Hepatitis c virus inhibitors

European).

Attention:

Within nine months of publication of the information on the grant of the European patent, any person may lodge an objection to the European Patent Office regarding the granted European patent. The objection shall be made in the form of a reasoned statement. It is considered to be filed only when the opposition fee is paid (Article 99 (1) of the Convention on the Grant of European Patents).

18142/13 / P-RO / DR

EP 2 049 522

Hepatitis C inhibitors

Description

REFERENCE TO RELATED NOTIFICATIONS

This application reserves the benefit of US provisional application with serial number 60 / 836.996 filed on August 11, 2006.

The disclosure relates generally to antiviral compounds, in particular to compounds that can inhibit the function of the NS5A protein, encoded by the hepatitis C virus (IICV), compositions containing such compounds, and methods for inhibiting the function of the NS5A protein.

TICV is a major human pathogen, infecting an estimated 170 million people worldwide - about five times more than the number infected with human type 1 immunodeficiency virus. A significant proportion of these people infected with HCV develop serious progressive liver disease, including cirrhosis and hepatocellular carcinoma.

Currently, the most effective HCV therapy uses a combination of interferon alpha and ribavirin, leading to lasting efficacy in 40% of patients. Recent clinical results show that pegylated interferon alfa is better than unmodified interferon alfa alone. However, even with an experimental therapeutic dosing regimen involving combinations of pegylated interferon alpha and ribavirin, a significant fraction of patients do not permanently reduce viral load. Thus, there is a clear and long-felt need to develop effective drugs for the treatment of HCV infection.

HCV is a positive polarity RNA virus. Based on a comparison of the deduced amino acid sequence and the significant similarity in the 5 'non-coding region, HCV was classified as a separate genus in the FIaviviridae family. All members of the Flaviviridae family have enveloped virions containing the positive-polarity RNA genome encoding all known virus-specific proteins by translating a single, uninterrupted, open reading frame.

Significant heterogeneity was found within the nucleotide and encoded amino acid sequence within the IICV genome. At least six major genotypes have been characterized and over 50 subtypes have been described. The main ITCV genotypes differ in their distribution around the world and the clinical significance of HCV genetic heterogeneity remains undefined, despite numerous studies of the possible impact of the genotype on pathogenesis and therapy.

The single-stranded HCV RNA genome has an approximate length of 9,500 nucleotides and has a single open reading frame (ORF), encoding a single, large polyprotein, about 3000 amino acids in size. In infected cells, this polyprotein is cleaved at many places by cellular and viral proteases to produce structural and unstructured (NS) proteins. In the case of HCV, the production of mature unstructured proteins (NS2, NS3, NS4A, NS4B, NS5A and NS5B) is the result of the action of two viral proteases. The first is believed to be a metalloprotease and cleaves at the NS2-NS3 junction; the other is a serine protease, contained within the NS3 N-terminal region (also called NS3 protease here) and mediates all subsequent cleavages below NS3, both in the cis, at the NS3-NS4A cleavage site, and in the trans, for the remaining NS4A-NS4B sites , NS4B-NS5A, NS5A-NS5B. The NS4A protein appears to perform many functions by acting as a cofactor for the NS3 protease and possibly helping to membrane localize NS3 and other viral replicase components. Forming the NS3 protein complex with NS4A appears to be necessary for processing activities, enhancing proteolytic efficiency at all sites. The NS3 protein also has nucleoside triphosphatase and RNA helicase activities. NS5B (also referred to herein as HCV polymerase) is an RNA-dependent RNA polymerase that is involved in HCV replication.

Compounds useful for the treatment of HCV infected patients that selectively inhibit HCV viral replication are desired. In particular, compounds that are effective in inhibiting NS5A protein function are desirable. HCV NS5A protein is described, for example, in Tan, S. -T., Katzel, MG Cirology 2001, 284, 1-12; and in Park, K. -T; Choi, S.-H, J. Biological Chemistry 2003.

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

<img file="PL2049522T3_D0001.tif" />

or a pharmaceutically acceptable salt thereof, wherein min is independently 0, 1 or 2; qis independently represent 0, 1, 2, 3 or 4; u and v are independently 0, 1, 2 or 3;

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

wherein 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 C (R⁶)₂;

wherein, 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, hydroxyalkyl, -NR^andR^b, (NO^andR^b) alkyl, and (NR^andR^b) Carbonyl;

each R³ and R⁴ is 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^andR^bwherein the alkyl may optionally form a fused three- to six-membered ring with an adjacent carbon atom, the three- to six-membered ring being optionally substituted by one or two alkyl groups;

R⁷ and R⁸ each is independently selected from hydrogen, alkoxycarbonyl, alkyl, arylalkoxycarbonyl, carboxy, haloalkyl, (NR^andR^b) carbonyl, and trialkylsilylalkoxyalkyl; and each R⁹ is independently selected from alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonylalkyl, aryl, arylalkenyl, arylalkoxy, arylalkyl, aryloxyalkyl, cycloalkyl, (cycloalkyl) alkenyl, (cycloalkyl) alkyl, cykloalkiloksyalkilu, haloalkyl, heterocyclyl, heterocykliloalkenylu, heterocyclylalkoxy, heterocyclylalkyl, heterocyclyloxyalkyl, hydroxyalkyl, -NR^cR^d, (NO^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 each min is 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 each u and n is independently 0, 1 or 2; and each R¹ and R² is independently selected from alkoxy, alkoxyalkyl, alkyl, arylalkoxycarbonyl, carboxy, formyl, halo, haloalkyl, hydroxyalkyl, (NR^andR^b) alkyl, and (NR^andR^b) Carbonyl.

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

In a fifth embodiment of the first aspect, the present disclosure provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, 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 compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R and R are independently selected from hydrogen , alkoxycarbonyl, alkyl, arylalkoxycarbonyl, carboxy, haloalkyl and (NR^andR^b) Carbonyl.

In a ninth embodiment of the first aspect, the present disclosure provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein each R⁷ and R⁸ means hydrogen.

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

In an eleventh embodiment of the first aspect, the present disclosure provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein qis is independently 0 or 1; and when present, each R⁵ and / or R⁶ means hello.

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

In a thirteenth embodiment of the 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 means 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 each R³ and R⁴ means R⁹-WHAT)-.

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, alkylcarbonylalkyl, aryl, arylalkenyl, arylalkoxy, arylalkyl, aryloxyalkyl, cycloalkyl, (cycloalkyl) alkyl, cycloalkyloxyalkyl, heterocyclyl, heterocyclylalkyl, hydroxyalkyl, NR^cR^d, (NO^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="PL2049522T3_D0002.tif" />

or a pharmaceutically acceptable salt thereof, wherein qis is 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^andR^b) alkiIu and (NO^andR^b) Carbonyl;

each R³ and R⁴ is independently selected from hydrogen and R⁹-WHAT)-;

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

R⁷ and R⁸ each is independently selected from hydrogen, alkoxycarbonyl, alkyl, arylalkoxycarbonyl, carboxy, haloalkyl and (NR^andR^b) Carbonyl; and each R⁹ is independently selected from alkoxy, alkoxyalkyl, alkyl, alkylcarbonylalkyl, aryl, arylalkenyl, arylalkoxy, arylalkyl, aryloxyalkyl, cycloalkyl, (cycloalkyl) alkyl, cycloalkyloxyalkyl, heterocyclyl, heterocyclylalkyl, hydroxyalkyl,

-NR^cR^d, (NO^cR^d) alkenyl, (NR^cR^d) alkyl and (NR^cR^d) Carbonyl.

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

<img file="PL2049522T3_D0003.tif" />

(Ul), or a pharmaceutically acceptable salt thereof, wherein qis is 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 halo is fluoro; each R³ and R⁴ means R⁹-WHAT)-;

when present, R⁵ and / or R⁶ are halo, wherein 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, cykloalkiloksyalkilu, haloalkyl, heterocyclyl, heterocykliloalkenylu, heterocyclylalkoxy, heterocyclylalkyl, heterocyclyloxyalkyl, hydroxyalkyl, -NR^cR^d, (NO^cR^d) alkenyl, (NR^cR^d) alkyl and (NR^cR^d) Carbonyl.

In a fourth aspect, the present disclosure provides a compound selected from ((1S) -1 - (((2S) -2- (5- (4 '- (2 - ((2S) -1 - ((2S) -2 - (( methoxycarbonyl) amino) -3-methylbutanoyl) -2-pyrrolidinyl) -1H-imidazol-5-yl) -4-biphenyl) -1H-imidazol-2-yl) -1-pyrrolidinyl) carbonyl) -2-methylpropyl) carbamate ;

(1R, 1'R) -2,2 '- (4,4'-biphenyldiylbis (1H-imidazol-5,2-diyl (2S) -2, 1-pyrrolidinyl)) bis (N, N-dimethyl-2-oxo -1-phenyl oetanamine);

((S) -2 - ((2S) -2- (5- (4 '- (2 - ((2S) -l - ((2R) -2- (diethylamino) -2-phenylacetyl) -2-pyrrolidinyl ) 1H-imidazol-5-yl) -4-biphenylyl) -1H-imidazol-2-yl) -1-pyrrolidinyl) -1-methyl-2-oxoethylcarbamate;

((S) -l - (((2S) -2- (4- (4 '- (2 - ((2S) -4,4-difluoro-l - ((2S) -2 - ((methoxycarbonyl) amino ) -3-methylbutanoyl) -2-pyrrolidinyl) -1H-imidazol-4-yl) -4-biphenylyl) -1H-imidazol-2-yl) -4,4-difluoro-1-pyrrolidinyl) carbonyl) -2-methylpropyl) carbamate ;

((S) -l - (((lR, 3R, 5R) -3- (5- (4 '- (2 - ((lR, 3R, 5R) -2 - ((2S) -2- ((methoxycarbonyl) amino) -3-methylbutanoyl) -2-azabicyclo [3.1.0] hex-3-yl) -1Himidazol-5-yl) -4-biphenylyl) -1H-imidazol-2-yl) -2-azabicyclo [3.1. 0] hex-2-yl) carbonyl) 2-methylpropyl) carbamate methyl;

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

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

((R) -2 - ((2S) -2- (5- (4 '- (2 - ((2S) -l - ((2R) -2- (dimethylamino) -2-phenylacetyl) -2-pyrrolidinyl ) 1-methyl-H-imidazol-5-yl) -4-biphenylyl) -1H-imidazol-2-yl) -1-pyrrolidinyl) -2-oxo-1 phenylethyl) carbamate;

(4,4'-biphenyldiylbis (1H-imidazol-5,2-diyl (2S) -2,1-pyrrolidinidiyl ((1R) 2-oxo-1-phenyl-2,1-ethanediyl)) dimethyl biscarbamate;

(R) -N, N-dimethyl-2-oxo-l-phenyl-2 - ((2S) -2- (5- (4 '- (2 - ((2S) -l - ((2R) -tetrahydro -2-furanylcarbonyl) -2-pyrrolidinyl) -1H-imidazol-5-yl) -4-biphenyl) -1H-imidazol-2-yl) -1-pyrrolidinyl) ethanamine;

((1 S) -2 - ((2S) -2- (5- (4 '- (2 - ((2S) -1 - (N- (methoxycarbonyl) -L-alanyl) -2-pyrrolidinyl) -1Himidazole Methyl -5-yl) -4-biphenyl) -1H-imidazol-2-yl) -1-pyrrolidinyl) -1-methyl-2-oxoethyl) carbamate; and ((1S) -1 - (((2S) -2- (5- (4 '- (2 - ((2S) -1 - ((2S) -2 - ((methoxycarbonyl) amino) -3,3-dimethylbutanoyl ) -2-pyrrolidinyl) -1H-imidazol-5-yl) -4-biphenylyl) -1H-imidazol-2-yl) -1-pyrrolidinyl) carbonyl) -2,2-dimethylpropyl) carbamate; or a pharmaceutically acceptable salt thereof.

In a first embodiment of the fifth aspect, the pharmaceutically acceptable salt is the 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 interferon or ribavirin. In a third embodiment, the interferon is selected from interferon alfa 2B, pegylated interferon alpha, consensus interferon, interferon alpha 2A and lymphoblastoid interferon tau.

In a fourth embodiment of the sixth aspect, the composition further comprises one or two additional compounds with anti-HCV activity, wherein at least one of the additional compounds is selected from interleukin 2, interleukin 6, interleukin 12, a compound supporting the development of a type 1 helper cell response. interfering RNA, antisense RNA, imiquimod, ribavirin, inosine-5'-monophosphate dehydrogenase inhibitor, amantadine and rimantadine.

In a fifth embodiment of the sixth aspect, the composition further comprises one or two additional compounds with anti-HCV activity, wherein at least one of the additional compounds is effective in inhibiting the function of the target selected from HCV metalloprotease, HCV serine protease, HCV polymerase, HCV helicase, protein NS4B HCV, HCV entry, HCV splicing, HCV output, NS5A HCV protein and IMPDH for the treatment of HCV infection.

In a seventh aspect, the present disclosure provides a method of treating 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 with anti-HCV activity before, after or simultaneously with the compound of general formula (I), or a pharmaceutically acceptable salt thereof. In a second embodiment, at least one of the additional compounds is interferon or ribavirin. In a third embodiment, the interferon is selected from interferon alfa 2B, pegylated interferon alpha, consensus interferon, interferon alpha 2A and lymphoblastoid interferon tau.

In a fourth embodiment, the method further comprises administering one or two additional compounds with anti-HCV activity before, after or simultaneously with the compound of general 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 supporting the development of type 1 helper T cell responses, interfering RNA, antisense RNA, imiquimod, ribavirin, Inosine-5'-monophosphate dehydrogenase inhibitor, Amantadine and Rimantadine.

In a fifth embodiment, the method further comprises administering one or two additional compounds having anti-HCV activity before, after or simultaneously with the compound of general formula (I), or a pharmaceutically acceptable salt thereof, wherein at least one of the additional compounds is effective in inhibiting target function selected from HCV metalloprotease, HCV serine protease, HCV polymerase, HCV helicase, HCV NS4B protein, HCV input, HCV splicing, HCV output, NS5A HCV and IMPDH proteins for the treatment of HCV infection.

Other embodiments of the present disclosure may include a suitable combination of two or more embodiments and / or aspects disclosed herein.

Still other embodiments and aspects of the invention will be apparent as described below.

The compounds of the present disclosure also exist as tautomers, therefore the disclosure also includes all tautomeric forms.

The description of this disclosure should be interpreted in accordance with the laws and principles of chemical binding. In some cases it may be necessary to remove a hydrogen atom to place a substituent in a given position. For example, in the structure shown below

<img file="PL2049522T3_D0004.tif" />

R^and

R⁸ can be attached to a carbon atom on the imidazole ring or alternatively,

R⁸ can take the place of a hydrogen atom on the nitrogen ring to form N-substituted imidazole.

It should be understood that the compounds included in the present disclosure are those that are sufficiently stable for use as a pharmaceutical.

It is understood that the definition of any substituent or variable (e.g., R¹, R², R⁵, R⁶, etc.) at a specific location in the molecule is independent of their definition elsewhere in the molecule. For example, when u is 2, each of two R groups¹ can be the same or different.

All patents, patent applications and references cited in the description are incorporated by reference in their entirety. In the event of non-compliance, this disclosure, including definitions, will prevail.

The terms used in this specification have the following meanings;

The singular forms used herein include references to the plural, unless the context clearly indicates otherwise.

Unless otherwise stated, all of the aryl, cycloalkyl, and heterocyclyl groups of the present disclosure may be substituted as described in each of their definitions. For example, the aryl portion 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 group of straight or branched chain of two to six carbon 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 having from one to six carbon atoms. In the compounds of the present disclosure, when mi / or n is 1 or 2, respectively; X and / or Y is CHR⁵ and / or CHR⁶and R⁵ and / or R⁶ is alkyl, each alkyl may optionally form a fused three- to six-membered ring with an adjacent carbon atom to form one of the following structures:

<img file="PL2049522T3_D0005.tif" />

<img file="PL2049522T3_D0006.tif" />

<img file="PL2049522T3_D0007.tif" />

where z is 1, 2, 3 or 4, w is 0, 1 or 2, and R⁵⁰ is alkyl. When w is 2, two alkyl groups R⁵⁰ they can 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 bicyclic fused ring system, in which one or both of the rings are a phenyl group. Bicyclic fused ring systems consist of a fused phenyl group with a four to six membered aromatic or non-aromatic carbocyclic ring. The aryl groups of the present disclosure may be attached to the parent molecular moiety through any substitutable ring carbon atom in the group. Representative examples of aryl groups include, but are not limited to, indanyl, indenyl, kerosene 1, 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, second aryl, arylalkoxy, arylalkyl, arylcarbonyl, cyano, halo, haloalkoxy, haloalkyl, heterocyclyl , heterocyclylalkyl, heterocyclylcarbonyl, hydroxy, hydroxyalkyl, nitro, NR^xR^s, (NO^xR^s) alkyl, oxo, and

-P (O) OR2, wherein each R is independently selected from hydrogen and alkyl; and wherein the alkyl part of arylalkyl and heterocyclylalkyl are unsubstituted and wherein the second aryl group, aryl part of arylalkyl, aryl part of arylcarbonyl, heterocyclyl, and heterocyclyl portion of heterocyclylalkyl and 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 optionally further substituted with one or two additional groups independently selected from alkoxy, alkylcarbonyloxy, halo, haloalkoxy, haloalkyl, heterocyclyl, hydroxy, and -NR^cR^dwherein the heterocyclyl is optionally further substituted with one or two substituents independently selected from alkoxy, alkyl, unsubstituted aryl, unsubstituted arylalkoxy, unsubstituted arylalkoxycarbonyl, halo, haloalkoxy, haloalkyl, hydroxy, and -NR^xR^s.

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 a group that is located on the nitrogen atom of a nitrogen-containing final ring, i.e. the pyrrolidine rings of compound le. It should be understood that "Cap" or "cap" may refer to the reagent used to attach groups to the nitrogen-containing end ring or to the fragment in the final product, ie "Cap-51" or "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 from 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^s, wherein aryl and heterocyclyl are optionally further 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 (cycloalkylalkyl is optionally further substituted by 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 likes.

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 with one, two, three or four halogen atoms.

The term "heterocyclyl" as used herein, refers to a four, five, six or seven membered ring containing one, two, three or four heteroatoms independently selected from nitrogen, oxygen and sulfur. A four-membered ring has zero double bonds, a five-membered ring has zero to two double bonds, and six- and seven-membered rings have zero to three double bonds. The term "heterocyclyl" also includes bicyclic groups in which the heterocyclyl ring is fused to another monocyclic heterocyclic group, or a four to six membered aromatic or non-aromatic carbocyclic ring, as well as bridged bicyclic groups such as 7azabicyclo [2.2.1] hept-7 -yl, 2-azabicyclo [2.2.2] ok-2-tyl, and 2-azabicyclo [2.2.2] ok-3-tyl. The heterocyclyl groups of the present disclosure can be attached to the parent molecular moiety through any carbon or nitrogen atom in the group. Examples of heterocyclyl groups include, without limitation, benzothienyl, furyl, imidazolyl, indolinyl, indolyl, isothiazolyl, isoxazolyl, morpholinyl, oxazolyl, piperazinyl, piperidinyl, pyrazolyl, pyridinyl, pyrrolidinyl, pyrrolopyridinyl, pyrrolyl, thiazolyl, thiazolyl, thiazolyl, thiazolyl. 1] hept-7-yl, 2-azabicyclo [2.2.2] ok-2-tyl, and 2-azabicyclo [2.2.2] ok-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, second heterocyclyl, heterocyclyl , heterocyclylcarbonyl, hydroxy, hydroxyalkyl, nitro, -NR^xR^s, (NO^xR^s) alkyl and oxo, wherein the alkyl part of the arylalkyl and heterocyclylalkyl are unsubstituted and wherein the aryl, aryl part of the arylalkyl, aryl part of the arylcarbonyl, second heterocyclyl group, and heterocyclyl part of heterocyclylalkyl and heterocyclylcarbonyl are further optionally substituted with one, two or three substituents independently selected among 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 optionally further substituted with one or two additional groups independently selected from alkoxy, alkylcarbonyloxy, aryl, halo, haloalkoxy, haloalkyl, hydroxy, and -NR^cR^dwherein aryl is optionally further substituted with one or two substituents independently selected from alkoxy, alkyl, unsubstituted aryl, unsubstituted arylalkoxy, unsubstituted arylalkoxycarbonyl, halo, haloalkoxy, haloalkyl, hydroxy and -NR^xR^s.

The term "heterocyclylalkylcarbonyl," as 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^andR^b"As used herein, refers to two groups, R^and and R^bwhich are attached to the parent molecular moiety through a nitrogen atom. R^and and R^b are independently selected from hydrogen, alkenyl and alkyl.

The term ,, (NO^andR^b) alkyl "as used herein, refers to an alkyl group substituted with one, two or three -NR groups^andR^b.

The term ,, (NO^andR^b) carbonyl "as used herein, refers to the group NR^andR^b the parent molecular moiety attached to the moiety through a carbonyl group.

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

The term ,, (NO^cR^d) alkenyl "as used herein, refers to an alkenyl group substituted with one, two or three -NR groups^cR^d.

The term ,, (NO^cR^d) alkyl "as used herein, refers to an alkyl group substituted with one, two or three -NR groups^cR^d. Alkyl part (NR^cR^d) alkyl is optionally further substituted by one or two additional groups selected from alkoxy, alkoxyalkylcarbonyl, alkoxycarbonyl, alkylsulfanyl, arylalkoxyalkylcarbonyl, carboxy, heterocyclyl, heterocyclylcarbonyl, hydroxy and (NR^cR^d) Carbonyl; wherein the heterocyclyl is optionally further substituted with one, two, three, four or five substituents independently selected from alkoxy, alkyl, cyano, halo, haloalkoxy, haloalkyl, and nitro.

The term ,, (NO^cR^d) carbonyl "as used herein, refers to the group -NR^cR^d the parent molecular moiety attached to the moiety through a carbonyl group.

The term ,, - NR^eR^f"As used herein, refers to two groups, R^e and R^fwhich 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 (cyclalkyl) alkyl, unsubstituted heterocyclyl, unsubstituted heterocyclylalkyl, (NR^xR^s) alkyl and (NR^xR^s) Carbonyl.

The term ,, (NO^eR^f) alkyl "as used herein, refers to an alkyl group substituted with one, two or three -NR groups^eR^f.

The term ,, (NO^eR^f) alkylcarbonyl "as used herein, refers to the group (NR^eR^f) alkyl attached to the parent molecular moiety through a carbonyl group.

The term ,, (NO^eR^f) carbonyl "as used herein, refers to the group -NR^eR^f the parent molecular moiety attached to the moiety through a carbonyl group.

The term ,, (NO^eR^f) sulfonyl "as used herein, refers to the group -NR^eR^f the parent molecular moiety attached to the moiety through a sulfonyl group.

The term ,, - NR^xR^s"As used herein, refers to two groups, R^x and R^swhich are attached to the parent molecular moiety through a nitrogen atom. R^x and R^s are independently selected from hydrogen, alkoxycarbonyl, alkyl, alkylcarbonyl, unsubstituted aryl, unsubstituted arylalkoxycarbonyl, unsubstituted arylalkyl, unsubstituted cycloalkyl, unsubstituted heterocyclyl and (NR^xR^s carboncaryl, with R^x and R^s are independently selected from hydrogen and alkyl.

The term ,, (NO^xR^s) alkyl "as used herein, refers to an alkyl group substituted with one, two or three -NR groups^xR^s.

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 -SiR₃wherein 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 marked with the symbols "R" or "S", depending on the configuration of substituents around the chiral carbon atom. It should be understood that the disclosure includes all stereochemical isomeric forms, or mixtures thereof, that have the ability to inhibit NS5A. Individual stereoisomers of the compound can be made artificially from commercially available starting materials containing chiral centers or by preparing 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 commercially available or can be prepared and separated by techniques known in the art.

Some compounds of the present disclosure may exist in various stable conformational forms, which may be separable. Torsion asymmetry, resulting from limited rotation around an asymmetric single bond, for example, due to steric hindrance or ring tension, may allow 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 terms are intended to include compounds of Formula (I), and pharmaceutically acceptable enantiomers, diastereomers and salts thereof. Similarly, references to intermediates are intended to include their salts, if the context allows.

The compounds of the present disclosure may exist as pharmaceutically acceptable salts. The term "pharmaceutically acceptable salt" as used herein, means salts or amphoteric forms of the compounds of this disclosure that are water-soluble or oil-dispersible or that are, within reasonable medical judgment, suitable for use in contact with the patient's tissues without undue toxicity, irritation, an allergic response or other problem or complication commensurate with a reasonable profit-risk ratio and is effective when intended for them. Salts can be prepared during final isolation and purification of the compound or separately by reacting the appropriate nitrogen atom with the appropriate acid. Representative acid addition salts include acetate, adipate, alginate, citrate, aspartame, benzoate, benzosulfonate, bisulfate, butyrate, camphors, camphorsulfonate, digluconate. dihydrochloride, dihydrochloride, dihydride, glycerophosphate, hemisulfate, heptanoate, formate, fumarate, hydrochloride, hydrobromide, hydrogen hydride, 2-hydroxyethane sulfonate, lactate, maleate, mesitylene sulfonate, methanesulfonate, naphthalene sulfonate, nicotinate, 2-naphthalene sulfonate, oxalate, palminate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, phosphate, phosphonate, succinate glutamate, bicarbonate, para-toluenesulfonate and undecanoate. Examples of acids that can be used 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.

Base addition salts can be prepared during the final isolation and purification of compounds by reacting a carboxyl group with a suitable base such as a metal cation hydroxide, carbonate or bicarbonate or with ammonia or an organic primary, secondary or tertiary amine. Pharmaceutically acceptable salt cations include lithium, sodium, potassium, calcium, magnesium and aluminum, as well as non-toxic quaternary amine cations such as ammonium, tetramethylammonium, tetraethylammonium, methylamines, dimethylamines, trimethylamines, triethylamines, diethylamines, ethylamines, tributylamines, pyridines Ν-dimethylaniline, N-methylpiperidine, N-methylmorpholine, dicyclohexylamine, procaine, dibenzylamine, Ν, Ν-dibenzylphenylamine and Ν, Ν'-dibenzylenediamine. Other representative organic amines useful for forming base addition salts include ethylenediamine, ethanolamine, diethanolamine, piperidine and piperazine.

