrogen gas and a transition metal catalyst such as Pd/C (R¹² = R¹³ = benzyl). Acylation can be affected with a carboxylic acid (R⁹CO2H) in a manner similar to the conversion of 27 to 22. Urea formation can be accomplished by treatment with an appropriate isocycante (R⁹ = R²⁴R²⁵N; R²⁵ =H) or carbamoyl chloride (R⁹ = R²⁴R²⁵N; R²⁵ is other than hydrogen).

<img file="IL196813A_D0010.tif" />

Scheme 5: Starting Materials 25 and 2

Scheme 5 describes the preparation of some of the starting materials required for the synthetic sequences depicted in Schemes 1-4. Key intermediate 25 (analogous to 1 in Scheme 1) is prepared from keto-amide 24 or keto-ester 27 via heating with ammonium acetate under thermal or microwave conditions. Keto-amide 24 can be prepared from 23 via condensation with an appropriate cyclic or acyclic amino acid under standard amide formation conditions. Bromide 26 can give rise to

23 by treatment with a nucleophile such as azide, phthalimide or sodium diformylamide (Synthesis 1990, 122) followed by deprotection. Bromide 26 can also be converted to 27 by reacting with an appropriate cyclic or acyclic N-protected amino acid in the presence of base such as potassium carbonate or sodium bicarbonate. Bromination of 28 with a source of bromonium ion such as bromine,

NBS, or CBr₄ results in the formation of 26. Bromide 25 can be converted to boronic ester 2 via treatment with bis-pinacalotodiboron under palladium catalysis according to the method described in Journal of Organic Chemistry 1995, 60, 7508, or variations thereof.

<img file="IL196813A_D0011.tif" />

(R’k

<img file="IL196813A_D0012.tif" />

Scheme 6: Starting Material 31a

In another embodiment, starting materials such as 31a (analogous to 25 in Scheme 5 and I in Scheme 1) may be prepared by reacting bromoimidazole derivatives 31 under Suzuki-type coupling conditions with a variety of chlorosubstituted aryl boronic acids which can either be prepared by standard methodologies (see, for example, Organic Letters 2006,8, 305 and references cited therein) or purchased from commercial suppliers. Bromoimidazole 31 can be obtained by brominating imidazole 30 with a source of bromonium ion such as bromine, CBr₄, or N-bromosuccinimide. Imidazole 30 can be prepared from Nprotected amino acids which are appropriately substituted by reacting with glyoxal in a methanolic solution of ammonium hydroxide.

<img file="IL196813A_D0013.tif" />

Scheme 7: Heteroaryls

In yet another embodiment of the current disclosure, aryl halide 32 can be coupled under Suzuki-Miyaura palladium catalyzed conditions to form the heteroaryl derivative 34. Compound 34 can be elaborated to 35 by treatment to hydrogenolytic conditions with hydrogen and a transition metal catalyst such as palladium on carbon (R¹³ = benzyl). Acylation of 35 can be accomplished with an appropriate acid chloride (R⁹COC1) in the presence of a base such as triethylamine, with an appropriately substituted carboxylic acid (R⁹CO₂H) in the presence of a standard coupling reagent such as HATU, or with an isoscyanate (R²⁷NCO wherein R⁹ =

R²⁷R²⁸N-; R²⁸ =H)or carbamoyl chloride (R²⁷R²⁸NCOC1 wherein R⁹ = R²⁷R²⁸N-).

Compound 37 can be prepared from 36 (R¹² = t-Bu) via treatment with strong acid such as HC1 or trifluoroacetic acid. Acylation ofthe resulting amine in 37 to give 38 can be accomplished as in the transformation of 35 to 36. In cases where R = R , 34 can be directly transformed into 39 by treatment with strong acid such as HC1 or trifluoroacetic acid (R¹² = R¹³ = t-Bu) or by employing hydrogenolytic conditions with hydrogen and a transition metal catalyst such as palladium on carbon (R = R = benzyl). Acylation of 39 can be accomplished in analogous fashion to that described for the transformation of 35 to 36.

<img file="IL196813A_D0014.tif" />

R¹² and R¹³ are Independently alkoxymethyl or H Q = a or Br

<img file="IL196813A_D0015.tif" />

Scheme 8

Heteroaryl chloride 29 can be converted to symmetrical analog 40 via treatment with a source of palladium such as dichlorobis(benzonitrile) palladium in the presence of tetrakis(dimethylamino)ethylene at elevated temperature. Removal of 5 the SEM ether and Boc carbamates found in 40 can be accomplished in one step by treatment with a strong acid such as HCI or trifluoroacetic acid providing 41. Conversion to 42 can be accomplished in similar fashion to the conditions used to convert 38 to 39 in Scheme 7.

<img file="IL196813A_D0016.tif" />

R²® ״ alkoxymethyl or H

W. X. Y־. Z > C or N with at least one of W. X. Y*. and Z must be C R® can be alkyl er NR^R²⁸

<img file="IL196813A_D0017.tif" />

Scheme 9: Symmetric Cap Substituted Heteroaryls

Compound 43 (analogous to 42 wherein R23 = -CH(NHB0c)R24) may be elaborated to 45, 46, and 47 via similar methodologies to those described in Scheme 3. In cases where R₂0 = alkoxymethyl (ie; SEM), removal can be accomplished simultaneously with removal ofthe Boc carbamate (cf; 43 to 44) using strong acid 15 such as HCI or trifluoroacetic acid.

<img file="IL196813A_D0018.tif" />

Rjq » elkoxymethyl or H

W, X. Y, Z ^B C or N with at least one of W, X. Y. and Z must be C; at least one of W, X, Y. and Z must be N

<img file="IL196813A_D0019.tif" />

Scheme 10: Starting Material 29

Heteroaryl bromides 54 may be reacted with a vinyl stannane such as tributyl( 1-ethoxyviny !)tin in the presence of a source of palladium such as dichlorobis(triphenylphosphine)palladium (Π) to provide 55 which can be subsequently transformed into bromoketone 51 via treatment with a source of bromonium ion such as N-bormosuccinimide, CBr₄, or bromine. Alternatively, ketosubstituted heteroaryl bromides 53 may be directly converted to 51 via treatment with a source of bromonium ion such as bromine, CBr₄, or N-bromosuccinimide. Bromide 51 can be converted to aminoketone 48 via addition of sodium azide, potassium phthalimide or sodium diformylamide (Synthesis 1990 122) followed by deprotection. Aminoketone 48 can then be coupled with an appropriately substituted amino acid under standard amide formation conditions (i.e.; a coupling reagent such as HATU in the presence of a mild base such as Hunig’s base) to provide 49. Compound 49 can then be further transformed into imidazole 50 via reacting with ammonium acetate under thermal or microwave conditions. Alternatively, 57 can be directly reacted with an appropriately substituted amino acid in the presence of a base such as sodium bicarbonate or potassium carbonate providing 52 which can in turn be reacted with ammonium acetate under thermal or microwave conditions to provide 50. Imidazole 50 can be protected with an alkoxylmethyl group by treatment with the appropriate alkoxymethyl halide such as 2-(trimethylsilyl)ethoxymethyl chloride after first being deprotonated with a strong base such as sodium hydride.

<img file="IL196813A_D0020.tif" />

Scheme 11: Substituted Phenylglycine Derivatives

Substituted phenylglycine derivatives can be prepared by a number of methods shown below. Phenylglycine t-butyl ester can be reductively alkylated (pathyway A) with an appropriate aldehyde and a reductant such as sodium cyanoborohydride in acidic medium. Hydrolysis of the t-butyl ester can be accomplished with strong acid such as HC1 or trifluoroacetic acid. Alternatively, phenylglycine can be alkylated with an alkyl halide such as ethyl iodide and a base such as sodium bicarbonate or potassium carbonate (pathway B). Pathway C illustrates reductive alkylation of phenylglycine as in pathway A followed by a second reductive alkylation with an alternate aldehyde such as formaldehyde in the presence of a reducing agent and acid. Pathway D illustrates the synthesis of substituted phenylglycines via the corresponding mandelic acid analogs. Conversion of the secondary alcohol to a competent leaving group can be accomplished with ptoluensulfonyl chloride. Displacement of the tosylate group with an appropriate amine followed by reductive removal of the benzyl ester can provide substituted phenylglycine derivatives. In pathway E a racemic substituted phenylglycine derivative is resolved by esterification with an enantiomerically pure chiral auxiliary such as but not limited to (+)-1-phenylethanol, (-)-1-phenylethanol, an Evan’s oxazolidinone, or enantiomerically pure pantolactone. Separation of the diastereomers is accomplished via chromatography (silica gel, HPLC, crystallization, etc) followed by removal ofthe chiral auxiliary providing enantiomerically pure phenylglycine derivatives. Pathway H illustrates a synthetic sequence which intersects with pathway E wherein the aforementioned chiral auxiliary is installed prior to amine addition. Alternatively, an ester of an arylacetic acid can be brnminated with a source of bromonium ion such as bromine, N-bromosuccinimide, or CBr₄. The resultant benzylic bromide can be displaced with a variety of mono- or disubstituted amines in the presence of a tertiary amine base such as triethylamine or Hunig’s base. Hydrolysis ofthe methyl ester via treatment with lithium hydroxide at low temperature or 6N HCI at elevated temperature provides the substituted phenylglycine derivatives. Another method is shown in pathway G. Glycine analogs can be derivatized with a variety of aryl halides in the presence of a source of palladium (0) such as palladium bis(tributylphosphine) and base such as potassium phosphate. The resultant ester can then be hydrolyzed by treatment with base or acid. It should be understood that other well known methods to prepare phenylglycine derivatives exist in the art and can be amended to provide the desired compounds in this description. It should also be understood that the final phenylglycine derivatives can be purified to enantiomeric purity greater than 98%ee via preparative HPLC.

<img file="IL196813A_D0021.tif" />

NH₂JL .OH r²⁷cho

Λ

<img file="IL196813A_D0022.tif" />

^Ar 1Γ

O

Ar ^R?iNH

OH

<img file="IL196813A_D0023.tif" />

R²⁷1 .N.

G

<img file="IL196813A_D0024.tif" />

COjEt reductant base

R²!. .-R²⁸

Ar (R²⁷ = R²⁸) r_30X

B

<img file="IL196813A_D0025.tif" />

CO₂Bn

OH־ separation of d'mers

R“m'^R2?N

OH

Ar^COjBn | TsCI p28 p27

R^NHR²⁷ OTs

Ar CO₂Bn

Ar

N'^R2e

<img file="IL196813A_D0026.tif" />

R²⁷ * _R28N^CO₂Et

Ar COjMe j R^aNHR²⁷

Ar O (R³² = chiral auxiliary)

R²⁷ R²⁸N

<img file="IL196813A_D0027.tif" />

Ar 0

Η I

027 R²⁸ esterification '׳ןא

OH

<img file="IL196813A_D0028.tif" />

Ar 0 bromination

Ar^COjMe ־׳

Br

<img file="IL196813A_D0029.tif" />

Ar 0

Br

OH

<img file="IL196813A_D0030.tif" />

Ar 0

Scheme 12: Acylated Amino Acid Derivatives

In another embodiment ofthe present disclosure, acylated phenylglycine derivatives may be prepared as illustrated below. Phenylglycine derivatives wherein the carboxylic acid is protected as an easily removed ester, may be acylated with an acid chloride in the presence of a base such as triethylamine to provide the corresponding amides (pathway A). Pathway B illustrates the acylation of the starting phenylglycine derivative with an appropriate chloroformate while pathway C shows reaction with an appropriate isocyanate or carbamoyl chloride. Each of the three intermediates shown in pathways A - C may be deprotected by methods known by those skilled in the art (ie; treatment of the t-butyl ester with strong base such as HCI or trifluoroacetic acid).

<img file="IL196813A_D0031.tif" />

<img file="IL196813A_D0032.tif" />

<img file="IL196813A_D0033.tif" />

O 027 JI ^vN׳^NR³⁰R³⁹

<img file="IL196813A_D0034.tif" />

Scheme 13

Ammo-substituted phenylacetic acids may be prepared by treatment of a chloromethylphenylacetic acid with an excess of an amine.

<img file="IL196813A_D0035.tif" />

R³^ ,R⁴⁰N ___H___»

R³⁹

<img file="IL196813A_D0036.tif" />

Compound analysis conditions

Purity assessment and low resolution mass analysis were conducted on a Shimadzu LC system coupled with Waters Micromass ZQ MS system. It should be noted that retention times may vary slightly between machines. The LC conditions employed in determining the retention time (RT) were:

<td> Condition 1</td><td></td>

<td> Column</td><td> = Phenomenex-Luna 3.OX 50 mm S10</td>

<td> Start %B</td><td> = 0</td>

<td> Final %B</td><td> = 100</td>

<td> Gradient time</td><td> = 2 min</td>

<td> Stop time</td><td> = 3 min</td>

<td> Flow Rate</td><td> = 4 mL/min</td>

<td> Wavelength</td><td> = 220 nm</td>

<td> Slovent A</td><td> = 0.1% TFA in 10% methanoV90%H₂O</td>

<td> Solvent B</td><td> = 0.1% TFA in 90% methanol/10% H₂O</td>

<td> Condition 2</td><td></td>

<td> Column</td><td> = Phenomenex-Luna 4.6X50 mm S10</td>

<td> Start %B</td><td> = 0</td>

<td> Final %B</td><td> = 100</td>

<td> Gradient time</td><td> = 2 min</td>

<td> Stop time</td><td> = 3 min</td>

<td> Flow Rate</td><td> = 5 mL/min</td>

<td> Wavelength</td><td> = 220 nm</td>

<td> Slovent A</td><td> = 0.1% TFA in 10% methanol/90%H₂O</td>

<td> Solvent B</td><td> = 0.1% TFA in 90% methanol/10% H₂O</td>

<td> Condition 3</td><td></td>

<td> Column</td><td> = HPLC XTERRA Cl8 3.0 x 50mm S7</td>

<td> Start %B</td><td> = 0</td>

<td> Final %B</td><td> = 100</td>

<td colspan="2"> Gradient time = 3 min</td>

<td> Stop time</td><td> = 4 min</td>

<td> Flow Rate</td><td> = 4 mL/min</td>

<td> Wavelength</td><td> = 220 nm</td>

Slovent A = 0.1% TFA in 10% methanol/90%H₂O

Solvent B = 0.1 % TFA in 90% methanol/10% H2O

Condition Ml

Column: Luna 4.6X 50 mm S10

Start %B = 0

Final %B = 100

Gradient time = 3 min

Stop time = 4 min

Flow rate = 4 mL/min

Solvent A: = 95% H₂0: 5% CH₃CN, 10 mm Ammonium acetate

Solvent B: = 5% H₂O : 95% CH₃CN; 10 mm Ammonium acetate

Synthesis of common caps

Cap-1

<img file="IL196813A_D0037.tif" />

A suspension of 10% Pd/C (2.0g) in methanol (10 mL) was added to a mixture of (R)-2-phenylglycine (10g, 66.2 mmol), formaldehyde (33 mL of 37% wt. in water), IN HC1 (30 mL) and methanol (30 mL), and exposed to H₂ (60 psi) for 3 hours. The reaction mixture was filtered through diatomaceous earth (Celite®), and the filtrate was concentrated in vacuo. The resulting crude material was recrystallized from isopropanol to provide the HC1 salt of Cap-1 as a white needle (4.0 g). Optical rotation: -117.1° [c = 9.95 mg/mL in H₂O; λ = 589 nm], ¹H NMR (DMSO-d6, δ = 2.5 ppm, 500 MHz): δ 7.43-7.34 (m, 5H), 4.14 (s, 1H), 2.43 (s, 6H); LC (Cond. 1): RT = 0.25; LC/MS: Anal. Calcd. for [M+H]⁺C10H14NO2180.10; found 180.17; HRMS: Anal. Calcd. for [M+H]⁺ C10H1₄NO₂ 180.1025; found 180.1017.

Cap-2

<img file="IL196813A_D0038.tif" />

N3BH3CN (6.22g, 94 mmol) was added in portions over a few minutes to a cooled (ice/water) mixture of (R)-2-Phenylglycine (6.02 g, 39.8 mmol) and MeOH (100 mL), and stirred for 5 min. Acetaldehyde (10 mL) was added drop-wise over 10 min and stirring was continued at the same cooled temperature for 45 min and at ambient temperature for ~6.5 hr. The reaction mixture was cooled back with icewater bath, treated with water (3 mL) and then quenched with a drop-wise addition of concentrated HCI over ~ 45 min until the pH of the mixture is ~ 1.5 - 2.0. The cooling bath was removed and the stirring was continued while adding concentrated HCI in order to maintain the pH of the mixture around 1.5-2.0. The reaction mixture was stirred over night, filtered to remove the white suspension, and the filtrate was concentrated in vacuo. The crude material was recrystallized from ethanol to afford the HCI salt of Cap-2 as a shining white solid in two crops (crop-1: 4.16 g; crop-2: 2.19 g). ¹H NMR (DMSO-d6, 5= 2.5 ppm, 400 MHz): 10.44 (1.00, br s, 1H), 7.66 (m, 2H), 7.51 (m, 3H), 5.30 (s, 1H), 3.15 (br m, 2H), 2.98 (br m, 2H), 1.20 (app br s, 6H). Crop-1: [a]²⁵.21° (c = 0.357, H2O); crop-2: [a]²⁵.7° (c = 0.357, H2O). LC (Cond. 1): RT = 0.43 min; LC/MS: Anal. Calcd. for [M+H]⁺ C!2H18NO₂: 208.13; found 208.26

Cap-3

Acetaldehyde (5.0 mL, 89.1 mmol) and a suspension of 10% Pd/C (720 mg) in methanol/H₂O (4mL/l mL) was sequentially added to a cooled (~ 15 °C) mixture of (R)-2-phenylglycine (3.096g, 20.48 mmol), IN HCI (30 mL) and methanol (40 mL). The cooling bath was removed and the reaction mixture was stirred under a balloon of H₂ for 17 hours. An additional acetaldehyde (10 mL, 178.2 mmol) was added and stirring continued under H₂ atmosphere for 24 hours [Note: the supply of H2 was replenished as needed throughout the reaction]. The reaction mixture was filtered through diatomaceous earth (Celite®), and the filtrate was concentrated in vacuo. The resulting crude material was recrystallized from isopropanol to provide the HC1 salt of (R)-2-(ethylamino)-2-phenylacetic acid as a shining white solid (2.846g). ¹H NMR (DMSO-d₆, δ = 2.5 ppm, 400 MHz): δ 14.15 (br s, 1H), 9.55 (br s, 2H), 7.55-7.48 (m, 5H), 2.88 (br m, 1H), 2.73 (br m, 1H), 1.20 (app t, J= 7.2, 3H). LC (Cond. 1): RT = 0.39 min; >95% homogeneity index; LC/MS: Anal. Calcd. for [M+H]⁺ C10H14NO2: 180.10; found 180.18.

A suspension of 10% Pd/C (536 mg) in methanol/H₂O (3 mL/Ι mL) was added to a mixture of (R)-2-(ethylamino)-2-phenylacetic acid/HCl (1.492g, 6.918 mmol), formaldehyde (20 mL of 37% wt. in water), IN HC1 (20 mL) and methanol (23 mL). The reaction mixture was stirred under a balloon of H₂ for ~72 hours, where the H₂ supply was replenished as needed. The reaction mixture was filtered through diatomaceous earth (Celite®) and the filtrate was concentrated in vacuo. The resulting crude material was recrystallized from isopropanol (50 mL) to provide the HC1 salt of Cap-3 as a white solid (985 mg). ¹H NMR (DMSO-d6, δ = 2.5 ppm, 400 MHz): δ 10.48 (br s, 1H), 7.59-7.51 (m, 5H), 5.26 (s, 1H), 3.08 (app br s, 2H), 2.65 (br s, 3H), 1.24 (br m, 3H). LC (Cond. 1): RT = 0.39 min; >95 % homogeneity index; LC/MS: Anal. Calcd. for [M+H]⁺ C״H16NO2: 194.12; found 194.18; HRMS: Anal. Calcd. for [M+H]⁺ C11H16NO2:194.1180; found 194.1181.

Cap-4

<img file="IL196813A_D0039.tif" />

ClCO₂Me (3.2 mL, 41.4 mmol) was added dropwise to a cooled (ice/water) THF (410 mL) semi-solution of (R)-tert-butyl 2-amino-2-phenylacetate/HCl (9.877 g, 40.52 mmol) and diisopropylethylamine (14.2 mL, 81.52 mmol) over 6 min, and stirred at similar temperature for 5.5 hours. The volatile component was removed in vacuo, and the residue was partitioned between water (100 mL) and ethyl acetate (200 ml.) The organic layer was washed with IN HCI (25 mL) and saturated NaHCO3 solution (30 mL), dried (MgSO4), filtered, and concentrated in vacuo. The resultant colorless oil was triturated from hexanes, filtered and washed with hexanes (100 mL) to provide (R)-tert-butyl 2-(methoxycarbonylamino)2־-phenylacetate as a 5 white solid (7.7 g). ¹H NMR (DMSO-d6, δ = 2.5 ppm, 400 MHz): 7.98 (d, J = 8.0, 1H), 7.37-7.29 (m, 5H), 5.09 (d, J= 8,1H), 3.56 (s, 3H), 1.33 (s, 9H). LC (Cond. 1): RT = 1.53 min; ~90 % homogeneity index; LC/MS: Anal. Calcd. for [M+Na]⁺C14H19NNaO4: 288.12; found 288.15.

TFA (16 mL) was added dropwise to a cooled (ice/water) CH₂C1₂ (160 mL) 10 solution of the above product over ר minutes, and the cooling bath was removed and the reaction mixture was stirred for 20 hours. Since the deprotection was still not complete, an additional TFA (1.0 mL) was added and stirring continued for an additional 2 hours. The volatile component was removed in vacuo, and the resulting oil residue was treated with diethyl ether (15 mL) and hexanes (12 mL) to provide a 15 precipitate. The precipitate was filtered and washed with diethyl ether/hexanes (~1.3 ratio; 30 mL) and dried in vacuo to provide Cap-4 as a fluffy white solid (5.57 g). Optical rotation: -176.9° [c = 3.7 mg/mL in H₂O; λ = 589 nm]. ¹H NMR (DMSO-d6, δ = 2.5 ppm, 400 MHz): δ 12.84 (br s, 1H), 7.96 (d, J = 8.3, 1H), 7.41-7.29 (m, 5H), 5.14 (d, J = 8.3, 1H), 3.55 (s, 3H). LC (Cond. 1): RT = 1.01 min; >95 % 20 homogeneity index; LC/MS: Anal. Calcd. for [M+H] C10H!2NO4 210.08; found 210.17; HRMS: Anal. Calcd. for [M+H]⁺C10H!₂NO4 210.0766; found 210.0756.

Cap-5 Qi ό

A mixture of (R)- 2-phenylglycine (1.0 g, 6.62 mmol), 1,4-dibromobutane (1.57 g, 7.27 mmol) andNa₂CO₃ (2.10 g, 19.8 mmol) in ethanol (40 mL) was heated at 100 °C for 21 hours. The reaction mixture was cooled to ambient temperature and filtered, and the filtrate was concentrated in vacuo. The residue was dissolved in ethanol and acidified with IN HCI to pH 3-4, and the volatile component was 30 removed in vacuo. The resulting crude material was purified by a reverse phase

HPLC (water/methanol/TFA) to provide the TFA salt of Cap-5 as a semi-viscous white foam (1.0 g). ¹HNMR (DMSO-d₆, δ = 2.5, 500 MHz) δ 10.68 (br s, 1H), 7.51 (m, 5H), 5.23 (s, 1H), 3.34 (app br s, 2H), 3.05 (app br s, 2H), 1.95 (app br s, 4H);

RT = 0.30 min (Cond. 1); >98% homogeneity index; LC/MS: Anal. Calcd. for

[M+H]⁺ C12H16NO2: 206.12; found 206.25.

Cap-6

The TFA salt of Cap-6 was synthesized from (R)-2-phenylglycine and 1bromo-2-(2-bromoethoxy)ethane by using the method of preparation of Cap-5. ¹H NMR (DMSO-d6, δ = 2.5, 500 MHz) δ 12.20 (br s, 1H), 7.50 (m, 5H), 4.92 (s, 1H), 3.78 (app br s, 4H), 3.08 (app br s, 2H), 2.81 (app br s, 2H); RT = 0.32 min (Cond. 1); >98%; LC/MS: Anal. Calcd. for [M+H]⁺ C12H!6NO3: 222.11; found 222.20; HRMS: Anal. Calcd. for [M+H]⁺C12H!6NO₃: 222.1130; found 222.1121.

Cap-7

Cap-7a: enantiomer-1

Cap-7b: enantiomer-2

A CH2C12 (200 mL) solution of p-toluenesulfonyl chloride (8.65 g, 45.4 mmol) was added dropwise to a cooled (-5 °C) CH2C12 (200 mL) solution of (S)benzyl 2-hydroxy-2-phenylacetate (10.0 g, 41.3 mmol), triethylamine (5.75 mL, 41.3 mmol) and 4-dimethylaminopyridine (0.504 g, 4.13 mmol), while maintaining the temperature between -5 °C and 0 °C. The reaction was stirred at 0 °C for 9 hours, and then stored in a freezer (-25 °C) for 14 hours. It was allowed to thaw to ambient temperature and washed with water (200 mL), IN HCI (100 mL) and brine (100 mL), dried (MgSO4), filtered, and concentrated in vacuo to provide benzyl 2-phenyl-2 (tosyloxy)acetate as a viscous oil which solidified upon standing (16.5 g). The chiral integrity ofthe product was not checked and that product was used for the next step without further purification. ¹H NMR (DMSO-d6, δ = 2.5, 500 MHz) δ 7.78 (d, J = 8.6, 2H), 7.43-7.29 (m, 10H), 7.20 (m, 2H), 6.12 (s, 1H), 5.16 (d, J= 12.5,1H), 5.10 (d, J = 12.5,1H), 2.39 (s, 3H). RT = 3.00 (Cond. 3); >90% homogeneity index; LC/MS: Anal. Calcd. for [M+H]⁺C₂₂H₂₀NaO₅S: 419.09; found 419.04.

A THF (75 mL) solution of benzyl 2-phenyl-2-(tosyloxy)acetate (6.0 g, 15.1 mmol), 1-methylpiperazine (3.36 mL, 30.3 mmol) and N,N-diisopropylethylamine (13.2 mL, 75.8 mmol) was heated at 65 °C for 7 hours. The reaction was allowed to cool to ambient temperature and the volatile component was removed in vacuo. The residue was partitioned between ethylacetate and water, and the organic layer was washed with water and brine, dried (MgSO₄), filtered, and concentrated in vacuo. The resulting crude material was purified by flash chromatography (silica gel, ethyl acetate) to provide benzyl 2-(4-methylpiperazin-l-yl)-2-phenylacetate as an orangishbrown viscous oil (4.56 g). Chiral HPLC analysis (Chiralcel OD-H) indicated that the sample is a mixture of enantiomers in a 38.2 to 58.7 ratio. The separation of the enantiomers were effected as follow: the product was dissolved in 120 mL of ethanol/heptane (1:1) and injected (5 mL/injection) on chiral HPLC column (Chiracel OJ, 5 cm ID x 50 cm L, 20 pm) eluting with 85:15 Heptane/ethanol at 75 mL/min, and monitored at 220 nm. Enantiomer-1 (1.474 g) and enantiomer-2 (2.2149 g) were retrieved as viscous oil. ¹H NMR (CDC13, δ = 7.26, 500 MHz) 7.44-7.40 (m, 2H), 7.33-7.24 (m, 6H), 7.21-7.16 (m, 2H), 5.13 (d,J = 12.5,1H), 5.08 (d, J= 12.5, 1H), 4.02 (s, 1H), 2.65-2.38 (app br s, 8H), 2.25 (s, 3H). RT = 2.10 (Cond. 3); >98% homogeneity index; LC/MS: Anal. Calcd. for [M+H]⁺ C20H25N2O2: 325.19; found 325.20.

A methanol (10 mL) solution of either enantiomer of benzyl 2-(4methylpiperazin-l-y 1)-2-phenylacetate (1.0 g, 3.1 mmol) was added to a suspension of 10% Pd/C (120 mg) in methanol (5.0 mL). The reaction mixture was exposed to a balloon of hydrogen, under a careful monitoring, for &lt;50 min. Immediately after the completion ofthe reaction, the catalyst was filtered through diatomaceous earth (Celite®) and the filtrate was concentrated in vacuo to provide Cap-1, contaminated with phenylacetic acid as a tan foam (867.6 mg; mass is above the theoretical yield).

The product was used for the next step without further purification. Ή NMR (DMSO-d_6> δ = 2.5, 500 MHz) δ 7.44-7.37 (m, 2H), 7.37-7.24 (m, 3H), 3.92 (s, IH), 2.63-2.48 (app. bs, 2H), 2.48-2.32 (m, 6H), 2.19 (s, 3H); RT = 0.31 (Cond. 2); >90% homogeneity index; LC/MS: Anal. Calcd. for [M+H]⁺ C13H19N2O2:235.14; found 235.15; HRMS: Anal. Calcd. for [M+H]⁺ C13H19N2O2: 235.1447; found 235.1440.

The synthesis of Cap-8 and Cap-9 was conducted according to the synthesis of Cap-1 by using appropriate amines for the SN2 displacement step (i.e., 4hydroxypiperidine for Cap-8 and (S)3־-fluoropyrrolidine for Cap-9) and modified conditions for the separation of the respective stereoisomeric intermedites, as described below.

Cap-8

8a: enantiomer-1

8b: enantiomer-2

The enantiomeric separation of the intermediate benzyl 2-(4hydroxypiperidin-l-yl)-2-phenyl acetate was effected by employing the following conditions: the compound (500 mg) was dissolved in ethanol/heptane (5 mL/45 mL). The resulting solution was injected (5 mL/injection) on a chiral HPLC column (Chiracel OJ, 2 cm ID x 25 cm L, 10 pm) eluting with 80:20 heptane/ethanol at !0 mL/min, monitored at 220 nm, to provide 186.3 mg of enantiomer-1 and 209.1 mg of enantiomer-2 as light-yellow viscous oils. These benzyl ester was hydrogenolysed according to the preparation of Cap-1 to provide Cap-8:¹H NMR (DMSO-d6, δ = 2.5, 500 MHz) 7.40 (d, J = 7, 2H), 7.28-7.20 (m, 3H), 3.78 (s IH), 3.46 (m, IH), 2.93 (m, IH), 2.62 (m, IH), 2.20 (m, 2H), 1.70 (m, 2H), 1.42 (m, 2H). RT = 0.28 (Cond. 2); >98% homogeneity index; LC/MS: Anal. Calcd. for [M+H]⁺ C13H18NO3: 236.13; found 236.07; HRMS: Calcd. for [M+H]⁺ C13H18NO3: 236.1287; found 236.1283.

Cap-9

<img file="IL196813A_D0040.tif" />

9a: diastereomer-1

9b: diastereomer-2

The diastereomeric separation of the intermediate benzyl 2-((S)-3fluoropyrrolidin-l-yl)-2-phenylacetate was effected by employing the following conditions: the ester (220 mg) was separated on a chiral HPLC column (Chiracel OJH, 0.46 cm ID x 25 cm L, 5 pm) eluting with 95% CO₂1 5% methanol with 0.1% TFA, at 10 bar pressure, 70 mL/min flow rate, and a temperature of 35 °C. The HPLC elute for the respective stereiosmers was concentrated, and the residue was dissolved in CH₂C1₂ (20 mL) and washed with an aqueous medium (10 mL water + 1 mL saturated NaHCO₃ solution). The organic phase was dried (MgSO₄), filtered, and concentrated in vacuo to provide 92.5 mg of fraction-1 and 59.6 mg of fraction-2. These benzyl esters were hydrogenolysed according to the preparation of Cap-7 to prepare Caps 9a and 9b. Cqp-9a (diastereomer-1; the sample is a TFA salt as a result of purification on a reverse phase HPLC using H₂O/methanol/TFA solvent): H NMR (DMSO-d₆, δ = 2.5,400 MHz) 7.55-7.48 (m, 5H), 5.38 (d of m, J = 53.7,1H), 5.09 (br s, 1H), 3.84-2.82 (br m, 4H), 2.31-2.09 (m, 2H). RT = 0.42 (Cond. 1); >95% homogeneity index; LC/MS: Anal. Calcd. for [M+H]⁺ C12H!5FNO2: 224.11; found 224.14; Cap-9b (diastereomer-2): ¹H NMR (DMSO-d6, δ = 2.5, 400 MHz) 7.43-7.21 (m, 5H), 5.19 (d of m, J= 55.9,1H), 3.97 (s, 1H), 2.95-2.43 (m, 4H), 2.19-1.78 (m, 2H). RT = 0.44 (Cond. 1); LC/MS: Anal. Calcd. for [M+H]⁺ C!2H15FNO₂: 224.11; found 224.14.

Cap-10

To a solution of D-proline (2.0 g, 17 mmol) and formaldehyde (2.0 mL of 37% wt. in H₂O) in methanol (15 mL) was added a suspension of 10% Pd/C (500 mg) in methanol (5 mL). The mixture was stirred under a balloon of hydrogen for 23 hours. The reaction mixture was filtered through diatomaceous earth (Celite®) and concentrated in vacuo to provide Cap-10 as an off-white solid (2.15 g). H NMR (DMSO-d6, δ = 2.5, 500 MHz) 3.42 (m, 1H), 3.37 (dd, J = 9.4, 6.1, 1H), 2.85-2.78 (m, 1H), 2.66 (s, 3H), 2.21-2.13 (m, 1H), 1.93-1.84 (m, 2H), 1.75-1.66 (m, 1H). RT = 0.28(Cond. 2); >98% homogeneity index; LC/MS: Anal. Calcd. for[M+H]⁺C6H12NO2: 130.09; found 129.96.

Cap-11

<img file="IL196813A_D0041.tif" />

A mixture of (2S,4R)-4-fluoropyrrolidine-2-carboxylic acid (0.50 g, 3.8 mmol), formaldehyde (0.5 mL of 37% wt. in H₂O), 12 N HCI (0.25 mL) and 10% Pd/C (50 mg) in methanol (20 mL) was stirred under a balloon of hydrogen for 19 hours. The reaction mixture was filtered through diatomaceous earth (Celite ) and the filtrate was concentrated in vacuo. The residue was recrystallized from isopropanol to provide the HCI salt of Cap-11 as a white solid (337.7 mg). ¹H NMR (DMSO-de, δ = 2.5, 500 MHz) 5.39 (d m, J = 53.7, 1H), 4.30 (m, 1H), 3.90 (ddd, J = 31.5,13.5,4.5, 1H), 3.33 (dd, J = 25.6,13.4,1H), 2.85 (s, 3H), 2.60-2.51 (m, 1H), 2.39-2.26 (m, 1H). RT = 0.28 (Cond. 2); >98% homogeneity index; LC/MS: Anal. Calcd. for [M+H]⁺ C6H1!FNO2: 148.08; found 148.06.

Cap-12

H U x׳°Y^N>A0H ο ^Ξ

L-Alanine (2.0 g, 22.5 mmol) was dissolved in 10% aqueous sodium carbonate solution (50 mL), and a THF (50 mL) solution of methyl chloroformate (4.0 mL) was added to it The reaction mixture was stirred under ambient conditions for 4.5 hours and concentrated in vacuo. The resulting white solid was dissolved in water and acidified with IN HCI to a pH ~ 2-3. The resulting solutions was extracted with ethyl acetate (3 x 100 mL), and the combined organic phase was dried (Na₂SO₄), filtered, and concentrated in vacuo to provide a colorless oil (2.58 g). 500 mg of this material was purified by a reverse phase HPLC (H20/methanol/TFA) to provide 150 mg of Cap-12 as a colorless oil. ¹H NMR (DMSO-d₆, δ = 2.5, 500 MHz) 7.44 (d, J = 7.3,0.8H), 7.10 (br s, 0.2H), 3.97 (m, 1H), 3.53 (s, 3H), 1.25 (d, J = 7.3, 3H).

Cap-13

<img file="IL196813A_D0042.tif" />

A mixture of L-alanine (2.5 g, 28 mmol), formaldehyde (8.4 g, 37 wt. %), IN HCI (30 mL) and 10% Pd/C (500 mg) in methanol (30 mL) was stirred under a hydrogen atmosphere (50 psi) for 5 hours. The reaction mixture was filtered through diatomaceous earth (Celite®) and the filtrate was concentrated in vacuo to provide the HCI salt of Cap-13 as an oil which solidified upon standing under vacuum (4.4 g; the mass is above theoretical yield). The product was used without further purification. ¹H NMR (DMSO-d₆, δ = 2.5, 500 MHz) δ 12.1 (br s, 1H), 4.06 (q, J = 7.4, 1H), 2.76 (s, 6H), 1.46 (d, J = 7.3, 3H).

<img file="IL196813A_D0043.tif" />

<img file="IL196813A_D0044.tif" />

Cap-14

Step 1: A mixture of (R)-(-)-D-phenylglycine tert-butyl ester (3.00 g, 12.3 mmol), NaBH₃CN (0.773 g, 12.3 mmol), KOH (0.690 g, 12.3 mmol) and acetic acid (0.352 mL, 6.15 mmol) were stirred in methanol at 0 °C. To this mixture was added glutaric dialdehyde (2.23 mL, 12.3 mmol) dropwise over 5 minutes. The reaction mixture was stirred as it was allowed to warm to ambient temperature and stirring was continued at the same temperature for 16 hours. The solvent was subsequently removed and the residue was partitioned with 10% aqueous NaOH and ethyl acetate. The organic phase was separated, dried (MgSO4), filtered and concentrated to dryness to provide a clear oil. This material was purified by reverse-phase preparative HPLC (Primesphere C-18, 30 x 100mm; CH3CN-H2O-0.1% TFA) to give the intermediate ester (2.70 g, 56%) as a clear oil. ¹HNMR (400 MHz, CDC13) δ 7.53-7.44 (m, 3H), 7.40-7.37 (m, 2H), 3.87 (d, J = 10.9 Hz, IH), 3.59 (d, J = 10.9 Hz, IH), 2.99 (t, J= 11.2 Hz, IH), 2.59 (t, J= 11.4 Hz, IH), 2.07-2.02 (m, 2H), 1.82 (d,J= 1.82 Hz, 3H), 1.40 (s, 9H). LC/MS: Anal. Calcd. for C17H25NO2: 275; found: 276 (M+H)⁺.

Step 2: To a stirred solution ofthe intermediate ester (1.12g, 2.88mmol) in dichloromethane (10 mL) was added TFA (3 mL). The reaction mixture was stirred at ambient temperature for 4 hours and then it was concentrated to dryness to give a light yellow oil. The oil was purified using reverse-phase preparative HPLC (Primesphere C-18, 30 x 100mm; CH3CN-H₂O-0.1% TFA). The appropriate fractions were combined and concentrated to dryness in vacuo. The residue was then dissolved in a minimum amount of methanol and applied to applied to MCX LP extraction cartridges (2x6 g). The cartridges were rinsed with methanol (40 mL) and then the desired compound was eluted using 2M ammonia in methanol (50 tnL). Product-containing fractions were combined and concentrated and the residue was taken up in water. Lyophilization of this solution provided the title compound (0.492 g, 78%) as a light yellow solid. ¹HNMR (DMSO-d6) δ 7.50 (s, 5H), 5.13 (s, IH), 3.09 (br s, 2H), 2.92-2.89 (m, 2H), 1.74 (m, 4H), 1.48 (br s, 2H). LC/MS: Anal. Calcd. for C13H17NO2: 219; found: 220 (M+H)⁺.

Cap-15

<img file="IL196813A_D0045.tif" />

<img file="IL196813A_D0046.tif" />

Step 1; (S)-l-Phenylethyl 2-bromo־2־phenylacetate: To a mixture of abromophenylacetic acid (10.75 g, 0.050 mol), (S)-(-)-l-phenylethanol (7.94 g, 0.065 mol) and DMAP (0.61 g, 5.0 mmol) in dry dichloromethane (100 mL) was added solid EDCI (12.46 g, 0.065 mol) all at once. The resulting solution was stirred at room temperature under Ar for 18 hours and then it was diluted with ethyl acetate, washed (H₂O x 2, brine), dried (Na₂SO₄), filtered, and concentrated to give a pale yellow oil. Flash chromatography (SiO₂/ hexane-ethyl acetate, 4:1) of this oil provided the title compound (11.64 g, 73%) as a white solid. ¹HNMR (400 MHz,

CDC13) δ 7.53-7.17 (m, 10H), 5.95 (q, J = 6.6 Hz, 0.5H), 5.94 (q, J = 6.6 Hz, 0.5H),

5.41 (s, 0.5H), 5.39(8,0.5H), 1.58 (d, J = 6.6 Hz, 1.5H), 1.51 (d, J=6.6Hz, 1.5H).

Step 2; (S)-l-Phenylethyl (R)-2-(4-hydroxy-4-methylpiperidin-l-yl)- 2phenylacetate: To a solution of (S)-l ־phenylethyl 2-bromo-2-phenylacetate (0.464 g, 1.45 mmol) in THF (8 mL) was added triethylamine (0.61 mL, 4.35 mmol), followed by tetrabutylammonium iodide (0.215 g, 0.58 mmol). The reaction mixture was stirred at room temperature for 5 minutes and then a solution of 4-methyl-4hydroxypiperidine (0.251 g, 2.18 mmol) in THF (2 mL) was added. The mixture was stirred for 1 hour at room temperature and then it was heated at 5560־ °C (oil bath temperature) for 4 hours. ^,The cooled reaction mixture was then diluted with ethyl acetate (30 mL), washed (H2O x2, brine), dried (MgSO4), filtered and concentrated. The residue was purified by silica gel chromatography (060%־ ethyl acetate-hexane) to provide first the (S,R)־isomer ofthe title compound (0.306 g, 60%) as a white solid and then the corresponding (S,S)־isomer (0.120 g, 23%), also as a white solid. (S,R)־isomer: ¹HNMR (CD3OD) δ 7.517.45־ (m, 2H), 7.41-7.25 (m, 8H), 5.85 (q, J = 6.6 Hz, 1H), 4.05 (s, 1H), 2.562.45־ (m, 2H), 2.412.29־ (m, 2H), 1.711.49־ (m, 4H), 1.38(d, J =6.6 Hz, 3H), 1.18 (s,3H). LCMS:Anal. Calcd. for C22H27NO3: 353; found: 354 (M+H)⁺. (S,S)־isomer: ¹HNMR (CD3OD) δ 7.417.30־ (m, 5H), 7.20-7.14 (m, 3H), 7.067.00־ (m, 2H), 5.85 (q, J = 6.6 Hz, 1H), 4.06 (s, 1H), 2.70־ 2.60 (m, 1H), 2.51 (dt, J= 6.6, 3.3 Hz, 1H), 2.442.31־ (m, 2H), 1.751.65־ (m, 1H), 1.651.54־ (m, 3H), 1.50 (d, J= 6.8 Hz, 3H), 1.20 (s, 3H). LCMS: Anal. Calcd. for C22H27NO3: 353; found: 354 (M+H)⁺.

Step 3; (R)4)־2־-Hydroxy־4־methylpiperidin־l-yl)2־-phenylacetic acid: To a solution of (S)-l-phenylethyl (R)־4)־2־hydroxy־4־methylpiperidin־l־yl)־2־ phenylacetate (0.185 g, 0.52 mmol) in dichloromethane (3 mL) was added trifluoroacetic acid (1 mL) and the mixture was stirred at room temperature for 2 hours. The volatiles were subsequently removed in vacuo and the residue was purified by reverse-phase preparative HPLC (Primesphere C-18, 20 x 100mm; CH3CN־H200.1%־ TFA) to give the title compound (as TFA salt) as a pale bluish solid (0,128 g, 98%). LCMS: Anal. Calcd. for C14H19NO3: 249; found: 250 (M+H)⁺.

Cap-16

<img file="IL196813A_D0047.tif" />

(R)-Cap-16

Stepl; (S)-1 ־Phenylethyl 2-(2־fluorophenyl)acetate: A mixture of 2־ fluorophenylacetic acid (5.45 g, 35.4 mmol), (S)-l-phenylethanol (5.62 g, 46.0 mmol), EDCI (8.82 g, 46.0 mmol) and DMAP (0.561 g, 4.60 mmol) in CH₂C1₂ (100 mL) was stirred at room temperature for 12 hours. The solvent was then concentrated and the residue partitioned with H₂O-ethyl acetate. The phases were separated and the aqueous layer back-extracted with ethyl acetate (2x). The combined organic phases were washed (H₂O, brine), dried (Na₂SO4), filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (Biotage/ 0-20% ethyl acetate-hexane) to provide the title compound as a colorless oil (8.38 g, 92%). ¹HNMR (400 MHz, CD3OD) δ 7.32 - 7.23 (m, 7H), 7.10-7.04 (m, 2), 5.85 (q, J = 6.5 Hz, IH), 3.71 (s, 2H), 1.48 (d, J = 6.5 Hz, 3H).

Step 2; (R)-((S)-1 -Phenylethyl) 2-(2-fluorophenyl)-2-(pipendin-l-y!)acetate: To a solution of (S)-l-phenylethyl 2-(2-fluorophenyl)acetate (5.00 g, 19.4 mmol) in THF (1200 mL) at 0°C was added DBU (6.19 g, 40.7 mmol) and the solution was allowed to warm to room temperature while stirring for 30 minutes. The solution was then cooled to -78 °C and a solution of CBr₄(13.5 g, 40.7 mmol) in THF (100 mL) was added and the mixture was allowed to warm to -10 °C and stirred at this temperature for 2 hours. The reaction mixture was quenched with saturated aq. NH4CI and the layers were separated. The aqueous layer was back-extracted with ethyl acetate (2x) and the combined organic phases were washed (H₂O, brine), dried (Na₂SO4), filtered, and concentrated in vacuo. To the residue was added piperidine (5.73 mL, 58.1 mmol) and the solution was stirred at room temperature for 24 hours. The volatiles were then concentrated in vacuo and the residue was purified by silica gel chromatography (Biotage/ 0-30% diethyl ether-hexane) to provide a pure mixture of diastereomers (2:1 ratio by ¹HNMR) as a yellow oil (2.07 g, 31%), along with unreacted starting material (2.53 g, 51%). Further chromatography of the diastereomeric mixture (Biotage/ 0-10% diethyl ether-toluene) provided the title compound as a colorless oil (0.737 g, 11%). ¹HNMR (400 MHz, CD₃OD) δ 7.52 (ddd, J = 9.4, 7.6, 1.8 Hz, IH), 7.33 - 7.40 (m, 1), 7.23 - 7.23 (m, 4H), 7.02 - 7.23 (m, 4H), 5.86 (q, J = 6.6 Hz, IH), 4.45 (s, IH), 2.39 - 2.45 (m, 4H), 1.52 - 1.58 (m, 4H), 1.40 - 1.42 (m, IH), 1.38 (d, J = 6.6 Hz, 3H). LCMS: Anal. Calcd. for C21H24FNO2: 341; found: 342 (M+H)⁺.

Step 3; (R)-2-(2-fluorophenyl)-2-(piperidin-l-yl)acetic acid: A mixture of (R)-((S)-1-phenylethyl) 2-(2-fluorophenyl)-2-(piperidin-l-yl)acetate (0.737 g, 2.16 mmol) and 20% Pd(OH)₂/C (0.070 g) in ethanol (30 mL) was hydrogenated at room temperature and atmospheric pressure (H₂ balloon) for 2 hours. The solution was then purged with Ar, filtered through diatomaceous earth (Celite®), and concentrated in vacuo. This provided the title compound as a colorless solid (0.503 g, 98%). ¹HNMR (400 MHz, CD3OD) δ 7.65 (ddd, J = 9.1, 7.6, 1.5 Hz, IH), 7.47-7.53 (m, IH), 7.21-7.30 (m, 2H), 3.07-3.13 (m, 4H), i.84 (br s, 4H), 1.62 (br s, 2H). LCMS: Anal. Calcd. for C״H16FNO₂:237; found: 238 (M+H)⁺.

<img file="IL196813A_D0048.tif" />

Step 1; (S)-l-Phenylethyl (R)-2-(4-hydroxy-4-phenylpiperidin-l-yl)- 2phenylacetate: To a solution of (S)-l-phenylethyl 2-bromo-2-phenylacetate (1.50 g, 4.70 mmol) in THF (25 mL) was added triethylamine (1.31 mL, 9.42 mmol), 25 followed by tetrabutylammonium iodide (0.347 g, 0.94 mmol). The reaction mixture was stirred at room temperature for 5 minutes and then a solution of 4-phenyl-4hydroxypiperidine (1.00 g, 5.64 mmol) in THF (5 mL) was added. The mixture was stirred for 16 hours and then it was diluted with ethyl acetate (100 mL), washed (H₂O x2, brine), dried (MgSO₄), filtered and concentrated. The residue was purified on a silica gel column (0-60% ethyl acetate-hexane) to provide an approximately 2:1 mixture of diastereomers, as judged by ¹HNMR. Separation of these isomers was performed using supercritical fluid chromatography (Chiralcel OJ-H, 30 x 250mm, 20% ethanol in CO2 at 35 °C), to give first the (R)-isomer of the title compound (0.534 g, 27%) as a yellow oil and then the corresponding (S)-isomer (0.271 g, 14%), also as a yellow oil. (S,R)-isomer: ¹HNMR (400 MHz, CD3OD) δ 7.55-7.47 (m, 4H), 7.44-7.25 (m, 10H), 7.25-7.17 (m, 1H), 5.88 (q, J = 6.6 Hz, 1H), 4.12 (s, 1H), 2.82-2.72 (m, 1H), 2.64 (dt, J = 11.1, 2.5 Hz, 1H), 2.58-2.52 (m, 1H), 2.40 (dt, J = 11.1,2.5 Hz, 1H), 2.20 (dt, J= 12.1,4.6 Hz, 1H), 2.10 (dt, J = 12.1,4.6 Hz, 1H), 1.72-1.57 (m, 2H), 1.53 (d, J= 6.5 Hz, 3H). LCMS: Anal. Calcd. for C27H₂₉NO₃: 415; found: 416 (M+H)⁺; (S,S)-isomer: ¹HNMR (400 MHz, CD3OD) δ 7.55-7.48 (m, 2H), 7.45-7.39 (m, 2H), 7.38-7.30 (m, 5H), 7.25-7.13 (m, 4H), 7.08-7.00 (m, 2H), 5.88 (q, 7 = 6.6 Hz, 1H), 4.12 (s, 1H), 2.95-2.85 (m, 1H), 2.68 (dt,J = 11.1,2.5 Hz, 1H), 2.57-2.52 (m, 1H),2.42 (dt, 7 = 11.1, 2.5 Hz, 1H), 2.25 (dt, J = 12.1,4.6 Hz, 1H), 2.12 (dt, J = 12.1,4.6 Hz, 1H), 1.73 (dd, J = 13.6, 3.0 Hz, 1H), 1.64 (dd,J = 13.6, 3.0 Hz, 1H), 1.40 (d, J = 6.6 Hz, 3H). LCMS: Anal. Calcd. for C₂₇H₂₉NO₃: 415; found: 416 (M+H)⁺.

The following esters were prepared in similar fashion employing step 1 in the synthesis of Cap-17. _________________

<td> Intermediate-17a</td><td> o_YojO O N</td><td> Diastereomer 1: *HNMR (500 MHz, DMSO-d6) δ ppm 1.36 (d, 7=6.41 Hz, 3H) 2.23 - 2.51 (m, 4H) 3.35 (s,4H) 4.25 (s, 1H) 5.05 (s, 2H) 5.82 (d, 7=6.71 Hz, 1H) 7.15-7.52 (m, 15H). LCMS: Anal. Calcd. for: C28H30N2O4 458.55; Found: 459.44 (M+H)⁺.</td>

<td></td><td></td><td> Diastereomer 2: ¹H NMR (500 MHz, DMSO-de) δ ppm 1.45 (d, 7=6.71 Hz, 3H) 2.27 - 2.44 (m, 4H) 3.39 (s, 4H) 4.23 (s, 1H) 5.06 (s, 2H)5.83 (d, 7=6.71 Hz, 1H) 7.12 (dd, 7=6.41, 3.05 Hz, 2H) 7.19-7.27 (m, 3H) 7.44 - רב ר (m, 10H). LCMS: Anal. Calcd. for: C28H30N2O4 458.55; Found: 459.44 (M+H)⁺.</td>

<td> Intermediate -17b</td><td> o o /—\ / ° iz ^Z~\</td><td> Diasteromer 1: RT= 11.76 min (Cond’n II); LCMS: Anal. Calcd. for: C₂0H22N2O₃ 338.4 Found: 339.39 (M+H)⁺; Diastereomer 2: RT = 10.05 min (Cond’n Π); LCMS: Anal. Calcd. for: C20H22N2O3 338.4; Found: 339.39 (M+H)⁺.</td>

<td> Intermediate -17c</td><td> ό N</td><td> Diastereomer 1: T_R=4.55 min (Cond’n I); LCMS: Anal. Calcd. for: C21H26N2O2 338.44 Found: 339.45 (M+H)⁺; Diastereomer 2: Tr=6.00 min (Cond’n I); LCMS: Anal. Calcd. for: C₂₁H₂₆N₂O2 338.44 Found: 339.45 (M+H)⁺.</td>

<td> Intermediate -17d</td><td> 0</td><td> Diastereomer 1: RT= 7.19 min (Cond’n I); LCMS: Anal. Calcd. for: C27H29NO2 399.52 Found: 400.48 (M+H)⁺; Diastereomer 2: RT = 9.76 min (Cond’n I); LCMS: Anal. Calcd. for: C27H29NO2 399.52 Found: 400.48 (M+H)⁺.</td>

Chiral SFC Conditions for determining retention time for intermediates 17b-l 7d

Condition 1

Column: Chiralpak AD-H Column, 4.6X250 mm, 5pm

Solvents: 90% CO2 10% ־ methanol with 0.1%DEA

Temp: 35 °C

Pressure: 150 bar

Flow rate: 2.0 mL/min.

UV monitored @ 220 nm

Injection: 1.0 mg/3mL methanol

Condition 2

Column: Chiralcel OD-H Column, 4.6X250 mm, 5pm

Solvents: 90% CO2 10% ־ methanol with 0.1%DEA

Temp: 35 °C

Pressure: 150 bar

Flow rate: 2.0 mL/min.

UV monitored @ 220 nm

Injection: 1.0 mg/mL methanol

Cap-17, Step 2; (R)-2-(4-Hydroxy-4-phenylpiperidin-l-yl)-2-phenylacetic acid: To a solution of (S)-l-phenylethyl (R)-2-(4-hydroxy-4-phenylpiperidin-l-yl)-261 phenylacetate (0.350 g, 0.84 mmol) in dichloromethane (5 mL) was added trifluoroacetic acid (1 mL) and the mixture was stirred at room temperature for 2 hours. The volatiles were subsequently removed in vacuo and the residue was purified by reverse-phase preparative HPLC (Primesphere C-18,20 x 100mm;

CH3CN-H2O-0.1% TFA) to give the title compound (as TFA salt) as a white solid (0.230 g, 88%). LCMS: Anal. Calcd. for C19H21NO3: 311; found: 312 (M+H)⁺.

The following carboxylic acids were prepared in a similar fashion:

<td> Cap-17a</td><td> Sf Cn</td><td> RT=2.21 (Cond’n II); ¹H NMR (500 MHz, DMSOd6) δ ppm 2.20 - 2.35 (ni, 2H) 2.34 - 2.47 (m, 2H) 3.37 (s,4H) 3.71 (s, 1H) 5.06 (s, 2H) 7.06 - 7.53 (m, 10H). LCMS: Anal. Calcd. for: C20H22N2O4 354.40; Found: 355.38 (M+H)⁺.</td>

<td> Cap-17b</td><td> H cY N o!</td><td> RT=0.27 (Cond’n HI); LCMS: Anal. Calcd. for: C₁₂H14N2O₃ 234.25; Found: 235.22 (M+H)⁺.</td>

<td> Cap-17c</td><td> 0 N ⁰</td><td> RT = 0.48 (Cond’n II); LCMS: Anal. Calcd. for: C13H1₈N2O2 234.29; Found: 235.31 (M+H)⁺.</td>

<td> Cap-17d</td><td> 0 Cn</td><td> RT= 2.21 (Cond’n I); LCMS: Anal. Calcd. for: C19H21NO2 295.38; Found: 296.33 (M+H)⁺.</td>

LCMS Conditions for determining retention time for Caps 17a-l 7d

Condition 1

Column: Phenomenex-Luna 4.6 X 50 mm S10

Start % B = 0

Fianl % B = 100

Gradient Time = 4 min

Flow Rate = 4 mL/min

Wavelength = 220

Solvent A = 10% methanol - 90% H₂O - 0.1% TFA

Solvent B = 90% methanol - 10% H₂O -0.1% TFA

Condition 2

Column: Waters-Sunfire 4.6 X 50 mm S5

Start % B = 0

Fianl % B = 100

Gradient Time = 2 min

Flow Rate = 4 mL/min

Wavelength = 220

Solvent A = 10% methanol - 90% H₂O - 0.1% TFA

Solvent B = 90% methanol - 10% H₂O - 0.1% TFA

Condition 3

Column: Phenomenex 10μ 3.0 X 50 mm

Start % B = 0

Fianl % B = 100

Gradient Time = 2 min

Flow Rate = 4 mL/min

Wavelength = 220

Solvent A = 10% methanol - 90% H₂O - 0.1% TFA

Solvent B = 90% methanol - 10% H₂O - 0.1% TFA

<img file="IL196813A_D0049.tif" />

<img file="IL196813A_D0050.tif" />

<img file="IL196813A_D0051.tif" />

Step 1; (R,S)-Ethyl 2-(4-pyridyl)-2-bromoacetate: To a solution of ethyl 4pyridylacetate (1.00 g, 6.05 mmol) in dry THF (150 mL) at 0 °C under argon was added DBU (0.99 mL, 6.66 mmol). The reaction mixture was allowed to warm to room temperature over 30 minutes and then it was cooled to -78 °C. To this mixture was added CBr₄ (2.21 g, 6.66 mmol) and stirring was continued at -78 °C for 2 hours. The reaction mixture was then quenched with sat. aq. NH4C1 and the phases were separated. The organic phase was washed (brine), dried (Na2SO4), filtered, and concentrated in vacuo. The resulting yellow oil was immediately purified by flash chromatography (SiO2/ hexane-ethyl acetate, 1:1) to provide the title compound (1.40 g, 95%) as a somewhat unstable yellow oil. ¹HNMR (400 MHz, CDC13) δ 8.62 (dd, J = 4.6,1.8 Hz, 2H), 7.45 (dd, J = 4.6, 1.8 Hz, 2H), 5.24 (s, 1H), 4.21-4.29 (m, 2H), 1.28 (t, J= 7.1 Hz, 3H). LCMS: Anal. Calcd. for C₉H1₀BrNO₂: 242, 244; found: 243, 245 (M+H)⁺.

Step 2; (R,S)-Ethyl 2-(4-pyridyl)-2-(N,N-dimethylamino)acetate: To a solution of (R,S)-ethyl 2-(4-pyridyl)-2-bromoacetate (1.40 g, 8.48 mmol) in DMF (10 mL) at room temperature was added dimethylamine (2M in THF, 8.5 mL, 17.0 mmol). After completion of the reaction (as judged by tic) the volatiles were removed in vacuo and the residue was purified by flash chromatography (Biotage, 40+M SiO2 column; 50%-100% ethyl acetate-hexane) to provide the title compound (0.539 g, 31%) as a light yellow oil. ¹HNMR (400 MHz, CDC13) δ 8.58 (d, J = 6.0 Hz, 2H), 7.36 (d, J = 6.0 Hz, 2H), 4.17 (m, 2H), 3.92 (s, 1H), 2.27 (s, 6H), 1.22 (t, J = 7.0 Hz). LCMS: Anal. Calcd. for C_״H16N₂O₂: 208; found: 209 (M+H)⁺.

Step 3; (R,S)-2-(4-Pyridyl)-2-(N,N-dimethylamino)acetic acid: To a solution of (R,S)-ethyl 2-(4-pyridyl)-2-(N,N-dimethylamino)acetate (0.200 g, 0.960 mmol) in amixture of THF-methanol-H₂O (1:1:1, 6 mL) was added powdered LiOH (0.120 g,

4.99 mmol) at room temperature. The solution was stirred for 3 hours and then it was acidified to pH 6 using IN HC1. The aqueous phase was washed with ethyl acetate and then it was lyophilized to give the dihydrochloride of the title compound as a yellow solid (containing LiCl). The product was used as such in subsequent steps.

^lHNMR (400 MHz, DMSO-de) δ 8.49 (d, J = 5.7 Hz, 2H), 7.34 (d, J = 5.7 Hz, 2H), 3.56 (s, 1H), 2.21 (s, 6H).

The following examples were prepared in similar fashion using the method described in Example 4;

<td> Cap-19</td><td> NMe₂rj^x%p^xCO₂H</td><td> LCMS: Anal. Calcd. for C9H12N2O2: 180; found: 181 (M+H)⁺.</td>

<td> Cap-20</td><td> NMe₂&lt;^^x^co₂h</td><td> LCMS: no ionization. ¹HNMR (400 MHz, CD3OD) δ 8.55 (d, J = 4.3 Hz, 1H), 7.84 (app t, J = 5.3 Hz, 1H), 7.61 (d, J = 7.8 Hz, 1H), 7.37 (appt, J = 5.3 Hz, 1H), 4.35 (s, 1H), 2.60 (s, 6H).</td>

<td> Cap-21</td><td> NMe₂ CI^IV</td><td> LCMS: Anal. Calcd. for C9Hnc1N₂O2: 214,216; found: 215, 217 (M+H)⁺.</td>

<td> Cap-22</td><td> NMe₂&lt;^&lt;S5%fp'CO₂H</td><td> LCMS: Anal. Calcd. for C10H!2N2O4: 224; found: 225 (M+H)⁺.</td>

<td> Cap-23</td><td> NMe₂jj^j^CO₂H</td><td> LCMS: Anal. Calcd. for C14H15NO2: 247; found: 248 (M+H)⁺.</td>

<td> Cap-24</td><td> NMe₂^F3Cx!T^f^^Xc02H</td><td> LCMS: Anal. Calcd. for CnH12F₃NO2: 247; found: 248 (M+H)⁺.</td>

<td> Cap-25</td><td colspan="2"> NMe₂&lt;^ζϊϊ־γ^&gt;'002Η</td><td> LCMS: Anal. Calcd. for C11H12F3NO2: 247; found: 248 (M+H)⁺.</td>

<td> Cap-26</td><td colspan="2"> NMe₂ |j^pCO₂H</td><td> LCMS: Anal. Calcd. for C10H12FNO2: 247; found: 248 (M+H)⁺.</td>

<td> Cap-27</td><td> u</td><td> NMe₂/\θ₂Η</td><td> LCMS: Anal. Calcd. for C10H12FNO2: 247; found: 248 (M+H)⁺.</td>

<td> Cap-2 8</td><td></td><td> NMe₂γ׳χο₂Η</td><td> LCMS: Anal. Calcd. for C10H12C1NO2: 213, 215; found: 214, 217 (M+H)⁺.</td>

<td> Cap-29</td><td colspan="2"> NMe₂ί|^Χϊϊϊγ^ΧθΟ₂Η</td><td> LCMS: Anal. Calcd. for C10H12C1NO2: 213, 215; found: 214,217 (M+H)⁺.</td>

<td> Cap-30</td><td> Γ</td><td> NMe₂γ\0₂Η</td><td> LCMS: Anal. Calcd. forC!0H12ClNO2: 213, 215; found: 214, 217 (M+H)⁺.</td>

<td> Cap-31</td><td> s⁷/ y=N</td><td> NMe₂׳״^COzH</td><td> LCMS: Anal. Calcd. for C8H11N2O2S: 200; found: 201 (M+H)⁺.</td>

<td> Cap-32</td><td> C-s</td><td> NMe₂״O0₂H</td><td> LCMS: Anal. Calcd. forC8H11NO₂S: 185; found: 186 (M+H)⁺.</td>

<td> Cap-33</td><td> 0</td><td> NMe₂-׳־־X0₂H</td><td> LCMS: Anal. Calcd. forC8H_״NO2S: 185; found: 186 (M+H)⁺.</td>

<td> Cap-34</td><td> y/^^\ vr ־0</td><td> NMe₂y^COzH -N</td><td> LCMS: Anal. Calcd. for ChH!2N2O3: 220; found: 221 (M+H)⁺.</td>

<td> Cap-35</td><td> /^*\ s-</td><td> NMe₂ Y^COzH</td><td> LCMS: Anal. Calcd. for C!2H!3NO2S: 235; found: 236 (M+H)⁺.</td>

<img file="IL196813A_D0052.tif" />

<img file="IL196813A_D0053.tif" />

Step 1; (R,S)-Ethyl 2-(quinolin-3-yl)2־-(N,N-dimethylamino)־acetate: A mixture of ethyl Ν,Ν-dimethylaminoacetate (0.462 g, 3.54 mmol), K3PO4 (1.90 g, 8.95 mmol), Pd(t-Bu₃P)₂ (0.090 g, 0.176 mmol) and toluene (10 mL) was degassed with a stream of Ar bubbles for 15 minutes. The reaction mixture was then heated at 100 °C for 12 hours, after which it was cooled to room temperature and poured into H₂O. The mixture was extracted with ethyl acetate (2x) and the combined organic phases were washed (H₂O, brine), dried (Na₂SO₄), filtered, and concentrated in vacuo. The residue was purified first by reverse-phase preparative HPLC (Primesphere C-18, 30 x 100mm; CH₃CN-H₂O-5 mM NH4OAc) and then by flash chromatography (SiO₂/ hexane-ethyl acetate, 1:1) to provide the title compound (0.128 g, 17%) as an orange oil. ^lHNMR (400 MHz, CDCI3) δ 8.90 (d, J = 2.0 Hz, IH), 8.32 (d, J = 2.0 Hz, IH), 8.03-8.01 (m, 2H), 7.77 (ddd, J = 8.3, 6.8, 1.5 Hz, IH), 7.62 (ddd, J= 8.3, 6.8,1.5 Hz, IH), 4,35 (s, IH), 4.13 (m, 2H), 2.22 (s, 6H), 1.15 (t, J = 7.0 Hz, 3H). LCMS: Anal. Calcd. for C15H1₈N₂O₂: 258; found: 259 (M+H)⁺.

Step 2; (R,S) 2-(Quinolin-3-yl)-2-(N,N-dimethylamino)acetic acid: A mixture of (R,S)-ethyl 2-(quinolin-3-yl)-2-(N,N-dimethylamino)acetate (0.122 g, 0.472 mmol) and 6M HC1 (3 mL) was heated at 100 °C for 12 hours. The solvent was removed in vacuo to provide the dihydrochloride of the title compound (0.169 g, >100%) as a light yellow foam. The unpurified material was used in subsequent steps without further purification. LCMS: Anal. Calcd. for C13H14N2O2: 230;

found: 231 (M+H)⁺.

Cap-38

<img file="IL196813A_D0054.tif" />

^B Cap-38

Step 1; (R)-((S)-1-phenylethyl) 2-(dimethylamino)-2-(2-fluoropheny!)acetate and (S)-((S)-1 -phenylethyl) 2-(dimethylamino)-2-(2-fluorophenyl)acetate: To a mixture of (RS)-2-(dimethylamino)-2-(2-fluorophenyl)acetic acid (2.60 g, 13.19 mmol), DMAP (0.209 g, 1.71 mmol) and (S)-l-phenylethanol (2.09 g, 17.15 mmol) in CH2C12 (40 mL) was added EDCI (3.29 g, 17.15 mmol) and the mixture was allowed to stir at room temperature for 12 hours. The solvent was then removed in vacuo and the residue partitioned with ethyl acetate-H2O. The layers were separated, the aqueous layer was back-extracted with ethyl acetate (2x) and the combined organic phases were washed (H₂O, brine), dried (Na₂SO4), filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (Biotage/ 0-50% diethyl ether-hexane). The resulting pure diastereomeric mixture was then separated by reverse-phase preparative HPLC (Primesphere C-18, 30 x 100mm; CH3CN-H2O0.1% TFA) to give first (S)-l -phenethyl (R)-2-(dimethylamino)-2-(2fluorophenyl)acetate (0.501 g, 13%) and then (S)-l-phenethyl (S)-2(dimethylamino)-2-(2-fluorophenyl)-acetate (0.727 g. 18%), both as their TFA salts. (S,R)-isomer: ¹HNMR (400 MHz, CD3OD) δ 7.65 - 7.70 (m, 1H), 7.55-7.60 (ddd, J = 9.4, 8.1, 1.5 Hz, 1H), 7.36-7.41 (m, 2H), 7.28-7.34 (m, 5H), 6.04 (q, J= 6.5 Hz, 1H), 5.60 (s, 1H), 2.84 (s, 6H), 1.43 (d, J = 6.5 Hz, 3H). LCMS: Anal. Calcd. for C18H20FNO2: 301; found: 302 (M+H)⁺; (S,S)-isomer: ¹HNMR (400 MHz, CD₃OD) δ 7.58-7.63 (m, 1H), 7.18-7.31 (m, 6H), 7.00 (dd, J = 8.5,1.5 Hz, 2H), 6.02 (q, J = 6.5

Hz, 1H), 5.60 (s, 1H), 2.88 (s, 6H), 1.54 (d, J = 6.5 Hz, 3H). LCMS: Anal. Calcd.

for C18H20FNO2: 301; found: 302 (M+H)⁺.

Step 2; (R)-2-(dimethylamino)2)-2־-fluorophenyl)acetic acid: A mixture of (R)-((S)-1-phenylethyl) 2-(dimethylamino)-2-(2־fluorophenyl)acetate TFA salt (1.25 g, 3.01 mmol) and 20% Pd(OH)₂/C (0.125 g) in ethanol (30 mL) was hydrogenated at room temperature and atmospheric pressure (H₂ balloon) for 4 hours. The solution was then purged with Ar, filtered through diatomaceous earth (Celite®), and concentrated in vacuo. This gave the title compound as a colorless solid (0.503 g, 98%). ¹HNMR (400 MHz, CD₃OD) δ 7.53-7.63 (m, 2H), 7.33-7.38 (m, 2H), 5.36 (s, 1H), 2.86 (s, 6H). LCMS: Anal. Calcd. for C1₀H1₂FNO₂: 197; found: 198 (M+H)⁺.

The S-isomer could be obtained from (S)-((S)-1 -phenylethyl) 2(dimethylamino)-2-(2-fluorophenyl)acetate TFA salt in similar fashion.

Cap-39

<img file="IL196813A_D0055.tif" />

cap-39

A mixture of (R)-(2-chlorophenyl)glycine (0.300 g, 1.62 mmol), formaldehyde (35% aqueous solution, 0.80 mL, 3.23 mmol) and 20% Pd(OH)₂/C (0.050 g) was hydrogenated at room temperature and atmospheric pressure (H₂balloon) for 4 hours. The solution was then purged with Ar, filtered through diatomaceous earth (Celite®) and concentrated in vacuo. The residue was purified by reverse-phase preparative HPLC (Primesphere C-18, 30 x 100mm; CH3CN-H2O0.1% TFA) to give theTFA salt of the title compound (R)-2-(dimethylamino)2)-2־chlorophenyl)acetic acid as a colorless oil (0.290 g, 55%). ¹H NMR (400 MHz, CD3OD) δ 7.59-7.65 (m, 2H), 7.45-7.53 (m, 2H), 5.40 (s, 1H), 2.87 (s, 6H). LCMS: Anal. Calcd. for C10H12C1NO2: 213, 215; found: 214,216 (M+H)⁺.

Cl NH₂

<img file="IL196813A_D0056.tif" />

Cap-40 ־׳Cl HN O X A .oh

<img file="IL196813A_D0057.tif" />

cap-40

To an ice-cold solution of (R)-(2-chlorophenyl)glycine (1.00 g, 5.38 mmol) and NaOH (0.862 g, 21.6 mmol) in H₂O (5.5 mL) was added methyl chloroformate (1.00 mL, 13.5 mmol) dropwise. The mixture was allowed to stir at 0 °C for 1 hour and then it was acidified by the addition of cone. HC1 (2.5 mL). The mixture was extracted with ethyl acetate (2x) and the combined organic phase was washed (H₂O, brine), dried (Na₂SO₄), filtered, and concentrated in vacuo to give the title compound (R)2־-(methoxycarbonylamino)2)-2־-chlorophenyl)acetic acid as a yellow-orange foam (1.31 g, 96%). ^lH NMR (400 MHz, CD3OD) δ 7.39 - 7.43 (m, 2H), 7.29 7.31 (m, 2H), 5.69 (s, IH), 3.65 (s, 3H). LCMS: Anal. Calcd. for C10H10ClNO₄: 243, 245; found: 244, 246 (M+H)⁺.

Cap-41 ,N cap-41

To a suspension of 2-(2-(chloromethyl)phenyl)acetic acid (2.00 g, 10.8 mmol) in THF (20 mL) was added morpholine (1.89 g, 21.7 mmol) and the solution was stirred at room temperature for 3 hours. The reaction mixture was then diluted with ethyl acetate and extracted with H₂O (2x). The aqueous phase was lyophilized and the residue was purified by silica gel chromatography (Biotage/ 010%־ methanolCH₂C1₂) to give the title compound 2-(2-(Morpholinomethyl)phenyl)acetic acid as a colorless solid (2.22 g, 87%). ¹HNMR (400 MHz, CD₃OD) δ 7.37-7.44 (m, 3H), 7.297.33־ (m, IH), 4.24 (s, 2H), 3.83 (br s, 4H), 3.68 (s, 2H), 3.14 (br s, 4H). LCMS: Anal. Calcd. for C13H17NO3: 235; found: 236 (M+H)⁺.

The following examples were similarly prepared using the method described for Cap-41:

<td> Cap-42</td><td> o \ ^0H</td><td> LCMS: Anal. Calcd. for C14H19NO2: 233; found: 234 (M+H)⁺.</td>

<td> Cap-43</td><td> nC? \ zV&gt; ^oh</td><td> LCMS: Anal. Calcd. for C13H17NO2: 219; found: 220 (M+H)⁺.</td>

<td> Cap-44</td><td> Me ,N-Me °׳^\ z ^H°</td><td> LCMS: Anal. Calcd. for C״H15NO₂: 193; found: 194 (M+H)⁺.</td>

<td> Cap-45</td><td> a&gt; ζ־־־Χ X C2</td><td> LCMS: Anal. Calcd. for C14H20N2O2: 248; found: 249 (M+H)⁺.</td>

Cap-45

<img file="IL196813A_D0058.tif" />

Cap-45

HMDS (1.85 mL, 8.77 mmol) was added to a suspension of (R)-2-amino-2phenylacetic acid p-toluenesulfonate (2.83 g, 8.77 mmol) in CH2C12 (10 mL) and the mixture was stirred at room temperature for 30 minutes. Methyl isocyanate (0.5 g, 10 8.77 mmol) was added in one portion stirring continued for 30 minutes. The reaction was quenched by addition of ¾0 (5 mL) and the resulting precipitate was filtered, washed with H₂O and n-hexanes, and dried under vacuum. (R)-2-(3-methylureido)

2-phenylacetic acid (1.5 g; 82 %).was recovered as a white solid and it was used without further purification. ¹H NMR (500 MHz, DMSO-d6) δ ppm 2.54 (d, 7=4.88 Hz, 3H) 5.17 (d, 7=7.93 Hz, 1H) 5.95 (q, 7=4.48 Hz, 1H) 6.66 (d, 7=7.93 Hz, 1H) 7.26 7.38 ־ (m, 5H) 12.67 (s, 1H). LCMS: Anal. Calcd. for C10H12N₂O₃ 208.08 found 209.121 (M+H)⁺; HPLC Phenomenex C-18 3.0 x 46 mm, 0 to 100% B over 2 minutes, 1 minute hold time, A = 90% water, 10% methanol, 0.1% TFA, B = 10% water, 90% methanol, 0.1% TFA, RT = 1.38 min, 90% homogeneity index.

Cap-46

<img file="IL196813A_D0059.tif" />

<img file="IL196813A_D0060.tif" />

The desired product was prepared according to the method described for Cap45. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 0.96 (t, 7=7.17 Hz, 3H) 2.94 - 3.05 (m, 2H) 5.17 (d, 7=7.93 Hz, 1H) 6.05 (t, 7=5.19 Hz, 1H) 6.60 (d, 7=7.63 Hz, 1H) 7.26 7.38 (m,5H) 12.68 (s, 1H). LCMS: Anal. Calcd. for CnH14N₂O₃ 222.10 found 209.121 (M+H)⁺.

HPLC XTERRA C-18 3.0 x 506 mm, 0 to 100% B over 2 minutes, 1 minutes hold time, A = 90% water, 10% methanol, 0.2% H3PO4, B = 10% water, 90% methanol, 0.2% H3PO4, RT = 0.87 min, 90% homogeneity index.

<img file="IL196813A_D0061.tif" />

<img file="IL196813A_D0062.tif" />

<img file="IL196813A_D0063.tif" />

Cap-47

Step 1; (R)-tert-butyl 2-(3,3-dimethylureido)-2-phenylacetate: To a stirred solution of (R)-tert-butyl-2-amino-2-phenylacetate (1.0 g, 4.10 mmol) and Hunig’s base (1.79 mL, 10.25 mmol) in DMF (40 mL) was added dimethylcarbamoyl chloride (0.38 mL, 4.18 mmol) dropwise over 10 minutes. After stirring at room temperature for 3 hours, the reaction was concentrated under reduced pressure and the resulting residue was dissolved in ethyl acetate. The organic layer was washed with HjO, IN aq. HC1 and brine, dried (MgSO₄), filtered and concentrated under reduced pressure. (R)-tert-butyl 2-(3,3-dimethylureido)2־-phenylacetate was obtained as a white solid (0.86 g; 75%) and used without further purification. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.33 (s, 9H) 2.82 (s, 6H) 5.17 (d, /=7.63 Hz, 1H) 6.55 (d, /=7.32 Hz, 1H) 7.24 - 7.41 (m, 5H). LCMS: Anal. Calcd. for C15H22N2O3 278.16 found 279.23 (M+H)⁺; HPLC Phenomenex LUNA C-18 4.6 x 50 mm, 0 to 100% B over 4 minutes, 1 minutes hold time, A = 90% water, 10% methanol, 0.1% TFA, B = 10% water, 90% methanol, 0.1% TFA, RT = 2.26 min, 97% homogeneity index.

Step 2; (R)-2-(3,3-dimethyh1reido)-2-phenylacetic acid: To a stirred solution of ((R)-tert-butyl 2-(3,3-dimethylureido)-2-phenylacetate (0.86 g, 3.10 mmol) in CH2C12 (250 mL) was added TFA (15 mL) dropwise and the resulting solution was stirred at rt for 3 h. The desired compound was then precipitated out of solution with a mixture of EtOAC:Hexanes (5:20), filtered off and dried under reduced pressure. (R)-2-(3,3-dimethylureido)-2-phenylacetic acid was isolated as a white solid (0.59g, 86%) and used without further purification. ¹H NMR (500 MHz, DMSO-d6) δ ppm 2.82 (s, 6H) 5.22 (d, /=7.32 Hz, 1H) 6.58 (d, /=7.32 Hz, 1H) 7.28 (t, /=7.17 Hz, 1H) 7.33 (t, /=7.32 Hz, 2H) 7.38 - 7.43 (m, 2H) 12.65 (s, 1H). LCMS: Anal. Calcd. for C11H14N2O3: 222.24; found: 223.21 (M+H)⁺. HPLC XTERRA C-18 3.0 x 50 mm, 0 to 100% B over 2 minutes, 1 minutes hold time, A = 90% water, 10% methanol, 0.2% H₃PO₄, B = 10% water, 90% methanol, 0.2% H₃PO₄, RT = 0.75 min, 93% homogeneity index.

<img file="IL196813A_D0064.tif" />

Step 1; (R)-tert-butyl 2-(3-cyclopentylureido)-2-phenylacetate: To a stined solution of (R)-2-amino-2־phenylacetic acid hydrochloride (1.0 g, 4.10 mmol) and Hunig’s base (1.0 mL, 6.15 mmol) in DMF (15 mL) was added cyclopentyl isocyanate (0.46 mL, 4.10 mmol) dropwise and over 10 minutes. After stirring at room temperature for 3 hours, the reaction was concentrated under reduced pressure and the resulting residue was traken up in ethyl acetate. The organic layer was washed with H₂O and brine, dried (MgSO4), filtered, and concentrated under reduced pressure. (R)-tert-butyl 2-(3-cyclopentylureido)-2-pheny !acetate was obtained as an opaque oil (1.32 g; 100 %) and used without further purification. ¹H NMR (500 MHz, CD3C1-D) δ ppm 1.50 - 1.57 (m, 2H) 1.58 - 1.66 (m, 2H) 1.87 - 1.97 (m, 2H) 3.89 - 3.98 (m, 1H) 5.37 (s, 1H) 7.26 - 7.38 (m, 5H). LCMS: Anal. Calcd. for C18H26N₂O3 318.19 found 319.21 (M+H)⁺; HPLC XTERRA C-18 3.0 x 50 mm, 0 to 100% B over 4 minutes, 1 minutes hold time, A = 90% water, 10% methanol, 0.1% TFA, B = 10% water, 90% methanol, 0.1% TFA, RT = 2.82 min, 96% homogeneity index.

Step 2; (R)-2-(3-cyclopentylureido)-2-phenylacetic acid: To a stirred solution of (R)-tert-butyl 2-(3-cycropentylureido)-2-phenylacetate (1.31 g, 4.10 mmol) in CH2C12 (25 mL) was added TFA (4 mL) and trietheylsilane (1.64 mL; 10.3 mmol) dropwise, and the resulting solution was stined at room temperature for 6 hours. The volatile components were removed under reduced pressure and the crude product was recrystallized in ethyl acetate/pentanes to yield (R)-2-(3-cyclopentylureido)2־phenylacetic acid as a white solid (0.69 g, 64%). ¹H NMR (500 MHz, DMSO-dg) δ ppm 1.17 - 1.35 (m, 2H) 1.42 - 1.52 (m, 2H) 1.53 - 1.64 (m, 2H) 1.67 - 1.80 (m, 2H) 3.75 - 3.89 (m, 1H) 5.17 (d, 7=7.93 Hz, 1H) 6.12 (d, 7=7.32 Hz, 1H) 6.48 (d, 7=7.93 Hz, 1H) 7.24 - 7.40 (m, 5H) 12.73 (s, 1H). LCMS: Anal. Calcd. for C14H18N2O3:

262.31; found: 263.15 (M+H)⁺. HPLC XTERRA C-18 3.0 x 50 mm, 0 to 100% B over 2 minutes, 1 minutes hold time, A = 90% water, 10% methanol, 0.2% H3PO4, B = 10% water, 90% methanol, 0.2% H3PO4, RT = 1.24 min, 100% homogeneity index.

Cap-49

<img file="IL196813A_D0065.tif" />

cap-49

To a stirred solution of 2-(benzylamino)acetic acid (2.0 g, 12.1 mmol) in formic acid (91 mL) was added formaldehyde (6.94 mL, 93.2 mmol). After five hours at 70 °C, the reaction mixture was concentrated under reduced pressure to 20 mL and a white solid precipitated. Following filtration, the mother liquors were collected and further concentrated under reduced pressure providing the crude product. Purification by reverse-phase preparative HPLC (Xterra 30 X 100 mm, detection at 220 nm, flow rate 35 mL/min, 0 to 35% B over 8 min; A = 90% water, 10 % methanol, 0.1% TFA, B = 10% water, 90 % methanol, 0.1% TFA) provided the title compound 2-(benzyl(methyl)-amino)acetic acid as its TFA salt (723 mg, 33%) as a colorless wax. ¹H NMR (300 MHz, DMSO-d6) δ ppm 2.75 (s, 3H) 4.04 (s, 2H) 4.34 (s, 2H) 7.29 - 7.68 (m, 5H). LCMS: Anal. Calcd. for: C10H13NO2 179.22; Found: 180.20 (M+H)⁺.

Cap-50

<img file="IL196813A_D0066.tif" />

<img file="IL196813A_D0067.tif" />

Cap-50

To a stirred solution of 3-methyl-2-(methylamino)butanoic acid (0.50 g, 3.81 mmol) in water (30 mL) was added K₂CO₃ (2.63 g, 19.1 mmol) and benzyl chloride (1.32 g, 11.4 mmol). The reaction mixture was stirred at ambient temperature for 18 hours. The reaction mixture was extracted with ethyl acetate (30 mL x 2) and the aqueous layer was concentrated under reduced pressure providing the crude product which was purified by reverse-phase preparative HPLC (Xterra 30 x 100mm, detection at 220 nm, flow rate 40 mL/min, 20 to 80% B over 6 min; A = 90% water, 10 % methanol, 0.1% TFA, B = 10% water, 90 % methanol, 0.1% TFA) to provide 2(benzyl(methyl)amino)-3-methylbutanoic acid, TFA salt (126 mg, 19%) as a colorless wax. ¹H NMR (500 MHz, DMSO-d6) δ ppm 0.98 (d, 3H) 1.07 (d, 3H) 2.33 - 2.48 (m, IH) 2.54 - 2.78 (m, 3H) 3.69 (s, IH) 4.24 (s, 2H) 7.29 - 7.65 (m, 5H). LCMS: Anal. Calcd. for: C!₃H1₉NO₂ 221.30; Found: 222.28 (M+H)⁺.

Cap-51

<img file="IL196813A_D0068.tif" />

Na₂CO₃ (1.83g, 17.2 mmol) was added to NaOH (33 mL of 1M/H₂O, 33 mmol) solution of L-valine (3.9 g, 33.29 mmol) and the resulting solution was cooled with ice-water bath. Methyl chloroformate (2.8 mL, 36.1 mmol) was added dropwise over 15 min, the cooling bath was removed and the reaction mixture was stirred at ambient temperature for 3.25 hr. The reaction mixture was washed with ether (50 mL, 3x), and the aqueous phase was cooled with ice-water bath and acidified with concentrated HC1 to a pH region of 1-2, and extracted with CH₂C1₂ (50 mL, 3x). The organic phase was dried (MgSO₄), filtered, and concentrated in vacuo to afford Cap51 as a white solid (6 g). ¹H NMR for the dominant rotamer (DMSO-d₆, δ= 2.5 ppm, 500 MHz): 12.54 (s, IH), 7.33 (d, J = 8.6, IH), 3.84 (dd, J = 8.4,6.0, IH), 3.54 (s, 3H), 2.03 (m, IH), 0.87 (m, 6H). HRMS: Anal. Calcd. for [M+H]⁺ C7H14NO4: 176.0923; found 176.0922

Cap-52

<img file="IL196813A_D0069.tif" />

Cap-52 was synthesized from L-alanine according to the procedure described for the synthesis of Cap-51. For characterization purposes, a portion of the crude material was purified by a reverse phase HPLC (H₂O/MeOH/TFA) to afford Cap-52 as a colorless viscous oil. ¹H NMR (DMSO-d6, &lt;5= 2.5 ppm, 500 MHz): 12.49 (br s,

1H), 7.43 (d, J = 7.3,0.88H), 7.09 (app br s, 0.12H), 3.97 (m, 1H), 3.53 (s, 3H), 1.25 (d, J = 7.3, 3H).

Cap-53 to -64 were prepared from appropriate starting materials according to the procedure described for the synthesis of Cap-51, with noted modifications if any.