When it is possible that a therapeutically effective amount of a compound of formula (I), as well as a pharmaceutically acceptable salt thereof, for use in therapy can be administered as a chemical raw material, it is possible to present the active ingredient as a pharmaceutical composition. Accordingly, the disclosure further provides pharmaceutical compositions comprising 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 ingredient that is sufficient to show a significant benefit to the patient, e.g. reduction of viral titers. In relation to a single active ingredient, given alone, the expression refers only to that ingredient. With regard to combinations, the expression refers to the combined amounts of active ingredients that produce a therapeutic effect, whether administered in combination, serially or simultaneously. The compounds of formula (I) and their pharmaceutically acceptable salts are as described above. The carrier (s), diluent (diluents) or excipient (excipients) must be acceptable in the sense of being compatible with the other ingredients of the formulation and not injurious to the recipient. With respect to other aspects of the disclosure, there is also provided a method of making a pharmaceutical formulation, comprising adding admixtures of 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 ingredients, materials, compositions and / or dosage forms that are, within reasonable medical judgment, suitable for use in contact with patient tissues without excessive toxicity, irritation, or an allergic response or other problem or complication commensurate with a reasonable profit-risk ratio and are effective when intended for them.

Pharmaceutical formulations may be presented in unit dose forms containing a predetermined amount of active ingredient per unit dose. Dosage levels of the compound of the present disclosure between about 0.01 and about 250 milligrams per kilogram ("mg / kg") body weight per day, preferably between about 0.05 and about 100 mg / kg body weight per day are typical as monotherapy for the prevention and treatment of diseases dependent on HCV. Typically, the pharmaceutical composition of the present disclosure will be administered from about 1 to about 5 times a day, or alternatively, as a continuous infusion. Such administration can be used as chronic or acute treatment. The amount of active ingredient that can be combined with carrier materials to form a single dose will vary depending on the condition being treated, the severity of the condition, time of administration, route of administration, rate of excretion of the compound used, duration of treatment and age, sex , weight and condition of the patient. Preferred unit dosage formulations are those which contain the daily dose or sub-dose of active ingredient as those cited above, or the appropriate portion thereof. Treatment can be started at low doses, significantly less than the optimal dose of the compound. The dosage is then increased in small increments until optimal effect is achieved under the conditions. In general, it is most desirable to administer the compound at a concentrated level that will generally provide antiviral effective results without causing any harmful or adverse side effects.

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

Pharmaceutical formulations can be adapted for administration by any appropriate route, for example, oral (including buccal or sublingual), rectal, nasal, topical (including buccal, sublingual or transdermal), vaginal or parenteral (including subcutaneous, intradermal, intramuscular, intramuscular, intramuscular, intramuscular or intra-articular injection). , intrasynovial, intrasternal, intrathecal, intrathecal, intravenous or intrathecal). Such formulations can be prepared by any method known in the art of pharmaceutical technology, for example by bringing into association the active ingredient with the carrier (s) or excipient (s). Oral or injectable administration is preferred.

Pharmaceutical formulations adapted for oral administration may exist as separate units such as capsules or tablets; powders or granules; solutions or suspensions in the form of aqueous or non-aqueous liquids; edible foams or mousses; or liquid oil-in-water emulsions or water-in-oil emulsions.

For example, for oral administration in the form of a tablet or capsule, the active drug ingredient may be combined with an oral, non-toxic, pharmacologically acceptable, inert carrier such as ethanol, glycerol, water and the like. Powders are prepared by grinding the compound to a suitably fine size and mixing with a similarly finely divided pharmaceutical carrier such as an edible carbohydrate, such as, for example, starch or mannitol. Flavoring, preserving, dispersing and coloring agents may also be present.

Capsules are made by preparing a powder mix as described above and filling formed gelatin sheaths. Before the filling operation, glidants and lubricants such as colloidal silica, talc, magnesium stearate, calcium stearate or solid polyethylene glycol may be added to the powder mixture. Disintegrating or dissolving agents such as agar-agar, calcium carbonate or sodium carbonate can also be added to improve drug availability after swallowing the capsule.

Moreover, if necessary or necessary, suitable binders, lubricants, disintegrants and dyes can also be incorporated into the mixture. Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, carboxymethyl cellulose, polyethylene glycol and the like. Lubricants used in these dosage forms include sodium oleate, sodium chloride and the like. Disintegrating agents include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum and the like. Tablets are formulated, for example, by preparing a powder mixture, granulating or kneading, adding a lubricant and disintegrant, and extruding into tablet form. The powder mixture is produced by mixing the compound, a suitable chopper with a diluent or base as described above and optionally with a binder such as carboxymethyl cellulose, alginate, gelatin or polyvinylpyrrolidone, a substance that delays the formation of a solution such as paraffin, an absorption accelerator such as quaternary salt and / or absorbent agent such as bentonite, kaolin or dicalcium phosphate. The powder mixture can be granulated by wetting with a binder such as syrup, starch paste, acacia glue or solutions of cellulosic or polymeric materials and forcing through a screen. As an alternative to granulation, the powder mixture can be passed through a tabletting machine and the result is heterogeneously formed nuggets, broken into granules. To prevent sticking to the tablet-forming matrix, the granules can be coated with lubricants by adding stearic acid, stearic salt, talc or mineral oil. Then, the lubricated mixture is compressed into tablets. The compounds of the present disclosure can also be combined with an easily flowing inert carrier and compressed into tablets directly, without undergoing granulation or kneading steps. A transparent or opaque coating may be provided, comprising a shellac sealing layer, a sugar or polymeric coating, and a waxy gloss coating. Dyes can be added to these coating units to distinguish between different unit doses.

Oral fluids such as solutions, syrups and elixirs can be prepared in unit dosage form such that a given amount contains a specific amount of compound. Syrups can be made by dissolving the compound in a suitable flavored aqueous solution, while elixirs are made by using a non-toxic vehicle. Solubilizing agents and emulsifiers such as ethoxylated isostearyl alcohols and polyoxyethylene sorbitol esters, preservatives, flavor additives such as peppermint oil or natural sweeteners or saccharin or other artificial sweeteners and the like may also be added.

Where appropriate, unit dose formulations for oral administration may be microencapsulated. The formulation can be prepared to extend or sustain release, for example, by coating or embedding a given material in polymers, wax or the like.

The compounds of formula (I), and their pharmaceutically acceptable salts, may also be administered in the form of liposomal delivery systems such as small monolayer vesicles, large monolayer vesicles and multilayer vesicles. Liposomes can be formed from various phospholipids such as cholesterol, searylamine or phosphatidylcholines.

The compounds of formula (I) and their pharmaceutically acceptable salts can also be delivered using monoclonal antibodies as specific carriers to which the compound molecules are attached. The compounds can also be combined with soluble polymers as targeted drug carriers. Such polymers may include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropyl methacrylamidophenol, polyhydroxyethylaspartamidophenol, or polyethyleneoxydolysinol substituted with palitooyl residues. In addition, the compounds can be combined with a class of biodegradable polymers useful for controlled drug release, for example, polylactic acid, polypsilon caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydropyranes, polycycloacylates and crosslinked or amphipathic block copolymers.

Pharmaceutical formulations adapted for transdermal administration may be present as separate patches to be in direct contact with the skin of the recipient for an extended period of time. For example, the active ingredient may be delivered from the patch by iontophoresis as described generally in Pharmaceutical Research 1986, 5 (6), 318.

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

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

Pharmaceutical formulations adapted for intranasal administration, wherein the carrier is in solid form, include coarse powder, with a particle size, for example, in the range from 20 to 500 microns, administered by sniffing, i.e. by rapid inhalation through the nasal passages of a container with a powder held close nose. Formulations in which the carrier is a liquid, suitable for administration as a nasal nebulization fluid or nasal drops, include aqueous or oily solutions of the active ingredient.

Pharmaceutical formulations adapted for administration by inhalation include fine-grained dusts or mists, which can be generated by various types of pressurized aerosols, nebulizers or insufflators.

Pharmaceutical formulations adapted for vaginal administration may be present as pessaries, tampons, creams, gels, pastes, foams or in aerosol formulations.

Pharmaceutical formulations adapted for parenteral administration include sterile aqueous and non-aqueous injections, which may contain antioxidants, buffers, bacteriostats and solutes, providing the formulation isotonic with the recipient's blood; and aqueous or non-aqueous sterile suspensions which may include suspending agents and thickening agents. The formulations can be presented in single-dose or multi-dose containers, for example sealed ampoules or vials and can be stored in a lyophilized state requiring only the addition of a sterile liquid carrier, for example water for injections, immediately before use, Solutions and suspensions prepared immediately before use. can be made from sterile powders, granules and tablets.

It should be understood that, in addition to the individual ingredients mentioned above, the formulations may contain other agents typical in the art having regard to the type of formulation concerned, for example those suitable for oral administration may contain flavoring agents.

The term "patient" includes both humans and other mammals.

The term "treatment" refers to: (i) preventing the occurrence of a disease, disorder or condition in a patient who 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.

Compounds of the present disclosure can also be administered with cyclosporin, for example cyclosporin A. It has been shown that cyclosporin A has anti-HCV activity in clinical studies (Hepatology 2003, 38, 1282; Biochem. Biophys. Res. Commun. 2004, 313, 42; J. Gastroenterol. 2003, 38, 567).

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

Table 1

<td>trade name</td><td>Grade physiological</td><td>Inhibitor or target type</td><td>Supplier company</td>

<td>NIM811</td><td></td><td>Cyclophilin inhibitor</td><td>Novartis</td>

<td>Zadaxin</td><td></td><td>immunomodulator</td><td>made upon</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>antineoplastic</td><td>B-tubulin inhibitor</td><td>Tularik Inc., South San Francisco, CA</td>

<td>ISIS 14803</td><td>antiviral</td><td>antisense</td><td>ISIS Pharmaceuticals Inc, Carlsbad, CA / Elan Phamaceuticals Inc., New York, NY</td>

<td>Summetrel</td><td>antiviral</td><td>antiviral</td><td>Endo Pharmaceuticals</td>

<td></td><td></td><td></td><td>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 of WO-2005047288 May 26, 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 (VX497)</td><td>antiviral</td><td>IMPDH inhibitor</td><td>Vertex Pharmaceuticals Inc., Cambridge, MA</td>

<td>XTL-6865 (XTL-002)</td><td>antiviral</td><td>antibody monoclonal</td><td>XTL Biopharmaceuticals Ltd., Rehovot, Isreal</td>

<td>Telaprevir (VX-950, LY-570310)</td><td>antiviral</td><td>NS3 Serine Protease Inhibitor</td><td>Vertex Pharmaceuticals Inc., Cambridge, MA / Eli Lilly and What. Inc., Indianapolis, ION</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></td><td></td><td></td><td></td>

<td>2'C MeA</td><td>antiviral</td><td>NS5B Replicase Inhibitor</td><td>Gilead</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 Pharmaceuticals, Costa Mesa, CA</td>

<td>ribavirin</td><td>antiviral</td><td>ribavirin</td><td>Schering-Plow Corporation, Kenilworth, NJ</td>

<td>viramidine</td><td>antiviral</td><td>Ribavirin Prodrugs</td><td>Ribapharm Inc., Costa Mesa, CA</td>

<td>heptazyme</td><td>antiviral</td><td>ribozyme</td><td>Ribozyme Pharmaceuticals 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 Plow</td>

<td>Zadazim</td><td>immunomodulator</td><td>immunomodulator</td><td>SciClone Pharmaceuticals</td>

<td></td><td></td><td></td><td>Inc., San Mateo, CA</td>

<td>Ceplene</td><td>Immunomodulalor</td><td>immunomodulator</td><td>Maxim Pharmaceuticals Inc., San Diego, CA</td>

<td>CellCept</td><td>Immunosupressa nt</td><td>immunosuppressant HCV IgG</td><td>F. Hoffmann- La Roche LTD, Basel, Switzerland</td>

<td>civacir</td><td>Immunosupressa nt</td><td>immunosuppressant HCV IgG</td><td>Nabi Biopharmaceuticals Inc., Boca Raton, FL</td>

<td>Albuferon-α</td><td>interferon</td><td>IFN-a2b albumin</td><td>Uman Genome Sciences Inc., Rockville, MD</td>

<td>Infergen A.</td><td>interferon</td><td>IFN alfacon-1</td><td>InlerMune Pharmaceuticals Inc., Brisbane, CA</td>

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

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

<td>Rebif</td><td>interferon</td><td>FN-fila</td><td>Serono, Geneva, Sz wajcaria</td>

<td>Roferon A.</td><td>interferon</td><td>IFN-a2a</td><td>F. Hoffmann- La Roche LTD, Basel, Switzerland</td>

<td>Intron A.</td><td>interferon</td><td>IFN-a2b</td><td>Schering-Plow Corporation, Kenilworth, NJ</td>

<td>Intron A and Zadaxin</td><td>interferon</td><td>IFN-a2b / a 1-thymosin</td><td>RegeneRx Biopharmiceu ticals Inc., Belhesda,</td>

<td></td><td></td><td></td><td>MD / SciClone Pharmaceuticals Inc, San Mateo, CA</td>

<td>Rebetron</td><td>interferon</td><td>IFN-a2b / ribavirin</td><td>Schering-Plow Corporation, Kenilworth, NJ</td>

<td>Actimmune®</td><td>interferon</td><td>INF-γ</td><td>InterMune Inc., Brisbane, CA</td>

<td>Interferon-B</td><td>interferon</td><td>Interferon-B-la</td><td>Serono</td>

<td>Multiferon</td><td>interferon</td><td>IFN long-acting</td><td>Viragen / V alentis</td>

<td>Wellferon</td><td>interferon</td><td>lymphoblastoid IFN-anl</td><td>GlaxoSmithkline ple, Uxbridge, UK</td>

<td>Oinniferon</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. Hoffmann- La Roche LTD, Basel, Switzerland</td>

<td>Pegasys and Ceplene</td><td>interferon</td><td>PEGylated IFNa2a / immunomodulator</td><td>Maxim Pharmaceuticals Inc., San Diego, CA</td>

<td>Pegasys and Ribavirin</td><td>interferon</td><td>PEGylated IFNa2a / ribavirin</td><td>F. Hoffmann- La Roche LTD, Basel, Switzerland</td>

<td>PEG-Intron</td><td>interferon</td><td>PEGylated IFN-a2b</td><td>Schering-Plow Corporation, Kenilworth, NJ</td>

<td>PEG-Intron / ribavirin</td><td>interferon</td><td>PEGylated IFNa2b / ribavirin</td><td>Schering-Plow Corporation, Kenilworth, NJ</td>

<td>IP-501</td><td>Liver protection</td><td>antithrombotic</td><td>Indevus Pharmaceuticals Inc., Lexington, MA</td>

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

<td>ITMN-191 (R-7227)</td><td>antiviral</td><td>serine protease inhibitor</td><td>InterMune Pharmaceuticals 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 can be used as laboratory reagents. The compounds can be helpful in providing research tools for research design for virus replication assays, validation of animal research systems and structural biology studies to further increase knowledge of the mechanisms of HCV disease. In addition, the compounds of the present disclosure are useful in establishing or determining binding sites for other antiviral compounds, for example, by competitive inhibition. The compounds of the present disclosure can also be used to treat or prevent virus infection of materials, reducing the risk of viral infection by laboratory or medical personnel or patients who have been in contact with such materials, e.g., blood, tissue, tools and surgical clothing, tools and laboratory clothing, blood collection or transfusion devices and materials.

The disclosure is intended to include compounds of formula (I) when produced by synthetic or metabolic processes, including those occurring in the human or animal body (in vivo) or in vitro processes.

Abbreviations used in the application, including particularly those in the following diagrams and examples, are well known to those skilled in the art. Some abbreviations used are: HATU for O- (7-azabenzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium hexafluorophosphate; Boc or BOC for tert-butoxycarbonyl; NBS for Nbromosukcinimide; tBu or t-Bu for tert-butyl; SEM for - (trimethylsilyl) ethoxymethyl; DMSO for dimethyl sulfoxide; MeOH for methanol; TFA for trifluoroacetic acid; RT for room temperature or retention time (as indicated by the context); tR for retention time; EDCI for 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride; DMAP for 4-dimethylaminopyridine; THF for tetrahydrofuran; DBU for 1,8-diazabicyclo [5.4.0] undec7-ene; t-Bu; DEA for diethylamine; HMDS for hexamethyldisilazide; DMF for N, N-dimethylformamide; Bzl benzyl; EtOH for ethanol; iPrOH or i-PrOH for isopropanol; Me₂S for dimethyl sulfide; Et3N or TEA for triethylamine; Ph for phenyl; OAc for acetate; EtOAc for ethyl acetate; dppf for 1,1'-bis (diphenylphosphino) ferrocene; Pr₂EtN or DIPEA for diisopropylethylamine; Cbz for carbobenzyloxy; n-BuLi for n-butyllithium; ACN for acetonitrile; h or h for hours; m or min for minutes; s for seconds; LiHMDS for lithium hexamethyldisilazide; DIBAL for diisobutylaluminum hydride; TBDMSC1 for tert-butyldimethylsilyl chloride; Me for methyl; approx. for about; OAc for acetate; iPr for isopropyl; Et for ethyl; Bn for benzyl; and HO AT for 1-hydroxy-7-azabenzotriazole.

Abbreviations used in the application, including in particular those in the following illustrative diagrams and examples, are well known to those skilled in the art. Some of the abbreviations have the following meanings:

The compounds and processes of the present disclosure will be better understood in connection with the following synthetic schemes that illustrate methods by which the compounds of the present disclosure can be obtained. Starting materials may be obtained from commercial sources or prepared by well-known literature methods known to those skilled in the art. It will be apparent to those skilled in the art that the compounds defined above can be synthesized by substituting the appropriate reagents and factors in the syntheses shown below. It will also be apparent to those skilled in the art that the selective protection and deprotection steps as well as the order of the same steps can be carried out in a different order depending on the nature of the variables to successfully complete the following syntheses. Variables are as defined above, unless otherwise noted below.

Diagram 1: Symmetrical or Asymmetrical Biphenyls

Aryl halide 1 and boronic ester 2 can be coupled to form biaryl 3 using Suzuki Miayura standard coupling conditions (Angew Chem. Int. Ed. Engl 2001, 40, 4544). It should be noted that a boronic acid analog 2 may be used instead of the ester. A mono-protected pyrrolidine moiety can be obtained when R¹² and R¹³ are different. When R = benzyl and R = t-butyl treatment with hydrogenolysis conditions gave 4. For example, a Pd / C catalyst may be used in the presence of a base such as potassium carbonate. Acylation 4 can be carried out under standard acylation conditions. In this regard, a coupling reagent such as HATU can be used in combination with an amine base such as Hunig's base. Alternatively, 4 may be reacted with carbamoyl chloride or isocyanate to provide compounds of formula 5 where R⁹ is an amine. Further deprotection can be achieved by treatment with a strong acid such as HCl or trifluoroacetic acid. Standard conditions analogous to those used for the conversion of 4 into 5 can be used to obtain 7 out of 6. In another embodiment, where R¹²= R¹³ = t-Bu, direct conversion to 8 can be achieved by treatment with 3 strong acid such as HCl or trifluoroacetic acid. The conversion of 8 to 7 takes place in a manner analogous to the methods used to obtain 5 from. 4 or 7 from 6. In this case, however, the cap in 7 will be identical.

<img file="PL2049522T3_D0008.tif" />

RJ3 R.

° and ° ji &lt;^H (R \ | R'k

<img file="PL2049522T3_D0009.tif" />

X? ' "

R '²

<img file="PL2049522T3_D0010.tif" />

<img file="PL2049522T3_D0011.tif" />

(R⁵),

<img file="PL2049522T3_D0012.tif" />

Scheme 2: Asymmetrically Cap-Biphenyls

Conversion 6 (from Scheme 1) to 10 can be performed using standard amide coupling conditions such as HATU with an amine base such as Hunig's base. Deprotection can be achieved with a strong acid such as HCl or trifluoroacetic acid to give 11. Compound 11 can then be converted to 12, 13 or 14 using acid chloride, isocyanate or carbamoyl chloride, respectively, or chloroformate, respectively.

<img file="PL2049522T3_D0013.tif" />

Scheme 3: Biphenyls with Added Symmetrical Cap

Compound 15 (75 = 7 (Scheme 1), wherein each R⁹ is -CH (NHBoc) R¹⁸) can be converted to 16 by treatment with a strong acid such as HCl or trifluoroacetic acid. Compounds 77, 18 and 19 can be obtained from 16 by treatment of 16 with the appropriate chloroformate, carbamoyl chloride or isocyanate or acid chloride, respectively.

<img file="PL2049522T3_D0014.tif" />

Symmetrical biphenyl analogues (compounds of formula 7 where both halves of the molecule are equivalent) can be synthesized starting from bromoketone 20. Amination by replacement with a nucleophile such as azide, phthalimide or more preferably sodium diformylamide (Yinglin and Hongwen, Synthesis 1990, 122), followed by deprotection gives 27. Condensation under standard amination conditions such as HATU and Hunig's base with the corresponding protected amino acid provides 22. Heating with ammonium acetate under thermal or microwave conditions leads to the formation of 3, which can be deprotected with a strong acid such as HCl or trifluoroacetic acid (R¹² = R¹³ = t-Bu) or hydrogenation with hydrogen gas and a transition metal catalyst such as Pd / C (R¹² = R¹³ = benzyl). Acylation can be carried out with carboxylic acid (R⁹WHAT₂H) in a manner similar to the conversion of 21 into 22. The production of urea can be achieved by treatment with the appropriate isocyanate (R⁹ = R²⁴R²⁵N; R²⁵ = H) or carbamoyl chloride (R⁹ = R²⁴R²⁵N; R²⁵ is other than hydrogen).

<img file="PL2049522T3_D0015.tif" />

Diagram 5: Starting Materials 25 and 2

Scheme 5 describes the preparation of some starting materials necessary for the synthesis of the sequences shown in Schemes 1-4. Key intermediate 25 (analogous to 1 in Scheme 1) is obtained from keto-24 or keto-27 by heating with ammonium acetate under thermal or microwave conditions. Keto-amide 24 can be obtained from 23 by condensation with the appropriate cyclic or acyclic amino acid under standard amide-forming 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 reaction with the appropriate cyclic or acyclic N-protected amino acid in the presence of a base such as potassium carbonate or sodium bicarbonate. Bromination with a bromonium ion source such as bromine, NBS or CBr₄ leads to 26. Bromide 25 can be converted to boronic ester 2 by treatment with bispinacalotodibor under palladium catalysis according to the method described in Journal of Organic Chemistry 1995, 60, 7508 or variants thereof.

<img file="PL2049522T3_D0016.tif" />

Scheme 6: Starting material 31α

In another embodiment, starting materials such as 3a (analogous to 25 in Scheme 5 and 1 in Scheme 1) can be obtained by reacting bromoimidazole derivatives 31 under Suzuki coupling reaction conditions with various chlorosubstituted aryl boronic acids, which may or may be prepared by standard techniques (see, for example, Organic Letters 2006, 8, 305 and literature cited therein), or purchased from commercial suppliers. Bromoimidazole 31 can be obtained by brominating imidazole 30 with a bromonium ion source such as bromine, CBr₄, or N-bromosuccinimide. Imidazole can be obtained from N-protected amino acids that are appropriately substituted by reaction with glyoxal in a methanolic solution of ammonium hydroxide.

<img file="PL2049522T3_D0017.tif" />

<img file="PL2049522T3_D0018.tif" />

Scheme 7: Heteroaryls

In yet another embodiment of the present disclosure, the aryl halide 32 can be coupled with palladium catalyzed Suzuki-Miyaur conditions to form a heteroaryl derivative 34. Compound 34 can be converted to 35 by treatment with hydrogenation conditions using hydrogen and a transition metal catalyst such as palladium on carbon (R = benzyl). Acylation can be achieved with the 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 isocyanate (R²⁷NCO, with R⁹ = R²⁷R²⁸N-; R²⁸ = H) or carbamoyl chloride (R²⁷R²⁸NCOC1, with R⁹ = R²⁷R²⁸N-). Compound 37 can be obtained from 36 (R = t-Bu) by treatment with a strong acid such as HCl or trifluoroacetic acid. Acylation of the resulting amine at 37 to give 38 can be achieved as in the transformation of 35 into 36. In cases where R¹² = R¹³, 34 can be directly converted to 39 by treatment with a strong acid such as HCl or trifluoroacetic acid (R¹² = R¹³= t-Bu) or by using hydrogenation conditions with hydrogen and a transition metal catalyst such as palladium on carbon (R¹² = R¹³ = benzyl). Acylation 39 can be achieved in a manner analogous to that described for the conversion of 35 into 36.

<img file="PL2049522T3_D0019.tif" />

<img file="PL2049522T3_D0020.tif" />

R¹* j is independently alkoxymethyl or HO 'Cl or Br

<img file="PL2049522T3_D0021.tif" />

Diagram 8

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

Alternatively, the aryl acetic acid ester may be brominated with a bromonium ion source such as bromine, N-bromosuccinimide, or CBr₄. The resulting benzyl bromide can be substituted with various mono- or disubstituted amines in the presence of a tertiary amine as a base such as triethylamine or Hunig's base. Hydrolysis of the methyl ester by treatment with lithium hydroxide at low temperature or 6N HCl at elevated temperature provides substituted phenylglycine derivatives. Another way is presented on the path G. Glycine analogs can be derivatized with various aryl halides in the presence of a palladium (0) source such as bis (tributylphosphine) palladium and a base such as potassium phosphate. The resulting ester can be hydrolyzed by treatment with an alkali or acid. It should be understood that there are other well known methods in the art for preparing phenylglycine derivatives and may be adapted to provide the desired compounds in this specification. It should also be understood that the final phenylglycine derivatives can be purified to enantiomeric purity greater than 98% preparative HPLC ee.

<img file="PL2049522T3_D0022.tif" />

Ar bromination «* · - A» »

<img file="PL2049522T3_D0023.tif" />

Scheme 12: Acylated Amino Acid Derivatives

In another embodiment of the present disclosure, acylated phenylglycine derivatives can be prepared as outlined below. Phenylglycine derivatives, where the carboxylic acid is protected as an easily removable ester, can be acylated with an acid chloride in the presence of a base such as triethylamine to provide the corresponding amides (path A). Lane B illustrates the acylation of the starting phenylglycine derivative with the appropriate chloroformate, and Lane C shows the reaction with the corresponding isocyanate or carbamoyl chloride. Each of the three intermediates shown on AC lanes can be deprotected by methods known to those skilled in the art (i.e., by treatment of the acid t-butyl ester with a strong base such as HCl or trifluoroacetic acid).

<img file="PL2049522T3_D0024.tif" />

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Λγ - o ¹ about

^ 'N ^ OR^{37 Acid} about ¹ about

R²⁷ JU_about Acid

N NO^mR^m «Body ¹

Diagram 13 sts

R²⁷ AND

NO³⁶OH ^ nAjr³⁷

ar⁰"

at o27 U

large pot³⁸^

<img file="PL2049522T3_D0025.tif" />

about

Amino-substituted phenylacetic acids can be prepared by treating chloromethylphenylacetic acid with an excess of amine.

R³⁹

<img file="PL2049522T3_D0026.tif" />

Compound Analysis Conditions

Purity evaluation and low resolution mass analysis were performed on a Shimadzu LC system connected to the Waters Micromass ZQ MS system. Note that retention times may vary slightly between devices. The LC conditions used to determine the retention time (RT) were:

Condition 1

Column = Phenomenex-Luna 3.0Χ 50 mm SIO

Initial% B = 0

Final% B = 100

Gradient time = 2 min

Stopping time = 3 min

Flow rate = 4 mL / min

Wavelength = 220 nm

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

<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 SIO</td>

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

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

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

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

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

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

<td>Solvent A</td><td>= 0.1% TFA in 10% methanol / 90% H₂ABOUT</td>

<td>Solvent B</td><td>= 0.1% TFA in 90% methanol / 10% H₂ABOUT</td>

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

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

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

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

<td>Gradient time</td><td>= 3 minutes</td>

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

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

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

<td>Solvent A</td><td>- 0.1% TFA in 10% methanol / 90% H₂ABOUT</td>

<td>Solvent B</td><td>= 0.1% TFA in 90% methanol / 10% H₂ABOUT</td>

<td>Condition Ml</td><td></td>

Column: Luna 4.6Χ 50 mm SIO

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

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

<td>Gradient time</td><td>= 3 minutes</td>

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

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

<td>Solvent A:</td><td>= 95% H₂A: 5% CH3CN, 10 mm Ammonium acetate</td>

<td>Solvent B:</td><td>= 5% H₂A: 95% CH3CN; 10 mm Ammonium acetate</td>

Synthesis of joint cap

Cap-1

<img file="PL2049522T3_D0027.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 37% by mass in water), IN HCl (30 mL) and methanol (30 mL) and treated with H₂ (60 psi) for 3 hours. The reaction mixture was filtered through diatomaceous earth (Celite®) and the filtrate concentrated in vacuo. The resulting crude material was recrystallized from isopropanol to provide the CapA HCl salt as white needles (4.0 g). Optical rotation: -117.1 ° [c = 9.95 mg / mL in H₂ABOUT; λ = 589 nm]. 1 H 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 (Condition 1): RT = 0.25; LC / MS: Anal. Obi. for [M + H]⁺ Ci0H14NO2 180.10; found 180.17; HRMS: Anal. Obi. for [M + H]⁺ C10Hi₄WELL₂ 180.1025; found 180.1017.

Cap-2

OA ri

NaBH₃CN (6.22g, 94 mmol) was added in portions over several minutes to a cooled (on 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 dropwise over 10 min and stirring was continued at the same reduced temperature for 45 min and at ambient temperature for ~ 6.5 hours. The reaction mixture was again cooled in an ice-water bath, treated with water (3 mL), and then quenched by the addition of concentrated HCl dropwise for ~ 45 min, until the mixture reached pH ~ 1.5-2.0. The cooling bath was removed and stirring was continued by adding concentrated HCl to maintain the pH of the mixture about

1.5-2.0. The reaction mixture was stirred overnight, filtered to remove the white suspension, and the filtrate was concentrated in vacuo. The crude material was recrystallized from ethanol to give the HCl Cap-2 salt as a shiny white solid in two sets (projection 1: 4.16 g; projection 2:

2.19 g). 1 H NMR (DMSO-d₆, δ = 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). Throw-1: [a]²⁵-102.21 ° (c = 0.357, H2O); Throw -2: [a]²⁵ -99.7 ° (c = 0.357, H2O). LC (Condition 1): RT = 0.43 min; LC / MS: Anal. Obi. for [M + H]⁺ these₂HisNO₂: 208.13; found 208.26

Cap-3

<img file="PL2049522T3_D0028.tif" />

Acetaldehyde (5.0 mL, 89.1 mmol) and a suspension of 10% Pd / C (720 mg) in methanol / H₂O (4mL / 1 mL) was successively added to a cooled (~ 15 ° C) mixture of (R) -2-phenylglycine (3.096g, 20.48 mmol), IN HCl (30 mL) and methanol (40 mL). The cooling bath was removed and the reaction mixture was stirred under a balloon with H₂ for 17 hours. Additional acetaldehyde (10 mL, 178.2 mmol) was added and stirring continued under H atmosphere₂ for 24 hours [Note: supply of H₂ replenished during the reaction as needed]. The reaction mixture was filtered through diatomaceous earth (Celite®) and the filtrate concentrated in vacuo. The resulting crude material was recrystallized from isopropanol to provide (R) 2- (ethylamino) -2-phenylacetic acid HCl salt as a shiny white solid (2.846g). 1 H 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 (Condition 1): RT = 0.39 min; homogeneity index&gt; 95%; LC / MS: Anal. Calc. for [M + H]⁺ CioHi4N0₂: 180.10; found 180.18.

A suspension of 10% Pd / C (536 mg) in methanol / H₂O (3 mL / 1 mL) was added to a mixture of (R) -2- (ethylamino) -2-phenylacetic acid / HCl (1.492g, 6.918 mmol), formaldehyde (20 mL 37% by mass in water), IN HCl (20 mL) and methanol (23 mL). The reaction mixture was stirred under a balloon of H2 for ~ 72 hours, where the supply of H₂ refilled as needed. The reaction mixture was filtered through diatomaceous earth (Celite®) and the filtrate concentrated in vacuo. The resulting crude material was recrystallized from isopropanol to provide the Cap-3 HCl salt as a white solid (985 mg).^!H NMR (DMSO-dó, 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 (Condition 1): RT = 0.39 min; &gt; 95% homogeneity index; LC / MS: Anal. Calc. for [M + H]⁺ CnHi6NO2: 194.12; found 194.18; HRMS: Anal. Calc. for [M + H]⁺C iHi6NO₂: 194.1180; found 194.1181.

Cap-4

OH

HVR

CICO₂Me (3.2 mL, 41.4 mmol) was added dropwise over 6 min to chilled (in ice water) THF (410 mL) tert-butyl / HCl (R) -2-amino-2-phenylacetate semi-solution (9.877 g, 40.52 mmol) and diisopropylethylamine (14.2 mL, 81.52 mmol) and stirred at a similar temperature for 5.5 hours. The volatiles were removed in vacuo and the residue was partitioned between water (100 mL) and ethyl acetate (200 mL). The organic layer was washed with IN HCl (25 mL) and saturated NaHCO solution₃ (30 mL), dried (MgSO₄), filtered and concentrated in vacuo. The resulting colorless oil was triturated with hexanes, filtered and washed with hexanes (100 mL) to provide (R) -tert-butyl-2- (methoxycarbonylamino) -2-phenylacetate as a white powder (7.7 g). 1 H 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 (Condition 1): RT = 1.53 min; homogeneity index -90%; LC / MS: Anal. Calc. for [M + Na]⁺ these₄hi₉NNaO₄: 288.12; found 288.15.

TFA (16 mL) was added dropwise for 7 min to a cooled (in ice water) solution of CH 2 Cl 2 (160 mL) of the above product and the cooling bath was removed and the reaction mixture was stirred for 20 hours. Because deprotection was still not complete, 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 ensure precipitation. The precipitate was filtered and washed with diethyl ether / hexanes (~ 1: 3 ratio; 30 mL) and dried in vacuo to provide Cap4 as a fluffy white solid (5.57 g). Optical rotation: -176.9 ° [c = 3.7 mg / mL in H₂ABOUT; λ = 589 nm], * H 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 (Condition 1): RT = 1.01 min; homogeneity index&gt; 95%; LC / MS: Anal. Calc. for [M + H]⁺ C10H12NO4: 210.08; found 210.17; HRMS: Anal. Calc. for [M + H]⁺ these₀hi₂WELL₄: 210.0766; found 210.0756.

Cap-5

<img file="PL2049522T3_D0029.tif" />

Mixture of (R) -2-phenylglycine (1.0 g, 6.62 mmol), 1,4-dibromobutane (1.57 g, 7.27 mmol) and Na2CO₃ (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 HCl to pH 3-4, and the volatile component was removed in vacuo. The resulting crude material was purified by reverse phase HPLC (water / methanol / TFA) to provide the TFA Cap-5 salt as a translucent white foam (1.0 g). * H NMR (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 (Condition 1); homogeneity index&gt; 98%; LC / MS: Anal. Calc. for [M + H]⁺C12H16NO2: 206.12; found 206.25.

Cap-6

<img file="PL2049522T3_D0030.tif" />

Cap-6 TFA salt was synthesized from (R) -2-phenylglycine and 1-bromo-2- (2-bromoethoxyjetane, using the Cap-5 production method. * H NMR (DMSO-de, 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 (Condition 1); &gt; 98%; LC / MS: Anal. Calc. for [M + H]⁺Ci2Hi6NO3: 222.11; found 222.20; HRMS: Anal. Calc. for [M + H]⁺ Ci2Hi₆WELL₃: 222.1130; found 222.1121.

<img file="PL2049522T3_D0031.tif" />

A solution of CH2Cl2 (200 mL) p-toluenesulfonyl chloride (8.65 g, 45.4 mmol) was added dropwise to a cooled (-5 ° C) solution of CH2Cl2 (200 mL) (S) -2-hydroxy-2-phenylacetate benzyl ( 10.0 g, 41.3 mmol), triethylamine (5.75 mL, 41.3 mmol) and 4-dimethylaminopyridine (0.504 g, 4.13 mmol), maintaining the temperature between -5 ° C and 0 ° C. The reaction was stirred at 0 ° C for 9 hours and then stored in the freezer (-25 ° C) for 14 hours. It was allowed to thaw and reach ambient temperature and washed with water (200 mL), IN HCl (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, solidifying on standing (16.5 g). The chiral integrity of the product was not checked and the product was used without further purification for the next step. * H 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 (Condition 3); homogeneity index&gt; 90%; TC / MS: Anal. Calc. for [M + H]⁺ C 22 H₂oNa05S: 419.09; experimental 419.04.

A solution of THF (75 mL) 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 to 65 ° C for 7 hours. The reaction was cooled to ambient temperature and the volatile component was removed in vacuo. The residue was partitioned between ethyl acetate 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-1-yl) -2-phenylacetate as an orange-brown viscous oil (4.56 g). Chiral HPLC (Chiralcel OD-H) analysis showed that the sample is a mixture of enantiomers in a ratio of 38.2 to 58.7. Separation of enantiomers was carried out as follows: the product was dissolved in 120 mL of ethanol / heptane (1: 1) and injected (5 mL / injection) onto a chiral HPLC column (Chiracel OJ, 5 cmID x 50 cmL, 20 mm), eluting with heptane / ethanol 85:15 at 75 mL / min and monitored at 220 nm. The enantiomer-1 (1.474 g) and enantiomer-2 (2.2149 g) were obtained in the form of a viscous oil. * H NMR (CDCl3, 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 (Condition 3); homogeneity index&gt; 98%; TC / MS: Anal. Calc. for [M + H]⁺C20H25N2O2: 325.19; experimental 325.20.

A methanolic solution (10 mT) of any of the benzyl 2- (4-methylpiperazinyl-yl) -2-phenylacetate enantiomers (1.0 g, 3.1 mmol) was added to a suspension of 10% Pd / C (120 mg) in methanol (5.0 mT). The reaction mixture under careful observation was exposed to a hydrogen balloon for &lt;50 min. Immediately after completion of the reaction, the catalyst was filtered through diatomaceous earth (Celite®) and the filtrate was concentrated in vacuo to provide Cap-Ί contaminated with phenylacetic acid as a tan colored foam (867.6 mg; mass above theoretical). The product was used for the next step without further purification. * H NMR DMSO-d₆, δ = 2.5, 500 MHz) 7.44-7.37 (m, 2H), 7.37-7.24 (m, 3H),

3.92 (s, 1H), 2.63-2.48 (app. Bs, 2H), 2.48-2.32 (m, 6H), 2.19 (s, 3H); RT = 0.31 (Condition

2); homogeneity index&gt; 90%; LC / MS: Anal. Calc. for [M + H]⁺ C13H19N2O2: 235.14; experimental 235.15; HRMS: Anal. Calc. for [M + H]⁺ C13H19N2O2: 235.1447; experimental 235.1440.

The synthesis of Cap-% and Cap-9 was performed according to the synthesis of: Cap-Ί by using amines suitable for the substitution step SN2 (i.e. 4-hydroxypiperidine for Cap-% and (S) -3-fluoropyrrolidine for Cap-9) and modified conditions for the separation of individual stereoisomeric intermediates as described below.

<img file="PL2049522T3_D0032.tif" />

The enantiomeric separation of intermediate 2- (4-hydroxypiperidin-1-yl) -2-phenylacetate benzyl was carried out by applying the following conditions: the compound (500 mg) was dissolved in ethanol / heptane (5 mL / 45 mL). The resulting solution was injected (5 mL / injection) onto a chiral HPLC column (Chiracel OJ, 2 cm ID x 25 cm L, 10 gm), eluting with heptane / ethanol 80:20 at 10 mL / min, monitoring at 220 nm to ensure 186.3 mg enantiomer-1 and 209.1 mg enantiomer-2, in the form of pale yellow viscous oils. These benzyl esters were subjected to hydrogenolysis according to the method of producing Cap-Ί to provide Cap-8: * H NMR (DMSO-d₆, δ = 2.5, 500 MHz) 7.40 (d, J = 7, 2H), 7.28-7.20 (m, 3H), 3.78 (s 1H), 3.46 (m, 1H), 2.93 (m, 1H), 2.62 ( m, 1H), 2.20 (m, 2H), 1.70 (m, 2H), 1.42 (m, 2H). RT = 0.28 (Condition 2); homogeneity index&gt; 98%; LC / MS: Anal. Calc. for [M + H]⁺ C13Hi8NO3: 236.13; experimental 236.07; HRMS: Anal. Calc. for [M + H]⁺Ci3Hi8NO3: 236.1287; experimental 236.1283.

<img file="PL2049522T3_D0033.tif" />

Diastereomeric separation of the intermediate product 2 - ((S) -3-fluoropyrrolidin-1-yl) -2-phenylacetate benzyl was carried out by applying the following conditions: ester (220 mg) separated on a chiral HPLC column (Chiracel OJ-H, 0.46 cm ID x 25 cm

L, 5 pm), eluted with 95% CO₂/ 5% methanol with 0.1% TFA, at 10 bar pressure, 70 mL / min flow rate and 35 ° C. The HPLC eluate for individual stereoisomers was concentrated and the residue was dissolved in CH₂C1₂ (20 mL) and washed in an aqueous medium (10mL waters + 1mL saturated NaHCO solution)₃). 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 subjected to hydrogenolysis according to the method of producing Cap-Ί to produce Cap 9a and 9b. Cap-9 &amp; (diastereomer-1; sample is the TFA salt as a result of reverse phase HPLC purification using solvent H₂O / methanol / TFA): * H NMR (DMSO-d₆, δ = 2.5, 400 MHz) 7.55-7.48 (m, 5H), 5.38 (dm, 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 (Condition 1); homogeneity index&gt; 95%; LC / MS: Anal. Obi. for [M + H]⁺C |₂Hi5FNO₂: 224.11; experimental 224.14.Cap-9b (diastereomer-2): * H NMR (DMSO-d₆, δ = 2.5, 400 MHz) 7.43-7.21 (m, 5H), 5.19 (dm, J = 55.9, 1H), 3.97 (s, 1H),

2.95-2.43 (m, 4H), 2.19-1.78 (m, 2H). RT = 0.44 (Condition 1); LC / MS: Anal. Obi. for [M + H]⁺ C₁₂H_I5FNO₂: 224.11; experimental 224.14.

Cap-10

HO

A solution of D-proline (2.0 g, 17 mmol) and formaldehyde (2.0 mL 37% by mass in H₂O) in methanol (15 mL) was added to a suspension of 10% Pd / C (500 mg) in methanol (5 mL). The mixture was stirred under a hydrogen balloon 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). 1 H NMR (DMSO-d₆, δ = 2.5, 500 MHz) 3.42 (m, 1H), 3.37 (dd, / = 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 (Condition 2); homogeneity index&gt; 98%; LC / MS: Anal. Obi. for [M + H]⁺ C₆H₁₂WELL₂: 130.09; experimental 129.96.

xj

Cap-11

<img file="PL2049522T3_D0034.tif" />

F

Mixture of (2S, 4R) -4-fluoropyrrolidine-2-carboxylic acid (0.50 g, 3.8 mmol), formaldehyde (0.5 mL 37% by mass in H₂O), 12 N HCl (0.25 mL) and 10% Pd / C (50 mg) in methanol (20 mL) was stirred under a hydrogen balloon for 19 hours. The reaction mixture was filtered through diatomaceous earth (Celite®) and the filtrate concentrated in vacuo. The residue was recrystallized from isopropanol to provide the Cap-11 HCl salt as a white solid (337.7 mg).^lH NMR (DMSO-d6, δ = 2.5, 500 MHz) 5.39 (dm, 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 (Condition 2); homogeneity index&gt; 98%; LC / MS: Anal. Obi. for [M + H]⁺ C6HnFNO2: 148.08; experimental 148.06.

Cap-12 <a name="caption1"></a>H j?

^ζ° γ^ΝL-Alanine (2.0 g, 22.5 mmol) was dissolved in a 10% aqueous sodium carbonate solution (50 mL) and a THF solution (50 mL) methyl chloroformate (4.0 mL) was added thereto. The reaction mixture was stirred under inert conditions for 4.5 hours and concentrated in vacuo. The resulting white solid was dissolved in water and acidified with IN HCl to pH ~ 2-3. The resulting solution 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 reverse phase HPLC (H2O / methanol / TFA) to provide 150 mg of Cap -1 as a colorless oil. 1 H 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

I °

A mixture of L-alanine (2.5 g, 28 mmol), formaldehyde (8.4 g, 37% by mass), IN HCl (30 mL) and 10% Pd / C (500 mg) in methanol (30 mL) was stirred under an atmosphere of hydrogen (50 psi) for 5 hours. The reaction mixture was filtered through diatomaceous earth (Celite®), and the filtrate was concentrated in vacuo to provide the Cap-13 HCl salt as an oil, solidifying on vacuum (4.4 g; mass above theoretical yield). The product was used without further purification. * H NMR (DMSO-de, 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="PL2049522T3_D0035.tif" />

<img file="PL2049522T3_D0036.tif" />

<img file="PL2049522T3_D0037.tif" />

Step 1: 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. This mixture was added dropwise to glutaraldehyde (2.23 mL, 12.3 mmol) over 5 minutes. The reaction mixture was stirred allowing it to warm to ambient temperature and continued stirring at the same temperature for 16 hours. The solvent was then removed and the residue was partitioned with 10% aqueous NaOH and ethyl acetate. The organic phase was separated, dried (MgSOG 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 an ester as an intermediate (2.70 g, 56%) as a clear oil. * H NMR (400 MHz, CDCl3) δ 7.537.44 (m, 3H), 7.40-7.37 (m, 2H), 3.87 (d, J = 10.9 Hz, 1H), 3.59 (d, J = 10.9 Hz, 1H ), 2.99 (t, J = 11.2 Hz, 1H), 2.59 (t, J = 11.4 Hz, 1H), 2.07-2.02 (m, 2H), 1.82 (d, J = 1.82 Hz, 3H), 1.40 (s , 9H). LC / MS: Anal. Calc. for C17H25NO2: 275; experimental: 276 (M + H)⁺.

Step 2: TFA (3 mL) was added to a mixed solution of the intermediate as an ester (1.12g, 2.88mmol) in dichloromethane (10 mL). The reaction mixture was stirred at ambient temperature for 4 hours and concentrated to dryness, which gave 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 an MCX LP extraction cartridge (2 x 6 g). The cartridges were washed with methanol (40 mL) and then the desired compound was eluted using 2M ammonia in methanol (50 mL). Product containing fractions were combined and concentrated and the residue was taken up in water. Lyophilisation of this solution provided the title compound (0.492 g, 78%) as a pale yellow solid. * H NMR (DMSO-dó) δ 7.50 (s, 5H), 5.13 (s, 1H), 3.09 (br s, 2H), 2.92-2.89 (m, 2H), 1.74 (m, 4H), 1.48 (br s, 2H). LC / MS: Anal. Calc. for C13H17NO2: 219; experimental: 220 (M + H)⁺.

Cap-15

<img file="PL2049522T3_D0038.tif" />

(R) -Cap-tS

Level 1; (S) -1-phenylethyl 2-bromo-2-phenylacetate: For a mixture of α-bromophenylacetic acid (10.75 g, 0.050 mol), (S) - (-) - 1-phenylethanol (7.94 g, 0.065 mol) and DMAP ( 0.61 g, 5.0 mmol) in dry dichloromethane (100 mL) once added solid EDCI (12.46 g, 0.065 mol). The resulting solution was stirred at room temperature under Ar for 18 hours, then diluted with ethyl acetate, washed (H₂O x 2, brine), dried (Na 2 SO₄), filtered and concentrated, which gave 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. 'HNMR (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 (s, 0.5H), 1.58 (d, J = 6.6 Hz, 1.5H), 1.51 (d, .7- 6.6 Hz, 1.5H).

Stage 2; (S) -1-Phenylethyl (R) -2- (4-hydroxy-4-methyl-piperidin-1-yl) -2-phenylacetate: To (S) -1-phenylethyl 2-bromo-2-phenylacetate solution (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, then a solution of 4-methyl-4-hydroxypiperidine (0.251 g, 2.18 mmol) in THF (2 mL) was added. The mixture was stirred for 1 hour at room temperature and then heated at 55-60 ° 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 (0-60% ethyl acetate-hexane) to provide first (S, R) -isomer of the title compound (0.306 g, 60%) as a white solid and then the appropriate (S, S) -isomer (0.120 g, 23%), also in the form of a white solid. (S, R) -isomer: * HNMR (CD₃OD) δ 7.51-7.45 (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), 2.41 -2.29 (m, 2H), 1.71-1.49 (m, 4H), 1.38 (d, J = 6.6 Hz, 3H), 1.18 (s, 3H). LCMS: Anal. Calc. for C22H27NO3: 353; experimental: 354 (M + H)⁺. (S, S) -isomer: 'HNMR (CD3OD) δ 7.41-7.30 (m, 5H), 7.20-7.14 (m, 3H), 7.06-7.00 (m, 2H), 5.85 (q, 7 = 6.6 Hz, 1H), 4.06 (s, 1H), 2.70-2.60 (m, 1H), 2.51 (dt, 7 = 6.6, 3.3 Hz, 1H), 2.44-2.31 (m, 2H), 1.75-1.65 (m, 1H) , 1.65-1.54 (m, 3H), 1.50 (d, J = 6.8 Hz, 3H), 1.20 (s, 3H). LCMS: Anal. Calc. for C22H27NO3: 353; experimental: 354 (M + H)⁺.

Stage 3; (R) -2- (4-hydroxy-4-methylpiperidin-1-yl) -2-phenylacetic acid: To a solution of (R) -2- (4-hydroxy-4-methylpiperidin-1-yl) -2-phenylacetate (S) -1-phenylethyl (0.185 g, 0.52 mmol) in dichloromethane (3 mL) trifluoroacetic acid (1 mL) was added and the mixture was stirred at room temperature for 2 hours. Then the volatiles were removed in vacuo and the residue was purified by preparative reverse phase HPLC (Primesphere C-18, 20 x 100mm; CHiCNĄO-OP / o TFA) to give the title compound (as the TFA salt) as a pale bluish solid ( 0.128 g, 98%). LCMS: Anal. Calc. for CHH19NO3: 249; experimental: 250 (M + H)⁺.

<img file="PL2049522T3_D0039.tif" />

OH

Cap-16

<img file="PL2049522T3_D0040.tif" />

<img file="PL2049522T3_D0041.tif" />

(R) -Cap-16

Level 1; (S) -1-phenylethyl 2- (2-fluorophenyl) acetate: A mixture of 2-fluorophenylacetic acid (5.45 g, 35.4 mmol), (S) -1-phenylethanol (5.62 g, 46.0 mmol), EDCI (8, 82 g, 46.0 mmol) and DMAP (0.561 g, 4.60 mmol) in CH 2 Cl 2 (100 mL) was stirred at room temperature for 12 hours. The solvent was then concentrated and the residue was partitioned with H2O-ethyl acetate. The phases were separated and the aqueous layer was extracted again 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%). * HNMR (400 MHz, CD3OD) δ

7.32 - 7.23 (m, 7H), 7.10-7.04 (m, 2), 5.85 (q, J = 6.5 Hz, 1H), 3.71 (s, 2H), 1.48 (d, J = 6.5 Hz, 3H).