<td> Cap</td><td> Structure</td><td> Data</td>

<td> Cap-53a: (R) Cap-53b: (S)</td><td>^H U ^χ°Υ^Νχ| ^{OH 0} \</td><td>¹H NMR (DMSO-de, δ = 2.5 ppm, 500 MHz): δ 12.51 (br s, 1H), 7.4 (d, J = 7.9, 0.9H), 7.06 (app s, 0.1H), 3.86-3.82 (m, 1H), 3.53 (s, 3H), 1.75-1.67 (m, 1H), 1.62-1.54 (m, 1H), 0.88 (d, J = 7.3,3H). RT = 0.77 minutes (Cond. 2); LC/MS:Anal. Calcd. for[M+Na]⁺C6H״NNaO4: 184.06; found 184.07. HRMS Calcd. for[M+Na]⁺C6H״NNaO4: 184.0586; found 184.0592.</td>

<td> Cap-54a׳. (R) Cap-54b׳. (S)</td><td> H U ^/Οχιί^Ν J״^OH</td><td>¹H NMR (DMSO-de, δ = 2.5 ppm, 500 MHz): δ 12.48 (s, 1H), 7.58 (d, J = 7.6, 0.9H), 7.25 (app s, 0.1H), 3.52 (s, 3H), 3.36-3.33 (m, 1H), 1.10-1.01 (m, 1H), 0.54-0.49 (m, 1H), 0.460.40 (m, 1H), 0.39-0.35 (m, 1H), 0.31-0.21 (m, 1H). HRMS Calcd. for [M+H]⁺C₇H₁₂NO₄: 174.0766; found 174.0771</td>

<td> Cap-55</td><td> H U ^/Ογ^ΝΥ^ΟΗ °</td><td>¹H NMR (DMSO-d6, δ = 2.5 ppm, 500 MHz): δ 12.62 (s, 1H), 7.42 (d, J = 8.2, 0.9H), 7.07 (app s, 0.1H), 5.80-5.72 (m, 1H), 5.10 (d, J = 17.1,1H), 5.04 (d, J = 10.4,1H), 4.01-3.96 (m, 1H), 3.53 (s, 3H), 2.47-2.42 (m, 1H), 2.352.29 (m, 1H).</td>

<td> Cap-56</td><td> Η ״ χ°γ^Ν&gt;׳Α0Η ⁰ '°</td><td>¹H NMR (DMSO-de, δ = 2.5 ppm, 500 MHz): δ 12.75 (s, 1H), 7.38 (d, J= 8.3, 0.9H), 6.96 (app s, 0.1H), 4.20-4.16 (m, 1H), 3.60-3.55 (m, 2H), 3.54 (s, 3H), 3.24 (s, 3H).</td>

<td> Cap-57</td><td> H U /⁰γΝ^ΛοΗ 0</td><td>¹H NMR (DMSO-de, δ = 2.5 ppm, 500 MHz): δ 12.50 (s, IH), 8.02 (d, J = 7.7, 0.08H), 7.40 (d, J = 7.9, 0.76H), 7.19 (d, J = 8.2,0.07H), 7.07 (d, J = 6.7, 0.09H), 4.21-4.12 (m, 0.08H), 4.06-3.97 (m, 0.07H), 3.96-3.80 (m, 0.85H), 3.53 (s, 3H), 1.69-1.51 (m, 2H), 1.39-1.26 (m, 2H), 0.85 (t, J = 7.4, 3H). LC (Cond. 2): RT = 1.39 LC/MS: Anal. Calcd. for [M+H]⁺C₇H₁₄NO₄: 176.09; found 176.06.</td>

<td> Cap-58</td><td> Η 5 ^χ0Υ^Ν׳,’ι ^0H0 0</td><td>¹H NMR (DMSO-de, δ = 2.5 ppm, 500 MHz): δ 12.63 (bs, IH), 7.35 (s,lH), 7.31 (d, J= 8.2, IH), 6.92 (s, IH), 4.33-4.29 (m, IH), 3.54 (s, 3H), 2.54(dd, J = 15.5,5.4, IH), 2.43 (dd, J = 15.6, 8.0, IH). RT = 0.16 min (Cond. 2); LC/MS: Anal. Calcd. for [M+H]⁺ C6H1!N₂O5: 191.07; found 191.14.</td>

<td> Cap-59a: (R) Cap-59b: (S)</td><td> Η ί ^⁰YⁿY%h 0 1</td><td>¹H NMR (DMSO-de, δ = 2.5 ppm, 400 MHz): δ 12.49 (br s, IH), 7.40 (d, J = 7.3, 0.89H), 7.04(brs, 0.1 IH), 4.00-3.95 (m, 3H), 1.24 (d,J = 7.3,3H), 1.15 (t, J = 7.2, 3H). HRMS: Anal. Calcd. for [M+H]⁺ C6H₁₂NO₄: 162.0766; found 162.0771.</td>

<td> Cap-60</td><td> H U -⁰γ^οκ 0</td><td> The crude material was purified with a reverse phase HPLC (H₂O/MeOH/TFA) to afford a colorless viscous oil that crystallized to a white solid upon exposure to high vacuum. ¹H NMR (DMSO-de, δ = 2.5 ppm, 400 MHz): δ 12.38 (br s, IH), 7.74 (s, 0.82H), 7.48 (s, 0.18H), 3.54/3.51 (two s, 3H), 1.30 (m, 2H), 0.98 (m, 2H). HRMS: Anal. Calcd. for[M+H]⁺C₆H₁₀NO₄: 160.0610; found 160.0604.</td>

<td> Cap-61</td><td> H U ^/Oyⁿ?\ ^oh0</td><td>^,H NMR (DMSO-de, δ = 2.5 ppm, 400 MHz): δ 12.27 (br s, IH), 7.40 (br s, IH), 3.50 (s, 3H), 1.32 (s,6H). HRMS: Anal. Calcd. for [M+H]⁺ C6H!₂NO₄: 162.0766; found 162.0765.</td>

<td> Cap-62</td><td> I u ^χ°γ^ΝχΤ OH O</td><td>^,H NMR (DMSO-de, δ = 2.5 ppm, 400 MHz): δ 12.74 (brs, 1H), 4.21 (6,J = 10.3,0.6H), 4.05 (d, J = 10.0,0.4H), 3.62/3.60 (two singlets, 3H), 3.0 (s, 3H), 2.14-2.05 (m, 1H), 0.95 (d, J = 6.3, 3H), 0.81 (d, J = 6.6, 3H). LC/MS: Anal. Calcd. for [M-H]' C8H14NO4: 188.09; found 188.05.</td>

<td> Cap-63</td><td> H § ^⁰γ^Νχ^ΌΗ ⁰ Cj</td><td> [Note: the reaction was allowed to run for longer than what was noted for the general procedure.] ¹HNMR (DMSO-de, δ = 2.5 ppm, 400 MHz): 12.21 (br s, 1H), 7.42 (br s, 1H), 3.50 (s, 3H), 2.02-1.85 (m, 4H), 1.66-1.58 (m, 4H). LC/MS: Anal. Calcd. for [M+H]⁺C₈H14NO4: 188.09; found 188.19.</td>

<td> Cap-64</td><td> H |j ^/0Y^N?\ ^0Ho \z</td><td> [Note: the reaction was allowed to run for longer than what was noted for the general procedure.] ^,H NMR (DMSO-d6, δ = 2.5 ppm, 400 MHz): 12.35 (br s, 1H), 7.77 (s, 0.82H), 7.56/7.52 (overlappingbr s, 0.18H), 3.50 (s, 3H), 2.47-2.40 (m, 2H), 2.14-2.07 (m, 2H), 1.93-1.82 (m,2H).</td>

Cap-65

<img file="IL196813A_D0070.tif" />

Methyl chloroformate (0.65 mL, 8.39 mmol) was added dropwise over 5 min 5 to a cooled (ice-water) mixture of Na₂CO3 (0.449 g, 4.23 mmol), NaOH (8.2 mL of 1M/H2O, 8.2 mmol) and (S)-3-hydroxy-2-(methoxycarbonylamino)-3methylbutanoic acid (1.04 g, 7.81 mmol). The reaction mixture was stirred for 45 min, and then the cooling bath was removed and stirring was continued for an additional 3.75 hr. The reaction mixture was washed with CH2C12, and the aqueous 10 phase was cooled with ice-water bath and acidified with concentrated HCI to a pH region of 1-2. The volatile component was removed in vacuo and the residue was taken up in a 2:1 mixture of MeOH/CH₂Cl₂ (15 mL) and filtered, and the filterate was rotervaped to afford Cap-65 as a white semi-viscous foam (1.236 g). ¹H NMR (DMSO-d6, δ = 2.5 ppm, 400 MHz): δ 6.94 (d, J = 8.5,0.9 H), 6.53 (br s, 0.1H), 3.89 (d, J = 8.8,1H), 2.94 (s, 3H), 1.15 (s, 3H), 1.13 (s, 3H).

Cap-66 and -67 were prepared from appropriate commercially available starting materials by employing the procedure described for the synthesis of Cap-65.

Cap-66

<img file="IL196813A_D0071.tif" />

¹H NMR (DMSO-d6, δ = 2.5 ppm, 400 MHz): δ 12.58 (br s, 1H), 7.07 (d, J = 8.3, 0.13H), 6.81 (d, J = 8.8,0.67H), 4.10-4.02 (m, 1.15H), 3.91 (dd, J = 9.1, 3.5, 0.85H), 3.56 (s, 3H), 1.09 (d, J = 6.2,3H). [Note: only the dominant signals ofNH were noted].

Cap-67

<img file="IL196813A_D0072.tif" />

¹H NMR (DMSO-d6, δ = 2.5 ppm, 400 MHz): 12.51 (br s, 1H), 7.25 (d, J = 8.4, 0.75H), 7.12 (br d, J = 0.4, 0.05H), 6.86 (br s, 0.08H), 3.95-3.85 (m, 2H), 3.54 (s, 3H), 1.08 (d, J = 6.3, 3H). [Note: only the dominant signals of NH were noted]

Cap-68

<img file="IL196813A_D0073.tif" />

Methyl chloroformate (0.38 ml, 4.9 mmol) was added drop-wise to a mixture of IN NaOH (aq) (9.0 ml, 9.0 mmol), IM NaHCO₃ (aq) (9.0 ml, 9.0 mol), L-aspartic acid β-benzyl ester (1.0 g, 4.5 mmol) and Dioxane (9 ml). The reaction mixture was stirred at ambient conditions for 3 hr, and then washed with Ethyl acetate (50 ml, 3x). The aqueous layer was acidified with 12N HCI to a pH ~ 12־, and extracted with ethyl acetate (3 x 50 ml). The combined organic layers were washed with brine, dried (Na₂SO₄), filtered, and concentrated in vacuo to afford Cap-68 as a light yellow oil (1.37g; mass is above theoretical yield, and the product was used without further purification). ¹H NMR (DMSO־d6, δ = 2.5 ppm, 500 MHz): δ 12.88 (br s, 1H), 7.55 (d,/ = 8.5, 1H), 7.40-7.32 (m, 5H), 5.13 (d,/ = 12.8, 1H), 5.10 (d, J = 12.9, 1H), 4.42-4.38 (m, 1H), 3.55 (s, 3H), 2.87 (dd, J= 16.2, 5.5, 1H), 2.71 (dd, /=16.2, 8.3, 1H). LC(Cond. 2): RT = 1.90 min; LC/MS: Anal. Calcd. For [M+H]⁺C13H16NO6־. 282.10; found 282.12.

Cap-69a and -69b l 2 Cap-69a: (R)-enantiomar

N Cap-69b: (S)-enantiomar

NaCNBH₃ (2.416 g, 36.5 mmol) was added in batches to a chilled (~15 °C) water (17 mL)/MeOH (10 mL) solution of alanine (1.338 g, 15.0 mmol). A few minutes later acetaldehyde (4.0 mL, 71.3 mmol) was added drop-wise over 4 min, the cooling bath was removed, and the reaction mixture was stirred at ambient condition for 6 hr. An additional acetaldehyde (4.0 mL) was added and the reaction was stirred for 2 hr. Concentrated HCI was added slowly to the reaction mixture until the pH reached ~ 1.5, and the resulting mixture was heated for 1 hr at 40 °C. Most ofthe volatile component was removed in vacuo and the residue was purified with a Dowex ® 50WX8-100 ion-exchange resin (column was washed with water, and the compound was eluted with dilute NH4OH, prepared by mixing 18 ml of NH4OH and 282 ml of water) to afford Cap-69 (2.0 g) as an off-white soft hygroscopic solid. ¹H NMR (DMSO־d₆, δ = 2.5 ppm, 400 MHz): δ 3.44 (q, J = 7.1, 1H), 2.992.90־ (m, 2H), 2.892.80־ (m, 2H), 1.23 (d, /= 7.1, 3H), 1.13 (t, /= 7.3, 6H).

Cap-70 to 74־ were prepared according to the procedure described for the synthesis of Cap-69 by employing appropriate starting materials.

<td> Cap-7 Oa\ (R) Cap-70b: (S)</td><td> ° ^Νγ^₀Η</td><td>¹H NMR (DMS0-d6, δ = 2.5 ppm, 400 MHz): δ 3.42 (q, J = 7.1, 1H), 2.68-2.60 (m, 4H), 1.53-1.44 (τη, 4H), 1.19 (d, J = 7.3,3H), 0.85 (t, J = 7.5, 6H). LC/MS: Anal. Calcd. for [M+H]⁺C9H20NO2: 174.15; found 174.13.</td>

<td> Cap-71 a. (R) Cap-7lb\ (S)</td><td> Wo״</td><td>¹H NMR (DMSO-d* δ = 2.5 ppm, 500 MHz): δ 3.18-3.14 (m, 1H), 2.84-2.77 (m, 2H), 2.762.68 (m, 2H), 1.69-1.54 (m, 2H), 1.05 (t, J = 7.2,6H), 0.91 (t, J = 7.3, 3H). LC/MS: Anal. Calcd. for [M+H]⁺C₈H₁₈NO2: 160.13; found 160.06.</td>

<td> Cap-72</td><td>⁰ ה'</td><td> ’H NMR (DMSO-dfe δ = 2.5 ppm, 400 MHz): δ 2.77-2.66 (m, 3H), 2.39-2.31 (m, 2H), 1.941.85 (m, 1H), 0.98 (t, J = 7.1,6H), 0.91 (d, J = 6.5, 3H), 0.85 (d, J = 6.5,3H). LC/MS: Anal. Calcd. for [M+H]⁺ C₉H2₀NO₂: 174.15; found 174.15.</td>

<td> Cap-73</td><td>⁰^k0</td><td>^,H NMR (DMSO-de, δ = 2.5 ppm, 500 MHz): δ 9.5 (br s, 1H), 3.77 (dd, J = 10.8,4.1,1H), 3.69-3.61 (m, 2H), 3.26 (s, 3H), 2.99-2.88 (m, 4H), 1.13 (t, J = 7.2, 6H).</td>

<td> Cap-74</td><td> 0 Vⁿ^A_Oh nh₂</td><td>¹H NMR (DMSO-d6, δ = 2.5 ppm, 500 MHz): δ 7.54 (s, 1H), 6.89 (s, 1H), 3.81 (t, J = 6.6, k,lH), 2.82-2.71 (m,4H),2.63 (dd,J= 15.6, 7.0, 1H), 2.36 (dd, J = 15.4,6.3,1H), 1.09 (t, J = 7.2,6H). RT = 0.125 minutes (Cond. 2); LC/MS: Anal. Calcd. for [M+H]⁺ C8H17N2O3: 189.12; found 189.13.</td>

<td> Cap-7 4x</td><td> —i ⁰ ^OH</td><td> LC/MS: Anal. Calcd. for [M+H]⁺ C10H22NO2: 188.17; found 188.21</td>

Cap-75

<img file="IL196813A_D0074.tif" />

Cap-75, step a

<img file="IL196813A_D0075.tif" />

NaBH₃CN (1.6 g, 25.5 mmol) was added to a cooled (ice/water bath) water (25 ml)/methanol (15 ml) solution of H-D-Ser-OBzl HC1 (2.0 g, 8.6 mmol). Acetaldehyde (1.5 ml, 12.5 mmol) was added drop-wise over 5 min, the cooling bath was removed, and the reaction mixture was stirred at ambient condition for 2 hr. The reaction was carefully quenched with 12N HC1 and concentrated in vacuo. The residue was dissolved in water and purified with a reverse phase HPLC (MeOH/H₂O/TFA) to afford the TFA salt of (R)-benzyl 2-(diethylamino)-3hydroxypropanoate as a colorless viscous oil (1 .9g). ¹H NMR (DMSO-d6, δ = 2.5 ppm, 500 MHz): δ 9.73 (br s, 1H), 7.52-7.36 (m, 5H), 5.32 (d, 7 = 12.2, 1H), 5.27 (d, 7= 12.5, 1H), 4.54-4.32 (m, 1H), 4.05-3.97 (m, 2H), 3.43-3.21 (m, 4H), 1.23 (t, 7 = 7.2, 6H). LC/MS (Cond. 2): RT = 1.38 min; LC/MS: Anal. Calcd. for [M+H]⁺C14H22NO3: 252.16; found 252.19.

Cap-75

NaH (0.0727 g, 1.82 mmol, 60%) was added to a cooled (ice-water) THF (3.0 mL) solution ofthe TFA salt (R)-benzyl 2-(diethylamino)-3-hydroxypropanoate (0.3019 g, 0.8264 mmol) prepared above, and the mixture was stirred for 15 min. Methyl iodide (56 pL, 0.90 mmol) was added and stirring was continued for 18 hr while allowing the bath to thaw to ambient condition. The reaction was quenched with water and loaded onto a MeOH pre-conditioned MCX (6 g) cartridge, and washed with methanol followed by compound elution with 2N NH₃/Methanol. Removal of the volatile component in vacuo afforded Cap-15, contaminated with (R)-2-(diethylamino)-3-hydroxypropanoic acid, as a yellow semi-solid (100 mg).

The product was used as is without further purification.

Cap-76

<img file="IL196813A_D0076.tif" />

NaCNBH₃ (1.60 g, 24.2 mmol) was added in batches to a chilled (~15 °C) water/MeOH (12 mL each) solution of (S)-4-amino-2־(tert-butoxyca1bonylamino) butanoic acid (2.17 g, 9.94 mmol). A few minutes later acetaldehyde (2.7 mL, 48.1 mmol) was added drop-wise over 2 min, the cooling bath was removed, and the reaction mixture was stirred at ambient condition for 3.5 hr. An additional acetaldehyde (2.7 mL, 48.1 mmol) was added and the reaction was stirred for 20.5 hr. Most of the MeOH component was removed in vacuo, and the remaining mixture was treated with concentrated HCI until its pH reached ~ 1.0 and then heated for 2 hr at 40 °C. The volatile component was removed in vacuo, and the residue was treated with 4 M HCl/dioxane (20 mL) and stirred at ambient condition for 7.5 hr. The volatile component was removed in vacuo and the residue was purified with Dowex ® 50WX8-100 ion-exchange resin (column was washed with water and the compound was eluted with dilute NH4OH, prepared from 18 ml of NH4OH and 282 ml of water) to afford intermediate (S)-2-amino-4-(diethylamino)butanoic acid as an off-white solid (1.73 g).

Methyl chloroformate (0.36 mL, 4.65 mmol) was added drop-wise over 11 min to a cooled (ice-water) mixture of Na₂CO3 (0.243 g, 2.29 mmol), NaOH (4.6 mL of 1M/H2O, 4.6 mmol) and the above product (802.4 mg). The reaction mixture was stirred for 55 min, and then the cooling bath was removed and stirring was continued for an additional 5.25 hr. The reaction mixture was diluted with equal volume of water and washed with CH₂C1₂ (30 mL, 2x), and the aqueous phase was cooled with ice-water bath and acidified with concentrated HCI to a pH region of 2. The volatile component was then removed in vacuo and the crude material was free-based with MCX resin (6.0g; column was washed with water, and sample was eluted with 2.0 M

NH₃/MeOH) to afford impure Cap-76 as an off-white solid (704 mg). ¹H NMR (MeOH-d4, δ = 3.29 ppm, 400 MHz): δ 3.99 (dd, J = 7.5, 4.7, IH), 3.62 (s, 3H),

3.25-3.06 (m, 6H), 2.18-2.09 (m, IH), 2.04-1.96 (m, IH), 1.28 (t, J = 7.3, 6H).

LC/MS: Anal. Calcd. for [M+H]⁺ C10H21N2O4: 233.15; found 233.24.

Cap-77 a and-77b

<img file="IL196813A_D0077.tif" />

Cap-77a: enantiomer-1

Cap-77b: enantiomer-2

The synthesis of Cap-77 was conducted according to the procedure described for Cap-7 by using 7-azabicyclo[2.2. !]heptane for the SN₂ displacement step, and by effecting the enantiomeric separation of the intermediate benzyl 2-(7azabicyclo[2.2. l]heptan-7-yl)-2-phenylacetate using the following condition: the intermediate (303.7 mg) was dissolved in ethanol, and the resulting solution was injected on a chiral HPLC column (Chiracel AD-H column, 30 x 250 mm, 5 um) eluting with 90% CO₂% EtOH at 70 mL/min, and a temperature of 35 °C to provide 124.5 mg of enantiomer-1 and 133.8 mg of enantiomer-2. These benzyl esters were hydrogenolysed according to the preparation of Cap-7 to provide Cap-77: ¹H NMR (DMSO-de, δ = 2.5 ppm, 400 MHz): δ 7.55 (m, 2H), 7.38-7.30 (m, 3H), 4.16 (s, IH), 3.54 (app br s, 2H), 2.08-1.88 (m, 4 H), 1.57-1.46 (m, 4H). LC (Cond. 1): RT = 0.67 min; LC/MS: Anal. Calcd. for [M+H]⁺ C14H!₈BrNO2: 232.13; found 232.18. HRMS: Anal. Calcd. for [M+H]⁺ C!4H18BrNO2: 232.1338; found

232.1340.

Cap-78

O

Άόη

NaCNBH₃ (0.5828 g, 9.27 mmol) was added to a mixture of the HC1 salt of (7?)-2-(ethylamino)-2-phenylacetic acid (an intermediate in the synthesis of Cap-3; 0.9923 mg, 4.60 mmol) and (l-ethoxycyclopropoxy)trimethylsilane (1.640 g, 9.40 mmol) in MeOH (10 mL), and foe semi-heterogeneous mixture was heated at 50 °C with an oil bath for 20 hr. More (l-ethoxycyclopropoxy)trimefoylsilane (150 mg, 0.86 mmol) and NaCNBH₃ (52 mg, 0.827 mmol) were added and the reaction mixture was heated for an additional 3.5 hr. It was then allowed to cool to ambient temperature and acidified to a ~ pH region of 2 with concentrated HC1, and the mixture was filtered and foe filtrate was rotervaped. The resulting crude material was taken up in z-PrOH (6 mL) and heated to effect dissolution, and foe non-dissolved part was filtered off and the filtrate concentrated in vacuo. About 1/3 of the resultant crude material was purified with a reverse phase HPLC (H2O/MeOH/TFA) to afford foe TFA salt of Cap-78 as a colorless viscous oil (353 mg). ¹HNMR (DMSO-d6, δ = 2.5 ppm, 400 MHz; after D2O exchange): δ 7.56-7.49 (m, 5H), 5.35 (S, IH), 3.35 (m, IH), 3.06 (app br s, IH), 2.66 (m, IH), 1.26 (t, J = 7.3, 3H), 0.92 (m, IH), 0.83-0.44 (m, 3H). LC(Cond. 1): RT = 0.64 min; LC/MS: Anal. Calcd. for[M+H]⁺C13H!8NO2: 220.13; found 220.21. HRMS: Anal. Calcd. for [M+H]⁺ C!₃H18NO₂: 220.1338; found 220.1343.

Cap-79

Ozone was bubbled through a cooled (-78 °C) CH₂C1₂ (5.0 mL) solution Cap55 (369 mg, 2.13 mmol) for about 50 min until foe reaction mixture attained a tint of blue color. Me₂S (10 pipet drops) was added, and the reaction mixture was stirred for 35 min. The -78 °C bath was replaced with a -10 °C bath and stirring continued for an additional 30 min, and then the volatile component was removed in vacuo to afford a colorless viscous oil.

NaBH₃CN (149 mg, 2.25 mmol) was added to a MeOH (5.0 mL) solution of foe above crude material and morpholine (500 pL, 5.72 mmol) and the mixture was stirred at ambient condition for 4 hr. It was cooled to ice-water temperature and treated with concentrated HC1 to bring its pH to ~2.0, and then stirred for 2.5 hr. The volatile component was removed in vacuo, and the residue was purified with a combination of MCX resin (MeOH wash; 2.0 N NH₃/MeOH elution) and a reverse phase HPLC (H₂O/MeOH/TFA) to afford Cap-79 containing unknown amount of morpholine.

In order to consume the morpholine contaminant, the above material was dissolved in CH₂C1₂ (1.5 mL) and treated with Et₃N (0.27 mL, 1.94 mmol) followed by acetic anhydride (0.10 mL, 1.06 mmol) and stirred at ambient condition for 18 hr. THF (1.0 mL) and H₂O (0.5 mL) were added and stirring continued for 1.5 hr. The volatile component was removed in vacuo, and the resultant residue was passed through MCX resin (MeOH wash; 2.0 N NH₃/MeOH elution) to afford impure Cap79 as a brown viscous oil, which was used for the next step without further purification.

Cap-80a and -80b

H ?

ζθ γ N '׳. z'xOH

Π I Cap-80a: S/S-diasteraomer ⁰ Cap-80b: S/R-diastereomer ⁰'#

SOC1₂ (6.60 mL, 90.5 mmol) was added drop-wise over 15 min to a cooled (ice-water) mixture of (S)-3-amino-4-(benzyloxy)-4-oxobutanoic acid (10.04g, 44.98 mmol) and MeOH (300 mL), the cooling bath was removed and the reaction mixture was stirred at ambient condition for 29 hr. Most of the volatile component was removed in vacuo and the residue was carefully partitioned between EtOAc (150 mL) and saturated NaHCO₃ solution. The aqueous phase was extracted with EtOAc (150 mL, 2x), and the combined organic phase was dried (MgSO4), filtered, and concentrated in vacuo to afford (S)-l-benzyl 4-methyl 2-aminosuccinate as a colorless oil (9.706g). ¹H NMR (DMSO-d6, δ = 2.5 ppm, 400 MHz): δ 7.40-7.32 (m, 5H), 5.11 (s, 2H), 3.72 (appt, J = 6.6, 1H),3.55 (s, 3H), 2.68 (dd, J = 15.9, 6.3,1H), 2.58 (dd, J = 15.9, 6.8,1H), 1.96 (s, 2H). LC (Cond. 1): RT = 0.90 min; LC/MS: Anal. Calcd. for [M+H]⁺ C!2H!6NO4: 238.11; found 238.22.

Pb(NO₃)₂ (6.06 g, 18.3 mmol) was added over 1 min to a CH₂C1₂ (80 mL) solution of (S)-l-benzyl 4-methyl 2-aminosuccinate (4.50 g, 19.0 mmol), 9-bromo-9 phenyl-9tf-fluorene (6.44 g, 20.0 mmol) and Et₃N (3.0 mL, 21.5 mmol), and the heterogeneous mixture was stirred at ambient condition for 48 hr. The mixture was filtered and the filtrate was treated with MgSO₄ and filtered again, and the final filtrate was concentrated. The resulting crude material was submitted to a Biotage purification (350 g silica gel, CH₂C1₂ elution) to afford (S)-l -benzyl 4-methyl 2-(9phenyl-9H-fluoren-9-ylamino)succinate as highly viscous colorless oil (7.93 g). ¹H NMR (DMSO-d6, δ = 2.5 ppm, 400 MHz): δ 7.82 (m, 2H), 7.39-7.13 (m, 16H), 4.71 (d,7 = 12.4, 1H), 4.51 (d,7= 12.6, 1H), 3.78 (d, J = 9.1,NH), 3.50 (s, 3H), 2.99 (m, 1H), 2.50-2.41 (m, 2H, partially overlapped with solvent). LC (Cond. 1): RT = 2.16 min; LC/MS: Anal. Calcd. for [M+H]⁺ C₃1H₂8NO₄: 478.20; found 478.19.

LiHMDS (9.2 mL of 1.0 M/THF, 9.2 mmol) was added drop-wise over 10 min to a cooled (-78 °C) THF (50 mL) solution of (S)-l-benzyl 4-methyl 2-(9phenyl-9H-fluoren-9-ylamino)succinate (3.907 g, 8.18 mmol) and stirred for -1 hr. Mel (0.57 mL, 9.2 mmol) was added drop-wise over 8 min to the mixture, and stirring was continued for 16.5 hr while allowing the cooling bath to thaw to room temperature. After quenching with saturated NH4C1 solution (5 mL), most of the organic component was removed in vacuo and the residue was partitioned between CH₂C1₂ (100 mL) and water (40 mL). The organic layer was dried (MgSO₄), filtered, and concentrated in vacuo, and the resulting crude material was purified with a Biotage (350 g silica gel; 25% EtOAc/hexanes) to afford 3.65 g of a 2S/3S and 2S/3R diastereomeric mixtures of 1-benzyl 4-methyl 3-methyl-2-(9-phenyl-9H-fluoren-9ylamino)succinate in-1.0:0.65 ratio (¹HNMR). The stereochemistry of the dominant isomer was not determined at this juncture, and the mixture was submitted to the next step without separation. Partial ¹H NMR data (DMSO-d6, δ = 2.5 ppm, 400 MHz): major diastereomer, δ 4.39 (d, J = 12.3, 1H of CH2), 3.33 (s, 3H, overlapped with H2O signal),3.50 (d,7= 10.9,NH), 1.13 (d, J= 7.1, 3H); minor diastereomer, δ 4.27 (d, 7 = 12.3,1H of CH2), 3.76 (d, 7 = 10.9, NH), 3.64 (s, 3H), 0.77 (d, 7 = 7.0, 3H). LC (Cond. 1): RT = 2.19 min; LC/MS: Anal. Calcd. for [M+H]⁺ C32H₃₀NO₄: 492.22; found 492.15.

Diisobutylaluminum hydride (20.57 ml of 1.0 M in hexanes, 20.57 mmol) was added drop-wise over 10 min to a cooled (-78 °C) THF (120 mL) solution of (2S)-l-benzyl 4-methyl 3-methyl-2-(9-phenyl-9H-fluoren-9-ylamino)succinate (3.37 g, 6.86 mmol) prepared above, and stirred at -78 °C for 20 hr. The reaction mixture was removed from the cooling bath and rapidly poured into ~1M H3PO4/H2O (250 ml.) with stirring, and the mixture was extracted with ether (100 mL, 2x). The combined organic phase was washed with brine, dried (MgSO4), filtered and concentrated in vacuo. A silica gel mesh of the crude material was prepared and submitted to chromatography (25% EtOAc/hexanes; gravity elution) to afford 1.1g of (2S,3S)-benzyl 4-hydroxy-3-methyl-2-(9-phenyl-9H-fluoren-9-ylamino)butanoate, contaminated with benzyl alcohol, as a colorless viscous oil and (2S,3R)-benzyl 4hydroxy-3-methyl-2-(9-phenyl-9/7-fluoren-9-ylamino)butanoate containing the (2S,3R) stereoisomer as an impurity. The later sample was resubmitted to the same column chromatography purification conditions to afford 750 mg of purified material as a white foam. [Note: the (2S, 3S) isomer elutes before the (2S,3R) isomer under the above condition], (2S, 3S) isomer: ¹H NMR (DMSO-d6, δ = 2.5 ppm, 400 MHz): 7.81 (m, 2H), 7.39-7.08 (m, 16H), 4.67 (d, J = 12.3, 1H), 4.43 (d, J = 12.4, 1H), 4.21 (app t, J = 5.2, OH), 3.22 (d, J = 10.1, NH), 3.17 (m, 1H), 3.08 (m, 1H), -2.5 (m, 1H, overlapped with the solvent signal), 1.58 (m, 1H), 0.88 (d, J = 6.8, 3H). LC (Cond. 1):RT = 2.00 min; LC/MS: Anal. Calcd. for [M+H]⁺ C31H30NO3: 464.45; found 464.22. (2S, 3R) isomer: ¹H NMR (DMSO-d6, δ = 2.5 ppm, 400 MHz): 7.81 (d, J = 7.5, 2H), 7.39-7.10 (m, 16H), 4.63 (d, J= 12.1,1H), 4.50 (app t, J = 4.9, 1H), 4.32 (d, J= 12.1,1H), 3.59-3.53 (m, 2H), 3.23 (m, 1H), 2.44 (dd, J= 9.0, 8.3,1H), 1.70 (m, 1H), 0.57 (d, J = 6.8, 3H). LC (Cond. 1): RT = 1.92 min; LC/MS: Anal. Calcd. for [M+H]⁺ C31H30NO3: 464.45; found 464.52.

The relative stereochemical assignments of the DIBAL-reduction products were made based on NOE studies conducted on lactone derivatives prepared from each isomer by employing the following protocol: LiHMDS (50 pL of 1.0 M/THF, 0.05 mmol) was added to a cooled (ice-water) THF (2.0 mL) solution of (2S,3S)benzyl 4-hydroxy-3-methyl-2-(9-phenyl-9H-fluoren-9-ylamino)butanoate (62.7 mg, 0.135 mmol), and the reaction mixture was stirred at similar temperature for -2 hr. The volatile component was removed in vacuo and the residue was partitioned between CH2C12 (30 mL), water (20 mL) and saturated aqueous NH4CI solution (1 ml.) The organic layer was dried (MgSO4), filtered, and concentrated in vacuo, and the resulting crude material was submitted to a Biotage purification (40 g silica gel; 10-15% EtOAc/hexanes) to afford (3S,4S)-4-methyl-3-(9-phenyl-9tt-fluoren-9 ylamino)dihydrofuran-2(3/7)־^{one 35 a} colorless film of solid (28.1 mg). (2S,3R)benzyl 4-hydroxy3־ -methyl-2-(9-phenyl-9H-fluoren-9-ylamino)butanoate was elaborated similarly to (3S,4R)-4-methyl-3-(9-phenyl-9H-fluoren-9ylamino)dihydrofuran3)2־H)־one. (3S,4S)-lactone isomer: ¹H NMR (DMSO-d6, δ = 2.5 ppm, 400 MHz), 7.83 (d, J = 7.5, 2H), 7.46-7.17 (m, 11H), 4.14 (app t, J = 8.3, 1H), 3.60 (d, J = 5.8, NH), 3.45 (app t, J = 9.2, 1H), -2.47 (m, 1H, partially overlapped with solvent signal), 2.16 (m, 1H), 0.27 (d, J = 6.6, 3H), LC (Cond. 1): RT = 1.98 min; LC/MS: Anal. Calcd. for [M+Na]⁺ C24H21NNaO2: 378.15; found 378.42. (3S,4R)-lactone isomer: ¹H NMR (DMSO-d6, δ = 2.5 ppm, 400 MHz), 7.89 (d, J = 7.6, 1H), 7.85 (d, J = 7.3,1H), 7.46-7.20 (m, 11H), 3.95 (dd, J = 9.1, 4.8, 1H), 3.76 (d, J = 8.8, 1H), 2.96 (d, J = 3.0, NH), 2.92 (dd, J = 6.8, 3, NCH), 1.55 (m, 1H), 0.97 (d, J = 7.0, 3H). LC (Cond. 1): RT = 2.03 min; LC/MS: Anal. Calcd. for [M+Na]⁺ C24H21NNaO2: 378.15; found 378.49.

TBDMS-C1 (48 mg, 0.312 mmol) followed by imidazole (28.8 mg, 0.423 mmol) were added to a CH₂C1₂ (3 ml) solution of (2S,3S)-benzyl 4-hydroxy-3methyl-2-(9-phenyl-9H-fluoren-9-ylamino)butanoate (119.5 mg, 0.258 mmol), and the mixture was stirred at ambient condition for 14.25 hr. The reaction mixture was then diluted with CH₂C1₂ (30 mL) and washed with water (15 mL), and the organic layer was dried (MgSO4), filtered, and concentrated in vacuo. The resultant crude material was purified with a Biotage (40 g silica gel; 5% EtOAc/hexanes) to afford (25.35) -benzyl 4-(tert-butyldimethylsilyloxy)-3-methyl-2-(9-phenyl-9H-fluoren-9ylamino)butanoate, contaminated with TBDMS based impurities, as a colorless viscous oil (124.4 mg). (2S,3R)-benzyl 4-hydroxy-3-methyl-2-(9-phenyl-9Hfluoren-9-ylamino)butanoate was elaborated similarly to (2S,3R)-benzyl 4-(tertbutyldimethylsilyloxy)-3-methyl-2-(9-phenyl-9H-fluoren-9-ylamino)butanoate.

(25.35) -silyl ether isomer: ¹H NMR (DMSO-d₆, δ = 2.5 ppm, 400 MHz), 7.82 (d, J = 4.1, 1H), 7.80 (d, J = 4.0, 1H), 7.38-7.07 (m, 16 H), 4.70 (d, J = 12.4, 1H), 4.42 (d, J = 12.3, 1H), 3.28-3.19 (m, 3H), 2.56 (dd, J= 10.1, 5.5, 1H), 1.61 (m, 1H), 0.90 (d, J = 6.8, 3H), 0.70 (s, 9H), -0.13 (s, 3H), -0.16 (s, 3H). LC (Cond. 1, where the run time was extended to 4 min): RT = 3.26 min; LC/MS: Anal. Calcd. for [M+H] C₃₇H44NO3Si: 578.31; found 578.40. (2S,3R)-silyl ether isomer: ‘HNMR(DMS0de, δ = 2.5 ppm, 400 MHz), 7.82 (d, J = 3.0, 1H), 7.80 (d, J = 3.1,1H), 7.39-7.10 (m,

16H), 4.66 (d, J = 12.4, IH), 4.39 (d, J = 12.4, IH), 3.61 (dd, J = 9.9, 5.6, IH), 3.45 (d,J=9.5,IH), 3.41 (dd,J= 10, 6.2, 1H),2.55 (dd, J =9.5, 7.3, IH), 1.74 (m, IH),

0.77 (s, 9H), 0.61 (d, J= 7.1, 3H), 0.06־ (s, 3H), -0.08 (s, 3H).

A balloon of hydrogen was attached to a mixture of (2S,3S)-benzyl 4-(tertbutyldimethyls ilyloxy)-3-methyl-2-(9-phenyl-9/7-fluoren-9-ylamino)butanoate (836 mg, 1.447 mmol) and 10% Pd/C (213 mg) in EtOAc (16 mL) and the mixture was stirred at room temperature for - 21 hr, where the balloon was recharged with H₂ as necessary. The reaction mixture was diluted with CH₂C1₂ and filtered through a pad of diatomaceous earth (Celite-545®), and the pad was washed with EtOAc (200 mL), EtOAc/MeOH (1:1 mixture, 200 mL) and MeOH (750 mL). The combined organic phase was concentrated, and a silica gel mesh was prepared from the resulting crude material and submitted to a flash chromatography (8:2:1 mixture of EtOAc/iPrOH/H₂O) to afford (2S,3S)-2-amino-4-(tert-butyldimethylsilyloxy)-3methylbutanoic acid as a white fluffy solid (325 mg). (2S,3R)-benzyl 4-(tertbutyldimethyls ilyloxy)-3-methyl-2-(9-phenyl-9H-fluoren-9-ylamino)butanoate was similarly elaborated to (2S,3R)-2-amino-4-(tert-butyldimethylsilyloxy)-3methylbutanoic acid. (2S,3S)-amino acid isomer: ¹H NMR (Methanol-d4, δ = 3.29 ppm, 400 MHz), 3.76 (dd, J = 10.5, 5.2, IH), 3.73 (d, J= 3.0, IH), 3.67 (dd, J = 10.5, 7.0, IH), 2.37 (m, IH), 0.97 (d, J = 7.0, 3H), 0.92 (s, 9H), 0.10 (s, 6H). LC/MS:Anal. Calcd. for [M+H]⁺C״H26NO3Si: 248.17; found 248.44. (2S,3R)amino acid isomer: ¹H NMR (Methanol-d4, δ = 3.29 ppm, 400 MHz), 3.76-3.75 (m, 2H), 3.60 (d, J = 4.1, lH),2.16(m, IH), 1.06 (d,J=7.3, 3H), 0.91 (s, 9H), 0.09 (s, 6H). Anal. Calcd. for [M+H]⁺C1!H26NO₃Si: 248.17; found 248.44.

Water (1 mL) and NaOH (0.18 mL of 1.0 M/H₂0, 0.18 mmol) were added to a mixture of (2S,3 S)-2-amino-4-(tert-butyldimethylsilyloxy)-3-methy!butanoic acid (41.9 mg, 0.169 mmol) and Na₂CO₃ (11.9 mg, 0.112 mmol), and sonicated for about 1 min to effect dissolution of reactants. The mixture was then cooled with an icewater bath, methyl chloroformate (0.02 mL, 0.259 mmol) was added over 30 s, and vigorous stirring was continued at similar temperature for 40 min and then at ambient temperature for 2.7 hr. The reaction mixture was diluted with water (5 mL), cooled with ice-water bath and treated drop-wise with 1.0 N HC1 aqueous solution (-0.23 mT,). The mixture was further diluted with water (10 mL) and extracted with CH₂C1₂ (15 mL, 2x). The combined organic phase was dried (MgSO₄), filtered, and concentrated in vacuo to afford Cap-80a as an off-white solid. (2S,3R)-2-amino-4(tert-butyldimethylsilyloxy)-3-methylbutanoic acid was similarly elaborated to Cap80b. Cap-80a: ^lH NMR (DMSO-d6, δ = 2.5 ppm, 400 MHz), 12.57 (br s, 1H), 7.64 (d, J = 8.3, 0.3H), 7.19 (d, J = 8.8, 0.7H), 4.44 (dd, /=8.1,4.6, 0.3H), 4.23 (dd, J = 8.7, 4.4, 0.7H), 3.56/3.53 (two singlets, 3H), 3.48-3.40 (m, 2H), 2.22-2.10 (m, 1H), 0.85 (s, 9H), -0.84 (d, 0.9H, overlapped with t-Bu signal), 0.79 (d, J = 7,2.1H), 0.02/0.01/0.00 (three overlapping singlets, 6H). LC/MS: Anal. Calcd. for[M+Na] C13H27NNaO5Si. 328.16; found 328.46. Cap-80b: ¹H NMR (CDC13, δ = 7.24 ppm, 400 MHz), 6.00 (br d,/= 6.8,1H), 4.36 (dd,/ = 7.1,3.1, 1H), 3.87 (dd,/= 10.5, 3.0, 1H), 3.67 (s, 3H), 3.58 (dd,/= 10.6, 4.8, 1H), 2.35 (m, 1H), 1.03 (d,/= 7.1, 3H), 0.90 (s, 9H), 0.08 (s, 6H). LC/MS: Anal. Calcd. for [M+Na]⁺ C13H27NNaO₅Si: 328.16; found 328.53. The crude products were utilized without further purification.

Cap-81

<img file="IL196813A_D0078.tif" />

Prepared according to the protocol described by Falb et al. Synthetic Communications 1993, 23, 2839.

Cap-82 to Cap-85

Cap-%2 to Cap-85 were synthesized from appropriate starting materials according to the procedure described for Cap-51. The samples exhibited similar spectral profiles as that of their enantiomers (i.e., Cap-4, Cap-13, Cap-51 and Cap25

52, respectively)

<img file="IL196813A_D0079.tif" />

O Ph

<img file="IL196813A_D0080.tif" />

<img file="IL196813A_D0081.tif" />

<img file="IL196813A_D0082.tif" />

Cap-82 Cap-83

Cap-84 Cap-85

Cap-86

MeO₂CHN

OMe °^H

To a mixture of O-methyl-L-threonine (3.0 g, 22.55 mmol), NaOH (0.902 g, 22.55 mmol) in H₂O (15 mL) was added ClCO₂Me (1.74 mL, 22.55 mmol) dropwise at 0°C. The mixture was allowed to stir for 12 h and acidified to pH 1 using IN HCI. The aqueous phase was extracted with EtOAc and (2x250 mL) and 10% MeOH in CH₂C1₂ (250 mL) and the combined organic phases were concentrated under in vacuo to afford a colorless oil (4.18 g, 97%) which was of sufficient purity for use in subsequent steps. ^lHNMR (400 MHz, CDC13) δ 4.19 (s, 1H), 3.92-3.97 (m, 1H), 3.66 (s, 3H), 1.17 (d, J = 7.7 Hz, 3H). LCMS: Anal. Calcd. for C₇H״NO5: 191; found: 190 (M-H)־.

Cap-87

MeO₂CHN

To a mixture of L־homoserine (2.0 g, 9.79 mmol), Na₂CO3 (2.08 g, 19.59 mmol) in H₂O (15 mL) was added ClCO₂Me (0.76 mL, 9.79 mmol) dropwise at 0°C. The mixture was allowed to stir for 48 h and acidified to pH 1 using IN HCI. The aqueous phase was extracted with EtOAc and (2X250 mL) and the combined organic phases were concentrated under in vacuo to afford a colorless solid (0.719 g, 28%) which was of sufficient purity for use in subsequent steps. ¹HNMR (400 MHz, CDC13) δ 4.23 (dd, J = 4.5, 9.1 Hz, 1H), 3.66 (s, 3H), 3.43-3.49 (m, 2H), 2.08 - 2.14 (m, 1H), 1.82 - 1.89 (m, 1H). LCMS: Anal. Calcd. for C7H13NO5: 191; found: 192 (M+H)⁺.

Cap-88

<img file="IL196813A_D0083.tif" />

A mixture of L-valine (1.0 g, 8.54 mmol), 3-bromopyridine (1.8 mL, 18.7 mmol), K₂CO3 (2.45 g, 17.7 mmol) and Cui (169 mg, 0.887 mmol) in DMSO (10 mL) was heated at 100°C for 12h. The reaction mixture was cooled to rt, poured into H₂O (ca. 150 mL) and washed with EtOAc (x2). The organic layers were extracted with a small amount of H₂O and the combined aq phases were acidified to ca. pH 2 with 6N HC1. The volume was reduced to about one-third and 20g of cation exchange resin (Strata) was added. The slurry was allowed to stand for 20 min and loaded onto a pad of cation exchange resin (Strata) (ca. 25g). The pad was washed with H₂O (200 mL), MeOH (200 mL), and then NH₃ (3M in MeOH, 2X200 mL). The appropriate fractions was concentrated in vacuo and the residue (ca. 1.1g) was dissolved in H2O, frozen and lyophyllized. The title compound was obtained as a foam (1.02 g, 62%). ¹HNMR (400 MHz, DMSO-d6) δ 8.00 (s, br, 1H), 7.68 - 7.71 (m, 1H), 7.01 (s, br, 1H), 6.88 (d, J = 7.5 Hz, 1H), 5.75 (s, br, 1H), 3.54 (s, 1H), 2.04 - 2.06 (m, 1H), 0.95 (d, J = 6.0 Hz, 3H), 0.91 (d, J = 6.6 Hz, 3H). LCMS: Anal. Calcd. for C10H14N2O2: 194; found: 195 (M+H)⁺.

Cap-89

A mixture of L-valine (1.0 g, 8.54 mmol), 5-bromopyrimidine (4.03 g, 17.0 mmol), K2CO3 (2.40 g, 17.4 mmol) and Cui (179 mg, 0.94 mmol) in DMSO (10 mL) was heated at 100°C for 12h. The reaction mixture was cooled to RT, poured into H₂O (ca. 150 mL) and washed with EtOAc (x2). The organic layers were extracted with a small amount of H₂O and the combined aq phases were acidified to ca. pH 2 with 6N HC1. ^,The volume was reduced to about one-third and 20g of cation exchange resin (Strata) was added. The slurry was allowed to stand for 20 min and loaded onto a pad of cation exchange resin (Strata) (ca. 25 g). The pad was washed with H2O (200 mL), MeOH (200 mL), and then NH3 (3M in MeOH, 2x200 mL). The appropriate fractions was concentrated in vacuo and the residue (ca. 1.1g) was dissolved in H2O, frozen and lyophyllized. The title compound was obtained as a foam (1.02 g, 62%). ¹HNMR (400 MHz, CD3OD) showed the mixture to contain valine and the purity could not be estimated. The material was used as is in subsequent reactions. LCMS:

Anal. Calcd. for C9H13N3O2: 195; found: 196 (M+H)⁺.

<img file="IL196813A_D0084.tif" />

Cap-90

CO₂H

NMe₂

Cap-90 was prepared according to the method described for the preparation of Cap-1.

The crude material was used as is in subsequent steps. LCMS: Anal. Calcd. for

C11H15NO2: 193; found: 192 (M-H)־.

The following caps were prepared according to the method of example 51:

<td> Cap</td><td> Structure</td><td> LCMS</td>

<td> Cap-91</td><td> NHCO₂Me</td><td> LCMS: Anal. Calcd. for C״H13NO₄: 223; found: 222 (M-H)־.</td>

<td> Cap-92</td><td> NHCO₂Me QT</td><td> LCMS: Anal. Calcd. for C_״H13NO4: 223; found: 222 (M-H)־.</td>

<td> Cap-93</td><td> 1 °Y°O ^ην״.Αοη l^N</td><td> LCMS: Anal. Calcd. for C10H12N2O4: 224; found: 225 (M+H)⁺.</td>

<td> Cap-94</td><td> 0 V hn o_xh זו o</td><td> LCMS: Anal. Calcd. for C8H_״N3O4: 213; found: 214 (M+H)⁺.</td>

<td> Cap-95</td><td> 0 0</td><td> LCMS: Anal. Calcd. for C13H17NO4: 251; found: 250 (M-H)־. _______________________________________________________________________'</td>

<td> Cap-96</td><td> 0 ^Ο^ΝΗ 0</td><td> LCMS: Anal. Calcd. for C12H15NO4: 237; found: 236 (M-H)־.</td>

<td> Cap-97</td><td> 0 ^O׳׳^NH 0 ό </td><td> LCMS: Anal. Calcd. for C9H15NO4:201; found: 200 (M-H)־.</td>

<td> Cap-98</td><td> / ^\ °&gt;° ( )־.Z \__/ ב: / ° O z</td><td> LCMS: Anal. Calcd. for C9H15NO4: 201; found: 202 (M+H)⁺.</td>

<td> Cap-99</td><td> 0 NH co₂h</td><td>¹HNMR (400 MHz, CD₃OD) δ 3.88 - 3.94 (m, 1H), 3.60, 3.61 (s, 3H),2.80(m, 1H), 2.20 (m 1H), 1.82-1.94 (m, 3H), 1.45-1.71 (m, 2H).</td>

<td> Cap-99a</td><td> 0 ^O׳^NH ύ ׳co₂h</td><td>¹HNMR (400 MHz, CD₃OD) δ 3.88 - 3.94 (m, 1H), 3.60, 3.61 (s, 3H), 2.80 (m, 1H), 2.20 (m 1H), 1.82 - 1.94 (m, 3 H), 1.45 - 1.71 (m, 2H).</td>

<td> Cap-100</td><td> 0 \/׳^NH 0 X)</td><td> LCMS: Anal. Calcd. for C12H₁₄NO4F: 255; found: 256 (M+H)⁺.</td>

<td> Cap-101</td><td> 0 ^O^NH</td><td> LCMS: Anal. Calcd. for C״H1₃NO4: 223; found: 222 (M-H)־.</td>

<td> Cap-102</td><td> 0 ^O^NH ^^CO₂H</td><td> LCMS: Anal. Calcd. for C11H13NO4: 223; found: 222 (M-H)־</td>

<td> Cap-103</td><td> ΓΎ־ά °&gt;° \=z )׳iz o ¹o K&gt; x</td><td> LCMS: Anal. Calcd. for C1₀H₁₂N₂O4: 224; found: 225 (M+H)⁺.</td>

<td> Cap-104</td><td> HN—( &gt;CO₂H o=K VV /°</td><td>¹HNMR (400 MHz, CD₃OD) 5 3.60 (s, 3H), 3.50-3.53 (m, 1H), 2.66 - 2.69 and 2.44 -2.49 (m, 1H), 1.91 -2.01 (m, 2H), 1.62- 1.74 (m,4H), 1.51-1.62 (m, 2H).</td>

<td> Cap-105</td><td> HN.( Y-CO₂H o־&lt; Nj ?</td><td>¹HNMR (400 MHz, CD3OD) 5 3.60 (s, 3H), 3.33-3.35 (m, 1H, partially obscured by solvent), 2.37 - 2.41 and 2.16-2.23 (m, 1H), 1.942.01 (m, 4H), 1.43- 1.53 (m, 2H), 1.17-1.29 (m,2H).</td>

<td> Cap-106</td><td> /^N־^ ^־^C°2^H</td><td>¹HNMR (400 MHz, CD3OD) δ 3.16 (q, J= 7.3 Hz, 4H), 2.38 - 2.41 (m, 1H), 2.28 2.31 (m, 2H), 1.79- 1.89 (m, 2H), 1.74 (app, ddd J= 3.5, 12.5,15.9 Hz, 2H), 1.46 (app</td>

<td></td><td></td><td> dtJ = 4.0, 12.9 Hz, 2H), 1.26 (t,J = 7.3 Hz, 6H).</td>

<td> Cap-107</td><td> 0 ^HNy°\ 0</td><td> LCMS: Anal. Calcd. for C8H10N2O4S: 230; found: 231 (M+H)⁺.</td>

<td> Cap-108</td><td> 0 &lt;/^νυ^χΎ^^0η V hn^o^ pi-Y 0</td><td> LCMS: Anal. Calcd. for C15H17N3O4: 303; found: 304 (M+H)⁺.</td>

<td> Cap-109</td><td> 0 ^ΧΌ״־^ΝΗ r^COzH pil</td><td> LCMS: Anal. Calcd. for C10H₁₂N₂O₄: 224; found: 225 (M+H)⁺.</td>

<td> Cap-110</td><td>^z^y~\ °&gt;° \=/ \״_IZ o ¹o N4 X</td><td> LCMS: Anal. Calcd. for C!oH1₂N₂04: 224; found: 225 (M+H)⁺.</td>

<td> Cap-111</td><td> o Ά/'^νη Y'COzH 0 v° M־O' \_OH</td><td> LCMS: Anal. Calcd. for C₁₂H16NO₈P: 333; found: 334 (M+H)⁺.</td>

<td> Cap-112</td><td> 0 NH |׳׳Ύ0₂Η CtZ ^NH</td><td> LCMS: Anal. Calcd. for C״H₁₄N₂O4: 262; found: 263 (M+H)⁺.</td>

<td> Cap-113</td><td> 0 'W^NH OBn</td><td> LCMS: Anal. Calcd. for C18H₁₉NO₅: 329; found: 330 (M+H)⁺.</td>

<td> Cap-114</td><td>_zCO2M6 □I co₂h</td><td>¹HNMR (400 MHz, CDC1₃) δ 4.82 - 4.84 (m, IH), 4.00 -4.05 (m, 2H), 3.77 (s, 3H), 2.56 (s, br, 2H)</td>

<td> Cap-115</td><td> ^NHCOzMe</td><td>¹HNMR (400 MHz, CDClj) δ 5.13(8, br.lH), 4.13 (s, br, IH), 3.69 (s, 3H), 2.61 (d, J = 5.0 Hz, 2H), 1.28 (d, J = 9.1 Hz, 3H).</td>

<td> Cap-116</td><td> ׳״^Y^COzH NHCO₂Me</td><td>¹HNMR (400 MHz, CDC1₃) δ 5.10 (d, J = 8.6 Hz, IH), 3.74-3.83 (m, 1H),3.69 (s, 3H), 2.54-2.61 (m,2H), 1.88 (sept, J = 7.0 Hz, IH), 0.95 (d, J = 7.0 Hz, 6H).</td>

Cap-117 to Cap-123

For the preparation of caps Cap-111 to Cap-123 the the Boc amino acids were commercially available and were deprotected by treatment with 25% TFA in CH₂C1₂.

After complete reaction as judged by LCMS the solvents were removed in vacuo and the coresponding TFA salt of the amino acid was carbamoylated with methyl chloroformate according to the procedure for Cap-51.

<td> Cap</td><td> Structure</td><td> LCMS</td>

<td> Cap-117</td><td> 0 ^C/^NH 0</td><td> LCMS: Anal. Calcd. for C12H₁₅NO₄S: 237; found: 238 (M+H)⁺.</td>

<td> Cap-118</td><td> :ב O °=/ X / z—( c/v °=&lt; /</td><td> LCMS: Anal. Calcd. for C₁₀H1₃NO4S: 243; found: 244 (M+H)⁺.</td>

<td> Cap-119</td><td> 0 0 \ ^S</td><td> LCMS: Anal. Calcd. for C10H13NO4S: 243; found: 244 (M+H)⁺.</td>

<td> Cap-120</td><td> 0 ^O^NH 0 &lt;'^Λ'''־.^ΧΌΗ ^-S</td><td> LCMS: Anal. Calcd. for C₁₀H13NO4S: 243; found: 244 (M+H)⁺.</td>

<td> Cap-121</td><td> 0 ^O^NH ^2׳^&gt;.co₂h</td><td>¹HNMR (400 MHz, CDC13) δ 4.06-4.16 (m, 1H), 3.63 (s, 3H), 3.43 (s, 1H), 2.82 and 2.66 (s,br, 1H), 1.86-2.10 (m, 3H), 1.64-1.76 (m, 2H), 1.44 -1.53(m, 1H).</td>

<td> Cap-122</td><td> 0 NH ^yoC0₂H</td><td>¹HNMR (400 MHz, CDC13)6 5.28 and 5.12 (s, br, 1H), 3.66 (s, 3H), 2.64-2.74 (m, 1H), 1.86 -2.12(m,3H), 1.671.74 (m, 2H), 1.39-1.54 (m, 1H).</td>

<img file="IL196813A_D0085.tif" />

Preparation of Cap-124 . (4S,5R)-5-methyl-2-oxooxazolidine-4-carboxylic acid

<img file="IL196813A_D0086.tif" />

cap-124

The hydrochloride salt of L-threonine tert-butyl ester was carbamoylated according to the procedure for Cap-51. The crude reaction mixture was acidified with IN HCI to pH~l and the mixture was extracted with EtOAc (2X50 mL). The combined organic phases were concentrated in vacuo to give a colorless which solidified on standing. The aqueous layer was concentrated in vacuo and the resulting mixture of product and inorganic salts was triturated with EtOAc-CH2C12MeOH (1:1:0.1) and then the organic phase concentrated in vacuo to give a colorless oil which was shown by LCMS to be the desired product. Both crops were combined to give 0.52 g of a solid. ¹HNMR (400 MHz, CD3OD) δ 4.60 (m, 1H), 4.04 (d, J = 5.0 Hz, 1H), 1.49 (d, J = 6.3 Hz, 3H). LCMS: Anal. Calcd. for C5H7NO4: 145; found: 146 (M+H)⁺.

Preparation of Cap-125. (S)-2-(tert-butoxycarbonylamino)-4(dimethylamino)butanoic acid.

/

--N O

BocHN^^OH cap-125

Cap-125 was prepared according to the procedure for the preparation of Cap-1. The crude product was used as is in subsequent reactions. LCMS: Anal. Calcd. for C11H22N2O4: 246; found: 247 (M+H)⁺.

Preparation of (S)-2-(methoxycarbonylamino)1)- 3־ -methyl-1 H-imidazol-2yl)propanoic acid (Cap-126).

Z^־NMe ANMe &lt; A CICOoMe, NaHCO₃ ך״1\ז ___________► ^N ן

Am M ^{THF z h}2° ¹ °°^c MeOgCHN^COzH Π2Ν υυ2“ cj-25 cap-126

This procedure is a modification of that used to prepare Cap-51. To a suspension of (S)-2-amino-3-(l-methyl-lH-imidazol-2-y!)propanoic acid (0.80 g, 4.70 mmol) in THF (lOmL) and H₂O (10 mL) at 0°C was added NaHCO₃ (0.88 g, 10.5 mmol). The resulting mixture was treated with ClCO₂Me (0.40 mL, 5.20 mmol) and the mixture allowed to stir at 0°C. After stirring for ca. 2h LCMS showed no starting material remaining. The reaction was acidified to pH 2 with 6 N HCI.

The solvents were removed in vacuo and the residue was suspended in 20 mL of 20% MeOH in CH₂C1₂. The mixture was filtered and concentrated to give a light yellow foam (1.21 g,). LCMS and ¹H NMR showed the material to be a 9:1 mixture of the methyl ester and the desired product. This material was taken up in THF (lOmL) and H₂O (lOmL), cooled to 0°C and LiOH (249.1 mg, 10.4 mmol) was added. After stirring ca. Ih LCMS showed no ester remaining. Therefore the mixture was acidified with 6N HCI and the solvents removed in vacuo. LCMS and ¹H NMR confirm the absence of the ester. The title compound was obtained as its HCI salt contaminated with inorganic salts (1.91 g, >100%). The compound was used as is in subsequent steps without further purification.

¹HNMR (400 MHz, CD₃OD) δ 8.84, (s, 1H), 7.35 (s, IH), 4.52 (dd, J = 5.0, 9.1 Hz, IH), 3.89 (s, 3H), 3.62 (s, 3H), 3.35 (dd, 7= 4.5,15.6 Hz, IH, partially obscured by solvent), 3.12 (dd, 7= 9.0,15.6 Hz, IH).

LCMS: Anal. Calcd. for C17H!₅NO₂: 392; found: 393 (M+H)⁺.

Preparation of (S)-2-(methoxycarbonylamino)1)- 3־ -methyl- lH-imidazol-4yl)propanoic acid (Cap-127).

<img file="IL196813A_D0087.tif" />

CICO₂Me, NaHCO₃

THF / H₂O / 0°C

<img file="IL196813A_D0088.tif" />

cap-127

Cap-121 was prepared according to the method for Cap-126 above starting from (S)2-amino-3-(1-methyl-lH-imidazol-4-y!)propanoic acid (1,11 g, 6.56 mmol), NaHCO₃ (1.21 g, 14.4 mmol) and ClCO₂Me (0.56 mL, 7.28 mmol). The title compound was obtained as its HC1 salt (1.79 g, >100%) contaminated with inorganic salts. LCMS and ¹H NMR showed the presence of ca. 5% of the methyl ester. The crude mixture was used as is without further purification.

¹HNMR (400 MHz, CD₃OD) δ 8.90 (s, 1H), 7.35 (s, 1H), 4.48 (dd, J = 5.0, 8.6 Hz, 1H), 3.89 (s, 3H), 3.62 (s, 3H), 3.35 (m, 1H), 3.08 (m, 1H).

LCMS: Anal. Calcd. for C17H₁₅NO₂: 392; found: 393 (M+H)⁺.

Preparation of (S)-2-(methoxycarbonylamino)-3-(lH-l,2,3-triazol-4-yl)propanoic acid (Cap-128).

Cbz-CI / DMAP ן CH₂CI₂ / iPr₂NEt I

BnBr / CuSO₄H₂O

BocHN CO₂H cj-27a

0°C

BocHN CO₂Bn cj-27b sodium ascorbate NaN₃ / DMF / H₂O 65°C/12h

N~~.

nO

N^

BocHN CO₂Bn cj-28

<img file="IL196813A_D0089.tif" />

HN^ &lt; j!

N

MeO₂CHN CO₂H cap-128

Step 1. Preparation of (S)-benzyl 2-(tert-butoxycarbonylamino)pent-4-ynoate (cj27b).

BocHN CO₂Bn cj-27b

To a solution of cj-27a (1.01 g, 4.74 mmol), DMAP (58 mg, 0.475 mmol) and iPr₂NEt (1.7 mL, 9.8 mmol) in CH₂C12 (100 mL) at 0°C was added Cbz-Cl (0.68 mL, 4.83 mmol). The solution was allowed to stir for 4 h at 0°C, washed (IN KHSO4, brine), dried (Na₂SO4), filtered, and concentrated in vacuo. The residue was purified by flash column chromatography (TLC 6:1 hex:EtOAc) to give the title compound (1.30 g, 91%) as a colorless oil. ¹HNMR (400 MHz, CDC13) δ 7.35 (s, 5H), 5.35 (d, br, J = 8.1 Hz, IH), 5.23 (d, J = 12.2 Hz, IH), 5.17 (d, J = 12.2 Hz, IH), 4.48 - 4.53 (m, IH), 2.68 - 2.81 (m, 2H), 2.00 (t, J = 2.5 Hz, IH), 1.44 (s, 9H). LCMS: Anal. Calcd. for C1₇H₂1NO₄: 303; found: 304 (M+H)⁺.

Step 2. Preparation of (S)-benzyl 3-(l-benzyl-lH־l,2,3-triazol-4-yl)-2-(tertbutoxycarbonylamino)propanoate (cj -28).

BocHN CO₂Bn cj-28

To a mixture of (S)-benzyl 2-(tert-butoxycarbonylamino)pent-4-ynoate (0.50 g, 1.65 mmol), sodium ascorbate (0.036 g, 0.18 mmol), CuSO4-5H₂O (0.022 g, 0.09 mmol) and NaN₃ (0.13 g, 2.1 mmol) in DMF-H₂O (5 mL, 4:1) at rt was added BnBr (0.24 ml,, 2.02 mmol) and the mixture was warmed to 65°C . After 5h LCMS indicated low conversion. A further portion of NaN₃ (100 mg) was added and heating was continued for 12h. The reaction was poured into EtOAc and H₂O and shaken. The layers were separated and the aqueous layer extracted 3x with EtOAc and the combined organic phases washed (H₂O x3, brine), dried (Na₂SO4), filtered, and concentrated. The residue was purified by flash (Biotage, 40+M 0-5% MeOH in CH₂C1₂; TLC 3% MeOH in CH₂C1₂) to afford a light yellow oil which solidified on standing (748.3 mg, 104%). The NMR was consistent with the desired product but suggests the presence of DMF. The material was used as is without further purification. ¹HNMR (400 MHz, DMSO־d6) δ 7.84 (s, 1H), 7.27 - 7.32 (m, 10H),

5.54 (s, 2H), 5.07 (s, 2H), 4.25 (m, 1H), 3.16 (dd, J = 1.0, 5.3 Hz, 1H), 3.06 (dd, J =

5.3, 14.7 Hz), 2.96 (dd, J =9.1, 14.7 Hz, 1H), 1.31 (s, 9H).

LCMS: Anal. Calcd. for C24H28N4O4: 436; found: 437 (M+H)⁺.

Step 2. Preparation of (S)-benzyl 3-(l-benzyl־lH-l,2,3-triazol-4-yl)-2(methoxycarbonylamino)propanoate (cj-29).

Ph—y Ν—,

MeO₂CHN'^ZxCO₂Bn cj-29

A solution of (S)-benzyl 3-(l-benzyl־lH-l,2,3־triazol4־-yl)-2-(tertbutoxycarbonylamino)propanoate (0.52 g, 1.15 mmol) in CH2C12 was added TFA (4 ml,) The mixture was allowed to stir at room temperature for 2h. The mixture was concentrated in vacuo to give a colorless oil which solidified on standing. This material was dissolved in THF-H2O and cooled to 0°C. Solid NaHCO3 (0.25 g, 3.00 mmol) was added followed by ClCO₂Me (0.25 mL, 3.25 mmol). After stirring for 1.511 the mixture was acidified to pH~2 with 6N HCI and then poured into H2OEtOAc. The layers were separated and the aq phase extracted 2x with EtOAc. The combined org layers were washed (H₂O, brine), dried (Na₂SO₄), filtered, and concentrated in vacuo to give a colorless oil (505.8 mg, 111%, NMR suggested the presence of an unidentified impurity) which solidified while standing on the pump. The material was used as is without further purification. ¹HNMR (400 MHz, DMSOd6) δ 7.87 (s, 1H), 7.70 (d, J =8.1 Hz, 1H), 7.27-7.32 (m, 10H), 5.54 (s, 2H), 5.10 (d, J = 12.7 Hz, 1H), 5.06 (d, J = 12.7 Hz, 1H), 4.32 - 4.37 (m, 1H), 3.49 (s, 3H), 3.09 (dd, J = 5.6,14.7 Hz, 1H), 2.98 (dd, J = 9.6, 14.7 Hz, 1H). LCMS: Anal. Calcd. for C21H22N4O4: 394; found: 395 (M+H)⁺.

Step 3. Preparation of (S)-2-(methoxycarbonylamino)-3-(lH-l,2,3-triazol-4yl)propanoic acid (Cap-128).

^HN־T1 N. JL ^Nl MeO₂CHN׳־OO₂H

Cep-128 (S)-benzyl 3-(l-benzyl-lH-l,2,3-triazol-4-yl)-2-(methoxycarbonylamino)propanoate (502 mg, 1.11 mmol) was hydrogenated in the presence of Pd-C (82 mg) in MeOH (5 mL) at atmospheric pressure for 12h. The mixture was filtered through diatomaceous earth (Celite®) and concentrated in vacuo. (S)-2-(methoxycarbonylamino)-3-(lHl,2,3-triazol4־-yl)propanoic acid was obtained as a colorless gum (266 mg, 111%) which was contaminated with ca. 10% of the methyl ester. The material was used as is without further purification.

¹HNMR (400 MHz, DMSO-d₆) δ 12.78 (s, br, 1H), 7.59 9s, 1H), 7.50 (d, J = 8.0 Hz, 1H), 4.19 - 4.24 (m, 1H), 3.49 (s, 3H), 3.12 (dd, 7= 4.8 Hz, 14.9 Hz, 1H), 2.96 (dd, J = 9.9,15.0 Hz, 1H). LCMS: Anal. Calcd. for C7H10N4O4: 214; found: 215 (M+H)⁺.

Preparation of (S)-2-(methoxycarbonylamino)-3 -(1 H-pyrazol-1 -yl)propanoic acid (Cap-129).

1) H₂ Pd-C / MeOH

CbzHN 0 CH₃CN / 50°C _CbzHN״׳^_C0₂H ²) ^clc02Me MeO₂CHN CO₂H C/-30 _Cj_₃₁ NaHCO₃ / THF-H₂O cap-129

Step 1. Preparation of (S)-2-(benzyloxycarbonylamino)-3-(1 H-pyrazol-1 yl)propanoic acid (cj-31).

CbzHN

<img file="IL196813A_D0090.tif" />

cj-31

A suspension of (S)-benzyl 2־oxooxetan-3-ylcarbamate (0.67 g, 3.03 mmol), and pyrazole (0.22 g, 3.29 mmol) in CH3CN (12 mL) was heated at 50°C for 24h. The mixture was cooled to rt overnight and the solid filtered to afford (S)-2(benzyloxycarbonylamino)-3-(lH-pyrazol-l-yl)propanoic acid (330.1 mg). The filtrate was concentrated in vacuo and then triturated with a small amount of CH3CN (ca. 4 mL) to afford a second crop (43.5 mg). Total yield 370.4 mg (44%).

m.p. 165.5 - 168°C. lit m.p. 168.5 - 169.5 Vederas et al. J. Am. Chem. Soc. 1985,707,7105.

¹HNMR (400 MHz, CD3OD) δ 7.51 (d, J = 2.0, 1H), 7.48 (s, J = 1.5 Hz, 1H), 7.24 7.34 (m, 5H), 6.23 m, 1H), 5.05 (d, 12.7 Η, 1H), 5.03 (d, J = 12.7 Hz, 1H), 4.59 4.66 (m,2H), 4.42-4.49 (m, 1H). LCMS: Anal. Calcd. for C14H15N3O4: 289; found: 290 (M+H)⁺.

Step 2. Preparation of (S)-2-(methoxycarbonylamino)-3-(IH-pyrazol-1 -yl)propanoic acid (Cap-129).

I

MeO₂CHN'^A'CO₂H cap-129 (S)-2-(benzyloxycarbonylamino)3־-(lH־pyrazol-l-yl)propanoic acid (0.20 g, 0.70 mmol) was hydrogenated in the presence of Pd-C (45 mg) in MeOH (5 mL) at atmospheric pressure for 2h. The product appeared to be insoluble in MeOH, therefore the rxn mixture was diluted with 5mL H₂O and a few drops of 6N HC1.

The homogeneous solution was filtered through diatomaceous earth (Celite ), and the MeOH removed in vacuo. The remaining solution was frozen and lyophyllized to give a yellow foam (188.9 mg). This material was suspended in THF-H₂O (1:1, lOmL) and then cooled to 0°C. To the cold mixture was added NaHCO3 (146.0 mg, 1.74 mmol) carefully (evolution of CO₂). After gas evolution had ceased (ca. 15 min) ClCO₂Me (0.06 mL, 0.78 mmol) was added dropwise. The mixture was allowed to stir for 2h and was acidified to pH~2 with 6N HC1 and poured into EtOAc. The layers were separated and the aqueous phase extract with EtOAC (x5).

The combined organic layers were washed (brine), dried (Na₂SO4), filtered, and concentrated to give the title compound as a colorless solid (117.8 mg, 79%). ¹HNMR (400 MHz, DMSO-d6) δ 13.04 (s, IH), 7.63 (d, J = 2.6 Hz, IH), 7.48 (d, J = 8.1 Hz, IH), 7.44 (d, J = 1.5 Hz, IH), 6.19 (app t, J = 2.0 Hz, IH), 4.47 (dd, J = 3.0, 12.9 Hz, IH), 4.29-4.41 (m, 2H), 3.48 (s, 3H). LCMS: Anal. Calcd. for C₈HuN₃O4: 213; found: 214 (M+H)⁺.

Cap-130. N-Acetyl -(R)-Phenylglycine O

AcHN־^CO2H cap-130

Cap-130 was prepared by acylation of commercially available (R)-phenylglycine analgous to the procedure given in: Calmes, M.; Daunis, J.; Jacquier, R.; Verducci, J. Tetrahedron, 1987, 43(10), 2285.

EXAMPLES

The present disclosure will now be described in connection with certain embodiments which are not intended to limit its scope. On the contrary, the present disclosure covers all alternatives, modifications, and equivalents as can be included within the scope of the claims. Thus, the following examples, which include specific embodiments, will illustrate one practice of the present disclosure, it being understood that the examples are for the purposes of illustration of certain embodiments and are presented to provide what is believed to be the most useful and readily understood description of its procedures and conceptual aspects.

Solution percentages express a weight to volume relationship, and solution ratios express a volume to volume relationship, unless stated otherwise. Nuclear magnetic resonance (NMR) spectra were recorded either on a Bruker 300,400, or 500 MHz spectrometer; the chemical shifts (δ) are reported in parts per million. Flash chromatography was carried out on silica gel (SiO2) according to Still’s flash chromatography technique (J. Org. Chem. 1978, 43,2923).

Purity assessment and low resolution mass analysis were conducted on a

Shimadzu LC system coupled with Waters Micromass ZQ MS system. It should be noted that retention times may vary slightly between machines. The LC conditions employed in determining the retention time (RT) were:

<td rowspan="2"> 5</td><td colspan="2"> Condition 1</td>

<td> Column Start %B</td><td> = Phenomenex-Luna 3.OX 50 mm S10 = 0</td>

<td></td><td> Final %B</td><td> = 100</td>

<td></td><td> Gradient time</td><td> = 2 min</td>

<td> 10</td><td> Stop time</td><td> = 3 min</td>

<td></td><td> Flow Rate</td><td> = 4 mL/min</td>

<td></td><td> Wavelength</td><td> = 220 nm</td>

<td></td><td> Solvent A</td><td> = 0.1% TFA in 10% methanol/90%H₂O</td>

<td></td><td> Solvent B</td><td> = 0.1% TFA in 90% methanol/10% H₂O</td>

<td> 15</td><td> Condition 2 Column</td><td> = Phenomenex-Luna 4.6X50 mm S10</td>

<td></td><td> Start %B</td><td> = 0</td>

<td></td><td> Final %B</td><td> = 100</td>

<td> 20</td><td> Gradient time</td><td> = 2 min</td>

<td></td><td> Stop time</td><td> = 3 min</td>

<td></td><td> Flow Rate</td><td> = 5 mL/min</td>

<td></td><td> Wavelength</td><td> = 220 nm</td>

<td></td><td> Solvent A</td><td> = 0.1% TFA in 10% methanol/90%H₂O</td>

<td> 25</td><td> Solvent B</td><td> = 0.1% TFA in 90% methanol/10% H₂O</td>

<td></td><td> Condition 3 Column</td><td> = HPLC XTERRA C18 3.0 x 50mm S7</td>

<td></td><td> Start %B</td><td> = 0</td>

<td> 30</td><td> Final %B</td><td> = 100</td>

<td></td><td colspan="2"> Gradient time = 3 min</td>

<td></td><td> Stop time</td><td> = 4 min</td>

<td></td><td> Flow Rate</td><td> = 4 mL/min</td>

Wavelength = 220 nm

Solvent A = 0.1 % TFA in 10% methanol/90%H2O

Solvent B = 0.1% TFA in 90% methanol/10% H₂O

Method A: LCMS - Xterra MS C-18 3.0 x 50mm, 0 to 100% B over 30.0 minute gradient, 1 minute hold time, A = 5% acetonitrile, 95% water, 10mm ammonium acetate, B = 95% acetonitrile, 5% water, 10mm ammonium acetate.

Method B: HPLC - X-Terra C-18 4.6 x 50mm, 0 to 100% B over 10.0 minute gradient, 1 minute hold time, A = 10% methanol 90% water 0.1% TFA, B = 90% methanol 10% water 0.1% TFA

Method C: HPLC - YMC C-18 4.6 x 50mm, 0 to 100% B over 10.0 minute gradient, 1 minute hold time, A = 10% methanol 90% water 0.2% H3PO4, B = 90% methanol 10% water 0.2% H3PO4.

Method D: HPLC - Phenomenex C-18 4.6 x 150mm, 0 to 100% B over 10.0 minute gradient, 1 minute hold time, A = 10% methanol 90% water 0.2% H3PO4, B = 90% methanol 10% water 0.2% H3PO4

Method E: LCMS - Gemini C-18 4.6 x 50mm, 0 to 100% B over 10.0 minute gradient, 1 minute hold time, A = 5% acetonitrile, 95% water, 10mm ammonium acetate, B = 95% acetonitrile, 5% water, 10mm ammonium acetate.

Method F: LCMS-Luna C-18 3.0 x 50mm, 0 to 100% B over 7.0 minute gradient, 1 minute hold time, A = 5% acetonitrile, 95% water, 10mm ammonium acetate, B = 95% acetonitrile, 5% water, 10mm ammonium acetate.

Example 1 (lR,rR)-2,2'-(4,4 '-biphenyldiylbis(lH-imidazole-5,2-diyl(2S)-2,1pyrrolidinediyl))bis(N,N-dimethyl-2-oxo-l-phenylethanamine)

<img file="IL196813A_D0091.tif" />

ΛζΝ-Diisopropylethylamine (18 mL, 103.3 mmol) was added dropwise, over 15 minutes, to a heterogeneous mixture of N-Boc-L-proline (7.139 g, 33.17 mmol), HATU (13.324 g, 35.04 mmol), the HC1 salt of 2-amino-l-(4-bromopheny !)ethanone (8.127 g, 32.44 mmol), and DMF (105 mL), and stirred at ambient condition for 55 minutes. Most of the volatile component was removed in vacuo, and the resulting residue was partitioned between ethyl acetate (300 mL) and water (200 mL). The organic layer was washed with water (200 mL) and brine, dried (MgSO4), filtered, and concentrated in vacuo. A silica gel mesh was prepared from the residue and submitted to flash chromatography (silica gel; 5060־ % ethyl acetate/hexanes) to provide ketoamide la as a white solid (12.8 g). ¹H NMR (DMSO-d6, δ = 2.5 ppm, 400 MHz): δ 8.258.14־ (m, 1H), 7.92 (br d, J = 8.0, 2H), 7.75 (br d, J = 8.6, 2H), 4.61 (dd, J= 18.3,5.7,1H), 4.53 (dd, J= 18.1,5.6, 1H), 4.22-4.12 (m, 1H), 3.433.35 (m, 1H), 3.30-3.23 (m, 1H), 2.18-2.20 (m, 1H), 1.90-1.70 (m, 3H), 1.40/1.34 (two app br s, 9H). LC(Cond. 1): RT = 1.70 min; LC/MS: Anal. Calcd. for [M+Na]⁺ C18H₂₃BrN2NaO4: 433.07; found 433.09.

Analogous compounds such as intermediate 1-la to l-5a can be prepared by incorporating the appropriately substituted amino acid and aryl bromide isomer.

<img file="IL196813A_D0092.tif" />

1-la ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.35/1.40 (two br s, 9H), 2.27-2.42 (m, 1H), 2.73-2.95 (m, 1H), 3.62-3.89 (m, 2H), 4.36-4.50 (m, 1H), 4.51-4.60 (m, 1H), 4.624.73 (m, 1H), 7.75 (d, 7=8.24 Hz, 2H), 7.92 (d, 7=7.63 Hz, 2H), 8.31-8.49 (m, 1H). HPLC XTERRA C-18 4.6 x 30 mm, 0 to 100% B over 4 minutes, 1 minute hold time, A = 90% water, 10% methanol, 0.2% H3PO4, B = 10% water, 90% methanol, 0.2% H3PO4, RT = 1.59 minutes, 99% homogeneity index. LCMS: Anal. Calcd. for C18H21BrF₂N₂O4: 446.06; found: 445.43 (M-H)־.

<img file="IL196813A_D0093.tif" />

t)H l-2a ¹H NMR (500 MHz, DMSO-d₆) δ ppm (8.25 1H, s), 7.91 (2H, d, 7=8.24Hz), 7.75 (2H, d, 7=8.24 Hz), 4.98 (1H, s), 4.59-4.63 (1H, m), 4.46-4.52 (1H, m), 4.23 (1H, m), 3.37 (1H, s), 3.23-3.28 (1H, m), 2.06 (1H, m), 1.88 (1H, s), 1.38 (3H, s), 1.33 (6H, s). LCMS - Phenomenex C-18 3.0 x 50mm, 0 to 100% B over 4.0 minute gradient, 1 minute hold time, A = 10% methanol 90% water 0.1% TFA, B = 90% methanol 10% water 0.1% TFA mobile phase, RT = 3.34 minutes, Anal Calcd. for C18H23BrN2O5 427.30; found 428.08 (M+H)⁺.

<img file="IL196813A_D0094.tif" />

OH l-3a ¹H NMR (500 MHz, DMSO-d₆) δ ppm 8.30 (1H, s) 7.93-7.96 (2H, m) 7.76 (2H d, 7=8.24 Hz) 5.13 (1H, s) 4.66-4.71 (1H, m) 4.52-4.55 (1H, m) 4.17 (1H, m) 3.51 (1H,

s) 3.16-3.19 (1H, m) 2.36 (1H, m) 1.78 (1H, s) 1.40 (s, 3H), 1.34 (s, 6H). LCMS Phenomenex C-18 3.0 x 50mm, 0 to 100% B over 4.0 minute gradient, 1 minute hold time, A = 10% methanol 90% water 0.1% TFA, B = 90% methanol 10% water 0.1%

TFA, RT= 3.69 minutes, Anal Calcd. for C!8H23BrN2O5 427.30; found 428.16 (M+H)⁺.

<img file="IL196813A_D0095.tif" />

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.29-1.47 (m, 9H), 1.67-1.90 (m, 3H), 2.002.20 (m, 1H), 3.23-3.30 (m, 1H), 3.34-3.44 (m, 1H), 4.16 (dd, 1H), 4.57 (q, 2H), 7.51 (t, 7=7.78 Hz, 1H), 7.86 (dd, 7=7.93, 1.22 Hz, 1H), 7.98 (d, 7=7.63 Hz, 1H), 8.11 (s, 1H), 8.15-8.29 (m, 1H). LC/MS (M+Na)⁺ = 433.12/435.12.

<img file="IL196813A_D0096.tif" />

l-5a

LCMS conditions: Phenomenex LUNA C-18 4.6 x 50 mm, 0 to 100% B over 2 minutes, 1 minute hold time, A = 90% water, 10% methanol, 0.1% TFA, B = 10% water, 90% methanol, 0.1% TFA, 220nm, 5 pL injection volume. RT = 1.93 min;

LRMS: Anal. Calcd. for C1₉H1₈BrN₂O4 418.05; found: 419.07 (M+H)⁺.

Example 1, Step b

<img file="IL196813A_D0097.tif" />

1b

A mixture of ketoamide la (12.8 g, 31.12 mmol) andNH4OAc (12.0 g, 155.7 mmol) in xylenes (155 mL) was heated in a sealed tube at 140 °C for 2 hours. The volatile component was removed in vacuo, and the residue was partitioned carefully between ethyl acetate and water, whereby enough saturated NaHCOj solution was added so as to make the pH of the aqueous phase slightly basic after the shaking of the biphasic system. The layers were separated, and the aqueous layer was extracted with an additional ethyl acetate. The combined organic phase was washed with brine, dried (MgSO4), filtered, and concentrated in vacuo. The resulting material was recrystallized from ethyl acetate/hexanes to provide two crops of imidazole lb as a light-yellow dense solid, weighing 5.85 g. The mother liquor was concentrated in vacuo and submitted to a flash chromatography (silica gel; 30% ethyl acetate/hexanes) to provide an additional 2.23 g of imidazole lb. ¹H NMR (DMSOd6, δ = 2.5 ppm, 400 MHz); δ 12.17/11.92/11.86 (m, 1H), 7.72-7.46/7.28 (m, 5H), 4.86-4.70 (m, 1H), 3.52 (app br s, 1H), 3.36 (m, 1H), 2.30-1.75 (m, 4H), 1.40/1.15 (app br s, 9H). LC (Cond. 1): RT = 1.71 min; >98% homogeneity index; LC/MS: Anal. Calcd. for [M+H]⁺C18H23BrN3O₂: 392.10; found 391.96; HRMS: Anal. Calcd. for [M+H]⁺ C18H₂₃BrN3O₂: 392.0974; found 392.0959

The optical purity of the two samples of lb were assessed using the chiral HPLC conditions noted below (ee > 99% for the combined crops; ee = 96.7% for the sample from flash chromatography):

Column: Chiralpak AD, 10 um, 4.6 x 50 mm Solvent: 2% ethanol/heptane (isocratic) Flow rate: 1 mL/min

Wavelength: either 220 or 254 nm

Relative retention time: 2.83 minutes (R\ 5.34 minutes (S)

Analogous compounds such as intermediates 1-lb to l-4b can be prepared by incorporating the appropriate ketoamide.

<img file="IL196813A_D0098.tif" />

1-lb ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.17/1.40 (two br s, 9H), 2.50-2.74 (m, 7=25.64 Hz, IH), 2.84-3.07 (m, IH), 3.88 (d, 7=10.07 Hz, 2H), 5.03 (s, IH), 7.50 (d, 7=8.55 Hz, 2H), 7.60 (s, IH), 7.70 (d, 7=8.55 Hz, 2H), 12.10 (s, IH). HPLC XTERRA C-18 4.6 x 30 mm, 0 to 100% B over 4 minutes, 1 minute hold time, A = 90% water, 10% methanol, 0.2% H3PO4, B = 10% water, 90% methanol, 0.2% H3PO4, RT = 1.59 minutes, 99% homogeneity index; LCMS: Anal. Calcd. for C1₈H20BrF₂N3O2: 428.27; found: 428.02 (M)⁺.

OH

<img file="IL196813A_D0099.tif" />

l-2b ¹H NMR (500 MHz, DMSO-d₆) δ ppm 11.89-11.99 (IH, m), 7.68 (2H, d, 7=8.54 Hz), 7.52-7.59 (IH, m), 7.48 (2H, d, 7=8.54 Hz), 4.80 (IH, m), 4.33 (IH, s), 3.513.60 (IH, m), 3.34 (IH, d, 7=10.99 Hz), 2.14 (IH, s), 1.97-2.05 (IH, m), 1.37 (3H, s), 1.10 (6H, s); LCMS - Phenomenex C-18 3.0 x 50mm, 0 to 100% B over 4.0 minute gradient, 1 minute hold time, A = 10% methanol 90% water 0.1% TFA, B = 90% methanol 10% water 0.1% TFA, (RT= 3.23 min) Anal Calcd. for C18H₂2BrN₃O3 408.30; found 409.12 (M+H)⁺.

OH

<img file="IL196813A_D0100.tif" />

l-3b ¹H NMR (500 MHz, DMSO-d₆) δ ppm 12.06-12.24 (IH, m), 7.58-7.69 (5H, m), 4.84-4.95 (IH, m), 4.34 (IH, s), 3.61 (IH, s), 3.34-3.40 (IH, m), 2.52 (IH, s), 1.922.20 (IH, m), 1.43 (3H, s), 1.22 (6H, s); LCMS - Phenomenex C-18 3.0 x 50mm, 0 to 100% B over 4.0 minute gradient, 1 minute hold time, A = 10% methanol 90% water 0.1% TFA, B = 90% methanol 10% water 0.1% TFA, (RT= 3.41 min) Anal Calcd. for C1₈H22BrN₃O3 408.30; found 409.15 (M+H)⁺.

<img file="IL196813A_D0101.tif" />

l-4b ¹H NMR (500 MHz, DMSO-d₆) δ ppm 0.981.51־ (m, 9H), 1.82-2.12 (m, 3H), 2.312.48 (m, IH), 3.30-3.51 (m, IH), 3.52-3.66 (m, IH), 4.88-5.16 (m, IH), 7.47 (t,

7=7.93 Hz, IH), 7.61 (d, 7=7.93 Hz, IH), 7.81 (d, 7=7.93 Hz, IH), 8.04 (s, IH), 8.12 (d, 7=28.38 Hz, IH), 14.65 (s, IH). LC/MS (M+H)⁺= 391.96/393.96.