Stage 2; (R) - ((S) -1-phenylethyl) 2- (2-fluorophenyl) -2- (piperidin-1-yl) acetate: To (S) -1-phenylethyl 2- (2-fluorophenyl) acetate ( 5.00 g, 19.4 mmol) in THF (1200 mL) at 0 ° C, DBU (6.19 g, 40.7 mmol) was added 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. NH4Cl and layers were separated. The aqueous layer was extracted again with ethyl acetate (2x) and the combined organic phases were washed (H2O, brine), dried (Na₂SO₄), filtered and concentrated in vacuo. Piperidine (5.73 mL, 58.1 mmol) was added to the residue, and the solution was stirred at room temperature for 24 hours. The volatiles were then concentrated in vacuo and the residue purified by silica gel chromatography (Biotage / 0-30% diethyl ether-hexane) to provide a pure mixture of diastereomers (2: 1 ratio, based on * HNMR) as a yellow oil ( 2.07 g, 31%), together with unreacted starting material (2.53 g, 51%). Additional chromatography of the diastereomeric mixture (Biotage / 0-10% diethyl ether-toluene) provided the title compound as a colorless oil (0.737 g, 11%). 'HNMR (400 MHz, CD3OD) δ 7.52 (ddd, J = 9.4, 7.6, 1.8 Hz, 1H), 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, 1H), 4.45 (s, 1H), 2.39 - 2.45 (m, 4H),

1.52 - 1.58 (m, 4H), 1.40 - 1.42 (m, 1H), 1.38 (d, J = 6.6 Hz, 3H). LCMS: Anal. Calc. for C2iH2₄FNO2: 341; experimental: 342 (M + H)⁺.

Stage 3; (R) -2- (2-Fluorophenyl) -2- (piperidin-1-yl) acetic acid: Mixture of (R) - ((S) - 2- (2-fluoro-phenyl) -2- (piperidin-1-yl) acetate 1-phenylethyl) (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 cleaned with Ar, filtered through diatomaceous earth (Celite®) and concentrated in vacuo. This provided the title compound as a colorless solid (0.503 g, 98%). 'HNMR (400 MHz, CD3OD) δ 7.65 (ddd, J = 9.1, 7.6, 1.5 Hz, 1H), 7.47-7.53 (m, 1H), 7.21-7.30 (m, 2H), 3.073.13 (m , 4H), 1.84 (br s, 4H), 1.62 (br s, 2H). LCMS: Anal. Calc. for Ci3Hi₆FNO₂: 237; experimental: 238 (M + H)⁺.

<img file="PL2049522T3_D0042.tif" />

<img file="PL2049522T3_D0043.tif" />

(R) -Cap-17

Level 1; (S) -1-phenylethyl (R) -2- (4-hydroxy-4-phenylpiperidin-1-yl) -2-phenylacetate: To (S) -1-phenylethyl 2-bromo-2-phenylacetate solution (1.50 g , 4.70 mmol) in THF (25 mT), triethylamine (1.31 mL, 9.42 mmol) was added, followed by tetrabutylammonium iodide (0.347 g, 0.94 mmol). The reaction mixture was stirred at room temperature for 5 minutes, then a solution of 4-phenyl-4-hydroxypiperidine (1.00 g, 5.64 mmol) in THF (5 mL) was added. The mixture was stirred for 16 hours and then 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 assessed by 'HNMR. Separation of these isomers was carried out by supercritical phase chromatography (Chiralcel OJ-H, 30 x 250mm; 20% ethanol in CO2 at 35 ° C), which gave first (R) -isomer of the title compound (0.534 g, 27%) as yellow oil followed by the corresponding (S) -isomer (0.271 g, 14%), also in the form of a yellow oil. (S, R) -isomer: 'HNMR (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, 7 = 6.6 Hz, 1H), 4.12 (s, 1H), 2.82-2.72 (m, 1H), 2.64 (dt, 7 = 11.1, 2.5 Hz, 1H), 2.582.52 (m, 1H) , 2.40 (dt, 7 = 11.1, 2.5 Hz, 1H), 2.20 (dt, 7 = 12.1, 4.6 Hz, 1H), 2.10 (dt, 7 =

12.1, 4.6 Hz, 1H), 1.72-1.57 (m, 2H), 1.53 (d, 7 = 6.5 Hz, 3H). LCMS: Anal. Calc. for C27H29NO3: 415; experimental: 416 (M + H)⁺; (S, S) -isomer: * HNMR (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, 7 = 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, 7 = 12.1, 4.6 Hz, 1H), 2.12 (dt, 7 = 12.1.4.6 Hz, 1H), 1.73 (dd, 7 = 13.6, 3.0 Hz, 1H), 1.64 (dd, 7 = 13.6,3.0 Hz, 1H), 1.40 (d, 7 = 6.6 Hz, 3H). LCMS: Anal. Calc. for C27H29NO3: 415; experimental: 416 (M + H)⁺. The following esters were prepared as in Step 1 during the synthesis of Cap-YJ.

<td>Intermediate-17a</td><td>° s ° xO ύ N oYx</td><td>Diastereomer 1: ^[H NMR (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. Calc. for: C28H3oN₂0₄: 458.55; Experimental: 459.44 (M + H)⁺. Diastereomer 2: 1 H 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) 7.27- 7.44 (m, 10H). LCMS: Anal. Calc. for: C 28 H₃oN20₄: 458.55; Experimental: 459.44 (M + H)⁺.</td>

<td>Intermediate-17b</td><td>cT</td><td>Diastereomer 1: RT = 11.76 min (Condition II); LCMS: Anal. Calc. for: C20H22N2O3: 338.4 Experimental: 339.39 (M + H)⁺; Diastereomer 2: RT = 10.05 min (Condition II); LCMS: Anal. Calc. for: C20H22N2O3: 338.4; Experimental: 339.39 (M + H)⁺.</td>

<td>Intermediate-17c</td><td> 1</td><td>Diastereomer 1: tR = 4.55</td>

<td></td><td>AT</td><td>min (Condition I); LCMS: Anal. Calc. for: C21H26N2O2 338.44</td>

<td></td><td>a / Y / Oa</td><td>Experimental: 339.45</td>

<td></td><td></td><td>(M + H)⁺;</td>

<td></td><td> 44</td><td>Diastereomer 2: Tr = 6.00 min (Condition I); LCMS: Anal. Calc. for: C21H26N2O2 338.44 Experimental: 339.45 (M + H)⁺.</td>

<td>Intermediate-17d</td><td> 9</td><td>Diastereomer 1: RT = 7.19 min (Condition I); LCMS: Anal. Calc. for: C27H29NO2 399.52</td>

<td></td><td></td><td>Experimental: 400.48</td>

<td></td><td></td><td>(M + H)⁺;</td>

<td></td><td>44 θ</td><td>Diastereomer 2: RT = 9.76</td>

<td></td><td></td><td>min (Condition I); LCMS: Anal. Calc. for: C27H29NO2 399.52 Experimental: 400.48 (M + H)⁺.</td>

Chiral SFC conditions for determining the retention time for intermediates 17b-17d

Condition 1

Column: Chiralpak AD-H Column, 4.6X250 mm, 5pm Solvents: 90% CO2 - 10% methanol with 0.1% DE A Temp: 35 ° C Pressure: 150 bar

Flow rate: 2.0 mL / min.

UV monitoring @ 220 nm

Injection: 1.0 mg / 3mL methanol

Condition 2

Column: Chiralpak 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 monitoring @ 220 nm Injection: 1.0 mg / mL methanol

Cap-17, Stage 2; (R) -2- (4-hydroxy-4-phenylpiperidin-1-yl) -2-phenylacetic acid: To a solution of (R) -2- (4-hydroxy-4-phenylpiperidin-1-yl) -2-phenylacetate (S) -1-phenylethyl (0.350 g, 0.84 mmol) in dichloromethane (5 mL) trifluoroacetic acid (1 mL) was added and the mixture was stirred at room temperature for 2 hours. The volatiles were then removed in vacuo and the residue purified by reverse phase preparative HPLC (Primesphere C-18, 20 x 100mm; CH3CN-H2O-0.1% TFA) to give the title compound (as the TFA salt) as a white solid (0.230 g, 88%). LCMS: Anal. Calc. for C19H21NO3: 311; experimental: 312 (M + H)⁺

The following carboxylic acids were similarly prepared:

Cap-VJ

<img file="PL2049522T3_D0044.tif" />

Cap-17b

<img file="PL2049522T3_D0045.tif" />

RT = 2.21 (Condition II); H NMR (500 MHz, DMSO-dó) δ ppm 2.20 - 2.35 (m, 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. Calc. for: C20H22N2O4 354.40; Experimental: 355.38 (M + H)⁺.

RT = 0.27 (Condition III); LCMS: Anal. Calc. for: Ci2H, 4N₂ABOUT₃ 234.25;

Experimental: 235.22 (M + H)⁺.

<td rowspan="2">Cap-YLC</td><td colspan="3">c N</td><td rowspan="2">RT = 0.48 (Condition II); LCMS: Anal. Obi. for:₃hi₈N₂ABOUT₂: 234.29; Experimental: 235.31 (M + H)⁺.</td>

<td></td><td>★ A / 0</td><td>.OH</td>

<td>Cap-YLD.</td><td>f</td><td>""AND</td><td></td><td>RT = 2.21 min (Condition I); LCMS: Anal.</td>

<td></td><td></td><td></td><td></td><td>Obi. for:₉H₂Ino₂ 295.38; Experimental: 296.33 (M + H)⁺.</td>

<td></td><td></td><td>^ TT</td><td></td><td></td>

<td></td><td></td><td> *^^srf^from</td><td>OH</td><td></td>

<td></td><td></td><td> 0</td><td></td><td></td>

LCMS conditions for determining the retention time for Cap 17a-l7d Condition 1

Column: Phenomenex-Luna 4.6 X 50 mm SIO

Initial% B = 0

Final% Β = 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

Initial% B = 0

Final% Β = 100

Gradient time = 2 min

Flow rate: = 4 mL / min

Wavelength = 220

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

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

Condition 3

Column: Phenomenex 10μ 3.0 X 50 mm

Initial% 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

<img file="PL2049522T3_D0046.tif" />

AND:

B:

X = H.

X = Br l · c

<img file="PL2049522T3_D0047.tif" />

Level 1; Ethyl (R, S) -2- (4-pyridyl) -2-bromoacetate: To a solution of ethyl 4-pyridylacetate (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 cooled to -78 ° C. CBr was added to this mixture₄ (2.21 g, 6.66 mmol) and stirring continued at -78 ° C for 2 hours. The reaction mixture was then quenched with saturated 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 slightly unstable yellow oil. 'HNMR (400 MHz, CDC1₃) δ 8.62 (dd, J = 4.6, 1.8 Hz, 2H), 7.45 (dd, 7 = 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. Calc. for C.₉hi₀BRNO₂: 242, 244; experimental: 243, 245 (M + H)⁺.

Stage 2; (R, S) -2- (4-Pyridyl) -2- (N, N-dimethylamino) ethyl acetate: 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 to dimethylamine (2M in THF, 8.5 mL, 17.0 mmol). After completion of the reaction (as assessed by tlc), the volatiles were removed in vacuo and the residue was purified by flash chromatography (Biotage, 40 + M SiO column₂; 50% -100% ethyl acetate-hexane) to provide the title compound (0.539 g, 31%) as a pale yellow oil. 'HNMR (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. Calc. for CuHi₆N₂ABOUT₂: 208; experimental: 209 (M + H)⁺.

Stage 3; (R, S) -2- (4-pyridyl) -2- (N, N-dimethylamino) acetic acid: To (R, S) -2- (4-pyridyl) -2- (N, N-dimethylamino) solution ) ethyl acetate (0.200 g, 0.960 mmol) in a THF-methanol-H mixture₂O (1: 1: 1, 6 mL) powdered LiOH (0.120 g, 4.99 mmol) was added at room temperature. The solution was stirred for 3 hours and then acidified to pH 6 using IN HCL. The aqueous phase was washed with ethyl acetate and then lyophilized to give the dihydrochloride salt of the title compound as a yellow solid (containing LiCl). Such a product was used in subsequent stages. * HNMR (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 similarly using the method described in Example 4;

<td>Cap-19</td><td>NMe₂οΛ °°^2ΗN</td><td>LCMS: Anal. Calc. for C.₉H_I2N₂O2: 180; experimental: 181 (M + H)⁺.</td>

<td>Cap-20</td><td>NMe₂θχ0Ο₂Η</td><td>LCMS: no ionization. * HNMR (400 MHz, CD₃OD) δ 8.55 (d, 7 = 4.3 Hz, 1H), 7.84 (app t, 7 = 5.3 Hz, 1H), 7.61 (d, 7 = 7.8 Hz, 1H), 7.37 (app t, 7 = 5.3 Hz, 1H), 4.35 (s, 1H), 2.60 (s, 6H).</td>

<td>Cap-21</td><td>NMe₂γ / \ θ₂Η Cl ^ hT</td><td>LCMS: Anal. Calc. for C9Hi, C1N₂O2: 214, 216; experimental: 215.217 (M + H)⁺.</td>

<td>Cap-22</td><td>NMe₂| YY "WHAT₂H about₂n ^^</td><td>LCMS: Anal. Calc. for CioHi₂N₂0₄: 224; experimental: 225 (M + H)⁺.</td>

<td>Cap-23</td><td>NMe₂</td><td>LCMS: Anal. Calc. for C14H15NO2: 247; experimental: 248 (M + H)⁺.</td>

<td>Cap-24</td><td>NMe₂WHAT₂H</td><td>LCMS: Anal. Calc. for CiiHi₂F₃WELL₂: 247; experimental: 248 (M + H)⁺.</td>

<td>Cap-25</td><td>NMe₂What₂h ^ cf₃</td><td>LCMS: Anal. Calc. for CnH₁₂F₃WELL₂: 247; experimental: 248 (M + H)⁺.</td>

<td>Cap-26</td><td>NMe₂O&gt; "</td><td>LCMS: Anal. Calc. for you₀H₁₂FNO₂: 247; experimental: 248 (M + H)⁺.</td>

<td>Cap-27</td><td>NMe₂</td><td>LCMS: Anal. Calc. for C,₀H_l2FNO₂: 247; experimental: 248 (M + H)⁺.</td>

<td>Cap-28</td><td>NMe₂^ΩΊ0^Λ°^θ2Η</td><td>LCMS: Anal. Calc. for C._IOH₁₂C1N0₂: 213.215; experimental: 214.217 (M + H)⁺.</td>

<td>Cap-29</td><td>NMe₂CM</td><td>LCMS: Anal. Calc. for C.₁₀H₂ClNO₂: 213.215; experimental: 214.217 (M + H)⁺.</td>

<td>Cap-30</td><td>NMe₂</td><td>LCMS: Anal. Calc. for C.₁₀hi₂C1NO₂: 213.215; experimental: 214.217 (M + H)⁺.</td>

<td>Cap-31</td><td>NMe₂</td><td>LCMS: Anal. Calc. for C.₈H ,, N₂ABOUT₂S: 200; experimental: 201 (M + H)⁺.</td>

<td>Cap-3 2</td><td>NMe₂cY "·"</td><td>LCMS: Anal. Calc. for C.₈HnNO₂S: 185; experimental: 186 (M + H)⁺.</td>

<td>Cap-3 3</td><td>NMe₂_s/ ^ J^X^ 'CO₂H</td><td>LCMS: Anal. Calc. for C.₈H, NOS₂S: 185; experimental: 186 (M + H)⁺.</td>

<td>Cap-3 4</td><td>ZM NMe₂kXY ^^xWhat₂H _</td><td>LCMS: Anal. Calc. for you, Hi₂N₂ABOUT₃: 220; experimental: 221 (M + H)⁺.</td>

<td>Cap-3 5</td><td>NMe₂V ^ Jt ^ CO₂H</td><td>LCMS: Anal. Calc. for you₂H13NO₂S: 235; experimental: 236 (M + H)⁺.</td>

<td>Cap-36</td><td>NMe₂</td><td>LCMS: Anal. Calc. for Ci2H, 4N₂ABOUT₂S: 250; experimental: 251 (M + H)⁺.</td>

Cap-37

<img file="PL2049522T3_D0048.tif" />

• HCl ⁰

Β cap-37

Level 1; (R, S) -2- (4-quinolin-3-yl) -2- (N, N-dimethylamino) ethyl acetate: A mixture of ethyl Ν, Ν-dimethylaminoacetate (0.462 g, 3.54 mmol), K.3PO4 (1.90 g, 8.95 mmol), Pd (tBu3P) 2 (0.090 g, 0.176 mmol) and toluene (10 mL) were 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 first purified by reverse phase preparative HPLC (Primesphere C-18, 30 x 100mm; CH3CN-H2O5 mM NH4OAC) followed by flash chromatography (S1O2 / hexane-ethyl acetate 1: 1) to provide the title compound (0.128 g, 17%) as an orange oil. * HNMR (400 MHz, CDC1₃) δ 8.90 (d, J = 2.0 Hz, 1H), 8.32 (d, J = 2.0 Hz, 1H), 8.03-8.01 (m, 2H), 7.77 (ddd, J = 8.3, 6.8, 1.5 Hz, 1H), 7.62 (ddd, J = 8.3, 6.8, 1.5 Hz, 1H), 4.35 (s, 1H),

4.13 (m, 2H), 2.22 (s, 6H), 1.15 (t, J = 7.0 Hz, 3H). LCMS: Anal. Calc. for you₅hi₈N₂ABOUT₂: 258; experimental: 259 (M + H)⁺.

Stage 2; (R, S) -2- (quinolin-3-yl) -2- (N, N-dimethylamino) acetic acid: A mixture of (R, S) -2- (quinolin-3-yl) -2- (N, Ethyl N-dimethylamino) acetate (0.122 g, 0.472 mmol) and 6M HCl (3 mL) was heated at 100 ° C for 12 hours. The solvent was removed in vacuo to provide the dihydrochloride salt of the title compound (0.169 g,&gt; 100%) as a light yellow foam. The crude material was used in subsequent stages without further purification. LCMS: Anal. Calc. for C13H14N2O2: 230; experimental: 231 (M + H)⁺.

F NR'R²

AND

<img file="PL2049522T3_D0049.tif" />

<img file="PL2049522T3_D0050.tif" />

OH

F +

<img file="PL2049522T3_D0051.tif" />

OH

Cap-38

Level 1; (R) -2- (dimethylamino) -2- (2-fluorophenyl) acetate ((S) -1-phenylethyl) and 2- (dimethylamino) -2- (2-fluorophenyl) acetate (S) - ((S) - 1-phenylethyl): 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) -1- phenylethanol (2.09 g, 17.15 mmol) in CH2Cl2 (40 mL) EDCI (3.29 g, 17.1 mmol) was added and the mixture was allowed to stir at room temperature for 12 hours. The solvent was then removed in vacuo and the residue was partitioned with ethyl acetate₂A. The layers were separated, the aqueous layer was extracted again 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 mixture of diastereomers was then separated by reverse phase preparative HPLC (Primesphere C-18, 30 x 100mm; CH3CN-H₂O-0.1% TL A), which gave first (R) -2- (dimethylamino) -2- (2-fluorophenyl) acetate (S) -1-phenoethyl (0.501 g, 13%), then (S) - 2- (dimethylamino) -2- (2-fluorophenyl) -acetate (S) -1-phenoethyl (0.727 g. 18%), both as the TLA salt. (S, R) -isomer: 'HNMR (400 MHz, CD3OD) δ 7.65-7.70 (m, 1H), 7.55-7.60 (ddd, 7 = 9.4, 8.1, 1.5 Hz, 1H), 7.36-7.41 (m, 2H), 7.28-7.34 (m, 5H), 6.04 (q, 7 =

6.5 Hz, 1H), 5.60 (s, 1H), 2.84 (s, 6H), 1.43 (d, 7 = 6.5 Hz, 3H). LCMS: Anal. Calc. for C18H20FNO2: 301; experimental: 302 (M + H)⁺; (S, S) -isomer: * HNMR (400 MHz, CD3OD) δ 7.58-7.63 (m, 1H), 7.18-7.31 (m, 6H), 7.00 (dd, 7 = 8.5, 1.5 Hz, 2H), 6.02 (q, 7 =

6.5 Hz, 1H), 5.60 (s, 1H), 2.88 (s, 6H), 1.54 (d, 7 = 6.5 Hz, 3H). LCMS: Anal. Calc. for C18H20FNO2: 301; experimental: 302 (M + H)⁺.

Stage 2; (R) -2- (dimethylamino) -2- (2-fluorophenyl) acetic acid: Mixture of TFA (R) -2- (dimethylamino) -2- (2-fluorophenyl) acetate ((S) -1-phenylethyl) 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 (H balloon₂) for 4 hours. The solution was then purified with Ar, filtered through diatomaceous earth (Celite®) and concentrated in vacuo. This gave the title compound as a colorless solid (0.503 g, 98%). * HNMR (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. Calc. for C10H12FNO2: 197; experimental: 198 (M + H)⁺.

The S isomer can be obtained from the TFA (S) -2- (dimethylamino) -2- (2-fluorophenyl) acetate ((S) -1-phenylethyl) TFA salt in a similar manner.

Cap-39

<img file="PL2049522T3_D0052.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 at atmospheric pressure (H2 balloon) for 4 hours. The solution was then purified 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-H2O- 0.1% TFA), which gave the TFA salt of the title compound (R) -2- (dimethylamino) -2- (2- chlorophenyl) acetic oil as a colorless oil (0.290 g, 55%). * H 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. Calc. for CioH₁₂C1N0₂: 213.215; experimental: 214, 216 (M + H)⁺.

Cap-40

<img file="PL2049522T3_D0053.tif" />

<img file="PL2049522T3_D0054.tif" />

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 dropwise methyl chloroformate (1.00 mL,

13.5 mmol). The mixture was allowed to stir at 0 ° C for 1 hour and then it was acidified by adding conc. HCl (2.5 mL). The mixture was extracted with ethyl acetate (2x) and the combined organic phases were 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%). * H NMR (400 MHz, CD3OD) δ 7.39 - 7.43 (m, 2H), 7.29 - 7.31 (m, 2H), 5.69 (s, 1H), 3.65 (s, 3H). LCMS: Anal. Calc. for CioHioC1N0₄: 243. 245; experimental: 244.246 (M + H)⁺.

Cap-41

<img file="PL2049522T3_D0055.tif" />

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 freeze-dried and the residue purified by silica gel chromatography (Biotage / 0-10% methanol-CH₂cl₂), which gave the title compound 2- (2- (morpholinomethyl) phenyl) acetic acid as a colorless solid (2.22 g, 87%). * HNMR (400 MHz, CD₃OD) δ 7.37-7.44 (m, 3H), 7.29-7.33 (m, 1H),

4.24 (s, 2H), 3.83 (br s, 4H), 3.68 (s, 2H), 3.14 (br s, 4H). LCMS: Anal. Obi. for you₃hi₇WELL₃: 235; experimental: 236 (M + H)⁺.

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

<td>Cap-42</td><td>^ P "</td><td>LCMS: Anal. Obi. for you₄H₁₉WELL₂: 233; experimental: 234 (M + H)⁺.</td>

<td>Cap-43</td><td>about OI "</td><td>LCMS: Anal. Obi. for you₃hi₇WELL₂: 219; experimental: 220 (M + H)⁺.</td>

<td>Cap-44</td><td>Me AME</td><td>LCMS: Anal. Obi. for C,, H,₅WELL₂: 193; experimental: 194 (M + H)⁺.</td>

<td>Cap-45</td><td>VNMe \) ^ P ™</td><td>LCMS: Anal. Obi. for you₄H₂₀N₂ABOUT₂: 248; experimental: 249 (M + H)⁺.</td>

Cap-45

<img file="PL2049522T3_D0056.tif" />

NH₂ • pTsOH salt

<img file="PL2049522T3_D0057.tif" />

_XNH

Cap-45

HMDS (1.85 mL, 8.77 mmol) was added to a suspension of (R) -2-amino-2-phenylacetic acid p-toluenesulfonate (2.83 g, 8.77 mmol) in CH 2 Cl 2 (10 mL) and the mixture was stirred at room temperature for 30 minutes. Methyl isocyanate (0.5 g, 8.77 mmol) was added as one portion, continuing to stir for 30 minutes. The reaction was quenched by the addition of H2O (5 mL) and the resulting precipitate was filtered, washed with H2O and n-hexanes and dried in vacuo. (R) -2- (3-methylureido) -2-phenylacetic acid (1.5 g; 82%) was recovered as a white solid and used without further purification. 1 H 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. Calc. for C10H12N2O3 208.08 experimental 209.121 (M + H)⁺; HPLC Phenomenex C-18 3.0 x 46 mm, 0 to 100% B for 2 minutes, 1 minute hold, 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="PL2049522T3_D0058.tif" />

• pTsOH cap-46 salt

The desired product was prepared according to the method described for Cap-45. * H 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. Calc. dlaCnHi₄N2O3 222.10 experimental 209.121 (M + H)⁺.

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

Cap-47

<img file="PL2049522T3_D0059.tif" />

Level 1; Tert-butyl (R) -2- (3,3-dimethylureido) -2-phenylacetate: For a mixed 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 dropwise over 10 minutes dimethylcarbamoyl chloride (0.38 mL, 4.18 mmol). After stirring at room temperature for 3 hours, the reaction was concentrated under reduced pressure, and the obtained residue was dissolved in ethyl acetate. The organic layer was washed with H2O, IN aq. HCl and brine, dried (MgSO₄), filtered and concentrated under reduced pressure (R) -2- (3,3-dimethylureido) -261 tert-butyl phenylacetate was obtained as a white solid (0.86 g; 75%) and used without further purification. * H NMR (500 MHz, DMSO-dń) δ ppm 1.33 (s, 9H) 2.82 (s, 6H)

5.17 (d, 7 = 7.63 Hz, 1H) 6.55 (d, 7 = 7.32 Hz, 1H) 7.24 - 7.41 (m, 5H). LCMS: Anal. Calc. for C15H22N2O3 278.16 experimental 279.23 (M + H)⁺; HPLC Phenomenex LUNA C-18 4.6 x 50 mm, 0 to 100% B for 4 minutes, 1 minute hold, A = 90% water, 10% methanol, 0.1% TFA, B = 10% water, 90% methanol, 0.1% TFA, RT = 2.26 min, homogeneity index 97%.

Stage 2; (R) -2- (3,3-dimethylureido) -2-phenylacetic acid: To a mixed solution of tert-butyl ((R) -2- (3,3-dimethylureido) -2-phenylacetate (0.86 g, 3.10 mmol) in CH2Cl2 (250 mL), TFA (15 mL) was added dropwise, and the resulting solution was stirred at rt for 3 h. The desired compound was then precipitated from the solution with EtOAc: Hexanes (5:20), filtered 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. 1 H NMR (500 MHz, DMSO-d₆) δ ppm 2.82 (s, 6H) 5.22 (d, 7 = 7.32 Hz, 1H) 6.58 (d, 7 = 7.32 Hz, 1H) 7.28 (t, 7 = 7.17 Hz, 1H) 7.33 (t, 7 = 7.32 Hz , 2H) 7.38 - 7.43 (m, 2H) 12.65 (s, 1H). LCMS: Anal. Calc. for C11H14N2O3: 222.24; experimental: 223.21 (M + H)⁺. HPLC XTERRA C-18 3.0 x 50 mm, 0 to 100% B for 2 minutes, 1 minute hold, A = 90% water, 10% methanol, 0.2% H3PO4, B = 10% water, 90% methanol, 0.2% H3PO4 , RT = 0.75 min, 93% homogeneity index.

Cap-48

<img file="PL2049522T3_D0060.tif" />

B Cap-48

Level 1; Tert-butyl (R) -2- (3-cyclopentylureido) -2-phenylacetate: For a mixed 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 dropwise over 10 minutes with cyclopentyl isocyanate (0.46 mL, 4.10 mmol). 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 H₂O and brine, dried (MgSO₄), filtered and concentrated under reduced pressure (R) -2- (3-cyclopentylureido) -2-phenylacetate tert-butyl acetate as a cloudy oil (1.32 g; 100%) and used without further purification. * H NMR (500 MHz, CD3CI-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. Calc. for C ^ HióAOa

318.19 experimental 319.21 (M + H)⁺; HPLC XTERRA C-18 3.0 x 50 mm, 0 to 100% B for 4 minutes, 1 minute hold, A = 90% water, 10% methanol, 0.1% TFA, B = 10% water, 90% methanol, 0.1% TFA , RT = 2.82 min, 96% homogeneity index.

Stage 2; (R) -2- (3-cyclopentylureido) -2-phenylacetic acid: To a mixed solution of tert-butyl (R) -2- (3-cyclopentylureido) -2-phenylacetate (1.31 g, 4.10 mmol) in CH2Cl2 ( 25 mL) were added dropwise with TFA (4 mL) and triethylsilane (1.64mL; 10.3 mmol), and the resulting solution was stirred at room temperature for 6 hours. The volatiles were removed under reduced pressure and the crude product was recrystallized in ethyl acetate / pentanes to obtain (R) -2- (3-cyclopentylureido) -2-phenylacetic acid as a white solid (0.69 g, 64%). 1 H NMR (500 MHz, DMSO-d₆) 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. Calc. for Ci4H_I8N₂ABOUT₃: 262.31; experimental: 263.15 (M + H)⁺. HPLC XTERRA C-18 3.0 x 50 mm, 0 to 100% B for 2 minutes, 1 minute hold, 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 cr * T - omr cap-49

Formaldehyde (6.94 mL, 93.2 mmol) was added to a mixed solution of 2- (benzylamino) acetic acid (2.0 g, 12.1 mmol) in formic acid (91 mL). After five hours at 70 ° C, the reaction mixture was concentrated under reduced pressure to 20 mL and a white solid precipitated. After filtration, the mother liquors were collected and further concentrated under reduced pressure to obtain a crude product. Preparative reverse phase HPLC (Xterra 30 X 100 mm, detection at 220 nm, flow rate 35 mL / min, 0 to 35% B for 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 the TFA salt (723 mg, 33%) as a colorless wax. 1 H 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. Calc. for: C10H13NO2 179.22; Experimental: 180.20 (M + H)⁺.

Cap-50

<img file="PL2049522T3_D0061.tif" />

Cap-50

To a mixed 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 a crude product that was purified by reverse phase preparative HPLC (Xterra 30 x 100 mm, detection at 220 nm, flow rate 40 mL / min, 20 to 80% B for 6 min; A = 90% water, 10% methanol, 0.1% TFA, B = 10% water, 90% methanol, 0.1% TFA) to provide 2 (benzyl (methyl) amino) acid - 3-methylbutane, TFA salt (126 mg, 19%) as a colorless wax. 1 H NMR (500 MHz, DMSO-d₆) δ ppm 0.98 (d, 3H) 1.07 (d, 3H) 2.33 - 2.48 (m, 1H)

2.54 - 2.78 (m, 3H) 3.69 (s, 1H) 4.24 (s, 2H) 7.29 - 7.65 (m, 5H). LCMS: Anal. Obi. for: C13H19NO2 221.30; Experimental: 222.28 (M + H)⁺.

Cup-51 ° Y ° o ^hn'-Aoh

On₂WHAT₃ (1.83g, 17.2 mmol) was added to the NaOH solution (33 mL 1M / H₂0.33 mmol) L-valine (3.9 g, 33.29 mmol) and the resulting solution was cooled in an 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 in an ice-water bath and acidified with concentrated HCl to pH around 1-2 and extracted with CH₂C1₂(50 mL, 3x). The organic phase was dried (MgSO₄), filtered and concentrated in vacuo to provide Cap-51 as a white solid (6g). * H NMR for the dominant rotamer (DMSO-dó, δ = 2.5 ppm, 500 MHz): 12.54 (s, 1H), 7.3 (d, J = 8.6, 1H), 3.84 (dd, J = 8.4, 6.0, 1H) , 3.54 (s, 3H), 2.03 (m, 1H), 0.87 (m, 6H). HRMS: Anal. Obi. for [M + Hf C₇hi₄WELL₄: 176.0923; experimental 176.0922.

Cap-52

<img file="PL2049522T3_D0062.tif" />

Cap-52 was synthesized from L-alanine according to the procedure described for the synthesis of Cap-51. For characterization purposes, part of the raw material was purified by reverse phase HPLC (H₂O / MeOH / TFA) to give Cap-52 as a colorless, viscous oil. 'H NMR (DMSO-dó, δ = 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 was prepared from the appropriate starting materials following the procedures described for the synthesis of Cap-51, noting modifications if present.

<td>goat</td><td>Structure</td><td>Data</td>

<td>C&gt; -53a: (R) Cap-53b: (S)</td><td></td><td>1 H NMR (DMSO-d₆, 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 (rn, 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 (Condition 2);</td>

<td></td><td></td><td>LC / MS: Anal. Calc. for [M + Naf CeHnNNaCfi: 184.06; experimental 184.07. HRMS Anal. Calc. for [M + Na]⁺CóHnNNaO ^ 184.0586; experimental 184.0592.</td>

<td>Cap-5 4a: (R) Cap-54 \ r. (S)</td><td>H u - °_Y^N J^0H</td><td>1 H NMR (DMSO-d₆, δ = 2.5 ppm, 500 MHz): δ 12.48 (s, 1H), 7.58 (d, 7 = 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 Anal. Calc. for [M + H]⁺C7H12NO4: 174.0766; experimental 174.0771</td>

<td>Cap-55</td><td>H? ° 'Ί</td><td>1 H NMR (DMSO-d₆, δ = 2.5 ppm, 500 MHz): δ 12.62 (s, 1H), 7.42 (d, 7 = 8.2, 0.9H), 7.07 (app s, 0.1H), 5.80-5.72 (m, 1H), 5.10 ( d, 7 = 17.1, 1H), 5.04 (d, 7 = 10.4, 1H), 4.01-3.96 (m, 1H), 3.53 (s, 3H), 2.47-2.42 (m, 1H), 2.35- 2.29 (m, 1H).</td>

<td>Cap-56</td><td>Η? Χγ^Ν-Λ_0Η ° % 1</td><td>1 H NMR (DMSO-d₆, δ = 2.5 ppm, 500 MHz): δ 12.75 (s, 1H), 7.38 (d, 7 = 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-5!</td><td>H? Αγ^ΝΎ_ΟΗ⁰ 'ί</td><td>* H NMR (DMSO-d₆, δ = 2.5 ppm, 500 MHz): δ 12.50 (s, 1H), 8.02 (d, 7 = 7.7, 0.08H), 7.40 (d, 7 = 7.9, 0.76H), 7.19 (d, 7 = 8.2, 0.07H) 7.07 (d, 7 = 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 (Condition 2): RT = 1.39 LC / MS: Anal. Calc. for [M + H]⁺C7H14NO4: 176.09; experimental 176.06.</td>

<td>Cap-58</td><td>Η u^/0Y^N'and ^0H0 Υ-ΝΗ₂ 0</td><td>* H NMR (DMSO-d₆, δ = 2.5 ppm, 500 MHz): δ 12.63 (bs, 1H), 7.35 (s, 1H), 7.31 (d, 7 = 8.2, 1H), 6.92 (s, 1H), 4.33-4.29 (m , 1H), 3.54 (s, 3H), 2.54 (dd, 7 = 15.5.5.4, 1H), 2.43 (dd, 7 = 15.6, 8.0, 1H). RT = 0.16 min (Condition 2); LC / MS: Anal. Calc. for [M + H]⁺ C₆H, IN₂ABOUT₅: 191.07; experimental 191.14.</td>

<td>C «/? - 59a: (R) C 'p-59b: (S)</td><td>H 0</td><td>ABOUT y ^ OH</td><td>'H NMR (DMSO-dg, δ = 2.5 ppm, 400 MHz): δ 12.49 (br s, 1H), 7.40 (d, J = 7.3, 0.89H), 7.04 (br s, 0.11H), 4.00-3.95 (m, 3H), 1.24 (d, J = 7.3, 3H), 1.15 (t, 7 = 7.2, 3H). HRMS: Anal. Calc. for [M + H]⁺ C₆H₁₂WELL₄: 162.0766; experimental 162.0771.</td>

<td>Cap-60</td><td>AND 0</td><td>0 Λη</td><td>The crude material was purified on the road Reverse phase HPLC (H2O / MeOH / TFA) to obtain a colorless, viscous oil that crystallizes to a white solid on exposure to high vacuum. 'Η NMR (DMSO-dó, δ = 2.5 ppm, 400 MHz): δ 12.38 (br s, 1H ), 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. Calc. for [M + H]⁺C₆H₁₀WELL₄: 160.0610; experimental 160.0604.</td>

<td>Cap-61</td><td>A 0 ⁷</td><td>0 Α, η</td><td>* H NMR (DMSO-d₆, δ = 2.5 ppm, 400 MHz): δ 12.27 (br s, 1H), 7.40 (br s, 1H), 3.50 (s, 3H), 1.32 (s, 6H). HRMS: Anal. Calc. for [M + H]⁺C₆H₁₂WELL₄: 162.0766; experimental 162.0765.</td>

<td>Cap-62</td><td colspan="2">ABOUT</td><td>'H NMR (DMSO-dć, δ = 2.5 ppm, 400 MHz): δ 12.74 (br s, 1H), 4.21 (d, 7 = 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, 7 = 6.3, 3H) , 0.81 (d, 7 = 6.6, 3H). LC / MS: Anal. Calc. for [MH] 'C₈H₄WELL₄: 188.09; experimental 188.05.</td>

<td>Cap-63</td><td>'AND</td><td>0 ^ OH</td><td>[Note: the reaction was allowed to run longer than noted in the general procedure.] * H NMR (DMSO-d₆, 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. Calc. for [M + H]⁺ C₈hi₄WELL₄: 188.09; experimental 188.19.</td>

Cap-64

<img file="PL2049522T3_D0063.tif" />

[Note: the reaction was allowed to run longer than noted in 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 (imposed br 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).

<img file="PL2049522T3_D0064.tif" />

Methyl chloroformate (0.65 mL, 8.39 mmol) was added dropwise over 5 min to the cooled (in ice water) Na mixture₂CO3 (0.449 g, 4.23 mmol), NaOH (8.2 mL 1M / H₂O, 8.2 mmol) and (S) -3-hydroxy-2- (methoxycarbonylamino) -3-methylbutanoic acid (1.04 g, 7.81 mmol). The mixture was stirred for 45 min, then the cooling bath was removed and stirring was continued for an additional 3.75 hours. The reaction mixture was washed with CH₂C1₂and the aqueous phase was cooled in an ice-water bath and acidified with concentrated HCl to a pH in the range 1-2. The volatile component was removed in vacuo and the residue was taken up in a 2: 1 MeOH / CH mixture₂cl₂ (15 mL) and filtered, and the filtrate was evaporated on a rotary vacuum evaporator to afford Cap-65 as a white, semi-viscous foam (1.236 g). * H NMR (DMSO-dć, 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 using the procedures described for the synthesis of Cap-65.

<img file="PL2049522T3_D0065.tif" />

* H NMR (DMSO-de, 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, 7 = 9.1, 3.5, 0.85H), 3.56 (s, 3H), 1.09 (d, 7 = 6.2, 3H). [Note: only dominant NH signals were found],

<img file="PL2049522T3_D0066.tif" />

* H NMR (DMSO-d₆, δ = 2.5 ppm, 400 MHz): 12.51 (br s, 1H), 7.25 (d, 7 = 8.4, 0.75H), 7.12 (br d, 7 = 0.4, 0.05H), 6.86 (br s, 0.08H), 3.95-3.85 (m, 2H), 3.54 (s, 3H), 1.08 (d, 7 = 6.3, 3H). [Note: only dominant NH signals were found],

Cap-68

<img file="PL2049522T3_D0067.tif" />

Methyl chloroformate (0.38 mL, 4.9 mmol) was added dropwise 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 hours and then washed with ethyl acetate (50 mL, 3x). The aqueous layer was acidified with 12N HCl to pH ~ 1-2, and extracted with ethyl acetate (3 x 50 mL). The combined organic phases were washed with brine, dried (Na₂SO₄), filtered and concentrated in vacuo to provide Cap-68 as a pale yellow oil (1.37g; mass is above theoretical yield and the product was used without further purification). H

NMR (DMSO-d₆, δ = 2.5 ppm, 500 MHz): δ 12.88 (br s, 1H), 7.55 (d, J = 8.5, 1H), 7.40-7.32 (m, 5H), 5.13 (d, J = 12.8, 1H), 5.10 (d, J = 12.9, 1H), 4.42-4.38 (m, 1H), 3.55 (s, 3H), 2.87 (dd, 7 = 16.2, 5.5, 1H), 2.71 (dd, 7 = 16.2, 8.3, 1H). LC (Condition 2): RT = 1.90 min; LC / MS: Anal. Calc. for [M + H]⁺ C ^ H ^ NCk, 282.10; experimental 282.12.

Cap-69a and -69b

<img file="PL2049522T3_D0068.tif" />

NaCNBH₃ (2.416 g, 36.5 mmol) was added in batches to cooled (~ 15 ° C) aqueous (17 mL) / MeOH (10 mL) alanine solution (1.338 g, 15.0 mmol). After several minutes, acetaldehyde (4.0 mL, 71.3 mmol) was added dropwise over 4 min, the cooling bath was removed and the reaction mixture was stirred at ambient conditions for 6 hours. Additional acetaldehyde (4.0 mL) was added to the reaction and stirred for 2 hours. Concentrated HCl was slowly added to the reaction mixture until the pH reached ~ 1.5, and the resulting mixture was heated for 1 h. at 40 ° C. Most of the volatile component was removed in vacuo and the residue was purified on Dowex® 50WX8-100 ion exchange resin (the column was washed with water and the compound was eluted with diluted NH₄OH, prepared by mixing 18 ml NH₄OH and 282 ml of water) to obtain Cap-69 (2.0 g) as an off-white, soft, hygroscopic solid. ^l1 H NMR (DMSO-d₆, δ = 2.5 ppm, 400 MHz): δ 3.44 (q, 7 = 7.1, 1H), 2.99-2.90 (m, 2H), 2.89-2.80 (m, 2H), 1.23 (d, 7 = 7.1, 3H) , 1.13 (t, 7 = 7.3, 6H).

Cap-19 to -74 were prepared according to the procedure described for the synthesis of Cap-69, using appropriate starting materials.

<td>Cap-lose. (R) CQP-70b; (S)</td><td>/ = ΧγΧ</td><td>'HNMR (DMSO-d₆, δ = 2.5 ppm, 400 MHz): δ 3.42 (q, J = 7.1, 1H), 2.68-2.60 (m, 4H), 1.531.44 (m, 4H), 1.19 (d, 7 = 7.3, 3H), 0.85 (t, 7 = 7.5, 6H). LC / MS: Anal. Calc. for [M + H]⁺C9H20NO2: 174.15; experimental 174.13.</td>

<td>Cap-lin. (R) Cap-lttr. (S)</td><td>ΧΛΟΗ</td><td>1 H NMR (DMSO-d₆, δ = 2.5 ppm, 500 MHz): δ 3.18-3.14 (m, 1H), 2.84-2.77 (m, 2H), 2.76-2.68 (m, 2H), 1.69-1.54 (m, 2H), 1.05 (t , 7 = 7.2, 6H), 0.91 (t, 7 = 7.3, 3H). LC / MS: Anal. Calc. for [M + H]⁺ C₈hi₈WELL₂: 160.13; experimental 160.06.</td>

<td>Cap-12</td><td>Ά o ^ γΟΗ</td><td>1 H NMR (DMSO-d₆, δ = 2.5 ppm, 400 MHz): δ 2.77-2.66 (m, 3H), 2.39-2.31 (m, 2H), 1.94-1.85 (m, 1H), 0.98 (t, 7 = 7.1, 6H), 0.91 (d, 7 = 6.5, 3H), 0.85 (d, 7 = 6.5, 3H). LC / MS: Anal. Calc. for [M + H]⁺ C9H₂on0₂: 174.15; experimental 174.15.</td>

<td>Cap-13</td><td>&gt; o ^ Yoh 1</td><td>1 H NMR (DMSO-d₆, δ = 2.5 ppm, 500 MHz): δ 9.5 (br s, 1H), 3.77 (dd, 7 = 10.8, 4.1, 1H), 3.693.61 (m, 2H), 3.26 (s, 3H), 2.99- 2.88 (m, 4H), 1.13 (t, 7 = 7.2, 6H).</td>

<td>Cap-14</td><td>"η 0 Y ^ °^Hnh₂</td><td>* H NMR (DMSO-d₆, δ = 2.5 ppm, 500 MHz): δ 7.54 (s, 1H), 6.89 (s, 1H), 3.81 (t, 7 = 6.6, k, 1H), 2.82-2.71 (m, 4H), 2.63 (dd, 7 = 15.6, 7.0, 1H), 2.36 (dd, 7 = 15.4, 6.3, 1H), 1.09 (t, 7 = 7.2, 6H). RT = 0.125 minutes (Condition 2); LC / MS: Anal. Calc. for [M + H]⁺ C₈H₁₇N₂ABOUT₃: 189.12; experimental 189.13.</td>

<td>~ Lax CAP-</td><td>"AND ⁰Xⁿ^ A&gt; h</td><td>LC / MS: Anal. Calc. for [M + H]⁺ these₀H₂₂WELL₂: 188.17; experimental 188.21.</td>

Cap-75

<img file="PL2049522T3_D0069.tif" />

Cap-75, stage a

<img file="PL2049522T3_D0070.tif" />

NaBELCN (1.6 g, 25.5 mmol) was added to the cooled (in an ice water bath) aqueous (25 mL) / methanol (15 mL) HD-Ser-OBzl HCl (2.0 g, 8.6 mmol). Acetaldehyde (1.5 mL, 12.5 mmol) was added dropwise over 5 min, the cooling bath was removed and the reaction mixture was stirred at ambient conditions for 2 h. The reaction was carefully quenched with 12N HCl and concentrated in vacuo. The residue was dissolved in water and purified by reverse phase HPLC (MeOH / H₂O / TFA) to obtain benzyl TFA (R) -2 (diethylamino) -3-hydroxypropanoate salt as a colorless, viscous oil (1.9g). A NMR (DMSO-dg, δ = 2.5 ppm, 500 MHz): δ 9.73 (br s, 1H), 7.52-7.36 (m, 5H), 5.32 (d, J = 12.2, 1H), 5.27 (d,. / = 12.5, 1H), 4.54-4.32 (m, 1H), 4.05-3.97 (m, 2H), 3.43-3.21 (m, 4H), 1.23 (t, J = 72, 6H). LC / MS (Condition 2): RT = 1.38 min; LC / MS: Anal. Calc. for [M + H]⁺Ci4H₂₂NO3: 252.16; experimental 252.19.

Cap-75

NaH (0.0727 g, 1.82 mmol, 60%) was added to a cooled (on ice water) solution of THF (3.0 mL) TFA (R) -2- (diethylamino) -3-hydroxypropanoate salt of benzyl (0.3019 g, 0.8264 mmol), prepared above, and the mixture was stirred for 15 min. Methyl iodide (56 mL, 0.90 mmol) was added and stirring continued for 18 hours, allowing the bath to thaw and reach ambient temperature. The reaction was quenched with water and applied to an MCX column (6 g), pre-prepared MeOH and washed with methanol, then the compound was eluted with 2N NH₃/ Methanol. Removal of the volatile component in vacuo gave Cap-75, contaminated with (R) -2- (diethylamino) -3-hydroxypropanoic acid, as a yellow semi-solid (100 mg). The product was used without further purification.

Cap-76

<img file="PL2049522T3_D0071.tif" />

<img file="PL2049522T3_D0072.tif" />

NaCNBIU (1.60 g, 24.2 mmol) was added in batches to the cooled (~ 15 ° C) aqueous / MeOH (12 mL each) (S) -4-amino-2- (tert-butoxycarbonylamino) butanoic acid (2.17 g, 9, 94 mmol). After a few minutes, acetaldehyde (2.7 mL, 48.1 mmol) was added dropwise over min, the cooling bath was removed, and the reaction mixture was stirred at ambient conditions for 3.5 hours. Additional acetaldehyde (2.7 mL, 48.1 mmol) was added to the reaction and stirred for 20.5 hours. Most of the MeOH component was removed in vacuo and the remaining mixture was treated with concentrated HCl until its pH reached ~ 1.0 and then heated for 2 hours at 40 ° C. The volatile component was removed in vacuo and the residue treated with 4 M HCl / dioxane (20 mL) and stirred under ambient conditions for 7.5 hours. The volatile component was removed in vacuo and the residue was purified on Dowex® 50WX8-100 ion exchange resin (the column was washed with water and the compound was eluted with diluted NH₄OH, prepared with 18 ml NH4OH and 282 ml water) to obtain (S) -2-amino-4- (diethylamino) butanoic intermediate as an off-white solid (1.73 g).

Methyl chloroformate (0.36 mL, 4.65 mmol) was added dropwise over 11 min to the cooled (in ice water) Na mixture₂WHAT₃ (0.243 g, 2.29 mmol), NaOH (4.6 mL 1M / H₂4.6 mmol) and the above product (802.4 mg). The mixture was stirred for 55 min, then the cooling bath was removed and stirring continued for an additional 5.25 h. The reaction mixture was diluted with an equal volume of water and washed with CH₂C1₂ (30 mL, 2x), and the aqueous phase was cooled from an ice-water bath and acidified with concentrated HCl to pH around 2. Then the volatile component was removed in vacuo and the crude material treated with the free base on MCX resin (6.0g; column washed with water, and the sample was eluted with 2.0 M NH₃/ MeOH) to obtain impure Cap-Ί 6 as an off-white solid (704 mg). * H NMR (MeOH-d₄, δ = 3.29 ppm, 400 MHz): δ 3.99 (dd, J = 7.5, 4.7, 1H), 3.62 (s, 3H), 3.25-3.06 (m, 6H), 2.18-2.09 (m, 1H), 2.04 -1.96 (m, 1H), 1.28 (t, J = 7.3, 6H). LC / MS: Anal. Calc. for [M + H]⁺ CioH₂iN₂0₄: 233.15; experimental 233.24.

Cap-77a and -77b * 1 O

<img file="PL2049522T3_D0073.tif" />

Cap-77e: enantiomer -1 Cep-77b: enantiomer - 2

Cap-ΊΊ synthesis was performed according to the procedure described for Cap-stosując, using SN substitution step₂ 7-azabicyclo [2.2.1] heptane and affecting the separation of enantiomers of intermediate 2- (7-azabicyclo [2.2.1] heptan-7-yl) -2-phenylacetate benzyl using the following conditions: intermediate (303.7 mg) was dissolved in ethanol and the resulting compound was injected onto a chiral HPLC column (Chiracel AD-H column, 30 x 250 mm, 5 µm), eluting with 90% CO₂-10% EtOH at 70 mL / min and 35 ° C to provide 124.5 mg of enantiomer-1 and 133.8 mg of enantiomer-2. These benzyl esters were subjected to hydrogenolysis according to the method of producing Cap-Ί to provide Cap-ΊΊ '. 1 H NMR (DMSO-d₆, δ = 2.5 ppm, 400 MHz): δ 7.55 (m, 2H), 7.38-7.30 (m, 3H), 4.16 (s, 1H),

3.54 (app br s, 2H), 2.08-1.88 (m, 4H), 1.57-1.46 (m, 4H). LC (Condition 1): RT = 0.67 min; LC / MS: Anal. Calc. for [M + H]⁺ Ci4Hi8BrNO2: 232.13; experimental 232.18. HRMS: Anal. Calc. for [M + H]⁺ Ci4Hi8BrNO₂: 232.1338; experimental 232.1340.

(washing with MeOH; eluting with 2.0 N NH₃/ MeOH) and reverse phase HPLC (H2O / MeOH / TFA) to give Cap-79 containing an unknown amount of morpholine.

To consume the morpholine impurity, the above material was dissolved in CH2Cl2 (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 conditions for 18 hours. THF (1.0 mL) and H2O (0.5 mL) were added and stirring continued for 1.5 hours. The volatile component was removed in vacuo and the resulting residue was passed through an MCX resin (washed with MeOH; eluted with 2.0 N NH₃/ MeOH) to obtain impure Cap-ΊΟ as a brown, viscous oil that was used in the next step without further purification.

Cap-80a and -80b

<img file="PL2049522T3_D0074.tif" />

Cap-80a: SżS- diastereomer - 1 Cap-80b: S / R- diastereomer - 2

SOCI2 (6.60 mL, 90.5 mmol) was added dropwise over 15 min to a cooled (in 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 conditions for 29 h. Most of the volatile component was removed in vacuo and the residue was carefully partitioned between EtOAc (150 mL) and saturated NaHCO solution₃. The aqueous phase was extracted with EtOAc (150 mL, 2x) and the combined organic phase was dried (MgSO 4), filtered and concentrated in vacuo to give 4-methyl (benzyl) 1-benzyl 4-aminosuccinate as a colorless oil (9.706g). * H NMR (DMSO-dć, δ = 2.5 ppm, 400 MHz): δ 7.40-7.32 (m, 5H), 5.11 (s, 2H), 3.72 (app t, 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 (Condition 1): RT = 0.90 min; LC / MS: Anal. Calc. for [M + H]⁺ C12H16NO4: 238.11; experimental 238.22.