Additional imidazole analogs made following procedures similar to those described above.

LC conditions: Condition 1: Phenomenex LUNA C-18 4.6 x 50 mm, 0 to 100% B over 3 minutes, 1 minute hold time, A = 90% water, 10% methanol, 0.1% TFA, B = 10% water, 90% methanol, 0.1% TFA, 220nm, 5 pL injection volume.

Condition 2: Phenomenex LUNA C-18 4.6 x 50 mm, 0 to 100% B over 2 minmes, 1 minute hold time, A = 90% water, 10% methanol, 0.1% TFA, B = 10% water, 90% methanol, 0.1% TFA, 220nm, 5 gL injection volume.

<td> Example</td><td> Structure</td><td> Data</td>

<td> l-5b</td><td> y—NH z—/A * ^—0' O</td><td> RT = 1.70 minutes (condition 2, 98%); LRMS: Anal. Calcd. for C19H1₈BrN3O₂ 399.05; found: 400.08 (M+H)⁺.</td>

<td> l-6b</td><td> y~ 0</td><td> RT = 1.64 minutes (condtion 2, 98%); LRMS: Anal. Calcd. for C17H₂2N3O₂ 379.09; found: 380.06 (M+H)⁺.</td>

<td> l-7b</td><td> q_ V-O / xz r (/ ffi</td><td> RT = 2.28 minutes (95%); LRMS: Anal. Calcd. for C20H21BrN₃O2</td>

<td></td><td></td><td> 414.08; found: 414.08 (M+H)⁺; HRMS: Anal. Calcd. for C20H2!BrN3O2 414.0817; found: 414.0798 (M+H)⁺.</td>

Example 1, Step c

<img file="IL196813A_D0102.tif" />

1c

Pd(Ph₃P)₄ (469 mg, 0.406 mmol) was added to a pressure tube containing a mixture of bromide lb (4.008 g, 10.22 mmol), bis(pinacolato)diboron (5.422 g, 21.35 mmol), potassium acetate (2.573g,'26.21 mmol) and 1,4-dioxane (80 mL). ^,The reaction flask was purged with nitrogen, capped and heated with an oil bath at 80 °C for 16.5 hours. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The crude material was partitioned carefully between CH2C12 (150 mL) and an aqueous medium (50 mL water + 10 mL saturated NaHCO3 solution). The aqueous layer was extracted with CH2C12, and the combined organic phase was dried (MgSO4), filtered, and concentrated in vacuo. The resulting material was purified with flash chromatography (sample was loaded with eluting solvent; 2035%־ ethyl acetate/CH2C12) to provide boronate 1c, contaminated with pinacol, as an off-white dense solid; the relative mole ratio of 1c to pinacol was about 10:1 (¹H NMR). The sample weighed 3.925 g after ~2.5 days exposure to high vacuum. ¹H NMR (DMSO-d6, δ= 2.5 ppm, 400 MHz): 12.22/11.94/ 11.87 (m, 1H), 7.79-7.50/ 7.347.27 (m, 5H), 4.86-4.70 (m, 1H), 3.52 (app br s, 1H), 3.36 (m, 1H), 2.27-1.77 (m, 4H), 1.45-1.10 (m, 21H). LC (Cond. 1): RT = 1.64 min; LC/MS: Anal. Calcd. for [M+H]⁺ C24H35BN3O4: 440.27; found 440.23.

Analogous compounds such as intermediates 1-lc to l-4c can be prepared by incorporating the appropriate aryl bromide.

<img file="IL196813A_D0103.tif" />

1-lc ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.16 (s, 8H), 1.29 (s, 13H), 2.512.72־ (m, IH), 2.84-3.03 (m, IH), 3.79-4.00 (m, 2H), 4.88-5.21 (m, IH), 7.62 (d, 7=7.93 Hz, 2H), 7.67 (s, IH), 7.76 (d, 7=7.93 Hz, 2H), 12.11/12.40 (two br s, IH). HPLC GEMINI C-18 4.6 x 50 mm, 0 to 100% B over 4 minutes, 1 minute hold time, A = 95% water, 5% acetonitrile, 0.1% NH4OAc, B = 5% water, 95% acetonitrile, 0.1% NH4OAc,RT= 1.62 minutes, 99% homogeneity index. LCMS: Anal. Calcd. for C34H32BF2N3O4: 475.34; found: 474.78 (M-H)־.

OH

<img file="IL196813A_D0104.tif" />

l-2c ¹H NMR (500 MHz, DMSO-d₆) δ ppm 11.97 (IH, m), 7.62-7.75 (5H, m), 5.05 (IH d, 7=3.36 Hz), 4.82 (m, IH), 4.35 (m, IH), 3.58 (IH, m), 2.389 (IH, s), 2.17 (1 H, m), 1.38 (3H, s), 1.30 (12H, s), 1.1 (6H, s); LCMS - Phenomenex C-18 3.0 x 50mm, 0 to 100% B over 4.0 minute gradient, 1 minute hold time, A = 5% acetonitrile, 95% water, 10mm ammonium acetate, B = 95% acetonitrile, 5% water, 10mm ammonium acetate, RT= 3.63 minutes, Anal. Calcd. for C24H34BN3O5 455.30; found 456.31 (M+H)⁺.

OH

<img file="IL196813A_D0105.tif" />

l-3c ¹H NMR (500 MHz, DMSO-d₆) δ ppm 12.05-12.24 (IH, m), 7.61-7.73 (5H, m), 4.83-5.01 (IH, m), 4.33 (IH, s), 3.54-3.63 (IH, m), 3.39-3.80 (IH, m), 2.38-2.49 (IH, m), 1.98-2.01 (IH, m), 1.42 (3H, s), 1.34 (12H, s), 1.21 (6H, s); LCMS Phenomenex C-18 3.0 x 50mm, 0 to 100% B over 4.0 minute gradient, 1 minute hold time, A = 10% methanol 90% water 0.1% TFA, B = 90% methanol 10% water 0.1%

TFA, RT= 3.64 minutes, Anal. Calcd. for C24H34BN3O5 455.30; found 456.30 (M+H)⁺.

<img file="IL196813A_D0106.tif" />

¹HNMR (500 MHz, DMSO-d₆) δ ppm 1.02-1.54 (m, 21H), 1.75-2.07 (m, 3H), 2.092.33 (m, IH), 3.32-3.44 (m, IH), 3.55 (s, IH), 4.69_;4.94 (m, IH), 7.33 (t, 7=7.32 Hz, IH), 7.41-7.57 (m, 2H), 7.84 (d, 7=7.32 Hz, IH), 8.08 (s, IH), 11.62-12.07 (m, IH). LC/MS (M+H)⁺ = 440.32.

Additional boronic esters: Conditions for l-5c through l-10c

LCMS conditions: Condition 1: Phenomenex LUNA C-18 4.6 x 50 mm, 0 to 100% B over 3 minutes, 1 minute hold time, A = 90% water, 10% methanol, 0.1% TFA, B = 10% water, 90% methanol, 0.1% TFA, 220nm, 5 μΤ injection volume.

Condition 2: Phenomenex LUNA C-18 4.6 x 50 mm, 0 to 100% B over 2 minutes, 1 minute hold time, A = 90% water, 10% methanol, 0.1% TFA, B = 10% water, 90% methanol, 0.1% TFA, 220nm, 5 pL injection volume.

<td> l-5c</td><td> cd—O ׳s-tp</td><td> RT = 1.84 minutes (condition 2); LCMS: Anal. Calcd. for C27H₃₂BN₃O4 473; found: 474 (M+H)⁺.</td>

<td> l-6c</td><td> \/~0 ΗΝ-/* /NH 0</td><td> RT = 1.84 minutes (condition 2); LCMS: Anal. Calcd. for C22H32BN3O4 413; found: 414 (M+H)⁺.</td>

<td> l-7c</td><td> /—°\ ¹d&gt;X O—co</td><td> RT = 1.85 minutes (condition 2); LRMS: Anal. Calcd. for C25H31BN3O4 448; found: 448 (M+H)⁺.</td>

<td> l-8c</td><td> מז—O A Ax°, ־° ׳t</td><td> RT = 2.49 (76%, boronic ester) and 1.81 (21.4%, boronic acid); LCMS: Anal. Calcd. for C23H35N3O4B 428.27; found: 428.27 (M+H)⁺; HRMS: Anal. Calcd. for C23H35N3O4B 428.2721; found: 428.2716 (M+H)⁺.</td>

<td> l-9c</td><td> /—O. 1 xz ״ 0 Q—CD</td><td> RT = 2.54 (74.2%, boronic ester) and 1.93 (25.8%, boronic acid); LRMS: Anal. Calcd. for C26H33N3O4B 462.26; found: 462.25 (M+H)⁺; HRMS: Anal. Calcd. for C26H33N3O4B 462.2564; found: 462.2570 (M+H)⁺.</td>

<td> 1-1 Oc</td><td> ro-o</td><td> RT= 1.91 (64.5 %, boronic ester) and 1.02 (33.8 %, boronic acid); LRMS: Anal. Calcd. for C26H32N₄O3¹⁰B 458.26; found: 458.28 (M+H)⁺; HRMS: Anal. Calcd. forC26H32N₄O3¹⁰B 458.2604; found: 458.2617 (M+H)⁺.</td>

Example 1, Step d di-tert-butyl (2S,2’S)-2,2-(4,4'-biphenyldiylbis(lH-imidazole-5,2-diyl))di(lpyrrolidinecarboxylate)

<img file="IL196813A_D0107.tif" />

Pd(Ph₃P)₄ (59.9 mg, 0.0518 mmol) was added to a mixture of bromide lb (576.1 mg, 1.469 mmol), boronate lc (621.8 mg, 1.415 mmol), NaHCO₃ (400.4 mg, 4.766 mmol) in 1,2-dimethoxyethane (12 mL) and water (4 mL). The reaction mixture was flushed with nitrogen, heated with an oil bath at 80 °C for 5.75 hours, and then the volatile component was removed in vacuo. The residue was partitioned between 20% methanol/ CHC1₃ (60 mL) and water (30 mL), and the aqueous phase was extracted with 20% methanol/CHCl₃ (30 mL). The combined organic phase was washed with brine, dried (MgSO4), filtered, and concentrated in vacuo. A silica gel mesh was prepared from the resulting crude material and submitted to flash chromatography (ethyl acetate) to provide dimer Id, contaminated with Ph₃PO, as an off-white solid (563 mg). ¹H NMR (DMSO-d6, δ = 2.5 ppm, 400 MHz): δ 12.21-1216/11.95-11.78 (m, 2H), 7.85-7.48/ 7.32-7.25 (m, 10H), 4.90-4.71 (m, 2H), 3.60-3.32 (m, 4H), 2.30-1.79 (m, 8H), 1.461.10־ (m, 18H). LC (Cond. lb): RT = 1.77 min; LC/MS: Anal. Calcd. for [M+H]⁺ C36H45BN₆O₄: 625.35; found 625.48.

Additional symmetric analogs can be prepared in similar fashion.

OH

<img file="IL196813A_D0108.tif" />

HO

1-ld

Example 1-ld was prepared using intermediates l-2c and l-2b. ¹H NMR (500 MHz, DMSO-d6) δ ppm 11.94-12.22 (2H, m) 7.53-7.82 (10H, m) 4.82-4.92 (2 H, m) 4.344.43 (2 H, m) 3.55-3.64 (2 H, m) 3.36 (2 H, d, 7=11.29 Hz) 2.12-2.22 (2 H, m) 2.02121

2.11 (2 H, m) 1.40 (6 Η, s) 1.14 (12 Η, s); LCMS - Phenomenex C-18 3.0 x 50mm, 0 to 100% B over 4.0 minute gradient, 1 minute hold time, A = 10% methanol 90% water 0.1% TFA, B = 90% methanol 10% water 0.1% TFA, RT= 3.32min, Anal.

Calcd. for 656.79; found 657.40 (M+H)⁺. Nominal/LRMS - (M+H)⁺ 657.42, (M-H) .28.

<img file="IL196813A_D0109.tif" />

l-2d

Example l-2d was prepared using intermediates l-3b and l-3c. ^lH NMR (500 MHz, DMSO-d₆) δ ppm 12.00-12.20 (2H, m) 7.56-7.76 (10H, m) 4.90 (IH, s) 4.82 (IH, s) 4.25-4.34 (2H, m) 3.56 (2H, s) 3.34-3.47 (2H, m) 1.97-2.13 (4H, m) 1.39 (9H, m) 1.20 (9H, s); LCMS - Phenomenex C-18 3.0 x 50mm, 0 to 100% B over 4.0 minute gradient, 1 minute hold time, A = 10% methanol 90% water 0.1% TFA, B = 90% methanol 10% water 0.1% TFA; RT= 3.35min, Anal. Calcd. for 656.79; found 657.30 (M+H)⁺.

<img file="IL196813A_D0110.tif" />

tert-butyl (2S)-2-(4-(3'-(2-((2S)-l-(tert-butoxycarbonyl)-2-pyrrolidinyl)-lH-imidazol5-yl)-3-biphenylyl)-lH-imidazol-2-yl)-l-pyrrolidinecarboxylate

Example l-2d-l was prepared using intermediates l4־c and l-4b. ¹H NMR (500 MHz, DMSO-d6) δ ppm 1.09-1.51 (m, 18H), 1.84-2.15 (m, 6H), 2.34-2.50 (m, 2H),

3.353.52־ (m, 2H), 3.54-3.67 (m, 2H), 5.08 (d, 7=5.49 Hz, 2H), 7.68 (t, 7=7.78 Hz,

2H), 7.78-7.92 (m, 4H), 8.11-8.30 (m, 4H), 14.81 (s, 2H). LC/MS (M+H)⁺= 625.48.

l-2d-2

Diol 1-ld (0.15g, 0.23mmol) was added as a solid to a solution of bis(2methoxyethyl) aminosulfur trifluoride (0.1 mL, 0.51 mmol) in l.OmL CH2C12 cooled to -78 °C. The reaction was stirred at -78 °C for two hours and then warmed to room temperature and stirred for 2 hours. The reaction was poured into saturated sodium bicarbonate solution and stirred until bubbling ceased. The layers were separated and the aqueous layer was extracted one time with CH2C12. The combined organics were washed with brine, dried (MgSO₄), filtered, and concentrated to give a yellow oil. The oil was triturated with CH₂C12 and pentane to provide the desired product as a tan solid (0.092g, 61%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 11.76-11.94 (2H, m), 7.77 - 7.85 (4 H, m), 7.66 - 7.72 (4 H, m), 7.60 - 7.66 (2 H, m, 7=11.60 Hz), 5.39 (1 H, s), 5.28 (1 H, s), 5.03 (2 H, s), 3.66 - 3.79 (4 H, m), 2.61 - 2.70 (2 H, m), 2.28 2.38 (2 H, m), 1.42 (10 H, s), 1.24 (8 H, s). LCMS - Phenomenex C-18 3.0 x 50mm, 0 to 100% B over 4.0 minute gradient, 1 minute hold time, A = 10% methanol 90% water 0.1% TFA, B = 90% methanol 10% water 0.1% TFA, (t_R= 3.58 min) Anal Calcd. for C36H42F2N6O4 660.70; found 661.68 (M+H)⁺.

<img file="IL196813A_D0111.tif" />

Prepared from 1-lb and 1-lc in the same manner as the preparation of Id from lb and 1c. Ή NMR (500 MHz, DMSO-d₆) δ ppm 1.18/1.40 (two br. s., 18H),

2.53 - 2.75 (m, 7=25.94 Hz, 2H), 2.86 - 3.06 (m, 2H), 3.78 - 4.02 (m, 4H), 5.04 (br s, 2H), 7.17 - 8.24 (m, 10H), 12.07/12.37 (two br. s., 2H); HPLC XTERRA C-18 3.0 x 50 mm, 0 to 100% B over 2 minutes, 1 minutes hold time, A = 90% water, 10% methanol, 0.2% H3PO4, B = 10% water, 90% methanol, 0.2% H3PO4, RT = 1.31 min, 99% homogeneity index. LCMS: Anal. Calcd. for C36H40F4N6O4: 696.73; found: 967.64 (M+H)⁺.

Dissymmetric compounds such as intermediate l-3d and l-4d can be prepared by the same method. For example, reaction of 1-lc with lb in the same manner as described above for the preparation of Id provided l-3d. Similarly, reaction of l-4c with lb in the same manner as described above for the preparation of Id provideed 14d.

N Boc l-3d ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.40/1.18 (two br s, 18H), 1.90-2.02 (m, 2H), 2.02-2.12 (m, 1H), 2.28-2.46 (m, 2H), 2.68-2.87 (m, 1H), 3.35-3.49 (m, 1H), 3.533.62 (m, 1H), 3.82-4.10 (m, 2H), 4.92-5.11 (m, 1H), 5.28 (s, 1H), 7.79-8.00 (m, 8H), 8.03-8.25 (m, 2H), 13.77-15.16 (m, 2H); HPLC XTERRA C-18 3.0 x 50 mm, 0 to 100% B over 4 minutes, 1 minute hold time, A = 90% water, 10% methanol, 0.2% H3PO4, B = 10% water, 90% methanol, 0.2% H3PO4, RT = 1.22 minutes, 99% homogeneity index. LCMS: Anal. Calcd. for C36H42F2N6O4: 660.75; found: 661.98 (M+H)⁺.

<img file="IL196813A_D0112.tif" />

l-4d

Example l-4d was prepared from l-4c and lb in similar fashion to the preparation of Id from lb and 1c. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 0.99 - 1.60 (m, 18 H) 1.75 - 2.11 (m, 7=73.24 Hz, 6 H) 2.12 - 2.32 (m, 2 H) 3.32 - 3.41 (m, 2 H) 3.56 (s, 2 H) 4.63 - 5.02 (m, 2 H) 6.98 - 8.28 (m, 10 Η) 11.67 - 12.33 (m, 2 H); LC conditions: Phenomenex Luna 3.0 X 5.0mm S10, Solvent A - 0.1% TFA in 10% MeOH/90%H₂O, Solvent B - 0.1% TFA in 90% MeOH/10% H₂0,0 to 100% B over ?min, Stop time = 3min, Flow rate = 4ml/min, Wavelength = 220nm, LC/MS (M+H)⁺= 625.32. Retention time = 1.438 min

Additional biphenyl analogs were prepared similarly.

LC conditions for Examples l-5d through l7־d: Condition 1: Phenomenex LUNA C-18 4.6 x 50 mm, 0 to 100% B over 3 minutes, 1 minute hold time, A = 90% water, 10% methanol, 0.1% TFA, B = 10% water, 90% methanol, 0.1% TFA, 220nm, 5 pL injection volume.

Condition 2: Phenomenex LUNA C-18 4.6 x 50 mm, 0 to 100% B over 2 minutes, 1 minute hold time, A = 90% water, 10% methanol, 0.1% TFA, B = 10% water, 90% methanol, 0.1% TFA, 220nm, 5 pL injection volume.

<td> Example</td><td> Compound Name</td><td> Structure</td><td> Characterization Data</td>

<td> l-5d</td><td> di-tert-butyl (4,4'biphenyldiylbis( 1Himidazole-5,2diyl(lS)-l,lethanediyl))bis(meth</td><td> &lt; W1 *“.N ^r״״ Prepared from l-8c and l-6b</td><td> RT = 1.64 minutes (&gt;95%); Condition 2; LCMS: Anal. Calcd Cj4H45N6O₄</td>

<td></td><td> ylcarbamate)</td><td></td><td> 601.35; found: 601.48 (M+H)⁺; LRMS: Anal. Calcd. for C34H44N6O4 600.34; found: 601.32 (M+H)⁺.</td>

<td> l-6d</td><td> tert-butyl (2S)-2-(5(4-(2-(( 1S)-1-((tertbutoxycarbonyl)(me thyl)amino)ethyl)lH-imidazol-5-yl)4-biphenylyl)-lHimidazol-2-yl)-l pyrrolidinecarboxyla te</td><td> \ V 1Y1 י IHJ Prepared from l-8c and lb</td><td> RT = 1.63 minutes (&gt;95%); Condition 2; LCMS: Anal. Calcd C35H45N6O4 613.34; found: 613.56 (M+H)⁺; LRMS: Anal. Calcd. for C35H44N6O4 612.34; found: 613.33 (M+H)⁺-</td>

<td> l-7d</td><td> benzyl (28)-2-(5-(4(2-((18)-1-((tertbutoxycarbonyl)(me thyl)amino)ethyl)lH-imidazol-5-yl)4-bipheny ly 1)-1Himidazol-2-yl)-lpyrrolidinecarboxyla te</td><td> .hk Ok \ ^H 11 1 Ao 0^,0 IW י—N Prepared from l-6b and l5־c</td><td> RT = 1.65 minutes (&gt;95%); Condition 2; LCMS: Anal. Calcd C38H43N6O4 647.33; found: 647.44 (M+H)⁺; LRMS: Anal. Calcd. for C38H42N6O4 646.33; found: 647.34 (M+H)⁺.</td>

Example 1, Step e

5,5 '-(4,4 '-biphenyldiyl)bis(2-((2S)-2-pyrrolidinyl)-lH-imidazole)

<img file="IL196813A_D0113.tif" />

A mixture of carbamate Id (560 mg) and 25% TFA/CH2C12 (9.0 mL) was stirred at ambient condition for 3.2 hours. The volatile component was removed in vacuo, and the resulting material was free based using an MCX column (methanol wash; 2.0 M NH₃/methanol elution) to provide pyrrolidine le as a dull yellow solid (340 mg). ¹H NMR (DMSO-d6, <3= 2.5 ppm, 400 MHz): δ 11.83 (br s, 2H), 7.80 (d, 7= 8.1, 4H), 7.66 (d, 7= 8.3, 4H), 7.46 (br s, 2H), 4.16 (appt, 7= 7.2, 2H), 2.992.69 (m, 6H), 2.09-2.00 (m, 2H), 1.94-1.66 (m, 6H). LC (Cond. 1): RT = 1.27 min; > 98% homogeneity index; LC/MS: Anal. Calcd. for [M+H]⁺ C26H29N6: 425.25; found 425.25; HRMS: Anal. Calcd. for [M+H]⁺ C26H29N₆: 425.2454; found 425.2448

Additional analogs such as 1-le to l-4e can be prepared in a similar fashion.

<img file="IL196813A_D0114.tif" />

• 4HCI

1-le

To a solution of 1-ld (3R,3'R,5S,5'S)-tert-butyl 5,5’-(5,5'-(biphenyl-4,4'diyl)bis(lH-imidazole-5,2-diyl))bis(3-hydroxypyrrolidine-l-carboxylate) in 3mL dioxane was added 0.8mL of a 4.0M solution of HC1 in dioxane. The reaction was stirred for 2 hours at room temperature and concentrated under reduced pressure. The resulting tan solid was dried under vacuum to give 1-le (3R,3'R,5S,5'S)-5,5'(5,5'-(biphenyl-4,4'-diyl)bis(l H-imidazole-5,2-diyl))dipyrrolidin-3 oltetrahydrochloride (0.55g, 100%yield). Used without further purification. ¹H NMR (500 MHz, DMSO-d6) δ ppm 10.33 (s, 2H), 9.85 (s, 2H), 8.09 (s, 2H), 8.01 (d, 7=8.24 Hz, 4H), 7.88 (d, 7=8.24 Hz, 4H), 5.14 (m, 2H), 4.62 (m, 2H), 3.61 (m, 2H),

3.23 (d, /=11.29 Hz, 2H), 2.64 (m, 2H), 2.44 (dd, /=13.43, 6.71 Hz, 2H); LCMS Waters-Sunfire C-18 4.6 x 50mm, 0 to 100% B over 4.0 minute gradient, 1 minute hold time, A = 10% methanol 90% water 0.1% TFA, B = 90% methanol 10% water

0.1% TFA, RT= 1.35 minutes Anal. Calcd. for 456.30; found 457.25 (M+H)⁺;

Nominal/LRMS - (M+H)⁺457.35־.

<img file="IL196813A_D0115.tif" />

• 4 HCI l-2e

Example 1 -2e was prepared in similar fashion to the method described for the preparation of 1-le. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 10.32 (1 H, s) 8.01 (2 H, s) 7.97 (4 H, d, /=8.24 Hz) 7.86 (4 H, d, /=8.24 Hz) 5.01-5.10 (2 H, m) 4.52-4.60 (2 H, m) 3.36-3.45 (2 H, m) 3.25 (2 H, s) 2.60-2.68 (2 H, m) 2.40-2.48 (2 H, m); LCMS - Phenomenex C-18 3.0 x 50mm, 0 to 100% B over 4.0 minute gradient, 1 minute hold time, A = 10% methanol 90% water 0.1% TFA, B = 90% methanol 10% water 0.1% TFA, RT= 2. lOmin., Anal. Calcd. for 456.30; found 457.22 (M+H)⁺

<img file="IL196813A_D0116.tif" />

l-2e-l

2-((2S)-2-pyrrolidinyl)-4-(3'-(2-((2S)-2-pyrrolidinyl)-lH-imidazol-5-yl)-3biphenylyl)-IH-imidazole

Example l-2e-l was prepared from l-2d-l in similar fashion described for the preparation of 1-le. ¹H NMR (500 MHz, DMSO-de) δ ppm 1.74-2.44 (m, 12H), 4.83 (s, 2H), 7.37-7.72 (m, 4H), 7.74-8.03 (m, 4H), 8.10 (s, 2H), 9.14 (s, 2H), 9.81 (s, 2H). LC/MS (M+H)⁺= 425.30.

<img file="IL196813A_D0117.tif" />

l-2e-2

To a solution of l-2d-2 (0.084g, 0.13mmol) in ImL dioxane was added

SmT. of a 4.0M solution of HCI in dioxane. The reaction was stirred for 2 hours at room temperature and concentrated under reduced pressure. The resulting tan solid was dried under vacuum to give l-2e-2 (0.077g, 100%yield). The compound was used without further purification. ¹H NMR (500 MHz, DMSO־d6) δ ppm 8.00 (2H, s), 7.97 (4H, d, 7=8.55 Hz), 7.85 (4H, d, 7=8.24 Hz), 5.63 (1H, s), 5.52 (1H, s), 5.09 - 5.17 (2H, m), 3.67 - 3.74 (2H, m), 3.63 - 3.67 (2H, m), 3.07 - 3.14 (1H, m), 2.89 2.96 (1H, m), 2.81 2) 2.87 ־H, m); LCMS - Phenomenex C-18 3.0 x 50mm, 0 to 100% B over 4.0 minute gradient, 1 minute hold time, A = 10% methanol 90% water 0.1% TFA, B = 90% methanol 10% water 0.1% TFA, (t_R= 2.22 min) Anal Calcd. for C26H26F2N6 460.53; found 461.37 (M+H)⁺.

<img file="IL196813A_D0118.tif" />

Prepared from l-2d-3 in the same manner as the preparation of 11־ e from 1Id. ¹HNMR (500 MHz, DMSO-d₆) δ ppm 2.97 - 3.13 (m, 4H), 3.64 - 3.91 (m, 4H), 5.16 (d, 7=6.41 Hz, 2H), 7.84 (d, 7=7.93 Hz, 4H), 7.96 (d, 7=7.93 Hz, 4H), 8.00 (s, 2H); HPLC XTERRA C-18 3.0 x 50 mm, 0 to 100% B over 4 minutes, 1 minutes hold time, A = 90% water, 10% methanol, 0.2% H₃PO₄, B = 10% water, 90% methanol, 0.2% H3PO4, RT = 1.66 min, 92% homogeneity index. LCMS: Anal. Calcd. for C26H24F4N6: 496.50; found: 495.53 (M-H)־.

Analogous dissymmetric compounds such as intermediates l3־e and l-4e can be prepared by the same method.

<img file="IL196813A_D0119.tif" />

l-3e ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.87-2.09 (m, IH), 2.13-2.26 (m, IH), 2.372.47 (m, 2H), 2.92-3.12 (m, 2H), 3.37 (s, IH), 3.40-3.49 (m, IH), 3.67-3.91 (m, 2H), 4.96-5.05 (m, IH), 5.14 (t, 7=8.70 Hz, IH), 7.86 (t, 7=9.00 Hz, 4H), 7.93-8.03 (m, 5H), 8.10 (s, IH), 10.26/9.75 (two br s., 2H); HPLC XTERRA C-18 3.0 x 50 mm, 0 to 100% B over 4 minutes, 1 minute hold time, A = 90% water, 10% methanol, 0.2% H3PO4, B = 10% water, 90% methanol, 0.2% H3PO4, RT = 0.8622 minutes, 99% homogeneity index; LCMS: Anal. Calcd. for C26H26F2N6: 460.52; found: 461.45 (M+H)⁺.

<img file="IL196813A_D0120.tif" />

Example l-4e was prepared from l-4d in similar fashion to that described for the preparation of 1-le from 1-ld. ¹H NMR (500 MHz, DMSO-d6) δ ppm 1.90 - 2.13 (m, 2 H) 2.12 - 2.31 (m, 2 H) 2.36 - 2.60 (m, 4 H) 3.29 - 3.55 (m, 4 H) 5.00 (s, 2 H) 7.35 - 8.50 (m, 10 H) 9.76 (s, 2 H) 10.12 - 10.45 (m, 2 H). LC conditions: Phenomenex Luna 3.0 X 5.0mm S10, Solvent A - 0.1% TFA in 10% MeOH/90%H₂O, Solvent B - 0.1% TFA in 90% MeOH/10% H₂0,0 to 100% B over ?.min, Stop time = 3min, Flow rate = 4ml/min, Wavelength = 220nm, LC/MS (M+H)⁺ = 425.28. Retention time = 0.942 min

Additional analogs were prepared similarly:

<td> Example</td><td> Compound Name</td><td> Structure</td><td> Data</td>

<td> l-5e</td><td></td><td> 7-¢ 1 — N ^{H H} 1 11 11 1 Η H !kj Prepared from l-6d</td><td> RT = 1.37 min; LCMS: Anal. Calcd. for C25H2₈N₆412; found: 413 (M+H)⁺.</td>

<td> l-6e</td><td></td><td> Hl L jL Η H | 1 UO X τ &gt;-cj Prepared from l-7d</td><td> RT = 1.43 min; LCMS: Anal. Calcd. for C₃₃H₃₅N6O2 547; found: 547 (M+H)⁺.</td>

<td> 1-7e</td><td></td><td> ״O! Z־־NH &lt; 1 Prepared from l-5d</td><td> RT = 1.12 min; LRMS: Anal. Calcd. for C24H28N6 400.24; found: 401.22 (M+H)⁺.</td>

LC Conditions for l-5e through l-7e: Phenomenex LUNA C-18 4.6 x 50 mm, 0 to 100% B over 2 minutes, 1 minute hold time, A = 90% water, 10% methanol, 0.1% TFA, B = 10% water, 90% methanol, 0.1% TFA, 220nm, 5 pL injection volume.

Alternative Synthesis of Example 1, Step e 5_i5’-(4_!4'-biphenyldiyl)bis(2-((2S)-2-pyrrolidinyl)-lH-imidazole)

<img file="IL196813A_D0121.tif" />

Example A-le-1

<img file="IL196813A_D0122.tif" />

A 1 L, 3-neck round bottom flask, fitted with a nitrogen line, overhead stirrer and thermocouple was charged with 20 g (83.9 mmol, 1 equiv) l,r־(biphenyl-4,4’diyl)diethanone, 200 mL CH₂C1₂ and 8.7 mL (27.1g, 169.3 mmol, 2.02 quiv) bromine. The mixture was allowed to stir under nitrogen for about 20h under ambient conditions. The resulting slurry was charged with 200 mL CH₂C1₂ and concentrated down to about 150 mL via vacuum distillation. The slurry was then solvent exchanged into THF to a target volume of 200 mL via vacuum distillation. The slurry was cooled to 2025־ °C over Ih and allowed to stir at 20-25 °C for an additional hour. The off-white crystalline solids were filtered and washed with 150 mL CH₂C1₂. The product was dried under vacuum at 60 °C to provide 27.4 g (69.2 mmol, 82%) of the desired product: ¹H NMR (400 MHz, CDC13) δ 7.95-7.85 (m, 4H), 7.60-7.50 (m, 4H), 4.26 (s, 4H); ¹³C NMR (100 MHz, CDCI3) δ 191.0, 145.1, 133.8, 129.9,127.9, 30.8; IR (KBr, cm-1) 3007, 2950,1691, 1599,1199; Anal calcd for C16H1₂Br₂O₂: C, 48.52; H, 3.05; Br, 40.34. Found: C, 48.53; H, 3.03; Br, 40.53. HRMS calcd for C16H13Br₂O₂(M + H;DCI⁺): 394.9282. Found: 394.9292. mp 224-226 °C.

Example A-le-2

<img file="IL196813A_D0123.tif" />

A 500 mL jacketed flask, fitted with a nitrogen line, thermocouple and overhead stirrer, was charged with 20 g (50.5 mmol, 1 equiv) of Example A-le-1, 22.8 g (105.9 moles, 2.10 equiv) l-(zert-butoxycarbonyl)-L-proline, and 200 mL acetonitrile. The slurry was cooled to 20 °C followed by the addition of 18.2 mL (13.5 g, 104.4 mmol, 2.07 equiv) DIPEA. The slurry was warmed to 25 °C and allowed to stir for 3h. The resulting clear, organic solution was washed with 3 x 100 ml. 13 wt% aqueous NaCl. The rich acetonitrile solution was solvent exchanged into toluene (target volume = 215 mL) by vacuum distillation until there was less than 0.5 vol% acetonitrile.

<img file="IL196813A_D0124.tif" />

The above toluene solution of Example A-le2־ was charged with 78 g (1.011 moles, 20 equiv) ammonium acetate and heated to 95-100 °C. The mixture was allowed to stir at 95-100 °C for 15h. After reaction completion, the mixture was cooled to 70-80 °C and charged with 7 mL acetic acid, 40 mL n-butanol, and 80 mL of 5 vol% aqueous acetic acid. The resulting biphasic solution was split while maintaining a temperature > 50 °C. The rich organic phase was charged with 80 mL of 5 vol% aqueous acetic acid, 30 mL acetic acid and 20 mL n-butanol while maintaining a temperature > 50 °C. The resulting biphasic solution was split while maintaining a temperature > 50 °C and the rich organic phase was washed with an additional 80 mL of 5 vol% aqueous acetic acid. The rich organic phase was then solvent exchanged into toluene to a target volume of 215 mL by vacuum distillation. While maintaining a temperature > 60 °C, 64 mL MeOH was charged. The resulting slurry was heated to 70-75 °C and aged for Ih. The slurry was cooled to 20-25 °C over Ih and aged at that temperature for an additional hour. The slurry was filtered and the cake was washed with 200 mL 10:3 toluene:MeOH. The product was dried under vacuum at 70 °C, resulting in 19.8 g (31.7 mmol, 63%) of the desired product: Ή NMR (400 MHz, DMSO-7₀) δ 13.00-11.00 (s, 2H), 7.90-7.75 (m, 4H), 7.75-7.60 (m, 4H), 7.60-7.30 (s, 2H), 4.92-4.72 (m, 2H), 3.65-3.49 (m, 2H), 3.49-3.28 (m, 2H), 2.39-2.1 (m, 2H), 2.10-1.87 (m, 6H), 1.60-1.33 (s, 8H), 1.33-1.07 (s, 10H); ¹³CNMR (100 MHz, DMSO-76) δ 154.1, 153.8, 137.5, 126.6, 125.0, 78.9, 78.5, 55.6, 55.0, 47.0,46.7,33.7, 32.2, 28.5, 28.2, 24.2, 23.5; IR (KBr, cm-1) 2975, 2876, 1663, 1407, 1156,1125; HRMS calcd for C36H45N6O4 (M + H; ESI*): 625.3502. Found: 625.3502. mp 190-195 °C (decomposed).

Example A-le-4

<img file="IL196813A_D0125.tif" />

To a 250 ml reactor equipped with a nitrogen line and overhead stirrer, 25.0 g of Example A-le-3 (40.01 mmol, 1 equiv) was charged followed by 250 mL methanol and 32.85 mL (400.1 mmol, 10 equiv) 6M aqueous hydrogen chloride. The temperature was increased to 50 °C and agitated at 50 °C for 5h. The resulting slurry was cooled to 20-25 °C and held with agitation for ca. 18h. Filtration of the slurry afforded a solid which was washed successively with 100 ml 90% methanol/water (V/V) and 2x100 ml of methanol. The wet cake was dried in a vacuum oven at 50 °C overnight to give 18.12 g (31.8 mmol, 79.4%) of the desired product.

Recrystallization of Example A-le-4

To a 250 ml reactor equipped with a nitrogen line and an overhead stirrer, 17.8g of crude Example A-le-4 was charged followed by 72 mL methanol. The resulting slurry was agitated at 50 °C for 4h, cooled to 20-25 °C and held with agitation at 20-25 °C for lh. Filtration of the slurry afforded a crystalline solid which was washed with 60 ml methanol. The resulting wet cake was dried in a vacuum oven at 50 °C for 4 days to yield 14.7 g (25.7 mmol, 82.6%) of the desired product: ¹H NMR (400 MHz, DMSO-4/6) δ 10.5-10.25 (br, 2H), 10.1-9.75 (br, 2H), 8.19 (s, 2H), 7.05 (d, J = 8.4, 4H), 7.92 (d, J = 8.5, 4H), 5.06 (m, 2H), 3.5-3.35 (m, 4H), 2.62.3 (m, 4H), 2.25-2.15 (m, 2H), 2.18-1.96 (m, 2H); ¹³C NMR (100 MHz, DMSO- d₆) δ 156.6, 142.5,139.3,128.1,127.5,126.1, 116.9, 53.2,45.8, 29.8, 24.3; IR (KBr, cm1028 ,1428 ,1493 ,1567 ,1636 ,2627 ,3429 (¹־. Anal calcd for C26H32N6CI4: C, 54.75; H, 5.65; Cl, 24.86; Adjusted for 1.9% water: C, 53.71; H, 5.76; N, 14.46; Cl, 24.39. Found: C, 53.74; H, 5.72; N, 14.50; Cl, 24.49; KF = 1.9. mp 240 °C (decomposed)

N

N H

H N

Example 1 (lR,rR)-2,2'-(4,4'-biphenyldiylbis(lH-imidazole-5,2-diyl(2S)-2,lpyrrolidinediyl))bis(N,N-dimethyl-2-oxo-l-phenylethanamine)

HATU (44.6 mg, 0.117 mmol) was added to a mixture of pyrrolidine le (22.9 mg, 0.054 mmol), diisopropylethylamine (45 pL, 0.259 mmol) and Cap-1 (28.1 mg, 0.13 mmol) in DMF (1.5 mL), and the resulting mixture was stirred at ambient for 90 minutes. The volatile component was removed in vacuo, and the residue was purified first by MCX (methanol wash; 2.0 M NH3/methanol elution) and then by a reverse phase HPLC system (H2O/methanol/TFA) to provide the TFA salt of Example 1 as an off-white foam (44.1 mg). ¹H NMR (DMSO-d6, δ= 2.5 ppm, 400 MHz): δ 10.25 (br s, 2H), 8.20-7.10 (m, 20H), 5.79-5.12 (m, 4H), 4.05-2.98 (m, 4H), 2.98-2.62 (m, 6H), 2.50-1.70 (m, 14H), [Note: the signal of the imidazole NH was too broad to assign a chemical shift]; LC (Cond. 1): RT - 1.40 min; > 98% homogeneity index; LC/MS: Anal. Calcd. for [M+H]⁺ C46H₅1N₈O₂: 747.41; found

747.58

Examples 2 to 24-4d

<img file="IL196813A_D0126.tif" />

Examples 2 to 24-4h were prepared as TFA salts by substituting the respective acids for Cap-1 using the same method described for Example 1. Caps in the following table without a number are commercially available.

<td> Example</td><td> Compound Name</td><td> 0 rAjS</td><td> RT (LC-Cond.); % homogeneity index; MS data</td>

<td> 2</td><td> (lR,l'R)-2,2'-(4,4'biphenyldiylbis( 1 H-imidazole5,2-diyl(2S)-2,lpyrrolidinediyl))bis(2-oxo-1 - phenylethanol)</td><td> 0 ^ΡΡΛ HO</td><td> 1.55 minutes (Cond. 1); &gt;98%; LC/MS: Anal. Calcd. for [M+H]⁺C42H41N6O4: 693.32; found 693.46; HRMS: Anal. Calcd. for[M+H]⁺C42H41N₆O4:693.3189; found 693.3182</td>

<td> 3</td><td> (2S^'S)-l,r-(4,4'- biphenyldiylbis( 1 H-imidazole- 5,2-diyl(2S)-2,lpyrrolidinediyl))bis( 1 -oxo-2phenyl-2-propanol)</td><td> 0 ^PhxS &lt; *OH</td><td> 1.77 minutes (Cond. 1); &gt;98%; LC/MS: Anal. Calcd. for [M+H]⁺C44H45N6O4: 721.35; found 721.52; HRMS: Anal. Calcd. for[M+H]⁺C44H45N6O4: 721.3502; found 721.3515</td>

<td> 4</td><td> dimethyl (4,4'biphenyldiylbis( 1 H-imidazole5,2-diyl(2S)-2,lpyrrolidinediyl(( 1 R)-2-oxo-1 - phenyl-2,1ethanediyl)))biscarbamate</td><td> 0 ״^,Ά HN^O Π 0 Cap-4</td><td> 1.64 minutes (Cond. 1); &gt;98%; LC/MS: Anal. Calcd. for[M+H]⁺C46H47N8O6: 807.36; found 807.58</td>

<td> 5</td><td> (lS,rS)-2,2'-(4,4'biphenyldiylbis( 1 H-imidazole5,2-diyl(2S)2־,lpyrrolidinediyl))bis(N,Ndimethyl-2-oxo-l phenylethanamine)</td><td> 0 ^ρκΆ ent of Cap-1</td><td> 1.33 minutes (Cond. 1); &gt;98%; LC/MS: Anal. Calcd. for[M+H]⁺C46H51N8O2: 747.41; found 747.64; HRMS: Anal. Calcd. for[M+H]⁺C46H51N8O2: 747.4135; found 747.4103</td>

<td> 6</td><td> 5,5 '-(4,4'-biphenyldiyl)bis(2- ((2S)-l-benzoyl-2- pyrrolidinyl)-1 H-imidazole)</td><td> 0 Ph׳־^^</td><td> 1.65 minutes (Cond. 1); &gt;98%; LC/MS: Anal. Calcd. for[M+H]⁺C40H37N6O2: 633.30; found 633.51</td>

<td> ר</td><td> 5,5'-(4,4'-biphenyldiyl)bis(2- ((2 S)-1 -(phenylacetyl)-2pyrrolidinyl)-1 H-imidazole)</td><td> 0 r Γ</td><td> 1.71 minutes (Cond. 1); &gt;98%; LC/MS: Anal. Calcd. for[M+H]⁺C42H41N6O2: 661.33; found 661.53; HRMS: Anal. Calcd. for[M+H]⁺C42H₄₁N₆O2: 661.3291; found 661.3300</td>

<td> 8</td><td> 5,5 '-(4,4'-biphenyldiyl)bis(2((2S)-l-((2R)-2-methoxy-2phenylacetyl)-2-pyrrolidinyl)1 H-imidazole)</td><td> סי□ Ofl-Z ⁷ &lt; °</td><td> 1.63 minutes (Cond. 1); &gt;98%; LC/MS: Anal. Calcd. for [M+H]⁺C44H45N6O4: 721.35; found 721.59; HRMS: Anal. Calcd. for [M+H]⁺C44H45N6O4: 721.3502; found 721.3536</td>

<td> 9</td><td> (2R,2'R)-l,r4,4)־'biphenyldiylbis( 1 H-imidazole5,2-diyl(2S)-2,lpyrrolidinediyl))bis( 1 -oxo-3 - phenyl-2-propanol)</td><td> 0 OH</td><td> 1.71 minutes (Cond. 1); &gt;98%; LC/MS: Anal. Calcd. for [M+H]⁺C44H45N6O4: 721.35; found 721.58; HRMS: Anal. Calcd. for[M+H]⁺C44H45N6O4: 721.3502; found 721.3497</td>

<td> 10</td><td> 5,5'-(4,4'-biphenyldiyl)bis(2- ((2 S)-1 -propiony 1-2pyrrolidinyl)-1 H-imidazole)</td><td> 0</td><td> 1.47 minutes (Cond. 1); &gt;98%; LC/MS: Anal. Calcd. for[M+H]⁺C32H37N6O2: 537.30; found 537.40; HRMS: Anal. Calcd. for [M+H]⁺C32H37N6O2: 537.2978; found 537.2952</td>

<td> 11</td><td> 5,5'-(4,4'-biphenyldiyl)bis(2- ((2S)-1 -(cyclopropylcarbonyl)- 2-pyrrolidinyl)-1 H-imidazole)</td><td> 0 F</td><td> 1.48 minutes (Cond. 1); &gt;98%; LC/MS: Anal. Calcd. for [M+H]⁺C34H37N₆O2: 561.30; found 561.44</td>

<td> 12</td><td> 5,5'-(4,4'-biphenyldiyl)bis(2((2 S)-1 -(cyclopropylacety 1)-2pyrrolidinyl)-1 H-imidazole)</td><td> Λ ⁰</td><td> 1.57 minutes (Cond. 1); &gt;98%; LC/MS: Anal. Calcd. for[M+H]⁺C36H41N6O2: 589.33; found 589.48; HRMS: Anal. Calcd. for [M+H]⁺C36H41N6O2: 589.3291; found 589.3268</td>

<td> 13</td><td> 5,5 '-(4,4'-biphenyldiyl)bis(2((2 S)-1 -((2R)-tetrahy dro-2furanylcarbonyl)-2pyrrolidinyl)-1 H-imidazole)</td><td> 0</td><td> 1.44 minutes (Cond. 1); &gt;98%; LC/MS: Anal. Calcd. for[M+H]⁺C36H41N₆O₄: 621.32; found 621.52; HRMS: Anal. Calcd. for[M+H]⁺</td>

<td></td><td></td><td></td><td> C36H41N6O4: 621.3189; found 621.3191</td>

<td> 14</td><td> 2,2'-(4,4'-bipl1enyldiylbis( 1 Ηimidazole-5,2-diyl(2S)-2,l pyrrolidmediyl))bis(N,Ndimethyl-2-oxoethanamine)</td><td> » ן</td><td> 1.27 minutes (Cond. 1); &gt;98%; LC/MS: Anal. Calcd. for [M+H]⁺C34H43N8O2: 595.35; found 595.54; HRMS: Anal. Calcd. for [M+H]⁺C34H43N8O2: 595.3509; found 595.3503</td>

<td> 15</td><td> (2R,2'R)-1,1-(4,4'biphenyldiylbis( 1 H-imidazole- 5,2-diyl(2S)-2,lpyrrolidinediyl))bis( 1 -oxo-2propanol)</td><td> 0 OH</td><td> 1.36 minutes (Cond. 1); &gt;98%; LC/MS: Anal. Calcd. for [M+H]⁺C32H₃₇N₆O4: 569.29; found 569.44; HRMS: Anal. Calcd. for[M+H]⁺C32H37N6O4: 569.2876; found 569.2872</td>

<td> 16</td><td> (2R,2'R)-l,r4,4)־'- biphenyldiylbis( 1 H-imidazole- 5,2-diyl(2S)-2,l- pyrrolidinediyl))bis(3-methyl- l-oxo-2-butanol)</td><td> 1 ⁰ A/v OH</td><td> 1.51 minutes (Cond. 1); &gt;98%; LC/MS: Anal. Calcd. for [M+H]⁺C36H45N6O4: 625.35; found 625.50; HRMS: Anal. Calcd. for [M+H]⁺C36H45N6O4: 625.3502; found 625.3517</td>

<td> 17</td><td> 5,5'-(4,4'-biphenyldiyl)bis(2((2S)-1 -((2R)-2-phenyl-2-(l pyrrolidinyl)acetyl)-2pyrrolidinyl)-1 H-imidazole)</td><td> 0 ό Cap-5</td><td> 1.13 minutes (Cond. 1); &gt;98%; LC/MS: Anal. Calcd. for[M+H]⁺C50H55N8O2: 799.45; found 799.67</td>

<td> 18</td><td> 4,4'-(4,4'-biphenyldiylbis( 1Himidazole-5,2-diy 1(28)-2,1 pyrrolidinediyl(( 1 R)-2-oxo-1 phenyl-2,1-</td><td> 0 ^PhAy ό</td><td> 1.11 minutes (Cond. 1); &gt;98%; LC/MS: Anal. Calcd. for [M+H]⁺C50H55N8O4: 831.44; found</td>

<td></td><td> ethanediyl)))dimorpholine</td><td> Cap-6</td><td> 831.71</td>

<td> 19</td><td> 5,5'-(4,4'-biphenyldiyl)bis(2((2S)-l-(((3S)-3-fluoro-lpyrrolidinyl)(phenyl)acetyl)-2pyrrolidinyl)-1 H-imidazole)</td><td> 0 ^ph Diastereomer-1 Cap-9a</td><td> 1.17 minutes (Cond. 1); 97%; LC/MS: Anal. Calcd. for [M+H]⁺ C50H53F2N8O2: 835.43; found 835.51; HRMS: Anal. Calcd. for [M+H]⁺C50H₅₃F2N₈O2: 835.4260; found 835.4261</td>

<td> 20</td><td> 5,5'-(4,4'־biphenyldiyl)bis(2((2S)-l-(((3S)-3-fluoro-lpyrrolidinyl)(phenyl)acetyl)-2pyrrolidinyl)-1 H-imidazole)</td><td> 0 Ph γΛγ Diastereomer-2 Cap-9b</td><td> 1.03 minutes (Cond. 1); &gt;98%; LC/MS: Anal. Calcd. for [M+H]⁺C50H₅₃F₂N₈O2: 835.43; found 835.51; HRMS: Anal. Calcd. for [M+H]⁺C₅0H₅₃F₂N₈O2: 835.4260; found 835.4266</td>

<td> 21</td><td> (lR,l'R)-2,2'-(4,4'biphenyldiylbis( 1 H-imidazole5,2-diyl(2S)-2,lpyrrolidinediyl))bis(N,Ndiethyl-2-oxo-lphenylethanamine)</td><td> 0 Cap-2</td><td> 1.13 minutes (Cond. 1); &gt;98%; LC/MS: Anal. Calcd. for [M+H]⁺C50H59N8O2: 803.48; found 803.56; HRMS: Anal. Calcd. for [M+H]⁺C50H59N8O₂: 803.4761; found 803.4728</td>

<td> 22</td><td> (lR,rR)-2,2'-(4,4'biphenyldiylbis( 1 H-imidazole5,2-diyl(2S)-2,lpyrrolidinediyl))bis(N-ethylN-methyl-2-oxo-1 phenylethanamine)</td><td> 0 ^PhXX־Xj X/N'x Cap-3</td><td> 1.10 minutes (Cond. 1); &gt;98%; LC/MS: Anal. Calcd. for [M+H]⁺C48H55N8O2: 775.45; found 775.52; HRMS: Anal. Calcd. for [M+H]⁴־ C50H₅₉N₈O2: 775.4448; found 775.4456</td>

<td> 23</td><td> N,N'-(4,4'-biphenyldiylbis( 1 Ηimidazole-5,2-diyl(2S)-2,l pyrrolidinediyl(( 1 R)-2-oxo-1 phenyl-2,1ethanediyl)))diformamide</td><td> 0 HN. 1) 0</td><td> 1.22 minutes (Cond. 1); &gt;98%; LC/MS: Anal. Calcd. for [M+H]⁺C44H43N8O4: 747.34; found 747.38</td>

<td> 24</td><td> 1,1 '-(4,4'-biphenyldiylbis( 1Himidazole-5,2-diyl(2S)-2,1 pyrrolidinediylcarbonyl))dicyc lopropanol</td><td> 0 OH</td><td> 1.77 minutes (Cond. 2); &gt;98%; LC/MS: Anal. Calcd. for [M+H]⁺C34H37N6O4: 593.29; found 593.16</td>

<td> 24-1</td><td> 1,1 '-(4,4'-biphenyldiylbis( 1Himidazole-5,2-diyl(2S)-2,l pyrrolidinediyl(( 1 R)-2-oxo-l phenyl-2,1ethanediyl)))dipiperidine</td><td> 0 Cap-14</td><td>¹HNMR (400 MHz, DMSOd6) δ 12.18 (m, 0.4H), 11.96 (m, 0.4H), 11.79(m, 1.2H), 7.84-7.70 (m, 4H), 7.69-7.65 (m, 4H), 7.53-7.50 (m, 2H), 7.43- 7.28 (m,4H), 7.09-7.01 (m, 2H), 6.87-6.85 (m, 2H), 5.51-5.48 (m, 0.5H), 5.014.98 (m, 1.5H), 4.29 (m, 1.5H), 4.16 (m, 0.5H), 3.98 (m, 2H), 3.65-3.49 (m, 2H), 3.43- 3.36 (m, 2H), 2.41-2.31 (m, 8H), 2.14-1.82 (m, 8H), 1.47-1.31 (m, 12H);LCMS: Anal. Calcd. for C52H58N₈O2: 826; found: 827 (M+H)⁺.</td>

<td> 24-2</td><td> 1,1 '-(4,4'-biphenyldiylbis( 1Himidazole-5,2-diyl(2S)2,1־ pyrrolidinediyl(( 1 R)-2-oxo-1 phenyl-2,1 -ethanediyl)))bis(4methyl-4-piperidinol)</td><td> 0 Φ Me׳־» OH Cap-15</td><td>¹HNMR (400 MHz, DMSO&lt;16)612.02(brs, IH), 11.82 (br s, IH), 7.90-7.79 (m, 4H), 7.79-7.65 (m, 5H), 7.55 (brs, 2H),.7.45 (d, J = 7.6 Hz, 2H), 7.39-7.25 (m, 3H),</td>

<td></td><td></td><td></td><td> 7.34 (d, J =7.6 Hz, 2H), 7.04 (t, 7 = 7.6 Hz, 2H), 6.85 (d,7 = 8.1 Hz, 2H), 5.15-4.96 (m, 2H), 4.31-3.96 (m, 6H), 2.35-2.20 (m, 2H), 2.05-1.94 (m,4H), 1.94-1.81 (m, 4H), 1.50-1.35 (m, 9H), 1.35-1.20 (m,5H), 1.09 (s, 2H), 1.05 (s, 4H); LCMS: Anal. Calcd. for C54H62NgO4: 886: found: 887 (M+H)⁺.</td>

<td> 24-3</td><td> dimethyl (4,4biphenyldiylbis( 1 H-imidazole5,2-diyl(2S)-2,lpyrrolidinediyl(( 1R)-1 -(2chlorophenyl)-2-oxo-2,1 ethanediyl)))biscarbamate</td><td> NHCO₂Me ^Clo</td><td> LCMS: Anal. Calcd. for C46H44C12N8O6: 874; found: 875 (M+H)⁺.</td>

<td> 24-4a _</td><td> Ν',Ν'-(4,4'biphenyldiylbis( 1 H-imidazole4,2-diyl(2S)-2,lpyrrolidinediyl(( 1 R)-2-oxo-1 phenyl-2,1ethanediyl)))bis( 1,1 dimethylurea)</td><td>⁰ NH Cap-47</td><td>¹HNMR (500 MHz, DMSO-d6) δ ppm 1.89-2.00 (m, 7=17.09, 7.02 Hz,4H), 2.06-2.13 (m, 7= 14.95, 3.97 Hz, 3H), 2.24-2.33 (m, 7=8.70, 6.56 Hz, 2H), 2.792.84 (m, 12H), 3.29 (q, 2H), 3.95-4.03 (m, 3H), 5.26 (dd, 7=8.55, 2.14 Hz, 3H), 5.52 (d, 7=5.80 Hz, 3H), 6.72 (d, 7=6.10 Hz, 3H), 7.02-7.07 (m, IH), 7.29-7.36 (m, 3H), 7.39 (t, 7=7.17 Hz, 4H), 7.46 (d, 7=7.02 Hz, 3H), 7.92 (s, 8H), 8.12 (s, 2H); HPLC XTERRA C-18 4.6 x</td>

<td></td><td></td><td></td><td> 30 mm, 0 to 100% B over 4 minutes, 1 minute hold time, A = 90% water, 10% methanol, 0.2% H3PO4, B = 10% water, 90% methanol, 0.2% H3PO4, RT = 2.13 minutes, 96% homogeneity index; LCMS: Anal. Calcd. forC48H53N₁₀O₄: 832.42; found: 833.43 (M+H)⁺; HRMS: Anal. Calcd. for C48H54N₁₀O₄ 833.4251; found: 833.4267 (M+H)⁺.</td>

<td> 24-4b</td><td> Ν',Ν^,-(4,4'- biphenyldiylbis( 1 H-imidazole- 5,2-diyl(2S)-2,l- pyrrolidinediyl(( 1 R)-2-oxo-1 phenyl-2,1 -ethanediyl)))bis( 1 methylurea)</td><td> 0, *cr ־^HN _χΝΗ 45-Cap</td><td> RT = 4.45 minutes (Gemini C-l 8 4.6 x 50mm, 0 to 100% B over 10.0 minute gradient, 1 minute hold time, A = 5% acetonitrile, 95% water, 10mm ammonium acetate, B = 95% acetonitrile, 5% water, 10mm ammonium acetate); LCMS: Anal. Calcd. for C46H48N10O4 804.95; found: 805.41 (M+H)⁺; HRMS: Anal. Calcd. for C46H49N₁₀O4 805.3938; found: 805.3929 (M+H)⁺.</td>

<td> 24-4c</td><td> N',N'-(4,4'- biphenyldiylbis( 1 H-imidazole52,־-diyl(2S)-2,l- pyrrolidinediyl(( 1 R)-2-oxo-1 phenyl-2,1 -ethanediyl)))bis( 1 ethylurea)</td><td> 0 ^NH Cap-46</td><td> RT = 4.20 minutes (Gemini C-l 8 4.6 x 50mm, 0 to 100% B over 10.0 minute gradient, 1 minute hold time, A = 5% acetonitrile, 95% water, 10mm ammonium acetate, B = 95%</td>

<td></td><td></td><td></td><td> acetonitrile, 5% water, 1 Omm ammonium acetate);LCMS: Anal. Calcd. for C48H52N10O4 833.00; found: 833.48 (M+H)⁺.</td>

<td> 24-4d</td><td> N',N'-(4,4'- biphenyldiylbis( 1 H-imidazole5,2-diyl(2S)-2,l- pyrrolidinediyl(( 1 R)-2-oxo-1 phenyl-2,1 -ethanediy l)))bis (1 cyclopentylurea)</td><td> O Cap-48</td><td> RT = 4.92 minutes (Gemini C-18 4.6 x 50mm, 0 to 100% B over 10.0 minute gradient, 1 minute hold time, A = 5% acetonitrile, 95% water, 1 Omm ammonium acetate, B = 95% acetonitrile, 5% water, 10mm ammonium acetate); LCMS: Anal. Calcd. for C54H60N10O4 912.49; found: 913.68 (M+H)⁺; HRMS: Anal. Calcd. for C54H61N10O4 913.4877; found: 913.4899 (M+H)⁺.</td>

<td> 24-4e</td><td> 2,2'-(4,4'-biphenyldiylbis( 1Himidazole-5,2-diyl(2S)-2,l pyrrolidinediyl))bis(N-benzylN-methyl-2-oxoethanamine)</td><td> Me׳ V Cap-49</td><td>¹H NMR (500 MHz, DMSOde) δ ppm 1.97-2.43 (m,8H), 2.64-2.91 (m, 6H), 3.45-3.63 (m, 2H), 3.62-3.76 (m, 2H), 4.14 (dd, 4H), 4.22-4.45 (m, 4H), 5.29 (s, 2H), 7.28-7.65 (m, 10H), 7.90 (s, 8H), 8.06 (s, 2H), 14.62 (s, 2H); HPLC Xterra 4.6 X 50 mm, 0 to 100% B over 10 minutes, one minute hold time, A = 90% water, 10%&gt; methanol, 0.2% phosphoric acid, B =</td>

<td></td><td></td><td></td><td> 10% water, 90% methanol, 0.2% phosphoric acid. RT = 3.06 min; LCMS: Anal. Calcd. for: C46H50N8O2 746.96; Found: 747.41 (M+H)⁺.</td>

<td> 24-4f</td><td> (2S^'S)-l,l'-(4,4’biphenyldiylbis(lH-imidazole5,2-diyl(2S)-2,lpyrrolidinediyl))bis(N-benzylN-methyl-1 -oxo-2propanamine)</td><td> ׳Ύ Me Μ-, Me' \—_to</td><td> RT = 2.95 minutes (99%); HPLC Xterra 4.6 X 50 mm, 0 to 100% B over 10 minutes, one minute hold time, A = 90% water, 10% methanol, 0.2% phosphoric acid, B = 10% water, 90% methanol, 0.2% phosphoric acid; LCMS: Anal. Calcd. for: C48H54N8O2 775.02; Found: 775.45 (M+H)⁺.</td>

<td> 24-4g</td><td> 1,1 '-(4,4'-biphenyldiylbis( 1Himidazole-5,2-diyl(2S)-2,l pyrrolidinediyl))bis(N-benzylN,3-dimethyl-l -oxo-2butanamine)</td><td> Me \____t o Cap-50</td><td> RT= 3.86 minutes (100%); HPLC Xterra 4.6 X 50 mm, 0 to 100% B over 10 minutes, one minute hold time, A = 90% water, 10% methanol, 0.2% phosphoric acid, B = 10% water, 90% methanol, 0.2% phosphoric acid; LCMS: Anal. Calcd. for: C52H62N8O2 831.13; Found: 831.51 (M+H)⁺.</td>

<td> 24-4h</td><td> 1,1 '-(4,4'-biphenyldiylbis( 1Himidazole-5,2-diyl(2S)-2,1 pyrrolidinediyl(2-oxo-1 phenyl-2,1 -ethanediyl)))di(4piperidinol)</td><td> o ⁰ Ν—, Q OH Cap-8</td><td> RT = 2.86 minutes (100%); HPLC Xterra 4.6 X 50 mm, Oto 100%B over 10 minutes, one minute hold time, A = 90% water, 10% methanol, 0.2% phosphoric acid, B = 10% water, 90%</td>

<td></td><td></td><td></td><td> methanol, 0.2% phosphoric acid; LCMS: Anal. Calcd. for: C52H₅₈N₈O4 859.09; Found: 859.45 (M+H)⁺.</td>

Examples 24-5 to 24-18

<td> Example</td><td> Compound Name</td><td> Structure</td><td> Data</td>

<td> 24-5</td><td> 1,Γ-(4,4'biphenyldiylbis(l H-imidazole-5,2- diyl((2S,4S)-4fluoro-2,1pyrrolidinediyl)(( 1 R)-2-oxo-1phenyl-2,1ethanediyl)))dipip eridine</td><td> «״״N z^N** from l-2e-2 and Cap-l</td><td> Gemini C-18 4.6 x 50mm, 0 to 100% B over 10.0 minute gradient, 1 minute hold time, A = 5% acetonitrile, 95% water, 10mm ammonium acetate, B = 95% acetonitrile, 5% water, 10mm ammonium acetate. (RT=4.163 min); Nominal/LRMS Calcd. for C46H48F2N8O2 782.93; found 783.40 (M+H)⁺; Accurate/HRMS Calcd. for C46H49F2N8O2 783.3946; 783.3934 (M+H)⁺.</td>

<td> 24-6</td><td> (1R,1'R)־'2,2־ (4,4'biphenyldiylbis(! H-imidazole-5,2diyl((2S,4S)-4fluoro-2,1pyrrolidinediyl)))b is(N,N-diethyl-2oxo-1- phenylethanamine )</td><td> ח ח from l-2e2־ and Cap-2</td><td> Gemini C-18 4.6 x 50mm, 0 to 100% B over 10.0 minute gradient, 1 minute hold time, A = 5% acetonitrile, 95% water, 10mm ammonium acetate, B = 95% acetonitrile, 5% water, 10mm ammonium acetate. (RT = 3.76 min); LCMS: Anal. Calcd. for C50H56F2N8O2 839.04; found: 839.49 (M+H)⁺; HRMS: Anal. Calcd. for C50H57F2N8O2 839.4572; found: 839.4590 (M+H)⁺.</td>

<td> 24-7</td><td> (lR,l'R)-2,2'(4,4’biphenyldiylbis( 1 H-imidazole-5,2- diyl((2S,4S)-4fluoro-2,1pyrrolidinediyl)))b is(N,N-dimethyl- 2-oxo-1phenylethanamine</td><td> 0 0 from l-2e-2 and Cap-14</td><td> Gemini C-18 4.6 x 50mm, 0 to 100% B over 10.0 minute gradient, 1 minute hold time, A = 5% acetonitrile, 95% water, 10mm ammonium</td>

<td></td><td> )</td><td></td><td> acetate, B = 95% acetonitrile, 5% water, 10mm ammonium acetate. RT = 3.99 min; LCMS: Anal. Calcd. for C52H56F2N8O2 863.06; found: 863.47 (M+H)⁺; HRMS: Anal. Calcd. for C52H57F2N8O2 863.4572; found: 863.4553 (M+H)⁺.</td>

<td> 24-8</td><td> 1,1’-(4,4’biphenyldiylbis(l H-imidazole-4,2- diyl((2S)-4,4difluoro-2,1pyrrolidinediyl)(( 1 R)-2-oxo-1phenyl-2,1ethanediyl)))dipip eridine</td><td> \₌/\=/ VnH from l-2e-3 and Cap-14</td><td> RT = 1.64 minutes, method B; LCMS: Anal. Calcd. for C52H54F4N8O6: 898.43; found: 899.46 (M+H)⁺; HRMS: Anal. Calcd. for C52H55F4N8O6 899.4384; found: 899.4380 (M+H)⁺.</td>

<td> 24-9</td><td> dimethyl (4,4biphenyldiylbis(! H-imidazole-4,2diyl((2S)-4,4difluoro-2,1pyrrolidinediyl)(( 1 R)-2-oxo-1phenyl-2,1ethanediyl)))biscar</td><td> °\ Λ from l-2e-3 and Cap-4</td><td> RT = 2.62 minutes, method C; LCMS: Anal. Calcd. for C46H42F4N8O6: 878.88; found: 879.81 (M+H)⁺; HRMS: Anal. Calcd. for</td>

<td></td><td> bamate</td><td></td><td> C46H43F4N8O6 879.33242; found: 879.3273 (M+H)⁺.</td>

<td> 24-10</td><td> l-((lR)-2-((2S)-2(4-(4'-(2-((2S)4,4-difluoro-l- ((2R)-2-phenyl-2(1- piperidinyl)acetyl) -2-pyrrolidinyl)lH-imidazol-4yl)-4-biphenylyl)lH-imidazol-2yl)-lpyrrolidinyl)-2oxo-1phenylethyl)piperi dine</td><td> hn^/\₌₌/\₌/Vnh 0 0 from l-3e and Cap-14.</td><td> RT = 1.54 minutes, method B; LCMS: Anal. Calcd. for C52H56F2N8O6: 862.45; found: 863.46 (M+H)⁺; HRMS: Anal. Calcd. for C52H57F2N8O6 863.4573; found: 863.4572 (M+H)⁺.</td>

<td> 24-11</td><td> dimethyl (4,4biphenyldiylbis( 1 H-imidazole-5,2- diyl((2S,4R)-4hydroxy-2,1pyrrolidinediyl)(( 1 R)-2-oxo-1phenyl-2,1ethanediyl)))biscar bamate</td><td> HQ OH _n 4%, HN^/ \_/ \—/^^NH _Λ -^ΝΗ ΗΝ~γ° °χ ζ'° from 1-le and Cap-4</td><td> RT = 8.54 minutes, method A; LCMS: Anal. Calcd. for C46H46N8O8 838.93; found: 839.41 (M+H)⁺; HRMS: Anal. Calcd. for C46H47N8O8 839.9300; found: 839.3527 (M+H)⁺.</td>

<td> 24-12</td><td> (3R,5S,3'R,5’S)5,5'-(4,4'biphenyldiylbis( 1 H-imidazole-5,2diyl))bis(l-((2R)2-hydroxy-2phenylacetyl)-3-</td><td> HQ OH 'JL η h l) /®⁵ד HO ^{U U} OH from 1-le and mandelic acid</td><td> RT = 6.92 minutes , method A; LCMS: Anal. Calcd. for C42H40N₆O₆ 724.81; found: 725.43 (M+H)⁺; HRMS: Anal. Calcd. for</td>

<td></td><td> ?yrrolidinol)</td><td></td><td> C42H41N6O6 725.3087; found: 725.3088 (M+H)⁺.</td>

<td> 24-13</td><td> N,N-(4,4'biphenyldiylbis(l H-imidazole-5,2diyl((2S,4R)-4iydroxy-2,1pyrrolidinediyl)((l R)-2-oxo-1phenyl-2,1ethanediyl)))bis(3methyhirea)</td><td> HQ PH ^H\־° ,NH Prepared from 1-le and Cap-45</td><td> RT = 3.80 minutes, method C; LCMS: Anal. Calcd. for C₄6H4₈N₁₀O6 836.95; found: 837.52 (M+H)⁺; HRMS: Anal. Calcd. for C46H49N10O6 837.3836; found: 837.3809 (M+H)⁺.</td>

<td> 24-14</td><td> N’,N'-(4,4’biphenyldiylbis( 1 H-imidazole-5,2diyl((2S,4R)-4hydroxy-2,1pyrrolidinediy 1)((1 R)-2-oxo-1phenyl-2,1ethanediyl)))bis(lethylurea)</td><td> HQ OH ^HV0° 0־־^ HN___ ___,NH Prepared from 1-le and Cap-46</td><td> RT = 4.39 minutes, method C; LRMS: Anal. Calcd. for C48H52N10O6 865.003; found: 865.56 (M+H)⁺; HRMS: Anal. Calcd. for C48H53N10O6 865.4149; found: 865.4139 (M+H)⁺.</td>

<td> 24-15</td><td> N',N^,-(4,4'biphenyldiylbis( 1 H-imidazole-5,2diyl((2S,4R)-4hydroxy-2,1pyrrolidinediy 1)((1 R)-2-oxo-lphenyl-2,1ethanediyl)))bis( 1 cyclopentylurea)</td><td> HQ OH ^H1y₀ 0^^NH HN .NH ט σ Prepared from 1-le and Cap-48</td><td> RT = 4.88 minutes, method B; LRMS: Anal. Calcd. for C54H60NJ0O6 944.13; found: 945.65 (M+H)⁺; HRMS: Anal. Calcd. for C54H61N10O6 945.4775; found: 945.4769 (M+H)⁺.</td>

<td> 24-16</td><td> (3S,5S,3'S,5'S)5,5'-(4,4'?ipheny Idiy Ibis( 1 H-imidazole-5,2diyl))bis(l-((2R)2idimethylamino)2-phenylacetyl)-3pyrrolidinol)</td><td> HO ?Η ⁰ y Prepared from l-2e and Cap-1</td><td> RT = 3.66 minutes, method D; LRMS: Anal. Calcd. for C46H50N8O4 778.39 found: 779.39 (M+H)⁺; HRMS: Anal. Calcd. for C46H51N8O4 779.4033; found: 779.4021 (M+H)⁺.</td>

<td> 24-17</td><td> dimethyl (4,4'biphenyldiylbis(l H-imidazole-5,2diyl((2S,4S)-4hydroxy-2,1pyrrolidinediyl)((l R)-2-oxo-lphenyl-2,1ethanediyl)))biscar bamate</td><td> HO pH HN ⁰ ״ _yNH ן Prepared from l-2e and Cap-4</td><td> RT = 5.75 minutes, method C; LRMS: Anal. Calcd. for C46H46NA 838.93; found: 839.44 (M+H)⁺; HRMS: Anal. Calcd. for C46H47N8O8 839.3517 found: 839.3519 (M+H)⁺.</td>

<td> 24-18</td><td> (3S,5S,3'S,5'S)5,5'-(4,4'biphenyldiylbis(! H-imidazole-5,2- diyl))bis(l-((2R)2-hydroxy-2phenylacetyl)-3pyrrolidinol)</td><td> HO pH H0 ^{0 0} OH from l-2e and mandelic acid</td><td> RT = 4.41 minutes, method D; LRMS: Anal. Calcd. for C42H40N₆O6 724.81; found: 725.13 (M+H)⁺.</td>

<td> 24-18-1</td><td> dimethyl (4,4biphenyldiylbis( 1 H-imidazole-5,2- diyl(lS)-l,lethanediyl(methyli mino)((lR)-2-oxo- 1-phenyl-2,1-</td><td> 0 N 0 / n from l-7e and Cap-4</td><td> RT= 1.55 min¹; LRMS: Anal. Calcd. for C44H46N8O6 782.35; found: 783.37 (M+H)⁺; HRMS: Anal. Calcd. for</td>

<td> ί</td><td> jthanediyl)))biscar jamate</td><td colspan="3"> I C44H47N8O6 783.3619 found: 783.3630 (M+H)⁺.</td>

<td> 24-18-2</td><td> (2R,2'R)-N,N’- (4,4'- 7iphenyldiylbis(l H-imidazole-5,2- diyl(lS)-l,l- ethanediyl))bis(2(dimethylamino)N-methyl-2phenylacetamide)</td><td>⁰_o from l-7e and Cap-1</td><td colspan="2"> RT = 1.16 mm ; LRMS: Anal. Calcd. for C44H₅oN₈02 722.41; _י found: 723.41 f (M+H)⁺; HRMS: ¾/ Anal. Calcd. for C44H51N8O2 723.4135 found: 723.4152 (M+H)⁺.</td>

<td> 24-18-3</td><td> (2R,2'R)-N,N'(4,4’biphenyldiylbis( 1 H-imidazole-5,2diyl(lS)-l,lethanediyl))bis(Nmethyl-2-phenyl2-(1piperidinyl)acetam ide)</td><td> OA'Q”! Γ» X from l-7e and Cap-14</td><td colspan="2"> RT = 1.28 mm¹; LRMS: Anal. Calcd. for C50H58N8O2 802.47; found: 803.50 Q (M+H)⁺; HRMS: 3 Anal. Calcd. for C50H59N8O2 803.4761 found: 803.4778 (M+H)⁺.</td>

<td> 24-18-4</td><td> methyl ((lR)-2((2S)-2-(5-(4'-(2((1S)-1-(((2R)2־((methoxycarbony l)amino)-2phenylacetyl)(met hyl)amino)ethyl)lH-imidazol-5yl)-4-biphenylyl)lH-imidazol-2yl)-l-</td><td colspan="2"> ״*0 / a Prepared from l-5e and Cap-4</td><td> RT= 1.53 min¹; LRMS: Anal. Calcd. for C45H46N8O6 794.35; found: 795.39 (M+H)⁺; HRMS: Anal. Calcd. for C45H47N8O6 795.3619 found: 795.3616 (M+H)⁺.</td>

<td></td><td> pyrrolidinyl)-2oxo-1phenylethyl)carba mate</td><td></td><td></td>

<td> 24-18-5</td><td> (2R)-2- (dimethylamino)N-((lS)-l-(5-(4'(2-((2 S)-1-((2R)2- (dimethylamino)2-phenylacetyl)-2pyrrolidinyl)-lHimidazol-5-y 1)-4biphenylyl)-IHimidazol-2yl)ethyl)-Nmethyl-2phenylacetamide</td><td> CrVCn ^{0 Λ} UL. VS Prepared from l-5e and Cap-1</td><td> RT= 1.21¹; LRMS: Anal. Calcd. for C45H50N8O2 734.41; found: 735.46 (M+H)⁺; HRMS: Anal. Calcd. for C45H51N8O2 735.4135 found: 735.4136 (M+H)⁺.</td>

<td> 24-18-6</td><td> (2R)-N-methyl-2phenyl-N-((lS)-l(5-(4'-(2-((2S)-l((2R)-2-phenyl-2- ־1) piperidinyl)acetyl) -2-pyrrolidinyl)lH-imidazol-5yl)-4-biphenylyl)lH-imidazol-2yl)ethyl)-2-(lpiperidinyl)acetam ide</td><td> Prepared from l-5e and Cap-14</td><td> RT=1.30'; LRMS: Anal. Calcd. for C51H58N8O2 814.47; found: 815.48 (M+H)⁺; HRMS: Anal. Calcd. for C51H59N8O2 815.4761 found: 815.4744 (M+H)⁺.</td>

¹LC Conditions for 24-181־ through 24-18-6: Phenomenex LUNA C-18 4.6 x 50 mm, 0 to 100% B over 2 minutes, 1 minute hold time, A = 90% water, 10% methanol, 0.1% TFA, B = 10% water, 90% methanol, 0.1% TFA, 220nm, 5 pL injection volume.

Examples 24-19 to 24-20

<img file="IL196813A_D0127.tif" />

Example 2419־ and 24-20 were prepared as TFA salts from l-2e-l and the respective acids using the same method described for Example 1.

<td> Example</td><td> Compound Name</td><td> 0</td><td> Data</td>

<td> 24-19</td><td> methyl ((1^)-2-((25)-2-(4(3’-(2-((2S׳)-l-((2R)-2((methoxycarbonyl)amino)2-phenylacetyl)-2pyrrolidinyl)- 1/f-imidazol5-y 1)-3 -biphenylyl)- IHimidazol-2-yl)-lpyrrolidinyl)-2-oxo-1 phenylethyl)carbamate</td><td> 0 ^phA ^HNX/O. Y 0 Cap-4</td><td>¹HNMR (500 MHz, DMSO-d6) δ ppm 1.821.97 (m, 2H), 1.97-2.17 (m, 4H), 2.18-2.37 (m, 2H), 3.18 (d, 7=9.77 Hz, 2H), 3.44-3.58 (m, 6H), 3.79-4.04 (m, 2H), 5.095.46 (m, 2H), 5.45-5.84 (m, 2H), 6.97-7.49 (m, 10H), 7.61-7.74 (m, 4H), 7.75-7.93 (m, 4H), 8.108.32 (m, 4H), 14.48 (app br s, 2H); RT = 1.34 min; LC/MS: Anal. Calcd. for [M+H]⁺ C46H47N8O6: 807.36; found 807.40</td>

<td> 24-20</td><td> (lR)-2-((2S)-2-(4-(3’-(2- ((25)-l-((2R)-2- (dimethylamino)-2- phenylacetyl)-2-</td><td>^ד=ס\ / X 2'\ $ Q.</td><td>¹HNMR (500 MHz, DMSO-de) δ ppm 1.712.32 (m, 8H), 3.33-3.68 (m, 2H), 3.89-4.16 (m,</td>

<td></td><td> pyrrolidinyl)- 177-imidazol5-yl)-3 -biphenylyl)-177imidazol-2-yl)-lpyrrolidinyl)-?/,TVdimethyl-2-oxo-lphenylethanamine</td><td></td><td> /=2.75 Hz, 2H), 4.96 (app br s, 12H), 5.26 (s, 2H), 5.45 (s, 2H), 7.03-7.78 (m, 12H), 7.84 (s, 4H), 8.07-8.43 (m, 4H), 9.9010.87 (m, 2H);RT = 1.10 min; LC/MS: Anal. Calcd. for[M+H]⁺C46H51N8O2: 747.41; found 747.45</td>

LC conditions for 24-19 and 24-20:

Column = Phenomenex-Luna 3.OX 50 mm S10

Start %B

Final %B = 100

Gradient time = 2 min

Stop time = 3 min

Flow Rate = 4 mL/min

Wavelength = 220 nm

Slovent A = 0.1% TFA in 10% methanol/90%H2O

Solvent B = 0.1% TFA in 90% methanol/10% H₂O

<img file="IL196813A_D0128.tif" />

Example 24-21 and 24-22 were prepared as TFA salts from l-4e and the respective 15 carboxylic acids using the same method described for Example 1.

<td> Example</td><td> Compound Name</td><td> 0 rAjS</td><td> Data</td>

<td> 24-21</td><td> methyl ((lR)-2-((2R)-2(4-(3'-(2-((2S)-l-((2R)2- ((methoxycarbonyl)ami no)-2-phenylacetyl)-2pyrrolidinyl)-lffimidazol-4-yl)-4biphenylyl)-Iffimidazol-2-yl)-lpyrrolidinyl)-2-oxo-1 ־ phenylethyl)carbamate</td><td> 0 HN^O. Y 0 Cap-4</td><td>¹H NMR (500 MHz, DMSOd6) δρριη 1.732.37 (m, 8H), 3.13(8, 2H), 3.36-4.29 (m, 8H), 5.26 (s, 2H), 5.53 (s, 2H), 6.99-8.61 (m, 22H), 14.51 (s, 2H); RT = 1.33min; LC/MS: Anal. Calcd. for [M+H]⁺C46H47N8O6: 807.36; found 807.58</td>

<td> 24-22</td><td> (lR)-2-((2R)-2-(4-(3׳(2-((25)-l-((2R)-2(dimethylamino)-2phenylacetyl)-2pyrrolidinyl)-lffimidazol-4-yl)-4biphenylyl)-Iffimidazol-2-yl)-lpyrrolidinylj-ffffdimethyl-2-οχο-1 phenylethanamine</td><td> 0 x׳^N_x Cap-1</td><td>¹HNMR (500 MHz, DMSOde) δ ppm 1.842.32 (m, 8H), 2.92-3.10 (m, 2H), 3.92-4.08 (m, 2H), 4.43 (app brs, 12H), 5.16-5.37 (m, 2H), 5.39-5.58 (m, 2H), 7.168.24 (m, 20H),</td>

<td></td><td></td><td></td><td> 9.60-10.46 (m, 2H);RT= 1.08 min; LC/MS: Anal. Calcd. for [M+H]⁺C46H51N8O2: 747.41; found 747.45</td>

LC conditions for 24-21 and 24-22:

<td> Column</td><td> = Phenomenex-Luna 3.OX 50 mm S10</td>

<td> Start %B</td><td> = 0</td>

<td> Final %B</td><td> = 100</td>

<td> 5 Gradient time</td><td> = 2 min</td>

<td> Stop time</td><td> = 3 min</td>

<td> Flow Rate</td><td> = 4 mL/min</td>

<td> Wavelength</td><td> = 220 nm</td>

<td> Slovent A</td><td> = 0.1% TFA in 10% methanol/90%H₂O</td>

<td> 10 Solvent B</td><td> = 0.1% TFA in 90% methanol/10% H₂O</td>

Example 24-23

<img file="IL196813A_D0129.tif" />

methyl ((lS)-l-(((2S)-2-(5-(4'-(2-((2S)-l-((2S)-2-((methoxycarbonyl)amino)-3methylbutanoyl)-2-pyrrolidinyl)-lH-imidazol-5-yl)-4-biphenylyl)-lH-imidazol-2-yl)l-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate

A 50 mL flask equipped with a stir bar was sequentially charged with 2.5 mL acetonitrile, 0.344 g (2.25 mmol, 2.5 equiv) hydroxy benzotriazole hydrate, 0.374 g 20 (2.13 mmol, 2.4 equiv) 7V-(methoxycarbonyl)-L-valine, 0.400 g (2.09 mmol, 2.4 equiv) 1 -(3 -dimethyaminopropyl)-3-ethylcarbodiimide hydrochloride and an additional 2.5 mL acetonitrile. The resulting solution was agitated at 20 °C for 1 hour and charged with 0.501 g (0.88 mmol, 1 equiv) Example A-le-4. The slurry was cooled to about 0 °C and 0.45 g (3.48 mmol, 4 equiv) diisopropylethylamine was added over 30 minutes while maintaining a temperature below 10 °C. The solution was slowly heated to 15 °C over 3 hours and held at 15 °C for 16 hours. The temperature was increased to 20 °C and stirred for 3.25 hours. The resulting solution was charged with 3.3 g of 13 wt% aqueous NaCl and heated to 50 °C for 1 hour. After cooling to 20 °C, 2.5 mL of isopropyl acetate was added. The rich organic phase was washed with 2 x 6.9 g of a 0.5 N NaOH solution containing 13 wt% NaCl followed by 3.3 g of 13 wt% aqueous NaCl. The mixture was then solvent exchanged into isopropyl acetate by vacuum distillation to a target volume of 10 mL. The resulting hazy solution was cooled to 20 °C and filtered through a 0.45 pm filter. The clear solution was then solvent exchanged into ethanol by vacuum distillation with a target volume of 3 mL. 1.67 mL (2.02 mmol, 2.3 equiv) of 1.21 M HC1 in ethanol was added. The mixture was then stirred at 25 °C for 15 hours. The resulting slurry was filtered and the wet cake was washed with 2.5 mL of 2:1 acetone:ethanol. The solids were dried in a vacuum oven at 50 °C to give 0.550 g (0.68 mmol, 77 %) of the desired product.

Recrystallization of Example 24-23

A solution of Example 24-23 prepared above was prepared by dissolving 0.520 g of the above product in 3.65 mL methanol. The solution was then charged with 0.078 g of type 3 Cuno Zeta loose carbon and allowed to stir for 0.25 hours. The mixture was then filtered and washed with 6 ml of methanol. The product rich solution was concentrated down to 2.6 mL by vacuum distillation. 7.8 mL acetone was added and allowed to stir at 25 °C for 15 h. The solids were filtered, washed with 2.5 mL 2:1 acetone :ethanol and dried in a vacuum oven at 70 °C to give 0.406 g (57.0%) of the desired product as white crystals: ¹H NMR (400 MHz, DMSO-/5,80 °C): 8.02 (d, /=8.34 Hz, 4 H), 7.97 (s, 2 H), 7.86 (d, /=8.34 Hz, 4 H), 6.75 (s, 2 H), 5.27 (t, /=6.44 Hz, 2 H), 4.17 (t, /=6.95 Hz, 2 H), 3.97 - 4.11 (m, 2 H), 3.74 - 3.90 (m, 2 H), 3.57 (s, 6 H), 2.32 - 2.46 (m, 2 H), 2.09 - 2.31 (m, 6 H), 1.91 - 2.07 (m, 2 H), 0.88 (d, /=6.57 Hz, 6 H), 0.79 (d, /=6.32 Hz, 6 H); ¹³C NMR (75 MHz, DMSO d₆): δ 170.9, 156.9, 149.3, 139.1, 131.7, 127.1, 126.5, 125.9, 115.0, 57.9, 52.8, 51.5, 47.2,31.1,28.9, 24.9, 19.6, 17.7; IR (neat, cm2669,1731 ,2873 ,2971 ,3385 :(¹־, 1650. Anal. Calcd for C40H₅₂N_gO6C12: C, 59.18; H, 6.45; N, 13.80; Cl, 8.73. Found C, 59.98; H, 6.80; N, 13.68; Cl, 8.77. mp 267 °C (decomposed). Characteristic diffraction peak positions (degrees 2Θ ± 0.1) @ RT, based on a high quality pattern collected with a diffractometer (CuKa) with a spinning capillary with 2Θ calibrated with a NIST other suitable standard are as follows: 10.3,12.4, 12.8,13.3, 13.6, 15.5, 20.3,21.2, 22.4, 22.7, 23.7.

Example 25

N,N'-(4,4'-biphenyldiylbis(lH-imidazole-5,2-diyl(2S)-2,l-pyrrolidinediyl((lR)-2-oxol-phenyl-2,l-ethanediyl)))diacetamide

<img file="IL196813A_D0130.tif" />

di-tert-butyl (4,4'-biphenyldiylbis(lH-imidazole-5,2-diyl(2S)-2,lpyrrolidinediyl((lR)-2-oxo-l-phenyl-2,l-ethanediyl)))biscarbamate and

<img file="IL196813A_D0131.tif" />

HATU (96.2 mg, 0.253 mmol) was added to a mixture of pyrrolidine le (52.6 mg, 0.124 mmol), diisopropylethylamine (100 pL, 0.57 mmol) and Boc-D-Phg-OH (69 mg, 0.275 mmol) in DMF (3.0 mL). The reaction mixture was stirred for 25 minutes, and then diluted with methanol and purified by a reverse phase HPLC system (H₂O/methanol/TFA). The HPLC elute was neutralized with excess 2.0 M/NH3 in CH3OH and the volatile component was removed in vacuo. The residue was carefully partitioned between CH₂C1₂ and saturated NaHCO3. The aqueous phase was extracted with more CH₂C1₂ (2x). The combined organic phase was dried (MgSO4), filtered, and concentrated in vacuo to provide 25 a as a film of semisolid oil (78.8 mg). LC (Cond. 1): RT = 1.99 min; >98% homogeneity index. LC/MS: Anal. Calcd. for [M+H]⁺ C5₂H₅₉N₈O₆: 891.46; found 891.55.