Pb (NO₃) 2 (6.06 g, 18.3 mmol) was added over 2 min to a solution of CH2Cl2 (80 mL) (S) -2-4-methyl 1-benzyl succinate (4.50 g, 19.0 mmol), 9-bromo-9-phenyl-9H -fluoren (6.44 g, 20.0 mmol) and Et₃N (3.0 mL, 21.5 mmol), and the heterogeneous mixture was stirred at ambient conditions for 48 hours. The mixture was filtered and the filtrate was treated with MgSO 4 and filtered again and the final filtrate was concentrated. The resulting crude material was subjected to Biotage purification (350 g silica gel, CH 2 Cl 2 elution) to give 1-benzyl 4-methyl (S) -2- (9-phenyl-9H-fluorene-9-ylamino) succinate in highly viscous form, colorless oil (7.93 g). * H NMR (DMSO-dó, 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 applied with a solvent). LC (Condition 1): RT = 2.16 min; LC / MS: Anal. Calc. for [M + H]⁺C₃IH2₈NO4: 478.20; experimental 478.19.

LiHMDS (9.2 mL 1.0 M / THF, 9.2 mmol) was added dropwise over 10 min to the cooled (-78 ° C) THF solution (50 mL) (S) -2- (9-phenyl-9H-fluorene-9-ylamino) succinate 1 -benzyl 4-methyl (3.907 g, 8.18 mmol) and stirred for ~ 1 hour. Mel (0.57 mL, 9.2 mmol) was added dropwise to the mixture over 8 minutes and stirring was continued for 16.5 hours, allowing the bath to thaw and reach room temperature. After quenching with saturated NH solution₄C1 (5 mL), most of the organic component was removed in vacuo and the residue was partitioned between CH2Cl2 (100 mL) and water (40 mL). The organic layer was dried (MgSO₄), filtered and concentrated in vacuo, and the resulting crude material was purified on Biotage (350 g silica gel; 25% EtOAc / hexanes) to obtain 3.65 g of 2S / 3S and 2S / 3R 3-methyl-2- (9-diastereomeric mixtures) phenyl-9H-fluorene-9-ylamino) 1-benzyl 4-methyl succinate in a ratio of ~ 1.0: 0.65 (1H NMR). At this time, the stereochemistry of the dominant isomer was not determined, and the mixture for the next step was taken without separation. Partial data * H NMR (DMSO-dó, δ = 2.5 ppm, 400 MHz): main diastereomer, δ 4.39 (d, J = 12.3.1H with CH₂), 3.33 (s, 3H, superimposed with the H signal₂O), 3.50 (d, J = 10.9, NH), 1.13 (d, J = 7.1, 3H); minor diastereomer, δ 4.27 (d, J = 12.3, 1H with CHJ, 3.76 (d, J = 10.9, NH), 3.64 (s, 3H), 0.77 (d, J = 7.0, 3H). LC (Condition 1) : RT = 2.19 min; LC / MS: Anal. Calc for [M + H]⁺ C₃₂H₃on0₄: 492.22; experimental 492.15.

Diisobutylaluminum hydride (20.57 mL 1.0 M in hexanes, 20.57 mmol) was added dropwise over 10 min to a cooled (-78 ° C) solution of THF (120 mL) (2S) -3-methyl-2 (9-phenyl-9H-fluoreno- 4-methyl 1-benzyl 9-ylamino) succinate (3.37 g, 6.86 mmol) prepared above and stirred at -78 ° C for 20 hours. The reaction mixture was removed from the cooling bath and quickly poured into ~ 1M H with stirring₃PO 4 / H₂O (250 mL) and the mixture was extracted with ether (100 mL, 2x). The combined organic phase was washed with brine, dried (Na₂SO₄), filtered and concentrated in vacuo. A silica gel sieve was prepared with the crude material and subjected to chromatography (25% EtOAc / hexanes; gravity elution) to give 1.g (2S, 3S) -4-hydroxy-3-methyl-2- (9-phenyl-9H-fluoreno- Benzyl 9-ylamino) butanoate, contaminated with benzyl alcohol, in the form of a colorless, viscous oil and benzyl (2S, 3R) -4-hydroxy-3-methyl-2- (9-phenyl-9H-fluorene-9-ylamino) butanoate containing stereoisomer (2S, 3R) as an impurity. A later sample was again used for column chromatography under the same conditions to obtain 750 mg of purified material as white foam. [Note: under the above conditions the (2S, 3S) isomer elutes before the (2S, 3R) isomer]. Isomer (2S, 3S): 1 H NMR (DMSO-d₆, δ = 2.5 ppm, 400 MHz): 7.81 (m, 2H), 7.39-7.08 (m, 16H),

4.67 (d, 7 = 12.3, 1H), 4.43 (d, J = 12.4, 1H), 4.21 (app t, J = 5.2, OH), 3.22 (d, 7 = 10.1, NH),

3.17 (m, 1H), 3.08 (m, 1H), ~ 2.5 (m, 1H, superimposed with a solvent signal), 1.58 (m, 1H), 0.88 (d, J = 6.8, 3H). LC (Condition 1): RT = 2.00 min; LC / MS: Anal. Obi. for [M + H]⁺C 31 H 30 NO 3: 464.45; experimental 464.22. (2S, 3R) isomer: * H NMR (DMSO-dó, δ = 2.5 ppm, 400 MHz): 7.81 (d, J = 7.5, 2H), 7.39-7.10 (m, 16H), 4.63 (d, 7 = 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, 7 = 6.8, 3H). LC (Condition 1): RT = 1.92 min; LC / MS: Anal. Obi. for [M + H]⁺ C3iH₃qNO₃: 464.45; experimental 464.52.

Relative stereochemical assignments of DIB AL reduction products were made based on NOE tests performed on lactone derivatives prepared from each isomer by the following protocol: LiHMDS (50 mL 1.0 M / THF, 0.05 mmol) was added to the chilled (in ice water) solution THF (2.0 mL) (2S, 3S) -4-hydroxy-3-methyl-2- (9-phenyl-9H-fluorene-9-ylamino) benzyl butanoate (62.7 mg, 0.135 mmol) and the reaction mixture was stirred at a similar temperature for ~ 2 hours. The volatile component was removed in vacuo and the residue was partitioned between CH2Cl2 (30 mL), water (20 mL) and saturated NH4Cl solution (1 mL). The organic layer was dried (MgSO₄), filtered and concentrated in vacuo, and the resulting crude material was subjected to Biotage purification (40 g silica gel; 10-15% EtOAc / hexanes) to afford (3S, 4S) -4-methyl-3- (9-phenyl- 9H-fluorene-9-ylamino) dihydrofuran-2 (3H) -one as a colorless solid film (28.1 mg). Benzyl (2S, 3R) -4-hydroxy-3-methyl-2- (9-phenyl-9H-fluorene-9-ylamino) butanoate was similar to (3S, 4R) -4-methyl-3- (9-phenyl) -9H-fluorene-9yloamino) dihydrofuran-2 (3H) -one. (3S, 4R) -lactone isomer: * H NMR (DMSO-dć, 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 superimposed with a signal from the solvent), 2, 16 (m, 1H), 0.27 (d, J = 6.6, 3H). LC (Condition 1): RT = 1.98 min; LC / MS: Anal. Calc. for [M + Na]⁺ C24H2iNNaO2: 378.15; experimental 378.42. (3S, 4R) -lactone isomer: 'H NMR (DMSO-d6, δ = 2.5 ppm, 400 MHz), 7.89 (d, J = Ί.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, 7 = 6.8, 3, NCH), 1.55 (m, 1H), 0.97 (d, 7 = 7.0, 3H). LC (Condition 1): RT = 2.03 min; LC / MS: Anal. Calc. for [M + Na]⁺ C24H2iNNaO2: 378.15; experimental 378.49.

TBDMS-C1 (48 mg, 0.312 mmol) followed by imidazole (28.8 mg, 0.423 mmol) was added to a solution of CH2Cl2 (3 mL) (2S, 3S) -4-hydroxy-3-methyl-2- (9- benzyl phenyl-9H-fluorene-9-ylamino) butanoate (119.5 mg, 0.258 mmol) and the mixture was stirred at ambient conditions for 14.25 hours. The reaction mixture was then diluted with CH2Cl2 (30 mL) and washed with water (15 mL) and the organic layer was dried (MgSO₄), filtered and concentrated in vacuo. The resulting crude material was purified on Biotage (40 g silica gel; 5% EtOAc / hexanes) to give (2S, 3S) -4- (tert-butyldimethylsilyloxy) -3-methyl-2- (9-phenyl9H-fluorene-9-ylamino) benzyl butanoate, contaminated with TBDMS-based impurities, as a colorless, viscous oil (124.4 mg).

Benzyl (2S, 3R) -4-hydroxy-3-methyl-2- (9-phenyl-9H-fluorene-9-ylamino) butanoate was similar to (2S, 3R) -4- (tert-butyldimethylsilyloxy) -3- benzyl methyl-2- (9-phenyl-9H-fluorene-9-ylamino) butanoate. Isomer (2S, 3S) silyl ether: * H NMR (DMSO-dś, δ =

2.5 ppm, 400 MHz), 7.82 (d, 7 = 4.1, 1H), 7.80 (d, 7 = 4.0, 1H), 7.38-7.07 (m, 16 H), 4.70 (d, 7 = 12.4 , 1H), 4.42 (d, J = 12.3, 1H), 3.28-3.19 (m, 3H), 2.56 (dd, 7 = 10.1, 5.5, 1H), 1.61 (m, 1H), 0.90 (d, 7 = 6.8, 3H), 0.70 (s, 9H), -0.13 (s, 3H), -0.16 (s, 3H). LC (Condition 1, where the run time was extended to 4 min): RT = 3.26 min; LC / MS: Anal. Calc. for [M + H]⁺C37H₄₄NO3Si: 578.31; experimental 578.40. (2S, 3R) -silyl ether isomer: * H NMR (DMSO-d₆, δ = 2.5 ppm, 400 MHz), 7.82 (d, 7 = 3.0, 1H), 7.80 (d, 7 = 3.1, 1H), 7.39-7.10 (m, 16H), 4.66 (d, 7 = 12.4, 1H ), 4.39 (d, 7 = 12.4, 1H), 3.61 (dd, 7 = 9.9, 5.6, 1H), 3.45 (d, 7 =

9.5, ΙΗ), 3.41 (dd, 7 = 10, 6.2, 1H), 2.55 (dd, 7 = 9.5, 7.3, 1H), 1.74 (m, 1H), 0.77 (s, 9H), 0.61 (d, 7 = 7.1, 3H), -0.06 (s, 3H), -0.08 (s, 3H).

To a mixture of benzyl (2S, 3S) -4- (tert-butyldimethylsilyloxy) -3-methyl-2- (9-phenyl-9H-fluorene-9-ylamino) butanoate (836 mg, 1.447 mmol) and 10% Pd / C (213 mg) in EtOAc (16 mL), a hydrogen balloon was attached and the mixture was stirred at room temperature for - 21 hours, during which the balloon was topped up if necessary₂. The reaction mixture was diluted with CH₂C1₂ and filtered through a pad of diatomaceous earth (Celite-545®) and the pad 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 sieve was prepared from the obtained crude material and subjected to flash chromatography (8: 2: 1 mixture of EtOAc / i-PrOH / H₂O) to obtain (2S, 3S) -2-amino-4- (tert-butyldimethylsilyloxy) -3-methylbutanoic acid as a white, flocculent solid (325 mg).

Benzyl (2S, 3R) -4- (tert-butyldimethylsilyloxy) -3-methyl-2- (9-phenyl-9H-fluorene-9-ylamino) butanoate was similar to (2S, 3R) -2-amino-4- ( tertbutylodimetylisililoksy) -3-methylbutanoic acid.

(2S, 3S) -amino acid isomer: * H NMR (Methanol-d ^ δ = 3.29 ppm, 400 MHz), 3.76 (dd, 7 = 10.5, 5.2, 1H), 3.73 (d, 7 = 3.0, 1H), 3.67 (dd, 7 = 10.5, 7.0, 1H), 2.37 (m, 1H), 0.97 (d, 7 = 7.0, 3H), 0.92 (s, 9H), 0.10 (s, 6H). LC / MS: Anal. Calc. for [M + H]⁺ Cn₂₆WELL₃Si: 248.17; experimental 248.44. (2S, 3R) -amino acid isomer: 'H NMR (Methanol-dzt, δ =

3.29 ppm, 400 MHz), 3.76-3.75 (m, 2H), 3.60 (d, 7 = 4.1, 1H), 2.16 (m, 1H), 1.06 (d, 7 = 7.3, 3H), 0.91 (s , 9H), 0.09 (s, 6H). Anal. Calc. for [M + H]⁺ Those H₂₆WELL₃Si: 248.17; experimental 248.44.

Water (1mL) and NaOH (0.18 mL 1.0 M / H₂0.18 mmol) was added to a mixture of (2S, 3S) -2-amino-4- (tert-butyldimethylsilyloxy) -3-methylbutanoic acid (41.9 mg, 0.169 mmol) and Na₂WHAT₃ (11.9 mg, 0.112 mmol) and sonicated for about 1 min to affect the dissolution of the reagents. The mixture was then cooled in an ice-water bath, methyl chloroformate (0.02 mL, 0.259 mmol) was added over 30 s and vigorous stirring was continued at a similar temperature for 40 min and then at ambient temperature for 2.7 hours. The reaction mixture was diluted with water (5 mL), cooled in an ice-water bath and treated with an aqueous 1.0 N HCl solution (-0.23 mL) dropwise. 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 provide Cap-80a as an off-white solid. (2S, 3R) -2-amino-4- (tert-butyldimethylsilyloxy) -3-methylbutanoic acid was obtained similarly to Cap-80b. Cap-80a: 'H NMR (DMSO-de, δ = 2.5 ppm, 400 MHz), 12.57 (br s, 1H), 7.64 (d, 7 = 8.3, 0.3H), 7.19 (d, 7 = 8.8 , 0.7H), 4.44 (dd, 7 = 8.1, 4.6, 0.3H), 4.23 (dd, 7 = 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, superimposed on the t-Bu signal), 0.79 (d, 7 = 7, 2.1H), 0.02 /0.01/0.00 (three superimposed singlets, 6H). LC / MS: Anal. Calc. for [M + Na]⁺ these₃H₂7NNaO5Si: 328.16; experimental 328.46. Cap-80b: 1 H NMR (CDCl₃, δ = 7.24 ppm, 400 MHz), 6.00 (br d, 7 = 6.8, 1H), 4.36 (dd, 7 = 7.1, 3.1, 1H), 3.87 (dd, 7 = 10.5, 3.0, ΙΗ), 3.67 (s, 3H), 3.58 (dd, 7 = 10.6, 4.8, 1H), 2.35 (m, 1H), 1.03 (d, 7 =

7.1, 3H), 0.90 (s, 9H), 0.08 (s, 6H). LC / MS: Anal. Calc. for [M + Naf Ci3H₂7NNaO₅Si: 328.16; experimental 328.53. The crude products were used without further purification.

Cap-8I &lt;* &lt;

OH

Produced according to the protocol described by Falb et al. Synthetic Communications 1993.23, 2839.

Cap-% 2 to Cćzp-85

Cop-82 to Cap-% 5 were synthesized from appropriate starting materials following the procedure described for Cap-51. Samples showed similar spectral profiles as their enantiomers (i.e. Cap-A, Cap-13, Cap-51 and Cap-52, respectively)

<img file="PL2049522T3_D0075.tif" />

About Ph

Gdp-32 and ° "γΑ

Cap-83

<img file="PL2049522T3_D0076.tif" />

HU o 'Cap-85

Cap-86 MeO₂CHN

0 ° ohms «,^oh

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 dropwise with ClCO₂Me (1.74 mL, 22.55 mmol) at 0 ° C. The mixture was allowed to stir for 12 h and acidified to pH 1 using IN HCl. The aqueous phase was extracted with EtOAc and (2x250 mL) and 10% MeOH in CH₂C1₂ (250 mL), and the combined organic phases were concentrated in vacuo to give a colorless oil (4.18 g, 97%), which was of sufficient purity for use in the next steps. * HNMR (400 MHz, CDCl3) δ 4.19 (s, 1H), 3.92-3.97 (m, 1H), 3.66 (s, 3H), 1.17 (d, 7 = 7.7 Hz, 3H). LCMS: Anal. Calc. for C7H13NO5: 191; experimental: 190 (MH) '.

Cap-87

MeOjCHN

AND

MeO OH

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 dropwise with ClCO₂Me (0.76 mL, 9.79 mmol) at 0 ° C. The mixture was allowed to stir for 48 h and acidified to pH 1 using IN HCl. The aqueous phase was extracted with EtOAc and (2X250 mL), and the combined organic phases were concentrated in vacuo to give a colorless solid (0.719 g, 28%), which was of sufficient purity for use in the next steps. 'HNMR (400 MHz, CDCI3) 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. Calc. for C7H13NO5: 191; experimental: 192 (M + H)⁺.

Cap-88

<img file="PL2049522T3_D0077.tif" />

OH

Mixture of L-valine (1.0 g, 8.54 mmol), 3-bromopyridine (1.8 mL, 18.7 mmol), K₂WHAT₃(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 (approx. 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 about pH 2 with 6N HCl. The volume was reduced to about one third and 20g of cation exchange resin (Strata) was added. The suspension was allowed to stand for 20 minutes and was applied to a cation exchange resin (Strata) cartridge (approx. 25g). The refill was washed with H₂O (200 mL), MeOH (200 mL) followed by NH₃ (3M in MeOH, 2X200 mL). The appropriate fractions were concentrated in vacuo and the residue (approx. 1.1 g) was dissolved in H₂Oh, frozen and freeze-dried. The title compound was obtained as foam (1.02 g, 62%). 'ΗΝΜΕ (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, 7 = 6.0 Hz, 3H), 0.91 (d, 7 = 6.6 Hz, 3H). LCMS: Anal. Calc. for CioHi4N₂0₂: 194; experimental: 195 (M + H)⁺.

Cap-89

<img file="PL2049522T3_D0078.tif" />

Mixture of L-valine (1.0 g, 8.54 mmol), 5-bromopyrimidine (4.03 g, 17.0 mmol), K₂WHAT₃(2.40 g, 17.4 mmol) and Cul (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 (approx. 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 about pH 2 with 6N HCl. The volume was reduced to about one third and 20g of cation exchange resin (Strata) was added. The suspension was allowed to stand for 20 minutes and was applied to a cation exchange resin (Strata) cartridge (approx. 25g). The refill was washed with H₂O (200 mL), MeOH (200 mL) followed by NH₃ (3M in MeOH, 2x200 mL). The appropriate fractions were concentrated in vacuo and the residue (approx. 1.1 g) was dissolved in H₂Oh, frozen and freeze-dried. The title compound was obtained as foam (1.02 g, 62%). 'HNMR (400 MHz, CD₃OD) showed that the mixture contained valine and the purity could not be estimated. Such material was used in subsequent stages. LCMS: Anal. Calc. for C9Hi₃N₃ABOUT₂: 195; experimental: 196 (M + H)⁺.

Cap-90

<img file="PL2049522T3_D0079.tif" />

Cap-90 was prepared according to the method described for the production of Cap-1. Such crude material was used in subsequent stages. LCMS: Anal. Calc. for C11H15NO2: 193; experimental: 192 (MH) '.

The following cap was made according to the method of Example 51:

<td>goat</td><td>Structure</td><td>LCMS</td>

<td>Cap-91</td><td>NHCO₂Me</td><td>LCMS: Anal. Calc. for you, Hi₃WELL₄: 223; experimental: 222 (MH) '</td>

<td>Cap-92</td><td>NHCO₂Me X ^^ \ ^ CO₂H here</td><td>LCMS: Anal. Calc. for C, iH, 3NO₄: 223; experimental: 222 (MH) '</td>

<td>Cap-93</td><td>° Y ° of^ην'·· Αοη</td><td>LCMS: Anal. Calc. for C₁₀H, 2N₂ABOUT₄: 224; experimental: 225 (M + H)⁺.</td>

<td>Cap-94</td><td> 0 &lt;/ⁿJ &lt;^ Y^ohbr HN Η T. ABOUT</td><td>LCMS: Anal. Calc. for C.₈hNN₃ABOUT₄: 213; experimental: 214 (M + H)⁺.</td>

<td>Cap-95</td><td>0 X ABOUT NH 0 - ^ OH</td><td>LCMS: Anal. Calc. for you₃hi₇WELL₄: 251; experimental: 250 (MH) '</td>

<td>Cap-96</td><td>0 X. A. 0 NH 0 γΆ_0Η</td><td>LCMS: Anal. Calc. for you₂H₁₅WELL₄: 237; experimental: 236 (MH) '</td>

<td>Cap-91</td><td>X about Q / / C) about /</td><td>LCMS: Anal. Calc. for C.₉hi₅WELL₄: 201; experimental: 200 (MH) '</td>

<td>Cap-9%</td><td>about AND About NH ..... s</td><td>LCMS: Anal. Calc. for C9H₁₅WELL₄: 201; experimental: 202 (M + H)⁺.</td>

<td>Cap-99</td><td>0 Ατ ^ νη L What₂h</td><td>'HNMR (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>about N-NH about^xWhat₂h</td><td>'HNMR (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-100</td><td>0 AND 0 NH 0 ΛΑ,</td><td>LCMS: Anal. Calc. for C₂H₁₄WELL₄F: 255; experimental: 256 (M + H)⁺.</td>

<td>Cap-101</td><td>ABOUT = O ^ NH AcOjH about</td><td>LCMS: Anal. Obi. for C, iHi₃WELL₄: 223; experimental: 222 (MH) "</td>

<td>Cap-102</td><td>0 in Rao₂H about</td><td>LCMS: Anal. Obi. for CnHi₃WELL₄: 223; experimental: 222 (MH) '</td>

<td>Cap-103</td><td>0 --oĄ V ^ CO₂H about</td><td>LCMS: Anal. Obi. for C₁₀H₁₂N₂ABOUT₄: 224; experimental: 225 (M + H)⁺.</td>

<td>Cap-104</td><td>HN— &lt;Y-COoH oa W / °</td><td>'HNMR (400 MHz, CD₃OD) δ 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 "(V-CO₂H 0 /</td><td>'HNMR (400 MHz, CD₃OD) δ 3.60 (s, 3H), 3.33 - 3.35 (m, 1H, partially obscured by the solvent), 2.37 - 2.41 and 2.16 -2.23 (m, 1H), 1.94 -2.01 (m, 4H), 1.43 - 1.53 (m, 2H), 1.171.29 (m, 2H).</td>

<td>Cap-106</td><td> 3-0^</td><td>'HNMR (400 MHz, CD₃OD) δ 3.16 (q, J = 7.3 Hz, 4H), 2.382.41 (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 dt J = 4.0, 12.9 Hz, 2H), 1.26 (t, 7 = 7.3 Hz, 6H).</td>

<td>Cap-107</td><td> &lt;/^ναΆ^ηHN ^ o ^ 0</td><td>LCMS: Anal. Obi. for C₈H_I0N₂ABOUT₄S: 230; experimental: 231 (M + H)⁺.</td>

<td>Cap-108</td><td> 0 &lt;/^νΤ^χΎ ^ '^οηX HN 0 ^ Ph- ^ Ϊ</td><td>LCMS: Anal. Calc. for these₅H₁₇N₃O4: 303; experimental: 304 (M + H)⁺.</td>

<td>Cap-109</td><td>0 μΑνη &lt;^ Which₂h Γη V</td><td>LCMS: Anal. Calc. for these₀H₁₂N₂O4: 224; experimental: 225 (M + H)⁺.</td>

<td>Cap-110</td><td>about ύΑνη ό Ν</td><td>LCMS: Anal. Calc. for C_l0H₁₂N₂ABOUT₄: 224; experimental: 225 (M + H)⁺.</td>

<td>Cap-111</td><td>0 ύΑνη Υ ~ Ύο₂η Φ 'Εο ΜβΟ '+ Η</td><td>LCMS: Anal. Calc. for these₂H₆WELL₈P: 333; experimental: 334 (M + H)⁺.</td>

<td>Cap-112</td><td>Ο ύΑνΗ C3^NH</td><td>LCMS: Anal. Calc. for C₁₃hi₄N₂ABOUT₄: 262; experimental: 263 (M + H)⁺.</td>

<td>Cap-113</td><td>0 Μ ^ νη M ^ which₂h φ ΟΒη</td><td>LCMS: Anal. Calc. for C,₈hi₉WELL₅: 329; experimental: 330 (M + H)⁺.</td>

<td>Cap-114</td><td>,WHAT₂Me ι-Ν Μο₂η</td><td>'HNMR (400 MHz, CDC1₃) δ 4.82 -4.84 (m, 1H), 4.00 -4.05 (m, 2H), 3.77 (s, 3H), 2.56 (s, br, 2H)</td>

<td>Cap-115</td><td>* Y ^^x'What₂h NHCO₂Me</td><td>'HNMR (400 MHz, CDC1₃) δ 5.13 (s, br, 1H), 4.13 (s, br, 1H), 3.69 (s, 3H), 2.61 (d, J = 5.0 Hz, 2H), 1.28 (d, 7 = 9.1 Hz, 3H).</td>

<td>Cap-116</td><td> •^x^ Y '^' which₂h NHCO₂Me</td><td>'HNMR (400 MHz, CDCI3) δ 5.10 (d, 7 = 8.6 Hz, 1H), 3.74 - 3.83 (m, 1H), 3.69 (s, 3H), 2.54 - 2.61 (m, 2H), 1.88 ( sept, 7 = 7.0 Hz, 1H), 0.95 (d, 7 = 7.0 Hz, 6H).</td>

Cap-117 to Cap-123

Boc amino acids for cap-iYl to Cap-123 production were commercially available and deprotected by treatment with 25% TFA in CH2Cl2. After completion of the reaction, as judged by LCMS, the solvents were removed in vacuo and the corresponding TFA amino acid salt was carbamoylated with methyl chloroformate according to the procedure for Cap-51.

<td>goat</td><td>Structure</td><td>LCMS</td>

<td>Cap-117</td><td>ABOUT^Xtr'NH O Λλ °_η</td><td>LCMS: Anal. Calc. for C, 2H, 5NO₄S: 237; experimental: 238 (M + H)⁺.</td>

<td>Cap-118</td><td> 0 0</td><td>LCMS: Anal. Calc. for you₀hi₃WELL₄S: 243; experimental: 244 (M + H)⁺.</td>

<td>Cap-119</td><td>ABOUT 0</td><td>LCMS: Anal. Calc. for C, oHi₃N0₄S: 243; experimental: 244 (M + H)⁺.</td>

<td>Cap-120</td><td>ABOUT /</td><td>LCMS: Anal. Calc. for C.₁₀hi₃WELL₄S: 243; experimental: 244 (M + H)⁺.</td>

<td>Cap-121</td><td>ABOUT</td><td>'HNMR (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>ABOUT ^ Yy, the CO₂H</td><td>'HNMR (400 MHz, CDC1₃) δ 5.28 and 5.12 (s, br, 1H), 3.66 (s, 3H), 2.64 2.74 (m, 1H), 1.86 - 2.12 (m, 3H), 1.67 -1.74 (m, 2H), 1.39 - 1.54 (m, 1H).</td>

<td>Cap-123</td><td>ABOUT / 7 — NH λ — λ O YZY&gt; ° / /) - \) "NH νΧ ° = &lt; X OH</td><td>LCMS: Anal. Calc. for C.₂₇H₂₆N2O₆: 474; experimental: 475 (M + H)⁺.</td>

Preparation of Cap-124, (4S, 5R) -5-methyl-2-oxo-oxazolidine-4-carboxylic acid 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 HCl to pH ~ 1 and the mixture was extracted with EtOAc (2X50 mL). The combined organic phases were concentrated in vacuo, which gave colorless, solidifying on standing. The aqueous layer was concentrated in vacuo and the resulting mixture of product and inorganic salts was triturated with EtOAc-CH₂Cl2-MeOH (1: 1: 0.1) and then the organic phase was concentrated in vacuo to give a colorless oil which was indicated by LCMS as the desired product. Both sets were combined, resulting in 0.52 g of solid. HNMR (400 MHz, CD₃OD) δ 4.60 (m, 1H), 4.04 (d, 7 = 5.0 Hz, 1H), 1.49 (d, 7 = 6.3 Hz, 3H). LCMS: Anal. Calc. for C5H7NO4: 145; experimental: 146 (M + H)⁺.

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

o 'OH /

-N

E cap-125

Cap-125 was prepared according to the Cap-1 production procedure. Such a crude product was used in subsequent reactions. LCMS: Anal. Calc. for CnH₂₂N₂O4: 246; experimental: 247 (M + H)⁺.

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

<img file="PL2049522T3_D0080.tif" />

cj-25

CICO₂Me, NaHCO₃

THF / H₂0 From O'C er

Λ

Meo₂CHN CO₂H cap-126

This procedure is a modification of the Cap-51 used to make it. To a suspension of (S) -2-amino-3- (1-methyl-1H-imidazol-2-yl) propanoic acid (0.80 g, 4.70 mmol) in THF (10mL) 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 was allowed to stir at 0 ° C. After stirring for approximately 2 hours, LCMS showed no remaining starting material. The reactions were acidified to pH 2 with 6 N HCl.

The solvents were removed in vacuo and the residue suspended in 20 mL 20% MeOH in CH₂C1₂. The mixture was filtered and concentrated to give a light yellow foam (1.21 g,). LCMS and * H NMR showed that the material is a 9: 1 mixture of methyl ester and the desired product. This material was taken to THF (10mL) and H₂O (10mL), cooled to 0 ° C and LiOH (249.1 mg, 10.4 mmol) was added. After stirring for approx. 2 hours, LCMS showed no residual ester. Therefore, the mixture was acidified with 6N HCl and the solvents removed in vacuo. LCMS and^l1 H NMR confirmed the absence of ester. The title compound was obtained as HCl salt, contaminated with inorganic salts (1.91 g,&gt; 100%). Such a compound was used in subsequent steps without further purification.

'HNMR (400 MHz, CD₃OD) δ 8.84, (s, 1H), 7.35 (s, 1H), 4.52 (dd, J = 5.0, 9.1 Hz, 1H), 3.89 (s, 3H), 3.62 (s, 3H), 3.35 (dd, J = 4.5, 15.6 Hz, 1H, partly covered by solvent),

3.12 (dd, 7 = 9.0, 15.6 Hz, 1H).

LCMS: Anal. Calc. for Ci7Hi5NO₂: 392; experimental: 393 (M + H)⁺.

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

<img file="PL2049522T3_D0081.tif" />

CICO₂Me, NaHCO₃

THF / H₂O / 0 C

<img file="PL2049522T3_D0082.tif" />

Meo₂CHN cap-127

WHAT₂H

Cap-127 was prepared according to the method for Cap-126 above, starting with (S) -2-amino-3- (1-methyl-1H-imidazol-4-yl) 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 HCl salt, contaminated with inorganic salts (1.79 g,&gt; 100%). LCMS and * H NMR showed the presence of about 5% methyl ester. This crude mixture was used without further purification.^JHNMR (400 MHz, CD₃OD) δ 8.90 (s, 1H), 7.35 (s, 1H), 4.48 (dd, 7 = 5.0, 8.6 Hz, 1H), 3.89 (s, 3H), 3.62 (s, 3H), 3.35 (m, 1H ), 3.08 (m, 1H).

LCMS: Anal. Calc. for C17H15NO2: 392; experimental: 393 (M + H)⁺.

Preparation of (S) -2- (methoxycarbonylamino) -3- (1Η-1,2,3-triazol-4-yl) propanoic acid {Cap-128).

III Cbz-CI / DMAP |, |

111 CH₂CI₂ / iPrjNEt l | J

, .x

BocHN CO₂H cj-27a o ° c

BocHfAcOzBn NaN₃/ DMF / H₂ABOUT

BnBr / CuS0 "-5H₂ABOUT

Sodium ascorbate

<img file="PL2049522T3_D0083.tif" />

BocHN CO₂Bn cj-23

65 "C / 12h cj-27b

Ph-y

1) TFA / CH₂CI₂

2) CICO₂Me and NaHCO₃THF-H₂ABOUT

<img file="PL2049522T3_D0084.tif" />

H₂ / Pd-C MeOH

<img file="PL2049522T3_D0085.tif" />

MeOjCHN 'CO₂H cap-128

Step 1. Preparation of benzyl (S) -2- (tert-butoxycarbonylamino) pent-4-ynoate (Ci-27b).

BocHN CO₂Bn cj-27b

To a solution of cj-27a (1.01 g, 4.74 mmol), DMAP (58 mg, 0.475 mmol) and iP ^ NEt (1.7 mL, 9.8 mmol) in CH2Cl2 (100 mL) at 0 ° C was added Cbz-CI (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 hexane: EtOAc) to give the title compound (1.30 g, 91%) as a colorless oil. 'HNMR (400 MHz, CDCI3) δ 7.35 (s, 5H), 5.35 (d, br, J = 8.1 Hz, 1H), 5.23 (d, J = 12.2 Hz, 1H), 5.17 (d, 7 = 12.2 Hz, 1H), 4.48 - 4.53 (m, 1H), 2.68 2.81 (m, 2H), 2.00 (t, 7 = 2.5 Hz, 1H), 1.44 (s, 9H). LCMS: Anal. Calc. for you₇H₂Ino₄: 303; experimental: 304 (M + H)⁺.

Step 2. Preparation of benzyl (S-28) (S) -3- (1-benzyl-1H-1,2,3-triazol-4-yl) -2- (tert-butoxycarbonylamino) propanoate.

<img file="PL2049522T3_D0086.tif" />

To a mixture of benzyl (S) -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) BtBr (0.24 mL, 2.02 mmol) was added at rt and the mixture was heated to 65 ° C. After 5h LCMS showed low conversion. An additional NaN portion has been added₃ (100 mg) and heating continued for 12h. The reaction was poured into EtOAc and

H₂0 and shaken. The layers were separated and the aqueous layer was extracted 3x with EtOAc and the combined organic phases were washed (H₂O, brine), dried (Na₂SO₄), filtered and concentrated. The residue was purified by flash type (Biotage, 40 + M 0-5% MeOH in CH₂C1₂; TLC 3% MeOH in CH₂C1₂) to obtain a pale yellow oil that solidifies on standing (748.3 mg, 104%). NMR corresponded to the desired product, but suggested the presence of DMF. Such material was used without further purification. 'HNMR (400 MHz, DMSO-dó) 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, 7 = 1.0,

5.3 Hz, 1H), 3.06 (dd, 7 = 5.3, 14.7 Hz), 2.96 (dd, 7 = 9, 1, 14.7 Hz, 1H), 1.31 (s, 9H).

LCMS: Anal. Calc. for C.₂₄H₂₈N₄ABOUT₄: 436; experimental: 437 (M + H)⁺.

Step 2. Preparation of benzyl (S) -3- (1-benzyl-1H-1,2,3-triazol-4-yl) -2- (tert-methoxycarbonylamino) propanoate.

<img file="PL2049522T3_D0087.tif" />

A solution of benzyl (S) -3- (1-benzyl-1 Hl, 2,3-triazol-4-yl) -2-tert-butoxycarbonylamino) propanoate (0.52 g, 1.15 mmol) in CH₂C1₂ TFA (4 mL) was added. The mixture was allowed to stir at room temperature for 2 hours. The mixture was concentrated in vacuo, which gave a colorless oil, solidifying on standing. This material was dissolved in THF-H₂Oh and cooled to 0 ° C. Solid NaHCO was added₃ (0.25 g, 3.00 mmol) followed by ClCO₂Me (0.25 mL, 3.25 mmol). After stirring for 1.5 hours, the mixture was acidified with 6N HCl to pH ~ 2, and then poured into H₂O-EtOAc. The layers were separated and the aq phase was extracted 2x with EtOAc. Combined org layers washed (H₂O, brine), dried (Na₂SO₄), filtered and concentrated in vacuo, which gave a colorless oil (505.8 mg, 111%, NMR suggested the presence of unidentified impurities), setting on standing at the pump. Such material was used without further purification. 'HNMR (400 MHz, DMSO-d₆) δ 7.87 (s, 1H), 7.70 (d, 7 = 8.1 Hz, 1H), 7.27 7.32 (m, 10H), 5.54 (s, 2H), 5.10 (d, 7 = 12.7 Hz, 1H), 5.06 ( d, 7 = 12.7 Hz, 1H), 4.32 - 4.37 (m, 1H), 3.49 (s, 3H), 3.09 (dd, 7 = 5.6, 14.7 Hz, 1H), 2.98 (dd, 7 = 9.6, 14.7 Hz, 1H). LCMS: Anal. Calc. for C.₂H₂₂N₄ABOUT₄: 394; experimental: 395 (M + H)⁺.

Step 3. Preparation of (S) -2- (methoxycarbonylamino) -3- (1H-1,2,3-triazol-4-yl) propanoic acid (Cap-128).

Meo₂CHN CO2H Ca 0-128 (S) -3- (1-benzyl-1 Hl, 2,3-triazol-4-yl) -2- (methoxycarbonylamino) benzyl 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. Obtained (S) -2- (methoxycarbonylamino) -3- (1H-1,2,3-triazol-487-yl) propanoic acid as a colorless gum (266 mg, 111%), denatured with approx. 10% methyl ester. Such material was used without further purification.

'HNMR (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, 7 = 9.9, 15.0 Hz, 1H).

LCMS: Anal. Obi. for C7H10N4O4: 214; experimental: 215 (M + H)⁺.

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

<td></td><td>HN ^ /</td><td>N = \</td><td>1) H.₂ Pd-C / MeOH</td><td>N == \</td>

<td>FROM-% CbzHN O</td><td>CH₃CN / 50 ° C</td><td>CbzHI \ vco₂H</td><td colspan="2">2) CICO₂Me MeO₂CHN "Ao₂H</td>

<td>EJ-30</td><td></td><td>cj-31</td><td>NaHCO₃/ THF-H₂ABOUT</td><td>Cap-129</td>

Step 1. Preparation of (S) -2- (benzyloxycarbonylamino) -3- (1H-pyrazol-lilojpropanoic acid (Ci-31).

N = \

CbzHN ^ 'CO₂H cj-31

A suspension of benzyl (S) -2-oxo-oxetane-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 overnight to room temperature and the solid was filtered to give (S) -2 (benzyloxycarbonylamino) -3- (1H-pyrazol-1-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 give a second harvest (43.5 mg). Total yield = 370.4mg (44%). mp 165.5-168 ° C. lit mp 168.5-169.5 Vederas et al. 7 Am. Chem. Soc. 1985.107, 7105.

'HNMR (400 MHz, CD₃OD) δ 7.51 1 (d, 7 = 2.0, 1H), 7.48 (s, 7 = 1.5 Hz, 1H), 7.24 - 7.34 (m, 5H), 6.23 m, 1H), 5.05 (d, 12.7 Η, 1H ), 5.03 (d, 7 = 12.7 Hz, 1H), 4.59 - 4.66 (m, 2H),

4.42 -4.49 (m, 1H). LCMS: Anal. Obi. for C14H15N3O4: 289; experimental: 290 (M + H)⁺.

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

N = \

Meo₂CHNAo₂H cap-129

(S) -2- (benzyloxycarbonylamino) -3- (1H-pyrazol-1-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 insoluble in MeOH, therefore the reaction mixture was diluted with 5mL H₂O and a few drops of 6N HCl. The homogeneous solution was filtered through diatomaceous earth (Celite®) and MeOH was removed in vacuo. The remaining solution was frozen and lyophilized to give a yellow foam (188.9 mg). This material was suspended in THF-H₂O (1: 1, 10 mL) and then cooled to 0 ° C. NaHCO3 (146.0 mg, 1.74 mmol) (CO2 evolution) was carefully added to the cold mixture. When gas evolution stopped (about 15 min) ClCO was added dropwise₂Me (0.06 mL, 0.78 mmol). Stirring was allowed to stir for 2h and acidified with 6N HCl to pH-2 and poured into EtOAc. The layers were separated and the aqueous phase was extracted with EtOAC (5x).

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%).

'HNMR (400 MHz, DMSO-d₆) δ 13.04 (s, 1H), 7.63 (d, J = 2.6 Hz, 1H), 7.48 (d, J = 8.1 Hz, IH), 7.44 (d, 7 = 1.5 Hz, 1H), 6.19 (app t, 7 = 2.0 Hz, 1H), 4.47 (dd, 7 = 3.0, 12.9 Hz, 1H), 4.29 -4.41 (m, 2H), 3.48 (s, 3H). LCMS: Anal. Calc. for C8H11N3O4: 213; experimental: 214 (M + H)⁺.

Cap-130. N-acetyl- (R) -phenylalanine

AcHN co₂h cap-130

Cop-130 was prepared by acylation of commercially available (R) -phenylglycine, analogously 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 conjunction with specific embodiments that are not intended to limit its scope. Thus, the following examples, including specific embodiments, will illustrate the practice of disclosure, it being understood that the examples are for the purpose of illustrating individual embodiments and are presented to provide what is considered to be the most useful and broadly understood description of its procedures and aspects. Framework.

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 on a Bruker 300, 400, or 500 MHz spectrometer; Chemical shifts (δ) were recorded in parts per million. Flash chromatography was performed on silica gel (SiO₂) in accordance with the flash chromatography technique (7 Org. Chem. 1978, 43, 2923).

The purity and low-resolution mass analysis was carried out in a Shimadzu LC system connected to the Waters Micromass ZQ MS system. It should be noted that retention times may vary slightly between devices. The LC conditions used to determine the retention time (RT) were:

Condition 1

<td>Column</td><td>= Phenomenex-Luna 3.0Χ 50 mm SIO</td>

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

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

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

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

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

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

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

<td>Solvent B</td><td>= 0.1% TFA in 90% methanol / 10% H₂ABOUT</td>

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

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

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

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

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

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

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

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

<td>Solvent A</td><td>= 0.1% TFA in 10% methanol / 90% H₂ABOUT</td>

<td>Solvent B</td><td>= 0.1% TFA in 90% methanol / 10% H₂ABOUT</td>

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

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

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

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

<td>Gradient time</td><td>= 3 minutes</td>

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

<td>Flow rate ^:</td><td>= 4 mL / min</td>

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

<td>Solvent A</td><td>= 0.1% TFA in 10% methanol / 90% H₂ABOUT</td>

<td>Solvent B</td><td>= 0.1% TFA in 90% methanol / 10% H₂ABOUT</td>

Method A: LCMS - Xterra MS C-18 3.0 x 50mm, 0 to 100% B for 30.0 minutes gradient, 1 minute hold, 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 for 10.0 minutes gradient, 1 minute hold, A = 10% water, 90% methanol, 0.1% TFA, B = 90% water, 10 % methanol, 0.1% TFA

Method C: HPLC - YMC C-18 4.6 x 50mm, 0 to 100% B for 10.0 minutes gradient, 1 minute hold, 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 for 10.0 minutes gradient, 1 minute hold, 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 for 10.0 minutes gradient, 1 minute hold, 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 for 7.0 minutes gradient, 1 minute hold, A = 5% acetonitrile, 95% water, 10mm ammonium acetate, B = 95% acetonitrile, 5% water , 1 Omm ammonium acetate.

Example 1 (IR, rR) -2.2 '- (4,4'-biphenyldiylbis (1H-imidazol-5,2-diyl (2S) -2, 1-pyrrolidinyl)) bis (N, N-dimethyl-2-oxo l-fenyloetanamina)

<img file="PL2049522T3_D0088.tif" />

Y, Y-Diisopropylethylamine (18 mL, 103.3 mmol) was added dropwise, over 15 minutes, to the heterogeneous mixture of Y-Boc-L-proline (7.139 g, 33.17 mmol), HATU (13.324 g, 35.04 mmol), HCl 2- salt amino-1- (4-bromophenyl) ethanone (8.127 g, 32.44 mmol), and DMF (105 mL), and stirred at ambient conditions 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. The residue gave a silica gel mesh and was subjected to flash chromatography (silica gel; 50-60% ethyl acetate / hexanes) to provide ketoamide 1a as a white solid (12.8 g). 'H NMR (DMSO-dó, δ = 2.5 ppm,

400 MHz): δ 8.25-8.14 (m, ΙΗ), 7.92 (br d, J = 8.0, 2H), 7.75 (br d, J = 8.6, 2H), 4.61 (dd, 7 =

18.3, 5.7, 1H), 4.53 (dd, 7 = 18.1, 5.6, 1H), 4.22-4.12 (m, 1H), 3.43-3.35 (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 (Condition 1): RT = 1.70 min; LC / MS: Anal. Calc. for [M + Naf C ^ Br ^ NaO ^ 433.07; found 433.09.

Analogous compounds such as intermediate 1a-1-5a can be obtained by introducing the appropriately substituted amino acid and aryl bromide isomer.

<img file="PL2049522T3_D0089.tif" />

1 H NMR (500 MHz, DMSO-d₆) δ ppm 1.35 / 1.40 (twobr 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), 4.62-4.73 (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 in 4 minutes, 1 minute stop 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. Calc. for Ci8H₂iBrF₂N₂O4: 446.06; found:

445.43 (Μ-H) '.

<img file="PL2049522T3_D0090.tif" />

* H NMR (500 MHz, DMSO-d₆) δ ppm (8.25 IH, 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 a 4 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. Calc. for Ci8H₂₃BrN₂O5 427.30; found 428.08 (M + Hf.

<img file="PL2049522T3_D0091.tif" />

1 H 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,

O to 100% Β over a 4 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. Calc. for Ci8H₂₃BrN₂O5 427.30; found 428.16 (M + H)⁺.

<img file="PL2049522T3_D0092.tif" />

1 H NMR (500 MHz, DMSO-d₆) δ ppm 1.29-1.47 (m, 9H), 1.67-1.90 (m, 3H), 2.00-2.20 (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="PL2049522T3_D0093.tif" />

LCMS conditions: Phenomenex LUNA C-18 4.6 x 50 mm, 0 to 100% B in 2 minutes, 1 minute stop 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. Calc. for Ci9Hi8BrN₂O4 418.05; found: 419.07 (M + H)⁺.

<img file="PL2049522T3_D0094.tif" />

A mixture of ketoamide Ia (12.8 g, 31.12 mmol) and NH₄OAc (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 carefully partitioned between ethyl acetate and water, with sufficiently saturated NaHCO solution added.₃ in such a way as to make the pH of the aqueous phase slightly alkaline after shaking in a two-phase system. The layers were separated, and the aqueous layer was extracted with additional ethyl acetate. The combined organic phases were 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 1b as a light yellow thick solid, weighing 5.85 g. The mother liquor was concentrated in vacuo and subjected to flash chromatography (silica gel; 30% ethyl acetate / hexanes) to provide additional 2.23 g imidazole lb. '' NMR (DMSO-d₆, 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 (Condition 1): RT = 1.71 min; &gt; 98% homogeneity index; LC / MS: Anal. Calc. for [M + H]⁺Ci8H23BrN3O2: 392.10; found 391.96; HRMS: Anal. Calc. for [M + H]⁺ Ci8H23BrN3O2: 392.0974; found 392.0959

The optical purity of both lb samples was estimated using the chiral HPLC conditions indicated below (ee&gt; 99% for combined views; ee = 96.7% for sample from flash column):

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 (/?), 5.34 minutes (S)

Analogous compounds such as intermediates 1-1b to 1-4b can be obtained by introducing the corresponding ketoamide.

<img file="PL2049522T3_D0095.tif" />

1 H NMR (500 MHz, DMSO-d₆) δ ppm 1.17 / 1.40 (two br s, 9H), 2.50-2.74 (m, 7 = 25.64 Hz, 1H), 2.84-3.07 (m, 1H), 3.88 (d, 7 = 10.07 Hz, 2H), 5.03 (s, 1H), 7.50 (d, 7 = 8.55 Hz, 2H), 7.60 (s, 1H), 7.70 (d, 7 = 8.55 Hz, 2H), 12.10 (s, 1H). HPLC XTERRA C-18 4.6 x 30 mm, 0 to 100% B in 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. Calc. for you₈H2oBrF2N302: 428.27; found: 428.02 (M)⁺.

<img file="PL2049522T3_D0096.tif" />

* H NMR (500 MHz, DMSO-d₆) δ ppm 11.89-11.99 (1H, m), 7.68 (2H, d, 7 = 8.54 Hz), 7.527.59 (1H, m), 7.48 (2H, d, 7 = 8.54 Hz), 4.80 (1H, m ), 4.33 (1H, s), 3.51-3.60 (1H, m), 3.34 (1H, d, 7 = 10.99 Hz), 2.14 (1H, s), 1.97-2.05 (1H, m), 1.37 (3H, s), 1.10 (6H, s); LCMS Phenomenex C-18 3.0 x 50mm, 0 to 100% B over a 4 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. Calc. for you₈H22BrN₃ABOUT₃ 408.30; found 409.12 (M + H)⁺.

<img file="PL2049522T3_D0097.tif" />

1 H NMR (500 MHz, DMSO-d₆) δ ppm 12.06-12.24 (1H, m), 7.58-7.69 (5H, m), 4.84-4.95 (1H, m), 4.34 (1H, s), 3.61 (1H, s), 3.34-3.40 ( 1H, m), 2.52 (1H, s), 1.92-2.20 (1H, m), 1.43 (3H, s), 1.22 (6H, s); LCMS - Phenomenex C-18 3.0 x 50mm, 0 to 100% B in 4 minutes gradient, 1 minute stop time, A = 10% methanol 90% water 0.1% TFA, B = 90% methanol 10% water 0.1% TFA, (RT = 3.41 min) Anal. Calc. for C108 BrNaCb 408.30; found 409.15 (M + H)⁺.

<img file="PL2049522T3_D0098.tif" />

Boc 1-4b 'H NMR (500 MHz, DMSO-d₆) δ ppm 0.98-1.51 (m, 9H), 1.82-2.12 (m, 3H), 2.31-2.48 (m, 1H), 3.30-3.51 (m, 1H), 3.52-3.66 (m, 1H), 4.88- 5.16 (m, 1H), 7.47 (t, 7 = 7.93 Hz, 1H), 7.61 (d, 7 = 7.93 Hz, 1H), 7.81 (d, 7 = 7.93 Hz, 1H), 8.04 (s, 1H), 8.12 (d, 7 = 28.38 Hz, 1H), 14.65 (s, 1H). LC / MS (M + H)⁺= 391.96/393.96.

Additional imidazole analogs are prepared according to procedures similar to those described above.

LC conditions: Condition 1; Phenomenex LUNA C-18 4.6 x 50 mm, 0 to 100% B in 3 minutes, 1 minute stop 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 in 2 minutes, 1 minute stop 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>I-5b</td><td>about</td><td>RT = 1.70 minutes (condition 2, 98%); LRMS: Anal. Calc. for C ^ HisBrNaOa 399.05; found: 400.08 (M + H)⁺.</td>

<td>l-6b</td><td>"Ϊ́γ. HN -! ( Fi ABOUT</td><td>RT = 1.64 minutes (condition 2, 98%); LRMS: Anal. Calc. for you₇H₂₂N₃ABOUT₂379.09; found: 380.06 (M + H)⁺.</td>

<td>l-7b</td><td>AND "ΎΤ" °^Ύ°</td><td>RT = 2.28 minutes (95%); LRMS: Anal. Calc. for C.₂oH2iBrN₃0₂414.08; found: 414.08 (M + H)⁺; HRMS: Anal. Calc. for C.₂₀H₂iBrN₃O2 414.0817; found: 414.0798 (M + H)⁺.</td>

Example 1, Step c

<img file="PL2049522T3_D0099.tif" />

Pd (Ph₃Q)₄ (469 mg, 0.406 mmol) was added to a pressure tube containing a mixture of lb bromide (4.008 g, 10.22 mmol), bis (pinacolano) diborane (5.422 g, 21.35 mmol), potassium acetate (2.573g, 26.21 mmol) and 1.4- dioxane (80 mL). The reaction flask was flushed with nitrogen, sealed and heated in an oil bath at 80 ° C for 16.5 hours. The reaction mixture was filtered and the filtrate concentrated in vacuo. The crude material was carefully partitioned between CH2Cl2 (150 mL) and aqueous medium (50 mL water +10 mL saturated NaHCO3 solution). The aqueous layer was extracted with CH 2 Cl 2, and the combined organic phases were dried (MgSO₄), filtered and concentrated in vacuo. The resulting material was purified by flash chromatography (sample applied with elution solvent; 2035% ethyl acetate / CH 2 Cl) to provide lc boronate, contaminated with pinacol as an off-white thick solid; the relative molar ratio of lc to pinacol was about 10: 1 (¹1 H NMR). The sample weighed 3.925 g after -2.5 days of exposure to high vacuum. * H NMR (DMSO-d6, δ = 2.5 ppm, 400 MHz): 12.22 / 11.94 / 11.87 (m, 1H), 7.79-7.50 / 7.34- 7.27 (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 (Condition 1): RT = 1.64 min; LC / MS: Anal. Calc. for [M + H]⁺ C24h₃₅BN₃ABOUT₄: 440.27; found 440.23.