Carbamate 25a was converted to amine 25b according to the procedure described for the preparation of le. LC(Cond. 1): RT = 1.44 min; 97% homogeneity index. LC/MS: Anal. Calcd. for [M+H]⁺ C4₂H43N8O₂: 691.35; found 691.32

Example 25

N,N'-(4,4 '-biphenyldiylbis(lH-imidazole-5,2-diyl(2S)-2,1 -pyrrolidinediyl((lR)-2-oxol-phenyl-2,l-ethanediyl)))diacetamide

Acetic anhydride (20 pL, 0.21 mmol) was added to a DMF (1.5 mL) solution of amine 25b (29 mg, 0.042 mmol)and triethylamine (30 pL, 0.22 mmol) and stirred for 2.5 hours. ^,The reaction mixture was then treated with NH3/methanol (1 mL of 2 M) and stirred for an additional 1.5 hours. The volatile component was removed in vacuo and the residue was purified by a reverse phase HPLC system (H₂O/methanol/ TFA) to provide the TFA salt of Example 25 as a white foam (28.1 mg). LC (Cond.l): RT = 1.61 min; >98% homogeneity index; LC/MS: Anal. Calcd. for [M+H]⁺ C46H47N8O4: 775.37; found 775.40; HRMS: Anal. Calcd. for [M+H]⁺C46H47N8O4: 775.3720; found 775.3723

Example 25-1 to 25-5

<img file="IL196813A_D0132.tif" />

Examples 25-1 to 25-5 were prepared from 25b and the appropriate carboxylic acid using standard amide forming conditions similar to that described for the preparation of example 1 from le. Examples 25-6 to 25-8 were prepared from

25b and the appropriate carbamoyl chloride or isocyanate.

<td> Example Number</td><td> Compound Name</td><td> R</td><td> RT (LC-Cond.); % homogeneity index; MS data</td>

<td> 25-1</td><td> (2R,2'R)-N,N'-(4,4'biphenyldiylbis( 1Himidazole-5,2-diyl(2S)-2,1 pyrrolidinediyl(( 1 R)-2-oxol-phenyl-2,1ethanediyl)))ditetrahydro-2furan carboxamide</td><td> ζ/</td><td> RT = 5.68 minutes; HPLC Xterra 4.6 X 50 mm, 0 to 100% B over 10 minutes, one minute hold time, A = 90% water, 10% methanol, 0.2% phosphoric acid, B = 10% water, 90% methanol, 0.2% phosphoric acid; LCMS: Anal. Calcd. for: C₅2H₅₄N₈O₆: 887.06; Found: 887.58 (M+H)⁺</td>

<td> 25-2</td><td> N,Ν'-(4,4'biphenyldiylbis( 1Himidazole-5,2-diyl(2S)-2,l pyrrolidinediyl(( 1 R)-2-oxol-phenyl-2,1ethanediyl)))bis( 1 -methyllH-imidazole-5carboxamide)</td><td> Dh N \</td><td> RT = 3.54 minutes; HPLC Xterra 4.6 X 50 mm, 0 to 100% B over 10 minutes, one minute hold time, A = 90% water, 10% methanol, 0.2% phosphoric acid, B = 10% water, 90% methanol, 0.2% phosphoric acid; LCMS: Anal. Calcd. for: C₅2H₅₀N12O₄: 907.06; Found: 907.42 (M+H)⁺</td>

<td> 25-3</td><td> (2S,2'S)-N,N'-(4,4’biphenyldiylbis( 1Himidazole-5,2-diyl(2S)-2,l pyrrolidinediyl(( 1 R)-2-oxo- 1- phenyl-2,1ethanediyl)))bis( 1 -methyl- 2- pyrrolidinecarboxamide)</td><td> Φ</td><td> RT= 3.1 minutes; HPLC Xterra 4.6 X 50 mm, 0 to 100% B over 10 minutes, one minute hold time, A = 90% water, 10% methanol, 0.2% phosphoric acid, B = 10% water, 90% methanol, 0.2% phosphoric acid; LCMS: Anal. Calcd. for: C54H60N ₎₀O₄ 913.14; Found: 913.54 (M+H)⁺</td>

<td> 25-4</td><td> N,N'-(4,4'biphenyldiylbis( 1Himidazole-5,2-diyl(2S)-2,lpyrrolidinediyl((lR)-2-oxo1-phenyl-2,1ethanediyl)))bis(2-(3pyridinyl)acetamide)</td><td> Z=־־N W</td><td> RT= 3.37 minutes; HPLC Xterra 4.6 X 50 mm, 0 to 100% B over 10 minutes, one minute hold time, A = 90% water, 10% methanol, 0.2% phosphoric acid, B = 10% water, 90% methanol, 0.2% phosphoric acid; LCMS: Anal. Calcd. for: C56H52N₁₀O4 929.10 Found: 929.42 (M+H)⁺</td>

<td> 25-5</td><td> N,N'-(4,4'biphenyldiylbis( 1Himidazole-5,2-diyl(2S)-2,l pyrrolidinediyl(( 1 R)-2-oxo1-phenyl-2,1ethanediyl)))bis(2(dimethylamino)acetamide) (non-preferred name)</td><td> '־'N^/ s</td><td> RT = 7.07 minutes; HPLC Xterra 4.6 X 5.0 mm, 0 to 100% B over 10 minutes, one minute hold time, A = 90% water, 10% methanol, 0.2% phosphoric acid, B = 10% water, 90% methanol, 0.2% phosphoric acid; LCMS: Anal. Calcd. for: C50H56NWO4 861.07 Found: 859.69 (M+H)⁺</td>

<td> 25-6</td><td> N,N'-(4,4'biphenyldiylbis( 1Himidazole-5,2-diyl(2S)-2,l pyrrolidinediyl(( 1 R)-2-oxo1-phenyl-2,1ethanediyl)))di(4morpholinecarboxamide)</td><td> O N 1 *ΛΛ/V</td><td>¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.86-2.18 (m, 6H), 2.23-2.39 (m, 2H), 3.20-3.40 (m, 8H), 3.403.61 (m, 8H), 3.90-4.19 (m, 4H), 5.27 (dd, 7=8.09,3.51 Hz, 2H), 5.37-5.63 (m, 2H), 6.92-7.11 (m, 3H), 7.30-7.45 (m, 5H), 7.44-7.56 (m, 4H), 7.83-8.04 (m, 8H), 8.15 (s, 2H), 14.29 (s, 2H); HPLC Xterra 4.6 X 50 mm, 0 to 100% B over 10 minutes, one minute hold time, A = 90% water, 10% methanol, 0.2% phosphoric acid, B = 10% water, 90% methanol, 0.2% phosphoric acid, RT = 6.01 minutes; LCMS: Anal. Calcd. for: C₅2H56N₁₀O6 917.09; Found:</td>

<td></td><td></td><td></td><td> 917.72 (M+H)⁺</td>

<td> 25-7</td><td> N,N'-(4,4'biphenyldiylbis( 1Himidazole-5,2-diyl(2S)-2,l pyrrolidinediyl(( 1 R)-2-oxol-phenyl-2,1ethanediyl)))bis(4-methyl1 -piperazinecarboxamide)</td><td> ό N 1 »/VW</td><td> RT = 3.74 minutes; HPLC Xterra 4.6 X 50 mm, 0 to 100% B over 10 minutes, one minute hold time, A = 90% water, 10% methanol, 0.2% phosphoric acid, B = 10% water, 90% methanol, 0.2% phosphoric acid; LCMS: Anal. Calcd. for:C54H₆₂N₁₂O₄943.17; Found: 943.84 (M+H)⁺</td>

<td> 25-8</td><td> N,N-(4,4'- biphenyldiylbis( 1Himidazole-5^-diyl(2S)-2,lpyrrolidinediyl(( 1 R)-2-oxol-phenyl-2,1- ethanediyl)))bis(3-(3pyridinyl)urea)</td><td> 9 HN—</td><td>¹H NMR (500 MHz, DMSO-d6) δ ppm 1.79-2.17 (m, 6H), 2.29 (d, /=9.77 Hz, 2H), 3.06-3.39 (m, 2H), 3.72-4.14 (m, 2H), 5.27 (dd, /=8.24, 2.75 Hz, 2H), 5.66 (d, /=7.02 Hz, 2H), 7.26-7.65 (m, 12H), 7.82-8.11 (m, 12H), 8.17 (s, 2H), 8.23-8.45 (m, 2H), 8.618.97 (m, 2H), 9.38 (s, 2H), 14.51 (s, 2H); HPLC Xterra 4.6 X 50 mm, 0 to 100% B over 10 minutes, one minute hold time, A = 90% water, 10% methanol, 0.2% phosphoric acid, B = 10% water, 90% methanol, 0.2% phosphoric acid, RT = 4.05 minutes; LCMS: Anal. Calcd. for: C54H₅0N₁₂O4 931.08; Found: 931.78 (M+H)⁺.</td>

Example 26 methyl ((lR)-l-(((2S)-2-(5-(4'-(2-((2S)-l-((2R)-2-((methoxycarbonyl)amino)-3methylbutanoyl)-2-pyrrolidinyl)-lH-imidazol-5-yl)-4-biphenylyl)-lH-imidazol-2-yl)l-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate o^z

<img file="IL196813A_D0133.tif" />

/°

Example 26, Step a (2R,2'R)-1,1 ’-(4,4'-biphenyldiylbis(lH-imidazole-5,2-diyl(2S)-2,1pyrrolidinediyl))bis(3-methyl-l-oxo-2-butanamine)

<img file="IL196813A_D0134.tif" />

Diamine 26a was prepared starting from pyrrolidine le and BOC-D־Val-OH according to the procedure described for the synthesis of diamine 25b.

Example 26 methyl ((lR)-l-(((2S)-2-(5-(4'-(2-((2S)-l-((2R)-2-((methoxycarbonyl)amino)-3methylbutanoyl)-2-pyrrolidinyl)-lH-imidazol-5-yl)-4-biphenylyl)-lH-imidazol-2-yl)l-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate

Methyl chloroformate (18 pL, 0.23 mmol) was added to a THF (1.5 mL) solution of diamine 26a (30 mg, 0.048 mmol) and triethylamine (30 pL, 0.22 mmol), and the reaction mixture was stirred at ambient condition for 3 hours. The volatile components was removed in vacuo, and the residue was treated with NH3/methanol (2 mL of 2 M) and stirred at ambient conditions for 15 minutes. All the volatile component was removed in vacuo, and the crude product was purified by reverse phase prep-HPLC (H₂O/methanol/TFA) to provide the TFA salt of Example 26 as a white solid (13.6 mg). LC (Cond.2): RT = 2.00 min; >98% homogeneity index;

LC/MS: Anal. Calcd. for [M+H]⁺ C40H₅1N₈O6: 739.39; found 739.67; HRMS: Anal.

Calcd. for [M+H]⁺ C40H₅!N₈O6: 739.3932; found 739.3966.

Example 27

N-((lR)-l-(((2S)-2-(5-(4'-(2-((2S)-l-((2R)-2-acetamido-3-methylbutanoyl)-2pyrrolidinyl)-lH-imidazol-5-yl)-4-biphenylyl)-lH-imidazol-2-yl)-lpyrrolidinyl)carbonyl)-2-methylpropyl)acetamide

<img file="IL196813A_D0135.tif" />

Diamine 26a was converted to Example 27 (TFA salt) according to a method described in the preparation of Example 25. LC (Cond.2): RT = 1.93min; >98% homogeneity index; LC/MS: Anal. Calcd. for [M+H] C40H5!N₈O4: 707.40; found 707.59; HRMS: Anal. Calcd. for [M+H]⁺ C40H51N₈O4: 707.4033; found 707.4054.

Example 28 methyl ((lR)-2-oxo-l~phenyl-2-((2S)-2-(5-(4'-(2-((2S)-l-(phenylacetyl)-2pyrrolidinyl)-lH-imidazol-5-yl)-4-biphenylyl)-lH-imidazol-2-yl)-l-

<img file="IL196813A_D0136.tif" />

28a

HATU (19.868g, 52.25 mmol) was added to a heterogeneous mixture of NCbz-L- proline (12.436 g, 49.89 mmol) and the HC1 salt of 2-amino-1-(4 bromophenyl) ethanone (12.157 g, 48.53 mmol) in DMF (156 mL). The mixture was lowered in an ice-water bath, and immediately afterward ΛζΝ-diisopropylethylamine (27 mL, 155 mmol) was added dropwise to it over 13 minutes. After the addition of the base was completed, the cooling bath was removed and the reaction mixture was stirred for an additional 50 minutes. The volatile component was removed in vacuo; water (125 mL) was added to the resulting crude solid and stirred for about 1 hour. The off-white solid was filtered and washed with copious water, and dried in vacuo to provide ketoamide 28a as a white solid (20.68 g). ¹H NMR (DMSO-d6, δ= 2.5 ppm, 400 MHz): δ 8.30 (m, 1H), 7.91 (m, 2H), 7.75 (d, J = 8.5, 2H), 7.38-7.25 (m, 5H), 5.11-5.03 (m, 2H), 4.57-4.48 (m, 2H), 4.33-4.26 (m, 1H), 3.53-3.36 (m, 2H), 2.23-2.05 (m, 1H), 1.94-1.78 (m, 3H); LC (Cond. 1): RT = 1.65 min; 98% homogeneity index; LC/MS: Anal. Calcd. for [M+H]⁺ C2!H22BrN2O4: 445.08; found 445.31.

Example 28, Step b

<img file="IL196813A_D0137.tif" />

28b

Ketoamide 28a (10.723g, 24.08 mmol) was converted to 28b according to the procedure described for the synthesis of carbamate lb, with the exception that the crude material was purified by flash chromatography (sample was loaded with eluting solvent; 50% ethyl acetate/hexanes). Bromide 28b was retrieved as an offwhite foam (7.622 g). ¹HNMR (DMSO-d6, 5= 2.5 ppm, 400 MHz): δ 12.23/12.04/11.97 (m, 1H), 7.73-6.96 (m, 10H), 5.11-4.85 (m, 3H), 3.61 (m, 1H), 3.45 (m, 1H), 2.33-184(m, 4H). LC (Cond.l): RT = 1.42 min; >95% homogeneity index; LC/MS: Anal. Calcd. for [M+H]⁺ C21H21BrN3O2:426.08; found 426.31; HRMS: Anal. Calcd. for [M+H]⁺ C21H21BrN₃O₂:426.0817; found: 426.0829. The optical purity of 28b was assessed using the following chiral HPLC methods, and an ee of 99% was observed.

Column: Chiralpak AD, 10 um, 4.6 x 50 mm Solvent: 20% ethanol/heptane (isocratic) Flow rate: 1 mL/min

Wavelength: 254 nm

Relative retention time: 1.82 minutes (R), 5.23 minutes (5)

Example 28, Step c benzyl tert-butyl (2S, 2 'S)-2,2 '-(4,4 '-biphenyldiylbis(1 H-imidazole-5,2-diyl))di(1pyrrolidinecarboxylate)

<img file="IL196813A_D0138.tif" />

Pd(Ph₃P)₄ (711.4 mg, 0.616 mmol) was added to a mixture of boronate ester 1c (7.582 g, ~ 17 mmol), bromide 28b (7.62 g, 17.87 mmol), NaHCO₃ (4.779 g, 56.89 mmol) in 1,2-dimethoxyethane (144 mL) and water (48 mL). The reaction mixture was purged with N2 and heated with an oil bath at 80 °C for 15.5 hours, and then the volatile component was removed in vacuo. The residue was partitioned between CH₂C1₂ and water, and the aqueous layer was extracted with CH₂C12. The combined organic phase was dried (MgSO4), filtered, and concentrated in vacuo. The resulting material was submitted to flash chromatography (sample was loaded as a silica gel mesh; ethyl acetate used as eluent) to provide biphenyl 28c as an offwhite foam containing Ph₃PO impurity (7.5 g). ¹H NMR (DMSO-d6, δ= 2.5 ppm, 400 MHz): δ 12.24-12.19 (m, 0.36H), 12.00-11.82 (m, 1.64H), 7.85-6.98 (15H), 5.12-4.74 (4H), 3.68-3.34(4H), 2.34-1.79 (8H), 1.41/1.17 (two br S, 9H); LC (Cond.l): RT = 1.41 minutes; LC/MS: Anal. Calcd. for [M+H]⁺C39H43N6O4: 659.34; found 659.52; HRMS: Anal. Calcd. for [M+H]⁺ C39H4₃N₆O4: 659.3346; found 659.3374.

Example 28, Step d tert-butyl (2S)-2-(5-(4'-(2-((2S)-2-pyrrolidinyl)-lH-imidazol-5-yl)-4-biphenylyl)-lH imidazol-2-yl)-l-pyrrolidinecarboxylate

<img file="IL196813A_D0139.tif" />

28d

K.2CO3 (187.8 mg, 1.36 mmol) was added to a mixture of catalyst (10% Pd/C;

205.3 mg), carbamate 28c (1.018 g, ~ 1.5 mmol), methanol (20 mL) and 3 pipetdrops of water. A balloon of H₂ was attached and the mixture was stirred for 6 hours. ^,Then, additional catalyst (10% Pd/C, 100.8 mg) and K2CO3 (101.8 mg, 0.738 mmol) were added and stirring continued for 3.5 hours. During the hydrogenation process, the balloon of H2 was changed at intervals three times. The reaction mixture was filtered through a pad of diatomaceous earth (Celite® 521), and the filterate was removed in vacuo. The resulting crude material was submitted to flash chromatography using a short column (sample was loaded as a silica gel mesh; 020% mefhanol/CH2Cl2 used as eluent) to provide 28d as a light-yellow foam (605.6 mg). ¹H NMR (DMSO-d6, δ= 2.5 ppm, 400 MHz): δ 12.18/11.89/11.82 (three br s, 2H), 7.83-7.29 (m, 10H), 4.89-4.73 (m, 1H), 4.19 (app t, J = 7.2, 1H), 3.55 (app br s, 1H), 3.40-3.35 (m, 1H), 3.02-2.96 (m, 1H), 2.91-2.84(m, 1H), 2.30-1.69(m, 8H), 1.41/1.16 (two br s, 9H). Note: the signal of pyrrolidine NH appears to have overlapped with signals in the 3.6-3.2 ppm region; LC (Cond.l): RT = 1.21 min; >95% homogeneity index; LC/MS: Anal. Calcd. for [M+H]⁺ C3!H37N6O2: 525.30; found 525.40.

Example 28, Step e-f

Example 28 step e tert-butyl (2S)-2-(5-(4'-(2-((2S)-l-((2R)-2-((methoxycarbonyl)amino)-2phenylacetyl)-2-pyrrolidinyl)-lH-imidazol-5-yl)-4-biphenylyl)-lH-imidazol-2-yl)-lpyrrolidinecarboxylate

Example 28 step f methyl ((lR)-2-oxo-l-phenyl-2-((2S)-2-(5-(4'-(2-((2S)-2-pyrrolidinyl)-lH-imidazol-5yl)-4-biphenylyl)-lH-imidazol-2-yl)-l-pyrrolidinyl)ethyl)carbamate

<img file="IL196813A_D0140.tif" />

Step e: HATU (316.6 mg, 0.833 mmol) was added to a DMF (7.0 mL) solution of pyrrolidine 28d (427 mg, 0.813 mmol), Cap-4 (177.6 mg, 0.849 mmol) and diisopropylethylamine (0.32 mL, 1.84 mmol), and the reaction mixture was stirred for 45 minutes. The volatile component was removed in vacuo, and the residue was partitioned between CH₂C1₂ (50 mL) and an aqueous medium (20 mL H₂O + 1 mL saturated NaHCO₃ solution). The aqueous phase was re-extracted with CH₂C1₂, and the combined organic phase was dried (MgSO4), filtered, and concentrated in vacuo. The resulting yellow oil was purified by flash chromatography (silica gel; ethyl acetate) to provide 28e as a yellow foam (336 mg). LC (Cond. 1): RT = 1.68min; 91% homogeneity index; LC/MS: Anal. Calcd. for [M+H]⁺ C41H46N7O5: 716.35; found 716.53.

Step f: Carbamate 28e was elaborated to amine 28f by employing the procedure described in the conversion of Id to le. LC (Cond. 1): RT = 1.49min; >98% homogeneity index. LC/MS: Anal. Calcd. for [M+H]⁺ C36H38N7O3: 616.30; found 616.37; HRMS: Anal. Calcd. for [M+H]⁺C36H₃₈N₇O₃: 616.3036; found 616.3046.

Example 28 methyl ((lR)-2-oxo-l-phenyl-2-((2S)-2-(5-(4'-(2-((2S)-l-(phenylacetyl)-2pyrrolidinyl)-lH-imidazol-5-yl)-4-biphenylyl)-lH-imidazol-2-yl)-l-

<img file="IL196813A_D0141.tif" />

Amine 28f was converted to the TFA salt of Example 28 by employing the last step of the synthesis of Example 1. ¹H NMR (DMSO-d6, δ- 2.5 ppm, 400

MHz): δ 8.21-7.03 (m, 21H), 5.78-5.14 (3H), 3.98-3.13 (m, 9H; includes the signal for OCH3 at 3.54 & 3.53), 2.45-1.72 (m, 8H). LC (Cond. 1): RT = 1.66 minutes, >98% homogeneity index; LC/MS: Anal. Calcd. for [M+H]⁺ C44H44N7O4: 734.35;

found 734.48; HRMS: Anal. Calcd. for [M+H]⁺ C44H44N7O4: 734.3455; 734.3455.

Example 28-1 to 28-4

<img file="IL196813A_D0142.tif" />

Examples 28-1 through 28-4 (R groups shown in the table below) were prepared in similar fashion to example 28 via the intermediacy of intermediate 28d.

Example 28-1 (lR)-N,N-dimethyl-2-oxo-l-phenyl-2-((2S)-2-(5-(4'-(2-((2S)-l-((2R)-2-phenyl-2-(lpiperidinyl)acetyl)-2-pyrrolidinyl)-lH-imidazol-5-yl)-4-biphenylyl)-lH-imidazol-2yl)-l-pyrrolidinyl)ethanamine

Cap-1 was appended, the Boc carbamate was removed with TFA or HCI, and Cap-14 was appended.

Example 28-2 l-((lR)-2-oxo-l-phenyl-2-((2S)-2-(5-(4'-(2-((2S)-l-((2R)-tetrahydro-2furanylcarbonyl)-2-pyrrolidinyl)-lH-imidazol-5-yl)-4-biphenylyl)-lH-imidazol-2-yl)1-pyrrolidinyl) ethytypiperidine

Tetrahydrofuroic acid was appended, the Boc carbamate was removed with TFA or HCI, and Cap-14 was appended.

Example 28-3 methyl ((lR)-l-(2-chlorophenyl)-2-oxo-2-((2S)-2-(5-(4'-(2-((2S)-l-((2R)-2-phenyl-2(l-piperidinyl)acetyl)-2-pyrrolidinyl)-lH-imidazol-5-yl)-4-biphenylyl)-lH-imidazol2-yl)-l-pyrrolidinyl)ethyl)carbamate

Cap-40) was appended, the Boc carbamate was removed with TFA or HCI, and Cap-14 was appended.

Example 28-4 (lR)-l-(2-chlorophenyl)-N,N-dimethyl-2-oxo-2-((2S)-2-(5-(4'-(2-((2S)-l-((2R)-2phenyl-2-(l-piperidinyl)acetyl)-2-pyrrolidinyl)-lH-imidazol-5-yl)-4-biphenylyl)-lHimidazol-2-yl)-l-pyrrolidinyl)ethanamine

Cap-39 was appended, the Boc carbamate was removed with TFA or HCI, and Cap-14 was appended.

Example 28-5 (lR)-l-(2-fluorophenyl)-N,N-dimethyl-2-oxo-2-((2S)-2-(5-(4 ^,-(2-((2S)-1-((2R)-2phenyl-2-(l-piperidinyl)acetyl)-2-pyrrolidinyl)-lH-imidazol-5-yl)-4-biphenylyl)-lHimidazol-2-yl)-l-pyrrolidinyl)ethanamine

Cap-38 was appended, the Boc carbamate was removed with TFA or HCI, and Cap-14 was appended.

<td> Example</td><td> Compound Name</td><td> R</td><td> Data</td>

<td> 28-1</td><td> (1 R)-N,N-dimethyl-2-oxo- 1- phenyl-2-((2S)-2-(5-(4'(2-((2S)-l-((2R)-2-phenyl- 2- ( 1 -piperidinyl)acetyl)-2pyrrolidinyl)-1 H-imidazol- 5-yl)-4-biphenylyl)-1Himidazol-2-yl)-lpyrrolidinyl)ethanamine</td><td> 0</td><td> LCMS: Anal. Calcd. for C49H54N8O2: 786; found: 787 (M+H)⁺.</td>

<td> 28-2</td><td> 1 -((1 R)-2-oxo-l -phenyl-2((2S)-2-(5-(4'-(2-((2S)-l-</td><td> rA /°</td><td> LCMS: Anal. Calcd. for</td>

<td></td><td> ((2R)-tetrahydro-2furanylcarbonyl)-2pyrrolidinyl)- IH-imidazol5-yl)-4-biphenylyl)-1Himidazol-2-yl)-l pyrrolidinyl)ethyl)piperidine</td><td></td><td> C44H49N7O3: 723; found: 724 (M+H)⁺.</td>

<td> 28-3</td><td> methyl ((1R)-1-(2chlorophenyl)-2-oxo-2((2S)-2-(5-(4'-(2-((2S)-l((2R)-2-phenyl-2-(lpiperidiny l)acetyl)-2 pyrrolidinyl)-1 H-imidazol5-y l)-4-biphenylyl)-1Himidazol-2-y 1)-1pyrrolidinyl)ethyl)carbamate</td><td> OCX ΗΝ^_Ο_χ0</td><td> LCMS: Anal. Calcd. for C49H51C1N8O4: 850; found: 851 (M+H)⁺.</td>

<td> 28-4</td><td> (1R)-1 -(2-chlorophenyl)N,N-dimethyl-2-oxo-2((2S)-2-(5-(4'-(2-((2S)-l((2R)-2-phenyl-2-(lpiperidinyl)acetyl)-2pyrrolidinyl)-1 H-imidazol5-yl)-4-biphenyly 1)-1Himidazol-2-yl)-lpyrrolidinyl)ethanamine</td><td> OCX</td><td> LCMS: Anal. Calcd. for C49H53CIN8O2: 820; found: 821 (M+H)⁺.</td>

<td> 28-5</td><td> (1R)-1 -(2-fluorophenyl)N,N-dimethyl-2-oxo-2((2S)-2-(5-(4'-(2-((2S)-l((2R)-2-phenyl-2-(l piperidinyl)acetyl)-2pyrrolidinyl)-1 H-imidazol5-y l)-4-biphenylyl)-1Himidazol-2-y 1)-1pyrrolidinyl)ethanamine</td><td> Ζ.״ς'וד / y=o</td><td> LCMS: Anal. Calcd. for C49H53FN8O2: 804; found: 805 (M+H)⁺.</td>

Example 29 methyl ((lR)-2-((2S)-2-(5-(4'-(2-((2S)-l-((4-methyl-l-piperazinyl)carbonyl)-2pyrrolidinyl)-lH-imidazol-5-yl)-4-biphenylyl)-lH-imidazol-2-yl)-l-pyrrolidinyl)-2oxo-1-phenylethyl) carbamate

<img file="IL196813A_D0143.tif" />

/°

4-Methylpiperazine-l-carbonyl chloride/HCl (11.6 mg, 0.58 mmol) was added to a mixture of 28f (30 mg, 0.049 mmol), triethylamine (15 μΐ, 0.11 mmol) and THF (1.0 mL), and stirred at ambient conditions for 1 hour. The volatile component was removed in vacuo, and the residue was purified by a reverse phase HPLC (H₂O/methanol/TFA) to provide the TFA salt of Example 29 as a light yellow foam (29.3 mg). LC (Cond. 2): RT = 1.82 minutes, >98% homogeneity index; LC/MS: Anal. Calcd. for [M+H]⁺ C₄₂H4₈N9O4: 742.38; found 742.49.

Example 30 methyl ((lR)-2-((2S)-2-(5-(4’-(2-((2S)-l-glycyl-2-pyrrolidinyl)-lH-imidazol-5-yl)-4biphenylyl)-lH-imidazol-2-yl)-l-pyrrolidinyl)-2-oxo-l-phenylethyl)carbamate

<img file="IL196813A_D0144.tif" />

/°

Example 30, Step a methyl ((lR)-2-((2S)-2-(5-(4'-(2-((2S)-l-(N-(tert-butoxycarbonyl)glycyl)-2pyrrolidinyl)-lH-imidazol-5-yl)-4-biphenylyl)-lH-imidazol-2-yl)-l-pyrrolidinyl)-2oxo-1-phenylethyl) carbamate

<img file="IL196813A_D0145.tif" />

Carbamate 30a was prepared from pyrrolidine 28f and Boc-Glycine by using the procedure described for the preparation of 25 a from le. LC (Cond. 2): RT = 2.12 minutes, >98% homogeneity index; LC/MS: Anal. Calcd. for [M+H]⁴C43H49N8O6: 773.38; found 773.46

Example 30 methyl ((lR)-2-((2S)-2-(5-(4'-(2-((2S)-l-glycyl-2-pyrrolidinyl)-lH-imidazol-5-yl)-4biphenylyl)-lH-imidazol-2-yl)-l-pyrrolidinyl)-2-oxo-l-phenylethyl)carbamate

Carbamate 30a was converted to Example 30 according to the procedure described for the preparation of le from Id. LC (Cond. 2): RT = 1.81 minutes, >98% homogeneity index; LC/MS: Anal. Calcd. for [M+H]⁺ C38H41N8O4: 673.33; found 673.43

HRMS: Anal. Calcd. for [M+H]⁺ C38H41N8O4: 673.3251; found 673.3262

Example 30-1 methyl ((lS)-2-((2S)-2-(5-(4'-(2-((2S)-l-((2R)-2-(diethylamino)-2-phenylacetyl)-2pyrrolidinyl)-lH-imidazol-5-yl)-4-biphenylyl)-lH-imidazol-2-yl)-l-pyrrolidinyl)-lmethyl-2-oxoethyl)carbamate

O^Z

<img file="IL196813A_D0146.tif" />

Example 30-1 was prepared in three steps from Example 28d. Step one:

Append Cap-2 using the procedure describing the synthesis of 28e from 28d. Step two: Hydrolyze the Boc carbamate using the procedure describing the synthesis of

28f from 28e. Step three: Append Cap-52 using the procedure describing the synthesis of 28e from 28d. RT = 1.70 min (Cond. lb); >95% homogeneity index. LC/MS: Anal. Calcd. for [M+H]⁺ C43H51N8O4: 743.40; found, 743.50. HRMS: Anal. Calcd. for [M+H]⁺ C43H51N₈O₄: 743.4033; found, 743.4053

Substituting the appropriate acid chloride or carboxylic acid into Example 29 10 or 30, the following compounds (Example 31 to 84-87) were prepared as TFA salts.

Example 31 to 84-88

1) step a

2) step b

3) step c

Example 28d ----------

<img file="IL196813A_D0147.tif" />

O step a: Cap with cap-4 as in Example 28 ' step b: Same procedure as in conversion of Example 1d to 1e step c: As in the last step of Example 1 using 1.1 equiv. of the appropriate carboxylic acid and HATU

<td> Example</td><td> Compound Name</td><td> O κΆ*</td><td> Retention time (LCCondition); homogeneity index MS data</td>

<td> 31</td><td> methyl ((lR)-2-((2S)-2-(5-(4’(2-((2S)-l-acetyl-2pyrrolidinyl)-1 H-imidazol-5yl)-4-biphenylyl)-1 H-imidazol2-yl)-1 -pyrrolidinyl)-2-oxo-1 phenylethyl)carbamate</td><td></td><td> 1.54 minutes (Cond. 1); &gt;98%; LC/MS: Anal. Calcd. for [M+H]⁺C38H40N7O4: 658.31; found 658.42; HRMS: Anal. Calcd. for [M+H]⁺C38H40N7O4: 658.3142; found 658.3135</td>

<td> 32</td><td> methyl ((lR)-2-oxo-l-phenyl2-((2S)-2-(5-(4'-(2-((2S)-l3ropionyl-2-pyrrolidinyl)-1Himidazol-5-yl)-4-biphenylyl)lH-imidazol-2-yl)-1 pyrrolidinyl)ethyl)carbamate</td><td> 0</td><td> .57 minutes (Cond. 1); &gt;98%; LC/MS: Anal. Calcd. for [M+H]⁺C39H42N₇O4: 672.33; found 672.46; HRMS: Anal. Calcd. for [M+H]⁺ C39H42N7O4: 672.3298; found 672.3299</td>

<td> 33</td><td> methyl ((lR)-2-((2S)-2-(5-(4'(2-((2S)-l(cyclopropylcarbonyl)-2pyrrolidiny 1)-1 H-imidazol-5yl)-4-biphenylyl)- IH-imidazol2-yl)-1 -pyrrolidinyl)-2-oxo-1 phenylethyl)carbamate</td><td> O</td><td> 1.59 minutes (Cond. 1); &gt;98%; LC/MS: Anal. Calcd. for [M+H]⁺C40H42N7O4: 684.33; found 684.44; HRMS: Anal. Calcd. for M+H]⁺ C40H42N7O4: 684.3298; found 684.3324</td>

<td> 34</td><td> methyl ((lR)-2-((2S)-2-(5-(4'(2-((2S)-l-(cyclopropylacetyl)2-pyrrolidinyl)-1 H-imidazol-5yl)-4-biphenylyl)-1 H-imidazol2-yl)-1 -pyrrolidinyl)-2-oxo-1 phenylethyl)carbamate</td><td></td><td> 1.61 minutes (Cond. 1); &gt;98%; LC/MS: Anal. Calcd. for [M+H]⁺C40H42N7O4: 698.35; found 698.48; HRMS: Anal. Calcd. for [M+H]⁺ C40H42N7O4: 698.3455; found 698.3489</td>

<td> 35</td><td> methyl ((lR)-2-((2S)-2-(54)־'(2-((2S)-l-((2R)-2hydroxypropanoyl)-2pyrrolidinyl)-1 H-imidazol-5yl)-4-biphenylyl)-1 H-imidazol2-yl)-1 -pyrrolidinyl)-2-oxo-1 phenylethyl)carbamate</td><td> h6</td><td> 1.54 minutes (Cond. 1); &gt;98%; LC/MS: Anal. Calcd. for [M+H]⁺C39H42N7O5: 688.33; found 688.47</td>

<td> 36</td><td> methyl ((lR)-2-oxo-l-phenyl2-((2S)-2-(5-(4'-(2-((2S)-l((2R)-tetrahydro-2furanylcarbonyl)-2pyrrolidinyl)-l H-imidazol-5yl)-4-biphenylyl)-1 H-imidazol2-yl)-lpyrrolidinyl)ethyl)carbamate</td><td> 0 1 1.59 minutes (Cond. 1); /⁰γγ &gt;98%; '-J LC/MS: Anal. Calcd. for [M+H]⁺C41H44N7O5: 714.34; found 714.49; HRMS: Anal. Calcd. for [M+H]⁺ C41H44N7O5: 714.3404; found 714.3430</td>

<td> 37</td><td> methyl ((lR)-2-((2S)4)-5)-2־'- (2-((2S)-l-(N,N- dimethylglycyl)-2- pyrrolidinyl)-1 H-imidazol-5yl)-4-biphenylyl)-1 H-imidazol2-yl)-1 -pyrrolidinyl)-2-oxo-1 phenylethyl)carbamate</td><td> 1.48 0 ן minutes (Cond. 1); &gt;98%; LC/MS: Anal. Calcd. for [M+H]⁺C40H45N8O4: 701.36; found 701.49; HRMS: Anal. Calcd. for [M+H]⁺ C40H45N8O4: 701.3564; found 701.3553</td>

<td> 38</td><td> methyl ((lR)-2-((2S)-2-(5-(4'(2-((2S)-l-((2S)-2(dimethylamino)-2phenylacetyl)-2-pyrrolidinyl)1 H-imidazol-5 -y 1)-4biphenylyl)1 ־ H-imidazol-2-yl)1-pyrrolidiny l)-2-oxo-1 phenylethyl)carbamate</td><td> Me O 1.20 minutes (Cond. 1); 1 II Me^xN״'&lt;y &gt;98%; LC/MS: Anal. Ph Calcd. for [M+H]⁺ Cap-1 C46H49N8O4:777.39; found 777.61; HRMS: Anal. Calcd. for [M+H]⁺ C46H49N8O4: 777.3877; found 777.3909</td>

<td> 39</td><td> methyl ((lR)-2-((2S)-2-(5-(4'(2-((2S)-l-(4morpholinylacetyl)-2pyrrolidinyl)-l H-imidazol-5yl)-4-biphenylyl)-1 H-imidazol2-yl)-1 -pyrrolidinyl)-2-oxo-1 phenylethyl)carbamate</td><td> 0ן^׳׳־ O 1.79 minutes (Conii. 2); &gt;98%; LC/MS: Anal. Calcd. for [M+H]⁺C42H47N8O5: 743.37; found 743.49; HRMS: Anal. Calcd. for [M+H]⁺ C42H47N8O5: 743.3669; found</td>

<td></td><td></td><td></td><td> 743.367?</td>

<td> 40</td><td> methyl (2-((2S)-2-(5-(4’-(2((2S)-l-((2R)-2- 1 (methoxy carbonyl)amino)-2phenylacetyl)-?-pyrrolidinyl)lH-imidazol-5-yl)-4- ! jiphenylyl)-1 H-imidazol-2-yl)l-pyrrolidinyl)-2oxoethyl)carbamate</td><td> H ? 0</td><td> 1.9? minutes (Cond. ?); &gt;98%; LC/MS: Anal. Calcd. for[M+H]⁺C40H43N8O6: 731.33; found 731.4?; HRMS: Anal. Calcd. for [M+H]⁺ C40H43N8O₆: 731.3306; found 731.3333</td>

<td> 41</td><td> methyl ((lR)-?-((?S)-?-(5-(4'(2-((2S)-l-(N-acetylglycyl)-2pyrrolidinyl)-1 H-imidazol-5yl)-4-biphenylyl)-1 H-imidazol2-yl)-1 -pyrrolidiny 1)-2-oxo-1 phenylethyl)carbamate</td><td> H ״ V-O 0</td><td> 1.86 minutes (Cond. ?); &gt;98%; LC/MS: Anal. Calcd. for [M+H]⁺C40H43N8O5: 715.34; found 715.49; HRMS: Anal. Calcd. for [M+H]⁺ C40H43N8O5: 715.3356; found 715.3369</td>

<td> 42</td><td> methyl ((lR)-2-((2S)-2-(5-(4'(2-((2S)-l-((2R)-2(dimethylamino)-2phenylacetyl)-2 -pyrrolidinyl)- 1 H-imidazol-5 -y 1)-4biphenylyl)-1 H-imidazol-2-yl)1 -pyrrolidinyl)-? -oxo-1 phenylethyl)carbamate</td><td> Qa</td><td> 1.85 minutes (Cond. ?); &gt;98%; LC/MS: Anal. Calcd. for[M+H]⁺C46H49N8O4: 777.39; found 777.56</td>

<td> 43</td><td> methyl ((lR)-2-((2S)-2-(5-(4'(2-((2S)-l-((2R)-2-hydroxy-2phenylacetyl)-2-pyrrolidinyl)lH-imidazol-5-yl)-4biphenylyl)-1 H-imidazol-2-yl)1 -pyrrolidinyl)-?-oxo-1 phenylethyl)carbamate</td><td> Ola OH</td><td> 1.96 minutes (Cond. ?); &gt;98%; LC/MS: Anal. Calcd. for[M+H]⁺C44H44N7O5:750.34; found 750.51; HRMS: Anal. Calcd. for [M+H]⁺ C44H44N7O5: 750.3404; found</td>

<td></td><td></td><td></td><td> 750.3437</td>

<td> 44</td><td> methyl ((lR)-2-((2S)-2-(5-(4'(2-((2S)-l-((l-methyl-4pip eridinyl)carbony 1)-2pyrrolidinyl)-1 H-imidazol-5yl)-4-biphenylyl)-1 H-imidazol2-yl)-l -pyrrolidinyl)-2-oxo-1 phenylethyl)carbamate</td><td> 0 rVS⁵</td><td> 1.78 minutes (Cond. 2); &gt;98%; LC/MS: Anal. Calcd. for [M+H]⁺C43H49N8O4: 741.39; found 741.55; HRMS: Anal. Calcd. for [M+H]⁺C43H₄₉N₈O4: 741.3877; found 741.3893</td>

<td> 45</td><td> methyl ((lR)-2-oxo-l-phenyl2-((2S)-2-(5-(4'-(2-((2S)-l(tetrahydro-2H-pyran-4ylcarbonyl)-2-pyrrolidinyl)1 H-imidazol-5-y 1)-4biphenylyl)-! H-imidazol-2-yl)1 -pyrrolidinyl)ethyl)carbamate</td><td> 0 oA/</td><td> 1.87 minutes (Cond. 2); &gt;98%; LC/MS: Anal. Calcd. for [M+H]⁺C42H46N7O5: 728.36; found 728.52; HRMS: Anal. Calcd. for [M+H]⁺ C42H46N7O5: 728.3560; found 728.3587</td>

<td> 46</td><td> methyl ((lR)-2-oxo-l-phenyl2-((2S)-2-(5-(4'-(2-((2S)-l -(2pyridinylacetyl)-2pyrrolidinyl)-lH-imidazol-5yl)-4-biphenylyl)-1 H-imidazol- 2-yl)-l- pyrrolidinyl)ethyl)carbamate</td><td> f^N 0 L 1 1</td><td> 1.80 minutes (Cond. 2); &gt;98%; LC/MS: Anal. Calcd. for [M+H]⁺C43H43N8O4:735.34; found 735.51; HRMS: Anal. Calcd. for [M+H]⁺ C43H43N8O4: 735.3407; found 735.3416</td>

<td> 47</td><td> methyl ((1R)2־-oxo-1-phenyl2-((2S)-2-(5-(4'-(2-((2S)-l-(3pyridinylacetyl)-2pyrrolidinyl)-1 H-imidazol-5yl)-4-biphenylyl)-1 H-imidazol2-yl)-lpyrrolidinyl)ethyl)carbamate</td><td> o / °</td><td> 1.76 minutes (Cond. 2); &gt;98%; LC/MS: Anal. Calcd. for [M+H]⁺C43H43N8O4: 735.34; found 735.52</td>

<td> 48</td><td> methyl ((1R)2־-oxo-1 -phenyl2-((2S)-2-(5-(4'-(2-((2S)-l -(4pyridinylacetyl)-2pyrrolidinyl)-1 H-imidazol-5yl)-4-biphenylyl)- IH-imidazol2-yl)-lpyrrolidinyl)ethyl)carbamate</td><td> ° \ 0</td><td> 1.77 minutes (Cond. 2); &gt;98%; LC/MS: Anal. Calcd. for [M+H]⁺C43H43N8O4: 735.34; found 735.50; HRMS: Anal. Calcd. for M+H]⁺ C43H43N8O4: 735.3407; found 735.3405</td>

<td> 49</td><td> methyl ((lR)-2-((2S)-2-(5-(4'(2-((2S)-l-((l-methyl-lHimidazol-5-yl)carbonyl)-2pyrrolidinyl)-l H-imidazol-5yl)-4-biphenylyl)-1 H-imidazol2-yl)-1 -pyrrolidinyl)-2-oxo-1 phenylethyl)carbamate</td><td> ג S &lt;X hr</td><td> 1.77 minutes (Cond. 2); &gt;98%; LC/MS: Anal. Calcd. for [M+H]⁺C41H42N9O4: 724.34; found 724.51; HRMS: Anal. Calcd. for [M+H]⁺ C41H42N9O4: 724.3360; found 724.3380</td>

<td> 50</td><td> methyl ((lR)-2-((2S)-2-(5-(4'(2-((2S)-l(dimethylcarbamoyl)-2pyrrolidinyl)-l H-imidazol-5yl)-4-biphenylyl)-1 H-imidazol2-yl)-1 -pyrrolidinyl)-2-oxo-1 phenylethyl)carbamate</td><td> 0</td><td> 1.91 minutes (Cond. 2); &gt;98%; LC/MS: Anal. Calcd. for [M+H]⁺C39H43N8O4: 687.34; found 687.49; HRMS: Anal. Calcd. for [M+H]⁺ C39H43N8O4: 687.3407; found 687.3414</td>

<td> 51</td><td> methyl ((lR)-2-((2S)-2-(5-(4’(2-((2S)-l-(l-methyl-Dprolyl)-2-pyrrolidinyl)- 1Himidazol-5-yl)-4-biphenylyl)lH-imidazol-2-yl)-1 pyrrolidinyl)-2-oxo-l phenylethyl)carbamate</td><td> ' s Cap-10</td><td> 1.79 minutes (Cond. 2); &gt;98%; LC/MS: Anal. Calcd. for [M+H]⁺C42H47N8O4: 727.37; found 727.34; HRMS: Anal. Calcd. for [M+H]⁺C42H47N8O4: 727.3720; found</td>

<td></td><td></td><td></td><td> 727.3719</td>

<td> 52</td><td> methyl ((lR)-2-((2S)-2-(5-(4'(2-((2S)-l-(l-methyl-Lprolyl)-2-pyrrolidinyl)- 1Himidazol-5-yl)-4-biphenylyl)lH-imidazol-2-yl)-1 pynolidinyl)-2-oxo-l phenylethyl)carbamate</td><td> ' 1 enantiomer of Cap-10</td><td> 1.77 minutes (Cond. 2); &gt;98%; LC/MS: Anal. Calcd. for [M+H]⁺C42H47N8O4: 727.37; found 727.33; HRMS: Anal. Calcd. for [M+H]⁺C42H47N₈O4! 727.3720; found 727.3738</td>

<td> 53</td><td> methyl ((lR)-2-((2S)-2-(5-(4'(2-((2S)-l-(N-acetyl-Dalanyl)-2-pyrroiidinyl)-1Himidazol-5-yl)-4-biphenylyl)1 H-imidazol-2-yl)-1 pyrrolidinyl)-2-oxo-l phenylethyl)carbamate</td><td> H ״ υΛ 0 ¹</td><td> 1.92 minutes (Cond. 2); &gt;98%; LC/MS: Anal. Calcd. for [M+H]⁺C41H45N8O5: 729.35; found 729.33; HRMS: Anal. Calcd. for [M+H]⁺ C41H45N8O5: 729.3513; found 729.3530</td>

<td> 54</td><td> methyl ((lR)-2-((2S)-2-(5-(4'(2-((2S)-1 -(N-acetyl-L-alanyl)2-pyrrolidinyl)-1 H-imidazol-5yl)-4-biphenylyl)-1 H-imidazol2-yl)-1 -pyrrolidinyl)-2-oxo-1 phenylethyl)carbamate</td><td> H ? γΛ 0 =</td><td> 1.87 minutes (Cond. 2); &gt;98%; LC/MS: Anal. Calcd. for [M+H]⁺C41H45N8O5: 729.35; found 729.33</td>

<td> 55</td><td> methyl ((lR)-2-((2S)-2-(5-(4'(2-((2S)-1 -(methoxyacetyl)-2pyrrolidinyl)-1 H-imidazol-5yl)-4-biphenylyl)-1 H-imidazol2-yl)-1 -pyrrolidinyl)-2-oxo-1 phenylethyl)carbamate</td><td> o</td><td> 1.89 minutes (Cond. 2); &gt;98%; LC/MS: Anal. Calcd. for [M+H]⁺C39H42N7O5: 688.32; found 688.28; HRMS: Anal. Calcd. for [M+H]⁺ C39H42N7O5: 688.3247; found 688.3231</td>

<td> 56</td><td> methyl ((lR)-2-((2S)-2-(5-(4’(2-((2S)-l-((2R)-2hydroxybutanoyl)-2pyTrolidinyl)-lH-imidazol-5yl)-4-biphenylyl)-1 H-imidazol2-yl)-1 -pyrrolidinyl)-2-oxo-1 phenylethyl)carbamate</td><td> 0 ^Ά/ OH</td><td> 1.91 minutes (Cond. 2); &gt;98%; LC/MS: Anal. Calcd. for [M+H]⁺C40H44N7O5: 702.34; found 702.30; HRMS: Anal. Calcd. for M+H]⁺ C40H44N7O5: 702.3404; found 702.3393</td>

<td> 57</td><td> methyl ((lR)-2-((2S)-2-(5-(4’(2-((2S)-l-((4-methyl-lpiperazinyl)acetyl)-2pyrrolidinyl)-1 H-imidazol-5yl)-4-biphenylyl)-1 H-imidazol2-yl)-l -pyrrolidmy 1)-2-oxo-1 phenylethyl)carbamate</td><td> 0</td><td> 1.80 minutes (Cond 2); &gt;98%; LC/MS: Anal. Calcd. for [M+H]⁺C43H50N9O4: 756.40; found 756.36; HRMS: Anal. Calcd. for [M+H]⁺C43H50N₉O4: 756.3986; found 756.3965</td>

<td> 58</td><td> methyl ((1R)2־-oxo-1 -phenyl2-((2S)-2-(5-(4'-(2-((2S)-1-(1pyrrolidinylacetyl)-2pyrrolidinyl)-l H-imidazol-5y l)-4-biphenylyl)-1 H-imidazol- 2-yl)-l- pyrrolidinyl)ethyl)carbamate</td><td> /—\ °</td><td> 1.82 minutes (Cond. 2); &gt;98%; LC/MS: Anal. Calcd. for [M+H]⁺C42H47N8O4: 727.37; found 727.33; HRMS: Anal. Calcd. for [M+H]⁺ C42H47N8O4: 727.3720; found 727.3696</td>

<td> 59</td><td> methyl ((1R)2־-oxo-1 -phenyl2-((2S)-2-(5-(4'-(2-((2S)-l((2S)-tetrahydro-2furanylcarbonyl)-2pyrrolidinyl)-1 H-imidazol-5yl)-4-biphenylyl)-1 H-imidazol- 2-yl)-l- pyrrolidinyl)ethyl)carbamate</td><td> 0</td><td> 1.94 minutes (Cond. 2); &gt;98%; LC/MS: Anal. Calcd. for [M+H]⁺C41H43N7O5: 714.34; found 714.24</td>

<td> 60</td><td> methyl ((lR)-2-((2S)-2-(5-(4'(2-((2S)-1-((1hydroxycyclopropyl)carbonyl)2-pyrrolidinyl)-1 H-imidazol-5yl)-4-biphenylyl)-1 H-imidazol2-yl)-1 -pyrrolidinyl)-2-oxo-1 phenylethyl)carbamate</td><td></td><td> 1.93 minutes (Cond. 2); &gt;98%; LC/MS: Anal. Calcd. for [M+H]⁺C40H42N7O₅: 700.32; found 700.23; HRMS: Anal. Calcd. for [M+H]⁺ C40H42N7O5: 700.3247; found 700.3265</td>

<td> 61</td><td> methyl ((lR)-2-((2S)-2-(5-(4'(2-((2S)-1-(1 H-imidazol-5ylacetyl)-2 -pyrrolidinyl)-1Himidazol-5-yl)-4-biphenylyl)1 H-imidazol-2-yl)-1 pyrrolidinyl)-2-oxo-1 phenylethyl)carbamate</td><td> Z^-NH O</td><td> 1.84 minutes (Cond. 2); &gt;98%; LC/MS: Anal. Calcd. for[M+H]⁺C41H42N9O4: 724.34; found 724.21; HRMS: Anal. Calcd. for [M+H]⁺ C41H42N9O4: 724.3360; found 724.3365</td>

<td> 62</td><td> methyl ((lR)-2-((2S)-2-(5-(4'(2-((2S)-1-((1-methyl-1Himidazol-4-yl)acetyl)-2pyrrolidinyl)-1 H-imidazol-5yl)-4-biphenylyl)-1 H-imidazol2-yl)-1 -pyrrolidinyl)-2-oxo-1 phenylethyl)carbamate</td><td> /=N O —n A 11</td><td> 1.85 minutes (Cond. 2); &gt;98%; LC/MS: Anal. Calcd. for [M+H]⁺C42H44N9O4: 738.35; found 738.22; HRMS: Anal. Calcd. for [M+H]⁺ C42H44N9O4: 738.3516; found 738.3539</td>

<td> 63</td><td> methyl ((lR)-2-((2S)-2-(5-(4'(2-((2S)-1 -(1 H-imidazol-2ylcarbonyl)-2-pyrrolidinyl)1 H-imidazol-5 -yl)-4biphenylyl)-! H-imidazol-2-yl)1-pyrrolidiny 1)-2-oxo-1 phenylethyl)carbamate</td><td> 0 CA</td><td> 1.95 minutes (Cond. 2); &gt;98%; LC/MS: Anal. Calcd. for [M+H]⁺C40H41N9O4: 710.32; found 710.17</td>

<td> 64</td><td> methyl ((lR)-2-((2S)-2-(5-(4’(2-((2S)-l-((4-hydroxy-lpiperidinyl)(phenyl)acetyl)-2pyrrolidinyl)-l H-imidazol-5yl)-4-biphenylyl)- IH-imidazol2-yl)-1 -pyrrolidiny 1)-2-oxo-1 phenylethyl)carbamate</td><td> Q A 9 OH Cap-8 A single diastereomer</td><td> 1.92 minutes (Cond. 2); &gt;98%; LC/MS: Anal. Calcd. for [M+H]⁺C49H53N8O5: 833.41; found 833.32; HRMS: Anal. Calcd. for [M+H]⁺ C49H53N8O5: 833.4139; found 833.4163</td>

<td> 65</td><td> methyl ((1 R)-2-oxo-1-phenyl2-((2S)-2-(5-(4'-(2-((2S)-l(1 H-tetrazol5־-y lacety 1)-2pyrrolidinyl)-l H-imidazol-5yl)-4-biphenylyl)-1 H-imidazol2-yl)-lpyrrolidinyl)ethyl)carbamate</td><td> n i 11 H *</td><td> 1.92 minutes (Cond. 2); &gt;98%; LC/MS: Anal. Calcd. for [M+H]⁺ C39H40NUO4: 726.33; found 726.22; HRMS: Anal. Calcd. for [M+H]⁺ C39H40N11O4: 726.3265; found 726.3290</td>

<td> 67</td><td> methyl ((1R)2־-oxo-1 -phenyl2-((2S)-2-(5-(4'-(2-((2S)-l-(2pyridinylcarbonyl)-2pyrrolidinyl)-1 H-imidazol-5yl)-4-biphenylyl)-1 H-imidazol- 2-yl)-l- pyrrolidinyl)ethyl)carbamate</td><td> 0</td><td> 2.03 minutes (Cond. 2); &gt;98%; LC/MS: Anal. Calcd. for[M+H]⁺C42H41N8O4: 721.33; found 721.31; HRMS: Anal. Calcd. for [M+H]⁺ C42H41N8O4: 721.3251; found 721.3247</td>

<td> 68</td><td> methyl ((1 R)-2-oxo-1-phenyl2-((2S)-2-(5-(4'-(2-((2S)-l -(3pyridinylcarbonyl)-2pyrrolidinyl)-lH-imidazol-5yl)-4-biphenylyl)-1 H-imidazol2-yl)-lpyrrolidinyl)ethyl)carbamate</td><td> 0</td><td> 1.91 minutes (Cond. 2); &gt;98%; LC/MS: Anal. Calcd. for [M+H]⁺C42H41N8O4: 721.33; found 721.31; HRMS: Anal. Calcd. for [M+H]⁺ C42H41N8O4:</td>

<td></td><td></td><td></td><td> 721.3251; found 721.3226</td>

<td> 69</td><td> methyl ((lR)-2-((2S)-2-(5-(4'(2-((2S)-1 -isonicotinoyl-2py1rolidmyl)-lH-imidazol-5yl)-4-biphenylyl)-1 H-imidazol2-yl)-1 -pyrrolidinyl)-2-oxo-1 phenylethyl)carbamate</td><td> 0 iTvS¹‘</td><td> 1.89 minutes (Cond. 2); &gt;98%; LC/MS: Anal. Calcd. for[M+H]⁺C42H41N8O4: 721.33; found 721.29; HRMS: Anal. Calcd. for [M+H]⁺ C42H41N8O4: 721.3251; found 721.3251</td>

<td> •70</td><td> methyl ((lR)-2-((2S)-2-(5-(4’(2-((2S)-l-((4R)-4-fluoro־lmethyl-L-prolyl)-2pyrrolidinyl)-l H-imidazol-5yl)-4-bipheny ly 1)-1 H-imidazol2-yl)-1 -pyrrolidinyl)-2-oxo-1 phenylethyl)carbamate</td><td> F Cap-11</td><td> 1.84 minutes (Cond. 2); &gt;98%; LC/MS: Anal. Calcd. for[M+H]⁺C42H46FN8O4: 745.36; found 745.27; HRMS: Anal. Calcd. for [M+H]⁺ C42H46FN8O4: 745.3626; found 745.3658</td>

<td> 71</td><td> methyl ((lR)-2-((2S)-2-(5-(4'(2-((2S)-1 -(1,3-oxazol-2ylcarbonyl)-2-pyrrolidinyl)1 H-imidazol-5 -y 1)-4biphenylyl)-1 H-imidazol-2-yl)1 -pyrrolidinyl)-2-oxo-1 phenylethyl)carbamate</td><td> 0</td><td> 1.97 minutes (Cond. 2); &gt;98%; LC/MS: Anal. Calcd. for[M+H]⁺C40H39N8O5:711.30; found 711.27</td>

<td> 72</td><td> methyl ((lR)-2-((2S)-2-(5-(4'(2-((2S)-1 -(1,3-oxazol-5ylcarbonyl)-2-pyrrolidinyl)lH-imidazol-5-yl)-4biphenylyl)-1 H-imidazol-2-yl)1 -pyrrolidinyl)-2-oxo-1 phenylethyl)carbamate</td><td> 0</td><td> 1.95 minutes (Cond. 2); &gt;98%; LC/MS: Anal. Calcd. for [M+H]⁺C40H39N8O5: 711.30; found 711.27; HRMS: Anal. Calcd. for [M+H]⁺ C4QH39N8O5: 711.3043; found</td>

<td></td><td></td><td></td><td> 711.3078</td>

<td> 73</td><td> methyl ((lR)-2-((2S)-2-(5-(4'(2-((2S)-l((dimethylamino)(oxo)acetyl)2-pyrrolidinyl)-1 H-imidazol-5yl)-4-biphenylyl)-1 H-imidazol2-yl)-1 -pyrrolidinyl)-2-oxo-1 phenylethyl)carbamate</td><td> 1 ⁰zV/ 0</td><td> 1.92 minutes (Cond. 2); &gt;98%; LC/MS: Anal. Calcd. for [M+H]⁺C40H43N8O5: 715.34; :bund 715.40</td>

<td> 74</td><td> methyl ((1R)2־-oxo-1-phenyl2-((2S)-2-(5-(4'-(2-((2S)-l(tetrahydro-3furany lcarbonyl)-2 pyrrolidinyl)-1 H-imidazol5־yl)-4-biphenylyl)-1 H-imidazol- 2-yl)-lpyrrolidinyl)ethyl)carbamate</td><td> 0</td><td> 1.91 minutes (Cond. 2); &gt;98%; LC/MS: Anal. Calcd. for [M+H]⁺ C41H44N7O5: 714.34; found 714.39; HRMS: Anal. Calcd. for [M+H]⁺ C41H44N7O5: 714.3404; found 714.3433</td>

<td> 75</td><td> methyl ((lR)-2-((2S)-2-(5-(4'(2-((2S)-l-(N- (methoxy carbonyl)-L-alanyl)2-pyrrolidinyl)-1 H-imidazol-5 yl)-4-biphenylyl)-1 H-imidazol2-yl)-1 -pyrrolidinyl)-2-oxo-1 phenylethyl)carbamate</td><td> h U 0 = Cap-12</td><td> 1.94 minutes (Cond. 2); &gt;98%; LC/MS: Anal. Calcd. for[M+H]⁺C41H45N8O6: 745.35 found 745.34; HRMS: Anal. Calcd. for [M+H]⁺C41H45N8O6: 745.3462; found 745.3486</td>

<td> 76</td><td> methyl ((lR)-2-((2S)-2-(5-(4'(2-((2S)-1 -(N,N-dimethyl-Lalanyl)-2-pyrrolidinyl)-1Himidazol-5-yl)-4-biphenylyl)1 H-imidazol-2 -y 1)-1 pyrrolidinyl)-2-oxo-1 phenylethyl)carbamate</td><td> 1 °</td><td> 1.80 minutes (Cond. 2); &gt;98%; LC/MS: Anal. Calcd. for [M+H]⁺C41H47N8O4 715.37; found715.35 ;HRMS: Anal. Calcd. for [M+H]⁺ C41H47N8O4 715.3720; found 715.3737</td>

<td> 77</td><td> methyl (2S)-2-(5-(4'-(2-((2S)l-((2R)-2- ((methoxycarbonyl)amino)-2- phenylacetyl)-2-pyrrolidinyl)- 1 H-imidazol-5 -yl)-4- 7iphenylyl)-l H-imidazol-2-yl)- 1 -pyrrolidinecarboxylate</td><td> 0</td><td> 1.97 minutes (Cond. 2); &gt;98%; LC/MS: Anal. Calcd. for[M+H]⁺C₃₈H40N₇O5: 674.31; found 674.66; HRMS: Anal. Calcd. for M+H]⁺ C38H40N7O5: 674.3091; found 674.3110</td>

<td> 78</td><td> methyl ((lR)-2-((2S)-2-(5-(4'(2-((2S)-l-(4morpholinylcarbonyl)-2pyrrolidinyl)-lH-imidazol-5yl)-4-biphenyly 1)-1 H-imidazol2-yl)-1 -pyrrolidinyl)-2-oxo-1 phenylethyl)carbamate</td><td> 0</td><td> 1.95 minutes (Cond. 2); &gt;98%; LC/MS: Anal. Calcd. for[M+H]⁺C41H45N8O5: 729.35; found 729.40; HRMS: Anal. Calcd. for [M+H]⁺C41H45N8O₅: 729.3513; found 729.3502</td>

<td> 79</td><td> methyl ((lR)-2-((2S)-2-(5-(4’(2-((2S)-l-((4S)-4-fluoro-Lprolyl)-2-pyrrolidinyl)- IHimidazol-5-yl)-4-biphenylyl)lH-imidazol-2-yl)-1 pyrrolidiny 1)-2-oxo-1 phenylethyl)carbamate</td><td> Η Ϊ (J ^Z F*</td><td> 1.80 minutes (Cond. 2); &gt;98%; LC/MS: Anal. Calcd. for [M+H]⁺C41H44FN8O4: 731.84; found 731.26</td>

<td> 80</td><td> methyl ((lR)-2-oxo-1-phenyl2-((2S)-2-(5-(4'-(2-((2S)-l-Lprolyl-2 -pyrrolidiny 1)-1Himidazol-5-yl)-4-biphenylyl)lH-imidazol-2-yl)-1 pyrrolidinyl)ethyl)carbamate</td><td> Η Ϊ</td><td> 1.84 minutes (Cond. 2); &gt;98%; LC/MS: Anal. Calcd. for [M+H]⁺C41H45N8O4: 713.36; found 713.36; HRMS: Anal. Calcd. for [M+H]⁺ C41H45N8O4: 713.3564; found 713.3563</td>

<td> 81</td><td> methyl ((lR)-2-((2S)-2-(5-(4’(2-((2S)-1 -(4,4-difluoro־Lprolyl)-2 -pyrrolidinyl)-1Himidazol-5-yl)-4-biphenylyl)1 H-imidazol-2 -y 1)-1 pyrrolidinyl)-2-oxo-1 phenylethyl)carbamate</td><td> H 2 A F-Λ F</td><td> 1.88 minutes (Cond. 2); &gt;98%; LC/MS: Anal. Calcd. for [M+H]⁺C41H43F₂N₈O4: 749.34; found 749.31; HRMS: Anal. Calcd. for M+H]⁺ C41H43F2N8O4: 749.3375; found 749.3390</td>

<td> 82</td><td> methyl ((lR)-2-((2S)-2-(5-(4׳(2-((2S)-1 -((4R)-4-fluoro-Lprolyl)-2-pyrrolidinyl)-1Himidazol-5-yl)-4-biphenylyl)1 H-imidazol-2 -yl)-1 pyrrolidinyl)-2-oxo-l phenylethyl)carbamate</td><td> 0 Η II ΛΑ F</td><td> 1.83 minutes (Cond. 2); &gt;98%; LC/MS: Anal. Calcd. for [M+H]⁺C41H44FN₈O4: 731.35; found 731.37; HRMS: Anal. Calcd. for [M+H]⁺ C41H44FN8O4: 731.3470; found 731.3502</td>

<td> 83</td><td> methyl ((lR)-2-((2S)-2-(5-(4'(2-((2S)-l-((lS,3S,5S)-2azabicy clo[3.1.0]hex-3ylcarbonyl)-2-pyrrolidinyl)lH-imidazol-5-yl)-4biphenylyl)-l H-imidazol-2-yl)l-pyrrolidinyl)-2-oxo-1 phenylethyl)carbamate</td><td> 0 Η 1] /A</td><td> 1.82 minutes (Cond. 2); &gt;98%; LC/MS: Anal. Calcd. for [M+H]⁺C42H45N8O4: 725.36; found 725.39; HRMS: Anal. Calcd. for [M+H]⁺ C42H45N8O4: 725.3564; found 725.3574</td>

<td> 84</td><td> methyl ((lR)-2-((2S)-2-(5-(4'(2-((2S)-l-L-alanyl-2pyrrolidinyl)-1 H-imidazol-5yl)-4-biphenylyl)-1 H-imidazol2-yl)-1 -pyrrolidinyl)-2-oxo-1 phenylethyl)carbamate</td><td> 0 H₂nJ^</td><td> 1.82 minutes (Cond. 2); &gt;98%; LC/MS: Anal. Calcd. for[M+H]⁺C39H43N8O4: 687.34; found 687.32; HRMS: Anal. Calcd. for [M+H]⁺ C39H43N8O4: 687.3407; found</td>

<td></td><td></td><td></td><td> 687.3435</td>

<td> 84-1</td><td> methyl ((lR)-2-oxo-l-phenyl2-((2S)-2-(5-(4'-(2-((2S)-l((2R)-2-phenyl-2-(lpiperidinyl)acetyl)-2pyrrolidinyl)-! H-imidazol-5yl)-4-biphenylyl)-1 H-imidazol2-yl)-lpynolidinyl)ethyl)carbamate</td><td> 0 Ph^A- Cap-14</td><td>¹HNMR (400 MHz, CD₃OD) δ 7.90-7.85 (m, 9H), 7.81-7.79 (m, IH), 7.63-7.57 (m, 5H), 7.457.32 (m, 6H), 5.51 (s, IH), 5.45 (s, IH), 5.335.29 (m, 2H), 4.06-4.01 (m, 2H), 3.63 (d, 7 = 4.04 Hz, 3H), 3.59-3.50 (m, 2H), 3.19-3.12 (m, IH), 3.07-3.01 (m, IH), 2.93-2.76 (m, 2H), 2.572.51 (m, IH), 2.40-2.31 (m, 2H), 2.22-2.06 (m, 4H), 2.00-1.90 (m, 3H), 1.84-1.64 (m, 4H), 1.521.43 (m, 2H); LCMS: Anal. Calcd. for C49H52N8O4: 816; found: 817 (M+H)⁺.</td>

<td> 84-2</td><td> methyl ((lR)-2-((2S)-2-(5-(4'(2-((2S)-l-((2S)-2-(2fluorophenyl)-2hydroxypropanoyl)-2pyrrolidinyl)-lH-imidazol-5yl)-4-biphenylyl)-1 H-imidazol2-yl)-1 -pyrrolidinyl)-2-oxo-1 phenylethyl)carbamate</td><td> &lt; OH</td><td>¹HNMR (400 MHz, CD3OD) δ 7.89-7.85 (m, 8H), 7.81-7.73 (2H), 7.67-7.65 (m, IH), 7.457.26 (m,7H), 7.13-7.08 (m, IH), 6.94-6.89 (m, 0.5H), 6.72-6.67 (0.5H), 6.09-6.07 (m, 0.4H), 5.51 (s, IH), 5.32-5.25 (m, 1.6H), 4.08-3.95 (m, 2H), 3.85-3.79 (IH), 3.64-3.63 (m, 3H), 3.563.49 (IH), 3.09-3.03 (m, IH), 2.59-2.50 (m, IH),</td>

<td></td><td></td><td></td><td> 2.422.33־ (m, 2H), 2.21־ 2.00 (m, 6H), 1.82-1.74 (m, 1H), 1.66 (d,7 = 4.55 Hz, 3H); LCMS: Anal. Calcd. for C45H46FN7O3: 781; found: 782 (M+H)⁺.</td>

<td> 84-3</td><td> methyl ((lR)-2-oxo-2-((2S)-2(5-(4'-(22))־S)-l-(5-oxo-D־ prolyl)-2-pyrrolidinyl)-1Himidazol-5-yl)-4־biphenylyl)1 H-imidazol-2-yl)-1 pyrrolidinyl)-!־ phenylethyl)carbamate</td><td> J-NH ⁰0</td><td> LCMS: Anal. Calcd. for C41H42N8O5: 726; found: 727 (M+H)⁺.</td>

<td> 84-4</td><td> methyl ((lR)-22))־S)-2-(5-(4'־ (2-((2S)־l-((2R)4)-2־hydroxy-4-methyl-1 piperidmyl)2־-phenylacetyl)-2pyrrolidinyl)-1 H-imidazol-5yl)-4-biphenylyl)-1Himidazol-2־yl)-l -pyrrolidinyl)2-oxo-1phenylethyl)carbamate</td><td> OH כי? 0 Cap-15</td><td> LCMS: Anal. Calcd. for C50H54N8O5: 846; found: 847 (M+H)⁺.</td>

<td> 84-5</td><td> tert-butyl (4R)-4-(((2S)-2-(5(4^,-(2-((2S)־l2))־R)2־((methoxycarbonyl)amino)-2phenylacetyl)-2-pyrrolidinyl)1 H-imidazol-5 -y 1)-4biphenylyl)1 ־ H-imidazol-2yl)-1 -pyrrolidinyl)carbonyl)1,3-thiazolidine-3-carboxylate</td><td> M ⁰Boc</td><td> LCMS: Anal. Calcd. for C45H50N8O6S: 830; found: 831 (M+H)⁺.</td>

<td> 84-6</td><td> methyl ((lR)-2-((2S)-2-(5-(4'(2-((2S)-1-((1-((tert- butoxy carbonyl)amino)cy clop entyl)carbonyl)-2-</td><td> BocHN</td><td> LCMS: Anal. Calcd. for C47H54FN8O6: 826; found: 827 (M+H)⁺.</td>

<td></td><td> pyrrolidinyl)-1 H-imidazol-5yl)-4־biphenylyl)-1Himidazol-2-yl)-l -pyrrolidinyl)2-oxo-1phenylethyl)carbamate</td><td></td><td></td>

<td> 84-7</td><td> methyl ((lR)-2-((2S)-2-(5-(4'(2-((2S)-1 -(N-benzoylglycyl)2-pyrrolidinyl)-l H-imidazol-5yl)-4-biphenylyl)-1Himidazol-2-yl)-l -pyrrolidinyl)2-oxo-1phenylethyl)carbamate</td><td> Ph H ״&gt; N / נץ 0</td><td> LCMS: Anal. Calcd. for C45H44FN8O5: 776; found: 777 (M+H)⁺.</td>

<td> 84-8</td><td> methyl ((lR)-2-((2S)-2-(5-(4'(2-((2S)-l-(4-(4-methyl-lpiperazinyl)benzoyl)-2pyrrolidinyl)-1 H-imidazol-5yl)-4-biphenylyl)-1Himidazol-2-yl)-l -pyrrolidinyl)2-oxo-1phenylethyl)carbamate</td><td> 0 J ׳</td><td> LCMS: Anal. Calcd. for C48H51N₉O4: 817; found: 818 (M+H)⁺.</td>

<td> 84-9</td><td> methyl ((lR)-2-oxo-l-phenyl2-((2S)-2-(5-(4'-(2-((2S)-l-((5phenyl-2-thienyl)carbonyl)-2pyrrolidinyl)-1 H-imidazol-5y l)-4-biphenylyl)-1Himidazol-2-yl)-lpyrrolidinyl)ethyl)carbamate</td><td> Ph</td><td> LCMS: Anal. Calcd. for C47H43N7O4S: 801; found: 802 (M+H)⁺.</td>

<td> 84-10</td><td> methyl ((lR)-2-oxo-l -phenyl2-((2S)-2-(5-(4’-(2-((2S)-l-((4phenyl-1,2,3-thiadiazol-5yl)carbonyl)-2-pyrrolidinyl)1 H-imidazol-5 -y 1)-4biphenylyl)-1 H-imidazol-2yl)-lpyrrolidinyl)ethyl)carbamate</td><td> Ph n'V-A N-S °</td><td> LCMS: Anal. Calcd. for C45H41N9O4S: 803; found: 804 (M+H)⁺.</td>

<td> 84-11</td><td> methyl ((lR)-2-oxo-l-phenyl2-((2S)-2-(5-(4'-(2-((2S)-1-((2phenyl-1,3-thiazol-4yl)carbonyl)-2-pyrrolidinyl)1 H-imidazol-5 -yl)-4biphenylyl)-lH-imidazol-2yl)-lpyrrolidinyl)ethyl)carbamate</td><td> כו־ zr fl צ</td><td> LCMS: Anal. Calcd. for C46H42N8O4S: 802; found: 803 (M+H)⁺.</td>

<td> 84-12</td><td> tert-butyl 4-(((2S)-2-(5-(4'-(2((2S)-l-((2R)-2((methoxycarbonyl)amino)-2phenylacetyl)-2-pyrrolidinyl)1 H-imidazol-5 -yl)-4biphenylyl)-1 H-imidazol-2yl)-1 -pyrrolidinyl)carbony 1)-4methyl-1piperidinecarboxylate</td><td> Boc. N^׳י. \׳־׳ מך</td><td> LCMS: Anal. Calcd. forC48H₅6N₈O6: 840; found: 841 (M+H)⁺.</td>

<td> 84-13</td><td> methyl ((lR)-2-((2S)-2-(5-(4'(2-((28)-1-(4(dimethylamino)butanoyl)-2pyrrolidinyl)-1 H-imidazol-5yl)-4-biphenylyl)-1Himidazol-2-yl)-1 -pyrrolidinyl)2-oxo-1phenylethyl)carbamate</td><td></td><td> LCMS: Anal. Calcd. for C₄₂H4₈N₈O4: 728; found: 729 (M+H)⁺.</td>

<td> 84-14</td><td> methyl ((lR)-2-((2S)-2-(5-(4’(2-((28)-1-((3hydroxyphenyl)acetyl)-2pyrrolidinyl)-1 H-imidazol-5yl)-4-biphenylyl)-1Himidazol-2-yl)-1 -pyrrolidinyl)2-oxo-1- ן phenylethyl)carbamate</td><td> כץ/ Q</td><td> LCMS: Anal. Calcd. for C44H43N7O5: 749; found: 750 (M+H)⁺.</td>

<td> 84-15</td><td> methyl ((lR)-2-((2S)-2-(5-(4'(2-((2S)-l-(N,N-dimethyl?eta-alanyl)-2-pyrrolidinyl)lH-imidazol-5-yl)-43iphenylyl)-1 H-imidazol-2yl)-1 -pyrrolidinyl)-2-oxo-1 phenylethyl)carbamate</td><td> ׳׳N /</td><td> LCMS: Anal. Calcd. for C41H46N8O4: 714; found: 715 (M+H)⁺.</td>

<td> 84-16</td><td> methyl ((lR)-2-((2S)-2-(5-(4’(2-((2S)-l-(4(hydroxymethyl)benzoyl)-2pyrrolidinyl)-1 H-imidazol-5y l)-4-bipheny ly 1)-1Himidazol-2-yl)-1 -pyrrolidinyl)2-oxo-1phenylethyl)carbamate</td><td> ׳^7 HO. —ζ ⁰</td><td> LCMS: Anal. Calcd. for C44H43N7O5: 749; found: 750 (M+H)\</td>

<td> 84-17</td><td> methyl ((lR)-2-((2S)-2-(5-(4’(2-((2S)-l-(((3R)-1-benzyl-3pyrrolidinyl)carbonyl)-2pyrrolidinyl)-1 H-imidazol-5yl)-4-biphenyly 1)-1Himidazol-2-yl)-1 -pyrrolidinyl)2-oxo-1phenylethyl)carbamate</td><td> Ph</td><td> LCMS: Anal. Calcd. for C48H50N8O4: 802; found: 803 (M+H)⁺-</td>

<td> 84-18</td><td> tert-butyl (2S)-2-(2-((2S)-2-(5(4'-(2-((2S)-l-((2R)-2((methoxycarbonyl)amino)-2phenylacetyl)-2-pyrrolidinyl)1 H-imidazol-5 -y 1)-4biphenylyl)-l H-imidazol-2yl)-1 -pyn01־idinyl)-2oxoethyl)-!pyrrolidinecarboxylate</td><td> /Ό [2 N-Boc</td><td> LCMS: Anal. Calcd. for C47H54N8O6: 826; found: 827 (M+H)⁺. __</td>

<td> 84-19</td><td> methyl ((lR)-2-((2S)-2-(5-(4'(2-((2S)-l-((5-methyl-lHpyrazol-3-yl)acetyl)-2pyrrolidinyl)-1 H-imidazol-5y l)-4-bipheny ly 1)-1Himidazol-2-yl)-l -pyrrolidinyl)2-oxo-1phenylethyl)carbamate</td><td> N־=\. hnA</td><td> LCMS: Anal. Calcd. for C42H43N9O4: 737; found: 738 (M+H)⁺.</td>

<td> 84-20</td><td> methyl ((lR)-2-((2S)-2-(5-(4*(2-((2S)-l-(((3S)-7-hydroxy1,2,3,4-tetrahydro-3 isoquinolinyl)carbonyl)-2pyrrolidinyl)-1 H-imidazol-5yl)-4-bipheny lyl)-1Himidazol-2-yl)-l -pyrrolidinyl)2-oxo-1phenylethyl)carbamate</td><td> ho-QAA X-NH</td><td> LCMS: Anal. Calcd. for C46H46N₈O₅: 790; found: 791 (M+H)⁺.</td>

<td> 84-21</td><td> tert-butyl (2R)-2-(((2S)-2-(5(4'-(2-((2S)-l-((2R)-2((methoxycarbonyl)amino)-2phenylacetyl)-2-pyrrolidinyl)1 H-imidazol-5 -y 1)-4biphenylyl)-1 H-imidazol-2yl)-1 -pyrrolidiny !)carbonyl)-1 piperidinecarboxylate</td><td> Boc</td><td> LCMS: Anal. Calcd. for C47H54N₈O₆: 826; found: 827 (M+H)⁺.</td>

<td> 84-22</td><td> methyl ((1 R)-2-oxo-l-phenyl2-((2S)-2-(5-(4'-(2-((2S)-l-((5phenyl-4-isoxazolyl)carbonyl)2-pyrrolidinyl)-1 H-imidazol-5 y l)-4-biphenylyl)-1Himidazol-2-yl)-l pyrrolidinyl)ethyl)carbamate</td><td> νΛ.--Α ⁰ ץ-0 Ph</td><td> LCMS: Anal. Calcd. for C46H42N8O5: 786; found: 787 (M+H)⁺.</td>

<td> 84-23</td><td> methyl ((lR)-2-((2S)-2-(5-(4'(2-((2S)-l-(((lR,3S)-3-((tertbutoxycarbonyl)amino)cyclop</td><td> L/o BocHN*</td><td> LCMS: Anal. Calcd. for C47H54N8O6: 826; found: 827 (M+H)⁺.</td>

<td></td><td> entyl)carbonyl)-2pyrrolidinyl)-1 H-imidazol-5yl)-4-biphenylyl)-1Himidazol-2-yl)-1 -pyrrolidinyl)2-oxo-1- phenylethyl)carbamate</td><td></td><td></td>

<td> 84-24</td><td> methyl ((lR)-2-oxo-l-phenyl2-((2S)-2-(5-(4'-(2-((2S)-l-(3(1 -piperidinyl)propanoyl)-2pyrrolidinyl)-1 H-imidazol-5yl)-4-biphenylyl)-1Himidazol-2-yl)-lpyrrolidinyl)ethyl)carbamate</td><td></td><td> LCMS: Anal. Calcd. for C44H5QN8O4: 754; found: 755 (M+H)⁺.</td>

<td> 84-25</td><td> methyl ((lR)-2-((2S)-2-(5-(4’(2-((2S)-l-(2benzoylbenzoyl)-2pyrrolidinyl)-1 H-imidazol-5yl)-4-biphenylyl)-1Himidazol-2-yl)-l -pyrrolidinyl)2-oxo-1phenylethyl)carbamate</td><td> qA Ph</td><td> LCMS: Anal. Calcd. for C50H45N7O5: 823; found: 824 (M+H)⁺.</td>

<td> 84-26</td><td> methyl ((lR)-2-((2S)-2-(5-(4'(2-((2S)-l-((2methoxyphenoxy )acetyl)-2pyrrolidinyl)-1 H-imidazol-5yl)-4-biphenylyl)-1Himidazol-2-yl)-l -pyrrolidinyl)2-oxo-1phenylethyl)carbamate</td><td> °C^° ^Me0</td><td> LCMS: Anal. Calcd. for C45H45N7O6: 779; found: 780 (M+H)⁺.</td>

<td> 84-27</td><td> tert-butyl 3-(((2S)-2-(5-(4'-(2((2S)-l-((2R)-2((methoxycarbonyl)amino)-2phenylacetyl)-2-pyrrolidinyl)- 1 H-imidazol-5 -yl)-4biphenylyl)-! H-imidazol-2-</td><td></td><td> LCMS: Anal. Calcd. for C45H50N8O6: 798; found: 799 (M+H)⁺.</td>

<td></td><td> yl)-1 -pyrrolidiny !)carbonyl)-1 azetidinecarboxylate</td><td></td><td></td>

<td> 84-28</td><td> methyl ((lR)-2-((2S)-2-(5-(4'(2-((2S)-1 -(((3 S)-1 -benzyl-3 pyrrolidinyl)carbonyl)-2pyrrolidinyl)-1 H-imidazol-5yl)-4-biphenylyl)-1Himidazol-2-yl)-1 -pyrrolidinyl)2-oxo-1phenylethyl)carbamate</td><td> Ph 0</td><td> LCMS: Anal. Calcd. for C48H50N₈O4: 802; found: 803 (M+H)⁺.</td>

<td> 84-29</td><td> methyl ((lR)-2-oxo-l -phenyl2-((2S)-2-(5-(4'-(2-((2S)-1 -(3(1 -pyrrolidinyl)benzoy 1)-2pyrrolidinyl)-1 H-imidazol-5yl)-4-biphenylyl)-1Himidazol-2-yl)-lpyrrolidinyl)ethyl)carbamate</td><td></td><td> LCMS: Anal. Calcd. for C47H48N8O4: 788; found: 789 (M+H)⁺.</td>

<td> 84-30</td><td> methyl ((lR)-2-((2S)-2-(5-(4'(2-((2S)-l-(2-((tertbutoxycarbonyl)amino)benzoy 1)-2-pyrrolidinyl)-1Himidazol-5-yl)-4-biphenylyl)lH-imidazol-2-yl)-l pyrrolidinyl)-2-oxo-l phenylethyl)carbamate</td><td> (A ^SNHBoc</td><td> LCMS: Anal. Calcd. for C48H50N8O6: 834; found: 835 (M+H)⁺.</td>

<td> 84-31</td><td> tert-butyl (3R)-3-(((2S)-2-(5(4'-(2-((2S)-l-((2R)-2((methoxycarbonyl)amino)-2phenylacetyl)-2-pyrrolidinyl)- 1 H-imidazol-5 -y 1)-4biphenylyl)-1 H-imidazol-2yl)-1 -pyrrolidiny !)carbonyl)-1 piperidinecarboxylate</td><td> ( Jo hr Boc</td><td> LCMS: Anal. Calcd. for C47H54N8O6: 826; found: 827 (M+H)⁺.</td>

<td> 84-32</td><td> methyl ((1 R)-2-oxo-1 -phenyl2-((2S)-2-(5-(4'-(2-((2S)-l-((l(trifluoromethyl)cyclopropyl)c arbony 1)-2-pyrrolidinyl)-1Himidazol-5-yl)-4-biphenylyl)lH-imidazol-2־yl)-l pyTT01idinyl)ethyl)carbamate</td><td> F3C^°</td><td> LCMS: Anal. Calcd. for C41H40F3N7O4: 751; found: 752 (M+H)⁺.</td>

<td> 84-33</td><td> methyl ((lR)-2-((2S)-2-(5-(4'(2-((25)-1-(4(dimethylamino)benzoyl)-2pynOlidinyl)-1 H-imidazol-5yl)-4-biphenylyl)-1Himidazol-2-yl)-l -pyrrolidinyl)2-oxo-1phenylethyl)carbamate</td><td> /</td><td> LCMS: Anal. Calcd. for C45H46N8O4: 762; found: 763 (M+H)⁺.</td>

<td> 84-34</td><td> methyl ((lR)-2-((2S)-2-(5-(4׳(2-((2S)-l-(3benzoylbenzoyl)-?pyrrolidinyl)-lH-imidazol-5yl)-4-biphenyly 1)-1Himidazol-2-yl)-1 -pyrrolidinyl)2-oxo-1phenylethyl)carbamate</td><td> 0^0 ° Ph</td><td> LCMS: Anal. Calcd. for C₅₀H45N₇O5: 823; found: 824 (M+H)⁺.</td>

<td> 84-35</td><td> methyl ((lR)-2-((2S)-2-(5-(4'(2-((2S)-l-((cis-4-((tertbutoxycarbonyl)amino)cycloh exyl)carbonyl)-2-pyrrolidinyl)1 H-imidazol-5 -y 1)-4biphenylyl)-1 H-imidazol-2yl)-1 -pyrrolidinyl)-2-oxo-1 phenylethyl)carbamate</td><td> BocHN'״\_v_J 0</td><td> LCMS: Anal. Calcd. for C48H56N8O6: 840; found: 841 (M+H)⁺.</td>

<td> 84-36</td><td> tert-butyl 4-(((2S)-2-(5-(4’-(2- ((2S)-l-((2R)-2- ((methoxycarbonyl)amino)-2phenylacetyl)-?-pyrrolidinyl)-</td><td></td><td> LCMS: Anal. Calcd. for C47H54N8O6: 826; found: 827 (M+H)⁺.</td>

<td></td><td> 1 H-imidazol-5 -y 1)-4biphenylyl)-1 H-imidazol-2 yl)-1 -pyrrolidiny !)carbonyl)-1 piperidinecarboxylate</td><td></td><td></td>

<td> 84-37</td><td> methyl ((lR)-2-((2S)-2-(5-(4’(2-((2S)-l-((cis-4-((tertbutoxycarbonyl)amino)cycloh exyl)carbonyl)-2-pyrrolidinyl)1 H-imidazol-5 -yl)-4biphenylyl)1 ־ H-imidazol-2 yl)-1 -pyrrolidiny l)-2-oxo-1 phenylethyl)carbamate</td><td> BocHN״PP^°</td><td> LCMS: Anal. Calcd. for C48H₅6N_gO6: 840; found: 841 (M+H)⁺.</td>

<td> 84-38</td><td> methyl ((lR)-2-((2S)-2-(5-(4'(2-((2S)-1 -(diphenylacetyl)-2pyrrolidinyl)-1 H-imidazol-5yl)-4-biphenylyl)1 ־Himidazol-2-yl)-l -pyrrolidinyl)2-oxo-1phenylethyl)carbamate</td><td> Ph “7* Ph'*⁰</td><td> LCMS: Anal. Calcd. for C50H47N₇O₄: 809; found: 810 (M+H)⁺.</td>

<td> 84-39</td><td> methyl ((lR)-2-oxo-2-((2S)-2(5-(4'-(2-((2S)-1-(4oxopentanoyl)-2-pyrrolidinyl)1 H-imidazol-5-yl)-4biphenylyl)-1 H-imidazol-2yl)-1 -pyrrolidinyl)-1 phenylethyl)carbamate</td><td></td><td> LCMS: Anal. Calcd. for C41H43N7O5: 713; found: 714 (M+H)⁺.</td>

<td> 84-40</td><td> methyl ((lR)-2-((2S)-2-(5-(4'(2-((2 S)-1 -(2-fluorobenzoyl)2-pyrrolidinyl)-1 H-imidazol-5 yl)-4-biphenylyl)-1Himidazol-2-yl)-l -pyrrolidinyl)2-oxo-1־ phenylethyl)carbamate</td><td> (^0 F</td><td> LCMS: Anal. Calcd. for C43H40FN7O4: 737; found: 738 (M+H)⁺.</td>

<td> 84-41</td><td> methyl ((lR)-2-((2S)-2-(5-(4'(2-((2S)-l-(2biphenylylcarbonyl)-2pyrrolidinyl)- lH-imidazol-5yl)-4-biphenylyl)-1Himidazol-2-yl)-l -pyrrolidinyl)2-oxo-1phenylethyl)carbamate</td><td> q-c Ph</td><td> LCMS: Anal. Calcd. for C49H45N7O4: 795; found: 796 (M+H)⁺.</td>

<td> 84-42</td><td> methyl ((lR)-2-((2S)-2-(5-(4'(2-((2S)2)-1 ־-benzylbenzoyl)2-pyrrolidinyl)-l H-imidazol-5yl)-4-biphenylyl)-l Himidazol-2-yl)-1 -pyrrolidinyl)2-oxo-1phenylethyl)carbamate</td><td> QA Ph׳</td><td> LCMS: Anal. Calcd. for C50H47N₇O4: 809; found: 810 (M+H)⁺.</td>

<td> 84-43</td><td> methyl ((lR)-2-((2S)-2-(5-(4'(2-((2S)־l-((2E)-3-(4(dimethylamino)phenyl)-2propenoyl)-2-pyrrolidinyl)lH-imidazol5־-yl)-4biphenylyl)-1 H-imidazol-2yl)-1 -pyrrolidinyl)-2-oxo-1 phenylethyl)carbamate</td><td>ⁿ־\A /</td><td> LCMS: Anal. Calcd. forC₄7H4₈N₈0₄: 788; found: 789 (M+H)⁺.</td>

<td> 84-44</td><td> methyl ((lR)-2-oxo-l-phenyl2-((2S)-2-(5-(4'-(2-((2S)-l(l,3-thiazol-4-ylcarbonyl)-2pyrrolidinyl)-lH-imidazol-5yl)-4-biphenylyl)-1Himidazol-2-yl)-lpyrrolidinyl)ethyl)carbamate</td><td> V</td><td> LCMS: Anal. Calcd. for C40H38N8O4S: 726; found: 727 (M+H)⁺.</td>

<td> 84-45</td><td> methyl ((lR)-2-((2S)-2-(5-(4'(2-((2S)-l-((((lR,2S,5R)-2isopropyl-5- methylcyclohexyl)oxy )acetyl)2-pyrrolidinyl)-l H-imidazol-5-</td><td> of^°</td><td> LCMS: Anal. Calcd. for C48H57N₇O5: 811; found: 812 (M+H)⁺.</td>

<td></td><td> yl)-4-biphenylyl)-1 Ηimidazol-2-yl)-1 -pyrrolidinyl)2-oxo-1phenylethyl)carbamate</td><td></td><td></td>

<td> 84-46</td><td> methyl ((lR)-2-((2S)-2-(5-(4’(2-((2S)-l((dimethylamino)(2thienyl)acetyl)-2-pyrrolidinyl)1 H-imidazol-5 -y 1)-4biphenylyl)-1 H-imidazol-2 yl)-1 -pyrrolidinyl)-2-oxo-1 phenylethyl)carbamate</td><td>^s0 Qx( ^{S NMe}2 Cap-32</td><td> LCMS: Anal. Calcd. for C44H46N8O4S: 782; found: 782 (M+H)⁺.</td>

<td> 84-47</td><td> methyl ((lR)-2-((2S)-2-(5-(4'(2-((2S)-l((dimethylamino)(3 thienyl)acetyl)-2-pyrrolidinyl)1 H-imidazol-5 -y 1)-4biphenylyl)-! H-imidazol-2yl)-1 -pyrrolidinyl)-2-oxo-1 phenylethyl)carbamate</td><td> o Qx/ ^NMe2 Cap-33</td><td> LCMS: Anal. Calcd. for C44H46N8O4S: 782; found: 782 (M+H)⁺.</td>

<td> 84-48</td><td> methyl ((lR)-2-((2S)-2-(5-(4'(2-((2S)-l((dimethylamino)(2-methyl1,3 -thiazol-4-yl)acetyl)-2pyrrolidinyl)-lH-imidazol-5yl)-4-biphenylyl)-l H-. imidazol-2-yl)-1 -pyrrolidinyl)- 2-oxo-1phenylethyl)carbamate</td><td> N 1 7^״^ NMe₂ Cap-31</td><td> LCMS: Anal. Calcd. for C44H47N9O4S: 797j found: 798 (M+H)⁺.</td>

<td> 84-49</td><td> methyl ((lR)-2-((2S)-2-(5-(4'(2-((2S)-l-(l ,2-benzisoxazol3-yl(dimethylamino)acetyl)-2pyrrolidinyl)-lH-imidazol-5yl)-4-biphenyly 1)-1Himidazol-2-yl)-1 -pyrrolidinyl)-</td><td> Qx/ NM©2 Cap-34</td><td> LCMS: Anal. Calcd. for C47H47N9O5: 817; found: 818 (M+H)⁺.</td>

<td></td><td> 2-oxo-1phenylethyl)carbamate</td><td></td><td></td>

<td> 84-50</td><td> methyl ((lR)-2-((2S)-2-(5-(4'(2-((2S)1)- 1 ־ -benzothiophen3-yl(dimethylamino)acetyl)-2pyrrolidinyl)-lH-imidazol-5yl)-4-biphenylyl)-1Himidazol-2-yl)-1 -pyrrolidinyl)2-oxo-1phenylethyl)carbamate</td><td> ZA \--/ .r&gt; / \ Z A ך ό o'/</td><td> LCMS: Anal. Calcd. for C48H48N8O4S: 832; found: 833 (M+H)⁺.</td>

<td> 84-51</td><td> methyl ((lR)-2-((2S)-2-(5-(4'(2-((2S)-l((dimethylamino)( 1 naphthyl)acetyl)-2pyrrolidinyl)-1 H-imidazol-5 yl)-4-biphenylyl)-l Himidazol-2-yl)-1 -pyrrolidinyl)2-oxo-1phenylethyl)carbamate</td><td> NMe₂ Cap-13</td><td> LCMS: Anal. Calcd. for C50H50N8O4: 826; found: 827 (M+H)⁺.</td>

<td> 84-52</td><td> methyl ((lR)-2-((2S)-2-(5-(4'(2-((2S)-l((dimethylamino)(3 quinolinyl)acetyl)-2pyrrolidinyl)-lH-imidazol-5y l)-4-biphenylyl)-1Himidazol-2-yl)-1 -pyrrolidinyl)2-oxo-1phenylethyl)carbamate</td><td> o Ox( ^NMe2 Cap-31</td><td> LCMS: Anal. Calcd. for C49H49N9O4: 827; found: 828 (M+H)⁺.</td>

<td> 84-53</td><td> methyl ((lR)-2-((2S)-2-(5-(4'(2-((2S)-l- ((dimethylamino)(2-methyl1,3-benzothiazol-5-yl)acetyl)- 2-pyrrolidinyl)-l H-imidazol-5yl)-4-biphenylyl)-1Himidazol-2-yl)-1 -pyrrolidinyl)-</td><td> (y Ox/ Α”Υμθ₂ Cap-36</td><td> LCMS: Anal. Calcd. for C48H49N9O4S: 847; found: 848 (M+H)⁺.</td>

<td></td><td> 2-oxo-1phenylethyl)carbamate</td><td></td><td></td>

<td> 84-54</td><td> methyl ((lR)-2-((2S)-2-(5-(4'(2-((2S)-l((dimethylamino)(3 (trifluoromethyl)phenyl)acetyl )-2-pyrrolidinyl)-! H-imidazol5-yl)-4-biphenylyI)-1Himidazol-2-yl)-1 -pyrrolidinyl)2-oxo-1phenylethyl)carbamate</td><td> r^ycF₃^NM®2 Cap-24</td><td> LCMS: Anal. Calcd. for C47H47F₃N₈O4: 844; found: 845 (M+H)⁺.</td>

<td> 84-55</td><td> methyl ((lR)-2-((2S)-2-(5-(4'(2-((2S)-l- ((dimethylamino)(2(trifluoromethyl)phenyl)acetyl )-2-pyrrolidinyl)-l H-imidazol5-yl)-4-biphenylyl)-1Himidazol-2-yl)-1 -pyrrolidinyl)2-oxo-1־ phenylethyl)carbamate</td><td> o 0.QCF3 4״״ '^NMe2 Cap-25</td><td> LCMS: Anal. Calcd. for C47H47F3N8O4: 844; found: 845 (M+H)⁺.</td>

<td> 84-56</td><td> methyl ((lR)-2-((2S)-2-(5-(4'(2-((2S)-1-((2chlorophenyl)(dimethylamino) acetyl)-2-pyrrolidinyl)-l Himidazol-5-yl)-4-biphenylyl)1 H-imidazol-2-yl)-1 pyrrolidinyl)-2-oxo-l phenylethyl)carbamate</td><td> o 0.7(31 /NMe₂ Cap-29</td><td> LCMS: Anal. Calcd. for C46H47CIN8O4: 810; found: 811 (M+H/.</td>

<td> 84-57</td><td> methyl ((lR)-2-((2S)-2-(5-(4'(2-((2S)-1-((3chlorophenyl)(dimethylamino) acetyl)-2-pyrrolidinyl)-l Himidazol-5-yl)-4-biphenylyl)1 H-imidazol-2 -yl)-1 pyrrolidinyl)-2-oxo-1 -</td><td> Qr^aQx/ NMe₂ Cap-2%</td><td> LCMS: Anal. Calcd. for C46H47C1N8O4: 810; found: 811 (M+H)⁺.</td>

<td></td><td> phenylethyl)carbamate</td><td></td><td></td>

<td> 84-58</td><td> methyl ((lR)-2-((2S)-2-(5-(4'(2-((2S)-l-((4chlorophenyl)(dimethylamino) acetyl)-2-pyrrolidiny 1)-1Himidazol-5-yl)-4-biphenylyl)1 H-imidazol-2-yl)-1 pyrrolidinyl)-2-oxo-1 phenylethyl)carbamate</td><td> Cl O NMe₂ Cqp-30</td><td> LCMS: Anal. Calcd. for C46H47C1N₈O4: 810; found: 811 (M+H)⁺.</td>

<td> 84-59</td><td> methyl ((lR)-2-((2S)-2-(5-(4'(2-((2S)-l((dimethylamino)(2fluorophenyl)acetyl)-2pyrrolidinyl)-1 H-imidazol-5yl)-4-biphenylyl)-1Himidazol-2-yl)-l -pyrrolidinyl)2-oxo-1phenylethyl)carbamate</td><td> o (λ/Γ ״X^NMe₂ Cap-26</td><td> LCMS: Anal. Calcd. for C46H47FN8O4: 794; found: 795 (M+H)⁺.</td>

<td> 84-60</td><td> methyl ((lR)-2-((2S)-2-(5-(4'(2-((2S)-l((dimethylamino)(3 fluorophenyl)acetyl)-2pyrrolidinyl)-1 H-imidazol-5 yl)-4-bipheny lyl)-1Himidazol-2-yl)-l -pyrrolidinyl)2-oxo-1phenylethyl)carbamate</td><td> Qr^F^{S NMe}Z Cap-21</td><td> LCMS: Anal. Calcd. for C46H47FN8O4: 794; found: 795 (M+H)⁺.</td>

<td> 84-61</td><td> methyl ((lR)-2-((2S)-2-(5-(4'(2-((2S)-l((dimethylamino)(2pyridinyl)acetyl)-2pyrrolidinyl)-lH-imidazol-5yl)-4-biphenylyl)-1Himidazol-2-yl)-1 -pyrrolidinyl)2-oxo-1-</td><td> XssN Qx/ ^NMe2 Cap-20</td><td> LCMS: Anal. Calcd. for C45H47N9O4: 777; found: 778 (M+H)⁺.</td>

<td></td><td> phenylethyl)carbamate</td><td></td><td></td>

<td> 84-62</td><td> methyl ((lR)-2-((2S)-2-(4-(4'(2-((2S)-l((dimethylamino)(3 pyridinyl)acetyl)-2pyrrolidinyl)-1 H-imidazol-5y l)-4-biphenylyl)-1Himidazol-2-yl)-l -pyrrolidinyl)2-oxo-1phenylethyl)carbamate</td><td> θ NMe₂ Cap-19</td><td> LCMS: Anal. Calcd. for C45H47N9O4: 777: found: 778 (M+H)⁺.</td>

<td> 84-63</td><td> methyl ((lR)-2-((2S)-2-(5-(4'(2-((2S)-1-((4methoxyphenyl)acetyl)-2pyrrolidinyl)-1 H-imidazol-5yl)-4-bipheny lyl)-1Himidazol-2-yl)-l -pyrrolidinyl)2-oxo-1phenylethyl)carbamate</td><td> OMe A 0./</td><td> LCMS: Anal. Calcd. for C45H45N7O5: 763; found: 764 (M+H)⁺.</td>

<td> 84-64</td><td> methyl ((lR)-2-((2S)-2-(5-(4'(2-((2S)-1-((3methoxyphenyl)acetyl)-2pyrrolidinyl)-lH-imidazol-5yl)-4-biphenylyl)-1Himidazol-2-y 1)-1 -pyrrolidinyl)2-oxo-1phenylethyl)carbamate</td><td> Qx/</td><td> LCMS: Anal. Calcd. for C45H45N7O5: 763; found: 764 (M+H)⁺.</td>

<td> 84-65</td><td> methyl ((lR)-2-((2S)-2-(5-(4'(2-((2S)-1-((2methoxyphenyl)acetyl)-2 pyrrolidinyl)-lH-imidazol-5yl)-4-biphenyly 1)-1Himidazol-2-yl)-1 -pyrrolidinyl)2-oxo-1phenylethyl)carbamate</td><td> o 0.,/OMe</td><td> LCMS: Anal. Calcd. for C45H45N7O5: 763; found: 764 (M+H)⁺.</td>

<td> 84-66</td><td> methyl ((lR)-2-((2S)-2-(5-(4'(2-((2S)-1-((2chlorophenyl)acetyl)-2pyrrolidinyl)-lH-imidazol-5yl)-4-biphenylyl)-1Himidazol-2-yl)-l -pyrrolidinyl)2-oxo-1phenylethyl)carbamate</td><td> o</td><td> LCMS: Anal. Calcd. for C44H42C1N7O4: 767; found: 768 (M+H)⁺.</td>

<td> 84-67</td><td> methyl ((lR)-2-((2S)-2-(5-(4'(2-((2S)3))-1 ־chlorophenyl)acetyl)-2pyrrolidinyl)-1 H-imidazol-5y l)-4-biphenylyl)-1Himidazol-2-yl)-1 -pyrrolidinyl)2-oxo-1- ph enylethy !)carbamate</td><td> O'⁰¹ 0./</td><td> LCMS: Anal. Calcd. for C44H42C1N7O4: 767; found: 768 (M+H)⁺.</td>

<td> 84-68</td><td> methyl ((lR)-2-((2S)-2-(5-(4'(2-((28)-1-((4chlorophenyl)acetyl)-2pyrrolidinyl)-1 H-imidazol-5yl)-4-biphenyly 1)-1Himidazol-2־yl)-l -pyrrolidinyl)2-oxo-1phenylethyl)carbamate</td><td> Cl o</td><td> LCMS: Anal. Calcd. for C44H42CIN7O4: 767; found: 768 (M+H)⁺.</td>

<td> 84-69</td><td> methyl ((lR)-2-((2S)-2-(5-(4'(2-((2S)-1-((2methylphenyl)acetyl)-2pyrrolidinyl)-lH-imidazol-5yl)-4-biphenylyl)-1Himidazol-2-yl)-l -pyrrolidinyl)2-oxo-1phenylethyl)carbamate</td><td> O</td><td> LCMS: Anal. Calcd. for C45H45N₇O4: 747; found: 748 (M+H)⁺.</td>

<td> 84-70</td><td> methyl ((lR)-2-((2S)-2-(5-(4'(2-((2S)-1-((4methylphenyl)acetyl)-2pyrrolidinyl)-1 H-imidazol5־yl)-4-biphenylyl)-1Himidazol-2-yl)-1 -pyrrolidinyl)2-oxo-1phenylethyl)carbamate</td><td></td><td> LCMS: Anal. Calcd. for C45H45N7O4: 747; found: 748 (M+H)⁺.</td>

<td> 84-71</td><td> methyl ((lR)-2-((2S)-2-(5-(4'(2-((2S)-l-((3methylphenyl)acetyl)-2pyrrolidinyl)-1 H-imidazol-5yl)-4-biphenylyl)-l Himidazol-2-yl)-l -pyrrolidinyl)2-0x01 ־phenylethyl)carbamate</td><td></td><td> LCMS: Anal. Calcd. for C4₅H4₅N₇O4: 747; found: 748 (M+H)⁺.</td>

<td> 84-72</td><td> methyl ((lR)-2-((2S)-2-(5-(4'(2-((2S)-1-((2-methyl-1,3thiazol-4־yl)acetyl)-2pyrrolidinyl)-1 H-imidazol5־yl)-4-biphenylyl)-1Himidazol-2-yl)-l -pyrrolidinyl)2-oxo-1phenylethyl)carbamate</td><td> σ'!</td><td> LCMS: Anal. Calcd. for C42H42N8O4S: 754; found: 755 (M+H)⁺.</td>

<td> 84-73</td><td> methyl ((lR)-2-oxo-l-phenyl2-((2S)-2-(5-(4'-(2-((2S)-l-(3thienylacetyl)-2-pyrrolidinyl)1 H-imidazol-5 -y 1)-4biphenylyl)-l H-imidazol-2yl)-lpyrrolidinyl)ethyl)carbamate</td><td> Ο 0.J</td><td> LCMS: Anal. Calcd. for C42H41N7O4S: 739; found: 740 (M+H)⁺.</td>

<td> 84-74</td><td> methyl ((lR)-2-((2S)-2-(5-(4'(2-((2S)-l-((3-methyl-5isoxazolyl)acetyl)-2 pyrrolidinyl)-lH-imidazol-5-</td><td> Z'O</td><td> LCMS: Anal. Calcd. for C42H42N8O5: 738; found: 739 (M+H)⁺.</td>

<td></td><td> yl)-4-biphenylyl)-1 Ηimidazol-2-yl)-1 -pyrrolidinyl)2-oxo-1- ph enylethyl)carbamate</td><td></td><td></td>

<td> 84-75</td><td> methyl ((lR)-2-((2S)-2-(5-(4'(2-((2S)-1 -(cyclohexylacetyl)2-pyrrolidinyl)-1 H-imidazol-5 yl)-4-biphenylyl)-1Himidazol-2-y 1)-1 -pyrrolidinyl)2-oxo-1- phenylethyl)carbamate</td><td></td><td> LCMS: Anal. Calcd. for C44H49N7O4: 739; found: 740 (M+H)⁺.</td>

<td> 84-76</td><td> methyl ((lR)-2-oxo-l-phenyl2-((2S)-2-(5-(4'-(2-((2S)-l((2R)-2-phenylpropanoyl)-2pyrrolidinyl)-1 H-imidazol-5yl)-4-biphenylyl)-1Himidazol-2-y 1)-1pyrrolidinyl)ethyl)carbamate</td><td> O ΑΛίβ</td><td> LCMS: Anal. Calcd. for C45H45N7O4: 747; found: 748 (M+H)⁺.</td>

<td> 84-77</td><td> methyl ((lR)-2-oxo-l-phenyl2-((2S)-2-(5-(4'-(2-((2S)-l-((lphenylcyclopropyl)carbonyl)2-pyrrolidinyl)-1 H-imidazol-5yl)-4-biphenylyl)-1Himidazol-2-yl)-l pyrrolidinyl)ethyl)carbamate</td><td> o</td><td> LCMS: Anal. Calcd. for C46H45N7O4: 759; found: 760 (M+H)⁺.</td>

<td> 84-78</td><td> methyl ((lR)-2-((2S)-2-(5-(4'(2-((2S)-1-((1-(4chlorophenyl)cyclopropyl)carb onyl)-2-pyrrolidinyl)-1Himidazol-5-yl)-4-biphenylyl)lH-imidazol-2-yl)-l pyrrolidinyl)-2-oxo-1 phenylethyl)carbamate</td><td> Cl o ¾77</td><td> LCMS: Anal. Calcd. for C46H44CIN7O4: 793; found: 794 (M+H)⁺.</td>

<td> 84-79</td><td> methyl ((lR)-2-((2S)-2-(5-(4'(2-((2S)-1-(2-(4chlorophenyl)-2methylpropanoyl)-2pyrrolidiny 1)-1 H-imidazol- 5yl)-4-biphenylyl)-1Himidazol-2-yl)-1 -pyrrolidiny 1)2-oxo-1phenylethyl)carbamate</td><td> Cl o</td><td> LCMS: Anal. Calcd. for C46H46CIN7O4: 795; found: 796 (M+H)⁺.</td>

<td> 84-80</td><td> methyl ((lR)-2-((2S)-2-( 5-(4'(2-((2S)-l-((2R)-2-methoxy-2phenylacetyl)-2-pyrrolidinyl)1 H-imidazol-5 -y 1)-4biphenylyl)-1 H-imidazol-2yl)-1 -pyrrolidiny l)-2-oxo-1 phenylethyl)carbamate</td><td> O Ox/</td><td> LCMS: Anal. Calcd. for C45H45N7O5: 763; found: 764 (M+H)⁺.</td>

<td> 84-81</td><td> methyl ((lR)-2-oxo-l -phenyl2-((2S)-2-(5-(4'-(2-((2S)-l((2S)-3,3,3-trifluoro-2methoxy-2 -phenylpropanoyl)2-pyrrolidinyl)-1 H-imidazol-5yl)-4-biphenylyl)-1Himidazol-2-yl)-lpyrrolidinyl)ethyl)carbamate</td><td> O ⁰.K__LoMe &lt; ^SC^f3</td><td> LCMS: Anal. Calcd. for C46H44F3N7O5: 831; found: 832 (M+H)⁺.</td>

<td> 84-82</td><td> (lR)-2-((2S)-2-(5-(4'-(2-((2S)l-((2R)-2- ((methoxycarbonyl)amino)-2phenylacetyl)-2-pyrrolidinyl)1 H-imidazol-5 -y 1)-4biphenylyl)-! H-imidazol-2yl)-1 -pyrrolidiny !)-2-oxo-1 phenylethyl acetate</td><td> o q, / -ΓΜθ</td><td> LCMS: Anal. Calcd. for C46H45N7O6: 791; found: 792 (M+H)⁺.</td>

<td> 84-83</td><td> (1 S)-2-((2S)-2-(5-(4’-(2-((2S)l-((2R)-2- ((methoxycarbonyl)amino)-2phenylacetyl)-2-pyrrolidinyl)1 H-imidazol-5 -y 1)-4biphenylyl)-l H-imidazol-2yl)-1 -pyrrolidinyl)-2-oxo-1 phenylethyl acetate</td><td> o cl /</td><td> LCMS: Anal. Calcd. for C46H45N7O6: 791; found: 792 (M+H)⁺.</td>

<td> 84-84</td><td> methyl ((lR)-2-((2S)-2-(5-(4'(2-((2S)-l-((2-(4morpholinylmethyl)phenyl)ace tyl)-2-pynolidinyl)-lH-. imidazol-5-yl)-4-biphenylyl)- 1 H-imidazol-2-yl)-1 pyrrolidinyl)-2 -oxo-1 phenylethyl)carbamate</td><td> O °k7/ Cap-41</td><td> LCMS: Anal. Calcd. for C49H52N8O5: 832; found: 833 (M+H)⁺.</td>

<td> 84-85</td><td> methyl ((lR)-2-oxo-l-phenyl2-((2S)-2-(5-(4'-(2-((2S)-1 -((2(1piperidinylmethyl)phenyl)acet yl)-2-pyrrolidinyl)-1Himidazol-5-yl)-4-biphenylyl)- 1 H-imidazol-2-yl)-1 pyrrolidinyl)ethyl)carbamate</td><td> O Qx// Cap-42</td><td> LCMS: Anal. Calcd. for C50H54N8O4: 830; found: 831 (M+H)⁺.</td>

<td> 84-86</td><td> methyl ((lR)-2-oxo-l-phenyl2-((2S)-2-(5-(4'-(2-((2S)-l-((2(1pyrrolidinylmethyl)phenyl)ace tyl)-2-pyrrolidinyl)-1Himidazol-5-yl)-4-biphenylyl)- 1 H-imidazol-2-y 1)-1 pyrrolidinyl)ethyl)carbamate</td><td> o Cap-43</td><td> LCMS: Anal. Calcd. for C49H52N8O4: 816; found: 816 (M+H)⁺.</td>

<img file="IL196813A_D0148.tif" />

84-87 methyl ((lR)-2-((2S)-2-(5-(4'-(2((2S)-l-((2((dimethylamino)methyl)phenyl)a cetyl)2־ -pyrrolidinyl)-1Himidazol-5-yl)-4-biphenylyl)-1Himidazol-2-yl)-1 -pyn01־idinyl)-2oxo-1 -phenylethyl)carbamate

LCMS: Anal. Calcd. for C47H50N8O4: 790; found: 791 (M+H)⁺.

Examples 85-94

Example 28d

1) step a

2) step b

3) step c

<img file="IL196813A_D0149.tif" />

step a: Cap with cap-1 as in Example 28 step b: Same procedure as in conversion of Example 1d to 1e step c: As in the last step of Example 1 using 1.1 equiv. of the appropriate carboxylic acid and HATU

<td> Example</td><td> Compound Name</td><td> 0 /\׳׳R</td><td> Retention time (LCCondition); homogeneity index MS data</td>

<td> 85</td><td> (1 R)-N,N -dimethyl-2-oxo-1 phenyl-2-((2S)-2-(5-(4'-(2-((2S)1 -(3-pyridinylacetyl)-2pyrrolidinyl)-1 H-imidazol-5-yl)4-biphenylyl)-1 H-imidazol-2y 1)-1 -pyrrolidiny !)ethanamine</td><td> O / °</td><td> 1.64 minutes (Cond. 2); &gt;98%; LC/MS: Anal. Calcd. for [M+H]⁺C43H45N8O2: 705.37; found 705.43; HRMS: Anal. Calcd. for [M+H]⁺C43H45N8O₂: 705.3665; found 705.3675</td>

<td> 86</td><td> (1 R)-N,N -dimethyl-2-οχο-1 phenyl-2-((2S)-2-(5-(4'-(2-((2S)- 1 -((2R)-tetrahydro-2furanylcarbonyl)-2pyrrolidinyl)-1 H-imidazol-5 -y 1)4-biphenylyl)-1 H-imidazol-2-</td><td> 0</td><td> 1.73 minutes (Cond. 2); &gt;98%; LC/MS: Anal. Calcd. for [M+H]⁺C41H46N₇O3: 684.37; found 684.44; HRMS: Anal.</td>

<td></td><td> yl)1 ־ -pynolidiny !)ethanamine</td><td></td><td> Calcd. for [M+H]⁺C41H46N7O3: 684.3662; found 684.3671</td>

<td> 87</td><td> (1 R)-N,N -dimethyl-2־oxo-1 phenyl-2-((2S)-2-(5-(4'-(2-((2S)- 1 -((2S)-tetrahydro-2furanylcarbonyl)-2pyrrolidinyl)-1 H-imidazol-5-yl)4-biphenylyl)-1 H-imidazol-2yl)-1 -pyrrolidiny l)ethanamine</td><td> 0</td><td> 1.12 minutes (Cond. 2); &gt;98%; LC/MS: Anal. Calcd. for [M+H]⁺C41H46N₇O₃: 684.37; found 684.68; HRMS: Anal. Calcd. for [M+H]⁺C41H46N7O3: 684.3662; found 684.3692</td>

<td> 88</td><td> (lR)-N,N-dimethyl-2-((2S)-2(5-(4'-(2-((2S)-1 -((1 -methyl-1Himidazol-4-yl)acetyl)-2pyrrolidinyl)-1 H-imidazol-5 -yl)4-biphenylyl)-1 H-imidazol-2yl)-1 -pyrrolidiny 1)-2 -oxo-1 phenylethanamine</td><td> /=N o</td><td> 1.66 minutes (Cond. 2); &gt;98%; LC/MS: Anal. Calcd. for [M+H]⁺ C42H46N₉O₂: 708.38; found 708.36</td>

<td> 89</td><td> (lR)-N,N-dimethyl-2-((2S)-2(5-(42))-2)-׳S)-l-((2R)-2-(4morpholinyl)-2-phenylacetyl)-2pyrrolidinyl)-! H-imidazol-5-yl)4-biphenylyl)-1 H-imidazol-2yl)-1 -pyrrolidiny l)-2-oxo-1 phenylethanamine</td><td> Cap-6</td><td> 1.70 minutes (Cond. 2); &gt;98%; LC/MS: Anal. Calcd. for [M+H]⁺ C40H4₅N₈O4: 701.36; found 701.34; HRMS: Anal. Calcd. for [M+H]⁺C40H45N8O4: 701.3564; found 701.3576</td>

<td> 90</td><td> (lR)-N,N-dimethyl-2-oxo-1 phenyl-2-((2S)-2-(5-(4'-(2-((2S)l-((2R)-2-phenyl-2-(lpyrrolidinyl)acetyl)-2-</td><td> nj 0</td><td> 1.80 minutes (Cond. 2); &gt;98%; LC/MS: Anal. Calcd. for [M+H]⁺ C48H53N8O2:</td>

<td></td><td> pyrrolidinyl)-1 H-imidazol-5-yl)4-biphenylyl)-1 H-imidazol-2yl)-1 -pyrrolidiny !)ethanamine</td><td> Cap-5</td><td> 773.43; found 773.42; HRMS: Anal. Calcd. for [M+H]⁺C48H53N6O2: 773.4291; found 773.4309</td>

<td> 91</td><td> methyl (2-((2S)-2-(5-(4-(2((2S)-l-((2R)-2(dimethylamino)-2phenylacetyl)-2-pyrrolidinyl)- 1 H-imidazol-5-yl)-4biphenylyl)-1 H-imidazol-2-yl)l-pyrrolidinyl)-2oxoethyl)carbamate</td><td> °A IZ &gt;=° o \</td><td> 1.66 minutes (Cond. 2); &gt;98%; LC/MS: Anal. Calcd. for [M+H]⁺C42H46N₉O2: 708.38; found 708.36; HRMS: Anal. Calcd. for [M+H]⁺C42H46N9O2: 708.3744; found 708.3770</td>

<td> 92</td><td> methyl ((lS)-2-((2S)-2-(5-(4'-(2((2S)-l-((2R)-2(dimethylamino)-2phenylacetyl)-2-pyrrolidinyl)1 H-imidazol-5-yl)-4biphenylyl)-1 H-imidazol-2 -y 1)1 -pyrrolidinyl)-! -methyl-2oxoethyl)carbamate</td><td> H U '⁰Ύ 0 = Cap-12</td><td> 1.73 minutes (Cond. 2); &gt;98%; LC/MS: Anal. Calcd. for [M+H]⁺C₄₁H47N₈O4: 715.37; found 715.41; HRMS: Anal. Calcd. for [M+H]⁺C41H47N8O4: 715.3720; found 715.3729</td>

<td> 93</td><td> (lR)-N,N-dimethyl-2-((2S)-2(5-(4-(2-((28)-1-(4morpholinylcarbonyl)-2pyrrolidinyl)-1 H-imidazol-5-yl)4-biphenylyl)-1 H-imidazol-2yl)-1 -pyrrolidiny 1)-2-oxo-1 phenylethanamine</td><td> 0 My ⁰Ύ</td><td> 1.76 minutes (Cond. 2); &gt;98%; LC/MS: Anal. Calcd. for [M+H]⁺ C4₁H47N₈O3: 699.38; found 699.45; HRMS: Anal. Calcd. for [M+H]⁺ C41H47N8O3; 699.3771; found</td>

<td></td><td></td><td></td><td> 699.3803</td>

<td> 94</td><td> (1 R)-N,N -dimethyl-2-oxo-1 phenyl-2-((2S)-2-(5-(4'-(2-((2S)1 -(1 -pyrrolidinylcarbony 1)-2pyrrolidinyl)-! H-imidazol-5-yl)4-biphenyly 1)-1 H-imidazol-2yl)-1 -pyrrolidinyl)ethanamine</td><td> 0</td><td> 1.86 minutes (Cond, 2); &gt;98%; LC/MS: Anal. Calcd. for [M+H]⁺C41H47N₈O₂: 683.38; found 683.46; HRMS: Anal. Calcd. for [M+H]⁺C41H47N8O2: 683.3822; found 683.3835</td>

<td> 94-1</td><td> (2S)-l-((2S)-2-(5-(4'-(2-((2S)-l- ((2R)-2-(dimethylamino)-2- phenylacetyl)-2-pyrrolidinyl)- 1 H-imidazol-5-y 1)-4- biphenylyl)-1 H-imidazol-2 -yl)- 1 -pyrrolidinyl)-2-(2- fluorophenyl)-1 -oxo-2 -propanol</td><td> ׳׳\ OH 0 T/ O</td><td>¹HNMR (400 MHz, CD3OD) δ 7.90-7.84 (m, 9H), 7.79-7.73 (m, 2H), 7.67-7.65 (m, 1H), 7.63-7.52 (m, 5H), 7.39-7.36 (m, 1H), 7.30-7.26 (m, 1H), 7.13-7.08 (m, 1H), 6.93-6.88 (m, 0.5H), 6.72-6.67 (m, 0.5H), 5.51 (s, 0.2H), 5.46 (s, 0.8H), 5.33-5.30 (m, 1H), 5.28-5.24 (m, 1H), 4.05-3.94 (m, 2H), 3.84-3.73 (m, 1H), 3.69-3.55 (m, 1H), 3.21-3.04 (m, 2H), 2.79 (br s, 6H), 2.392.33 (m, 2H), 2.211.93 (m, 5H), 1.65 (d, J = 4.55 Hz, 3H).; LCMS: Anal. Calcd. for C45H46FN7O3:</td>

<td></td><td></td><td></td><td> 751; found: 752 (M+H)⁺.</td>

<td> 94-2</td><td> (5R)-5-(((2S)-2-(5-(4'-(2-((2S)- 1 -((2R)-2-(dimethylamino)-2- phenylacetyl)2־ -pyrrolidinyl)- 1 H-imidazol-5-y 1)-4- biphenylyl)-1 H-imidazol-2-yl)- 1 -pyrrolidinyl)carbonyl)-2pyrrolidinone</td><td> X־NH ⁰0</td><td> LCMS: Anal. Calcd. for C41H44N8O3: 696; found: 697 (M+H)⁺.</td>

<td> 94-3</td><td> l-((lR)-2-((2S)-2-(5-(4'-(2- ((2S)-l-((2R)-2(dimethylamino)-2phenylacetyl)-2 -pyrrolidinyl)- 1 H-imidazol-5-yl)-4biphenylyl)-1 H-imidazol-2-yl)1 -pyrrolidiny l)-2-oxo-1 phenylethyl)-4-methyl-4piperidinol</td><td> OH ?Ό o Cap-15</td><td> LCMS: Anal. Calcd. for C₅₀H₅₆N₈O3: 816; found: 817 (M+H)⁺.</td>

<td> 94-4</td><td> tert-butyl (4R)-4-(((2S)-2-(5-(4'- (2-((2S)-l-((2R)-2- (dimethylamino)-2- phenylacetyl)-2-pyrrolidinyl)- 1 H-imidazol-5-yl)-4- biphenylyl)- lH-imidazol-2-yl)- 1 -pyrrolidiny l)carbony 1)-1,3- thiazolidine-3 -carboxylate</td><td> M ⁰ Boc</td><td> LCMS: Anal. Calcd. for C45H52N8O4S: 800; found: 801 (M+H)⁺.</td>

<td> 94-5</td><td> tert-butyl (1 -(((2 S)-2-(5-(4'-(2((2S)-l-((2R)-2(dimethylamino)-2phenylacetyl)-2-pyrrolidinyl)1 H-imidazol-5-y 1)-4- biphenylyl)- lH-imidazol-2-yl)1- pyrrolidinyl)carbonyl)cyclopenty !)carbamate</td><td> BocHN</td><td> LCMS: Anal. Calcd. for C47H56FN8O4: 796; found: 797 (M+H)⁺.</td>

<td> 94-6</td><td> N-(2-((2S)-2-(5-(4'-(2-((2S)-l((2R)-2-(dimethylamino)-2phenylacetyl)-2 -pyrrolidinyl)1 H-itnidazol-5-yl)-4biphenylyl)-1 H-imidazol-2-yl)1 -pyrrolidinyl)-?oxoethyl)benzamide</td><td> 0</td><td> LCMS: Anal. Calcd. for C45H46FN8O3: 746; found: 747 (M+H)⁺.</td>

<td> 94-7</td><td> (lR)-N,N-dimethyl-2-((2S)-2-(5(4'-(2-((2S)-l-(4-(4-methyl-l piperazinyl)benzoyl)-2pyrrolidinyl)-1H -imidazol-5 -y 1)4-biphenylyl)-l H-imidazol-2yl)-l -pyrrolidinyl)-?-oxo-1 phenylethanamine</td><td> r־־\ TM ΜθνΥ_/^Ν⁰ ׳־־־א</td><td> LCMS: Anal. Calcd. for C48H53N9O2: 787; found: 788 (M+H)⁺.</td>

<td> 94-8</td><td> (1 R)-N,N-dimethyl-2-oxo-1 phenyl-2-((2S)-2-(5-(4'-(2-((2S)1 -((5-phenyl-2thienyl)carbonyl)-2- pyrrolidinyl)-1 H-imidazol-5 -yl)4-biphenylyl)-1 H-imidazol-2yl)-l -pyrrolidiny !)ethanamine</td><td> Ph</td><td> LCMS: Anal. Calcd. for C47H45N7O2S: 771; found: 772 (M+H)⁺.</td>

<td> 94-9</td><td> (lR)-N,N-dimethyl-2-((2S)-2-(5(4'-(2-((2S)-1-(4-(4morpholinyl)benzoyl)-2- pyrrolidinyl)-1 H-imidazol-5 -yl)4-biphenylyl)-1 H-imidazol-2yl)-l-pyrrolidinyl)-2-oxo-1 phenylethanamine</td><td>₀Qn־O^°</td><td> LCMS: Anal. Calcd. for C47H50N8O3: 774; found: 775 (M+H)⁺.</td>

<td> 94-10</td><td> (lR)-N,N-dimethyl-2-oxo-1 phenyl-2-((2S)-2-(5-(4'-(2-((2S)־ 1 -((4-phenyl-l ,2,3-thiadiazol-5yl)carbonyl)-2-pyrrolidinyl)-! Himidazol-5-yl)-4-biphenylyl)- 1 H-imidazol-2-yl)-l pyrrolidinyl)ethanamine</td><td> Ph νΑ-Λ nY °</td><td> LCMS: Anal. Calcd. for C45H43N9O2S: 773; found: 774 (M+H)⁺.</td>

<td> 94-11</td><td> (1 R)-N,N-dimethyl-2-oxo-1 phenyl-2-((2S)-2-(5-(4'-(2-((2S)1 -((2-phenyl-1,3-thiazol-4- yl)carbony 1)-2-pyrrolidinyl)-1Himidazol-5 -yl)-4-bipheny lyl)1 H-imidazol-2-yl)-1 - pyrrolidinyl)ethanamine</td><td> ס־ Γ_ζ\ ²S' ־Λ/</td><td> LCMS: Anal. Calcd. for C46H44N8O2S: 772; found: 773 (M+H)⁺.</td>

<td> 94-12</td><td> tert-butyl 4-(((2S)-2-(5-(4'-(2- ((2S)-l-((2R)-2- (dimethylamino)-2- phenylacetyl)-2-pyrrolidinyl)- 1 H-imidazol-5-yl)-4- biphenylyl)- lH-imidazol-2-yl)- 1 -pyrrolidinyl)carbony 1)-4- methyl-1 -piperidinecarboxylate</td><td> Boc. NX ץ״, ^/O</td><td> LCMS: Anal. Calcd. for C48H₅8N8O4: 810; found: 811 (M+H)⁺.</td>

<td> 94-13</td><td> 3 -(2-((2 S)-2-(5 -(4'-(2-((2S)-1 ((2R)-2-(dimethylamino)-2phenylacetyl)-2-pyrrolidinyl)- 1 H-imidazol-5-yl)-4biphenylyl)- lH-imidazol-2-yl)- 1 -pyrrolidinyl)-2oxoethyl)phenol</td><td> כץ/ Q OH</td><td> LCMS: Anal. Calcd. for C44H45N7O3: 719; found: 720 (M+H)⁺.</td>

<td> 94-14</td><td> 3-((2S)-2-(5-(4'-(2-((2S)-l- ((2R)-2-(dimethylamino)-2- phenylacety 1)-2 -pyrrolidinyl)- 1 H-imidazol-5-yl)-4- biphenylyl)-1 H-imidazol-2-yl)- 1 -pyrrolidinyl)-N,N-dimethyl-3- oxo-1 -propanamine</td><td> &gt;/vw 6 N /</td><td> LCMS: Anal. Calcd. for C41H48N8O2: 684; found: 685 (M+H)⁺.</td>

<td> 94-15</td><td> (4-(((2S)-2-(5-(4'-(2-((2S)-l((2R)-2-(dimethylamino)-2phenylacetyl)-2-pyrrolidinyl)- 1 H-imidazol-5-y 1)-4biphenylyl)-1 H-imidazol-2 -yl)1-</td><td> HO, jTX-4 ⁰</td><td> LCMS: Anal. Calcd. for C44H45N7O3: 719; found: 720 (M+H)⁺.</td>

<td></td><td> pyrrolidinyl)carbonyl)phenyl)me thanol</td><td></td><td></td>

<td> 94-16</td><td> (lR)-2-((2S)-2-(5-(4'-(2-((2S)-l(1 H-indol-3-ylcarbony 1)-2pyrrolidinyl)-1H -imidazol-5 -yl)4-biphenylyl)-l H-imidazol-2yl)-1 -pyrrolidiny 1)-N,Ndimethyl-2-oxo-lphenylethanamine</td><td> HN^\—4 1/ O O</td><td> LCMS: Anal. Calcd. for C45H44N8O2: 728; found: 729 (M+H)⁺.</td>

<td> 94-17</td><td> (1 R)-2-((2S)-2-(5-(4'-(2-((2S)-1 (((3R)-l-benzyl-3pyrrolidinyl)carbony 1)-2 pyrrolidinyl)-1 H-imidazol-5 -yl)4-biphenylyl)-1 H-imidazol-2y 1)-1 -pyrrolidiny 1)-N ,N dimethyl-2-oxo-1 phenylethanamine</td><td> Ph .׳vw</td><td> LCMS: Anal. Calcd. for C48H52N8O2: 772; found: 773 (M+H)⁺.</td>

<td> 94-18</td><td> tert-butyl (2S)-2-(2-((2S)-2-(5(4'-(2-((2S)-l-((2R)-2(dimethylamino)-2phenylacetyl)-2 -pyrrolidinyl)1 H-imidazol-5-yl)-4biphenylyl)-1 H-imidazol-2 -yl)1 -pyrrolidinyl)-2-oxoethyl)-lpyrrolidinecarboxylate</td><td> ט/ Γ N-Boc</td><td> LCMS: Anal. Calcd. forC47H₅₆N8O4: 796; found: 797 (M+H)⁺.</td>

<td> 94-19</td><td> (lR)-N,N-dimethyl-2-((2S)-2-(5(4'-(2-((2S)-1 -((5-methyl-1Hpyrazol-3-yl)acetyl)-2pyrrolidinyl)-1H -imidazol-5 -yl)4-biphenylyl)-1 H-imidazol-2yl)-1 -pyrrolidiny 1)-2-oxo-1 phenylethanamine</td><td> Ao nA hnA</td><td> LCMS: Anal. Calcd. for C42H45N9O2: 707; found: 708 (M+H)⁺.</td>

<td> 94-20</td><td> tert-butyl (2R)-2-(((2S)-2-(5-(4'- (2-((2S)-l-((2R)-2- (dimethylamino)-2-</td><td> qx Boc</td><td> LCMS: Anal. Calcd. for C47H56N8O4: 796; found: 797 (M+H)⁺.</td>

<td></td><td> pheny lacety 1)-2 -pyrrolidinyl)- 1 H-imidazol-5-yl)-4biphenylyl)-1 H-imidazol-2 -yl)- 1 -pyrrolidinyl)carbonyl)-l piperidinecarboxylate</td><td></td><td></td>

<td> 94-21</td><td> tert-butyl ((lS,3R)-3-(((2S)-2-(5(4'-(2-((2S)-l-((2R)-2(dimethylamino)-2phenylacetyl)2־-pyrrolidinyl)1 H-imidazol5־-y 1)-4- biphenylyl)-1 H-imidazol-2-yl)1- pyrrolidinyl)carbonyl)cyclopenty !)carbamate</td><td> BocHN</td><td> LCMS: Anal. Calcd. for C47H₅6N₈O4: 796; found: 797 (M+H)⁺.</td>

<td> 94-22</td><td> (1 R)-N,N-dimethyl-2-oxo-1 phenyl-2-((2S)-2-(5-(4'-(2-((2S)- 1 -(3-( 1 -piperidinyl)propanoyl)- 2 -pyrrolidinyl)-1 H-imidazol-5y l)-4-biphenylyl)-1 H-imidazol2-yl)-1 -pyrrolidinyl)ethanamine</td><td> ό</td><td> LCMS: Anal. Calcd. for C44H52N8O2: 724; found: 725 (M+H)⁺.</td>

<td> 94-23</td><td> (2-(((2S)-2-(5-(42))-2)-׳S)-l((2R)-2-(dimethylamino)-2pheny lacetyl)-2 -pyrrolidinyl)1 H-imidazol-5-y 1)-4biphenylyl)-lH-imidazol-2-yl)1- pyrrolidinyl)carbonyl)phenyl)(ph enyl)methanone</td><td> Ο־ζ Ph</td><td> LCMS: Anal. Calcd. for C50H47N7O3: 793; found: 794 (M+H)⁺.</td>

<td> 94-24</td><td> (lR)-2-((2S)-2-(5-(4’-(2-((2S)-l ((2-methoxyphenoxy)acetyl)-2pyrrolidinyl)-1H -imidazol- 5 -yl)4-biphenylyl)-lH-imidazol-2yl)-1 -pyrrolidinyl)-N,Ndimethyl-2-oxo־lphenylethanamine</td><td> MeO ־־N-gJ</td><td> LCMS: Anal. Calcd. for C45H47N7O4: 749; found: 750 (M+H)⁺.</td>

<td> 94-25</td><td> tert-butyl 3-(((2S)-2-(5-(4'-(2- ((2S)-l-((2R)-2- (dimethylamino)-2- phenylacetyl)2־-pyrrolidinyl)- 1 H-imidazol-5-yl)-4- biphenylyl)-1 H-imidazol-2-yl)- 1 -pyrrolidinyl)carbonyl)-l - azetidinecarboxylate</td><td> Boc'ⁿC/’</td><td> LCMS: Anal. Calcd. for C45H52N8O4: 768; found: 769 (M+H)⁺.</td>

<td> 94-26</td><td> (lR)-2-((2S)-2-(5-(4'-(2-((2S)-l(((3S)-l-benzyl-3pyrrolidinyl)carbony 1)-2 pyrrolidinyl)-1 H-imidazol-5 -yl)4-biphenylyl)-1 H-imidazol-2yl)-l -pyrrolidinyl)-N,Ndimethyl-2-oxo-1 phenylethanamine</td><td> Ph 0</td><td> LCMS: Anal. Calcd. for C48H52N8O2: 772; found: 773 (M+H)⁺.</td>

<td> 94-27</td><td> (lR)-N,N-dimethyl-2-oxo-1 phenyl-2-((2S)-2-(5-(4'-(2-((2S)- 1 -(3-(l-pyrrolidinyl)benzoyl)-2pyrrolidinyl)-1 H-imidazol-5 -yl)4-biphenylyl)-1 H-imidazol-2yl)-1 -pyrrolidinyl)ethanamine</td><td> qA</td><td> LCMS: Anal. Calcd. for C47H₅qN8O2: 758; found: 759 (M+H)⁺.</td>

<td> 94-28</td><td> tert-butyl (2-(((2S)-2-(5-(4'-(2((2S)-l-((2R)-2(dimethylamino)-2phenylacetyl)-2-pyrrolidinyl)1 H-imidazol-5-yl)-4- biphenylyl)-1 H-imidazol-2-y 1)1- pyrrolidinyl)carbonyl)phenyl)car bamate</td><td> qA *NHBoc</td><td> LCMS: Anal. Calcd. for C48H52N8O4: 804; found: 805 (M+H)⁺.</td>

<td> 94-29</td><td> tert-butyl (3R)-3-(((2S)-2-(5-(4'- (2-((2S)-l-((2R)-2- (dimethylamino)-2- pheny lacety 1)-2 -pyrrolidinyl)-</td><td> X 7Ό N⁷־־־ Boe</td><td> LCMS: Anal. Calcd. for C47H56N8O4: 796; found: 797 (M+H)⁺.</td>

<td></td><td> 1 H-imidazol-5-yl)-4biphenylyl)-1 H-imidazol-2-yl)- 1 -pyrrolidinyl)carbonyl)-l piperidinecarboxylate</td><td></td><td></td>

<td> 94-30</td><td> (1 R)-N,N-dimethyl-2-oxo-1 ־ phenyl-2-((2S)-2-(5-(4'-(2-((2S)1-((1- (trifluoromethyl)cyclopropyl)car bonyl)-2-pyrrolidinyl)-1Himidazol-5 -yl)-4-bipheny lyl)1 H-imidazol-2-yl)-l pyrrolidinyl)ethanamine</td><td> F^cT^⁰</td><td> LCMS: Anal. Calcd. for C41H42F3N7O2: 721; found: 722 (M+H)⁺.</td>

<td> 94-31</td><td> 4-(((2S)-2-(5-(4'-(2-((2S&gt;l- ((2R)-2-(dimethylamino)-2- phenylacetyl)-2-pyrrolidinyl)- 1 H-imidazol-5-y 1)-4- biphenylyl)-1 H-imidazol-2-yl)- 1 -pyrrolidinyl)carbonyl)-N,N- dimethylaniline</td><td> /</td><td> LCMS: Anal. Calcd. for C45H4₈N₈O2: 732; found: 733 (M+H)⁺.</td>

<td> 94-32</td><td> (3-(((2S)-2-(5-(4'-(2-((2S)־l((2R)-2-(dimethylamino)-2phenylacetyl)-2-pyrrolidinyl)- 1 H-imidazol-5-yl)-4biphenylyl)-1 H-imidazol-2-yl)1- pyrrolidinyl)carbonyl)phenyl)(ph enyl)methanone</td><td> 0A ° Ph</td><td> LCMS: Anal. Calcd. for C50H47N7O3: 793; found: 794 (M+H)⁺.</td>

<td> 94-33</td><td> tert-butyl (cis-4-(((2S)-2-(5-(4'(2-((2S)-l-((2R)-2(dimethylamino)-2phenylacetyl)-2-pyrrolidinyl)1 H-imidazol-5-yl)-4biphenylyl)-1 H-imidazol-2 -yl)1- pyrrolidinyl)carbonyl)cyclohexyl</td><td> BocHN'\___/ O</td><td> LCMS: Anal. Calcd. for C48H58N8O4: 810; found: 811 (M+H)⁺.</td>

<td></td><td> )carbamate</td><td></td><td></td>

<td> 94-34</td><td> *tert-butyl 4-(((2S)-2-(5-(4'-(2((28)-1-((2R)-2(dimethylamino)-2- phenylacetyl)-2-pyrrolidinyl)1 H-imidazol-5-yl)-4biphenylyl)- lH-imidazol-2-yl)- 1 -pyrrolidinyl)carbonyl)-l piperidinecarboxylate</td><td></td><td> LCMS: Anal. Calcd. for C47H₅₆N₈O4: 796; found: 797 (M+H)⁺.</td>

<td> 94-35</td><td> tert-butyl (cis-4-(((2S)-2-(5-(4'(2-((2S)-l-((2R)-2(dimethylamino)-2- phenylacetyl)-2-pyrrolidinyl)- 1 H-imidazol-5-yl)-4biphenylyl)-1 H-imidazol-2 -yl)1- pyrrolidinyl)carbonyl)cyclohexyl )carbamate</td><td></td><td> LCMS: Anal. Calcd. for C48H58N8O4: 810; found: 811 (M+H)⁺.</td>

<td> 94-36</td><td> (lR)-2-((2S)-2-(5-(4'-(2-((2S)-l- (diphenylacetyl)-2-pyrrolidinyl)- 1 H-imidazol-5-yl)-4- biphenylyl)-1 H-imidazol-2-y 1)- 1 -pyrrolidinyl)-N,N-dimethyl-2oxo-1 -pheny lethanamine</td><td> ? 0־</td><td> LCMS: Anal. Calcd. for C50H49N7O2: 779; found: 780 (M+H)⁺.</td>

<td> 94-37</td><td> 5-((2S)-2-(5-(4'-(2-((2S)-l((2R)-2-(dimethylamino)-2phenylacetyl)-2-pyrrolidinyl)1 H-imidazol-5-y 1)-4biphenylyl)- lH-imidazol-2-yl)1 -pyrrolidinyl)-5-oxo-2pentanone</td><td> 1/VW ל</td><td> LCMS: Anal. Calcd. for C41H45N₇O₃: 683; found: 684 (M+H)⁺.</td>

<td> 94-38</td><td> (1 R)-2-((2S)-2-(5-(4 ^,-(2-((28)-1 (2-fluorobenzoyl)-2pyrrolidinyl)-1 H-imidazol-5-yl)4-biphenylyl)-1 H-imidazol-2-</td><td> q-Λ ^XF</td><td> LCMS: Anal. Calcd. for C43H42FN7O2: 707; found: 708 (M+H)⁺.</td>

<td></td><td> yl)-l -pyrrolidinyl)-N dimethyl-2-oxo-lphenylethanamine</td><td></td><td></td>

<td> 94-39</td><td> (lR)-2-((2S)-2-(5-(4'-(2-((2S)-l (2-biphenylylcarbonyl)-2pyrrolidinyl)-lH-imidazol-5-yl)4-biphenylyl)-l H-imidazol-2yl)-1 -pyrrolidinyl)-N,Ndimethyl-2-oxo-lphenylethanamine</td><td> 0Λ Vh</td><td> LCMS: Anal. Calcd. for C49H47N7O2: 765; found: 766 (M+H)⁺.</td>

<td> 94-40</td><td> (lR)-2-((2S)-2-(5-(4'-(2-((2S)-l (2-benzylbenzoyl)-2pyrrolidinyl)-1 H-imidazol-5 -yl)4-biphenylyl)-1 H-imidazol-2yl)-1 -pyrrolidinyl)-N ,N dimethyl-2-oxo-lphenylethanamine</td><td> 03 Ph</td><td> LCMS: Anal. Calcd. for C₅0H49N7O2: 779; found: 780 (M+H)⁺.</td>

<td> 94-41</td><td> 4-((lE)-3-((2S)-2-(5-(4'-(2- ((2S)-l-((2R)-2- (dimethylamino)-2- phenylacetyl)-2-pyrrolidinyl)- 1 H-imidazol-5-yl)-4- biphenylyl)-1 H-imidazol-2-yl)- 1 -pyrrolidinyl)-3-oxo-1 -propen- 1 -y 1)-N,N -dimethylaniline</td><td> /</td><td> LCMS: Anal. Calcd. for C47H5qN₈O2: 758; found: 759 (M+H)⁺.</td>

<td> 94-42</td><td> (lR)-N,N-dimethyl-2-oxo-1 phenyl-2-((2S)-2-(5-(4'-(2-((2S)1 -(1,3-thiazol-4-ylcarbony 1)-2pyrrolidinyl)-1 H-imidazol-5 -yl)4-biphenylyl)-1 H-imidazol-2yl)-1 -pyrrolidinyl)ethanamine</td><td> °ס Ζ־// // \</td><td> LCMS: Anal. Calcd. for C40H40N8O2S: 696; found: 697 (M+H)⁺.</td>

<td> 94-43</td><td> (lR)-2-((2S)-2-(5-(4'-(2-((2S)-l((((lR,2S,5R)-2-isopropyl-5methylcyclohexyl)oxy)acetyl)-2pyrrolidinyl)-1 H-imidazol-5 -yl)-</td><td> 0f^° ⁰י \</td><td> LCMS: Anal. Calcd. for C48H59N7O3: 781; found: 782 (M+H)⁺.</td>

<td></td><td> 4-biphenylyl)-1 H-imidazol2־yl)-1 -pyrrolidinyl)-N,Ndimethyl-2-oxo-lphenylethanamine</td><td></td><td></td>

<td> 94-44</td><td> 1 -(6-chloro3־-pyridiny 1)-2((2S)-2-(5-(4'-(2-((2S)-l-((2R)2-(dimethylamino)-2phenylacetyl)-2-pyrrolidinyl)- 1 H-imidazol-5-yl)-4biphenylyl)-1 H-imidazol-2-yl)- 1 -pyrrolidinyl)-N,N-di1nethyl-2oxoethanamine</td><td> / —Ν_χ/ Cl Cap-21</td><td> LCMS: Anal. Calcd. for C45H48CIN9O2: 781; found: 782 (M+H)⁺.</td>

<td> 94-45</td><td> 2-((2S)-2-(5-(4'-(2-((2S)-l- ((2R)-2-(dimethylamino)-2- phenylacetyl)-2-pyrrolidinyl)- 1 H-imidazol-5-yl)-4- biphenylyl)-1 H-imidazol-2 -yl)- 1 -pyrrolidinyl)-N,N-dimethyl-2- oxo-1 -(3 -pyridinyl)ethanamine</td><td> I —־Ν_χ/ Cap-19</td><td> LCMS: Anal. Calcd. for C45H49N9O2: 747; found: 748 (M+H)⁺.</td>

<td> 94-46</td><td> 2-((2S)-2-(5-(4'-(2-((2S)-l- ((2R)-2-(dimethylamino)2־phenylacetyl)-2-pyrrolidinyl)- 1 H-imidazol-5-y 1)-4biphenylyl)-1 H-imidazol-2-yl)- 1 -pyrrolidinyl)-N,N-dimethyl-2oxo-1 -(2-pyridinyl)ethanamine</td><td> v׳^“ / 7\^N^׳ כר/ w Cap-20</td><td> LCMS: Anal. Calcd. for C45H49N9O2: 747; found: 748 (M+H)⁺.</td>

<td> 94-47</td><td> (1 R)-N,N -dimethyl-2-oxo-1 - phenyl-2-((2S)-2-(5-(4'-(2-((2S&gt; 1 -(2-thienylacetyl)-2- pyrrolidinyl)-1 H-imidazol-5-yl)4-biphenylyl)- lH-imidazol-2y 1)-1 -pyrrolidinyl)ethanamine</td><td> C^s</td><td> LCMS: Anal. Calcd. for C42H43N7O2S: 709; found: 710 (M+H)⁺.</td>

<td> 94-48</td><td> (1 R)-N,N -dimethyl-2-oxo-1 phenyl-2-((2S)-2-(5-(4'-(2-((2S&gt; 1 -(3-thienylacetyl)-2pyrrolidinyl)-1 H-imidazol-5-yl)4-biphenylyl)-1 H-imidazol-2yl)-1 -pyrrolidinyl)ethanamine</td><td> כר/ s־^</td><td> LCMS: Anal. Calcd. for C42H43N7O2S: 709; found: 710 (M+H)⁺.</td>

<td> 94-49</td><td> (1 R)-N,N-dimethyl-2-((2S)-2(5-(4'-(2-((2S)-l-(lnaphthylacetyl)-2-pyrrolidinyl)- 1 H-imidazol-5-yl)-4biphenylyl)-1 H-imidazol-2-yl)1 -pyrrolidinyl)-2-oxo-1 phenylethanamine</td><td> Cq</td><td> LCMS: Anal. Calcd. for C48H47N7O2: 753; found: 754 (M+H)⁺.</td>

<td> 94-50</td><td> (1 R)-2-((2S)-2-(5-(4'-(2-((2S)-1 (lH-imidazol-5-ylacety 1)-2pyrrolidinyl)-! H-imidazol-5-yl)4-biphenylyl)-1 H-imidazol-2y 1)-1 -pyrrolidiny 1)-N,N dimethyl-2-oxo-lphenylethanamine</td><td>³י? 1 NH Ν־ϊ/</td><td> LCMS: Anal. Calcd. for C41H43N9O2: 693; found: 694 (M+H)⁺.</td>

<td> 94-51</td><td> (lR)-2-((2S)-2-(5-(4'-(2-((2S)-l((2-fluorophenyl)acetyl)-2pyrrolidinyl)-1 H-imidazol-5-yl)4-biphenylyl)-1 H-imidazol-2yl)-1 -pyrrolidiny 1)-N,Ndimethyl-2-oxo-lphenylethanamine</td><td> / CT ח־</td><td> LCMS: Anal. Calcd. for C44H44FN7O2: 721; found: 722 (M+H)⁺.</td>

<td> 94-52</td><td> (lR)-2-((2S)-2-(5-(4'-(2-((2S)-l((3-fluorophenyl)acety 1)-2pyrrolidinyl)-1 H-imidazol-5-yl)4-biphenylyl)-lH-imidazol-2yl)-l -pyrrolidinyl)-N,Ndimethyl-2-oxo-lphenylethanamine</td><td> כר/ ο F</td><td> LCMS: Anal. Calcd. for C44H44FN7O2: 721; found: 722 (M+H)⁺.</td>

<td> 94-53</td><td> (lR)-2-((2S)-2-(5-(4’-(2-((2S)-l((4-fluorophenyl)acetyl)-2- pyrrolidinyl)-! H-imidazol-5-yl)4-biphenylyl)-1 H-imidazol-2yl)-l -pyrrolidinyl)-N,Ndimethyl-2-oxo-lphenylethanamine</td><td> כי/ o F</td><td> LCMS: Anal. Calcd. for C44H44FN7O2: 721; found: 722 (M+H)⁺.</td>

<td> 94-54</td><td> (lR)-2-((2S)-2-(5-(4'-(2-((2S)-l(1 -benzothiophen3־-ylacety 1)-2pyrrolidinyl)-! H-imidazol-5-yl)4-biphenylyl)- lH-imidazol-2yl)-1 -pyrrolidinyl)-N,Ndimethyl-2-oxo-lphenylethanamine</td><td> ג— σΊ</td><td> LCMS: Anal. Calcd. for C46H45N7O2S: 759; found: 760 (M+H)⁺.</td>

<td> 94-55</td><td> (lR)-2-((2S)-2-(5-(4'-(2-((2S)-l(1,2-benzisoxazol-3-ylacetyl)-2pyrrolidinyl)-1 H-imidazol-5-yl)4-biphenylyl)-1 H-imidazol-2yl)-1 -pyrrolidiny 1)-N,N dimethyl-2-oxo-lphenylethanamine</td><td> Λ.³fT׳^N</td><td> LCMS: Anal. Calcd. forC₄₅H44N₈O3:744; found: 745 (M+H)⁺.</td>

<td> 94-56</td><td> (lR)-2-((2S)-2-(5-(4'-(2-((2S)-l (1 H-indol-3 -ylacetyl)-2 pyrrolidinyl)-lH-imidazol-5-yl)4-biphenylyl)-1 H-imidazol-2yl)-1 -pyrrolidiny 1)-N,N dimethyl-2-oxo-lphenylethanamine</td><td> כי Co H</td><td> LCMS: Anal. Calcd. for C46H46N8O2: 742; found: 743 (M+H)⁺.</td>

Example 28d

1) step a

2) step b

3) step c

Examples 95-103

<img file="IL196813A_D0150.tif" />

step a: Cap w/ cap-5 as in Example 28 step b: Same procedure as in conversion of Example 1d to 1e step c: As in the last step of Example 1 using 1.1 equiv. of the appropriate carboxylic acid and HATU

<td> Example</td><td> Compound Name</td><td> 0</td><td> Retention time (LCCondition); homogeneity index MS data</td>

<td> 95</td><td> 2-((2S)-1 -((2R)-2-phenyl-2-( 1 pyrrolidinyl)acetyl)-2pyrrolidinyl)-5 -(4-(2 -((2S)-1 ((2S)-tetrahydro-2furanylcarbonyl)-2pyrrolidinyl)-1 H-imidazol-5-yl)4-biphenyly 1)-1 H-imidazole</td><td> 0 CA</td><td> 1.16 minutes (Cond. 1); &gt;98%; LC/MS: Anal. Calcd. for [M+H]⁺ C43H48N7O3: 710.38; found 710.60</td>

<td> 96</td><td> 4-(( 1 R)-2-oxo-1 -phenyl-2-((2 S)2-(5-(4'-(2-((2S)-l-((2R)-2phenyl-2-( 1 -pyrrolidinyl)acetyl)2-pyrrolidinyl)-1 H-imidazol-5 yl)-4-biphenylyl)-l H-imidazol2-yl)-lpyrrolidinyl)ethyl)morpholine</td><td> Q A 0 0 Cap-6</td><td> 1.82 minutes (Cond. 1); &gt;98%; LC/MS: Anal. Calcd. for [M+H]⁺ C₅oH₅5N803: 815.44; found . 815.45; HRMS: Anal. Calcd. for [M+H]⁺C50H55N8O3: 815.4397; found 815.4395</td>

<td> 97</td><td> 1 -(2-oxo-1 -phenyl-2-((2S)-2-(5(4'-(2-((2S)-l-((2R)-2-phenyl-2(1 -pyrrolidinyl)acety 1)-2 pyrrolidinyl)-1 H-imidazol-5-yl)4-biphenylyl)-1 H-imidazol-2y 1)-1 -pyrrolidiny l)ethy 1)-4piperidinol</td><td> ° ׳0 OH A single diastereomer Cap-8</td><td> 1.79 minutes (Cond. 2); &gt;98%; LC/MS: Anal. Calcd. for [M+H]⁺ C51H57N8O3: 829.46; found 829.43; HRMS: Anal. Calcd. for [M+H]⁺C51H57N8O3: 829.4554; found 829.4585</td>

<td> 98</td><td> 1 -methyl-4-(2-oxo-l -phenyl-2((2S)-2-(5-(4'-(2-((2S)-l-((2R)2-phenyl-2-(lpyrrolidinyl)acetyl)-2pyrrolidinyl)-1 H-imidazol-5-yl)4-biphenylyl)-1 H-imidazol-2yl)-lpyrrolidinyl)ethyl)piperazine</td><td> Q A ύ N 1 A single diastereomer Cap-17 c</td><td> 1.84 minutes (Cond. 2); &gt;98%; LC/MS: Anal. Calcd. for [M+H]⁺ C₅₁H58N9O2: 828.47; found 828.45; HRMS: Anal. Calcd. for [M+H]⁺C51H58N9O2: 828.4713; found 828.4722</td>

<td> 99</td><td> (1 R)-N,N -diethyl-2-oxo-1 phenyl-2-((2S)-2-(5-(4'-(2-((2S)- l-((2R)-2-pheny 1-2-(1pyrrolidinyl)acetyl)-2pyrrolidinyl)-! H-imidazol-5-yl)4-biphenylyl)-1 H-imidazol-2y 1)-1-pyrrolidiny l)ethanamine</td><td> Q A n Cap-2</td><td> 1.86 minutes (Cond. 2); &gt;98%; LC/MS: Anal. Calcd. for [M+H]⁺C₅₀H57N8O2: 801.46; found 801.44; HRMS: Anal. Calcd. for [M+H]⁺C50H57N8O2: 801.4604; found 801.4595</td>

<td> 100</td><td> methyl ((lR)-2-oxo-l-phenyl-2((2S)-2-(5-(4'-(2-((2S)-l-((2R)2-phenyl-2-(lpyrrolidinyl)acetyl)-2pyrrolidinyl)-lH-imidazol-5-yl)-</td><td> Cl A ΗΝγ&gt;0 Ο_χ Cap-4</td><td> 1.93 minutes (Cond. 2); LC/MS: Anal. Calcd. for [M+H]⁺C48H51N8O4: 803.40; found 803.47 ;</td>

<td></td><td> 4-biphenylyl)-1 H-imidazol-2yl)-l- pyrrolidinyl)ethyl)carbamate</td><td></td><td> HRMS: Anal. Calcd. for [M+H]⁺C48H51N8O4: 803.4033; found 803.4058</td>

<td> 101</td><td> methyl ((1 S)-l-:methyl-2-oxo-2((2S)-2-(5-(4'-(2-((2S)-l-((2R)2-phenyl-2-(lpyrrolidinyl)acetyl)-2pyrrolidinyl)-1 H-imidazol-5-yl)4-biphenylyl)-1 H-imidazol-2yl)-lpyrrolidinyl)ethyl)carbamate</td><td> H ? 0 = Cap-12</td><td> 1.80 minutes (Cond. 2); LC/MS: Anal. Calcd. for [M+H]⁺C43H49N₈O₄: 741.39; found 741.33; HRMS: Anal. Calcd. for [M+H]⁺C43H49N8O4: 741.3877; found 741.3900</td>

<td> 102</td><td> methyl (2-oxo-2-((2S)-2-(5-(4'(2-((2S)-l-((2R)-2-phenyl-2-(lpynolidinyl)acetyl)-2pyrrolidinyl)-1 H-imidazol-5-yl)4-biphenylyl)-1 H-imidazol-2yl)-lpyrrolidinyl)ethyl)carbamate</td><td> Η Ϊ 0</td><td> 1.80 minutes (Cond. 2); LC/MS: Anal. Calcd. for [M+H]⁺C42H47N8O4: 727.37; found 727.24; HRMS: Anal. Calcd. for [M+H]⁺C42H47N8O4: 727.3720; found 727.3743</td>

<td> 103</td><td> (2S)-N,N-dimethyl-1 -oxo-1 ((2S)-2-(5-(4'-(2-((2S)-l-((2R)2-phenyl-2-(lpyrrolidinyl)acetyl)-2pyrrolidinyl)-1 H-imidazol-5-yl)4-biphenylyl)-1 H-imidazol-2yl)-1 -pyrrolidiny 1)-2propanamine</td><td> 1 ⁰״^Νγ\ Cap-13</td><td> 1.69 minutes (Cond. 2); LC/MS: Anal. Calcd. for [M+H]⁺C43H51N8O2: 711.41; found 711.37; HRMS: Anal. Calcd. for [M+H]⁺C43H51N8O2: 711.4135; found 711.4154</td>

Examples 103-1 to 103-12

1) step a

2) step b

3) step c

Example 28d —-——

<img file="IL196813A_D0151.tif" />

step a: Cap with (R)-2-tetrahydrofuroic acid as in Example 28 step b: Same procedure as in the conversion of Example 1d to 1e step c: As in the last step of Example 1 using 1.1 equiv. of the appropriate carboxylic acid and HATU

<td> 103-1</td><td> 1 -(2-oxo-1 -phenyl-2-((2S)-2(5-(4'-(2-((2S)-l-((2R)tetrahydro-2-furanylcarbonyl)2-pyrrolidinyl)-lH-imidazol-4yl)-4-biphenyly 1)-1 H-imidazol2-yl)-1 -pyrrolidinyl)ethy 1)-4phenylpiperidine</td><td>⁰ Ph Diastereomer 1 Cap-17d</td><td> RT = 4.80 minutes; HPLC Xterra 4.6 X 50 mm, 0 to 100% B over 10 minutes, one minute hold time, A = 90% water, 10% methanol, 0.2% phosphoric acid, B = 10% water, 90% methanol, 0.2% phosphoric acid; LCMS: Anal. Calcd. for: C50H53N7O3 800.03 Found: 800.49 (M+H)⁺</td>

<td> 103-2</td><td> 1- (2-oxo-l-phenyl-2-((2S)-2(5-(4'-(2-((2S)-l-((2R)tetrahydro-2-furanylcarbonyl)- 2- pyrrolidinyl)-1 H-imidazol-4yl)-4-biphenylyl)-lH-imidazol2-yl)-1 -pyrrolidinyl)ethyl)-4phenylpiperidine</td><td>⁰k___ Ph Diastereomer 2 Cap-17d</td><td> RT = 4.59 minutes; HPLC Xterra 4.6 X 50 mm, 0 to 100% B over 10 minutes, one minute hold time, A = 90% water, 10% methanol, 0.2% phosphoric acid, B = 10% water, 90% methanol, 0.2%</td>

<td></td><td></td><td></td><td> phosphoric acid; LCMS: Anal. Calcd. for: C50H53N7O3 800.03 Found: 800.48 (M+H)⁺</td>

<td> 103-3</td><td> 1 -methyl-4-(2-oxo-1 -phenyl-2((2S)-2-(5-(4'-(2-((2S)-l-((2R)tetrahydro-2-furanylcarbonyl)2-pyrrolidinyl)-1 H-imidazol-4y l)-4-biphenylyl)-1 H-imidazol2-yl)-l: pyrrolidinyl)ethyl)piperazine</td><td> 0 Ph Diastereomer 1 Cap-17c</td><td> RT=3.36; HPLC Xterra 4.6 X 50 mm, 0 to 100% B over 10 minutes, one minute hold time, A = 90% water, 10% methanol, 0.2% phosphoric acid, B = 10% water, 90% methanol, 0.2% phosphoric acid; LCMS: Anal. Calcd. for: C44H50N8O3 738.94 Found: 739.49 (M+H)⁺</td>

<td> 103-4</td><td> 1 -methyl-4-(2-oxo-1 -phenyl-2((2S)-2-(5-(4'-(2-((2S)-l-((2R)tetrahydro-2-furanylcarbonyl)2-pyrrolidinyl)- lH-imidazol-4yl)-4-biphenylyl)-1 H-imidazol2-yl)-lpyrrolidinyl)ethyl)piperazine</td><td>^ΧΝ0 ^׳ Ph Diastereomer 2 Cap-17c</td><td> RT = 3.47 minutes; HPLC Xterra 4.6 X 50 mm, 0 to 100% B over 10 minutes, one minute hold time, A = 90% water, 10% methanol, 0.2% phosphoric acid, B = 10% water, 90% methanol, 0.2% phosphoric acid; LCMS: Anal. Calcd. for: C44H50N8O3 738.94</td>

<td></td><td></td><td></td><td> Found: 739.51 (M+H)⁺</td>

<td> 103-5</td><td> benzyl 4-(2-oxo-l-phenyl-2((2S)-2-(5-(4'-(2-((2S)-l-((2R)tetrahydro-2-furanylcarbonyl)2-pyrrolidinyl)-1 H-imidazol-4yl)-4-biphenylyl)-1 H-imidazol2-y 1)-1 -pyrrolidinyl)ethyl)-1 piperazinecarboxylate</td><td>⁰ ס^ן ן Ph Diastereomer 1 Cap-17a</td><td> RT = 5.00 minutes; HPLC Xterra 4.6 X 50 mm, 0 to 100% B over 10 minutes, one minute hold time, A = 90% water, 10% methanol, 0.2% phosphoric acid, B = 10% water, 90% methanol, 0.2% phosphoric acid; LCMS: Anal. Calcd. for: C₅₁H₅₄N₈O5 859.05 Found: 859.51 (M+H)⁺</td>

<td> 103-6</td><td> benzyl 4-(2-oxo-l-phenyl-2((2S)-2-(5-(4'-(2-((2S)-l-((2R)tetrahydro-2-furanylcarbonyl)2-pyrrolidinyl)-1 H-imidazol-4yl)-4-bipheny ly 1)-1 H-imidazol2 -yl)-1 -pyrrolidiny l)ethyl)-1 piperazinecarboxylate</td><td> 0 _____ JI ⁰ ן] k^N^Jly Ph Diastereomer 2 Cap-17 a</td><td> RT= 5.10 minutes; HPLC Xterra 4.6 X 50 mm, 0 to 100% B over 10 minutes, one minute hold time, A = 90% water, 10% methanol, 0.2% phosphoric acid, B = 10% water, 90% methanol, 0.2% phosphoric acid; LCMS: Anal. Calcd. for: C51H54N8O5 859.05 Found: 859.49 (M+H)⁺</td>

<td> 103-7</td><td> 1 -(2-oxo-1 -phenyl2))-2־S)-2(5-(4'-(2-((2S)-l-((2R)tetrahydro-2-furanylcarbonyl)־ 2 -pyrrolidinyl)-1 H-imidazol-4yl)-4-biphenylyl)-1 H-imidazol2-yl)-l- pyrrolidinyl)ethyl)piperazine</td><td> HN^X 0 Ph prepared by hydrogenolyzing 103-5</td><td> RT = 3.61 minutes; HPLC Xterra 4.6 X 50 mm, 0 to 100% B over 10 minutes, one minute hold time, A = 90% water, 10% methanol, 0.2% phosphoric acid, B = 10% water, 90% methanol, 0.2% phosphoric acid; LCMS: Anal. Calcd. for: C43H48N8O3 724.91 Found: 725.47 (M+H)⁺</td>

<td> 103-8</td><td> 4-(2-oxo-1 -phenyl-2-((2S)-2(5-(4'-(2-((2S)-l-((2R)tetrahydro-2-fi1ranylcarbonyl)2-pyrrolidinyl)-1 H-imidazol-4yl)-4-biphenylyl)-1H -imidazol2-yl)-1 -pyrrolidiny l)ethy 1)-2piperazinone</td><td> HN^| 0 cP—^NxPy Ph Cap-17b</td><td> RT= 3.97; HPLC Xterra 4.6 X 50 mm, 0 to 100% B over 10 minutes, one minute hold time, A = 90% water, 10% methanol, 0.2% phosphoric acid, B = 10% water, 90% methanol, 0.2% phosphoric acid; LCMS: Anal. Calcd. for: C43H46N8O4 738.90 Found: 739.56 (M+H)⁺</td>

<td> 103-9</td><td> l-methyl-3-((lR)-2-0x0-1־ phenyl-2-((2S)-2-(4-(4'-(2((2S)-1 -((2R)-tetrahydro-2furanylcarbonyl)-2-</td><td> °pQ׳° HN^</td><td> HPLC XTERRA C- 18 4.6 x 30 mm, 0 to 100% B over 4 minutes, 1 minute</td>

<td></td><td> pyrrolidinyl)-1 H-imidazol-4yl)-4-biphenylyl)-lH-imidazol- 2 -yl)-1 -pyrrolidiny l)ethyl)urea</td><td> employed Cap-45</td><td> hold time, A = 90% water, 10%&gt; methanol, 0.2% H₃PO4, B = 10% water, 90% methanol, 0.2% H₃PO4, RT = 1.81 minutes, 96% homogeneity index.; LCMS: Anal. Calcd. for C41H44N8O4: 712.84; found: 713.37 (M+H)⁺; HRMS: Anal. Calcd. for C41H45N8O4 713.3564; found: 713.3564 (M+H)⁺.</td>

<td> 103-10</td><td> 1- ethyl-3-((lR)-2-oxo-1phenyl-2-((2S)-2-(4-(4'-(2- ((2S)-1 -((2R)-tetrahydro-2furanylcarbonyl)-2pyrrolidinyl)-1 H-imidazol-4yl)-4-bipheny lyl)-1H -imidazol- 2- yl)-l -pyrrolidinyl)ethyl)urea</td><td> o HNemployed Cap-46</td><td> HPLC XTERRA C18 4.6 x 30 mm, 0 to 100% B over 2 minutes, 1 minute hold time, A = 90% water, 10% methanol, 0.2% H₃PO4, B = 10% water, 90% methanol, 0.2% H₃PO4, RT = 1.88 minutes, 95% homogeneity index; LCMS: Anal. Calcd. for C42H46N8O4: 726.87; found: 727.71 (M+H)⁺; HRMS: Anal. Calcd. for C42H47N8O4 727.3720; found:</td>

<td></td><td></td><td></td><td> 727.3695 (M+H)⁺.</td>

<td> 103-11</td><td> 1 -cyclopentyl-3-((l R)-2-oxo- 1- phenyl-2-((2S)-2-(4-(4'-(2((2S)-1 -((2R)-tetrahydro-2furanylcarbonyl)-2pyrrolidinyl)-1 H-imidazol-4yl)-4-biphenylyl)-1 H-imidazol- 2- yl)-1 -pyrrolidinyl)ethyl)urea</td><td> ^vw ץ y employed Cap-48</td><td> HPLC XTERRA C18 4.6 x 30 mm, 0 to 100% B over 2 minutes, 1 minute hold time, A = 90% water, 10% methanol, 0.2%H₃PO4,B = 10% water, 90% methanol, 0.2% H3PO4, RT = 2.11 minutes, 96% homogeneity index; LCMS: Anal. Calcd. for C45H50N8O4: 766.93; found: 767.45 (M+H)⁺; HRMS: Anal. Calcd. for C45H51N8O4 767.4033; found: 767.4032 (M+H)⁺.</td>

<td> 103-12</td><td> 1,1 -dimethyl-3 -((1 R)-2-oxo-1 phenyl-2-((2S)-2-(4-(4'-(2((2S)-1 -((2R)-tetrahydro-2furanylcarbonyl)-2pyrrolidinyl)-1 H-imidazol-4yl)-4-bipheny lyl)-1 H-imidazol2-yl)-l -pyrrolidinyl)ethyl)urea</td><td> *h/w ץ \\ ° Z^N^ employed Cap-47</td><td> HPLC XTERRA C18 4.6 x 30 mm, 0 to 100% B over 2 minutes, 1 minute hold time, A = 90% water, 10% methanol, 0.2% H3PO4, B = 10% water, 90% methanol, 0.2% H3PO4, RT = 1.87 minutes, 97% homogeneity index; LCMS: Anal. Calcd. for C42H46N8O4:</td>

<td></td><td></td><td></td><td> 726.87; found: 727.38 (M+H)⁺; HRMS: Anal. Calcd. for C42H47N 8Ο4 727.3720; found: 727.3723 (M+H)⁺.</td>

Example 28d

1) step a

2) step b

3) step c

Examples 104-107

<img file="IL196813A_D0152.tif" />

step a: Cap with (S)-2-tetrahyclrofuroic acid as in Example 28 step b: Same procedure as in the conversion of Example 1d to Example 1e step c: As in the last step of Example 1 using 1.1 equiv. of the appropriate carboxylic acid and HATU

<td> Example</td><td> Compound Name</td><td> O</td><td> Retention time (LCCondition); homogeneity index MS data</td>

<td> 104</td><td> 1 -methyl-4-(2-oxo-1 -phenyl-2((2S)-2-(5-(4'-(2-((2S)-l-((2S)tetrahydro-2-furanylcarbonyl)2-pyrrolidinyl)-1 H-imidazol-5yl)-4-biphenylyl)- IH-imidazol2-yl)-lpyrrolidinyl)ethyl)piperazine</td><td> n ן o Ph A single diastereomer Cap-17c</td><td> 1.12 minutes (Cond. 1); &gt;98%; LC/MS: Anal. Calcd. for [M+H]⁺ C44H51N8O3: 739.41; found 739.63; HRMS: Anal. Calcd. for [M+H]⁺ C44H₅₁N8O₃: 739.4084; found 739.4054</td>

<td> 105</td><td> 4-(( lR)-2-oxo-1 -phenyl-2-((2S)- 2-(5-(42))-2)-׳S)-l-((2S)- tetrahydro-2-furanylcarbonyl)- 2 -pyrrolidinyl)- lH-imidazol-5-</td><td> ?X ⁰ Ph Cap-6</td><td> 1.13 minutes (Cond. 1); &gt;98%; LC/MS: Anal. Calcd. for [M+H]⁺ C43H48N7O4:</td>

<td></td><td> y l)-4-biphenyly 1)-1 H-imidazol- 2-yl)-l- pyrrolidinyl)ethyl)morpholine</td><td></td><td> 726.38; found 726.63; HRMS: Anal. Calcd. for [M+H]⁺ C43H48N7O4: 726.3768; found 726.3803</td>

<td> 106</td><td> (1 R)-N,N-diethyl-2-oxo-1 - phenyl-2-((2S)-2-(5-(4'-(2- ((2S)-l-((2S)-tetrahydro-2- furanylcarbonyl)-2- pyrrolidinyl)-1 H-imidazol-5 -yl)4-biphenylyl)-1 H-imidazol-2yl)-1 -pyrrolidiny l)ethanamine</td><td> 0 ץ' Ph Cap-2</td><td> 1.12 minutes (Cond. 1); 97%; LC/MS: Anal. Calcd. for [M+H]⁺ C43H50N7O3: 712.40; found 712.45; HRMS: Anal. Calcd. for [M+H]⁺C43H5qN7O3: 712.3975; found 712.3998</td>

<td> 107</td><td> (1 R)-N-ethyl-N-methyl-2-oxo- 1 -phenyl-2-((2S)-2-(5-(4'-(2- ((2S)-1 -((2S)-tetrahydro-2- furanylcarbonyl)-2- pyrrolidinyl)-1 H-imidazol-5 -yl)- 4-biphenylyl)-1 H-imidazol-2yl)-1 -pyrrolidiny !)ethanamine</td><td>⁰ ל' Ph Cap-3</td><td> 1.10 minutes (Cond. 1); &gt;98%; LC/MS: Anal. Calcd. for [M+H]⁺ C42H48N7O3: 698.38; found 698.45; HRMS: Anal. Calcd. for [M+H]⁺C42H48N7O3: 698.3819; 698.3823</td>

Examples 107-1 to 107-30

1) step a

2) step b

3) step c

Example 28d ---------

<img file="IL196813A_D0153.tif" />

R step a: Cap with cap-14 as in Example 28 step b: Same procedure as in the conversion of Example 1d to 1e step c: As in the last step of Example 1 using 1.1 equiv. of the appropriate carboxylic acid and HATU

<td> Example Number</td><td> Compound Name</td><td> Structure</td><td> Data</td>

<td> Example 107-1</td><td> (lS)-2-oxo-l- phenyl-2-((2S)-2(5-(4-(2-((28)-1((2R)-2-phenyl2-(1- piperidinyl)acetyl )-2-pyirolidinyl)lH-imidazol-5yl)-4biphenylyl)-l Himidazol-2-yl)-lpyrrolidinyl)ethyl acetate</td><td> O O</td><td>¹HNMR (400 MHz, CDCb) δ 7.63-7.85 (m, 8H), 7.48- 7.54 (m, 2H), 7.26- 7.46 (m, 7H), 6.94-7.17 (m, 3H), 6.22 and 6.18 (s, IH, rotamers, 1:1), 5.99 and 5.68 (s, IH, rotamers, 1:1), 5.61 and 5.54 (d, J = 7.8 Hz, IH, rotamers, 1:1), 5.20-5.23 and 5.10-5.13 (m, IH, rotamers, 1:1), 4.46 and 4.43 (s, IH, rotamers, 1:1), 3.97- 4.06 (m, IH), 3.89-3.93 and 3.78- 3.84 (m, IH, rotamers, 1:1), 3.63- 3.72 and 3.46- 3.60 (m, IH, rotamers, 1:1), 3.23-3.32 (m, 2H), 2.41-2.59 (m, 4H), 2.13-2.26 (m, 2H), 2.11 and 2.10 (s, 3H, rotamers, 1:1), 2.05-2.09 (m, 2H), 1.97- 1.98 (m, IH), 1.82-1.90 (m, IH), 1.58 (br s, 4H),</td>

<td></td><td></td><td></td><td> 1.45 (brs, 2H); LCMS: Anal. Calcd. for C49H51N7O4: 801: found: 802 (M+H)⁺.</td>

<td> Example 107-2</td><td> 4-methyl-l((1R)2־-oxo-1phenyl-2-((2S)-2(5-(4-(2-((28)-1((2R)-2-phenyl2-(1piperidinyl)acetyl )-2-pyrrolidinyl)lH-imidazol-5- yl)-4biphenylyl)-1Himidazol-2-yl)-l pyrrolidinyl)ethyl )-4-piperidinol</td><td> OH ^־x o o</td><td> LCMS: Anal. Calcd. for C53H₆0N₈O₃: 856; found: 857 (M+H)⁺.</td>

<td> Example 107-3</td><td> 1- ((lR)-2-((2S)- 2- (5-(4'-(2-((2S)־ 1-(2- fluorobenzoyl)-2pyrrolidiny 1)-1Himidazol-5-yl)-4biphenylyl)-1Himidazol-2-yl)-lpyrrolidinyl)-2oxo-1phenylethyl)piper idine</td><td> An /=γ/=\^ΝγΟ θ Λ)</td><td> LCMS: Anal. Calcd. for C46H56FN7O2: 747; found: 748 (M+H)⁺.</td>

<td> Example 107-4</td><td> N,N-dimethyl-4(((2S)-2-(5-(4'(2-((2S)-l-((2R)-</td><td> A</td><td> LCMS: Anal. Calcd. for C48H52N8O2: 772;</td>

<td></td><td> 2-phenyl-2-(lpiperidinyl)acetyl )-2-pyrrolidinyl)1 H-imidazol-5yl)-4biphenylyl)-1Himidazol-2-yl)-l pyrrolidinyl)carb onyl)aniline</td><td></td><td> found: 773 (M+H)⁺.</td>

<td> Example 107-5</td><td> 5-oxo-5-((2S)-2(5-(4’-(2-((2S)-l- ((2R)-2-phenyl2-(1piperidinyl)acetyl )-2-pyrrolidinyl)1 H-imidazol-5yl)-4biphenylyl)-1Himidazol-2-yl)-l- pyrrolidinyl)-2pentanone</td><td> θ</td><td> LCMS: Anal. Calcd. for C44H49N7O3: 723; found: 724 (M+H)⁺.</td>

<td> Example 107-6</td><td> 1- ((1R)-22))־S)- 2- (5-(4--(2-((25)1(diphenylacetyl)2-pyrrolidinyl)- 1 H-imidazol-5yl)-4biphenylyl)-1Himidazol-2-yl)-lpyrrolidinyl)-2oxo-1phenylethyl)piper idine</td><td> Oh η Γ /</td><td> LCMS: Anal. Calcd. for C53H53N7O2: 819; found: 820 (M+H)⁺.</td>

<td> Example 107-7</td><td> 1- (3-oxo-3-((2S)- 2- (5-(4-(2-((2S)l-((2R)-2phenyl-2-(lpiperidinyl)acetyl )-2-pyrrolidinyl)1 H-imidazol-5yl)-4biphenylyl)-1Himidazol-2-yl)-lpyrrolidinyl)prop yl)piperidine</td><td> \ Π Η Η Γ / A ΜΙΑγΜ</td><td> LCMS: Anal. Calcd. for C47H₅₆N₈O2: 764; found: 765 (M+H)⁺.</td>

<td> Example 107-8</td><td> 1- ((1R)-22))־S)- 2- (5-(4'-(2-((2S)1-((2methoxyphenoxy )acetyl)-2pyrrolidinyl)-1Himidazol-5-yl)-4biphenylyl)-1Himidazol-2-yl)-lpyrrolidinyl)-2oxo-1phenylethyl)piper idine</td><td> Q.מ /= /= r JC 0 °F) UoO'^ggJ</td><td> LCMS: Anal. Calcd. for C48H51N7O4: 789; found: 790 (M+H)⁺.</td>

<td> Example 107-9</td><td> tert-butyl 4(((2S)-2-(5-(4'(2-((2S)-l-((2R)2-phenyl-2-(lpiperidinyl)acetyl )-2-pyrrolidinyl)1 H-imidazol-5yl)-4biphenylyl)-1Himidazol-2-yl)-l -</td><td> CL« /= /= r^Q 0 o</td><td> LCMS: Anal. Calcd. for C50H60N8O4: 836; found: 837 (M+H)⁺.</td>

<td></td><td> pyrrolidinyl)carb onyl)-loiperidinecarbox ylate</td><td></td><td></td>

<td> Example 107-10</td><td> 4-(4-(((2S)-2-(5(4'-(2-((2S)-l((2R)-2-phenyl2-(1piperidinyl)acetyl )-2-pyrrolidinyl)1 H-imidazol-5yl)-4biphenylyl)-IHimidazol-2-yl)-lpyrrolidinyl)carb onyl)phenyl)mor pholine</td><td> ¢^0^^0-0¾¾</td><td> LCMS: Anal. Calcd. for C50H54N8O3: 814; found: 815 (M+H)⁺.</td>

<td> Example 107-11</td><td> l-((lR)-2-oxo-lphenyl-2-((2S)-2- (5-(4'-(2-((2S)-l(l,3-thiazol-4ylcarbonyl)-2pyrrolidinyl)-IHimidazol-5-yl)-4biphenylyl)-IHimidazol-2-yl)-lpyrrolidinyl)ethyl )piperidine</td><td> \ J. Η Η Γ &gt; ΖΛ N׳״X-־״N /=\ /=\ N ' ) c/⁴□ _ο.Κ O</td><td> LCMS: Anal. Calcd. for C43H44N8O2S: 736; found: 737(M+H)⁺.</td>

<td> Example 107-12</td><td> tert-butyl 3(((2S)-2-(5-(4'(2-((2S)-l-((2R)2-phenyl-2-(lpiperidinyl)acetyl )-2-pyrrolidinyl)1 H-imidazol-5-</td><td> o</td><td> LCMS: Anal. Calcd. for C48H₅₆N₈O4: 808; found: 809 (M+H)⁺.</td>

<td></td><td> yl)-4biphenylyl)-1Himidazol-2-yl)-lpyrrolidinyl)carb onyl)-lazetidinecarboxyl ate</td><td></td><td></td>

<td> Example 107-13</td><td> tert-butyl (cis-4(((2S)-2-(5-(4(2-((2S)-l-((2R)2-phenyl-2-(lpiperidinyl)acetyl )-2-pyrrolidinyl)lH-imidazol-5yl)-4biphenylyl)-1Himidazol-2-yl)-lpyrrolidinyl)carb onyl)cyclohexyl) carbamate</td><td></td><td> LCMS: Anal. Calcd. for C₅₁H₆₂N₈O₄: 850; found: 851 (M+H)⁺.</td>

<td> Example 107-14</td><td> tert-butyl 4methyl-4-(((2S)2-(5-(4'-(2-((2S)l-((2R)-2phenyl-2-( 1piperidinyl)acetyl )-2-pyrrolidinyl)1 H-imidazol-5yl)-4biphenylyl)-1Himidazol-2-yl)-l pyrrolidinyl)carb ony 1)-1piperidinecarbox ylate</td><td> o</td><td> LCMS: Anal. Calcd. for C51H₆₂N₈O4: 850; found: 851 (M+H)⁺.</td>

<td> Example 107-15</td><td> 1-((1R)2־-oxo-1phenyl-2-((2S)-2(5-(4-(2-((25)-1((1(trifluoromethyl) cyclopropyl)carb onyl)-2pyrrolidinyl)-1Himidazol-5-yl)-4biphenylyl)-1Himidazol-2-yl)-lpyrrolidinyl)ethyl )piperidine</td><td> J Η Η Γ z ( \ \ /-*י. t׳ λ f Τ^Ν\_/⁼Λ_7⁼\_ζ^ΝΥ ^F3C /λ</td><td> LCMS: Anal. Calcd. for C44H46F3N7O2: 761; found: 762 (M+H)⁺.</td>

<td> Example 107-16</td><td> 1- ((1R)2))-2־S)- 2- (5-(4'-(2-((2S)1-((5-methyl-1Hpyrazol-3yl)acetyl)-2pyrrolidinyl)-1Himidazol-5-yl)-4biphenylyl)-1Himidazol-2-yl)-lpyrrolidinyl)-2oxo-1phenylethyl)piper idine</td><td> ?Λ /λ HN^׳ \sasX</td><td> LCMS: Anal. Calcd. for C45H49N9O2: 747; found: 748 (M+H)⁺.</td>

<td> Example 107-17</td><td> 1- ((1R)-22))־S)- 2- (5-(4'-(2-((2S)1-(((3R)-1benzyl-3pyrrolidinyl)carb onyl)-2pyrrolidinyl)-1Himidazol-5-yl)-4biphenylyl)-1H-</td><td> 7 \=/ ך=\ Pp ׳Q‘S&gt; ILrV־wv!1 ₀א</td><td> LCMS: Anal. Calcd. for C51H56N8O2: 812; found: 813 (M+H)⁺.</td>

<td></td><td> imidazol-2-yl)-lpyrrolidinyl)-2oxo-1phenylethyl)piper idine</td><td></td><td></td>

<td> Example 107-18</td><td> 1- ((1 R)-2-((2 S)- 2- (5-(4'-(2-((2S)1-(((3S)1־denzyl-3pyrrolidinyl)carb ony 1)-2pyrrolidinyl)-1Himidazol-5-yl)-4biphenylyl)-1Himidazol-2-yl)-lpyrrolidinyl)-2oxo-1phenylethyl)piper idine</td><td> YA JJAZV/A-'i א</td><td> LCMS: Anal. Calcd. for C51H56N₈O2: 812; found: 813 (M+H)⁺.</td>

<td> Example 107-19</td><td> 1- ((1R)2))-2־S)- 2- (5-(4'-(2-((2S)l-((2R)-2methoxy-2phenylacetyl)-2pyrrolidinyl)-1Himidazol-5-yl)-4biphenylyl)-1Himidazol-2-yl)-l pyrrolidinyl)-2oxo-1phenylethyl)piper idine</td><td> O O</td><td> LCMS: Anal. Calcd. for C48H51N7O3: 773; found: 774 (M+H)⁺.</td>

<td> Example 107-20</td><td> 1- ((lR)-2-((2S)- 2- (5-(4'-(2-((2S)- l-((2S)-2-</td><td> η h o o</td><td> LCMS: Anal. Calcd. for C48H51N7O3: 773;</td>

<td></td><td> methoxy-2phenylacetyl)-2pyrrolidinyl)-IHimidazol-5-yl)-4biphenylyl)-IHimidazol-2-yl)-lpyrrolidinyl)-2oxo-1phenylethyl)piper idine</td><td></td><td> found: 774 (M+H)⁺.</td>

<td> Example 107-21</td><td> (1R)2־-oxo-1phenyl-2-((2S)-2(5-(42))-2)-׳S)-l((2R)-2-phenyl2-(1piperidinyl)acetyl )-2-pyrrolidinyl)lH-imidazol-5- yl)-4biphenylyl)-IHimidazol-2-yl)-lpyrrolidinyl)ethyl acetate</td><td> 0 o</td><td> LCMS: Anal. Calcd. for C49H51N7O4: 801; found: 802 (M+H)⁺.</td>

<td> Example 107-22</td><td> 1-((1R)2־-oxo-1phenyl-2-((2S)-2(5-(4'-(2-((2S)-l((1phenylcycloprop yl)carbonyl)-2pyrrolidinyl)-IHimidazol-5-yl)-4biphenylyl)-IHimidazol-2-yl)-lpyrrolidinyl)ethy )piperidine</td><td> 0 o</td><td> LCMS: Anal. Calcd. for C49H5jN7O2: 769; found: 770 (M+H)⁺.</td>

<td> Example 107-23</td><td> N,N-dimethyl-l1'2-(2-oxo-2((2S)-2-(5-(4'-(2((2S)-l-((2R)-2±eny 1-2-(1piperidinyl)acetyl )-2-pyrrolidinyl)1 H-imidazol-5yl)-4biphenylyl)-1Himidazol-2-yl)-lpyrrolidinyl)ethyl )phenyl)methana mine</td><td> \ ZL Η Η Γ ) / \ O 0</td><td> LCMS: Anal. Calcd. for C₅0H56N8O₂: 800; found: 801 (M+H)⁺.</td>

<td> Example 107-24</td><td> 1- ((1R)-22))־S)- 2- (5-(4'-(2-((2S)l-((3-methyl-5isoxazolyl)acetyl) -2-pyrrolidinyl)lH-imidazol-5yl)-4biphenylyl)-1Himidazol-2-yl)-lpy1rolidinyl)-2oxo-1phenylethyl)piper idine</td><td> z=\ /=\ A SA fp \\ /*⁸⁸N ¾/</td><td> LCMS: Anal. Calcd. for C45H48N8O3: 748; found: 749 (M+H)⁺.</td>

<td> Example 107-25</td><td> 1- ((lR)-2-((2S)- 2- (5-(4'-(2-((2S)l-((2-methyl-l,3thiazol-4yl)acetyl)-2pyrrolidinyl)-1Himidazol-5-yl)-4biphenylyl)-1H-</td><td> rA_o J_oA y O</td><td> LCMS: Anal. Calcd. for C45H48N8O2S: 764; found: 765 (M+H)⁺.</td>

<td></td><td> imidazol-2-yl)-lpyrrolidiny 1)-2oxo-1phenylethyl)piper idine</td><td></td><td></td>

<td> Example 107-26</td><td> 4-(2-(2-oxo-2((2S)-2-(5-(4'-(2((2S)-l-((2R)-2phenyl-2-(lpiperidinyl)acetyl )-2-pyrrolidinyl)lH-imidazol-5yl)-4biphenylyl)-1Himidazol-2-yl)-lpyrrolidinyl)ethyl )benzyl)morpholi ne</td><td> 0 O</td><td> LCMS: Anal. Calcd. for C52H58N8O3: 842; found: 843 (M+H)⁺.</td>

<td> Example 107-27</td><td> 1-((1R)2־-oxo-1phenyl-2-((2S)-2(5-(4'-(2-((2S)-l((2-(1pyrrolidinylmeth yl)phenyl)acetyl) -2-pyrrolidinyl)1 H-imidazol-5yl)-4biphenylyl)-1Himidazol-2-yl)-lpyrrolidinyl)ethyl )piperidine</td><td> /1 Η Η Γ / ΖΛ /-( o o</td><td> LCMS: Anal. Calcd. for C52H58N8O2: 826; found: 827 (M+H)⁺.</td>

<td> Example 107-28</td><td> 1- ((1R)2))-2־S)- 2- (5-(4'-(2-((2S)- 1-((2fluorophenyl)acet</td><td> \ η h r &gt; /״״ά r Y^N&lt;_/⁼w⁼v^^N1־r ^ft M _F A_o /-( O O</td><td> LCMS: Anal. Calcd. for C47H48FN7O2: 800; found: 801</td>

<td></td><td> yl)-2pyrrolidinyl)-1Himidazol-5-yl)-4biphenylyl)-1Himidazol-2-y 1)-1pyrrolidinyl)-2oxo-1phenylethyl)piper idine</td><td></td><td> (M+H)⁺.</td>

<td> Example 107-29</td><td> 1- ((lR)-2-((2S)- 2- (5-(4'-(2-((2S)l-acetyl-2pyrrolidinyl)-1Himidazol-5-yl)-4biphenylyl)-1Himidazol-2-y 1)-1pyrrolidinyl)-2oxo-1phenylethyl)piper idine</td><td> (JI Η Η Γ Z ( λ N^X-N /=\ /=\ t N-/ O</td><td> LCMS: Anal. Calcd. for C41H45FN₇O₂: 667; found: 668 (M+H)⁺.</td>

<td> Example 107-30</td><td> 1- ((lR)-2-oxo-lphenyl-2-((2S)-2- (5-(4’-(2-((2S)-l(2-thienylacetyl)- 2- pyrrolidinyl)lH-imidazol-5- . yl)-4- biphenylyl)-1Himidazol-2-yl)-lpyrrolidinyl)ethyl )piperidine</td><td> \ J H - H f / (\ rYV^-rVT ד M A Λ /V V 0</td><td> LCMS: Anal. Calcd. for C45H47N7O2S: 749; found: 750 (M+H)⁺.</td>

Example 107-31 to 107-34 _r 'h' ״ ״ γγγ*

Examples 107-31 through 107-34 were prepared in similar fashion to example 28. Cap-38 was appended to intermediate 28d, the Boc carbamate was removed with 5 TFA or HC1 and the appropriate carboxylic acid was coupled.

<td> Example</td><td> Compound Name</td><td> Structure</td><td> Data</td>

<td> Example 107-31</td><td> (lR)-2-((2S)-2-(5-(4'-(2((2S)-l-((2R)-2(dimethylamino)-2-(2fluorophenyl)acetyl)-2pyrrolidinyl)-1 H-imidazol5-yl)-4-biphenylyl)1 ־Himidazol-2-yl)-lpyrrolidinyl)-N,Ndimethyl-2-oxo-lphenylethanamine</td><td> o r- _Λ _ y®׳</td><td> LCMS: Anal. Calcd. for C46H49FN8 02: 764; found: 765 (M+H)⁺.</td>

<td> Example 107-32</td><td> (1R)2)- 1 ־ -fluoropheny 1)-2((2S)-2-(5-(4'-(2-((2S)-l((2R)-2-methoxy-2phenylacetyl)-2pyrrolidinyl)-1 H-imidazol5-yl)-4-biphenylyl)-lHimidazol-2-yl)-lpyrrolidinyl)-N,Ndimethyl-2-oxoethanamine</td><td></td><td> LCMS: Anal. Calcd. for C45H46FN7 O₃:751; found: 752 (M+H)⁺.</td>

<td> Example 107-33</td><td> (lR)-2-((2S)-2-(5-(4'-(2((2S)-l-((2R)-2(dimethylamino)-2-(2fluorophenyl)acetyl)-2- pyrrolidinyl)-1 H-imidazol5-yl)-4-biphenylyl)-1H-</td><td></td><td> LCMS: Anal. Calcd. for C46H46FN7 04: 779; found: 780</td>

<td></td><td> imidazol-2-yl)-lpyrrolidinyl)-2 -oxo-1 phenylethyl acetate</td><td></td><td> (M+H)⁺.</td>

<td> Example 107-34</td><td> (1R)-1 -(2-fluorophenyl)N,N־dimethyl-2-oxo-2((2S)-2-(5-(4'-(2-((2S)-l((1phenylcyclopropyl)carbony l)-2-pyrrolidinyl)-l Himidazol-5-yl)-4biphenylyl)-! H-imidazol-2yl)-l- pyrrolidinyl)ethanamine</td><td> O</td><td> LCMS: Anal. Calcd. for C46H46FN7 02: 747; found: 748 (M+H)⁺.</td>

Example 107-35 to 107-38

<img file="IL196813A_D0154.tif" />

Examples 107-35 through 107-38 were prepared in similar fashion to example 5 28. Cap-39 was appended to intermediate 28d, the Boc carbamate was removed with

TFA or HCI and the appropriate carboxylic acid was coupled.

<td> Example</td><td> Compound Name</td><td> Structure</td><td> Data</td>

<td> Example 107-35</td><td> (1R)-1 -(2-chlorophenyl)2-((2S)-2-(5-(4'-(2-((2S)- 1- ((2R)-2(dimethylamino)-2 phenylacetyl)-2pyrrolidinyl)-1Himidazol-5-yl)-4biphenylyl)-1 H-imidazol- 2- yl)-l -pyrrolidinyl)N,N-dimethyl-2oxoethanamine</td><td> \JT ו 0</td><td> LCMS: Anal. Calcd. for C46H49CIN8O2: 780; found: 781 (M+H)⁺.</td>

<td> Example 107-36</td><td> methyl ((lR)-2-((2S)-2(5-(42))-2)-׳S)-l-((2R)-2(2-chlorophenyl)-2(dimethylamino)acetyl)2-pyrrolidinyl)-1Himidazol-5-yl)-4biphenylyl)-1 H-imidazol2-yl)-l -pyrrolidinyl)-2oxo-1phenylethyl)carbamate</td><td> ^^77-^-ןן/_^7==י NHCOjM.</td><td> LCMS: Anal. Calcd. for C46H47CIN 8Ο4: 810; found: 811 (M+H)⁺.</td>

<td> Example 107-37</td><td> (1R)-1 -(2-chlorophenyl)2-((2S)-2-(5-(4’-(2-((2S)1 -((2R)-2-methoxy-2phenylacetyl)-2pyrrolidinyl)-1Himidazol-5-y 1)-4biphenylyl)-1 H-imidazol2-yl)-1 -pyrrolidinyl)N,N-dimethyl-2oxoethanamine</td><td>⁰Ov VC θ ״³י.</td><td> LCMS: Anal. Calcd. for C45H46CIN7O3: 767; found: 768 (M+H)⁺.</td>

<td> Example 107-38</td><td> (1R)-1 -(2-chlorophenyl)N,N-dimethyl-2-oxo2־((2S)-2-(5-(4'-(2-((2S)-l((2R)-tetrahydro-2furanylcarbonyl)-2pyrrolidinyl)-1Himidazol-5-y 1)-4biphenylyl)-1 H-imidazol2-yl)-lpyrrolidinyl)ethanamine</td><td></td><td> LCMS: Anal. Calcd. for C41H44CIN 7Ο3: 717; found: 718(M+H)⁺.</td>

Example 107-39 to 107-43

O r, HN ״ _n

Examples 107-39 through 107-44 were prepared in similar fashion to example 28. Cap-40 was appended to intermediate 28d, the Boc carbamate was removed with 5 TFA or HC1 and the appropriate carboxylic acid was coupled.

<td> Example</td><td> Compound Name</td><td> Structure</td><td> Data</td>

<td> Example 107-39</td><td> methyl ((lR)-l-(2-. chlorophenyl)-2-oxo-2((2S)-2-(5-(4'-(2-((2S)-l((2R)-tetrahydro-2furanylcarbonyl)-2pyrrolidinyl)-1 H-imidazol5 -yl)-4-biphenylyl)-1Himidazol-2-yl)-lpyrrolidinyl)ethyl)carbamat e</td><td></td><td>¹HNMR (400 MHz, CD₃OD) δ 7.58-7.77 (m, 8H), 7.42- 7.55 (m, 2H), 7.197.39 (m, 4H), 5.94 and 5.89 (s, 1H, rotamers, 1:1),5.80 and 5.61 (s, 1H, rotamers, 1:1), 5.43-5.47 and 5.35-5.38 (m, 1H, rotamers, 1:1), 5.20-5.24 (m, 1H), 5.15-5.18 (m, 1H), 4.674.70 and 4.394.42 (m, 1H, rotamers, 1:1), 3.92-3.98 (m, 1H), 3.85-3.90 (m, 1H), 3.693.84 (m, 2H),</td>

<td></td><td></td><td></td><td> 3.64 and 3.63 (s, 3H, rotamers, 1:1), 3.53-3.59 (m, IH), 2.352.46 (m, IH), 2.21-2.29 (m, 2H), 2.06-2.17 (m, 3H), 1.842.01 (m, 4H), 1.66-1.76 and 1.41-1.47 (m, IH, rotamers, 1:1); LCMS: Anal. Calcd. for C41H42CIN7O5: 747; found: 748 (M+H)⁺.</td>

<td> Example 107-40</td><td> methyl ((1R)-12)־chlorophenyl)-2 -((2S)-2-(5 (4'-(2-((2S)-l-((2R)-2(dimethylamino)-2phenylacetyl)-2pyrrolidinyl)-1 H-imidazol5 -yl)-4-biphenylyl)-1Himidazol-2-yl)-lpyrrolidinyl)-2oxoethyl)carbamate</td><td> MeOjCHN</td><td> LCMS: Anal. Calcd. for C46H47C1N8O4: 810; found: 811 (M+H)⁺.</td>

<td> Example 107-41</td><td> methyl ((lR)-2-((2S)-2-(5(4'-(2-((2S)-l-((2R)-2-(2chlorophenyl)-2((methoxycarbonyl)amino)a cety 1)-2-pyrrolidinyl)-1Himidazol-5-yl)-4biphenylyl)-1 H-imidazol-2yl)-1 -pyrrolidiny l)-2-oxo-1 -</td><td> MeOjCHN Xa־־/</td><td> LCMS: Anal. Calcd. for C46H45CIN8O6: 840; found: 841 (M+H)⁺.</td>

<td></td><td> phenylethyl)carbamate</td><td></td><td></td>

<td> Example 107-42</td><td> methyl ((1R)-1-(2chlorophenyl)-2-((2S)-2-(5(4'-(2-((2S)-l-((2R)-2-(4hy droxy-4-methyl-1 piperidinyl)-2phenylacetyl)-2pyrrolidinyl)-1 H-imidazol5-yl)-4-biphenylyl)-l Himidazol-2-yl)-lpyrrolidiny 1)-2oxoethyl)carbamate</td><td> Q</td><td> LCMS: Anal. Calcd. for C50H53ClN₈O5: 880; found: 881 (M+H)⁺.</td>

<td> Example 107-43</td><td> methyl ((1R)-12)־chlorophenyl)-2-((2S)-2-(5(4'-(2-((2S)-l-((2R)-2methoxy-2-phenylacetyl)-2pyrrolidinyl)-1 H-imidazol5-yl)-4-biphenylyl)-l Himidazol-2-yl)-lpyrrolidiny 1)-2oxoethyl)carbamate</td><td> MeOjCHN V-־/</td><td> LCMS: Anal. Calcd. for C45H44CIN7O5: 797; found: 798 (M+H)⁺.</td>

<td> Example 107-44</td><td> methyl ((1R)-12)־chlorophenyl)-2-((2S)-2-(5(4'-(2-((2S)-l-((2R)-2-(2chlorophenyl)-2(dimethylamino)acetyl)-2pyrrolidinyl)-1 H-imidazol5 -yl)-4-biphenylyl)-1Himidazol-2-yl)-lpyrrolidinyl)-2oxoethyl)carbamate</td><td></td><td> LCMS: Anal. Calcd. for C46H46CI2N 8Ο4: 844; found: 845 (M+H)⁺.</td>

Example 108 methyl ((lR)-2-((2S)-2-(5-(4'-(2-((2S)-l-(ethylcarbamoyl)-2-pyrrolidinyl)-lHimidazol-5-yl)-4-biphenylyl)-lH-imidazol-2-yl)-l -pyrrolidinyl)-2-oxo-1 phenylethyl) carbamate

N

N

Ethyl isocyanate (5 gL, 0.063 mmol) was added to a methanol (1.0 mL) solution of 28f (30 mg, 0.049 mmol) and stirred at ambient condition for 1.8 hours. The residue was treated with 2.0 M NH₃/methanol (2 mL) and stirred for an additional 30 minutes, and all the volatile components were removed in vacuo. The resulting material was purified by a reverse phase HPLC (H2O/methanol/TFA) to provide the TFA salt of Example 108 as a light yellow foam (16.7 mg) LC: 1.95 minutes (Cond. 2); >98% homogeneity index; LC/MS: Anal. Calcd. for [M+H]+ C39H43N8O4: 687.34; found 687.53; HRMS: Anal. Calcd. for [M+H]⁺ C39H43N8O4: 687.3407; found 687.3417.

Example 109 dibenzyl (2S,2'S)-2,2'-(4,4'-biphenyldiylbis(lH-imidazole-5,2-diyl))di(lpyrrolidinecarboxylate)

N

N

Example 109, Step a benzyl (2S)-2-(5-(4'-(2-((2S)-2-pyrrolidinyl)-lH-imidazol-5-yl)-4-biphenylyl)-lHimidazol-2-yl)-l-pyrrolidinecarboxylate

<img file="IL196813A_D0155.tif" />

The Boc-deprotection of 28c using the procedure described for the synthesis of pyrrolidine le from carbamate Id provided 109a. RT = 1.92 minutes (Cond 2); > 98% homogeneity index; LC/MS: Anal. Calcd. C34H35N6O2: 559.28; found 559.44

Example 109 dibenzyl (2S, 2 8)-2,2 '-(4,4'-biphenyldiylbis(lH-imidazole-5,2-diyl))di(l-

<img file="IL196813A_D0156.tif" />

Benzyl chloroformate (10.5 pL, 0.0736 mmol) was added to a THF (2.0 mL) solution of 109a (37.1 mg, 0.664 mmol) and triethylamine (15 pl, 0.107 mmol), and 15 stirred under ambient conditions for 6 hours. The volatile component was removed in vacuo, and the residue was treated with 2N NH3/methanol (2 mL) and stirred for 15 minutes. The volatile component was removed in vacuo, and the residue purified by a reverse phase HPLC (H₂O/methanol/TFA) to provide the TFA salt of Example 109 as an off-white foam (37.9 mg). LC (Cond. 2): RT = 2.25 min; >98% homogeneity index; LC/MS: Anal. Calcd. for [M+H] C4₂H4!N6O4: 693.32; found 693.59; HRMS: Anal. Calcd. for [M+H]⁺ C₄₂H41N6O₄: 693.3189; found 693.3220.

Example 110 (2R)-N-((lR)-2-oxo-l-phenyl-2-((2S)-2-(5-(4'-(2-((2S)-l-((2S)-tetrahydro-2furanylcarbonyl)-2-pyrrolidinyl)-lH-imidazol-5-yl)-4-biphenylyl)-lH-imidazol-2-yl)l-pyrrolidinyl)ethyl)tetrahydro-2-furancarboxamide

<img file="IL196813A_D0157.tif" />

Example 110, Step a (lR)-2-oxo-l-phenyl-2-((2S)-2-(5-(4'-(2-((2S)-l-((2S)-tetrahydro-2-fi1ranylcarbonyl)-

2-pyrrolidinyl)-lH-imidazol-5-yl)-4-biphenylyl)-lH-imidazol-2-yl)-lpyrrolidinyl)ethanamine

<img file="IL196813A_D0158.tif" />

Amine 110a was synthesized starting from 28d and (S)-tetrahydrofuran-2carboxylic by sequentially employing procedures described in the preparation of 28f (from 28d) and 25b (from le). LC (Cond. 1): RT = 1.13 min; >98% homogeneity index; LC/MS: Anal. Calcd. for [M+H]⁺ C39H42N7O3: 656.34; found 656.49; HRMS: Anal. Calcd. for [M+H]⁺ C39H42N7O3: 656.3349; found 656.3377.

Example 110 (2R)-N-((lR)-2-oxo-l-phenyl-2-((2S)-2-(5-(4'-(2-((2S)-l-((2S)-tetrahydro-2fi_lranylcarbonyl)-2-pyrrolidinyl)-lH-imidazol-5-yl)-4-biphenylyl)-lH-imidazol-2-yl)l-pyrrolidinyl)ethyl)tetrahydro-2-furancarboxamide

<img file="IL196813A_D0159.tif" />

Example 110 (TFA salt) was prepared from Example 110a and (S)tetrahydrofuran-2-carboxylic acid using the conditions described for the synthesis

Example 1 from amine le. LC (Cond. 1): RT = 1.28 min; >98% homogeneity index;

LC/MS: Anal. Calcd. for [M+H]⁺C44H48N7O5: 754.37; found 754.60; HRMS: Anal.

Calcd. for [M+H]⁺ C44H48N7O5: 754.3717; found 754.3690.

Example 111

N-((lR)-2-oxo-l-phenyl-2-((2S)-2-(5-(4'-(2-((2S)-l-((2S)-tetrahydro-2furanylcarbonyl)-2-pyrrolidinyl)-lH-imidazol-5-yl)-4-biphenylyl)-lH-imidazol-2-yl) l-pyrrolidinyl)ethyl)-4-mo1pholinecarboxamide

HN

H

Example 111 (TFA salt) was prepared from amine 110a and morpholine 4carbonyl chloride using the procedure described for the synthesis of Example 29 from amine 28f. LC (Cond. 1): RT = 1.28 min; >98% homogeneity index; LC/MS: Anal. Calcd. for [M+H]⁺ C44H49N8O5: 769.38; found 769.60.

Using similar methods described for the preparation of Example 111, the following compounds (Example 112-120) were synthesized as TFA salts.

Example 112-117

<td> Example</td><td> Compound Name</td><td> 0</td><td> Retention time (LC-Condition); homogeneity index MS data</td>

<td> 112</td><td> (2S)-N-((lR)-2-oxo-lphenyl-2-((2S)-2-(5-(4'-(2((2S)-1-((2S)-tetrahydro2-furanylcarbonyl)-2pyrrolidiny 1)-1 H-imidazol5 -y l)-4-bipheny lyl)-1Himidazol-2-yl)-lpyrrolidinyl)ethyl)tetrahyd ro-2 -furancarboxamide</td><td> 0 CA</td><td> 1.28 minutes (Cond. 1); &gt;98%; LC/MS: Anal. Calcd. for [M+H]⁺C44H48N7O5: 754.37; found 754.59; HRMS: Anal. Calcd. for [M+H]⁺C44H48N7O5: 754.3717; found 754.3731</td>

<td> 113</td><td> 1 -methyl-N-((l R)-2-oxol-phenyl-2-((2S)-2-(5-(4'(2-((2S)-l-((2S)tetrahydro-2furanylcarbonyl)-2 pyrrolidinyl)-1 H-imidazol5 -yl)-4-biphenylyl)-1Himidazol-2-yl)-lpyrrolidinyl)ethyl)-Lprolinamide</td><td> \ u</td><td> 1.14 minutes (Cond. 1); &gt;98%; LC/MS: Anal. Calcd. for [M+H]⁺C44H51N8O4: 767.40; found 767.68; HRMS: Anal. Calcd. for [M+H]⁺C44H51N8O4: 767.4033; found 767.4035</td>

<td> 114</td><td> 1 -methyl-N-((l R)-2-oxol-phenyl-2-((2S)-2-(5-(4(2-((2S)-l-((2S)tetrahydro-2furanylcarbonyl)-2pyrrolidinyl)-1 H-imidazol5-yl)-4-biphenylyl)-l Himidazol-2-yl)-lpyrrolidinyl)ethyl)-4piperidinecarboxamide</td><td> 0</td><td> 1.12 minutes (Cond. 1); &gt;98%; LC/MS: Anal. Calcd. for [M+H]⁺C46H53N8O4: 781.42; found 781.67; HRMS: Anal. Calcd. for [M+H]⁺C46H53N8O4: 781.4190; found 781.4195</td>

<td> 115</td><td> N-(( 1 R)-2-oxo-1 -phenyl2-((2S)-2-(5-(4'-(2-((2S)1 -((2S)-tetrahydro-2furanylcarbonyl)-2 pyrrolidinyl)-1 H-imidazol5 -yl)-4-biphenylyl)-1Himidazol-2-yl)-lpyrrolidinyl)ethyl)tetrahyd ro-2H-pyran-4carboxamide</td><td> 0 ⁰Ά</td><td> 1.24 minutes (Cond. 1);&gt;98%; LC/MS: Anal. Calcd. for [M+H]⁺C45H50N7O5: 768.39; found 768.66; HRMS: Anal. Calcd. for[M+H]⁺C45H50N7O5: 768.3873; found 768.3897</td>

<td> 116</td><td> (4R)-4-fluoro-1 -methyl-N((1 R)-2-oxo-1-phenyl-2((2S)-2-(5-(4'-(2-((2S)-l((2S)-tetrahydro-2furanylcarbonyl)-2pyrrolidinyl)-lH-imidazol5 -yl)-4-biphenyly 1)-1Himidazol-2-yl)-lpyrrolidinyl)ethyl)-Lprolinamide</td><td> \ u F Cap-11</td><td> 1.16 minutes (Cond. 1); &gt;98%; LC/MS: Anal. Calcd. for [M+H]⁺C45H50FN8O4: 785.39; found 785.63; HRMS: Anal. Calcd. for [M+H]⁺ C45H50FN8O4: 785.3939; found: 785.3940</td>

<td> 117</td><td> 4-methyl-N-((l R)-2-oxo1 -phenyl-2-((2S)-2-(5-(4- (2-((2S)-l-((2S)tetrahydro-2furanylcarbonyl)-2pyrrolidinyl)-1 H-imidazol- 5 -yl)-4-biphenylyl)-1Himidazol-2-y 1)-1pyrrolidiny !)ethyl)-1 piperazinecarboxamide</td><td> 0 χ׳^νΆ</td><td> 1.15 minutes (Cond. 1); 97.6%; LC/MS: Anal. Calcd. for [M+H]⁺C45H52N9O4: 782.41; found 782.64; HRMS: Anal. Calcd. for [M+H]⁺C45H52N9O4: 782.4142; found 782.4161</td>

Examples 118 to 120-9

<img file="IL196813A_D0160.tif" />

R

Examples 118 to 120-9 were prepared as described in the preparation of Example 110a substituting (R)-tetrahydrofuryl carboxylic acid and the appropriate 5 carboxylic acid, carboxylic acid chloride, carbamoyl chloride, or isocyanate.

<td> Example</td><td> Compound Name</td><td> 0</td><td> Retention time (LCCondition); homogeneity index; MS data</td>

<td> 118</td><td> N-((lR)-2-oxo-l-phenyl2-((2S)-2-(5-(4'-(2-((2S)1 -((2R)-tetrahydro-2furanylcarbonyl)-2pyrrolidinyl)-1 H-imidazol5 -yl)-4-biphenylyl)-1Himidazol-2-yl)-lpyrrolidinyl)ethyl)acetami de</td><td> 0</td><td> 1.89 minutes (Cond. 2); &gt;98%; LC/MS: Anal. Calcd. for [M+H]⁺ C41H44N7O4: 698.35; found 698.25; HRMS: Anal. Calcd. for [M+H]⁺ C41H44N7O4! 698.3455; found 698.3474</td>

<td> 119</td><td> (2R)-N-((lR)-2-oxo-lphenyl-2-((2S)-2-(5-(4'-(2((2S)-1 -((2R)₇tetrahydro2-furanylcarbonyl)-2pyrrolidinyl)-1 H-imidazol5 -yl)4־-biphenylyl)-1Himidazol-2-y 1)-1pyrrolidinyl)ethyl)tetrahyd ro-2-furancarboxamide</td><td> O</td><td> 1.99 minutes (Cond. 2); &gt;98%; LC/MS: Anal. Calcd. for [M+H]⁺ C44H48N7O5: 754.37; found 754.28; HRMS: Anal. Calcd. for [M+H]⁺ C44H48N7O5: 754.3717; found 754.3705</td>

<td> 120</td><td> N-(( 1 R)-2-oxo-1 -phenyl2-((2S)-2-(5-(4'-(2-((2S)1 -((2R)-tetrahydro-2-</td><td> 0 θρ</td><td> 2.00 minutes (Cond. 2); &gt;98%; LC/MS: Anal. Calcd. for [M+H]⁺ C44H49N8O5:</td>

<td></td><td> furanylcarbonyl)-2pyrrolidinyl)-1 H-imidazol5 -y l)-4-biphenylyl)-1Himidazol-2־yl)-lpyrrolidinyl)ethyl)-4morpholinecarboxamide</td><td></td><td> 769.38; found 769.32</td>

<td> 120-5</td><td> 1 -methyl-N-(( 1 R)-2-oxol-phenyl-2-((2S)-2-(5-(4'(2-((2S)-l-((2R)tetrahydro-2furanylcarbonyl)-2pyrrolidinyl)-1 H-imidazol4-yl)-4-biphenylyl)-1Himidazol-2-yl)-lpyrrolidinyl)ethyl)-1Himidazole-5-carboxamide</td><td> \ s hk</td><td> RT = 4.02 (97%); HPLC XTERRA C-18 4.6 x 30 mm, 0 to 100% B over 2 minutes, 1 minute hold time, A = 90% water, 10% methanol, 0.2% H₃PO4, B = 10% water, 90% methanol, 0.2% H3PO4, RT = 1.87 minutes, 97% homogeneity index; LCMS: Anal. Calcd. for: C44H45N9O4 763.91; Found: 764.52 (M+H)⁺</td>

<td> 120-6</td><td> 1 -methyl-N-((lR)-2-oxol-phenyl-2-((2S)-2-(5-(4(2-((2S)-l-((2R)tetrahydro-2furanylcarbonyl)-2 pyrrolidinyl)-1 H-imidazol4-yl)-4-biphenylyl)-1Himidazol-2-yl)-lpyrrolidinyl)ethyl)-Lprolinamide</td><td> \</td><td> RT = 3.68 (99%); HPLC XTERRA C-18 4.6 x 30 mm, 0 to 100% B over 2 minutes, 1 minute hold time, A = 90% water, 10% methanol, 0.2% H3PO4, B = 10% water, 90% methanol, 0.2% H3PO4, RT = 1.87 minutes, 97% homogeneity index; LCMS: Anal. Calcd. for: C45H50N8O4 766.95; Found: 767.47 (M+H)⁺</td>

<td> 120-7</td><td> N-(( 1 R)-2-oxo-1 -phenyl2-((2S)-2-(5-(4’-(2-((2S)1 -((2R)-tetrahydro-2furanylcarbonyl)-2pyrrolidinyl)-1 H-imidazol-</td><td> o N־=Z</td><td> RT= 3.81 (99%); HPLC XTERRA C-18 4.6 x 30 mm, 0 to 100% B over 2 minutes, 1 minute hold time, A = 90% water, 10% methanol, 0.2%</td>

<td></td><td> 4-yl)-4-bipheny lyl)-1Himidazol-2-yl)-lpyrrolidinyl)ethy 1)-2-(3 pyridinyl)acetamide</td><td></td><td> H3PO4, B = 10% water, 90% methanol, 0.2% H3PO4, RT = 1.87 minutes, 97% homogeneity index; LCMS: Anal. Calcd. for: C46H46N8O4 774.93; Found: 775.47 (M+H)⁺</td>

<td> 120-8</td><td> N²,N²-dimethyl-N-((1R)2-oxo-l -phenyl-2-((2S)-2(5-(4'-(2-((2S)-l-((2R)tetrahydro-2furany Icarbony 1)-2 pyrrolidinyl)-1 H-imidazol4-yl)-4-biphenyly 1)-1Himidazol-2-yl)-lpyrrolidinyl)ethyl)glycina mide</td><td></td><td>¹HNMR (500 MHz, DMSOde) δ ppm 1.71-2.44 (m, 12H), 2.65-2.89 (m, 6H), 3.04-3.21 (m,7=8.55 Hz, IH), 3.46-3.68 (m, 1H),3.644.07 (m, 6H), 4.64 (dd, 7=8.09, 5.34 Hz, IH), 5.095.30 (m, 2H), 5.66-5.86 (m, IH), 7.32-7.49 (m, 4H), 7.828.22 (m, 10H), 9.15-9.38 (m, IH), 9.68 (s, IH), 14.60 (s, 2H); HPLC Xterra 4.6 X 50 mm, 0 to 100% B over 10 minutes, one minute hold time, A = 90% water, 10% methanol, 0.2% phosphoric acid, B = 10% water, 90% methanol, 0.2% phosphoric acid, RT = 3.61 min; LCMS: Anal. Calcd. for: C52H56N₁₀O6 740.91; Found: 741.48 (M+H)⁺.</td>

<td> 120-9</td><td> 1 -((1 R)-2-oxo-1 -phenyl-2 ((2S)-2-(5-(4'-(2-((2S)-l((2R)-tetrahydro-2 furanylcarbonyl)-2 pyrrolidinyl)-1 H-imidazol4-yl)-4-biphenylyl)-1H-</td><td> ^NH ά</td><td>¹H NMR (500 MHz, DMSOde) δ ppm 1.64-2.40 (m, 12H), 3.11-3.27 (m, IH), 3.51-3.65 (m, IH), 3.80 (dd, 7=18.46, 6.87 Hz, 3H), 3.964.11 (m, lH),4.64(dd,</td>

imidazol-2-y 1)-1pyrrolidinyl)ethyl)-3 -(3 pyridinyl)urea

7=7.78, 5.34 Hz, 1H),5.135.23 (m, IH), 5.21-5.35 (m, IH), 5.66 (d, 7=7.02 Hz, IH), 7.29-7.57 (m, 7H), 7.82-8.07 (m, 1 OH), 8.14 (s, IH), 8.22 (d, 7=4.58 Hz, IH), 8.68 (s, IH), 9.32 (s, IH), 14.46 (s, 2H); HPLC Xterra 4.6 X 50 mm, 0 to 100% B over 10 minutes, one minute hold time, A = 90% water, 10% methanol, 0.2% phosphoric acid, B = 10% water, 90% methanol, 0.2% phosphoric acid, RT = 3.83 min; LCMS: Anal. Calcd. for: C45H45N9O4 775.92; Found: 776.53 (M+H)⁺.

Example 121 (lR,l'R)-2,2-((2,2’-dimethyl-4,4'-biphenyldiyl)bis(lH-imidazole-5,2-diyl(2S)-2,lpyrrolidinediyl))bis(N,N-dimethyl-2-oxo-l-phenylethanamine)

<img file="IL196813A_D0161.tif" />

PdC12(Ph₃P)₂ (257 mg, 0.367 mmol) was added to a dioxane (45 mL) solution of l-bromo-4-iodo-2-methylbenzene (3.01 g, 10.13 mmol) and tri-n-butyl(l264 ethoxyvinyl)stannane (3.826 g, 10.59 mmol) and heated at 80 °C for ~17 hours. The reaction mixture was treated with water (15 mL), cooled to ~0 °C (ice/water), and then NBS (1.839 g, 10.3 mmol) was added in batches over 7 minutes. After about 25 minutes of stirring, the volatile component was removed in vacuo, and the residue was partitioned between CH2C12 and water. The aqueous layer was extracted with CH2C12, and the combined organic phase was dried (MgSO₄), filtered, and concentrated in vacuo. The resulting crude material was purified by a gravity chromatography (silica gel; 4% ethyl acetate/hexanes)to provide bromide 121a as a brownish-yellow solid (2.699 g); the sample is impure and contains stannane-derived impurities, among others. ¹H NMR (CDClj, δ = 7.24,400 MHz): 7.83 (s, 1H), 7.63 (s, 2H), 4.30 (s, 2H), 2.46 (s, 3H).

A CH₃CN (15 mL) solution of 121a (2.69 g, < 9.21 mmol) was added dropwise over 3 minutes to a CH₃CN ( 30 mL) solution of (S)-Boc-proline (2.215 g, 10.3 mmol) and triethylamine (1.40 mL, 10.04 mmol), and stirred for 90 minutes. The volatile component was removed in vacuo, and the residue was partitioned between water and CH2C12, and the organic phase was dried (MgSO₄), filtered, and concentrated in vacuo. The resulting crude material was purified by a flash chromatography (silica gel; 15-20% ethyl acetate/hexanes) to provide 121b as a colorless viscous oil (2.74g). ¹H NMR (DMSO-d6, δ = 2.50, 400 MHz): δ 7.98 (m, 1H), 7.78 (d, J = 8.3, 1H), 7.72-7.69 (m, 1H), 5.61-5.41 (m, 2H), 4.35-4.30 (m, 1H), 3.41-3.30 (m, 2H), 2.43 (s, 3H), 2.33-2.08 (m, 2H), 1.93-1.83 (m, 2H), 1.40/1.36 (s, 9H); LC (Cond. 1): RT = 1.91 min; >95% homogeneity index; LC/MS: Anal. Calcd. for [M+Na]⁺ C19H24BrNNaO5 448.07; found 448.10.

Additional keto-esters can be prepared in analogous fashion.

LC conditions: Condition 1: Phenomenex LUNA C-18 4.6 x 50 mm, 0 to 100% B over 3 minutes, 1 minute hold time, A = 90% water, 10% methanol, 0.1% TFA, B = 10% water, 90% methanol, 0.1% TFA, 220nm, 5 pL injection volume.

Condition 2: Phenomenex LUNA C-18 4.6 x 50 mm, 0 to 100% B over 2 minutes, 1 minute hold time, A = 90% water, 10% methanol, 0.1% TFA, B = 10% water, 90% methanol, 0.1% TFA, 220nm, 5 pL injection volume.

<td> Example</td><td> Structure</td><td> Data</td>

<td> 121b-l</td><td> 0 •0</td><td> RT = 2.15 minutes (condition 2, 98%); LRMS:Anal. Calcd. for C17H22NO5 399.07; found: 400.10 (M+H)⁺.</td>

<td> 121b-2</td><td></td><td> RT = 2.78 minutes (condition 1, &gt;90%); LRMS: Anal. Calcd. for C20H₂₀³⁷BrNO5 435.05 found: 458.02 (M+Na)⁺.</td>

Example 121, Step c

<img file="IL196813A_D0162.tif" />

H

N,

N N 121c ^Boc

A mixture ofketoester 121b (1.445 g, 3.39 mmol) andNH4OAc (2.93 g, 38.0 mmol) in xylenes (18 mL) was heated with a microwave at 140 °C for 80 minutes. The volatile component was removed in vacuo, and the residue was carefully partitioned between CH2C12 and water, where enough saturated NaHCO3 solution was added to neutralize the aqueous medium. The aqueous phase was extracted with CH₂C12, and the combined organic phase was dried (MgSO₄), filtered, and concentrated in vacuo. The crude product was purified by a flash chromatography (silica gel, 40% ethyl acetate/hexanes) to provide imidzaole 121c as an off-white solid (1.087 g). ¹H NMR (DMSO-d₆, δ = 2.50, 400 MHz): 12.15/11.91/11.84 (br s, 1H), 7.72-7.24 (m, 4H), 4.78 (m, 1H), 3.52 (m, 1H), 3.38-3.32 (m, 1H), 2.35 (s, 3H), 2.28-1.77 (m, 4H), 1.40/1.14 (s, 9H); LC (Cond. 1): RT = 1.91 min; >98% homogeneity index; LC/MS: Anal. Calcd. for [M+H] C1₉H25BrN3O₂ 405.96, found 406.11.

<img file="IL196813A_D0163.tif" />

PdCl₂dppf-CH₂Cl₂ (50.1 mg, 0.061 mmol) was added to a pressure tube containing a mixture of bromide 121c (538.3 mg, 1.325 mmol), bis(pinacolato)diboron (666.6 mg, 2.625 mmol), potassium acetate (365.8 mg, 3.727 mmol) and DMF (10 mL). The reaction mixture was flushed with N₂ and heated at 80 °C for 24.5 hours. The volatile component was removed in vacuo and the residue was partitioned between CH₂C1₂ and water, where enough saturated NaHCO₃solution was added to make the pH of the aqueous medium neutral. The aqueous phase was extracted with CH₂C1₂, and the combined organic phase was dried (MgSO₄), filtered, and concentrated in vacuo. The resulting material was purfied by a Biotage system (silica gel, 40-50% ethyl acetate/hexanes) to provide boronate 121 d as a white foam (580 mg). According to ¹H NMR the sample contains residual pinacol in a product/pinacol ratio of ~3. ¹H NMR (DMSO-d6, δ = 2.50, 400 MHz): δ 12.16/11.91/11.83 (br s, IH), 7.63-7.25 (m, 4H), 4.78 (m, IH), 3.53 (m, IH), 3.393.32 (m, IH), 2.48/2.47 (s, 3H), 2.28-1.78 (m, 4H), 1.40/1.14/1.12 (br s, 9H), 1.30 (s, 12H); LC (Cond. 1): RT = 1.62 min; LC/MS: Anal. Calcd. for [M+H]⁺C₂₅H₃₇BN₃O4 454.29; found 454.15

Example 121, Step e and

<img file="IL196813A_D0164.tif" />

Carbamate 12 le was prepared from bromide 121c and boronate 121 d according to the preparation of dimer Id; LC (Cond. 1): RT = 1.43 min; LC/MS:

Anal. Calcd. for [M+H]⁺C38H49N6O4 653.38; found 653.65.

The deprotection of carbamate 121 e, according to the preparation of pyrrolidine le, provided 121 f as an off-white foam. ¹H NMR (DMSO-d6, &lt;5 = 2.50, 400 MHz): 11.79 (br s, 2H), 7.66 (s, 2H), 7.57 (d, J = 7.8, 2H), 7.41 (br s, 2H), 7.02 (d, J = 7.8, 2H), 4.15 (app t, J = 7.2, 2H), 3.00-2.94 (m, 2H), 2.88-2.82 (m, 2H), 2.09-2.01 (m, 2H), 2.04 (s, 6H), 1.93-1.85 (m, 2H), 1.82-1.66 (m, 4H). Note: although broad signals corresponding to the pyrrolidine NH appear in the 2.8-3.2 ppm region, the actual range for their chemical shift could not be determined. LC (Cond. 1): RT = 1.03 min; LC/MS: Anal. Calcd. for [M+H]⁺ C28H33N6 453.28; found 453.53

<img file="IL196813A_D0165.tif" />

Example 121 (lR,rR)-2,2'-((2,2'-dimethyl-4,4’-biphenyldiyl)bis(lH-imidazole-5,2-diyl(2S)-2,1pyrrolidinediyl))bis(N,N-dimethyl-2-oxo-l-phenylethanamine)

Example 121 (TFA salt) was synthesized from 12 If according to the preparation of Example 1 from le; LC (Cond. 1): RT = 1.14 min; >98% homogeneity index; LC/MS: Anal. Calcd. for [M+H]⁺ C48H55N8O2 775.45; 775.75; HRMS: Anal. Calcd. for [M+H]⁺ C48H55N8O2 775.4448; found 775.4473

Example 122 dimethyl ((2,2'-dimethyl-4,4'-biphenyldiyl)bis(1 H-imidazole-5,2-diyl(2S)-2,1pyrrolidinediyl((lR)-2-oxo-l-phenyl-2,l-ethanediyl)))biscarbamate

<img file="IL196813A_D0166.tif" />

Example 122 (TFA salt) was prepared from pyrrolidine 121 f and Cap-4 by using the procedure described for the preparation of Example 1 from pyrrolidine le. LC (Cond. 1): RT = 1.35 min; >98% homogeneity index; HRMS: Anal. Calcd. for [M+H]⁺ C48H51N_gO6 835.3932; found 835.3954

<img file="IL196813A_D0167.tif" />

Example 123-125 were prepared starting from boronate 1c and bromide 121c by using the methods described in Example 1, step d, Example 1, step e, and in the step describing the final preparation of Example 1.

<td> Example</td><td> Compound Name</td><td> 0 /\׳־R</td><td> RT (LC-Cond.); % homogeneity index; MS data</td>

<td> 123</td><td> (lR,l'R)-2,2^,2))־-methyl4,4'-biphenyldiyl)bis( 1Himidazole-5,2-diy 1(2 S)2,1- pyrrolidinediyl))bis(N,Ndimethyl-2-oxo-lphenylethanamine)</td><td> 0 Cap-1</td><td> 1.12 minutes (Cond. 1); &gt;98%; LC/MS: Anal. Calcd. for [M+H]⁺ C47H₅₃N₈O₂: 761.43; found 761.49; HRMS: Anal. Calcd. for [M+H]⁺C47H53N8O2: 761.4291; found 761.4311</td>

<td> 124</td><td> dimethyl ((2-methyl-4,4'biphenyldiylbis( 1Himidazole-5,2-diyl(2 S)2,1 -pyrrolidinediyl(( 1R)2-oxo-l-phenyl-2,1ethanediyl)))biscarbamate</td><td> O 0 Cap-4</td><td> 1.34 minutes (Cond. 1); &gt;98%; LC/MS: Anal. Calcd. for [M+H]⁺ C47H49N8O6: 821.38; found 821.45; HRMS: Anal. Calcd. for [M+H]⁺C47H49N8O6: 821.3775; found 821.3785</td>

<td> 125</td><td> (lR,rR)-2,22))-׳-methyl4,4'-biphenyldiyl)bis( 1Himidazole-5,2-diyl(2 S)2,1pyrrolidinediyl))bis(2oxo-1 -phenylethanol)</td><td> 0 OH</td><td> 1.23 minutes (Cond. 1); &gt;98%; LC/MS: Anal. Calcd. for [M+H]⁺ C43H43N6O4: 707.34; found 707.38; HRMS: Anal. Calcd. for [M+H]⁺C43H43N6O4: 707.3346; found 707.3356</td>

Examples 126-128

<img file="IL196813A_D0168.tif" />

Example 126-128 were prepared starting from bromide 28b and boronate

12 Id by using the methods described in Example 28 starting with step c.

<td> Example</td><td> Compound Name</td><td> O R0</td><td> RT (LC-Cond.); % homogeneity index; MS data</td>

<td> 126</td><td> methyl ((1R)-22))־S)2-(5-(4'-(2-((2S)-l((2R)-2(dimethylamino)-2phenylacetyl)-2pyrrolidinyl)-1H-</td><td> O Cap-1</td><td> 1.22min (Cond. 1); &gt;98%; LC/MS: Anal. Calcd. for [M+H]⁺C47H51N8O4: 791.40; found 791.70; HRMS: Anal. Calcd. for [M+H]⁺ C47H51N8O4: 791.4033; found 791.4061</td>

<td></td><td> imidazol-5-yl)-2'methyl-4-biphenylyl)1 H-imidazol-2-yl)-1 pyrrolidinyl)-2-oxo-1 phenylethyl)carbamate</td><td></td><td></td>

<td> 127</td><td> methyl ((lR)-2-((2S)2-(5-(2'-methyl-4'-(2- ((2S)-l-(3pyridinylacetyl)-2pyrrolidinyl)-1Himidazol-5-yl)-4biphenylyl)-1Himidazol-2-yl)-lpyrrolidinyl)-2-oxo-1 phenylethyl)carbamate</td><td> Z—x Z׳ A / °</td><td> 1.19 minutes (Cond. 1); &gt;98%; LC/MS: Anal. Calcd. for [M+H]⁺ C44H45N8O4: 749.36; found 749.62; HRMS: Anal. Calcd. for [M+H]⁺ C44H45N8O4: 749.3564; found 749.3592</td>

<td> 128</td><td> methyl ((1R)-22))־S)־ 2-(5-(2'-methyl-4'-(2((2S)-1-((2S)tetrahydro-2furanylcarbonyl)-2pyrrolidinyl)-1Himidazol-5-yl)-4biphenylyl)-1Himidazol-2-yl)-lpyrrolidinyl)-2-oxo-1 phenylethyl)carbamate</td><td> 0</td><td> 1.27 minutes (Cond. 1); &gt;98%; LC/MS: Anal. Calcd. for [M+H]⁺ C42H46N7O5: 728.36; found 728.59; HRMS: Anal. Calcd. for [M+H]⁺ C₄₂H46N7O₅: 728.3560; found 728.3593</td>

Example 129 methyl ((lR)-2-((2S)-2-(5-(4’-(2-((2S)-l-((2R)-2-(dimethylamino)-2-phenylacetyl)-2pyrrolidinyl)-lH-imidazol-5-yl)-2,2'-dimethyl-4-biphenylyl)-lH-imidazol-2-yl)-lpyrrolidinyl)-2-oxo-l-phenylethyl)carbamate

<img file="IL196813A_D0169.tif" />

HATU (104.3 mg, 0.274 mmol) was added to a mixture of 12 If, Cap-4 (58.8 mg, 0.281 mmol) and diisopropylethylamine (110 pL, 0.631 mmol) in DMF (6.0 ml.), and stirred for 90 minutes. The volatile component was removed in vacuo and the resulting crude material was purified by reverse phase HPLC (H₂O/methanol/TFA), and free-based by MCX column (methanol wash; 2.0 M NH₃/methanol) to provide 129a (89.9 mg). LC (Cond. 1): RT = 1.22 min; 95% homogeneity index; LC/MS: Anal. Calcd. for [M+H]⁺ C₃8H4₂N₇O₃ 644.34; found 644.55.

Example 129 methyl ((lR)-2-((2S)-2-(5-(4'-(2-((2S)-l-((2R)-2-(dimethylamino)-2-phenylacetyl)-2pyrrolidinyl)-lH-imidazol-5-yl)-2,2'-dimethyl-4-biphenylyl)-lH-imidazol-2-yl)-lpyrrolidinyl)-2-oxo-l-phenylethyl)carbamate

<img file="IL196813A_D0170.tif" />

Example 129 (TFA salt) was prepared from 129a by the method used to convert Example le to Example 1. LC (Cond. 1): RT = 1.27 min; 97% homogeneity index; LC/MS: Anal. Calcd. for [M+H]⁺ C48H53N8O4 805.42; found 805.61.

Example 130 (lR,rR)-2,2'-((2-(trifluoromethyl)-4,4'-biphenyldiyl)bis(lH-imidazole-5,2-diyl(2S)-

2, l-pyrrolidinediyl))bis(N,N-dimethyl-2-oxo-l-phenylethanamine)

<img file="IL196813A_D0171.tif" />

Example 130, Step a

Boc 130a

Glyoxal (2.0 mL of 40% in water) was added dropwise over 11 minutes to a methanol solution of NH4OH (32 mL) and (S)-Boc-prolinal (8.564 g, 42.98 mmol) and stirred at ambient temperature for 19 hours. The volatile component was removed in vacuo and the residue was purified by a flash chromatography (silica gel, ethyl acetate) followed by a recrystallization (ethyl acetate, room temperature) to provide imidazole 130a as a white fluffy solid (4.43g). H NMR (DMSO-de, <5 — 2.50,400 MHz): 11.68/11.59 (br s, 1H), 6.94 (s, 1H), 6.76 (s, 1H), 4.76 (m, 1H), 3.48 (m, 1H), 3.35-3.29 (m, 1H), 2.23-1.73 (m, 4H), 1.39/1.15 (s, 9H). LC (Cond. 1): RT = 0.87 min; >95% homogeneity index; LC/MS: Anal. Calcd. for [M+H]

C12H20N3O2 238.16; found 238.22. Imidazole 130ahad an ee of 98.9% when analyzed under chiral HPLC condition noted below.

Column: Chiralpak AD, 10 um, 4.6 x 50 mm

Solvent: 1.7% ethanol/heptane (isocratic)

Flow rate: 1 mL/min

Wavelength: either 220 or 256 nm

Relative retention time: 3.25min (R), 5.78 minutes (S)

Example 130, Step b

<img file="IL196813A_D0172.tif" />

130b

N-Bromosuccinimide (838.4 mg, 4.71 mmol) was added in batches, over 15 minutes, to a cooled (ice/water) CH₂C12 (20 mL) solution of imidazole 130a (1.0689 g, 4.504 mmol), and stirred at similar temperature for 75 minutes. The volatile component was removed in vacuo. The crude material was purified by a reverse phase HPLC system (H₂O/methanol/TFA) to separate bromide 130b from its dibromo-analog and the non-consumed starting material. The HPLC elute was neutralized with excess NH3/methanol and the volatile component was removed in vacuo. The residue was partitioned between CH2C12 and water, and the aqueous layer was extracted with water. The combined organic phase was dried (MgSO₄), filtered, and concentrated in vacuo to provide 130b as a white solid (374 mg). ¹H NMR (DMSO־d6, δ = 2.50,400 MHz): 12.12 (br s, 1H), 7.10 (m, 1H), 4.70 (m, 1H), 3.31 (m, 1H; overlapped with water signal), 2.25-1.73 (m, 4H), 1.39/1.17 (s, 3.8H + 5.2H). LC (Cond. 1): RT = 1.10 min; >95% homogeneity index; LC/MS: Anal. Calcd. for [M+H]⁺ C1₂H1₉BrN3O₂ 316.07; found 316.10.

Example 130, Step c

<img file="IL196813A_D0173.tif" />

130c Boc

Pd(Ph₃P)₄ (78.5 mg, 0.0679 mmol) was added to a mixture of bromide 130b (545 mg, 1.724 mmol), 2-(4-chloro3־-(trifluoromethyl)phenyl-4,4,5,5-tetramethyl1,3,2-dioxaborolane (542.8 mg, 1.771 mmol) (commercially available), NaHCO₃(477 mg, 5.678 mmol) in 1,2-dimethoxyethane (12.5 mL) and water (4.2 mL). The reaction mixture was purged with nitrogen, heated with an oil bath at 80 °C for 27 hours, and then the volatile component was removed in vacuo. The residue was partitioned between CH₂C1₂ and water, and the organic layer was dried (MgSO₄), filtered, and concentrated in vacuo. The resulting crude material was purified by a Biotage system (silica gel, 40-50% ethyl acetate/hexanes) followed by a reverse phase HPLC (water/ methanol/TFA). The HPLC elute was treated with excess NH₃/methanol and concentrated. The residue was partitioned between water and CH₂C1₂, and the organic layer was dried (MgSO₄), filtered, and concentrated in vacuo to provide 130c as a white foam (317.4 mg). ¹H NMR (DMSO-d6, δ = 2.50, 400 MHz): 12.36/12.09/12.03 (br s, IH), 8.15 (d, J= 1.8,0.93H), 8.09 (br s, 0.07H), 8.01 (dd, J = 8.3/1.3, 0.93H), 7.93 (m, 0.07H), 7.74 (m, IH), 7.66 (d, J = 8.3, 0.93H), 7.46 (m, 0Ό7Η), 4.80 (m, IH), 3.53 (m, IH), 3.36 (m, IH), 2.30-1.77 (m, 4h), 1.40/1.15 (s, 3.8H+5.2H). LC (Cond. 1): RT = 1.52 min; >95% homogeneity index; LC/MS: Anal. Calcd. for [M+H]⁺ C!9H₂₂C1F₃N₃O₂416.14; found 416.17.

Example 130, Step d-e

<img file="IL196813A_D0174.tif" />

130e:R = H

Pd[P(z-Bu)₃]₂ (48 mg, 0.094 mmol) was added to a mixture of chloride 130c (245 mg, 0.589 mmol), boronate lc (277.1 mg, 0.631 mmol), KF (106.7 mg, 1.836 mmol) in DMF (6 mL), and heated at 110 °C for ~30 hours. The volatile component was removed in vacuo, and the residue was partitioned between CH2C12 (50 mL), water (20 mL) and saturated NaHCO3 (1 mL). The aquous layer was extracted with CH2C12 (2x), and the combined organic phase was dried (MgSO₄), filtered, and concentrated in vacuo. The resulting material was purified by a Biotage system (silica gel, ethyl acetate) to provide carbamate 130d as an off-white foam (297 mg). LC (Cond. 1): RT = 1.44 min; >95% homogeneity index; LC/MS: Anal. Calcd. for [M+H]⁺ C37H44F3N6O4 693.34; found 693.34.

The deprotection of 130d, which was conducted according to the preparation of pyrrolidine le, provideed 130e as a light yellow foam. ¹H NMR (DMSO-d₆, δ = 2.50,400 MHz): 11.88 (br s, 2H), 8.16 (d, J = 1.5,1H), 8.02 (d, J = 7.8, 1H), 7.78 (d, J= 8.1,2H), 7.66 (br s, 1H), 7.48 (br s, 1H), 7.37 (d, J = 8.1,1H), 7.28 (d, J= 8.3,. 2H), 4.18 (m, 2H), 2.99-2.93 (m, 2H), 2.89-2.83 (m, 2H), 2.11-2.01 (m, 2H), 1.941.85 (m, 2H), 1.82-1.67 (m, 4H). Note: although broad signals corresponding to the pyrrolidine NH appear in the 2.8-3.2 ppm region, the actual range for their chemical shift could not be determined. LC (Cond. 1): RT = 1.12 min; >95% homogeneity index; LC/MS: Anal. Calcd. for [M+H]⁺ C27H28F3N6 493.23; found 493.14.

Example 130 (lR,rR)-2,2'-((2-(trifluoromethyl)-4,4'-biphenyldiyl)bis(lH-imidazole-5,2-diyl(2S)-

2,l-pyrrolidinediyl))bis(N,N-dimethyl-2-oxo-l-phenylethanamine)

<img file="IL196813A_D0175.tif" />

Example 130 (TFA salt) was prepared from 130e and Cap-1 according to the preparation of Example 1 from pyrrolidine le. LC (Cond. 1): RT = 1.17 min; >98% homogeneity index; LC/MS: Anal. Calcd. for [M+H]⁺ C47H50F3N8O2 815.40; found 815.44; HRMS: Anal. Calcd. for [M+H]⁺ C47H50F3N8O2 815.4009; found 815.4013

Example 131

5,5'-(2-(trifluoromethyl)-4,4'-biphenyldiyl)bis(2-((2S)-l-((2R)-2-phenyl-2-(lpyrrolidinyl) acetyl)-2-pyrrolidinyl)-lH-imidazole)

<img file="IL196813A_D0176.tif" />

Example 131 (TFA salt) was synthesized from 130e and Cap-5 according to the preparation of Example 130.

LC (Cond. 1): RT = 1.19 min; >98% homogeneity index

LC/MS: Anal. Calcd. for [M+H]⁺C51H54F3N8O2 867.43; found 867.51

HRMS: Anal. Calcd. for [M+H]⁺ C51H54F3N8O2 867.4322; found 867.4315

<img file="IL196813A_D0177.tif" />

Examples 131.1-1 through 131.1-2 were prepared in similar fashion to example 28 via the intermediacy of intermediate l-6e after appending Cap-4.

Example 131.1-1 methyl ((1 R)-2-(((lS)-l-(5-(4'-(2-((2S)-l-((2R)-2-(dimethylamino)-2-phenylacetyl)-2pyrrolidinyl)-lH-imidazol-5-yl)-4-biphenylyl)-lH-imidazol-2yl)ethyl) (methyl)amino)-2-oxo-l-phenylethyl)carbamate

<img file="IL196813A_D0178.tif" />

Cap-1 was appended after the CBz carbamate was removed from l-6e with

Pd/C/H₂.

LCMS conditions: Phenomenex LUNA C-18 4.6 χ 50 mm, 0 to 100% B over 3 minutes, 1 minute hold time, A = 90% water, 10% methanol, 0.1% TFA, B = 10% water, 90% methanol, 0.1% TFA, 220nm, 5 pL injection volume. t_R = 1.42 min LRMS:Anal. Calcd. for C₄5H49N₈O₄765.39; found: 765.38 (M+H)⁺.

HRMS: Anal. Calcd. for C₄₅H₄9N₈O₄ Calcd 765.3877 found: 765.3905 (M+H)⁺.

Example 131.1-2 methyl ((lR)-2-(methyl((lS)-l-(5-(4'-(2-((2S)-l-((2R)-2-phenyl-2-(lpiperidinyl)acetyl)-2-pyrrolidinyl)-lH-imidazol-5-yl)-4-biphenylyl)-lH-imidazol-2yl)ethyl)amino)-2-oxo-l-phenylethyl)carbamate

<img file="IL196813A_D0179.tif" />

Cap-14 was appended after the CBz carbamate was removed from l-6e with Pd/C/H₂.

LCMS conditions: Phenomenex LUNA C-18 4.6 x 50 mm, 0 to 100% B over 3 minutes, 1 minute hold time, A = 90% water, 10% methanol, 0.1% TFA, B = 10% water, 90% methanol, 0.1% TFA, 220nm, 5 pL injection volume. t_R = 1.45 min (>95 %)

LRMS:Anal. Calcd. for C₄₈H₅₂N₈O₄ 805.42; found: 805.41 (M+H)⁺.

HRMS: Anal. Calcd. C₄₈H₅₂N₈O₄ Calcd 805.4190 found: 805.4214 (M+H)⁺.

Example 131.2 (2R)-2-(dimethylamino)-N-methyl-2-phenyl-N-((lS)-l-(5-(4'-(2-((2S)-l-((2R)-2phenyl-2-(l-piperidinyl)acetyl)-2-pyrrolidinyl)-lH-imidazol-5-yl)-4-biphenylyl)-lHimidazol-2-yl)ethyl)acetamide

<img file="IL196813A_D0180.tif" />

Example 131. 2 was prepared in similar fashion to example 131.1-1 and example 131.1-2 via the intermediacy of intermediate l-6e after appending Cap-1. Cap-14 was appended after the CBz carbamate was removed with Pd/C/H2. LCMS conditions: Phenomenex LUNA C-18 4.6 x 50 mm, 0 to 100% B over 3 minutes, 1 minute hold time, A = 90% water, 10% methanol, 0.1% TFA, B = 10% water, 90% methanol, 0.1% TFA, 220nm, 5 gL injection volume. t_R = 1.28 min LRMS: Anal. Calcd. for C₄8H₅₄N₈O2775.44; found: 775.45 (M+H)⁺. HRMS: Anal. Calcd. C₄8H₅₄N₈O2 Calcd 775.4448 found: 775.4460 (M+H)⁺.

Example 132 (lR)-2-((2S)-2-(5-(6-(4-(2-((2S)-l-((2R)-2-(dimethylamino)-2-phenylacetyl)-2pyrrolidinyl)-lH-imidazol-5-yl)phenyl)-3-pyridinyl)-lH-imidazol-2-yl)-lpyrrolidinyl)-N,N-dimethyl-2-oxo-l-phenylethanamine

<img file="IL196813A_D0181.tif" />

Example 132, Step a-b

<img file="IL196813A_D0182.tif" />

<img file="IL196813A_D0183.tif" />

A CH2C12 (10 mL) solution of Br₂ (7.63 g, 47.74 mmol) was added-drop wise over 5 min to a cooled (ice/water) CH2C12 (105 mL) solution of l-(6-bromopyridine3-yl)ethanone (9.496 g, 47.47 mmol) and 48% HBr (0.4 mL). The cooling bath was removed 40 min later, and stirring was continued at ambient temperature for about 66 hr. The cake of solid that formed was filtered, washed with CH₂C1₂ and dried in vacuo to afford impure 132a as an off-white solid (15.94 g).

Boc-L-proline (9.70 g, 45.06 mmol) was added in one batch to a heterogeneous mixture of crude 132a (15.4 g) and CH3CN (150 mL), and immediately afterward Et₃N (13.0 mL, 93.2 mmol) was added drop-wise over 6 min. The reaction mixture was stirred for 50 min, the volatile component was removed in vacuo and the residue was partitioned between CH2C12 and water. The CH2C12 layer was dried (MgSO₄), filtered and concentrated in vacuo, and the resultant material was purified by flash chromatography (silica gel; sample was loaded with eluting solvent; 25% EtOAc/hexanes) to afford 132b as a highly viscous yellow oil (11.44g). ¹H NMR (DMSO, δ = 2.5 ppm; 400 MHz): 8.95 (m, 1H), 8.25-8.21 (m, 1H), 7.88 (d, J = 8.3, 1H), 5.655.46־ (m, 2H), 4.36-4.31 (m, 1H), 3.413.29־ (m, 2H), 2.36-2.22 (m, 1H), 2.14-2.07 (m, 1H), 1.93-1.83 (m, 2H), 1.40 & 1.36 (two s, 9H). LC (Cond. 1): RT = 2.01 min; >90% homogeneity index LC/MS: Anal. Calcd. for [M+Na]⁺ C!7H21NaBrN2O5: 435.05; found 435.15 HRMS: Anal. Calcd. for [M+H]⁺ C!7H22BrN₂O5: 413.0712; found 413.0717

Example 132, Step c

<img file="IL196813A_D0184.tif" />

132c Boc

A mixture of ketoester 132b (1.318 g, 3.19 mmol) and NH4OAc (2.729 g, 35.4 mmol) in xylenes (18 mL) was heated with a microwave at 140 °C for 90 min. The volatile component was removed in vacuo and the residue was partitioned between CH₂C12 and water, where enough saturated NaHCO₃ solution was added to neutralize the aqueous medium. The aqueous phase was extracted with CH₂C1₂, and the combined organic phase was dried (MgSO₄), filtered, and concentrated in vacuo. The resulting crude material was purified by a Biotage system (silica gel; 50%

EtOAc/hexanes) to afford imidzaole 132c as an off-white foam (1.025 g). ¹H NMR (DMSO, δ = 2.5 ppm, 400 MHz): 12.33/12.09/12.02 (br m, IH), 8.74 (d, J = 2.3,

0.93H), 8.70 (app br s, 0.07H), 8.03/7.98 (dd for the first peak, J = 8.3, IH),

7.69/7.67 (br m, IH), 7.58/7.43 (d for the first peak, J = 8.3, IH), 4.80 (m, IH), 3.53 (m, IH), 3.36 (m, IH), 2.33-2.11 (m, IH), 2.04-1.79 (m, 3H), 1.39/1.15 (app brs,

3.9H+5.1H).

LC (Cond.l): RT = 1.52 min; >98% homogeneity index

LC/MS: Anal. Calcd. for [M+H]⁺C17H22BrN4O2: 393.09; found 393.19 HRMS: Anal. Calcd. for [M+H]⁺ C17H22BrN4O₂: 393.0926; found 393.0909

Example 132, Step d-e

N

N I R

H

I 1 '

'N

H

R

N

132d: R = Boc 132e:R = H

132d: R = Boc 132e:R = H

Pd(Ph₃P)₄ (115.1 mg, 0.10 mmol) was added to a mixture of bromide 132c (992mg, 2.52 mmol), boronate 1c (1.207 g, 2.747 mmol), NaHCO₃ (698.8 mg, 8.318 15 mmol) in 1,2-dimethoxyethane (18 mL) and water (4 mL). The reaction mixture was flushed with nitrogen, heated with an oil bath at 90 °C for 37 hr and allowed to cool to ambient temperature. The suspension that formed was filtered and washed with water followed by 1,2-dimethoxyethane, and dried in vacuo. A silica gel mesh was prepared from the crude solid and submitted to flash chromatography (silica gel; 20 EtOAc) to afford carbamate 132d as a white solid, which yellowed slightly upon standing at ambient conditions (1.124g). ¹H NMR indicated that the sample contains residual MeOH in a product/MeOH mole ratio of 1.3.

LC (Cond. 1): RT = 1.71 min; >98% homogeneity index

LC/MS: Anal. Calcd. for [M+H]⁺ C₃5H44N7O4: 626.35; found 626.64

HRMS: Anal. Calcd. for [M+H]⁺ C35H44N7O4: 626.3455; 626.3479

Carbamate 132d (217 mg) was treated with 25% TFA/CH2C12 (3.6 mL) and stirred at ambient condition for 6 hr. The volatile component was removed in vacuo, and the resultant material was free based by MCX column (MeOH wash; 2.0 M NH₃/MeOH elution) to afford 132e as a dull yellow foam that solidified gradually upon standing (150.5 mg; mass is above theoretical yield). ¹H NMR (DMSO, δ = 2.5 ppm; 400 MHz): 11.89 (very broad, 2H), 9.01 (d, J = 1.8, 1H), 8.13 (dd, J= 8.3, 2.2, 1H), 8.07 (d, J = 8.6, 2H), 7.92 (d, J = 8.3, 1H), 7.83 (d, J = 8.5, 2H), 7.61 (br s, 1H), 7.50 (br s, 1H), 4.18 (m, 2H), 3.00-2.93 (m, 2H), 2.90-2.82 (m, 2H), 2.11-2.02 (m, 2H), 1.94-1.85 (m, 2H), 1.83-1.67 (m, 4H). [Note: the exchangeable pyrrolidine hydrogens were not observed]

LC (Cond. 1): RT = 1.21 min; >98% homogeneity index

LC/MS: Anal. Calcd. for [M+H]⁺ C25H28N7: 426.24; found 426.40 HRMS: Anal. Calcd. for [M+H]⁺ C25H₂₈N₇: 426.2406; found 426.2425

Example 132 (lR)-2-((2S)-2-(5-(6-(4-(2-((2S)-l-((2R)-2-(dimethylamino)-2-phenylacetyl)-2pyrrolidinyl)-lH-imidazol-5-yl)phenyl)-3-pyridinyl)-lH-imidazol-2-yl)-lpyrrolidiny I)-N,N-dimethyl-2-oxo-l-phenylethanamine

<img file="IL196813A_D0185.tif" />

HATU (41.4 mg, 0.109 mmol) was added to a mixture of pyrrolidine 132e (23.1 mg, 0.054 mmol), (z-Pr)2EtN (40 pL, 0.23 mmol) and Cap-1 (25.3 mg, 0.117 mmol) in DMF (1.5 mL), and the mixture was stirred at ambient for 1 hr. The volatile component was removed in vacuo, and the residue was purified first by MCX (MeOH wash; 2.0 M NH₃/MeOH elution) and then by a reverse phase HPLC (H₂O/MeOH/TFA) to afford the TFA salt of Example 132 as a yellow foam (39.2 mg).

LC (Cond. 1): RT = 1.37min; >98% homogeneity index LC/MS: Anal. Calcd. for [M+H]⁺ C45H50N9O2: 748.41; found 748.53 HRMS: Anal. Calcd. for [M+H]⁺ C45H50N9O2: 748.4087; found 748.4090

Example 133-135 were prepared as TFA salts from 132e by using the same method of preparations as Example 132 and appropriate reagents.

Example 133-135

<img file="IL196813A_D0186.tif" />

<td> Example</td><td> Compound Name</td><td> O R^V</td><td> RT (LC-Cond.); % homogeneity index; MS data</td>

<td> 133</td><td> (lR)-2-((2S)-2-(5-(6-(4-(2((2S)-l-((2R)-2-hydroxy-2phenylacetyl)-2-pyrrolidinyl)- 1 H-imidazol-5 -yl)phenyl)-3pyridinyl)-! H-imidazol-2-yl)1 -pyrrolidinyl)-2-oxo-l phenylethanol</td><td> 0 H0</td><td> 1.49 min (Cond. 1); &gt;98% LC/MS: Anal. Calcd. for [M+H]⁺ C41H40N7O4: 694.31; found 694.42 HRMS: Anal. Calcd. for [M+H]⁺ C41H40N7O4: 694.3142, found: 694.3164</td>

<td> 134</td><td> methyl ((lR)-2-((2S)-2-(5-(6(4-(2-((2S)-l-((2R)-2((methoxycarbonyl)amino)-2phenylacetyl)-2-pyrrolidinyl)1 H-imidazol-5-yl)phenyl)-3pyridinyl)-l H-imidazol-2-yl)1-pyrrolidinyl)-2-oxo-1 ־ phenylethyl)carbamate</td><td> 0 PhxQty HN^O_X0 Cap-4 .</td><td> 1.60 min (Cond. 1); &gt;98% LC/MS: Anal. Calcd. for [M+H]⁺ C45H46N9O6: 808.36; found 808.51 HRMS: Anal. Calcd. for [M+H]⁺ C45H46N9O6: 808.3571; found 808.3576</td>

<td> 135</td><td> 5-(2-((2S)-l-((2R)-2methoxy-2-phenylacetyl)-2pyrrolidinyl)-1 H-imidazol-5 yl)-2-(4-(2-((2S)-l-((2R)-2methoxy-2-phenylacetyl)-2pyrrolidinyl)-1 H-imidazol-5 yl)phenyl)pyridine</td><td> O ^phQ</td><td> 1.60 min (Cond. 1); &gt;98% LC/MS: Anal. Calcd. for [M+H]⁺ C43H44N7O4: 722.35; found 722.40 HRMS: Anal. Calcd. for [M+H]⁺ C43H44N7O4: 722.3455; found 722.3464</td>

Example 136 (lR)-2-((2S)-2-(5-(6-(4-(2-((2S)-l-((2R)-2-(dimethylamino)-2-phenylacetyl)-2pyrrolidinyl)-lH-imidazol-5-yl)-2-methylphenyl)-3-pyridinyl)-lH-imidazol-2-yl)-lpyrrolidinyl)-N,N-dimethyl-2-oxo-l-phenylethanamine

<img file="IL196813A_D0187.tif" />

PdCl₂(Ph₃P)2 (257 mg, 0.367 mmol) was added to a dioxane (45 mL) solution of l-bromo-4-iodo-2-methylbenzene (3.01 g, 10.13 mmol) and tri-«-butyl(lethoxyvinyl)stannane (3.826 g, 10.59 mmol) and heated at 80 °C for ~17 hr. The reaction mixture was treated with water (15 mL), cooled to ~0 °C (ice/water), and then NBS (1.839 g, 10.3 mmol) was added in batches over 7 min. About 25 min of stirring, the volatile component was removed in vacuo, and the residue was partitioned between CH₂C1₂ and water. The aqueous layer was extracted with CH2C12, and the combined organic phase was dried (MgSO4), filtered, and concentrated in vacuo. The resulting crude material was purified by a gravity chromatography (silica gel; 4% EtOAc/hexanes)to afford bromide 136a as a brownish-yellow solid (2.699 g); the sample is impure and contains stannane-derived impurities, among others. ¹H NMR (CDC1₃, δ = 7.24,400 MHz): 7.83 (s, IH), 7.63 (s, 2H), 4.30 (s, 2H), 2.46 (s, 3H).

An CH₃CN (15 mL) solution of 136a (2.69 g, &lt; 9.21 mmol) was added drop wise over 3 min to a CH₃CN (30 mL) solution of (S)-Boc-proline (2.215 g, 10.3 mmol) and Et₃N (1.40 mL, 10.04 mmol), and stirred for 90 min. The volatile component was removed in vacuo, and the residue was partitioned between water and CH2C12, and the organic phase was dried (MgSO₄), filtered, and concentrated in vacuo. The resultant crude material was purified by a flash chromatography (silica gel; 15-20% EtOAc/hexanes) to afford 136b as a colorless viscous oil (2.74g). ¹H

NMR (DMSO-d6, δ = 2.50, 400 MHz): 7.98 (m, IH), 7.78 (d, J = 8.3, IH), 7.72-7.69 (m, IH), 5.61-5.41 (m, 2H), 4.35-4.30 (m, IH), 3.41-3.30 (m, 2H), 2.43 (s, 3H), 2.332.08 (m, 2H), 1.93-1.83 (m, 2H), 1.40/1.36 (s, 9H).

LC (Cond. 1): RT = 1.91 min; >95% homogeneity index

LC/MS: Anal. Calcd. for [M+Na]⁺ C!9H₂4BrNNaO5 448.07; found 448.10

Example 136, Step c

<img file="IL196813A_D0188.tif" />

A mixture of ketoester 136b (1.445 g, 3.39 mmol) andNH4OAc (2.93 g, 38.0 mmol) in xylenes (18 mL) was heated with a microwave at 140 °C for 80 min. The volatile component was removed in vacuo, and the residue was carefully partitioned between CH₂C1₂ and water, where enough saturated NaHCO3 solution was added to neutralize the aqueous medium. The aqueous phase was extracted with CH₂C1₂, and the combined organic phase was dried (MgSO4), filtered, and concentrated in vacuo. The crude was purified by a flash chromatography (silica gel, 40% EtOAc/hexanes) to afford imidzaole 136c as an off-white solid (1.087 g). ¹H NMR (DMSO-d6, <5 = 2.50, 400 MHz): 12.15/11.91/11.84 (brs, IH), 7.72-7.24 (m, 4H), 4.78 (m, IH), 3.52 (m, IH), 3.38-3.32 (m, IH), 2.35 (s, 3H), 2.28-1.77 (m, 4H), 1.40/1,14 (s, 9H). LC (Cond. 1): RT = 1.91 min; >98% homogeneity index LC/MS: Anal. Calcd. for [M+H]⁺ C19H₂₅BrN3O2 405.96; found 406.11

<img file="IL196813A_D0189.tif" />

PdC12dppf.CH₂Cl₂ (50.1 mg, 0.061 mmol) was added to a pressure tube containing a mixture of bromide 136c (538.3 mg, 1.325 mmol), bis(pinacolato)diboron (666.6 mg, 2.625 mmol), KOAc (365.8 mg, 3.727 mmol) and DMF (10 mL). The reaction mixture was flushed with N2 and heated at 80 °C for 24.5 hr. The volatile component was removed in vacuo and the residue was partitioned between CH2C12 and water, where enough saturated NaHCO₃ solution was added to make the pH of the aqueous medium neutral. The aqueous phase was extracted with CH₂C12, and the combined organic phase was dried (MgSO₄), filtered, and concentrated in vacuo. The resulting material was purfied by a Biotage system (silica gel, 40-50% EtOAc/hexanes) to afford boronate 136d as a white foam (580 mg). According to ¹H NMR the sample contains residual pinacol in a product/pinacol ratio of ~3. ¹H NMR (DMSO-d6, δ = 2.50, 400 MHz):

12.16/11.91/11.83 (br s, 1H), 7.63-7.25 (m, 4H), 4.78 (m, 1Ή), 3,53 (m, 1H), 3.393.32 (m, 1H), 2.48/2.47 (s, 3H), 2.28-1.78 (m, 4H), 1.40/1.14/1.12 (br s, 9H), 1.30 (s, 12H).

LC (Cond. 1):RT = 1.62 min LC/MS: Anal. Calcd. for [M+H]⁺ C25H₃₇BN₃O₄ 454.29; found 454.15

<img file="IL196813A_D0190.tif" />

Biaryl 136e was prepared from bromide 132c and boronate 136d according to the coupling condition described for the preparation of biaryl 132d.

LC(Cond. la):RT= 1.32 min; >90% homogeneity index

LC/MS: Anal. Calcd. for [M+H]⁺ C₃6H45N7O₄ 640.36; found 640.66

The deprotection of biaryl 136e was done according to the preparation of pyrrolidine 132e to afford 136f as a light yellow foam. ¹H NMR (DMSO-d6, δ = 2.50,400 MHz): 11.88 (br s, 2H), 9.02 (d, J = 2,1H), 8.12 (dd, J = 8.4, 2.3, 1H), 7.67 (s, 1H), 7.64-7.62 (m, 2H), 7.50 (d, J= 8.3,1H), 7.46 (br s, 1H), 7.40 (d, J= 7.8,1H), 4.214.14 (m, 2H), 3.00-2.93 (m, 2H), 2.90-2.82 (m, 2H), 2.40 (s, 3H), 2.11-2.01 (m, 2H), 1.94-1.85 (m, 2H), 1.82-1.66 (m, 4H). [Note: the signal for the pyrrolidine NH appears in the region 3.22-2.80 and is too broad to make a chemical shift assignment.]

LC (Cond. 1): RT = 0.84 min

LC/MS: Anal. Calcd. for [M+H]⁺ C26H30N7 440.26; found 440.50

Example 136 (lR)-2-((2S)-2-(5-(6-(4-(2-((2S)-l-((2R)-2-(dimethylamino)-2-phenylacetyl)-2pyrrolidinyl)-lH-imidazol-5-yl)-2-methylphenyl)-3-pyridinyl)-lH-imidazol-2-yl)-lpyrrolidinyl)-N,N-dimethyl-2-oxo-l-phenylethanamine

<img file="IL196813A_D0191.tif" />

Example 136 (TFA salt) was synthesized from 136f according to the preparation of Example 132 from 132e.

1.05 min (Cond.l); >98%

LC/MS: Anal. Calcd. for [M+H]⁺ C46H52N9O2: 762.42, found: 762.77

HRMS: Anal. Calcd. for [M+H]⁺ C46H52N9O2: 762.4244; found 762.4243

Example 138 methyl ((lR)-2-((2S)-2-(5-(6-(4-(2-((2S)-l-((2R)-2-((methoxycarbonyl)amino)-2phenylacetyl)-2-pyrrolidinyl)-lH-imidazol-5-yl)-2-methylphenyl)-3-pyridinyl)-lHimidazol-2-yl)-l-pyrrolidinyl)-2-oxo-l-phenylethyl)carbamate

<img file="IL196813A_D0192.tif" />

Example 138 was prepared similarly from pyrrolidine 136f and Cap-4.

1.60 min (Cond. 1); >98%

LC/MS: Anal. Calcd. for [M+H]⁺ C46H48N9O6: 822.37; found 822.74

HRMS: Anal. Calcd. for [M+H]⁺ C46H48N9O6: 822.3728; found 822.3760

Example 139

N-((lR)-2-((2S)-2-(5-(6-(4-(2-((2S)-l-((2R)-2-acetamido-2-phenylacetyl)-2pyrrolidinyl)-lH-imidazol-5-yl)phenyl)-3-pyridinyl)-lH-imidazol-2-yl)-lpyrrolidinyl)-2-oxo-1-phenylethyl) acetamide

<img file="IL196813A_D0193.tif" />

Example 139, Step a

<img file="IL196813A_D0194.tif" />

HATU (99.8 mg, 0.262 mmol) was added to a mixture of 132e (54.1 mg, 0.127 mmol), (R)-2-(i-butoxycarbonylamino)-2-phenylacetic acid (98.5 mg, 0.392 mmol) and z-Pr₂EtN (100 pL, 0.574 mol), and the reaction mixture was stirred for 70 min The volatile component was removed in vacuo, and the residue was purified by a reverse phase HPLC (H₂O/MeOH/TFA), where the HPLC elute was treated with excess 2.0 N NH₃/MeOH before the removal of the volatile component in vacuo. The resulting material was partitioned between CH₂C1₂ and water, and the aqueous phase was extracted with CH₂C1₂ (2x). The combined organic phase was dried (MgSO4), filtered, and concentrated in vacuo. Carbamate 139a was obtained as a white film of foam (82.3 mg).

LC (Cond. 1): RT = 1.97 min; >95% homogeneity index. LC/MS: Anal. Calcd. for [M+H]⁺ C51H58N9O6: 892.45; found 892.72

Example 139b, Step b

<img file="IL196813A_D0195.tif" />

139b

Carbamate 139a was deprotected to amine 139b by using the procedure described for the preparation of pyrrolidine 132e from 13 2d.

LC (Cond. 1): RT = 1.37 min; >95% homogeneity index

LC/MS: Anal. Calcd. for [M+H]⁺ C₄1H4₂N₉O₂: 692.35; found 692.32

Example 139

N-((lR)-2-((2S)-2-(5-(6-(4-(2-((2S)-l-((2R)-2-acetamido-2-phenylacetyl)-2pyrrolidinyl)-lH-imidazol-5-yl)phenyl)-3-pyridinyl)-lH-imidazol-2-yl)-lpyrrolidinyl) -2-oxo-1-phenylethyl) acetamide

O:

Acetic anhydride (20 pL, 0.212 mmol) was added to a DMF (1.5 mL) solution of 139b (31.2 mg, 0.045 mmol), and the reaction mixture was stirred for 1 hr. NH₃/MeOH (1.0 mL of 2N) was added to the reaction mixture and stirring continued for 100 min. The volatile component was removed in vacuo and the resulting crude material was purified by a reverse phase HPLC (H₂O/MeOH/TFA) to afford the TFA salt of Example 139 as a light yellow solid (24.1 mg). LC (Cond. 1): RT = 1.53 min; >98% homogeneity index LC/MS: Anal. Calcd. for [M+H]⁺ C45H46N9O4: 776.37; found 776.38 HRMS: Anal. Calcd. for [M+H]⁺ C45H46N9O4: 776.3673; found 776.3680

Example 140 methyl ((lR)-2-((2S)-2-(5-(4-(5-(2-((2S)-l-((2R)-2-(dimethylamino)-2-phenylacetyl)2-pyrrolidinyl)-lH-imidazol-5-yl)-2-pyridinyl)phenyl)-lH-imidazol-2-yl)-l pyrrolidinyl)-2-oxo-l-phenylethyl)carbamate ,Ph

Example 140, Step a

140a

HATU (19.868g, 52.25 mmol) was added to a heterogeneous mixture of /V-Cbz-Lproline (12.436 g, 49.89 mmol) and the HCI salt of 2-amino-l-(4־bromophenyl) ethanone (12.157 g, 48.53 mmol) in DMF (156 mL). The mixture was lowered in an ice-water bath, and immediately afterward N, A-diisopropylethylamine (27 mL, 155 mmol) was added drop wise to it over 13 min. After the addition of the base was completed, the cooling bath was removed and the reaction mixture was stirred for an additional 50 min. The volatile component was removed in vacuo׳, water (125 mL) was added to the resultant crude solid and stirred for about 1 hr. The off-white solid was filtered and washed with copious water, and dried in vacuo to afford ketoamide 140a as a white solid (20.68 g). ^lH NMR (DMSO-d₆, δ= 2.5 ppm, 400 MHz): 8.30 (m, 1H), 7.91 (m, 2H), 7.75 (d,7 = 8.5, 2H), 7.38-7.25 (m, 5H), 5.11-5.03 (m, 2H), 4.57-4.48 (m, 2H), 4.334.26־ (m, 1H), 3.53-3.36 (m, 2H), 2.23-2.05 (m, 1H), 1.941.78 (m, 3H).

LC (Cond. 1): RT = 1.65 min; 98% homogeneity index

LC/MS: Anal. Calcd. for [M+H]⁺ C21H₂₂BrN₂O4: 445.08; found 445.31

Example 140, Step b

<img file="IL196813A_D0196.tif" />

14UD ubz

Ketoamide 140a (10.723g, 24.08 mmol) was converted to 140b according to the procedure described for the synthesis of carbamate 132c, with the exception that the crude material was purified by flash chromatography (silica gel; 50% EtOAc/hexanes). Bromide 140b was retrieved as an off-white foam (7.622 g). ¹H NMR (DMSO-d₆, δ= 2.5 ppm, 400 MHz): 12.23/12.04/11.97 (m, 1H), 7.73-6.96 (m, 10H), 5.11-4.85 (m, 3H), 3.61 (m, 1H), 3.45 (m, 1H), 2.33-184(m, 4H).

LC (Cond.l): RT = 1.42 min; >95% homogeneity index

LC/MS: Anal. Calcd. for [M+H]⁺C₂1H₂!BrN₃O₂: 426.08; found 426.31

HRMS: Anal. Calcd. for [M+H]⁺C₂1H₂!BrN₃O₂: 426.0817; found: 426.0829

The optical purity of 140b was assessed using the following chiral HPLC methods, and an ee of 99% was observed.

Column: Chiralpak AD, 10 um, 4.6 x 50 mm

Solvent: 20% ethanol/heptane (isocratic)

Flow rate: 1 ml/min

Wavelength: 254 nm

Relative retention time: 1.82 min (R), 5.23 min (S)

Example 140, Step c

H N.

140c Cbz

Pd(Ph₃P)₄ (208 mg, 0.180 mmol) was added to a pressure tube containing a mixture of bromide 140b (1.80 g, 4.22 mmol), bis(pinacolato)diboron (2.146 g, 8.45 mmol), KOAc (1.8 g, 11.0 mmol) and 1,4-dioxane (34 mL). The reaction flask was purged with nitrogen, capped and heated with an oil bath at 80 °C for 23 hr. The volatile component was removed in vacuo, and the residue was partitioned carefully between CH₂C1₂ (70 mL) and an aqueous medium (22 mL water + 5 mL saturated NaHCO₃ solution). The aqueous layer was extracted with CH₂C1₂, and the combined organic phase was dried (MgSO₄), filtered, and concentrated in vacuo. The oily resdue was crystallized from EtOAc/hexanes to afford two crops of boronate 140c as a yellow solid (1.52 g). The mother liquor was evaporated in vacuo and the resulting material was purified by flash chromatography (silica gel; 20-35% EtOAc/CH₂Cl₂) to afford additional 140c as an off-white solid, containing residual pinacol (772 mg). LC(Cond. 1):RT= 1.95 min LC/MS: Anal. Calcd. for [M+H]⁺ C₂₇H₃₃BN₃O₄: 474.26; found 474.31

Example 140, Step d-e

<img file="IL196813A_D0197.tif" />

140e: R = H

Arylbromide 132c was coupled with boronate 140c to afford 140d by using the same procedure described for the synthesis of biaryl 132d. The sample contains the desbromo version of 132c as an impurity. Proceeded to the next step without further purification.

LC (Cond. 1): RT = 1.72 min; -85% homogeneity index

LC/MS: Anal. Calcd. for [M+H]⁺ C38H42N7O4: 660.33; found 660.30

A mixture of 10% Pd/C (226 mg), biaryl 140d (1.25 g) and MeOH (15 mL) was stirred under a balloon of hydrogen for -160 hr, where the hydrogen supply was replenished periodically as needed. The reaction mixture was filtered through a pad of diatomaceous earth (Celite ), and the filtrate was evaporated in vacuo to afford crude 140e as a yellowish-brown foam (911 mg). Proceeded to the next step without further purification.

LC(Cond. 1):RT= 1.53 min

LC/MS: Anal. Calcd. for [M+H]⁺ C30H36N7O2: 526.29; found 526.23

Example 140, Step f-g o^z

<img file="IL196813A_D0198.tif" />

140g: R = H

Pyrrolidine 140g was prepared from 140e and Cap-4, via the intermediacy of carbamate 140f, by sequentially employing the amide forming and Boc-deprotection protocols used in the synthesis of Example 132.

LC (Cond. 1): RT = 1.09 min; -94% homogeneity index

LC/MS: Anal. Calcd. for [M+H]⁺C35H37N8O3: 617.30; found 617.38

Example 140 methyl ((lR)-2-((2S)-2-(5-(4-(5-(2-((2S)-l-((2R)-2-(dimethylamino)-2-phenylacetyl)2-pyrrolidinyl)-lH-imidazol-5-yl)-2-pyridinyl)phenyl)-lH-imidazol-2-yl)-lpyrrolidinyl)-2-oxo-l-phenylethyl)carbamate o^z

<img file="IL196813A_D0199.tif" />

The TFA salt of Example 140 was synthesized from pyrrolidine 140g and Cap-\ by using the procedure described for the preparation of Example 132 from intermediate 132e.

1.15 min (Cond. 1); >98% homogeneity index

LC/MS: Anal. Calcd. for [M+H]⁺ C45H40N7O4: 778.38; found 778.48

HRMS: Anal. Calcd. for [M+H]⁺ C45H40N7O4: 778.3829; found 778.3849

The TFA salt of Example 141-143 were synthesized from intermediate 140g and appropriate reagents in a similar manner.

Example 141-143 o^z /=0

HN ״ Hl?

&lt; ב H

<td> Example</td><td> Compound Name</td><td> O A/</td><td> RT (LC-Cond); % homogeneity index; MS data</td>

<td> 141</td><td> methyl ((lR)-2-oxo-lphenyl-2-((2S)-2-(5-(4-(5(2-((2S)-l -((2R)-tetrahydro-</td><td> 0</td><td> 1.15 min (Cond. 1); &gt;98% LC/MS: Anal. Calcd. for</td>

<td></td><td> 2-furanylcarbonyl)-2pyrrolidinyl)-1 H-imidazol5 -yl)-2-pyridiny !)phenyl)1 H-imidazol-2-yl)-1 pyrrolidinyl)ethyl)carbamate</td><td> —</td><td> [M+H]⁺C40H4₃N_gO₅: 715.34; found 715.44 HRMS: Anal. Calcd. for [M+H]⁺C40H43N₈O₅: 715.3356; found 715.3381</td>

<td> 142</td><td> methyl ((lR)-2-((2S)-2-(5(4-(5-(2-((2 S)-1-((1-methyl4-piperidinyl)carbonyl)-2pyrrolidinyl)-1 H-imidazol5 -yl)-2-pyridiny l)phenyl)1 H-imidazol-2-yl)-1 pyrrolidiny l)-2-oxo-1 phenylethyl)carbamate</td><td> 0</td><td> 1.07 min (Cond. 1); &gt;98% LC/MS: Anal. Calcd. for [M+H]⁺C42H4₈N₉O4: 742.38; found 742.48 HRMS: Anal. Calcd. for [M+H]⁺ C42H48N9O4: 742.3829; found 742.3859</td>

<td> 143</td><td> methyl ((1R)2־-oxo-1phenyl-2-((2S)-2-(5-(4-(5(2-((2S)-l-(3pyridinylacetyl)-2pyrrolidinyl)-1 H-imidazol5 -yl)-2-pyridinyl)phenyl)1 H-imidazol-2-yl)-1 pyrrolidinyl)ethyl)carbamate</td><td> Z—Λ // V) / ^O</td><td> 1.09 min (Cond. 1); &gt;98% LC/MS: Anal. Calcd. for [M+H]⁺ C42H42N9O4: 736.34; found 736.44 HRMS: Anal. Calcd. for [M+H]⁺C42H42N₉O4: 736.3360; 736.3344</td>

Example 144 methyl ((lR)-2-((2S)-2-(5-(4-(5-(2-((2S)-l-(4-morpholinylcarbonyl)-2-pyrrolidinyl)lH-imidazol-5-yl)-2-pyridinyl)phenyl)-lH-imidazol-2-yl)-l-pyrrolidinyl)-2-oxo-l5 phenylethyl) carbamate o^z

<img file="IL196813A_D0200.tif" />

A DMF (1.5 mL) solution of moipholine-4-carbonyl chloride (8.5 mg, 0.057 mmol) was added to a mixture of z-Pr₂EtN (20 pL, 0.115 mmol) and 140g (27.3 mg,

0.044 mmol), and stirred for 100 min. The volatile component was removed in vacuo and the residue was purified by a reverse phase HPLC (H2O/MeOH/TFA) to afford the TFA salt of Example 144 as a yellow foam (34.6 mg).

1.17 min (Cond. 1); >98%

LC/MS: Anal. Calcd. for [M+H]⁺ C40H44N9O5: 730.35; found 730.42 HRMS: Anal. Calcd. for [M+H]⁺ C40H44N9O5: 730.3465; found 730.3477

Example 145 dimethyl (2,2 '-bipyridine-5,5 ’-diylbis(lH-imidazole-5,2-diyl(2S) -2,1 pyrrolidinediyl((lR)-2-oxo-l-phenyl-2, l-ethanediyl)))biscarbamate o^z

<img file="IL196813A_D0201.tif" />

/°

Example 145, Step a-b

<img file="IL196813A_D0202.tif" />

X__~ 145a: R = Boc

145b: R = H

Pd(Ph₃P)₄ (9.6 mg, 0.008 mmol) and LiCl (28 mg, 0.67 mmol) were added to a mixture of arylbromide 132c (98.7 mg, 0.251 mmol) and hexamethylditin (51.6 mg, 0.158 mmol), and heated at 80 °C for ~ 3 days. The volatile component was removed in vacuo and the resultant crude material was purified by flash chromatography (silica gel; 0-10% MeOH/EtOAc) followed by a reverse phase HPLC (H₂O/MeOH/TFA). The HPLC elute was neutralized with excess 2.0 N NH3/MeOH, and the volatile component was removed in vacuo. The residue was partitioned between CH₂C1₂ and water, and the aqueous phase was washed with CH₂C1₂ (2x).

The combined organic phase was dried (MgSO4), filtered, and concentrated in vacuo to afford carbamate 145a as a film of oil (8.7 mg).

LC (Cond. 1): RT = 1.68 min; >98% homogeneity index

LC/MS: Anal. Calcd. for [M+H]⁺ C34H43N₈O₄: 627.34; found 627.47

Carbamate 145a was elaborated to pyrrolidine 145b according to the preparation of 132e from 132d. ¹H NMR (DMSO, δ = 2.5 ppm; 400 MHz): 12.02 (br signal, 2H), 9.04 (d, J = 1.6, 2H), 8.34 (d, J = 8.3, 2H), 8.20 (dd, J = 8.3, 2.3, 2H), 7.67 (br s, 1H), 4.21 (m, 2H), 3.00-2.85 (m, 4H), 2.12-2.04 (m, 2H), 1.95-1.68 (m, 6H). [Note: the pyrrolidine-NH signal was not observed].

LC (Cond.l): RT = 1.17 min; >98% homogeneity index

LC/MS: Anal. Calcd. for [M+H]⁺C24H₂7N₈: 427.24; found 427.13

Example 145 dimethyl (2,2'-bipyridine-5,5'-diylbis(lH-imidazole-5,2-diyl(2S)-2,lpyrrolidinediyl((1R) -2-oxo- 1-pheny 1-2,1 -ethanediyl))) biscarbamate o^z

<img file="IL196813A_D0203.tif" />

/°

Example 145 (TFA salt) was synthesized from 145b according to the preparation of Example 132 from 132e.

LC (Cond. 1): RT = 1.63 min; 98% homogeneity index

LC/MS: Anal. Calcd. for [M+H]⁺ C44H45N1₀O₆: 809.35; found 809.40

Example 146 (lR)-2-((2S)-2-(5-(5-(4-(2-((2S)-l-((2R)-2-(dimethylamino)-2-phenylacetyl)-2pyrrolidinyl)-lH-imidazol-5-yl)phenyl)-2-pyridinyl)-lH-imidazol-2-yl)-lpyrrolidinyl)-N,N-dimethyl-2-oxo-l-phenylethanamine

<img file="IL196813A_D0204.tif" />

Example 146, Step a

<img file="IL196813A_D0205.tif" />

«-BuLi (12.0 mL of 2.5M/hexanes, 30 mmol) was added drop-wise over 15 min to a cooled (-78 °C) toluene (300 mL) semi-solution of 2,5-dibromopyridine (6.040 g, 25.5 mmol), and stirred for 2.5 hr. Z-Butyl 2-(methoxy(methyl)amino)-2oxoethylcarbamate (2.809 g, 12.87 mmol) was added in batches over 7 min, and stirring continued for 1.5 hr at -78 °C. The -78 °C bath was replaced with -60 °C bath, which was allowed to warm up to -15 °C over 2.5 hr. The reaction was quenched with saturated NH4C1 solution (20 mL), and the mixture was allowed to thaw to ambient temperature and the organic layer was separated and evaporated in vacuo. The resulting crude material was purified by flash chromatography (silica gel; 15 % EtOAc/hexanes) to afford a reddish brown semisolid, which was washed with hexanes to removed the colored residue. Pyridine 146a was retrieved as an ash colored solid (842 mg). ¹H NMR (DMSO, δ = 2.5 ppm; 400 MHz): 8.89 (d, J = 2.3, 1H), 8.30 (dd, J = 8.4, 2.4, 1H), 7.90 (d, J = 8.3,1H), 7.03(br t, J = 5.7; 0.88H), 6.63 (app br s, 0.12H), 4.55 (d,7= 5.8,2H), 1.40/1.28 (two app s, 7.83H + 1.17H). LC (Cond. 1): RT = 2.00 min; >95% homogeneity index

LC/MS: Anal. Calcd. for [M+Na]⁺C1₂H1₅BrNaN₂O₃: 337.02; found 337.13

Example 146, Step b

<img file="IL196813A_D0206.tif" />

146b

48% HBr (1.0 mL) was added drop-wise to a dioxane (5.0 mL) solution of carbamate 146a (840 mg, 2.66 mmol) over 3 min, and the reaction mixture was stirred at ambient temperature for 17.5 hr. The precipitate was filtered and washed with dioxane, and dried in vacuo to afford amine the HBr salt of 146b as an off-white solid (672.4 mg; the exact mole equivalent of the HBr salt was not determined). ¹H NMR (DMSO, δ = 2.5 ppm; 400 MHz): 8.95 (d, J = 2.3,1 H), 8.37 (dd, J = 8.4, 2.3, 1H), 8.2 (br s, 3H), 8.00 (d, J = 8.3, 1H), 4.61 (s, 2H).

LC (Cond. 1): RT = 0.53 min

LC/MS: Anal. Calcd. for [M+H]⁺C₇H₈BrN₂O: 214.98; found 215.00

Example 146, Step c

<img file="IL196813A_D0207.tif" />

146c z-Pr2EtN (2.3 mL, 13.2 mmol) was added drop-wise over 15 min to a heterogonous mixture of amine 146b (1.365g), (S)-Boc-proline (0.957 g, 4.44 mmol) and HATU (1.70 g, 4.47 mmol) in DMF (13.5 mL), and stirred at ambient temperature for 1 hr. The volatile component was removed in vacuo and the residue was partitioned between EtOAc (40 mL) and an aqueous medium (20 mL water + 1 ml saturated NaHCO3 solution). The aqueous layer was washed with EtOAc (20 mL), and the combined organic phase was dried (MgSO4), filtered, and concentrated in vacuo. The resultant crude material was purified by flash chromatography (silica gel; 40-50% EtOAc/hexanes) to afford ketoamide 146c as a faint-yellow foam (1.465g). ¹H NMR (DMSO, δ = 2.5 ppm; 400 MHz): 8.90 (d, J = 2.3,1H), 8.30 (dd, J = 8.5, 2.4,1H), 8.01-8.07 (m, 1H), 7.90 (d, J = 8.3, 1H), 4.6 (m, 1H), 4.64 (dd, J = 19.1, 5.5, 1H); 4.19 (m, 1H), 3.39 (m, 1H), 3.32-3.26 (m, 1H), 2.20-2.01 (m, 1H), 1.95-1.70 (m, 3H), 1.40/1.35 (two app s, 9H).

LC(Cond. 1): RT = 1.91 min

LC/MS: Anal. Calcd. for [M+Na]⁺ C1₇H22BrN₃NaO4: 434.07; found 433.96.

Example 146, Step d

<img file="IL196813A_D0208.tif" />

A mixture of ketoamide 146c (782.2 mg, 1.897 mmol) and NH4OAc (800 mg, 10.4 mmol) in xylenes was heated with a microwave (140 °C) for 90 min. The volatile component was removed in vacuo and the residue was carefully partitioned between CH2C12 and water, where enough saturated NaHCO3 solution was added to neutralize it. The aqueous phase was extracted with CH₂C12 (2x), and the combined organic phase was dried (MgSO4), filtered, and concentrated in vacuo. The resultant crude material was purified by flash chromatography (silica gel; 50% CH2C12/EtOAc) to afford imidazole 146d as an off-white solid (552.8 mg). ¹H NMR (DMSO, δ = 2.5 ppm; 400 MHz): 12.49/12.39/12.15/12.06 (br s, IH), 8.62 (app br s, 0.2H), 8.56 (d, J = 2,0.8H), 8.02 (br d, J = 8.5,0.2H), 7.97 (br d, J = 7.8, 0.8H), 7.77 (d, J = 8.6, 0.8H), 7.72 (d, J= 8.6, 0.2H), 7.61-7.49 (m, IH), 4.93-4.72 (m, IH), 3.53 (m, IH), 3.41-3.32 (m, IH), 2.33-1.77 (m, 4H), 1.39/1.14 (app br s, 3.7H+5.3H).

LC (Cond. 1): RT = 1.67 min; >95% homogeneity index LC/MS: Anal. Calcd. for [M+Na]⁺ C1₇H₂1BrN₄NaO2: 415.08; found 415.12

Example 146, Step e

<img file="IL196813A_D0209.tif" />

146e (R₁ = H, R₂ = SEM) or (R₁ = SEM, R₂ = H)

NaH (60%; 11.6 mg, 0.29 mmol) was added in one batch to a heterogeneous mixture of imidazole 146d (80 mg, 0.203 mmol) and DMF (1.5 mL), and stirred at ambient condition for 30 min. SEM-C1 (40 pL, 0.226 mmol) was added drop-wise over 2 min to the above reaction mixture, and stirring was continued for 14 hr. The volatile component was removed in vacuo and the residue was partitioned between water and CH2C12. The aqueous layer was extracted with CH₂C12, and the combined organic phase was dried (MgSO4), filtered, and concentrated in vacuo. The crude material was purified by a flash chromatography (silica gel; 20% EtOAc/hexanes) to afford 146e as a colorless viscous oil (87.5 mg). The exact regiochemistry of 146e was not determined. ¹H NMR (CDC13, δ = 7.4 ppm; 400 MHz): 8.53 (d, J = 2.2, IH), 7.90-7.72 (m, 2H), 7.52 (s, IH), 5.87 (m, 0.46H), 5.41 (m, 0.54H), 5.16 (d, J = 10.8, IH), 5.03-4.85 (m, IH), 3.76-3.42 (m, 4H), 2.54-1.84 (m, 4H), 1.38/1.19 (br s, 4.3H + 4.7H), 0.97-0.81 (m, 2H), -0.03 (s, 9H).

LC(Cond. l):RT = 2.1min

LC/MS: Anal. Calcd. for [M+H]⁺ C₂₃H₃₆BrN₄O₃Si: 523.17; found 523.24

Example 146, Step f

<img file="IL196813A_D0210.tif" />

146f: (F^ = H, R₂ = SEM) or (R₁ = SEM, R₂ = H)

Pd(Ph₃P)4 (24.4 mg, 0.021 mmol) was added to a mixture of imidazole 146e (280 mg, 0.535 mmol), 1c (241.5 mg, 0.55 mmol) and NaHCO₃ (148.6 mg, 1.769 mmol) in 1,2-dimethoxyethane (4.8 mL) and water (1.6 mL). The reaction mixture was flushed with nitrogen, heated with an oil bath at 80 °C for ~24 hr and then the volatile component was removed in vacuo. The residue was partitioned between CH2C12 and water, and the organic phase was dried (MgSO4), filtered, and concentrated in vacuo. The crude material was purified by a Biotage system (silica gel; 75-100% EtOAc/hexanes) followed by a reverse phase HPLC (H2O/MeOH/TFA). The HPLC elute was neutralized with 2M NH3/MeOH and evaporated in vacuo, and the residue was partitioned between water and CH₂C12. The organic layer was dried (MgSO4), filtered, and concentrated in vacuo to afford 146f as a white foam (162 mg).

LC (Cond. 1): RT = 2.1 min LC/MS: Anal. Calcd. for [M+H]⁺ C₄1H58N7O₅Si: 756.43; found 756.55

Example 146, Step g

<img file="IL196813A_D0211.tif" />

Carbamate 146f (208 mg, 0.275 mmol) was treated with 25% TFA/CH2C12 (4.0 mL) and stirred at ambient temperature for 10 hr. The volatile component was removed in vacuo and the residue was first free-based by MCX (MeOH wash; 2.0 M NH3/MeOH elution) and then purified by a reverse phase HPLC (H2O/MeOH/TFA), and the resultant material was free-based again (MCX) to afford pyrrolidine 146g as a film of oil (53.7 mg). ¹H NMR (DMSO, δ = 2.5 ppm; 400 MHz): 1.88 (app br s, 2H), 8.83 (d, J = 2.1,1H), 8.07 (dd, J = 8.3/2.3, 1H0, 7.87 (d, J= 8.5,1H), 7.84 (d, J = 8.3,2H), 7.71 (d, J= 8.3,2H), 7.55 (s, 1H), 7.50 (br s, 1H), 4.18 (m, 2H), 3.002.94 (m, 2H), 2.89-2.83 (m, 2H), 2.11-2.02 (m, 2H), 1.95-1.86 (m, 2H), 1.83-1.67 (m, 4H).

LC (Cond. 1): RT = 0.95 min; >98% homogeneity index LC/MS: Anal. Calcd. for [M+H]⁺C2₅H₂8N₇: 426.24; found 426.27

Example 146 (lR)-2-((2S)-2-(5-(5-(4-(2-((2S)-l-((2R)-2-(dimethylamino)-2-phenylacetyl)-2pyrrolidinyl)-lH-imidazol-5-yl)phenyl)-2-pyridinyl)-lH-imidazol-2-yl)-lpyrrolidinyl)-N,N-dimethyl-2-oxo-l-phenylethanamine

<img file="IL196813A_D0212.tif" />

Example 146 (TFA salt) was synthesized from pyrrolidine 146g according to the preparation of Example 132 from intermediate 132e.

LC (Cond. 1): RT = 1.42 min; 96.5% homogenity index

LC/MS: Anal. Calcd. for [M+H]⁺ C45H50N9O2: 748.41; found 748.57

HRMS: Anal. Calcd. for [M+H]⁺C45H50N9O2: 748.4087; found 748.4100

Example 147 methyl ((lR)-2-((2S)-2-(5-(5-(4-(2-((2S)-l-((2R)-2-((methoxycarbonyl)amino)-2phenylacetyl)-2-pyrrolidinyl)-lH-imidazol-5-yl)phenyl)-2-pyridinyl)-lH-imidazol-2yl)-l-pyrrolidinyl)-2-oxo-l-phenylethyl)carbamate

<img file="IL196813A_D0213.tif" />

The TFA salt of Example 147 was prepared similarly from intermediate 146g by using Cap-4.

LC (Cond. 1): RT = 1.66 min; 95% homogenity index

LC/MS: Anal. Calcd. for [M+H]⁺ C45H46N9O6: 808.36; found 808.55

Example 148 (1R,1 ^,R) -2,2-(4,4 '-biphenyldiylbis(1 H-imidazole-5,2-diyl(4R)-l,3-thiazolidine-4,3diyl))bis(N,N-dimethyl-2-oxo-l-phenylethanamine)

<img file="IL196813A_D0214.tif" />

A solution of bromine (1.3mL, 25.0mmol) in 15mL glacial acetic acid was added drop-wise to a solution of 4-4’-diacetylbiphenyl (3.0g, 12.5mmol) in 40mL acetic acid at 50°C. Upon completion of addition the mixture was stirred at room temperature overnight. The precipitated product was filtered off and re-crystallized from chloroform to give l,l’-(biphenyl4,4־’-diyl)bis(2-bromoethanone) (3.84g,

77.5%) as a white solid.

¹H NMR (500 MHz, CHLOROFORM-D) δ ppm 8.09 (4 H, d, 7=7.93 Hz) 7.75 (4 H, d, 7=8.24 Hz) 4.47 (4 H, s)

Nominal/LRMS - Anal. Calcd. for 369.07 found; (M+H)⁺.33, (M-H)395.14 - ־

Example 148, Step b

<img file="IL196813A_D0215.tif" />

.2HCI

Sodium diformylamide (3.66g, 38.5mmol) was added to a suspension of 1,1'10 (biphenyl-4,4'-diyl)bis(2-bromoethanone) (6.1g, 15.4mmol) in 85mL acetonitrile.

The mixture was heated at reflux for 4 hours and concentrated under reduced pressure. The residue was suspended in 300mL 5% HC1 in ethanol and heated at reflux for 3.5 hours. Reaction was cooled to room temperature and placed in the freezer for 1 hour. Precipitated solid was collected, washed with 200mL 1:1 ethanol/ether followed by 200mL pentane, and dried under vacuum to give 1, Γ(biphenyl-4,4'-diyl)bis(2-aminoethanone) dihydrochloride (4.85g, 92%). Carried on without further purification.

¹H NMR (300 MHz, DMSO-d₆) δ ppm 8.47-8.55 (4H, m) 8.11 - 8.17 (4 H, m) 8.00 (4 H, d, 7=8.42 Hz) 4.59 - 4.67 (4 H, m).

LCMS - Phenomenex C-18 3.0 x 50mm, 0 to 100% B over 4.0 minute gradient, 1 minute hold time, A = 10% methanol 90% water 0.1% TFA, B = 90% methanol 10% water 0.1% TFA, tR = 0.44 minutes, Anal. Calcd. for C16H!6N₂O2 268.31 found; 269.09 (M+H)⁺.

Example 148, Step c

<img file="IL196813A_D0216.tif" />

To a stirred solution of l,l'-(biphenyl-4,4'-diyl)bis(2־aminoethanone) dihydrochloride (0.7g, 2.1mmol), N-(tert-butoxy carbonyl) -L-thioproline (0.96g,

4.2mmol), and HATU(1.68g, 4.4mmol) in 14mL DMF was added diisopropylethyl amine (1.5mL, 8.4mmol) drop-wise over 5 minutes. The resulting clear yellow solution was stirred at room temperature overnight (14 hours) and concentrated under reduced pressure. The residue was partitioned between 20%methanol/chlorofonn and water. The aqueous phase was washed once with 20%methanol/chloroform. The combined organics were washed with brine, dried (MgSO4), filtered, and concentrated under reduced pressure. The crude product was chromatographed on silica gel by gradient elution with 10-50% ethyl acetate/CH2C12 to give (4S,4'S)-tertbutyl 4,4'-(2,2'-(biphenyl-4,4'-diyl)bis(2-oxoethane-2,1 diyl))bis(azanediyl)bis(oxomethylene)dithiazolidine-3-carboxylate (0.39g, 27%) as an orange foam.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.38 (2 H, s) 8.12 (4 H, d, /=8.56 Hz) 7.94 (4

H, d, /=8.56 Hz) 4.60 - 4.68 (4 H, m) 4.33 - 4.38 (2 H, m) 3.58 - 3.68 (2 H, m) 3.38 (2 H, s) 3.08 - 3.18 (2 H, m) 1.40 (18 H, s)

LCMS - Water-Sunfire C-18 4.6 x 50mm, 0 to 100% B over 4.0 minute gradient, 1 minute hold time, A = 10% methanol 90% water 0.1% TFA, B = 90% methanol 10% water 0.1% TFA, t_R = 3.69 min., Anal. Calcd. for C34H42N4O8S2 698.85 found;

699.12 (M+H)⁺.

Example 148, Step d (4S,4'S)-tert-butyl 4,4'-(5,5'-(biphenyl-4,4'-diyl)bis(lH-imidazole-5,225 diyl))dithiazolidine-3-carboxylate (0.39g, 0.56mmol) and ammonium acetate (0.43g, 5.6mmol) were suspended in 8mL o-xylene in a microwave reaction vessel. The mixture was heated under standard microwave conditions at 140°C for 70 minutes and concentrated under reduced pressure. The residue was dissolved in 30mL 20% methanol/chloroform and washed with 10% NaHCO₃(aq). The organic layer was washed with brine, dried (MgSO4), filtered, and concentrated under reduced pressure.

The crude product was chromatographed on silica gel by gradient elution with 1-6% methanol/CH₂C12 to give (4S,4'S)-tert-butyl 4,4’-(5,5'-(biphenyl-4,4'-diyl)bis(lHimidazole-5,2- diyl))dithiazolidine-3-carboxylate (0.15g, 41%) as a yellow solid.

Ή NMR (500 MHz, DMSO-d₆) δ ppm 12.02 (2 H, s) 7.70 - 7.88 (10 H, m) 5.28 5 5.37 (2 H, m) 4.68 (2 H, d, J=9.16 Hz) 4.47 - 4.55 (2 H, m) 3.46 (2 H, s) 3.23 (2 H,

s) 1.26- 1.43 (18H, m)

LCMS - Luna C-18 3.0 x 50mm, 0 to 100% B over 3.0 minute gradient, 1 minute hold time, A = 5% acetonitrile, 95% water, 10mm ammonium acetate, B = 95% acetonitrile, 5% water, 10mm ammonium acetate, tR = 1.96 min., Anal. Calcd. for

C34H40N6O4S2 660.85 found; 661.30 (M+H)⁺, 659.34 (M-H)־

Example 148, Step e zr-λ z=\ ״ υ-Ο־(Χί ^h .4HCI

To a solution of (4S,4’S)-tert-butyl 4,4'-(5,5’-(biphenyl-4,4'-diyl)bis(lH-imidazole15 5,2- diyl))dithiazolidine-3-carboxylate in 1 mL dioxane was added 0.3mL of a 4.0M solution of HC1 in dioxane. The reaction was stirred for 3 hours at room temperature and concentrated under reduced pressure. The resulting tan solid was dried under vacuum to give 4,4’-bis(2-((S)-thiazolidin-4-yl)-l H-imidazol-5-y!)biphenyl tetrahydrochloride (0.12g, 100%) as a yellow solid.

¹H NMR (500 MHz, DMSO-d₆) δ ppm 8.09 (2 H, s) 8.01 (4 H, d, 7=8.55 Hz) 7.90 (4 H, d, 7=8.55 Hz) 5.08 (2 H, t, 7=6.10 Hz) 4.38 (2 H, d, 7=9.16 Hz) 4.23 (2 H, d, 7=9.46 Hz) 3.48 - 3.54 (2 H, m,) 3.35 - 3.41 (2 H, m)

LCMS - Luna C-18 3.0 x 50mm, 0 to 100% B over 4.0 minute gradient, 1 minute hold time, A = 5% acetonitrile, 95% water, 10mm ammonium acetate, B = 95% acetonitrile, 5% water, 10mm ammonium acetate, t_R = 1.70 min., Anal. Calcd. for C24H24N6S2 460.62 found; 461.16 (M+H)⁺, 459.31 (M-H)־

Example 148 (lR,rR)-2,2'-(4,4'-biphenyldiylbis(lH-imidazole-5,2-diyl(4R)-l,3-thiazolidine-4,3diyl))bis(N,N-dimethyl-2-oxo-l-phenylethanamine)

<img file="IL196813A_D0217.tif" />

To a stirred solution of (4,4'-bis(2-((S)-thiazolidin-4-yl)-lH-imidazol-5-yl)biphenyl tetrahydrochloride (0.028g, 0.046mmol), (R)-2-(dimethylamino)-2-phenylacetic acid (Cap-1,0.017g, O.O.lOmmol), and HATU (0.039g, O.lOmmol) in 2mL DMF was added diisopropylethyl amine (0.05mL, 0.28mmol).The reaction was stirred at room temperature overnight (16 hours) and concentrated under reduced pressure. The crude product was purified by reverse-phase preparative HPLC to provide (2R,2'R)1,1 '-((4S,4'S)-4,4'-(5,5'-(biphenyl-4,4'-diyl)bis( 1 H-imidazole-5,2diyl))bis(thiazolidine-4,3-diyl))bis(2-(dimethylamino)-2-phenylethanone), TFA salt (0.012g, 21%) ¹H NMR (500 MHz, DMSO-d₆) δ ppm 7.59 - 7.91 (20 H, m) 5.62 (2 H, dd, /=6.56, 2.59 Hz) 4.99 (2 H, d, /=8.85 Hz) 4.82/4.35 (2 H, s) 4.22 (2 H, s) 3.42 (2 H, s) 3.25 (2 H, s) 2.35-2.61 (12H, m)

LCMS - Luna C-18 3.0 x 50mm, 0 to 100% B over 7.0 minute gradient, 1 minute hold time, A = 5% acetonitrile, 95% water, 10mm ammonium acetate, B = 95% acetonitrile, 5% water, 10mm ammonium acetate mobile phase t_R = 3.128 min.

Nominal/LRMS - Calcd. for C44H46N₈O₂S₂ 783.03; found 783.28 (M+H)⁺Accurate/HRMS - Calcd. for C44H47N₈O₂S₂783.3263; 783.3246 (M+H)⁺

Examples 149 and 150 were prepared in similar fashion as described for the preparation of example 148.

<td> Example</td><td> Compound Name</td><td> Structure</td><td> Data</td>

<td> Example 149</td><td> dimethyl (4,4- biphenyldiylbis( 1H-</td><td></td><td> t_R = 3.36 min (LCMS - Luna C-</td>

<td></td><td> imidazole-5,2-diyl(4R)1,3-thiazolidine-4,3diyl((lR)-2-oxo-lphenyl-2,1ethanediyl)))biscarbamate</td><td> ״V y from 148e and Cap-4</td><td> 18 3.0 x 50mm, 0 to 100% B over 7.0 minute gradient, 1 minute hold time, A = 5% acetonitrile, 95% water, 10mm ammonium acetate, B = 95% acetonitrile, 5% water, 10mm ammonium acetate) LRMS: Anal. Calcd. for C44H42N8O6S2 842.99 found: 843.25 (M+H)⁺ HRMS: Anal. Calcd. for C44H43N8O6S2 843.2747 found: 843.2724 (M+H)⁺</td>

<td> Example 150</td><td> (4R,4’R)-4,4'-(4,4’biphenyldiylbis( 1Himidazole-5,2-diyl))bis(3((2R)-tetrahydro-2furanylcarbonyl)-l ,3thiazolidine)</td><td> from 148e and tetrahydrofuroic acid</td><td> t_R = 4.32 min (HPLC - XTerra C-18 4.6 x 50mm, 0 to 100% B over 10.0 minute gradient, 1 minute hold</td>

<td></td><td></td><td></td><td> time, A = 10% methanol 90% water 0.1 % TFA, B = 90% methanol 10% water 0.1% TFA) LRMS: Anal. Calcd. for C34H36N6O4S2 656.83 found: 657.32 (M+H)⁺</td>

Example 151 (1R, 1 'R)-2,2-(4,4 ^,-biphenyldiylbis((!-methyl-1 H-imidazole-4,2-diyl) (2S)-2,1pyrrolidinediyl))bis(N,N-dimethyl-2-oxo-l-phenylethanamine)

<img file="IL196813A_D0218.tif" />

Example 151, Step a

<img file="IL196813A_D0219.tif" />

To a stirred solution of Id, (2S,2'S)-tert-butyl 2,2'-(4,4'־(biphenyl-4,4'10 diyl)bis( 1 H-imidazole-4,2-diy !))dipyrrolidine- 1 -carboxylate (100 mg, 0.16 mmole) and iodomethane (40 pL, 0.16 mmole) in CH2C12 ( 2 mL) was added sodium hydride (40%) (21.2 mg, 0.352 mmole). After five hours at ambient temperature, it was concentrated under reduced pressure. The crude reaction product 151a, (2S,2'S)-tertbutyl 2,2'-(4,4'-(biphenyl-4,4'-diyl)bis( 1 -methyl-1 H-imidazole-4,2diyl))dipyrrolidine-l-carboxylate (~ 90 mg) was moved onto next step without further purification (purity ~ 85%) LCMS: Anal. Calcd. for: C38H48N6O4 652.83; Found: 653.51 (M+H)⁺. It should be recognized that multiple methylation isomers are possible in this reaction and no attempt to assign these was made.

Example 151, Step b

<img file="IL196813A_D0220.tif" />

151a, (2S,2'S)-tert-butyl 2,2'-(4,4'-(biphenyl-4,4'-diyl)bis(l-methyl-lHimidazole-4,2-diyl))dipyrrolidine-l-carboxylate (100 mg, 0.153 mmole) treated with 4 M HCl/dioxane (20 mL). After three hours at ambient temperature, it was concentrated under reduced pressure. The crude reaction product, 4,4'-bis(l-methyl2-((S)-pyrrolidin-2-yl)-lH-imidazol-4-yl)biphenyl( ~110 mg, HC1 salt) was moved onto the next step without further purification (purity ~ 85%) LCMS: Anal. Calcd. for: C28H32N6 452.59; Found: 453.38 (M+H)⁺. Multiple imidazole isomers were present and carried forward.

Example 151

HATU ( 58.9 mg, 0.150 mmol) was added to a mixture of 151b, 4,4'-bis(lmethyl-2-((S)-pyrrolidin-2-yl)-lH-imidazol-4-yl)biphenyl (45.0 mg, 0.075 mmol), (zPr)₂EtN (78 pL, 0.451 mmol) and Cap-1, (7?)-2-(dimethylamino)-2-phenylacetic acid (0.026 mg 0.150mmol) in DMF (1.0 mL). The resultant mixture was stirred at ambient temperature until the coupling was complete as determined by LC/MS analysis. Purification was accomplished by reverse-phase preparative HPLC (Waters-Sunfire 30 X 100mm S5, detection at 220 nm, flow rate 30 mL/min, 0 to

90% B over 14 min; A = 90% water, 10 % ACN, 0.1% TFA, B = 10% water, 90 %

ACN, 0.1% TFA) to provide two isomer of 151, (2R,2׳R)-l,r-((2S,2'S)-2,2'-(4,4'(biphenyl-4,4'-diyl)bis( 1 -methyl-1 H-imidazole-4,2-diyl))bis(pyrrolidine-2,1 diyl))bis(2-(dimethylamino)-2-phenylethanone), TFA salts.

Isomer 1: (1R,1 'R)-2,2’-(4,4’-biphenyldiylbis((1 -methyl-lH-imidazole-4,2-diyl)(2S)-

2,l-pyrrolidinediyl))bis(N,N-dimethyl-2-oxo-l-phenylethanamine) (8 mg, 8.6%) as a colorless wax.

¹H NMR (500 MHz, DMSO-d₆) 5 ppm 1.84 - 2.25 (m, 8 H) 2.32 - 2.90 (m, 12 H)

3.67 - 3.92 (m, 8 H) 4.07 (s, 2 H) 5.23 (s, 2 H) 5.51 (s, 2 H) 7.51 - 7.91 (m, 20 H) HPLC Xterra 4.6 X 50 mm, 0 to 100% B over 10 minutes, one minutes hold time, A = 90% water, 10% methanol, 0.2% phosphoric acid, B = 10% water, 90% methanol, 0.2% phosphoric acid, RT = 2.74 min, 98%.

LCMS: Anal. Calcd. for: C₄₈H54N8O₂ 775.02; Found: 775.50 (M+H)⁺.

Isomer 2: (1R, 1 'R)-2,2'-(4,4'-biphenyldiylbis((l-methyl-lH-imidazole-4,2-diyl)(2S)-

2,l-pyrrolidinediyl))bis(N,N-dimethyl-2-oxo-l-phenylethanamine) (10.2 mg, 11%) as a colorless wax.

¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.83 - 2.26 (m, 8 H) 2.30 - 2.92 (m, 12 H)

3.68 - 3.94 (m, 8 H) 4.06 (s, 2 H) 5.25 (d, 7=2.14 Hz, 2 H) 5.50 (s, 2 H) 7.52 - 7.91 (m, 20 H).

HPLC Xterra 4.6 X 50 mm, 0 to 100% B over 10 minutes, one minutes hold time, A = 90% water, 10% methanol, 0.2% phosphoric acid, B = 10% water, 90% methanol, 0.2% phosphoric acid, RT = 2.75 min, 90%.

LCMS: Anal. Calcd. for: C48H54N8O2 775.02; Found: 775.52 (M+H)⁺.

Example 152

Ν' H

N R'

Example 152a-l step a.

2-Chloro-5-(l-ethoxyvinyl)pyrimidine

<img file="IL196813A_D0221.tif" />

To a solution of 5-bro mo-2-chloropyrimidine (12.5 g, 64.62 mmol) in dry DMF (175 mL) under N2 was added tributyl(l-ethoxyvinyl)tin (21.8 mL, 64.62 mmol) and dichlorobis(triphenylphosphine)palladium (Π) (2.27 g, 3.23 mmol). The mixture was heated at 100°C for 3h before being allowed to stir at room temperature for 16 hr. The mixture was then diluted with ether (200 mL) and treated with aqueous KF soln (55 g of potassium fluoride in 33 mL of water). The two phase mixture was stirred vigorously for Ih at room temperature before being filtered through diatomaceous earth (Celite ). The fitrate was washed with sat’d NaHCO3 soln and brine prior to drying (Na₂SO4). The original aqueous phase was extracted with ether (2x) and the organic phase was treated as above. Repetition on 13.5 g of 5-bromo-2-chloropyrimidine and combined purification by Biotage™ flash chromatography on silica gel (gradient elution on a 65M column using 3% ethyl acetate in hexanes to 25% ethyl acetate in hexanes with 3.0 L) afforded the title compound as a white, crystalline solid (18.2 g, 73%).

¹H NMR (500 MHz, DMSO-de) δ 8.97 (s, 2H), 5.08 (d, /=3.7 Hz, IH), 4.56 (d, /=3.4 Hz, IH), 3.94 (q, /=7.0 Hz, 2H), 1.35 (t, /=7.0 Hz, 3H).

LCMS Phenomenex LUNA C-18 4.6 x 50 mm, 0 to 100% B over 3 minutes, 1 minute hold time, A = 90% water, 10% methanol, 0.1% TFA, B = 10% water, 90% methanol, 0.1% TFA, RT = 2.53 min, 98.8% homogeneity index. LCMS: Anal. Calcd. for C₈H1₀ClN₂O 185.05; found: 185.04 (M+H)⁺.

HRMS: Anal. Calcd. for C₈H₁₀ClN₂O 185.0482; found: 185.0490 (M+H)⁺.

The same method was used for the preparation of Examples 152a-2 &amp; 152a-3:

LC conditions: Condition 1; Phenomenex LUNA C-18 4.6 x 50 mm, 0 to 100% B over 3 minutes, 1 minute hold time, A = 90% water, 10% methanol, 0.1% TFA, B =

10% water, 90% methanol, 0.1% TFA, 220nm, 5 gL injection volume.

Condition 2; Phenomenex LUNA C-18 4.6 x 50 mm, 0 to 100% B over 2 minutes, 1 minute hold time, A = 90% water, 10% methanol, 0.1% TFA, B = 10% water, 90% methanol, 0.1% TFA, 220nm, 5 gL injection volume.

<td> Example 152a-2</td><td> 1 ן 11 N^N 1Γ from dichloropyridazine</td><td> t_R= 2.24 min 96.4%, condition 1 LRMS: Anal. Calcd. for C₈H₁₀ClN₂O 185.05; found: 185.06 (M+H)⁺. HRMS: Anal. Calcd. for C₈H10ClN₂O 185.0482; found: 185.0476 (M+H)⁺.</td>

<td> Example 152a-3</td><td> from dibromopyrazine</td><td> t_R = 2.82 min (52.7%, inseparable with 2,5dibrompyrazine (t_R=1.99 min, 43.2%)); condition 1 LRMS: Anal. Calcd. for C₈H10BrN₂O 229.00; found: 228.93 (M+H)⁺.</td>

Example 152d-l to 152d-6

Example 152b-l, step b.

(S)-tert-Butyl 2-(5-(2-chloropyrimidin-5-yl)-lH-imidazol-2-yl)pyrrolidine-lcarboxylate or (S)-2-[5-(2-Chloro-pyrimidin-5-yl)-lH-imidazol-2-yl]-pyrrolidine-lcarboxylic acid tert-butyl ester

NBS (16.1 g, 90.7 mmol) was added in one portion to a stirred solution of 2-chloro5-(l-ethoxyvinyl)pyrimidine (152a-l, 18.2 g, 98.6 mmol) in THF (267 mL) and ¾0 (88 mL) at 0°C under N2. The mixture was stirred for Ih at 0°C before it was diluted with more H2O and extracted with ethyl acetate (2x). The combined extracts were washed with sat’d NaHCO3 soln and brine prior to drying (Na2SO4), filtration, and solvent evaporation. LCMS Phenomenex LUNA C-18 4.6 x 50 mm, 0 to 100% B over 3 minutes, 1 minute hold time, A = 90% water, 10% methanol, 0.1% TFA, B = 10% water, 90% methanol, 0.1% TFA, RT = 1.52 min (unsymmetrical peak). LCMS: Anal. Calcd. for C6H14BrClN₂O 235.92; found: 236.85 (M+H)⁺.

Example 152c-l, step c.

Half of the crude residue (2-bromo-l-(2-chloropyrimidin-5-yl)ethanone, ~14.5g) was dissolved into anhydrous acetonitrile (150 mL) and treated directly withN-Boc-Lproline (9.76 g, 45.35 mmol) and diisopropylethylamine (7.9 mL, 45.35 mmol).

After being stirred for 3h, the solvent was removed in vacuo and the residue was partitioned into ethyl acetate and water. The organic phase was washed with 0.1N hydrochloric acid, sat’d NaHCO₃ soln and brine prior to drying (Na₂SO4), filtration, and concentration. LCMS Phenomenex LUNA C-18 4.6 x 50 mm, 0 to 100% B over 3 minutes, 1 minute hold time, A = 90% water, 10% methanol, 0.1% TFA, B = 10% water, 90% methanol, 0.1% TFA, RT = 2.66 min.

The same method was used to prepare Examples 152c through 152c-6.

LC conditions: Condition 1: Phenomenex LUNA C-18 4.6 x 50 mm, 0 to 100% B over 3 minutes, 1 minute hold time, A = 90% water, 10% methanol, 0.1% TFA, B =

10% water, 90% methanol, 0.1% TFA, 220nm, 5 gL injection volume.

Condition 2: Phenomenex LUNA C-18 4.6 x 50 mm, 0 to 100% B over 2 minutes, 1 minute hold time, A = 90% water, 10% methanol, 0.1% TFA, B = 10% water, 90% methanol, 0.1% TFA, 220nm, 5 gL injection volume.

<td> Example 152c-2</td><td> Br^N θ 0 0</td><td> t_R= 1.81 min (condition 2, ~95 %) LRMS: Anal. Calcd. for C15H₁₉BrN₄O2 386.05 found: 387.07 (M+H)⁺.</td>

<td> Example 152c-3</td><td> Xl^x׳^ 0 * 0</td><td> t_R = 1.84 min (condition 2, 94%) LRMS: Anal. Calcd. for C1₅H₁₉BrN₂O5 386.05; found: 387.07 (M+H)⁺.</td>

<td> Example 152c-3a</td><td> —° O \ ° \ o / ° o \=z o</td><td> t_R = 2.65 min; condition 1 LCMS: Anal. Calcd. for C1₆H₂0ClN₃O5 369.11 found: 391.89 (M+Na)⁺.</td>

<td> Example 1520-4</td><td> סס d o=z o' / ° r\ o—</td><td> t_R = 1.94 min, (condition 2) LCMS: Anal. Calcd. for</td>

<td></td><td></td><td> C₁₆H21BrN₃O5 414.07 found: 414.11 (M+H)⁺.</td>

<td> Example 152c-5</td><td> o w ^o=\ o \=o *X o °—</td><td> t_R = 2.22 min; condition 1 LCMS: Anal. Calcd. for C14H1₈C1N3O₅ 343.09 found: undetermined.</td>

<td> Example 1520-6</td><td> CD d y—z °\ o' /° ס. A</td><td> t_R= 2.41 min, condition 1 LCMS: Anal. Calcd. for C14H₁₈³⁷BrN3O₅ 389.04 found: 412.03 (M+Na)⁺.</td>

Example 152d-l, step d.

This residue ((S)־l-tert-butyl 2-(2-(2-chloropyrimidin-5-yl)-2-oxoethyl) pyrrolidine-1,2-dicarboxylate) was taken up in xylenes (200 mL) and treated to

NH4OAc (17.5 g, 0.23 mol). The mixture was heated at 140°C for 2 hr in a thickwalled, screw-top flask before it was cooled to ambient temperature and suctionfiltered. The filtrate was then concentrated, partitioned into ethyl acetate and sat’d NaHCO3 soln and washed with brine prior to drying (Na2SO4), filtration, and concentration The original precipitate was partitioned into aqueous NaHCO3 soln and ethyl acetate and sonicated for 2 min before being suction-filtered. The filtrate was washed with brine, dried over (Na₂SO4), filtered, and concentrated to dryness. Purification of the combined residues by Biotage™ flash chromatography on silica gel (65M column, preequilibration with 2%B for 900mL followed by gradient elution with 2%B to 2%B for 450 ml followed by 2%B to 40%B for 3000mL where

B=methanol and A=dichloromethane) afforded the title compound (7.0 g, 44% yield, 2 steps, pure fraction) as an yellowish orange foam. The mixed fractions were subjected to a second Biotage™ chromatography on silica gel (40M column, preequilibration with 1%B for 600mL followed by gradient elution with 1%B to 1%B for 150 ml followed by 1%B to 10%B for 1500mL where B=MeOH and A=CH2C12) afforded additional title compound (2.8 g, 18%) as a brownish-orange foam. ¹H NMR (500 MHz, DMSO-d₆) δ 12.24-12.16 (m, 1H), 9.05 (s, 2H), 7.847.73 (m, 1H), 4.90-4.73 (m, 1H), 3.59-3.46 (m, 1H), 3.41-3.31 (m, 1H), 2.32-2.12 (m, 1H), 2.03-1.77 (m, 3H), 1.39 and 1.15 (2s, 9H).

LCMS Phenomenex LUNA C-18 4.6 x 50 mm, 0 to 100% B over 3 minutes, 1 minute hold time, A = 90% water, 10% methanol, 0.1% TFA, B = 10% water, 90% methanol, 0.1% TFA, RT = 1.92 min, 94.7% homogeneity index.

LRMS: Anal. Calcd. for C16H21C1N5O2 350.14; found: 350.23 (M+H)⁺. HRMS: Anal. Calcd. for C1₆H₂1C1N₅O2 350.1384; found: 350.1398 (M+H)⁺.

The same method was used to prepare Examples 152d-2 through 152d-6.

LC conditions: Condition 1: Phenomenex LUNA C-18 4.6 x 50 mm, 0 to 100% B over 3 minutes, 1 minute hold time, A = 90% water, 10% methanol, 0.1% TFA, B = 10% water, 90% methanol, 0.1% TFA, 220nm, 5 pL injection volume.

Condition 2: Phenomenex LUNA C-18 4.6 x 50 mm, 0 to 100% B over 2 minutes, 1 minute hold time, A = 90% water, 10% methanol, 0.1% TFA, B = 10% water, 90% methanol, 0.1% TFA, 220nm, 5 pL injection volume.

<td> Example 152d-2</td><td> H 1 h A ^N Ύ/λ-Q from 152c-3a</td><td> t_R= 1.92 min (86.5%); condition 1 LRMS: Anal. Calcd. for C16H21CIN5O2 350.14; found: 350.23 (M+H)⁺. HRMS: Anal. Calcd. for C16H21C1N₅O2 350.1384; found: 350.1393 (M+H)⁺.</td>

<td> Example 152d-3</td><td>^b'^n THj ^־N from 1520-4</td><td> t_R= 1.90min (&gt;95%); condition 1 LRMS:Anal. Calcd. for C16H₂1BrN₅O2 394.09; found: 393.82 (M+H)⁺. HRMS: Anal. Calcd. for C₁₆H₂1BrN₅O2 394.0879; found: 394.0884 (M+H)⁺.</td>

<td> Example 152d-4</td><td> 1 ״ ^NAxi\ hQ &gt;-NH 0 from 1520-3</td><td> t_R = 1.45 min (condition 2, 100%) LRMS: Anal. Calcd. for C15H₁₉BrN₄O2 366.07 found: 367.07 (M+H)⁺.</td>

<td> Example 152d-5</td><td>^b׳xx^n °v^ 11 1 h \ N_s^&lt;-N NH Tac from 152c-6</td><td> t_R = 1.88 min (&gt;95%); condition 1 LRMS: Anal. Calcd. for C₁₄H18BrN₅O2 367.06; found: 368.10 (M+H)⁺.</td>

<td> Example 152d-6</td><td> 1 ח η ' N^A^N NH Ύ/&gt;־C ^*N ^&gt; from 152c5־</td><td> t_R = 1.66 min (85%); condition 1 LRMS: Anal. Calcd. for C14H18C1N5O2 323.11; found: 324.15 (M+H)⁺.</td>

Example 152e-l, step e.

Example 152e-l: (S)-tert-Butyl 2-(5-(2-chloropyrimidin-5-yl)-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-imidazoT2-yl)pyrrolidine-l-carboxylate

<img file="IL196813A_D0222.tif" />

Sodium hydride (60% dispersion in mineral oil, 0.23 g, 5.72 mmol) was added in one portion to a stirred solution of (S)-tert-butyl 2-(5-(2chloropyrimidin-5-yl)-1 H-imidazol-2-y !)pyrrolidine-1 -carboxylate (152d-l,2.0 g, 5.72 mmol) in dry DMF (45 mL) at ambient temperature under N₂. The mixture was stirred for 5 min. before SEM chloride (1.01 mL, 5.72 mmol) was added in approx. 0.1 mL increments. The mixture was stirred for 3h before being quenched with sat’d NH4C1 soln and diluted with ethyl acetate. The organic phase was washed with sat’d NaHCO₃ soln and brine, dried over (Na₂SO₄), filtered, and concentrated. The original aqueous phase was extracted twice more and the combined residue was purified by Biotage™ flash chromatography (40M column, 50 mL/min, preequilibration with 5%B for 750mL, followed by step gradient elution with 5%B to 5%B for 150 mL, 5%B to 75%B for 1500 mL, then 75%B to 100%B for 750 mL where solvent B is ethyl acetate and solvent A is hexanes). Concentration of the eluant furnished the title compound as a pale yellow foam (2.35 g, 85%).

¹H NMR (500 MHz, DMSO-d₆) δ 9.04 (s, 2H), 7.98-7.95 (m, IH), 5.70-5.31 (3m, 2H), 5.02-4.91 (m, IH), 3.59-3.49 (m, 3H), 3.45-3.35 (m, IH), 2.30-2.08 (m, 2H), 1.99-1.83 (m, 2H), 1.36 and 1.12 (2s, 9H), 0.93-0.82 (m, 2H), -0.02 (s, 9H).

LCMS Phenomenex LUNA C-18 4.6 x 50 mm, 0 to 100% B over 2 minutes, 2 minute hold time, A = 90% water, 10% methanol, 0.1% TFA, B = 10% water, 90% methanol, 0.1% TFA, RT = 2.38 min, 95% homogeneity index.

LRMS: Anal. Calcd. for C₂₂H₃₅ClN₅O₃Si 480.22; found: 480.23 (M+H)⁺. HRMS: Anal. Calcd. for C₂₂H₃₅ClN₅O₃Si 480.2198; found: 480.2194 (M+H)⁺.

The same method was used to prepare 152e-2 through 152e-4

LC conditions: Condition 1: Phenomenex LUNA C-18 4.6 x 50 mm, 0 to 100% B over 3 minutes, 1 minute hold time, A = 90% water, 10% methanol, 0.1% TFA, B =

10% water, 90% methanol, 0.1% TFA, 220nm, 5 pL injection volume.

Condition 2: Phenomenex LUNA C-18 4.6 x 50 mm, 0 to 100% B over 2 minutes, 1 minute hold time, A = 90% water, 10% methanol, 0.1% TFA, B = 10% water, 90% methanol, 0.1% TFA, 220nm, 5 pL injection volume.

<td> Example 152e2־</td><td> \ / x^Si ד ו ך ץ II v—kJ from 152d-2</td><td> t_R= 2.34 min (85.7%); condition 1 LCMS: Anal. Calcd. for C22H₃₅ClN₅O3Si 480.22; found: 480.22 (M+H)⁺. HRMS: Anal. Calcd. for C22H₃₅ClN5O3Si 480.2198 found: 480.2198 (M+H)⁺.</td>

<td> Example 152e-3</td><td> X^s' Ύ/&gt;־־Ο from 152d-3</td><td> t_R= 3.18 min (&gt;95%); condition 1 LCMS: Anal. Calcd. for C22H₃₅³⁷BrN₅O3Si 526.17; found: 525.99 (M+H)⁺. HRMS: Anal. Calcd. for C22H₃5³⁷BrN₅O3Si 526.1692; found: 526.1674 (M+H)⁺.</td>

<img file="IL196813A_D0223.tif" />

Example 152f-l (S)-l-(2-(5-(2-chloropyrimidin-5-yl)-lH-imidazol-2-yl)pyrrolidin-l-yl)-2-(pyridin-3yl)ethanone

<img file="IL196813A_D0224.tif" />

Cold (0°C) 4 NHCl in dioxanes (5 mL) was added via syringe to (S)-tertbutyl 2-(5-(2-chloropyrimidin-5-yl)-lH-imidazol-2-yl)pyrrolidine-l-carboxylate (152d-l, 0.50 g, 1.43 mmol) in a 100 mL pear-shaped flask followed by MeOH (1.0 mL). The suspension was stirred at room temperature for 4h before it was concentrated down to dryness and placed under high vacuum for lh. There was isolated intermediate (S)-2-chloro-5-(2-(pyrrolidin-2-yl)- 177-imidazol-5yl)pyrimidine trihydrochloride as a pale yellow solid (with an orange tint) which was used without further purification.

HATU (0.60 g, 1.57 mmol) was added in one portion to a stirred solution of intermediate (S)-2-chloro-5-(2-(pyrrolidin-2-yl)-lH-imidazol-5-yl)pyrimidine trihydrochloride (0.46 g, 1.43 mmol, theoretical amount), 2-(pyridin-3-yl)acetic acid (0.25 g, 1.43 mmol) and DIEA (1.0 mL, 5.72 mmol) in anhydrous DMF (10 mL) at ambient temperature. The mixture was stirred at room temperature for 2h before the DMF was removed in vacuo. The residue was taken up in CH2C12 and subjected to

Biotage™ flash chromatography on silica gel (40M column, preequilibration with

0%B for 600mL followed by step gradient elution with 0%B to 0%B for 150 mL followed by 0%B to 15%B for 1500mL followed by 15%B to 25% B for 999 mL where B= MeOH and A= CH2C12). There was isolated the title compound (0.131 g,

25%, 2 steps) as a yellow solid.

^lH NMR (500 MHz, DMSO-d₆) δ 9.10-9.08 (2s, 2H), 8.72-8.55 (series of m, 2H), 8.21-8.20 and 8.11-8.10 (2m, IH), 8.00 and 7.93 (2s, IH), 7.84-7.77 (series of m, IH), 5.43-5.41 and 5.17-5.15 (2m, IH), 4.02-3.94 (3m, 2H), 3.90-3.58 (3m, 2H), 2.37-2.26 (m, IH), 2.16-1.85 (2m, 3H).

LCRMS Phenomenex LUNA C-18 4.6 x 50 mm, 0 to 100% B over 3 minutes, 1 minute hold time, A = 90% water, 10% methanol, 0.1% TFA, B = 10% water, 90% methanol, 0.1% TFA, RT = 0.92 min, 95.1 % homogeneity index.

LRMS: Anal. Calcd. for C1₈H1₈C1N₆O 369.12; found: 369.11 (M+H)⁺. HRMS: Anal. Calcd. for C1₈H!₈C1N₆O 369.1231; found: 369.1246 (M+H)⁺.

Example 152f-2 LCMS conditions: Phenomenex LUNA C-18 4.6 x 50 mm, 0 to 100% B over 3 minutes, 1 minute hold time, A = 90% water, 10% methanol, 0.1% TFA, B = 10% water, 90% methanol, 0.1% TFA, 220nm, 5 pL injection volume.

Example 152f-2

<img file="IL196813A_D0225.tif" />

prepared from lb with same procedure describing the preparation of 152f-l from 152d-l t_R= 1.56min(>95%)

LRMS: Anal. Calcd. for C20H20BrN4O 413.08; found: 412.99 (M+H)⁺.

Examples 152g-l to 152g-16

Example 152g-l from 1c and 152e-l. (S)-2-[5-(2-{4-[2-((S)-l-tert-Butoxycarbonylpyrrolidin-2-yl)-3H-imidazol-4-yl]-phenyl}-pyrimidin-5-yl)-l-(2-trimethylsilanylethoxymethyl)-lH-imidazol-2-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester :Si'

N Ν'

V H /⁵*O O

Pd (Ph₃)₄ (0.12 g, 0.103 mmol) was added in one portion to a stirred suspension of (S)-tert-butyl 2-(5-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan2־yl)phenyl)-lH-imidazol-2-yl)pyrrolidine-l-carboxylate (lc, 1.00 g, 2.27 mmol), (S)tert-butyl 2-(5-(2-chloropyrimidin-5-yl)-l-((2-(trimethylsilyl)ethoxy)methyl)-lHimidazol-2-yl)pyrrolidine-l-carboxylate (152c-l, 0.99 g, 2.06 mmol) and NaHCO₃(0.87 g, 10.3 mmol) in a solution of DME (20 mL) and H₂O (6 mL) at room temperature under N₂. The vessel was sealed and the mixture was placed into a preheated (80°C) oil bath and stirred at 80°C for 16h before additional catalyst (0.12 g) was added. After heating the mixture for an additional 12h at 80°C, the mixture was cooled to ambient temperature, diluted with ethyl acetate and washed with sat’d NaHCO3 soln and brine prior to drying over anhydrous sodium sulfate and solvent concentration. Purification ofthe residue by Biotage™ flash chromatography on silica gel using a 40M column (preequilibrated with 40% B followed by step gradient elution with 40%B to 40%B for 150mL, 40%B to 100%B for 1500mL, 100%B to 100%B for lOOOmL where B=ethyl acetate and A=hexanes) furnished the title compound as a yellow foam (1.533 g, 98%). A small amount of the yellow foam was further purified for characterization purposes by pHPLC (Phenomenex GEMINI, 30 x 100 mm, S10,10 to 100% B over 13 minutes, 3 minute hold time, 40 mL/min, A = 95% water, 5% acetonitrile, lOmM NH4OAc, B = 10% water, 90% acetonitrile, lOmM NH4OAc) to yield 95% pure title compound as a white solid.

¹H NMR (500 MHz, DMSO-d₆) δ 12.30-11.88 (3m, 1H), 9.17-9.16 (m, 2H), 8.438.31 (m, 2H), 7.99-7.35 (series of m, 4H), 5.72-5.30 (3m, 2H), 5.03-4.76 (2m, 2H), 3.64-3.50 (m, 4H), 3.48-3.31 (m, 2H), 2.36-2.07 (m, 2H), 2.05-1.80 (m, 4H), 1.461.08 (2m, 18H), 0.95-0.84 (m, 2H), -0.01 (s, 9H).

HPLC Phenomenex LUNA C-18 4.6 x 50 mm, 0 to 100% B over 3 minutes, 1 minute hold time, A = 90% water, 10% methanol, 0.1% TFA, B = 10% water, 90% methanol, 0.1% TFA, RT = 2.91 min, 95% homogeneity index.

LRMS: Anal. Calcd. for C40H57N₈O₅Si 757.42; found: 757.42 (M+H)⁺.

HRMS: Anal. Calcd. for C40H57N₈O₅Si 757.4221; found: 757.4191 (M+H)⁺.

The same procedure was used to prepare Examples 152g-2 through 152g-17:

LC conditions: Condition 1: Phenomenex LUNA C-18 4.6 x 50 mm, 0 to 100% B over 3 minutes, 1 minute hold time, A = 90% water, 10% methanol, 0.1% TFA, B =

10% water, 90% methanol, 0.1% TFA, 220nm, 5 pL injection volume.

Condition 2: Phenomenex LUNA C-18 4.6 x 50 mm, 0 to 100% B over 2 minutes, 1 minute hold time, A = 90% water, 10% methanol, 0.1% TFA, B = 10% water, 90% methanol, 0.1% TFA, 220nm, 5 pL injection volume.

<td> Example 152g-2</td><td> V ״ n ז י ר ך \ Ύ Prepared from Ic and 152e-2</td><td> t_R = 2.81 min (79%); Condition 1 LRMS: Anal. Calcd. for C40H₅7N_gO₅Si 757.42; found: 758.05 (M+H)⁺. HRMS: Anal. Calcd. for C40H₅₇N8O₅Si 757.4221; found: 757.4196 (M+H)⁺.</td>

<td> Example 152g-3</td><td> ''si'׳' Ο-Κ'Ι A N — Λ»^{0 H}⁰ H i 1 ו ' IHJ ^־N *״׳* Prepared from Ic and 152e-3</td><td> t_R = 2.89 min (&gt;95%); Condition 1 LRMS: Anal. Calcd. for C40H57N₈O5Si 757.42; found: 757.35 (M+H)⁺. HRMS: Anal. Calcd. for C40H57N8O₅Si 757.4221; found: 757.4191 (M+H)⁺.</td>

<td> Example 152g-4</td><td> ד «An 7 τ' 1 ^ל 1״ v N “A“j-0 Prepared from l6־c and 152e-2</td><td> t_R = 2.87 min (97%); Condition 1 LRMS: Anal. Calcd. for C₃8H₅5N8O5Si 731.41; found: 731.26 (M+H)⁺. HRMS: Anal. Calcd. for C₃8H₅₅N8O₅Si 731.4065; found: 731.4070 (M+H)⁺.</td>

<td> Example 152g-5</td><td> ־t 1 η T Π J I /⁵*O \ °&lt;^° f π ד ( ך ¹ IKj ^.N Prepared from l-6c and 152e־l</td><td> t_R = 2.94 min (&gt;95%); Condition 1 LRMS: Anal. Calcd. for C38H55N8O5S1 731.41; found: 731.26 (M+H)⁺. HRMS: Anal. Calcd. for C38H55N₈O5Si 731.4065; found: 731.4046 (M+H)⁺.</td>

<td> Example 152g-6</td><td> * H TZL- ojQ ־;s^'' J-NH y_ ' ₀F° Prepared from l-6c and 152e-4</td><td> t_R = 1.99 min (condition 2, 96%) LRMS: Anal. Calcd. for C₃₇H53N₇O2Si 703.39; found: 704.34 (M+H)⁺.</td>

<td> Example 152g-7</td><td> Av° ' N ר-א rV(׳l^ Uj* ^N0ך ר Τ־νΛ 0' Prepared from 1c and 152e-4</td><td> t_R = 1.99 min (condition 2, 96%) LRMS: Anal. Calcd. for C₃9H₅₅N7O5Si 729.40 found: 730.42 (M+H)⁺.</td>

<td> Example 152g-8</td><td> N־~, CwjL V « γΊι ו 0.^0 0־־? ? if 1 h 1 וץ v&gt;־־o Prepared from l-5c and 152d-l</td><td> t_R= 2.15 min (&gt;95%); Condition 1 LRMS: Anal. Calcd. for C37H41N8O4 661.33; found: 661.39 (M+H)⁺. HRMS: Anal. Calcd. for C37H41N8O4 661.3251; found: 661.3268 (M+H)⁺.</td>

<td> Example 152g-9</td><td> cv-^ji O 1 η I fl ״A׳, 0^0 ^ו׳&lt; --ί-- _y^N&gt; ¹ XW Prepared from 1c and 152f-l</td><td> t_R = . 1.71 min (&gt;95%); Condition 1 LRMS: Anal. Calcd. for C36H40N9O3 646.76; found: 646.47 (M+H)⁺. HRMS: Anal. Calcd. for C36H4QN9O3 not done found: not done (M+H)⁺.</td>

<td> Example 152g- 10</td><td> CW1 O ־« זτ'.ץ ״ 0^־&gt;0 נ\׳f JL Uu A ¹ iKj Prepared from 152d-l and l-10c</td><td> t_R = 1.71 min (&gt;95%); Condition 1 LRMS: Anal. Calcd. for C36H40N9O3 646.33; found: 646.37 (M+H)⁺. HRMS: Anal. Calcd. for C36H40N9O3 646.3254; found: 646.3240 (M+H)⁺.</td>

<td> Example 152g11</td><td> Φ \ Η | I 1 /=*0 0^0 ך וו ף η י a τ&gt;־־ο ^.N *-׳־^ Prepared from 1 -6c and 152e-4</td><td> t_R = 2.12 min (&gt;93.9%); Condition 1 LRMS: Anal. Calcd. for C33H42N7O4 600.33; found: 600.11</td>

<td></td><td></td><td> (M+H)⁺. HRMS: Anal. Calcd. for C33H42N7O4 600.3298; found: 600.3312 (M+H)⁺.</td>

<td> Example 152g- 12</td><td> Ml . u, hn Xa-* 1 η T 1 ’ Ao A/k 0*^,0 2 ^N ךןן h V ' T'ACj ^־“N **״^ Prepared from lc and 152d-5</td><td> t_R = 2.13 min (97.3%); Condition 1 LRMS: Anal. Calcd. for C32H41N8O4 601.33; found: 601.36 (M+H)⁺. HRMS: Anal. Calcd. for C32H41N8O4 601.3251; found: 601.3253 (M+H)⁺.</td>

<td> Example 152g- 13</td><td> Ml_ HN N'^r^X X/-* L ^H 1 ll » 0^&gt;0 °_Ύ° a Uj A ' TAQ Prepared from lc and 152d-6</td><td> t_R = 2.11 min (98.5%); Condition 1 LRMS: Anal. Calcd. for C32H41N8O4 601.33; found: 601.36 (M+H)⁺. HRMS: Anal. Calcd. for C32H41N8O4 601.3251; found: 601.3253 (M+H)⁺.</td>

<td> Example 152g- 14</td><td> &lt; N.^ 2-¢ jl _λ^S‘N N^Xf^X Χ/-*־ A ^H T 0 1 θΑ=Ό ⁰¾^° Λ AVo Prepared from l-8c and 152d-l</td><td> t_R= 2.18 min (&gt;95%); Condition 1 LRMS: Anal. Calcd. for C33H43N8O4 615.34; found: 615.38 (M+H)⁺. HRMS: Anal. Calcd. for C33H43N8O4 615.3407; found: 615.3433 (M+H)⁺.</td>

<td></td><td></td><td></td>

<td> Example 152g- 15</td><td> Hl ^HV «η ז /==0 0^.0 ? li ל h 1 L ,^N=s. ךוך T&gt;״Q Prepared from 1c and 152d-l</td><td> t_R = 2.20 min (97.7%); Condition 1 LRMS: Anal. Calcd. for C35H39N8O4 635.31; found: 635.36 (M+H)⁺. HRMS: Anal. Calcd. for C35H39N8O4 635.3094; found: 635.3119 (M+H)⁺.</td>

<td> Example 152g- 16</td><td> Hl *n ׳־־*-ד v ^H I 1 י /¾° 0^0 γ Prepared from 1-90 and 152d-l</td><td> t_R = 2.26 min (&gt;95%); Condition 1 LRMS: Anal. Calcd C36H41N8O4 649.33; found: 649.39 (M+H)⁺. HRMS: Anal. Calcd. for C36H41N8O4 649.3251; found: 649.3276 (M+H)⁺.</td>

<td> Example 152g- 17</td><td> y&lt;^N11 t ^HNv B rl / 1^ /=0 L. JC.N. o. ₀__0 Prepared from l-6c and 152e-3</td><td> t_R = 2.98 min (98.5%); Condition 1 LRMS: Anal. Calcd. for C38H54N₈O₅Si 730.39; found: 731.40 (M+H)⁺. HRMS: Anal. Calcd. for C₃8H54N8O₅Si 731.4065; found: 731.4045 (M+H)⁺.</td>

Example 152h-l-152h-7

Example 152h-l from 152g-l. 5-((S)-2-Pyrrolidin-2-yl-3H-imidazol-4-yl)-2-[4-((S)2-pyrrolidin-2-yl-3H-imidazol-4-yl)-phenyl]-pyrimidine

TFA (8 mL) was added in one portion to a stirred solution of (S)-2-[5-(2-{4[2-((S)1 ־ -tert-butoxycarbonyl-pyrrolidin2־-yl)-3H-imidazol-4-yl]-phenyl} -pyrimidin5-yl)- l-(2-trimethylsilanyl-ethoxymethyl)- lFAimidazol-2-yl] -pyrrolidine-1 carboxylic acid tert-butyl ester (1.50 g, 1.98 mmol) in dry CH2C12 (30 mL) at room temperature. The flask was sealed and the mixture was stirred at room temperature for 16h before the solvents) were removed in vacuo. The residue was taken up in methanol, filtered through a PVDF syringe filter (13mm x 0.45pm), distributed to 8 pHPLC vials and chromatographed by HPLC (gradient elution from 10%B to 100%B over 13 min on a Phenomenex C18 column, 30 x 100mm, 10pm, where A = 90% water, 10% methanol, 0.1% TFA, B = 10% water, 90% methanol, 0.1% TFA). After concentration of the selected test tubes by speed vacuum evaporation, the product was dissolved in methanol and neutralized by passing the solution through an UCT CHQAX 110M75 anion exchange cartridge. There was isolated the title compound as a yellow mustard-colored solid (306.7 mg, 36% yield) upon concentration of the eluant.

*HNMR(500 MHz, DMSO-d₆) μ 12.50-11.80 (brm, 2H), 9.18 (s, 2H), 8.36 (d, /=8.5 Hz, 2H), 7.89 (d, /=8.2 Hz, 2H), 7.77 (s, 1H), 7,61 (s, 1H), 4.34-4.24 (m, 2H), 3.09-2.89 (m, 4H), 2.18-2.07 (m, 2H), 2.02-1.89 (m, 2H), 1.88-1.72 (m, 4H).

LCMS Phenomenex LUNA C-18 4.6 x 50 mm, 0 to 100% B over 3 minutes, 1 minute hold time, A = 90% water, 10% methanol, 0.1% TFA, B = 10% water, 90% methanol, 0.1% TFA, RT = 1.33 min, >95% homogeneity index.

LRMS: Anal. Calcd. for C₂4H₂7N₈ 427.24; found: 427.01 (M+H)⁺. HRMS: Anal. Calcd. for C₂₄H27N₈ 427.2359; found: 427.2363 (M+H)⁺.

The same conditions were used to prepare Examples 152h-2 through 152h-14.

LC conditions: Condition 1: Phenomenex LUNA C-18 4.6 x 50 mm, 0 to 100% B over 3 minutes, 1 minute hold time, A = 90% water, 10% methanol, 0.1% TFA, B =

10% water, 90% methanol, 0.1% TFA, 220nm, 5 pL injection volume.

Condition 2; Phenomenex LUNA C-18 4.6 x 50 mm, 0 to 100% B over 2 minutes, 1 minute hold time, A = 90% water, 10% methanol, 0.1% TFA, B = 10% water, 90% methanol, 0.1% TFA, 220nm, 5 pL injection volume.

<td> Example 15211-2</td><td> r—&lt; ^NX CWJL מ rA Η Η ^ΝχΖχ^^Ν Ύ/&gt;-Cj Prepared from 152g-3</td><td> t_R= 1.36 min (98%); Condition 1 LRMS: Anal. Calcd. forC₂₄H₂₇N₈ 427.24; found: 427.48 (M+H)⁺. HRMS: Anal. Calcd. forC₂₄H₂₇N8 427.2359; found: 427.2339 (M+H)⁺.</td>

<td> Example 15211-3</td><td> h₂n jCm a ⁿ v&gt;-0 Preapared from 152g-4</td><td> t_R = 1.17 min (&gt;95%); Condition 1 LRMS: Anal. Calcd. forCaHwNs 401.22; found: 401.16 (M+H)⁺. HRMS: Anal. Calcd. forC₂₂H₂₅N₈ 401.2202; found: 401.2193 (M+H)⁺.</td>

<td> Example 152h-4</td><td> WK H₂N ^H 1 1 11 ן η h NkZKn /K Ύ/)-&lt;j י—N</td><td> t_R= 1.28 min (89.3%); Condition 1</td>

<td></td><td> Prepared from 152g-5</td><td> LRMS: Anal. Calcd. forC22H₂₅N8 401.22; found: 401.16 (M+H)⁺. HRMS: Anal. Calcd. forC₂₂H₂₅N₈ 401.2202; found: 401.2201 (M+H)⁺.</td>

<td> Example 15211-5</td><td> H N— &lt;-\_A Li Ap. n~7 7־NH₂ Prepared from 152g-7</td><td> t_R = 0.93 min; Condition 2 LRMS: Anal. Calcd. for C₂₃H₂₅N₇ 399; found: 400 (M+H)⁺.</td>

<td> Example 152h-6</td><td> 1&gt;ν׳^־Η^NXu \־־־&gt;^Nxi^X V .N NH₂~־y 6-Prepared from 152g</td><td> t_R= 0.81 min; Condition 2 LRMS: Anal. Calcd. for C_2]H₂₃N₇ 373; found: 374 (M+H)⁺.</td>

<td> Example 152h-7</td><td> * ^Ν~Ά^\ V ,N n-7 σ Prepared from 152g-ll</td><td> t_R = 1.14 min (&gt;95%); Condition 1 LRMS: Anal. Calcd. forC₂₃H₂₆N₇ 400.23; found: 400.14 (M+H)⁺. HRMS: Anal. Calcd. forC23H₂₆N₇ 400.2250; found: 400.2234</td>

<td></td><td></td><td> (M+H)⁺.</td>

<td> Example 15211-8</td><td>^N 01 Η H N *״׳^ Prepared from 152g12־</td><td> t_R = 1.29 min (&gt;95%); Condition 1 LRMS: Anal. Calcd. forC^HisNe 401.22; found: 401.21 (M+H)⁺. HRMS: Anal. Calcd. forC22H₂₅N₈ 401.2202; found: 401.2204 (M+H)⁺.</td>

<td> Example 152h-9</td><td> H'l H_ZN Ν-χ^Ν ^H L JL Η H LA^N 7Ά Ύ &gt;-Cj ^N *״־^ Prepared from 152g-13</td><td> t_R= 1.29 min (97.6%); Condition 1 LRMS: Anal. Calcd. forC22H₂₅N₈ 401.22; found: 401.21 (M+H)⁺. HRMS: Anal. Calcd. for C^Ng 401.2202; found: 401.2220 (M+H)⁺.</td>

<td> Example 152h- 10</td><td> r-־&lt; CAI _ B מ AQ1 1Aj ¹*־N Prepared from 152g-2</td><td> t_R= 1.26 min (86.4%); Condition 1 LRMS: Anal. Calcd. forC₂4H₂₇N₈ 427.24; found: 427.48 (M+H)⁺.</td>

<td></td><td></td><td> HRMS: Anal. Calcd. forC24H₂₇N₈ 427.2359; found: 427.2339 (M+H)⁺.</td>

<td> Example 152h11</td><td> 0־־&lt; Jl O η h 1 ן ץ N- כ&gt;-&lt;/1 Prepared from 152g-9</td><td> t_R = 1.26 min (&gt;95%); Condition 1 LRMS: Anal. Calcd. forC₃1H₃₂N₉O 546.27; found: 546.28 (M+H)⁺. HRMS: Anal. Calcd. for C3!H3₂N9O 546.2730 found: 546.2739 (M+H)⁺.</td>

<td> Example 152h12</td><td> Oh־ⁿ1_ O Η Η T ״ k JL ע^יס νΎ ך ULa Λ IW Prepared from 152g-10</td><td> t_R= 1.39 min (95%); Condition 1 LRMS: Anal. Calcd. for C31H₃₂N₉O 546.27; found: 546.32 (M+H)⁺. HRMS: Anal. Calcd. forC₃1H3₂N₉O 546.2730; found: 546.2719 (M+H)⁺.</td>

<td> Example 152h13</td><td> ט η η ז II 1 Η Η ν- IKJ Prepared from 152g-14</td><td> t_R= 1.42 min; Condition 1 LRMS: Anal. Calcd. for CANg 414.24; found: 415.27 (M+H)⁺.</td>

<td></td><td></td><td> HRMS: Anal. Calcd. forC₂₃H₂₆N₈ 415.2359; found: 415.2371 (M+H)⁺.</td>

<td> Example 152h14</td><td> OAK/S ^{H H} I 11 NH_־Ύ/&gt;—C ^־N . Prepared from 152g-17</td><td> t_R= 1.30 min; Condition 1 LRMS: Anal. Calcd. for C22H24N8 400.21; found: 401.24 (M+H)⁺. HRMS: Anal. Calcd. forC22H24N₈ 401.2202; found: 401.2198 (M+H)⁺.</td>

Example 1521-1 to 1521-3

Example 1521-1 from 152g-8. (S)-2-(5-{2-[4-((S)-2-Pyrrolidin-2-yl-3H-imidazol-4yl)-phenyl]-pyrimidin-5-yl}-lH-imidazol-2-yl)-pyrrolidine-l-carboxylicacid tert5 butyl ester

<img file="IL196813A_D0226.tif" />

A solution of (S)-2-[5-(2- {4-[2-((S)-l -Benzyloxycarbonyl-pyrrolidin-2-yl)3H-imidazol-4-yl]-phenyl} -pyrimidin-5-yl)- l//-imidazol-2-yl]-pynolidine-1carboxylic acid tert-butyl ester (317.1 mg, 0.48 mmol) in MeOH (1 mL) was added 10 to a stirred suspension of 10% palladium on carbon (60 mg) and K₂CO₃ (70 mg) in a solution of MeOH (5 mL) and H₂O (0.1 mL) at room temperature under N₂. The flask was charged and evacuated three times with H₂ and stirred for 3h at atmosphere pressure. Additional catalyst (20 mg) was then added and the reaction mixture was stirred further for 3h before it was suction-filtered through diatomaceous earth (Celite®) and concentrated. The residue was diluted with MeOH, filtered through a PVDF syringe filter (13mm x 0.45 pm), distributed into 4 pHPLC vials and chromatographed (gradient elution from 20%B to 100%B over 10 min on a Phenomenex-Gemini Cl8 column (30 x 100mm, lOprti) where A = 95% water, 5% acetonitrile, 10mMNH4OAc, B = 10% water, 90% acetonitrile, 10mMNH4OAc). After concentration of the selected test tubes by speed vacuum evaporation, there was isolated the title compound as a yellow solid (142.5 mg, 56% yield).

¹H NMR (400 MHz, DMSO-d₆) δ 12.35-12.09 (br m, 1H), 9.17 (s, 2H), 8.35 (d, J=8.3Hz, 2H), 7.87 (d, J=8.3Hz, 2H), 7.80-7.72 (m, 1H), 7.56 (s, 1H), 4.92-4.77 (m, 1H), 4.21-4.13 (m, 1H), 3.61-3.05 (2m, 4H), 3.02-2.80 (2m, 2H), 2.37-1.67 (series of m, 6H), 1.41 and 1.17 (2s, 9H).

LCMS Phenomenex LUNA C-18 4.6 x 50 mm, 0 to 100% B over 3 minutes, 1 minute hold time, A = 90% water, 10% methanol, 0.1% TFA, B = 10% water, 90% methanol, 0.1% TFA, RT = 1.77 min, >95 % homogeneity index.

LRMS: Anal. Calcd. for C29H35N8O2 527.29; found: 527.34 (M+H)⁺. HRMS: Anal. Calcd. for C29H35N8O2 527.2883; found: 527.2874 (M+H)⁺.

The same procedure was used to prepare Examples 1521-2 through 1521-3.

LC conditions: Condition 1: Phenomenex LUNA C-18 4.6 x 50 mm, 0 to 100% B over 3 minutes, 1 minute hold time, A = 90% water, 10% methanol, 0.1% TFA, B = 10% water, 90% methanol, 0.1% TFA, 220nm, 5 pL injection volume.

Condition 2; Phenomenex LUNA C-18 4.6 x 50 mm, 0 to 100% B over 2 minutes, 1 minute hold time, A = 90% water, 10% methanol, 0.1% TFA, B = 10% water, 90% methanol, 0.1% TFA, 220nm, 5 pL injection volume.

<img file="IL196813A_D0227.tif" />

<td></td><td></td><td> HRMS: Anal. Calcd. for C27H33N8O2 501.2726 found: 501.2709 (M+H)⁺.</td>

<td> Example 1521-3</td><td> 0^0 Prepared from 15 2g-16</td><td> t_R = 1.77 min (&gt;95%); Condition 1 LRMS: Anal. Calcd. for C28H35N8O2 515.29; found: 515.37 (M+H)⁺. HRMS: Anal. Calcd. for C28H35N8O2 515.2883 found: 515.2869 (M+H)⁺.</td>

Examples 152j-l to 152j-28

Examples 152j were isolated as TFA or AcOH salts prepared using the procedure to convert Example 148e to 148.

LC conditions: Condition 1: Phenomenex LUNA C-18 4.6 x 50 mm, 0 to 100% B over 3 minutes, 1 minute hold time, A = 90% water, 10% methanol, 0.1% TFA, B = 10% water, 90% methanol, 0.1% TFA, 220nm, 5 pL injection volume.

Condition 2\ Phenomenex LUNA C-18 4.6 x 50 mm, 0 to 100% B over 2 minutes, 1 minute hold time, A = 90% water, 10% methanol, 0.1% TFA, B = 10% water, 90% methanol, 0.1% TFA, 220nm, 5 pL injection volume.

<td> Example</td><td> Compound Name</td><td> Structure</td><td> Data</td>

<td> Example 152j-l</td><td> (lR)-2-((2S)-2-(5-(2(4-(2-((2S)-l-((2R)2-(dimethylamino)-2phenylacetyl)-2pyrrolidinyl)-1Himidazol-5yl)pheny 1)-5-</td><td> δ Λδδ Prepared from 152h-l and Cap-1.</td><td> t_R= 1.61 min; (&gt;95%); Condition 1 LRMS: Anal. Calcd. for C44H49N10O2</td>

<td></td><td> pyrimidinyl)-lHimidazol-2-y 1)-1pyrrolidinyl)-N,Ndimethyl-2-oxo-1 phenylethanamine</td><td></td><td> 749.40 found: 749.32 (M+H)⁺ HRMS: Anal. Calcd. for C44H49N10O2 749.4040 found: 749.4042 (M+H)⁺</td>

<td> Example 152j-2</td><td> methyl ((1R)-22))־S)2-(5-(2-(4-(2-((28)-1((2R)-2((methoxycarbonyl)a mino)-2phenylacetyl)-2pyrrolidinyl)-1Himidazol-5yl)pheny 1)-5pyrimidinyl)-lHimidazol-2-yl)-lpyrrolidinyl)-2-oxo1phenylethyl)carbamat e</td><td> 0/1 O 0 ן ^N Ah?״ ⁰0^^0, 4-Prepared from 152h-l and Cap</td><td> t_R = 1.99 min (&gt;95%); Condition 1 LRMS: Anal. Calcd. for C44H45N10O6 809.35 found: 809.17 (M+H)⁺ HRMS: Anal. Calcd. for C44H45N10O6 809.3524 found: 809.3505 (M+H)⁺</td>

<td> Example 152j-3</td><td> methyl ((lR)-2-oxo1 -phenyl-2-((2S)-2(5-(4-(5-(2-((28)-1(3-pyridinylacetyl)-2pyrrolidinyl)-1Himidazol-5-yl)-2pyrimidinyl)phenyl)lH-imidazol-2-yl)-1 pyrrolidinyl)ethyl)car bamate</td><td> Γ z~&lt; 1 ״ IL J °0 Aro Prepared from 152h-l 1 and Cap4</td><td> t_R = 1.65 min (92.3%); Condition 1 LRMS: Anal. Calcd. for C41H41N10O2 737.33 found: 737.49 (M+H)⁺</td>

<td></td><td></td><td></td><td> HRMS: Anal. Calcd. for C41H41N10O4 737.3312 found: 737.3342 (M+H)⁺</td>

<td> Example 152j-4</td><td> methyl ((lR)-2-oxol-phenyl-2-((2S)-2(5-(2-(4-(2-((2S)-l(3-pyridinylacetyl)-2pyrrolidinyl)-1Himidazol-5yl)phenyl)-5pyrimidinyl)-lH־ imidazol-2-y 1)-1pyrrolidinyl)ethyl)car hamate</td><td> γ־Λ 2S iHl _Λ nJ ״O Prepared from 152h-12 and Cap- 4</td><td> t_R = 1.64 min (&gt;95%); Condition 1 LRMS: Anal. Calcd. for C41H41N10O4 737.33 found: 737.75 (M+H)⁺ HRMS: Anal. Calcd. for C41H41N10O4 737.3312 found: 737.3284 (M+H)⁺</td>

<td> Example 152j-5</td><td> 5-(2-((2S)-l-((2R)-2phenyl-2-( 1piperidinyl)acetyl)-2pyrrolidinyl)-1Himidazol-5-yl)-2-(4(2-((2 S)-l-((2R)-2phenyl-2-( 1piperidinyl)acetyl)-2pyrrolidinyl)-1Himidazol-4yl)phenyl)pyrimidine</td><td> 9 (XA⁰ Prepared from 152h-l and Cap- 14</td><td> t_R= 1.70 min (&gt;95%); Condition 1 LRMS: Anal. Calcd. for C50H57N10O2 829.47 found: 829.39 (M+H)⁺ HRMS: Anal. Calcd. for C50H57N10O2</td>

<td></td><td></td><td></td><td> 829.4666 found: 829.4658 (M+H)⁺</td>

<td> Example 152j-6</td><td> (2R)-N-methyl-2phenyl-N-(( IS)-1-(4- (4-(5-(2-((2S)-l((2R)-2-phenyl-2-( 1 piperidinyl)acetyl)-2pyrrolidinyl)-IHimidazol-5-y 1)-2pyrimidinyl)phenyl)1 H-imidazol-2- yl)ethyl)-2-(lpiperidinyl)acetamide</td><td> Vss/ *—N ־־^ Prepared from 152h-13 and Cap14</td><td> t_R= 1.66 min (&gt;95%); Condition 1 LRMS: Anal. Calcd. for C49H57N10O2 817.47 found: 817.44 (M+H)⁺ HRMS: Anal. Calcd. for C49H57N10O2 817.4666 found: 817.4673 (M+H)⁺</td>

<td> Example 152j-7</td><td> (lR)-2-((2S)-2-(5-(5(4-(2-((2S)-1-((2R)2-(dimethylamino)-2phenylacetyl)-2pyrrolidinyl)-IHimidazol-5yl)phenyl)-2pyrazinyl)-lHimidazol-2-yl)-lpyrrolidinyl)-N,Ndimethyl-2-oxo-1 phenylethanamine</td><td> A- 5 $־׳ Prepared from 15211-2 and Cap-1</td><td> t_R= 1,60 min (&gt;95%); Condition 1 LRMS: Anal. Calcd. for C41H49N10O2 749.40 found: 749.31 (M+H)⁺ HRMS: Anal. Calcd. for C44H49N10O2 749.4040 found: 749.4031 (M+H)⁺</td>

<td> Example 152j-8</td><td> methyl ((lR)-2-((2S)2-(5-(5-(4-(2-((2S)-l((2R)-2((methoxy carbonyl)a mmo)-2₃henylacetyl)-2pyrrolidinyl)-IHimidazol-5yl)phenyl)-2pyrazinyl)-lHimidazol-2-yl)-lpyrrolidinyl)-2-oxo1- phenylethyl)carbamat e</td><td> «J״ ״־־ °O ^00־ Prepared from 152h-2 and Cap-4</td><td> t_R= 2.01 min (&gt;95%); Condition 1 LRMS: Anal. Calcd. for C44H45N10O6 809.35 found: 809.24 (M+H)⁺ HRMS: Anal. Calcd. for C44H45N10O6 809.3523 found: 809.3493 (M+H)⁺</td>

<td> Example 152j-9</td><td> (lR)-2-((2S)-2-(5-(6(4-(2-((2S)-1-((2R)2-(dimethylamn10)-2phenylacetyl)-2pyrrolidinyl)-IHimidazol-5yl)phenyl)-3pyridazinyl)-lHimidazol-2-y 1)-1pyrrolidinyl)-N,Ndimethyl-2-oxo-1 phenylethanamine</td><td> o Prepared from 152h-10 and Cap1</td><td> t_R= 1.76 min (&gt;95%); Condition 1 LRMS: Anal. Calcd. for C44H49N10O2 749.40 found: not obsd(M+H)⁺ HRMS: Anal. Calcd. for C44H49N10O2 749.4040 found: 749.4056 (M+H)⁺</td>

<td> Example 152j-10</td><td> methyl ((lR)-2-((2S)2-(5-(6-(4-(2-((2S)-l((2R)-2-</td><td> ו^׳י-ו CM1_Λ O ׳Ίλ ΧΑΟυ</td><td> t_R= 2.17 min (&gt;95%); Condition 1</td>

<td></td><td> 1 (methoxy carbonyl)a mino)-2phenylacetyl)-2pyrrolidinyl)-1Himidazol-5yl)phenyl)-3pyridazinyl)-lHimidazol-2-yl)-lpyrrolidinyl)-2-oxo1- 3henylethyl)carbamat e</td><td> Prepared from 152h-10 and Cap4</td><td> LRMS: Anal. Calcd. for C44H45N10O6 809.35 found: 809.59 (M+H)⁺ HRMS: Anal. Calcd. for C44H45N10O6 809.3524 found: 809.3499 (M+H)⁺</td>

<td> Example 152j-ll</td><td> (2R)-2(dimethylamino)-N((1 S)-l-(5-(4-(5-(2((2S)-l-((2R)-2(dimethylamino)-2phenylacetyl)-2pyrrolidinyl)-1Himidazol-5-yl)-2pyridinyl)phenyl)1 H-imidazol-2yl)ethyl)-2phenylacetamide</td><td> 5 0 Prepared from 152h-7 and Cap-1</td><td> t_R= 1.56 min (&gt;95%); Condition 1 LRMS: Anal. Calcd. for C43H48N9O2 722.39 found: 722.89 (M+H)⁺ HRMS: Anal. Calcd. for C43H48N9O2 722.3931 found: 722.3930 (M+H)⁺</td>

<td> Example 152j-12</td><td> methyl ((1R)-22))־S)2-(5-(6-(4-(2-((lS)-l(((2R)-2((methoxycarbonyl)a mino)-2phenylacetyl)amino)e</td><td> 0 ^071 ״ כל» ♦ο Prepared from 152h-7 and Cap-4</td><td> t_R= 1.95 min (&gt;95%); Condition 1 LRMS: Anal. Calcd. for</td>

<td></td><td> thyl)-1 H-imidazol-5 yl)phenyl)-3pyridinyl)-lHimidazol-2-yl)-lpyrrolidinyl)-2-oxo- phenylethyl)carbamat e</td><td></td><td> C43H44N9O6 782.34 found: 782.93 (M+H)⁺ HRMS: Anal. Calcd. for C43H44N9O6 782.3415 found: 782.3398 (M+H)⁺</td>

<td> Example 152j-13</td><td> (2R)-2- 1 dimethylamino)-N((18)-1-(5-(4-(6-(2((2S)-l-((2R)-21 dimethylamino)-2phenylacetyl)-2pyrrolidinyl)-1Himidazol-5-yl)-3pyridazinyl)phenyl)- 1 H-imidazol-2yl)ethyl)-2phenylacetamide</td><td> ov Q \A=O ^H Y״N^Z 0 ' Prepared from 152h-3 and Cap-1</td><td> t_R= 1.55 min &gt;95%); Condition 1 LRMS: Anal. Calcd. for C42H47N10O2 723.39 found: 723.88 (M+H)⁺ HRMS: Anal. Calcd. for C42H47N10O2 723.3883 found: 723.3903 (M+H)⁺</td>

<td> Example 152j-14</td><td> methyl ((1R)-22))־S)2-(5-(6-(4-(2-((1 S)-l(((2R)-2- ((methoxy carbonyl)a mino)-2phenylacetyl)amino)e thyl)-1 H-imidazol-5 - yl)phenyl)-3pyridazinyl)-lH-</td><td> CAa 0 ״ \ » n 11״/ «A °yS° ° O IK Prepared from 152h-3 and Cap-&lt; __</td><td> t_R= 1.95 min (&gt;95%); Condition 1 LRMS: Anal. Calcd. for C42H43N10O6 783.34 found: 783.95 (M+H)⁺</td>

<td></td><td> imidazol-2-yl)-lpyrrolidinyl)-2-oxo1- 7henylethyl)carbamat e</td><td></td><td> HRMS: Anal. Calcd. for C42H43N10O6 783.3367 found: 783.3337 (M+H)⁺</td>

<td> Example 152j-15</td><td> methyl ((lR)-2-((2S)2-(5-(2-(4-(2-((lS)-l(((2R)-2- 1 (methoxy carbonyl)a mino)-2phenylacetyl)amino)e thyl)-lH-imidazol-5yl)phenyl)-5pyrimidinyl)-lHimidazol-2-yl)-lpyrrolidinyl)-2-oxo1phenylethyl)carbamat e</td><td> 0 V mQl _מ v^{מ 0} O Prepared from 152h-4 and Cap-4</td><td> t_R= 1.97 min &gt;95%); Condition 1 LRMS: Anal. Calcd. for C42H43N10O6 783.34 found: 783.97 (M+H)⁺ HRMS: Anal. Calcd. for C42H43N10O6 783.3367 found: 783.3357 (M+H)⁺</td>

<td> Example 152j-16</td><td> (2R)-2(dimethylamino)-N((IS)-1-(5-(2-(4-(2((2S)-l-((2R)-2(dimethylamino)-2phenylacetyl)-2pyrrolidinyl)-1Himidazol-5yl)phenyl)-5pyrimidinyl)-lHimidazol-2-yl)ethyl)2-phenylacetamide</td><td> 0 O־° ^H *YYs 0 ׳Ύκ' Prepared from 152h-9 and Cap-1</td><td> t_R= 1.61 min (&gt;95%); Condition 1 LRMS: Anal. Calcd. for C42H47N10O2 723.39 found: 723.52 (M+H)⁺ HRMS: Anal. Calcd. for</td>

<td></td><td></td><td></td><td> C42H47N10O2 723.3883 found: 723.3893 (M+H)⁺</td>

<td> Example 152j-17</td><td> methyl ((1R)-22))־S)־ 2-(5-(4-(5-(2-((lS)-l(((2R)-2- 1 (methoxy carbonyl)a mino)-2- phenylacetyl)amino)e thyl)-1 H-imidazol-5 yl)-2pyrimidinyl)phenyl)1 H-imidazol-2-yl)-1 pyrrolidinyl)-2-oxo1- phenylethyl)carbamat e</td><td> ° o Prepared from 15211-9 and Cap-4</td><td> t_R= 1.99 min (95.6%); Condition LRMS: Anal. Calcd. for C42H43N10O6 783.34 found: 783.44 (M+H)⁺ HRMS: Anal. Calcd. for C42H43N10O6 783.3367 found: 783.3328 (M+H)⁺</td>

<td> Example 152j-18</td><td> (2R)-2(dimethylamino)-N((IS)-1-(5-(5-(4-(2((2S)-l-((2R)-2(dimethylamino)-2phenylacetyl)-2pyrrolidinyl)-1Himidazol-5yl)phenyl)-2pyrazinyl)-1Himidazol-2-yl)ethyl)2-phenylacetamide</td><td> w s Q.V לא O ^,Dm 1-Prepared from 152h-8 and Cap</td><td> t_R= 1.60 min (&gt;95%); Condition 1 LRMS: Anal. Calcd. for C42H47N10O2 723.39 found: 723.47 (M+H)⁺ HRMS: Anal. Calcd. for C42H47N10O2 723.3883 found: 723.3861 (M+H)⁺</td>

<td></td><td></td><td></td><td></td>

<td> Example 152j-19</td><td> methyl ((1R)-22))־S)2-(5-(4-(5-(2-((1 S)-l(((2R)-2- 1 (methoxycarbony l)a mino)-2phenylacetyl)amino)e thyl)-1H -imidazol-5 yl)-2pyrazinyl)phenyl)- 1 H-imidazol-2-yl)-1 pyrrolidinyl)-2-oxo1phenylethyl)carbamat e</td><td> ° 1 H !⁴^il \ nV'*'״ ״ ⁰'?‘J«, o v« ^N B H *׳** VsaZ 4-Prepared from 152h-8 and Cap</td><td> t_R= 1.97 min (94.7%); Condition 1 LRMS: Anal. Calcd. for C42H43N10O6 783.34 found: 783.69 (M+H)⁺ HRMS: Anal. Calcd. for C42H43N10O6 783.3367 found: 783.3345 (M+H)⁺</td>

<td> Example 152j-20</td><td> (2R)-2(dimethylamino)-N((1S)-1-(5-(4-(5-(2((2S)-l-((2R)-2(dimethylamino)-2phenylacetyl)-2pyrrolidinyl)-1Himidazol-5-yl)-2pyrimidinyl)phenyl)1 H-imidazol-2yl)ethyl)-N-methyl-2phenylacetamide</td><td> .j ־Vf Prepared from 1521113־ and Cap1</td><td> t_R= 1.54 min (&gt;95%); Condition 1 LRMS: Anal. Calcd. for C43H49N10O2 737.40 found: 737.54 (M+H)⁺ HRMS: Anal. Calcd. for C43H49N10O2 737.4040 found: 7374066 (M+H)⁺</td>

<td> Example 152j-21</td><td> methyl ((1R)-22))־S)2-(5-(2-(4-(2-((lS)-l-</td><td>⁰ fl ¾¾/ ^־N ’</td><td> t_R = 2.00 min (&gt;95%); Condition</td>

<td></td><td> (((2R)-2((methoxycarbonyl)a mino)-2phenylacetyl)(methyl )amino)ethyl)-lHimidazol-5yl)pheny 1)-5pyrimidinyl)-lHimidazol-2-yl)-lpyrrolidinyl)-2-oxo1phenylethyl)carbamat e</td><td> Prepared from 152h-13 and Cap4</td><td> 1 LRMS: Anal. Calcd. for C43H45N10O6 797.35 found: 797.38 (M+H)⁺ HRMS: Anal. Calcd. for C43H45N10O6 797.3524 found: 797.3528 (M+H)⁺</td>

<td> Example 152j-22</td><td> methyl ((lR)-2-((2S)2-(5-(4-(5-(2-((lS)־l(((2R)-2- ((methoxy carbonyl)a mino)-2- phenylacetyl)amn10)e thy 1)-1 H-imidazol-5 yl)-2pyridinyl)phenyl)1 H-imidazol-2-yl)-1 pyrrolidinyl)-2-oxo1- phenylethyl)carbamat e</td><td> Ar⁰N ^N*n &lt; p Prepared from 152h-5 and Cap-4</td><td> t_R = 1.46 min (condition 2, 98%) LRMS: Anal. Calcd. for C43H43N9O6 781.33; found: 782.34 (M+H)⁺. HRMS: Anal. Calcd. for C43H44N9O6 782.3415 found: 782.3417 (M+H)⁺</td>

<td> Example 152j-23</td><td> methyl ((lR)-2(((18)-1-(5-(6-(4-(2((1S)-1-(((2R)2־((methoxycarbonyl)a mino)-2phenylacetyl)amino)e</td><td>^N־־n ⁰ * ^N kl Γ N ⁰ Prepared from 15211-6 and Cap-4</td><td> t_R= 1.44 min condition 2,90%) LRMS: Anal. Calcd. for C41H41N9O6</td>

<td></td><td> thyl)-1 H-imidazol-5 yl)phenyl)-3pyridinyl)-lHimidazol-2yl)ethyl)amino)-2oxo-1phenylethyl)carbamat e</td><td></td><td> 755.32; found: 756.35 (M+H)⁺. HRMS: Anal. Calcd. for C41H42N9O6 756.3258 found: 756.3239 (M+H)⁺.</td>

<td> Example 152j-24</td><td> (2R)-2(dimethylamino)-N((18)-1-(5-(6-(4-(2((lS)-l-(((2R)-2(dimethylamino)-2phenylacetyl)amino)e thyl)-1 H-imidazol-5yl)phenyl)-3pyridinyl)-lHimidazol-2-yl)ethyl)2-phenylacetamide</td><td>^{4 N} Yr o Prepared from 152h-6 and Capl</td><td> t_R= 1.18 min (condition 2, 91%) LRMS: Anal. Calcd. for C41H45N9O2 695.37; found: 696.37 (M+H)⁺. HRMS: Anal. Calcd. for C41H46N9O2 696.3774 found: 696.3806 (M+H)⁺.</td>

<td> Example 152j-25</td><td></td><td> -¼½ Prepared from 1521-3 and Cap-4</td><td> t_R= 2.08 min (95.8 %); Condition 1 LRMS: Anal. Calcd. for C38H44N9O5 706.35; found: 706.53 (M+H)⁺. HRMS: Anal. Calcd. for</td>

<td></td><td></td><td></td><td> C38H44N9O5 706.3465; found: 706.3492 (M+H)⁺.</td>

<td> Example 152j-26</td><td></td><td> A ^C Prepared from 1521-2 and Cap-4</td><td> t_R = 2.04 min (96.4 %); Condition 1 LRMS: Anal. Calcd. for C37H42N9O5 692.33; found: 692.49 (M+H)⁺. HRMS: Anal. Calcd. for C37H42N9O5 692.3309; found: 692.3322 (M+H)⁺.</td>

<td> Example 152j-27</td><td></td><td> Γχΐ ~ ϊ tT'r'ii r '?־A . V 6 ״ Ayo Prepared from 1521-1 and Cap-4</td><td> t_R= 2.04 min (&gt;95 %); Condition 1 LRMS: Anal. Calcd. for C39H44N9O5 718.35; found: 718.49 (M+H)⁺. HRMS: Anal. Calcd. for C39H44N9O5 718.3465; found: 718.3483 (M+H)⁺.</td>

<td> Example 152j-28</td><td> methyl ((lR)-2-((2S)2-(5-(5-(4-(2-((lS)-l(((2R)-2- ((methoxy carbonyl)a mino)-2phenylacetyl)amino)e thyl)- lH-imidazol-5yl)phenyl)-2pyrazinyl)-lHimidazol-2-yl)-lpyrrolidinyl)-2-oxo1- phenylethyl)carbamat e</td><td> Prepared from 15211-14 and Cap4</td><td> t_R = 2.00 min (&gt;95%); Condition 1 LRMS: Anal. Calcd. for C42H43N10O6 783.34 found: 783.96 (M+H)⁺ HRMS: Anal. Calcd. for C42H43N10O6 783.3367 found: 783.3375 (M+H)⁺</td>

Examples 152k-l to 152kExample 152k-lfrom 152j-27. {(R)-2-Oxo-l-phenyl-2-[(S)-2-(5-{4-[5-((S)-2pyrrolidin-2-yl-3H-imidazol-4-yl)-pyrimidin-2-yl]-phenyl}-lH-imidazol-2-yl)5 pyrrolidin-l-yl]-ethyl}-carbamic acid methyl ester

<img file="IL196813A_D0228.tif" />

Cold (0°C) 4 AHCl in dioxanes (4 mL) was added via syringe to (S)-2-{5-[2(4-{2-[(S)-l-((R)-2-methoxycarbonylamino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3/fimidazol-4-yl}-phenyl)-pyrimidin-5-yl]-17/-imidazol-2-yl}-pyrrolidine-l-carboxylic 10 acid tert-butyl ester (104.6 mg, 0.146 mmol) in a 100 mL pear-shaped flask followed by MeOH (0.5 mL). The homogeneous mixture was stirred at room temperature for 15 min before a precipitate was observed. After stirring further for 1.75h, the suspension was diluted with ether and hexanes. Suction-filtration of a small portion of the suspension yielded the title compound as a yellow solid which was used for 15 characterization purposes. The balance of the suspension was concentrated down to dryness and placed under high vacuum for 16h. There was isolated the rest of the title compound also as a yellow solid (137.7 mg, 123%) which was used without further purification.

¹H NMR (500 MHz, DMSO-d₆) δ 15.20 and 14.66 (2m, 1H), 10,29 (br s, 0.7H), 9.38-9.36 (m, 2H), 8.55-8.00 (series of m, 4H), 7.42-7.28 (2m, 3H), 5.53-4.00 (series of m, 7H), 3.99-3.13 (series of m, 4H), 3.57 and 3.52 (2s, 3H), 2.50-1.84 (series of m, 8H).

LCMS Phenomenex LUNA C-18 4.6 x 50 mm, 0 to 100% B over 3 minutes, 1 minute hold time, A = 90% water, 10% methanol, 0.1% TFA, B = 10% water, 90% methanol, 0.1% TFA, RT = 1.79 min, >95 % homogeneity index.

LRMS: Anal. Calcd. for C34H36N9O3 618.29; found: 618.42 (M+H)⁺.

HRMS: Anal. Calcd. for C34H36N9O3 618.2921; found: 618.2958 (M+H)⁺.

The same procedure was used to prepare Examples 152k-2 through 152k-3.

LC conditions: Condition 1: Phenomenex LUNA C-18 4.6 x 50 mm, 0 to 100% B over 3 minutes, 1 minute hold time, A = 90% water, 10% methanol, 0.1% TFA, B = 10% water, 90% methanol, 0.1% TFA, 220nm, 5 pL injection volume.

Condition 2: Phenomenex LUNA C-18 4.6 x 50 mm, 0 to 100% B over 2 minutes, 1 minute hold time, A = 90% water, 10% methanol, 0.1% TFA, B = 10% water, 90% methanol, 0.1% TFA, 220nm, 5 pL injection volume.

<td> Example</td><td> Compound Name</td><td> Structure</td><td> Data</td>

<td> Example</td><td></td><td> f xz J A )=° 0 \</td><td> t_R = 1.74 min (&gt;95 %); Condition 1 LRMS: Anal. Calcd. for</td>

<td> 152k-2</td><td></td><td> '״‘N</td><td> C32H34N9O3</td>

<td></td><td></td><td> Prepared from 152j-26</td><td> 592.28; found: 592.41 (M+H)⁺. HRMS: Anal.</td>

<td></td><td></td><td></td><td> Calcd. for C32H34N9O3 592.2785; found: 592.2775 (M+H)⁺.</td>

<td> Example 152k-3</td><td></td><td> 2-¢ Jl Prepared from 152j-25</td><td> t_R = 1.79 min (&gt;95 %); Condition 1 LRMS: Anal. Calcd. for C33H36N9O3 606.29; found: 606.43 (M+H)⁺. HRMS: Anal. Calcd. for C33H36N9O3 606.2941; found: 606.2925 (M+H)⁺.</td>

Examples 1521-1 to 1521Examples 1521-1 through 1521-3 were isolated as TFA or AcOH salts prepared using the same procedure to convert Example 148e to 148.

LC conditions: Condition 1: Phenomenex LUNA C-18 4.6 x 50 mm, 0 to 100% B over 3 minutes, 1 minute hold time, A = 90% water, 10% methanol, 0.1% TFA, B = 10% water, 90% methanol, 0.1% TFA, 220nm, 5 pL injection volume.

Condition 2: Phenomenex LUNA C-18 4.6 x 50 mm, 0 to 100% B over 2 minutes, 1 minute hold time, A = 90% water, 10% methanol, 0.1% TFA, B = 10% water, 90% methanol, 0.1% TFA, 220nm, 5 pL injection volume.

<td> Example</td><td> Compound Name</td><td> Structure</td><td> Data</td>

<td> Example 1521-1</td><td> methyl ((lR)-2(methyl((lS)-l-(4-(4-(5(2-((2S)-l-((2R)-2phenyl-2-(lpiperidinyl)acetyl)-2pyrrolidinyl)-IHimidazol-5-yl)-2pyrimidinyl)pheny 1)-1Himidazol-2- yl)ethyl)amino)-2-oxo1 -phenylethy !)carbamate</td><td> __ 0 ^{N N} Til .o Prepared from 152k-3 and Cap14</td><td> t_R = 1.87 min &gt;95%); Condition 1 LRMS: Anal. Calcd. for C46H51N10O4 807.41 found: 807.57 (M+H)⁺ HRMS: Anal. Calcd. for C46H51N10O4 807.4095 found: 807.4128 (M+H)⁺</td>

<td> Example 1521-2</td><td> methyl ((lR)-2-oxo-lphenyl-2-((( IS)-1-(4-(4(5-(2-((2S)-l-((2R)-2phenyl-2-( 1piperidinyl)acetyl)-2pyrrolidinyl)-IHimidazol-5-y 1)-2pyrimidiny l)pheny 1)-1Himidazol-2yl)ethyl)amino)ethyl)car bamate</td><td> Prepared from 152k-2 and Cap14</td><td> t_R= 1.83 min (&gt;95%); Condition 1 LRMS: Anal. Calcd. for C45H49N10O4 793.39 found: 793.52 (M+H)⁺ HRMS: Anal. Calcd. for C45H49N10O4 793.3938 found: 793.3934 (M+H)⁺</td>

<td> Example 1521-3</td><td> methyl ((1 R)-2-oxo-1phenyl-2-((2S)-2-(4-(4-</td><td> .W, 2</td><td> t_R= 1.87 min (&gt;95%); Condition</td>

<td> (5-(2-((2S)-l-((2R)-2phenyl-2-(l-</td><td> Prepared from 152k-l and Cap-</td><td> 1</td>

<td> piperidinyl)acetyl)-2-</td><td> 14</td><td> LRMS: Anal.</td>

<td> pyrrolidinyl)-IH-</td><td></td><td> Calcd. for</td>

<td> imidazol-5-yl)-2-</td><td></td><td> C47H51N10O4</td>

<td> pyrimidinyl)phenyl)-l H-</td><td></td><td> 819.41 found:</td>

<td> imidazol-2-yl)-lpyrrolidinyl)ethyl)carba</td><td></td><td> 819.50 (M+H)⁺</td>

<td> mate</td><td></td><td> HRMS: Anal. Calcd. for C47H51N10O4 819.4095 found: 819.4127 (M+H)⁺</td>

Example 153a-l from 153a-4.

Example 153a-l prepared from 152e-l. (S)-2-[5-{5'-[2-((S)-l-tert-Butoxycarbonylpyrrolidin-2-yl)-3-(2-trimethylsilanyl-ethoxymethyl)-3H-imidazol-4-yl][2,2]bipyrimidinyl-5-yl}-l-(2-trimethylsilanyl-ethoxymethyl)-lH-imidazol-2-yl] pyrrolidine-1-carboxylic acid tert-butyl ester

<img file="IL196813A_D0229.tif" />

To a stirred solution of (S)-tert-butyl 2-(5-(2-chloropyrimidin-5-yl)-1-((2(trimethylsilyl)ethoxy)methyl)-lH-imidazol-2-yl)pyrrolidine-l-carboxylate (1.0 g, 10 2.08 mmol) and dichlorobis(benzonitrile) palladium (40 mg, 0.104 mmol) in dry

DMF (10 mL) at room temperature under argon was added neat tetrakis(dimethylamino)ethylene (1.0 mL, 4.16 mmol). The mixture was heated to 60°C for 15h before it was diluted with ethyl acetate and suction-filtered through diatomaceous earth (Celite®). The filtrate was washed with sat d NaHCO₃ soln and 15 brine prior to drying 0verNa2S04 and solvent evaporation. Purification of the residue by Biotage™ flash chromatography on silica gel (step gradient elution with 15%B to 15%B for 150 mL, 15%B to 75%B for 1500 mL, 75%B to 100%B for 1000 mL, 100%B to 100%B for 1000 mL where B=ethyl acetate and A=hexane followed by a second gradient elution with 10%B to 100%B for 700 mL where B=methanol and A=ethyl acetate) furnished the title compound as a caramel-colored, viscous oil (487.8 mg, 26% yield).

¹H NMR (500 MHz, DMSO-d₆) δ 9.27 (s, 4H), 8.09-8.06 (m, 2H), 5.73-5.66 and 5.50-5.44 (2m, 2H), 5.06-4.93 (m, 2H), 3.60-3.39 (2m, 8H), 2.32-2.08 (3m, 4H), 2.00-1.85 (m, 4H), 1.37 and 1.14 (2s, 18H), 0.95-0.84 (m, 4H), -0.01 (s, 18H). LCMS Phenomenex LUNA C-18 4.6 x 50 mm, 0 to 100% B over 3 minutes, 1 minute hold time, A = 90% water, 10% methanol, 0.1% TFA, B = 10% water, 90% methanol, 0.1% TFA, RT = 3.37min, >95% homogeneity index.

LRMS: Anal. Calcd. for C44H69N1₀O₆Si2 889.49 found: 889.57 (M+H)⁺.

HRMS: Anal. Calcd. for C44H69N1₀O6Si2 889.4940; found: 889.4920 (M+H)⁺.

The same procedure was used to prepare Examples 153a-2 through 153a-4.

LC conditions: Condition 1: Phenomenex LUNA C-18 4.6 x 50 mm, 0 to 100% B over 3 minutes, 1 minute hold time, A = 90% water, 10% methanol, 0.1% TFA, B = 10% water, 90% methanol, 0.1% TFA, 220nm, 5 pL injection volume.

Condition 2: Phenomenex LUNA C-18 4.6 x 50 mm, 0 to 100% B over 2 minutes, 1 minute hold time, A = 90% water, 10% methanol, 0.1% TFA, B = 10% water, 90% methanol, 0.1% TFA, 220nm, 5 pL injection volume.

<td> Example</td><td> Compound Name</td><td> Structure</td><td> Data</td>

<td> Example 153a-2</td><td></td><td> Γ&gt;71 ן ₀X0 k O 4 L0־־&lt;׳ Prepared from 152e-2</td><td> t_R= 3.37 min (89.6%); Condition 1 LRMS: Anal. Calcd. for C44H69N ₁₀O₆Si₂889.49; found: 889.56 (M+H)⁺. HRMS: Anal.</td>

<td></td><td></td><td></td><td> Calcd. for C44H69N10O6S12 889.494; found: 889.4951 (M+H)⁺.</td>

<td> Example 153a-3</td><td></td><td> CWl Y ־־־.ך ך 'ך ₀&gt;0 &lt; ץ־ O^O -Sk “־ Prepared from 152e-3</td><td> t_R = 3.37 min (95%); Condition 1 LRMS: Anal. Calcd. for C44H69N!0O6Si2 889.49; found: 889.51 (M+H)⁺. HRMS: Anal. Calcd. for C44H69N!0O6Si2 889.4940; found: 889.4915 (M+H)⁺.</td>

<td> Example 153a-4</td><td></td><td> ח׳זך* ם s Prepared from 152e-4</td><td> t_R = 2.3 min (condition 2) LRMS: Anal. Calcd. for C₄2H₆₆N₈Si₂ 834; found: 835 (M+H)⁺.</td>

Example 153b-l-153b-3

The hydrolysis reactions was performed as above for Example 152h.

LC conditions: Condition 1: Phenomenex LUNA C-18 4.6 x 50 mm, 0 to 100% B over 3 minutes, 1 minute hold time, A = 90% water, 10% methanol, 0.1% TFA, B = 10% water, 90% methanol, 0.1% TFA, 220nm, 5 pL injection volume.

Condition 2: Phenomenex LUNA C-18 4.6 x 50 mm, 0 to 100% B over 2 minutes, 1 minute hold time, A = 90% water, 10% methanol, 0.1% TFA, B = 10% water, 90% methanol, 0.1% TFA, 220nm, 5 pL injection volume.

<td> Example</td><td> Compound Name</td><td> Structure</td><td> Data</td>

<td> Example 153b-l</td><td></td><td> ך ⁿ τ יסר Prepared from 153a-l</td><td> t_R = 1.18 min (&gt;95%); Condition 1 LRMS: Anal. Calcd. for C22H₂₅N₁₀ 429.23; found: 429.01 (M+H)⁺. HRMS: Anal. Calcd. for C₂₂H₂5N!0 429.2264; found: 429.2259 (M+H)⁺.</td>

<td> Example 153b-2</td><td></td><td> r—&lt; ^V***N Prepared from 153a-2</td><td> t_R= 1.26 min (&gt;95%); Condition 1 LRMS: Anal. Calcd. for C41H41N10O₂ 737.33 found: 737.49 (M+H)⁺ HRMS: Anal. Calcd. for C41H41N10O4 737.3312 found: 737.3342 (M+H)⁺</td>

<td> Example 153b-3</td><td></td><td> ChI . מ b LKj w—׳׳ Prepared from 153a-3</td><td> t_R = 1.40 min (&gt;95%); Condition 1 LRMS: Anal. Calcd. for C22H25N429.23 (״; found: 429.20 (M+H)⁺. HRMS: Anal. Calcd. for C22H25N !ס: 429.2264; Found: 429.2254 (M+H)⁺</td>

<td> Example 153b-4</td><td></td><td>^H t JL ^N ιίη T /,^N Prepared from 153a-4</td><td> t_R= 0.85 min (condition 1) LCMS: Anal. Calcd. forC20H₂2N₈374; found: 375 (M+H)⁺. __</td>

Examples 153c-l to 153c-7

Examples 153c-l through 153c-7 were isolated as TFA or AcOH salts using the procedure used to convert Example 148e to 148.

LC conditions: Condition 1: Phenomenex LUNA C-18 4.6 x 50 mm, 0 to 100% B over 3 minutes, 1 minute hold time, A = 90% water, 10% methanol, 0.1% TFA, B = 10% water, 90% methanol, 0.1% TFA, 220nm, 5 pL injection volume.

Condition 2: Phenomenex LUNA C-18 4.6 x 50 mm, 0 to 100% B over 2 minutes, 1 10 minute hold time, A = 90% water, 10% methanol, 0.1% TFA, B = 10% water, 90% methanol, 0.1% TFA, 220nm, 5 pL injection volume.

<td> Example</td><td> Compound Name</td><td> Structure</td><td> Data</td>

<td> Example 153c-l</td><td> (lR,rR)-2,2'-(3,3')ipyridazine-6,6'diy Ibis( 1 H-imidazole- 5,2-diyl(2S)-2,lpyrrolidinediyl))bis(N, N-dimethyl-2-oxo-1 phenylethanamine)</td><td> ״X׳ Prepared from 153b-2 and Cap-1</td><td> t_R = 1.55 min (&gt;95%); Condition 1 LRMS: Anal. Calcd. for C42H47N12O2 751.39 found: 751.64 (M+H)⁺ HRMS: Anal. Calcd. for C42H47N12O2 751.3945 found: 751.3936 (M+H)⁺</td>

<td> Example 1530-2</td><td> dimethyl (3,3'bipyridazine-6,6'diy Ibis( 1 H-imidazole5,2־diyl(2S)-2,lpyrrolidinediyl(( 1R)2-oxo-1-phenyl-2,1ethanediyl)))biscarba mate</td><td> /⁰Ύ X ” o ^N ן &gt; ט Prepared from 153b-2 and Cap-4</td><td> t_R = 1.95 min (&gt;95%); Condition 1 LRMS: Anal. Calcd. for C42H43N!₂O6 811.34 found: 811.22 (M+H)⁺ HRMS: Anal. Calcd. for C42H43N12O6 811.3429 found: 811.3406 (M+H)⁺</td>

<td> Example 1530-3</td><td> (1Κ,1Τ&lt;)-2,2'-(2,2'bipyrimidine-5,5'diy Ibis( 1 H-imidazole5,2-diyl(2S)-2,lpyrrolidinediyl))bis(N, N-dimethyl-2-oxo-1 phenylethanamine)</td><td> 0 ψΑ _h a O Prepared from 153b-l and Cap-1</td><td> t_R= 1.51 min (&gt;90%*); Condition 1 LRMS: Anal. Calcd. for C42H47N12O2 751.39 found: 751.21 (M+H)⁺</td>

<td></td><td></td><td></td><td> HRMS: Anal. Calcd. or C42H47N12O2 751.3945 found: 751.3921 (M+H)⁺</td>

<td> Example 153c-4</td><td> dimethyl (2,21 )ipyrimidine-5,5'diy Ibis (1 H-imidazole5,2-diyl(2S)-2,lpyrrolidinediy 1(( 1R)2-oxo-1 -phenyl-2,1 ethanediyl)))biscarba mate</td><td> °O ^NA.r0 Prepared from 153b-l and Cap-4</td><td> t_R= 1.88 min (&gt;95%); Condition 1 LRMS: Anal. Calcd. for C42H43N12O6 811.34 found: 811.10 (M+H)⁺ HRMS: Anal. Calcd. for C42H43N12O6 811.3429 found: 811.3401 (M+H)⁺</td>

<td> Example 153c-5</td><td> (lR,rR)-2,2'-(2,2'bipyrazine-5,5'diy Ibis( IH-imidazole5,2-diyl(2S)-2,lpyrrolidmediyl))bis(N, N-dimethyl-2-oxo-1 phenylethanamine)</td><td> t Ty Prepared from 153b-3 and Cap-1</td><td> t_R= 1.61 min (&gt;95%); Condition 1 LRMS: Anal. Calcd. for C42H47N12O2 751.39 found: 751.30 (M+H)⁺ HRMS: Anal. Calcd. for C42H47N12O2 751.3945 found: 751.3943 (M+H)⁺</td>

<td> Example 153c-6</td><td> dimethyl (2,2'bipyrazine-5,5'diy Ibis( 1 H-imidazole5,2-diyl(2S)-2,l-</td><td> Prepared from 153b-3 and Cap-4</td><td> t_R = 2.00 min (&gt;95%); Condition 1 LRMS: Anal. Calcd.</td>

<td></td><td> pyrrolidinediyl(( 1R)2-oxo-l -phenyl-2,1 ethanediyl)))biscarba mate</td><td></td><td> for C42H43N12O6 811.34 found: 811.23 (M+H)⁺ HRMS: Anal. Calcd. for C42H43N12O6 811.3429 found: 811.3407 (M+H)⁺</td>

<td> Example 153C-7</td><td> dimethyl (2,2bipyridine-5,5'diylbis( 1 H-imidazole5,2-diyl(lS)-l,lethanediylimino(( 1R)2-oxo-l -phenyl-2,1 ethanediyl)))biscarba mate</td><td> O־^ ^N Λ O-gT Prepared from 153b-4 and Cap-4</td><td> t_R = 1.42 min (condition 2,94%) LRMS: Anal. Calcd. for C4qH4qN!0O6 756.31; found: 757.34 (M+H)⁺. HRMS: Anal. Calcd. for C40H41N10O6 757.3211 found: 757.3180 (M+H)⁺.</td>

Section LS LC Conditions:

Condition 1: Solvent A: 10%methanol/90% water/0.1% TFA; Solvent B: 90% methanol/10% water/0.1% TFA; Column: Phenomenex-Luna 3.0 x 5.0mm S10;

Wavelength: 220nM; Flow rate: 4mL/min; 0%B to 100% B over 4min with a Imin hold time

Condition 2: Solvent A: 10%methanol/90% water/0.1% TFA; Solvent B: 90% methanol/10% water/0.1% TFA; Column: Phenomenex lOu C18 3.0 x 5.0mm;

Wavelength: 220nM; Flow rate: 4mL/min; 0%B to 100% B over 4min with a Imin hold time

Condition 3: Solvent A: 5% acetonitrile/95% water/lOmmol ammonium acetate;

Solvent B: 95% acetonitrile/5% water/lOmmol ammonium acetate; Column;

Phenomenex lOu C18 4.6 x 5.0mm; Wavelength: 220nM; Flow rate: 4mL/min;

0%B to 100% B over 4min with a Imin hold time

Condition 4: Solvent A: 5% acetonitrile/95% water/lOmmol ammonium acetate; Solvent B: 95% acetonitrile/5% water/lOmmol ammonium acetate; Column: Luna 4.6 x 50mm S10; Wavelength: 220nM; Flow rate: 4mL/min; 0%B to 100% B over 3 min with a lmin hold time

Conditions: Solvent A: 10%methanol/90% water/0.1% TFA; Solvent B: 90% methanol/10% water/0.1% TFA; Column: Phenomenex lOu C18 3.0 x 5.0mm;

Wavelength: 220nM; Flow rate: 4mL/min; 0%B to 100% B over 3min with a lmin hold time

Condition 6: Solvent A: 5% acetonitrile/95% water/lOmmol ammonium acetate;

Solvent B: 95% acetonitrile/5% water/lOmmol ammonium acetate; Column: Phenomenex-Luna 3.0 x 50mm S10; Wavelength: 220nM; Flow rate: 4mL/min; 0%B to 100% B over 8min with a 2min hold time

Condition?: Solvent A: 10%methanol/90% water/0.1% TFA; Solvent B: 90% methanol/10% water/0.1% TFA; Column: Phenomenex-Luna 3.0 x 5.0mm S10; Wavelength: 220nM; Flow rate: 4mL/min; 0%B to 100% B over 3min with a lmin hold time

Conditions: Solvent A: 10%methanol/90% water/0.2% H₃PO₄; Solvent B: 90% methanol/10% water/0.2% H₃PO₄; Column: YMC ODS-A 4.6 x 50mm S5;

Wavelength: 220nM; Flow rate: 4mL/min; 0%B to 100% B over 4min with a lmin hold time

Condition 9: Solvent A: 10%methanol/90% water/0.2% H₃PO₄; Solvent B: 90% methanol/10% water/0.2% H₃PO₄; Column: YMC ODS-A 4.6 x 50mm S5;

Wavelength: 220nM; Flow rate: 2.5mL/min; 0%B to 50% B over 8min with a 3min hold time

Condition 10: Xbridge C18,150 x4.6 mm I.D. S-3.5um; Mobile Phase A: 95%Water5%־ Acetonitrile with 10 mM ammonium acetate (pH=5); Mobile phase B: 95% Acetonitrile-5% Water with 10 mM ammonium acetate (pH=5); Isocratic 30% B for 20 min; Flow rate: 1 mL/min; UV detection; 220 nm

Condition 11: Solvent A: 10%methanol/90% water/0.1% TFA; Solvent B: 90% methanol/10% water/0.1% TFA; Column: Phenomenex lOu C18 3.0 x 5.0mm;

Wavelength: 220nM; Flow rate: 4mL/min; 30%B to 100% B over 4min with a lmin hold time

Condition 12: Solvent A: 10%methanol/90% water/0.1% TFA; Solvent B: 90% methanol/10% water/0.1% TFA; Column: Phenomenex lOu C18 3.0 x 5.0mm;

Wavelength: 220nM; Flow rate: 4mL/min; 20%B to 100% B over 4min with a lmin hold time

Condition 13: Solvent A: 10%methanol/90% water/0.2% H3PO4; Solvent B: 90% methanol/10% water/0.2% H3PO4; Column: YMC ODS-A 4.6 x 50mm S5;

Wavelength: 220nM; Flow rate: 2.5mL/min; 0%B to 100% B over 8min with a 3 min hold time

Section LS Preparative HPLC Conditions:

Condition 1: Solvent A: 10%methanol/90% water/0.1% TFA; Solvent B: 90% methanol/10% water/0.1% TFA; Column: Phenomenex-Luna 30 x 100mm S10; Wavelength: 220nM; Flow rate: 30mL/min; 0%B to 100% B over lOmin with a 2min hold time

Condition 2: Solvent A: 10%methanol/90% water/0.1% TFA; Solvent B: 90% methanol/10% water/0.1% TFA; Column: Xterra Prep MS C18 30 x 50mm 5u;

Wavelength: 220nM; Flow rate: 30mL/min; 0%B to 100% B over 8min with a 3min hold time

Conditions: Solvent A: 10%methanol/90% water/0.1% TFA; Solvent B: 90% methanol/10% water/0.1% TFA; Column: Xterra Prep MS C18 30 x 50mm 5u; Wavelength: 220nM; Flow rate: 25mL/min; 10%B to 100% B over 8min with a 2min hold time

Condition 4: Solvent A: 10%methanoV90% water/0.1% TFA; Solvent B: 90% methanol/10% water/0.1% TFA; Column: Xterra 19 x 100mm S5; Wavelength:

220nM; Flow rate: 20mL/min; 30%B to 100% B over 5min with a 3min hold time

Conditions: Solvent A: 10%methanol/90% water/0.1% TFA; Solvent B: 90% methanol/10% water/0.1% TFA; Column: Phenomenex-Luna 30 x 100mm S10;

Wavelength: 220nM; Flow rate: 30mL/min; 10%B to 100% B over 8min with a 2min hold time

Condition 6: Solvent A: 10% Acetonitrile/90% water/0.1% TFA; Solvent B: 90% Acetonitrile/10% water/0.1% TFA; Column: Phenomenex-Luna 21 x 100mm S10;

Wavelength: 220nM; Flow rate: 25mL/min; 0%B to 60% B over lOmin with a 5min hold time

Experimentals:

Compound LS2 (IS, 1 ’S)-2,2'-(4,4 '-biphenyldiylbis(! H-imidazole-5,2-diyl(2S)-2,1pyrrolidinediyl))bis(l-cyclohexyl-2-oxoethanol)

<img file="IL196813A_D0230.tif" />

Step a: To Id (1.4g; 2.24mmol) was added 30mL 4N HCI in dioxane. After 3h, 60mL ether was added and the precipitate was filtered and dried under high vacuum 30 providing 1.02g (80%) intermediate LS1 as a pale yellow powder. ¹H NMR (DMSO d6, δ = 2.5 ppm, 500 MHz): δ 10.41 (s, 2H), 9.98 (s, 2H), 8.22 (s, 2H), 8.06 (d, J =

8.54Hz, 4H), 7.92 (d, J= 8.55Hz, 4H), 5.07 (s, 2H), 3.43-3.54 (m, 2H), 3.33-3.43 (m,

2H), 2.43-2.59 (m, 4H), 2.16-2.28 (m, 2H), 1.94-2.09 (m, 2H). LC (Cond. 1): RT =

1.28 min; MS: Anal. Calcd. for [M+H]⁺ C26H28N6:425.24; found 425.56.

Step b: To intermediate LSI (200mg; 0.35mmol) in 2mL DMF was added DIPEA (0.30mL; 1.75mmol), (S)-2-cyclohexyl-2־hydroxyacetic acid (61mg; O.39mmol), followed by HATU (147mg; 0.38mmol). After stirring at ambient temperature for 18h, the reaction mixture was split into two portions and purified via preparative HPLC (Cond’n 1). Fractions containing desired product were pooled and passed through an MCX cartridge (Oasis; 6g; preconditioned with two column lengths of methanol). The cartridge was washed with two column lengths of methanol and product was eluted with ammonia/methanol. Concentration provided 65mg of LS2 (26%) as a colorless powder. ¹H NMR (500 MHz, DMSO-d6) δ ppm 0.87-1.30 (m, 12H) 1.38-1.53 (m, 7=24.72, 11.90 Hz, 4H) 1.54-1.75 (m, 8H) 1.95-2.21 (m, 6H) 3.72-3.86 (m, 6H) 5.13 (t, 7=6.56 Hz, 2H) 7.87 (d, 7=7.93 Hz, 4H) 7.96 (d, 7=6.41 Hz, 4H) 8.13 (s, 2H) (imidazole NH and hydroxyl protons unaccounted for). LC (Cond’n 2): RT = 3.07 min; MS: Anal. Calcd. for [M+H]⁺ C42H52N6O4: 705.9; found 705.6.

The following analogs were prepared in similar fashion to the preparation of LS2 from intermediate LSI employing the appropriate carboxylic acid:

<td> Example Number</td><td> Compound Name</td><td> Structure</td><td> Analytical Data</td>

<td> LS3</td><td> (2S,2'S)-l,r-(4,4'biphenyldiylbis( 1H -imidazole-5,2diyl(2S)-2,lpyrrolidinediyl))bis (4-methy 1-1 -oxo-2pentanol)</td><td> H &gt;7</td><td> LC/MS: 2.02 min (Cond’n 1); Anal. Calcd. for [M+H]⁺C38H48N6O4: 653.4; found 653.2.</td>

<td> LS4</td><td> (2S,2'S)-l,r-(4,4'lipheny Idiy Ibis( 1H -imidazole-5,2diyl(2S)-2,lpyrrolidinediyl))bis (3-methyl-l-oxo-2butanol)</td><td></td><td> LC/MS: 1.99 min (Cond’n 3); Anal. Calcd. for [M+H]⁺C36H44N6O4: 625.3; found 625.3.</td>

<td> LS16</td><td> 3-buten-l-yl ((IS)l-(((2S)-2-(5-(4'(2-((2S)-l-((2S)-2(((3-buten-lyloxy)carbonyl)ami no)-3methylbutanoyl)-2pyrrolidinyl)-1Himidazol-5-yl)-4biphenylyl)-1Himidazol-2-yl)-lpyrrolidinyl)carbon yl)-2methylpropyl)carba mate</td><td> from intermediate LSI and (S)-2((but-3-enyloxy)carbonylan1ino)-3methylbutanoic which was prepared from L-valine and butenylchloroformate in similar fashion to the preparation of Cap51</td><td>¹HNMR (500 MHz, CH3OD) δ ppm 0.81-1.10 (m, 12H) 1.902.15 (m, 4H) 2.15-2.51 (m, 8H) 3.82-3.96 (m,2H)3.974.05 (m, 2H) 4.05-4.19 (m, 4H) 4.25 (d, 7=7.02 Hz, 2H) 4.62 (s, 2H) 5.005.17 (m, 4H) 5.20 (t, 7=5.65 Hz, 2H) 5.795.93 (m, 2H) 7.20-7.47 (m, 2H) 7.59-7.90 (m, 8H)</td>

Example LS6 (2S,2'S)-1,1 '-(4,4'-biphenyldiylbis(lH-imidazole-5,2-diyl(2S)-2,1pyrrolidinediyl))bis(N-methyl-l-oxo-2-propanamine) a

Intermediate LS1 ---

<img file="IL196813A_D0231.tif" />

intermediate LS5: R = Boc 2TFA

LS6: R = H4HCI

Step a: To intermediate LSI (64mg; 0.11 mmol) in 1 mL DMF was added (S)-2-(tertbutoxycarbonyl(methyl)amino)propanoic acid (48mg; 0.24mmol), Hunig’s base (0.12mL; 0.67mmol) and HATU (90mg; 0.24mmol). After 311, the reaction was purified via preparative HPLC (Cond’n 2). Fractions containing intermediate LS5 were pooled and concentrated providing intermediate LS5 as a colorless powder (43mg; 48%) after drying under high vacuum. LC (Cond’n 4): RT = 2.12 min; MS: Anal. Calcd. for [M+H]⁺ C44H58N8O6: 795.4; found 795.5.

Step b: Intermediate LS5 was allowed to stir in 2mL HCl/Dioxane (4N) for 18h at which time lOmL ether was added and the resultant precipitate was filtered and dried under high vacuum providing LS6 (45mg; 155%) as a colorless solid. ¹H NMR (500 MHz, DMSO-d6) δ ppm 2.00-2.11 (m, 2H) 2.12-2.27 (m, 4H) 2.38-2.47 (m, 2H) 2.39-2.48 (m, 2H) 2.58 (t, 7=5.19 Hz, 2H) 3.78-3.85 (m, 2H) 3.91-4.02 (m, 2H) 4.214.32 (m, 2H) 5.26 (t, 7=7.17 Hz, 2H) 7.93 (d, 7=7.32 Hz, 4H) 8.02 (d, 7=7.94 Hz, 4H) 8.12-8.21 (m, 2H) 8.69-8.81 (m, 2H) 9.09-9.17 (m, 2H); N-Me protons obscured by DMSO peak with 2 other protons unaccounted for. LC (Cond’n 5): RT = 1.71 min; MS: Anal. Calcd. for [M+H]⁺ C34H42N8O2: 595.3; found 595.6.

Example LSI 1 (4S, 4 'S)-4,4 '-(4,4 '-biphenyldiylbis(l H-imidazole-5,2-diyl(2S)-2,1pyrrolidinediylcarbonyl))bis(l,3-oxazinan-2-one)

<img file="IL196813A_D0232.tif" />

a intermediate LS1 ----

<img file="IL196813A_D0233.tif" />

intermediate LS9 Intermediate LS8

Intermediate LS7

Step a: To intermediate LSI (65mg; O.llmmol) in ImL DMF was added HATU (91mg; 0.24mmol), (S)-2-oxo-l,3-oxazinane-4-carboxylic acid (intermediate LS10; 35mg; 0.24mmol), followed by DIPEA (0.12mL; 0.68mmol. After 3h, the reaction mixture was twice purified via preparative HPLC (Cond’n 3). Appropriate fractions were pooled and concentrated under high vacuum providing 8mg (10%) bis TFA LSI 1 as a colorless oil. ¹H NMR (500 MHz, CH3OD) δ ppm ¹H NMR (500 MHz, CH3OD) δ ppm 1.99-2.43 (m, 10H) 2.48-2.66 (m, 1.98 Hz, 2H) 3.82-3.95 (m, 4H) 4.17-4.40 (_m> 4H) 4.57 (t, /=5.80 Hz, 2H) 5.23-5.41 (m, 2H) 7.73-7.97 (m, 10H); imidazole and carbamate NH protons are unaccounted for. LC (Cond’n 6): RT = 2.28 min; MS: Anal. Calcd. for [M+H]⁺ C₃4H4₂N8O₂: 679.3; found 679.4.

Step b: Performed as in Baldwin et al, Tetrahedron 1988,44, 637

Stepc: Performed as in Sakaitani and Ohfune, J. Am. Chem. Soc. 1990,772,1150 for the conversion of compound 1 to 5. Purification via Biotage (40M cartridge; 1:1 ether/ethyl acetate) then preparative HPLC (Cond’n 4) provided 77mg (8%) intermediate LS9 as a viscous oil. ¹H NMR (300 MHz, CDC13) δ ppm 2.02-2.21 (m, 1H) 2.23-2.41 (m, 1H) 4.11-4.38 (m, 3H) 5.11-5.31 (m, 2H) 6.15 (s, 1H) 7.27-7.46 (m, 5H). LC (Cond’n 7): RT = 1.24 min; MS: Anal. Calcd. for [M+H]⁺C34H42N₈O2: 236.1; found 236.4.

Step d: Intermediate LS9 was hydrogenated under 1 atm H2 in 3mL methanol with lOmg Pd/C (10%) for 18h. The reaction mixture was filtered through a pad of diatomaceous earth (Celite®) and concentrated to provide intermediate LS10 (40mg;

83%) as a colorless powder. ¹H NMR (500 MHz, CH₃OD) δ ppm 2.08-2.18 (m, 1H)

2.26-2.38 (m, 1H) 4.19 (t, 7=5.95 Hz, 1H) 4.25-4.40 (m, 2H).

Example LS14 methyl ((lS)-2-((2S)-2-(5-(4'-(2-((2S)-l-((2R)-2-(diethylamino)-2-phenylacetyl)-2pyrrolidinyl)-lH-imidazol-5-yl)-4-biphenylyl)-lH-imidazol-2-yl)-l-pyrrolidinyl)-2oxo-l-(tetrahydro-2H-pyran-4-yl)ethyl)carbamate

<img file="IL196813A_D0234.tif" />

<img file="IL196813A_D0235.tif" />

<img file="IL196813A_D0236.tif" />

<img file="IL196813A_D0237.tif" />

Intermediate LS15 Intermediate LS16

Step a: To 28 (1.5g; 2.86mmol) in 25mL DMF was added sequentially Cap-2 (697mg; 2.86mmol), HATU (1.2g; 3.14mmol), and Hunig’s base (1.5mL; 8.57mmol). After 311, the solution was concentrated to lOmL and partitioned between chloroform and water. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo to an amber oil which was subjected to silica gel chromatography (Biotage; loaded on 40 samplet with dichloromethane; eluted on 40M cartridge with 0 to 12% dichloromethane/methanol over 1200mL). Fractions containing intermediate LSI2 were pooled and concentrated to provide material which contained residual DMF. This material was redissolved in dichloromethane and washed with water (3 x 50mL) and then brine. The organic layer was dried over magnesium sulfate, filtered, and concentrated to 761 mg powder which was repurified via silica gel chromatography (Biotage; loaded on 40 samplet with dichloromethane; eluted on 40M cartridge with 0 to 80% 4:1 chloroform : methanol/ethyl acetate over 1500mL) to provide intermediate LSI2 (501mg; 25%) as a colorless powder. LC (Cond’n 8): RT = 1.24 min.

Step b: To intermediate LSI2 (490mg; 0.69mmol) was added 6mL HCl/Dioxane followed by 25mL dichloromethane. After 24h, 75mL ether was added, the reaction mixture was filtered and the precipitate was dried under vacuum providing intermediate LS13 4 ־HC1 (434mg; quant) as a tan solid. ¹H NMR (300 MHz, CH3OD) δ ppm 1.16-1.29 (m, 3H) 1.37 (t, 7=6.95 Hz, 3H) 1.89-2.06 (m, 6.95 Hz, 1H) 2.12-2.51 (m, 5H) 2.52-2.85 (m, 4H) 3.02-3.24 (m, 2H) 3.42-3.55 (m, 7.32 Hz, 1H) 3.58-3.71 (m, 2H) 4.26-4.41 (m, 1H) 5.18-5.37 (m, 2H) 5.65 (s, 1H) 7.57-7.66 (m, 3H) 7.67-7.75 (m, 1H) 7.86-8.04 (m, 10H) 8.14 (s, 1H). LC (Cond’n 8): RT = 1.92 min.

Step c: To intermediate LS13 4HC1 (75mg; 0.099mmol) in 0.7mL DMF was added sequentially intermediate LSI6 (26mg; 0.118mmol), HATU (45mg; 0.118mmol), and Hunig’s base (0. lOmL; 0.591mmol). After 2h, the reaction mixture was filtered through diatomaceous earth (Celite®), the pad washed with 0.3mL methanol and the resultant filtrate was purified via preparative HPLC (Cond’n 5) in two separate injections. The fractions containing desired product were passed through an MCX cartridge (Oasis; lg; preconditioned with two column lengths of methanol). The cartridge was washed with two column lengths of methanol and product was eluted with ammonia/methanol. Concentration provided 36mg of LS14 as a colorless powder which was assayed to be of 82% diastereomeric purity (most likely epimeric at the stereogenic carbon in intermediate 16). Resubjected to preparative HPLC purification (2x) providing LS14 (13mg; 16%) as a colorless solid. ¹H NMR (500 MHz, CH₃OD) δ ppm 0.99 (q, 7=6.92 Hz, 6H) 1.25-1.72 (m, 5H) 1.80-2.42 (m, 10H) 2.47-2.61 (m, 3H) 2.66-2.78 (m, 2H) 3.35-3.43 (m, 2H) 3.65-3.71 (m, 3H) 3.89-4.01 (m, 4H) 4.01-4.10 (m, 1H) 4.32 (d, 7=8.24 Hz, 1H) 5.11-5.22 (m, 1H) 6.95-7.17 (m, 3H) 7.30-7.44 (m, 3H) 7.53 (d, 7=7.02 Hz, 1H) 7.62-7.89 (m, 8H). LC (Cond’n 9): RT = 5.31 min.

Step d: Intermediate LSI6 was prepared in analogous fashion to the procedure describing the synthesis of Cap-51 substituting (S)-2-amino-2-(tetrahydro-2H-pyran4-yl)acetic acid (available from Astatech) for L-Valine. ¹H NMR (300 MHz, DMSO368 d6) δ ppm 1.15-1.63 (m, 5H) 1.75-2.03 (m, IH) 3.54 (s, 3H) 3.76-3.98 (m, 4H) 7.45 (d, 7=8.42 Hz, IH); one proton obscured by water peak.

Example LS20 methyl ((lS)-2-methyl-l-(((2S)-2-(5-(4'-(2-((2S)-l-(N-methylglycyl)-2-pyrrolidinyl)lH-imidazol-5-yl)-4-biphenylyl)-lH-imidazol-2-yl)-lpyrrolidinyl)carbonyl)propyl)carbamate

<img file="IL196813A_D0238.tif" />

Step a &amp; b: Intermediate LSI8 was prepared in analogous fashion to the procedure describing the synthesis of intermediate LSI3 substituting Cap-51 for Cap-2.

Step c: To intermediate LS18 (lOOmg; 0.14mmol) in 1.4mL DMF was added sequentially N-Boc Sarcosine (30mg; 0.16mmol), Hunig’s base (0.13mL; 0.72mmol) and HATU (60mg; 0.16mmol). After 2h the reaction mixture was partitioned into dichloromethane, washed with NaHCO₃ (aq), brine, dried over magnesium sulfate, filtered and concentrated to crude intermediate LSI9 which was used directly in the next step. LC (Cond’n 5): RT = 2.42 min; MS: Anal. Calcd. for [M+H]⁺C41H52N₈O₆: 753.4; found 753.9.

Step d: Crude intermediate LS19 was dissolved in 0.5mL methanol and 5mL 4N HCl/Dioxane. After stirring for Ih, the reaction was concentrated and purified via preparative HPLC (Cond’n 6) and the fractions containing desired product were passed through an MCX cartridge (Oasis; lg; preconditioned with two column lengths of methanol). The cartridge was washed with two column lengths of methanol and product was eluted with ammonia/methanol. Concentration provided LS20 (32mg; 34%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 0.74-0.98 (m, 6H) 1.792.24 (m, 9H) 2.29-2.38 (m, 2H) 3.19-3.51 (m, 8H) 3.50-3.56 (m, 3H) 3.59-3.71 (m, IH) 3.81 (s, IH) 3.97-4.17 (m, IH) 5.01-5.16 (m, 2H) 7.30 (d, 7=7.93 Hz, IH) 7.51 (s, IH) 7.59-7.74 (m, 4H) 7.79 (d, 7=7.63 Hz, 4H) 11.78 (s, IH). LC (Cond’n 5): RT = 2.00 min; MS: Anal. Calcd. for [M+H]⁺ C36H44N8O4: 653.4; found 653.7.

The following analogs were prepared in similar fashion to the preparation of LS20 from LSI8 substituting the appropriate carboxylic acid for N-Boc Sarcosine :

<td> Example Number</td><td> Compound Name</td><td> Structure</td><td> Analytical Data</td>

<td> LS21</td><td> methyl ((1S)-1(((2S)-2-(5-(4'-(2((2S)-1-(Nethylglycyl)-2pyrrolidinyl)-IHimidazol-5-yl)-4biphenylyl)-IHimidazol-2-yl)-lpyrrolidinyl)carbonyl ־2־( methylpropyl)carbam ate</td><td> xy y</td><td> LC/MS: 2.34 min (Cond’n 2); Anal. Calcd. for[M+H]⁺C37H46N₈O4: 667.4; found 667.7.</td>

<td> LS22</td><td> methyl ((1S)-1(((2S)-2-(5-(4'-(2((2S)-1-(Nbenzylglycyl)-2pyrrolidinyl)-IHimidazol-5-yl)-4biphenylyl)-IHimidazol-2-yl)-lpyrrolidinyl)carbonyl )-2methylpropyl)carbam ate</td><td> cr</td><td> LC/MS: 2.34 min (Cond’n 5); Anal. Calcd. for [M+H]⁺C42H48N8O4: 729.4; found 729.8.</td>

<td> LS23</td><td> methyl ((1S)-1(((2S)-2-(5-(4'-(2((2S)-1-(Nisobutylglycyl)-2pyrrolidinyl)-IHimidazol-5-yl)-4-</td><td> IV-O «</td><td> LC/MS: 2.07 min (Cond’n 5); Anal. Calcd. for[M+H]⁺C39H50N8O4: 695.4; found 695.8.</td>

<td></td><td> biphenylyl)-1 Ηimidazol-2-yl)-lpyrrolidinyl)carbonyl ־2־( methylpropyl)carbam ate</td><td></td><td></td>

<td> LS24</td><td> methyl ((1S)-1(((2S)-2-(5-(4'-(2((2S)-l־(N-secbutylglycyl)-2pyrrolidinyl)-IHimidazol-5-yl)-4biphenylyl)-IHimidazol-2-yl)-lpyrrolidinyl)carbonyl ־2-( methylpropyl)carbam ate</td><td> .0</td><td> LC/MS: 2.03 min (Cond’n 5); Anal. Calcd. for[M+H]⁺ C39H50N8O4: 695.4; found 695.9.</td>

<td> LS25</td><td> methyl ((1S)-1(((2S)-2-(5-(4'-(2((2S)-1-(Nisopropylglycyl)-2pyrrolidiny 1)-1 Himidazol-5-yl)-4biphenylyl)-IHimidazol-2-yl)-lpyrrolidinyl)carbonyl )-2methylpropyl)carbam ate</td><td> ivxxxxrT.</td><td> LC/MS: 1.97 min (Cond’n 5); Anal. Calcd. for[M+H]⁺C38H48N8O4: 681.4; found 681.7.</td>

Example LS26 methyl ((lS)-I-(((2S)-2-(5-(4'-(2-((2S)-l-(N,N-diisopropylglycyl)-2-pyrrolidinyl)-lHimidazol-5-yl)-4-biphenylyl)-lH-imidazol-2-yl)-l-pyrrolidinyl)carbonyl)-2methylpropyl)carbamate intermediate LS18

<img file="IL196813A_D0239.tif" />

Step a: Compound LS26 was prepared in a similar fashion to the preparation of intermediate LSI9 employing 2-(diisopropylamino)acetic acid as the carboxylic acid coupling partner. ¹H NMR (500 MHz, DMSO-d6) δ ppm 0.74-1.04 (m, 18H) 1.742.21 (m, 13H) 2.86-3.09 (m, 3H) 3.54 (s, 3H) 3.71-3.89 (m, 3H) 4.06 (t, 7=8.55 Hz, 1H) 4.98-5.13 (m, 2H) 5.56 (d, 7=8.55 Hz, 1H) 7.21-7.34 (m, 1H) 7.42-7.54 (m, 1H) 7.61-7.87 (m, 8H). LC (Cond’n 5): RT = 1.98 min; MS: Anal. Calcd. for [M+H]⁺C41H54N₈O4: 723.4; found 723.4.

Example LS27 Diastereomer 1 methyl ((lS)-l-(((2S)-2-(5-(4'-(2-((2S)-l-((2R)-2-((methoxycarbonyl)amino)-2-(3oxetanyl)acetyl)-2-pyrrolidinyl)-lH-imidazol-5-yl)-4-biphenylyl)-lH-imidazol-2-yl)l-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate

Example LS27 Diastereomer 2 methyl ((lS)-l-(((2S)-2-(5-(4'-(2-((2S)-l-((2S)-2-((methoxycarbonyl)amino)-2-(3oxetanyl)acetyl)-2-pyrrolidinyl)-lH-imidazol-5-yl)-4-biphenylyl)-lH-imidazol-2-yl)l-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate

<img file="IL196813A_D0240.tif" />

<img file="IL196813A_D0241.tif" />

Intermediate LS28

Step a: Compound LS27 was prepared in a similar fashion to the preparation of intermediate LSI9 employing 2-(methoxycarbonylamino)-2-(oxetan-3-yl)acetic acid (intermediate LS29) as the carboxylic acid coupling partner. The two diastereomers of LS27 were separated via preparative HPLC (Xbridge C18,100 x 19 mm I.D. S5pm; Mobile Phase A: 95%Water-5% Acetonitrile with 10 mM ammonium acetate (pH=5); Mobile phase B: 95%Acetonitrile-5% Water with 10 mM ammonium acetate (pH=5); Isocratic 30% B for 7 min; Flow rate: 25 mL/min; UV detection: 220 nm; Sample amount: ~5 mg/each injection, 300 pl sample solution in methanol (~17 mg/mL)). Diastereomer 1: ¹H NMR (500 MHz, DMSO-d6) δ ppm 0.80-0.96 (m, 6H) 1.91-2.06 (m, 6H) 2.09-2.21 (m, 3H) 3.54 (s, 3H) 3.59 (s, 3H) 3.77-3.83 (m, 2H) 3.87 (t, 7=7.63 Hz, IH) 4.06 (t, 7=8.24 Hz, IH) 4.31 (t, 7=6.41 Hz, IH) 4.43 (t, 7=6.10 Hz, IH) 4.49 (t, 7=7.17 Hz, IH) 4.51-4.57 (m, IH) 4.80 (t, 7=8.55 Hz, IH) 5.00-5.05 (m, IH) 5.06-5.11 (m, IH) 7.30 (d, 7=8.55 Hz, IH) 7.50 (s, IH) 7.58-7.89 (m, 8H) 11.77 (s, 2H). LC (Cond’n 10): RT = 7.14 min; MS: Anal. Calcd. for [M+H]⁺ C40H48N8O7: 753.4; found 753.9. Diastereomer 2: ¹H NMR (500 MHz, DMSO-d6) δ ppm 0.79-0.98 (m, 6H) 1.91-2.06 (m, 4H) 2.07-2.23 (m, 4H) 3.51-3.69 (m, 8H) 3.74-3.90 (m, 2H) 4.06 (t, 7=7.48 Hz, IH) 4.20-4.33 (m, IH) 4.36-4.49 (m, 2H) 4.55 (s, 2H) 4.71 (s, IH) 4.97-5.05 (m, IH) 5.08 (s, IH) 5.53 (s, IH) 7.30 (d, 7=7.93 Hz, IH) 7.51 (s, IH) 7.58-7.91 (m, 8H) 11.53 (s, IH) 11.78 (s, IH). LC (Cond’n 10): RT = 8.79 min; MS: Anal. Calcd. for [M+H]⁺ C40H48N8O7: 753.4; found 753.9.

Step b: A solution of methyl 2-(benzyloxycarbonylamino)-2-(oxetan-3ylidene)acetate (intermediate LS28; Source: Moldes et al, IlFarmaco, 2001, 56,609 and Wuitschik et al, Ang. Chem. Int. Ed. Engl, 2006,45,7736; 200 mg, 0.721 mmol) in ethyl acetate (7 mL) and CH₂C1₂ (4.00 mL) was degassed by bubbling nitrogen for lOmin. Dimethyl dicarbonate (0.116 mL, 1.082 mmol) and Pd/C (20 mg, 0.019 mmol) were then added, the reaction mixture was fitted with a hydrogen balloon and allowed to stir at ambient temperature overnight. The reaction mixture was filtered through diatomaceous earth (Celite®) and concentrated. The residue was purified via Biotage (load with dichloromethane on 25 samplet; elute on 25S column with dichloromethane for 3CV then 0 to 5% methanol/dichloromethane over 250mL then hold at 5% methanol/dichloromethane for 250mL; 9mL fractions). Fractions containing the desired product were concentrated to provide 167mg methyl 2(methoxycarbonylamino)-2-(oxetan-3-yl)acetate as a colorless oil which solidified on standing. ¹HNMR (500 MHz, CHLOROFORM-D) δ ppm 3.29-3.40 (m, 1H) 3.70 (s, 3H) 3.74 (s, 3H) 4.55 (t, /=6.41 Hz, 1H) 4.58-4.68 (m, 2H) 4.67-4.78 (m, 2H) 5.31 (brs, 1H). MS: Anal. Calcd. for [M+H]⁺C8H13NO5: 204.1; found 204.0. To methyl 2־(methoxycarbonylamino)-2-(oxetan-3-yl)acetate (50 mg, 0.246 mmol) in THF (2mL) and Water (0.5mL) was added lithium hydroxide monohydrate (10.33 mg, 0.246 mmol). The resultant solution was allowed to stir ovemite at ambient temperature then concentrated to dryness to provide intermediate LS29 as a colorless powder. ¹H NMR (500 MHz, CH₃OD) δ ppm 3.383.50־ (m, 1H) 3.67 (s, 3H) 4.28 (d, /=7.63 Hz, 1H) 4.57-4.79 (m, 4H).

Example LS36 methyl ((lS)-l-(((2S)-2-(5-(4'-(2-((2S)-l-((2S)-2-((methoxycarbonyl)amino)-3methylbutanoyl)-2-pyrrolidinyl)-lH-imidazol-5-yl)-4-biphenylyl)-lH-imidazol-2-yl)2-methyl-l-pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate

<img file="IL196813A_D0242.tif" />

intermediate LS3O intermediate LS31 intermediate LS32 R = Fmoc; R' = Η I c intermediate LS33 R = R' = Boc ------1

<img file="IL196813A_D0243.tif" />

Step a: To (S)-l-(((9H-fluoren-9־yl)methoxy)carbonyl)-2-methylpyrrolidine-2carboxylic acid (intermediate LS30; 1.5g; 4.3mmol) in 50mL DMF was added sequentially 2-amino־l-(4-bromopheny !)ethanone hydrochloride (1.2g; 4.7mmol), HOAT (290mg; 2.1mmol), Hunig’s base (0.7mL; 4.3mmol) and EDCI (1.2g; 6.4mmol). After Ih, the reaction mixture was poured into 150mL water and allowed to stir for 15min before filtering the resultant precipitate which was dissolved in dichloromethane and dried over magnesium sulfate. The dichloromethane mixture was filtered and applied to a Biotage 40 samplet. Chromatography on a 40M column (25 to 60% ethyl acetate/hexane over 1200mL) provided (S)-(9H-fluoren-9־yl)methyl 2-(2-(4-bromophenyl)-2-oxoethylcarbamoyl)-2-methylpyrrolidine-l-carboxylate (intermediate LS31; 2.4g; quant) as a yellow foam. LC (Cond n 11); RT — 3.75 min, MS: Anal. Calcd. for [M+H]⁺ C29H27BrN2O4: 547.1; found 547.0.

Step b: A mixture of ammonium acetate (844mg; 10.97mmol) and (S)-(9H-fluoren9-yl)methyl 2-(2-(4-bromophenyl)-2-oxoethylcarbamoyl)-2-methylpyrrolidine-lcarboxylate (intermediate LS31; 1.00g; 1.83mmol) was heated to 140°C in 25mL xylene for 2.5h at which time the reaction mixture was concentrated and loaded with dichloromethane onto a Biotage 40 samplet. Purification via Biotage (5 to 60% ethyl acetate /hexane over lOOOmL with 400mL hold time) provided (S)-(9H-fluoren9־375 yl)methyl 2-(5-(4-bromophenyl)-lH-imidazol-2-yl)-2-methylpyrolidine-lcarboxylate (intermediate LS32; 469mg; 49%) as an amber liquid. LC (Cond’n 12):

RT = 3.09 min; MS: Anal. Calcd. for [M+H]⁺ C29H26BrN₃O2: 528.1; found 528.5.

Step c: To (S)-(9H-fluoren-9-yl)methyl 2-(5-(4-bromophenyl)-lH-imidazol-2-y 1)-2methylpyrrolidine-1-carboxylate (intermediate LS32; 329mg; 0.62mmol) in 3mL DMF was added 1.5mL piperidine. The reaction mixture was concentrated via a nitrogen stream ovemite. The resultant residue was washed with hexane and passed through an MCX cartridge (Oasis; 6g; preconditioned with two column lengths of methanol). The cartridge was washed with two column lengths of methanol and product was eluted with ammonia/methanol. Concentration provided 193mg of (S)5-(4-bromophenyl)-2-(2-methylpyrrolidin-2-yl)-lH-imidazole which was dissolved in 6mL dichloromethane and combined with di-t-butyldicarbonate (413 mg; 1.89mmol), DMAP (15mg; 0.13mmol) and TEA (0.17mL; 1.30mmol). After 48h, the reaction mixture was concentrated and purified via chromatography on a Biotage system providing (S)-tert-butyl 5-(4-bromophenyl)-2-(l-(tert-butoxycarbonyl)-2methylpyrrolidin-2-yl)-lH-imidazole־l-carboxylate (intermediate LS33; 150mg; 48%) as an off white solid. LC (Cond’n 5): RT = 3.75 min; MS: Anal. Calcd. for [M+H]⁺ C₂₄H32BrN3O4: 506.2; found 506.4

Step d: (S)-tert-butyl 2-(5-(4’-(2-((S)-l-(tert-butoxycarbonyl)pyrrolidin-2-yl)-lHimidazol-5-yl)biphenyl-4-yl)-lH-imidazol-2-yl)-2-methylpyrrolidine-l-carboxylate (intermediate LS34) was prepared in a similar fashion to the preparation of Id employing intermediate LS33 in place of lb. ¹H NMR (300 MHz, DMSO-d6; 100 C) δ ppm 1.18-1.29 (m, 9H) 1.29-1.40 (m, 9H) 1.75-1.82 (m, 3H) 1.81-2.39 (m, 8H) 3.35-3.75 (m, 4H) 4.81-4.92 (m, 1H) 7.36-7.45 (m, 1H) 7.57-7.74 (m, 5H) 7.76-7.89 (m, 4H) 11.29-11.63 (m, 2H). LC (Cond’n 5): RT = 2.49 min; MS: Anal. Calcd. for [M+H]⁺ C37H46N6O4: 639.4; found 639.9.

Step e: 2-((S)-2-methylpyrrolidin-2-yl)-5-(4'-(2-((S)-pyrrolidin-2-yl)-1 H-imidazol-5yl)biphenyl-4-yl)-lH-imidazole (intermediate LS35) was prepared in a similar fashion to the preparation of le employing intermediate LS34 in place of Id. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.76-1.83 (m, 3H) 1.92-2.23 (m, 6H) 3.31-3.49 _(m 4H) 4.88-4.97 (m, IH) 7.76-7.88 (m, 5H) 7.90-8.04 (m, 5H) 9.72-9.82 (m, IH)

10.04-10.16 (m. IH); imidazole and pyrrolidine NH protons nnncconnted for. LC (Cond’n 5): RT - 1.79 min; MS: Anal. Calcd. for [M+Hf C_־,H_s״Ns:439.2; found

439.5.

Step f; Compound LS36 was prepared in a similar fashion to the prepamd־־ of example 1 employing intermediate LS35 in place of le and Cap-51 m place of Cap1 ^,H NMR (500 MHz, DMSO-d«) δ ppm 0.72-0.97 (m, 12H) 1.77 (s, 3H) 1.86-2.

(m, 8H) 2.09-2.19 (m, 2H) 2.25-2.39 (m, 2H) 3.49-3.59 (m, 6H) 3.81 (d, 7-6.71 Hz,

4H) 4 06 (q, 77.83־ Hz, 2H) 5.08 (dd, 7-7.02,3.05 Hz, IH) 7.12 (d, 7-8.85 Hz,

7.27-7.34 (m, IH) 7.46-7.55 (m, IH) 7.59-7.73 (m, 4H) 7.75-7.86 (m, 3H) 11.66 (s. IH) 11.77 (s, IH). LC (Cond’n 5): RT - 2.25 min; MS: Anal. Calcd. for [M+H] C41H52N8O6: 753.4; found 754.0.

Example LS37 _meif1yl((lS,2R)-2-1nethoxy-l-(((2S)-2-(5-(4'-(2-((2S)-l-(b:-(1nelhoxycarbonyl)-0methyl-L-lhreonyl)-2-py1'rolidinyl)-lH-imidazol-5-yl)-4-biphenylyl)-lH-1rn1dazol-2 _yl).2-methyl-l-pyrrolidinyl)carbonyl)propyl)carbamate

<img file="IL196813A_D0244.tif" />

Compound LS37 was prepared in ־ similar fashion to the preparation of LS36 from intermediate LS30 using Cap-86 in place of Cap-51. ׳HNMR (500 MHz, DMSOd.) δ ppm 0.99-1.17 (m, 6H) 1.76 (s, 3H) 1.87-2.09 (m, 4H) 2.10-2.23 (m, 2H) 2.342 38 (m 2H) 2.56-2.60 (m, IH) 2.63 (d, 7-1.83 Hz, IH) 3.17 (s, 3H) 3.19 (s, 3H)

3 37-3.51 (m, 2H) 3.54 (s, 6H) 3.75-3.96 (m, 4H) 4.13-4.36 (m, 2H) 5.07 (dd,

7-7.48, 3.20 Hz, IH) 7.20 (d, 7-8.54 Hz, IH) 7.24-7.34 (m, IH) 7.50 (dd, 77.17־, 1.98 Hz, IH) 7.59-7.73 (m, 4H) 7.76-7.86 (m, 3H) 11.65 (s, IH) 11.77 (s, IH). LC (Cond’n 13): RT - 4.30 min; MS: Anal. Calcd. for [M+H]* CiiHsjNsOs. 785.4, found 785.4.

Section F LC Conditions for determining retention time

Condition 1

Column: Phenomenex-Luna 4.6 X 50 mm S10

Start % B = 0

Final %B = 100

Gradient Time = 4 min

Flow Rate = 4 mL/Min

Wavelength = 220

Solvent A = 10% methanol - 90% ¾0 - 0.1% TFA

Solvent B = 90% methanol - 10% H2O - 0.1% TFA

Condition 2

Column: Waters-Sunfire 4,6 X 50 mm S5

Start % B = 0

Final % B = 100

Gradient Time = 2 min

Flow Rate = 4 mL/Min

Wavelength = 220

Solvent A = 10% methanol - 90% H₂O - 0.1% TFA Solvent B = 90% methanol - 10% H2O - 0.1% TFA

Condition 3

Column: Phenomenex lOu 3.0 X 50 mm

Start % B = 0

Final % B = 100

Gradient Time = 2 min

Flow Rate = 4 mL/Min

Wavelength = 220

Solvent A = 10% methanol - 90% H₂O -0.1% TFA Solvent B = 90% methanol - 10% H₂O - 0.1% TFA

Condition 4

Column: Phenomenex-Luna 3.0 X 50 mm S10

Start % B = 0

Final % B = 100

Gradient Time = 3 min

Flow Rate = 4 mL/Min

Wavelength = 220

Solvent A = 10% methanol - 90% H₂O - 0.1% TFA

Solvent B = 90% methanol - 10% H2O - 0.1% TFA

Condition 5

Column: Phenomenex-Luna 4.6 X 50 mm S10

Start % B = 0

Final % B = 100

Gradient Time = 3 min

Flow Rate = 4 mL/Min

Wavelength = 220

Solvent A = 10% methanol - 90% H2O - 0.1% TFA

Solvent B = 90% methanol - 10% H2O - 0.1% TFA

Condition 6

Column: Xbridge C18 4.6 X 50 mm S5

Start % B = 0

Final %B = 100

Gradient Time = 3 min

Flow Rate = 4 mL/Min

Wavelength = 220

Solvent A = H₂O : ACN 95% : 5% 10 mm Ammonium Acetate

Solvent B = H₂O : ACN 5%: 95% 10 mm Ammonium Acetate

Condition 7

Column: Phenomenex Cl8 lOu 4.6X30 mm

Start % B = 0

Final % Β = 100

Gradient Time = 3 min

Flow Rate = 4 mL/Min

Wavelength = 220

Solvent A = 10% methanol - 90% ¾0 - 0.1% TFA