Analogous compounds such as intermediates 1-lc to 1-4c can be obtained by introducing the corresponding aryl bromide.

<img file="PL2049522T3_D0100.tif" />

1 H NMR (500 MHz, DMSO-d₆) δ ppm 1.16 (s, 8H), 1.29 (s, 13H), 2.51-2.72 (m, 1H), 2.843.03 (m, 1H), 3.79-4.00 (m, 2H), 4.88-5.21 (m, 1H), 7.62 (d, 7 = 7.93 Hz, 2H), 7.67 (s, 1H),

7.76 (d, 7 = 7.93 Hz, 2H), 12.11 / 12.40 (two br s, 1H). HPLC GEMINI C-18 4.6 x 50 mm, 0 to 100% B in 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. Obi. for C34H32BF2N3O4: 475.34; found: 474.78 (MH) -.

<img file="PL2049522T3_D0101.tif" />

* H NMR (500 MHz, DMSO-d₆) δ ppm 11.97 (1H, m), 7.62-7.75 (5H, m), 5.05 (IH d, 7 = 3.36 Hz), 4.82 (m, 1H), 4.35 (m, 1H), 3.58 (1H, m) , 2.389 (1H, s), 2.17 (1H, 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 a 4 minute gradient, 1 minute stop time, A = 5% acetonitrile, 95% water, 10mm Ammonium acetate, B = 95% acetonitrile, 5% water, 10mm Ammonium acetate, RT = 3.63 minutes, Anal. Obi. for C24H34BN3O5 455.30; found 456.31 (M + H)⁺.

<img file="PL2049522T3_D0102.tif" />

* H NMR (500 MHz, DMSO-d₆) δ ppm 12.05-12.24 (1H, m), 7.61-7.73 (5H, m), 4.83-5.01 (1H, m), 4.33 (1H, s), 3.54-3.63 (1H, m), 3.39-3.80 ( 1H, m), 2.38-2.49 (1H, m), 1.98-2.01 (1H, 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 in 4 minutes gradient, 1 minute stop time, A = 10% methanol 90% water 0.1% TFA, B = 90% methanol 10% water 0.1% TFA, RT = 3.64 minutes, Anal. Obi. for C24H34BN3O5 455.30; found 456.30 (M + H)⁺.

<img file="PL2049522T3_D0103.tif" />

* H NMR (500 MHz, DMSO-d₆) δ ppm 1.02-1.54 (m, 21H), 1.75-2.07 (m, 3H), 2.09- 2.33 (m, 1H), 3.32-3.44 (m, 1H), 3.55 (s, 1H), 4.69- 4.94 (m, 1H), 7.33 (t, 7 = 7.32 Hz, 1H), 7.41-7.57 (m, 2H), 7.84 (d, 7 = 7.32 Hz, 1H), 8.08 (s, 1H), 11.62-12.07 (m, 1H). LC / MS (M + H)⁺ = 440.32.

Additional boron esters: Conditions for 1-5C to 1-1 Oc

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

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

<td>l-5c</td><td>AA</td><td>RT = 1.84 minutes (condition 2); LCMS: Anal. Calc. for C.₂7H₃₂BN₃ABOUT₄ 473; found: 474 (M + H)⁺.</td>

<td>l-6c</td><td>AND X 3-nh V ABOUT</td><td>RT = 1.84 minutes (condition 2); LCMS: Anal. Calc. for C.₂₂H₃₂BN₃ABOUT₄ 413; found: 414 (M + H)⁺.</td>

<td>l-7c</td><td>AND? AND ° γΤ. V</td><td>RT = 1.85 minutes (condition 2); LRMS: Anal. Calc. for C.₂₅H3iBN₃C4 448; found: 448 (M + H)⁺.</td>

<td>l-8c</td><td>Y? AND ° '^ΒγΑ η Y</td><td>RT = 2.49 (76%, boronic ester) and 1.81 (21.4%, boronic acid); LCMS: Anal. Calc. for C.₂₃H3₅N3O₄B 428.27; found: 428.27 (M + H)⁺; HRMS: Anal. Calc. for C.₂3H35N₃ABOUT₄B 428.2721; found: 428.2716 (M + H)⁺.</td>

<td>l-9c</td><td> °'^BY \ HV</td><td>RT = 2.54 (74.2%, boronic ester) and 1.93 (25.8%, boronic acid); LRMS: Anal. Calc. for C26H33N3O4B 462.26; found: 462.25 (M + H)⁺; HRMS: Anal. Calc. for C.₂₆H₃3N₃ABOUT₄B 462.2564; found: 462.2570 (M + H)⁺.</td>

<td>IOC-1</td><td>X 9 YR)</td><td>RT = 1.91 (64.5%, boronic ester) and 1.02 (33.8%, boronic acid); LRMS: Anal. Calc. for C.₂6H32N₄O3¹⁰B 458.26; found: 458.28 (M + H)⁺; HRMS: Anal. Calc. for 0₂6Η3₂Ν₄0₃^1θΒ 458.2604; found: 458.2617 (M + H)⁺.</td>

Example 1, Step d (2S, 2'S) -2,2 '- (4,4'-biphenyldiylbis (1H-imidazol-5,2-diyl)) di-tert-butyl di (pyrrolidinecarboxylate)

<img file="PL2049522T3_D0104.tif" />

Pd (Płi3P) 4 (59.9 mg, 0.0518 mmol) was added to the mixture of lb bromide (576.1 mg, 1.469 mmol), lc boronate (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 purged with nitrogen, heated in 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 / CHCl3 (60 mL) and water (30 mL), and the aqueous phase extracted with 20% methanol / CHCl3 (30 mL). The combined organic phases were washed with brine, dried (MgSO4), filtered and concentrated in vacuo. Silica gel mesh was obtained from the obtained crude material and subjected to flash chromatography (ethyl acetate) to give an Id dimer, contaminated with PI13PO, as an off-white solid (563 mg). 1 H NMR (DMSO-d₆, δ = 2.5 ppm, 400 MHz): δ 12.21-12- 16 / 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),

1.46-1.10 (m, 18H). LC (Condition 1b): RT = 1.77 min; LC / MS: Anal. Calc. for [M + H]⁺C36H45BN6O4: 625.35; found 625.48.

Additional symmetrical analogues can be obtained in a similar manner.

<img file="PL2049522T3_D0105.tif" />

L-LD

Example 1-ld was prepared using intermediates l-2c and l-2b. * H NMR (500 MHz, DMSOd₆) δ ppm 11.94-12.22 (2H, m) 7.53-7.82 (10H, m) 4.82-4.92 (2H, m) 4.34-4.43 (2H, m) 3.55-3.64 (2H, m) 3.36 ( 2 H, d, 7 = 1 1.29 Hz) 2.12-2.22 (2 H, m) 2.02-2.11 (2 H, m) 1.40 (6 H, s) 1.14 (12 H, s); LCMS - Phenomenex C-18 3.0 x 50mm, 0 to 100% B in 4 minutes gradient, 1 minute stop time, A = 10% methanol 90% water 0.1%

TFA, Β = 90% methanol 10% water 0.1% TFA, RT = 3.32min, Anal. Calc. for 656.79; found 657.40 (M + H)⁺. Nominal / LRMS - (M + H)⁺657.42, (MH) '-655.28.

<img file="PL2049522T3_D0106.tif" />

l-2d

Example 1-2 was prepared using intermediates 1-3b and 1-3c. 1 H NMR (500 MHz, DMSO-d₆) δ ppm 12.00-12.20 (2H, m) 7.56-7.76 (10H, m) 4.90 (1H, s) 4.82 (1H, 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 a 4 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. Calc. for 656.79; found 657.30 (M + H)⁺.

<img file="PL2049522T3_D0107.tif" />

(2S) -2- (4-3 '- (2 - ((2S) -1- (tert-butoxycarbonyl) -2-pyrrolidinyl) -1H-imidazol-5-yl) -3-biphenyl) -1H-imidazol-2 tert-butyl pyrrolidine carboxylate

Example 1-2d-1 was prepared using intermediates 1-4c and 1-4b. * H NMR (500 MHz, DMSO-d_about) δ ppm 1.09-1.51 (m, 18H), 1.84-2.15 (m, 6H), 2.34-2.50 (m, 2H), 3.35-3.52 (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.

<img file="PL2049522T3_D0108.tif" />

Diol 1-ld (0.15g, 0.23mmol) was added as a solid to a solution of bis (2-methoxyethyl) aminosulfur trifluoride (0.1 mL, 0.51mmol) in 1.0 mL CH2Cl2 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 once with CH₂C1₂. Combined organic phases

100 washed with brine, dried (MgSCL), filtered and concentrated to give a yellow oil. The oil was triturated with CH2Cl2 and pentane to give the desired product as a beige solid (0.092g, 61%). * H NMR (500 MHz, DMSO-d₆) δ ppm 11.76-11.94 (2H, m), 7.77 - 7.85 (4H, m), 7.66 - 7.72 (4H, m), 7.60 - 7.66 (2H, m, 7 = 1 1.60 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 (10H, s), 1.24 (8H, s). LCMS - Phenomenex C-18 3.0 x 50mm, 0 to 100% B in 4 minutes gradient, 1 minute stop time, A = 10% methanol 90% water 0.1% TFA, B = 90% methanol 10% water 0.1% TFA, (tR = 3.58 min) Anal. Calc. for C36H42F2N6O4 660.70; found 661.68 (M + H)⁺.

F.

<img file="PL2049522T3_D0109.tif" />

l-2d-3

Obtained from 1-lb and 1-lc in the same manner as obtaining ld from lb and lc. * H NMR (500 MHz, DMSO-d₆) δ ppm 1.18 / 1.40 (two br. pp., 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 p, 2H), 7.17 - 8.24 (m, 10H), 12.07 / 12.37 (two br. p. 2H); HPLC XTERRA C-18 3.0 x 50 mm, 0 to 100% B in 2 minutes, 1 minute stop 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. Calc. for C36H40F4N6O4: 696.73; found: 967.64 (M + H)⁺.

Unsymmetrical compounds such as intermediate 1 -3d and 1-4d can be obtained by the same method. For example, reacting 1-lc with 1b in the same manner as described above for the production of 1d provided 1-3d. Similarly, the reaction of 1-4c with 1b in the same manner as described above for the production of 1d provided 1-4d.

<img file="PL2049522T3_D0110.tif" />

1 H NMR (500 MHz, DMSO-d₆) δ ppm 1.40 / 1.18 (two br s, 18H), 1.90-2.02 (m, 2H), 2.022.12 (m, 1H), 2.28-2.46 (m, 2H), 2.68-2.87 (m, 1H), 3.35-3.49 (m, 1H), 3.53-3.62 (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 in 4 minutes, 1 minute stop 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. Calc. for C36H42F2N6O4: 660.75; found: 661.98 (M + H)⁺.

101

<img file="PL2049522T3_D0111.tif" />

at

I-4d

Example 1-4d was prepared from 1-4c and 1b in a similar manner to the production of 1d from 1b and 1c. * H 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 H) 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% H2O, 0 to 100% B within 2 min , Stop time = 3min, Flow rate = 4ml / min, Wavelength = 220nm, LC / MS (M + H)⁺ = 625.32. Retention time = 1.438 min

Additional biphenyl analogues were prepared similarly.

LC conditions for Examples 1-5d to 1-7d: Condition 1: Phenomenex LUNA C-18 4.6 x 50 mm, 0 to 100% B in 3 minutes, 1 minute retention 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 in 2 minutes, 1 minute stop 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>Union Name</td><td>Structure</td><td>Data characterizing</td>

<td>l-5d</td><td> (4,4'-</td><td rowspan="2">\ V "il A Ά A. _H γ</td><td>RT = 1.64 minutes</td>

<td></td><td>biphenyldiylbis (1H-</td><td>(&gt; 95%); Condition 2</td>

<td></td><td>imidazol-5,2-diyl (1S) -</td><td>N&gt;</td><td>LCMS: Anal. Obi.</td>

<td></td><td>1,1-ethanediyl)) di-tert-butyl bis (methylocarbamate)</td><td>Obtained from 1-8c and 1-6b</td><td>for C34H45N0O4 601.35; found: 601.48 (M + H)⁺; LRMS: Anal. Obi. for C34H44N0O4 600.34; found: 601.32 (M + H)⁺.</td>

102

<td>l-6d</td><td>(2S) -2- (5- (4 '- (2 - ((1S) -1 ((tert-butoxycarbonyl) (methyl) amino) ethyl) -1Himidazol-5-yl) -4-biphenyl) -1H-imidazol2- yl) -lpirolidynkarboksylan tert-butyl</td><td>Obtained from</td><td>β Y Η Y Λαό '' -M W-— ' l-8ci lb</td><td>RT = 1.63 minutes (&gt; 95%); Condition 2; LCMS: Anal. Calc. for C.₃5H₄5N6O4 613.34; found: 613.56 (M + H)⁺; LRMS: Anal. Calc. for C.₃5H₄₄N6O₄612.34; found: 613.33 (M + H)⁺.</td>

<td>l-7d</td><td>(2S) -2- (5- (4 '- (2 - ((lS) -l ((tert</td><td rowspan="2">Χ'ϊ N</td><td></td><td>RT = 1.65 minutes (&gt; 95%); Condition 2;</td>

<td></td><td>butoxycarbonyl) (methyl</td><td>and</td><td>LCMS: Anal. Calc.</td>

<td></td><td>o) amino) ethyl) -1 Himidazol-5-yl) -4-biphenylyl) -1H-imidazol-2-yl) -1-</td><td></td><td>Q "°^Y° Mo • -N W-—</td><td>for 0₃₈Η₄₃Ν6θ₄647.33; found: 647.44 (M + H)⁺; LRMS: Anal. Calc.</td>

<td></td><td>pirolidynkarboksylan benzyl</td><td colspan="2">Obtained from l-6b and l-5c</td><td>for C.₃₈H₄2N6O₄646.33; found: 647.34 (M + H)⁺.</td>

Example 1, Step e

5.5 '- (4,4'-biphenyldiyl) bis (2 - ((2S) -2-pyrrolidinyl) -1H-imidazole)

<img file="PL2049522T3_D0112.tif" />

A mixture of ld carbamate (560 mg) and 25% TFA / CH 2 Cl 2 (9.0 mL) was stirred at ambient conditions for 3.2 hours. The volatile component was removed in vacuo, and the resulting material was converted into the free base using an MCX column (methanol washing; 2.0 M NH elution₃/ methanol) to provide pyrrolidine as a dull yellow solid (340 mg). ^l1 H NMR (DMSO-d₆, δ = 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 (app t, 7 = 7.2, 2H), 2.99-2.69 (m, 6H), 2.09-2.00 (m, 2H), 1.94-1.66 (m, 6H). LC (Condition 1): RT = 1.27 min; &gt; 98% homogeneity index; LC / MS: Anal. Calc. for [M + H]⁺ C26H29N6: 425.25; found 425.25; HRMS: Anal. Calc. for [M + H]⁺ C26H29N6: 425.2454; found 425.2448

Additional analogues such as 1- to 1-4e can be obtained in a similar manner.

103

<img file="PL2049522T3_D0113.tif" />

• 4 HCl

1-le

To a solution of 1-ld (3R, 3'R, 5S, 5'S) -5,5 '- (5,5' - (biphenyl-4,4'-diyl) bis (1H-imidazol-5,2-diyl)) bis Tert-butyl (3-hydroxypyrrolidine-1-carboxylate) in 3mL dioxane, 0.8mL solution of 4.0 M HCl in dioxane was added. The reaction was stirred for 2 hours at room temperature and concentrated under reduced pressure. The resulting beige solid was dried under reduced pressure to give 1-le (3R, 3'R, 5S, 5'S) -5,5 '(5.5' - (biphenyl-4,4'-diyl) bis (1H-imidazole tetrachlorohydrochloride) -5.2-diyl)) dipyrrolidin-3-ol (0.55g, 100% yield). Used without further purification. * H NMR (500 MHz, DMSO-dć) 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, 7 = 1 1.29 Hz, 2H), 2.64 (m, 2H), 2.44 (dd, J = 13.43,

6.71 Hz, 2H); LCMS - Waters-Sunfire C-18 4.6 x 50mm, 0 to 100% B in 4 minutes 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. Calc. for 456.30; found 457.25 (M + H)⁺; Nominal / LRMS - (M + H)⁺457.35.

<img file="PL2049522T3_D0114.tif" />

l-2e

Example 1-2e was prepared in a similar manner to the method described for the preparation of 1-le. 1 H NMR (500 MHz, DMSO-d₆) δ ppm 10.32 (1 H, s) 8.01 (2 H, s) 7.97 (4 H, d, 7 = 8.24 Hz) 7.86 (4 H, d, 7 = 8.24 Hz) 5.01-5.10 (2 H, m) 4.52-4.60 (2H, m) 3.36-3.45 (2H, m) 3.25 (2H, s) 2.60-2.68 (2H, m) 2.40-2.48 (2H, m); LCMS - Phenomenex C-18 3.0 x 50mm, 0 to 100% B in 4 minutes gradient, 1 minute stop time, A = 10% methanol 90% water 0.1% TFA, B = 90% methanol 10% water 0.1% TFA, RT = 2. 10 min., Anal. Calc. for 456.30; found 457.22 (M + H)⁺

104

<img file="PL2049522T3_D0115.tif" />

! 2E-l

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

Example 1-2e-1 was prepared from 1-2d-1 in a similar manner described for the preparation of 11le. 1 H NMR (500 MHz, DMSO-d₆) 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="PL2049522T3_D0116.tif" />

To a solution of l-2d-2 (0.084g, 0.13mmol) in 1mL dioxane was added 0.5 mL of a 4.0 M HCl solution in dioxane. The reaction was stirred for 2 hours at room temperature and concentrated under reduced pressure. The resulting beige solid was dried under reduced pressure to give 1-2e-2 (0.077g, 100% yield). The compound was used without further purification.^[H NMR (500 MHz, DMSO-dć) 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) , 2.81-2.87 (2H, m); LCMS - Phenomenex C-18 3.0 x 50mm, 0 to 100% B in 4 minutes gradient, 1 minute stop time, A = 10% methanol 90% water 0.1% TFA, B = 90% methanol 10% water 0.1% TFA, (tR = 2.22 min) Anal. Calc. for C26H26F2N6 460.53; found 461.37 (M + H)⁺.

'ΑΟΑΧϊ l-2e-3

Obtained from l-2d-3 in the same manner as the preparation of 1-le from 1-1 d. 'H NMR (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 in 4 minutes, 1 minute stop time, A = 90% water, 10% methanol, 0.2% H3PO4, B = 10% water, 90% methanol, 0.2 % H3PO4, RT = 1.66 min, 92%

105 homogeneity index. LCMS: Anal. Calc. for C26H24F4N6: 496.50; found: 495.53 (MH) '.

Analogous asymmetrical intermediates such as 1-3e and 1-4e can be obtained by the same method.

<img file="PL2049522T3_D0117.tif" />

1 H NMR (500 MHz, DMSO-d₆) δ ppm 1.87-2.09 (m, 1H), 2.13-2.26 (m, 1H), 2.37-2.47 (m, 2H), 2.92-3.12 (m, 2H), 3.37 (s, 1H), 3.40-3, 49 (m, 1H), 3.67-3.91 (m, 2H), 4.96-5.05 (m, 1H), 5.14 (t, 7 = 8.70 Hz, 1H), 7.86 (t, 7 = 9.00 Hz, 4H), 7.93 -8.03 (m, 5H), 8.10 (s, 1H), 10.26 / 9.75 (two br p., 2H); HPLC XTERRA C-18 3.0 x 50 mm, 0 to 100% B in 4 minutes, 1 minute stop 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. Calc. for C26H₂₆F₂N6: 460.52; found: 461.45 (M + H)⁺.

<img file="PL2049522T3_D0118.tif" />

4e-l

Example 1-4e was prepared from 1-4d in a similar manner to that described for the preparation of 1-11d. 'HNMR (500 MHz, DMSO-d₆) δ ppm 1.90-2.13 (m, 2H) 2.12 - 2.31 (m, 2H) 2.362.60 (m, 4H) 3.29 - 3.55 (m, 4H) 5.00 (s, 2H) 7.35-8.50 ( m, 10H) 9.76 (s, 2H) 10.12 10.45 (m, 2H). LC conditions: Phenomenex Luna 3.0 X 5.Omm S10, Solvent A - 0.1% TFA in 10% MeOH / 90% H₂O, Solvent B - 0.1% TFA in 90% MeOH / 10% H₂O, 0 to 100% B within 2 min, Stopping time = 3min, Flow rate = 4ml / min, Wavelength = 220nm, LC / MS (M + H)⁺ = 425.28. Retention time = 0.942 min

Additional analogues were prepared analogously:

<td>Example</td><td>Union Name</td><td colspan="2">Structure</td><td>Data</td>

<td>l-5e</td><td></td><td></td><td></td><td>RT = 1.37 min; LCMS:</td>

<td></td><td></td><td>NN^HH T h</td><td></td><td>Anal. Calc. for C2₅H₂8N₆</td>

<td></td><td></td><td></td><td>Η H.</td><td>412; found: 413</td>

<td></td><td></td><td></td><td></td><td>(M + H)⁺.</td>

<td></td><td></td><td>Obtained from</td><td>l-6d</td><td></td>

106

<td>l-6e</td><td></td><td>x^Nx Approx H ^H YH 1 hv Obtained from 1-7d</td><td>RT = 1.43 min; LCMS: Anal. Calc. for C33H35N6O2 547; found: 547 (M + H) Y</td>

<td>l-7e</td><td></td><td>^ΗΝνΛ a ^N</td><td>RT = 1.12 min; LRMS: Anal. Calc. for C.₂₄H2₈N₆</td>

<td></td><td></td><td></td><td>400.24; found:</td>

<td></td><td></td><td></td><td>401.22 (M + H)⁺.</td>

<td></td><td></td><td>/ NH</td><td></td>

<td></td><td></td><td>Obtained from 1 -5d</td><td></td>

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

Alternative Synthesis of Example 1, Step e 5.5^&gt;- (4,4'-biphenyl diyl) bis (2 - ((2S) -2-pyrrolidinyl) -1H-imidazole)

<img file="PL2049522T3_D0119.tif" />

<img file="PL2049522T3_D0120.tif" />

A 1.3-necked round-bottomed flask equipped with a nitrogen line, stirrer and thermocouple was charged with 20 g (83.9 mmol, 1 eq.) Of 1,1 '- (biphenyl-4,4'-diyl) diethanone, 200 mL CH2Cl2 and 8.7 mL (27.1g, 169.3 mmol, 2.02 equiv.) bromine. The mixture was allowed to stir under nitrogen for about 20 h at ambient conditions. 200 mL CH2Cl2 was added to the resulting suspension and concentrated to about 150 mL by vacuum distillation. The suspension was then exchanged for THF to a target volume of 200 mL by vacuum distillation. The suspension was cooled to 20-25 ° C over 1 h and allowed to stir at 20-25 ° C for an additional hour. Whitish crystalline

107 solids were filtered and washed with 150 mL CH2Cl2. The product was dried under reduced pressure at 60 ° C to provide 27.4 g (69.2 mmol, 82%) of the desired product: 1 H NMR (400 MHz, CDCl 1₃) δ 7.95-7.85 (m, 4H), 7.60-7.50 (m, 4H), 4.26 (s, 4H); ^l3C NMR (100 MHz, CDCb) δ 191.0, 145.1, 133.8, 129.9, 127.9, 30.8; IR (KBr, cm-1) 3007, 2950, ​​1691, 1599, 1199; Anal. Calc. for you₆H₂br₂O2: C, 48.52; H, 3.05; Br, 40.34. Found: C, 48.53; H, 3.03; Br, 40.53. HRMS calculated for you₆H₁₂br₂ABOUT₂ (Μ + H; DCI⁺): 394.9282. Found: 394.9292. mp 224-226 ° C.

Example A-le-2

<img file="PL2049522T3_D0121.tif" />

500 A ml flask with a jacket, equipped with a nitrogen line, thermocouple and stirrer, was filled with 20 g (50.5 mmol, 1 equiv.) of Example A-le-1, 22.8 g (105.9 mol, 2.10 equiv.) 1- (tert-butoxycarbonyl) - L-proline, and 200 mL acetonitrile. The suspension was cooled to 20 ° C and then 18.2 mL (13.5 g, 104.4 mmol, 2.07 equiv.) DIPEA was added. The suspension was heated 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 acetonitrile-rich solution was exchanged for toluene (target volume = 215 mL) by vacuum distillation until less than 0.5 vol% acetonitrile remained.

<img file="PL2049522T3_D0122.tif" />

To the above toluene solution of Example A-le-2, 78 g (1.011 mol, 20 equiv.) Ammonium acetate was added and heated to 95-100 ° C. The mixture was allowed to stir at 95-100 ° C for 15h. After completion of the reaction, the mixture was cooled to 70-80 ° C and 7 mL of acetic acid, 40 mL of n-butanol, and 80 mL of 5% vol. Were added. aqueous acetic acid. The resulting biphasic solution was partitioned keeping the temperature&gt; 50 ° C. 80 mL 5% vol. Was added to the rich organic phase. aqueous acetic acid, 30 mL acetic acid and 20 mL n-butanol while maintaining the temperature&gt; 50 ° C. The resulting three-phase solution was divided keeping the temperature&gt; 50 ° C and the rich organic phase was washed with an additional 80 mL of 5% vol. aqueous acetic acid. In the rich organic phase, the solvent was then exchanged for toluene to a target volume of 215 mL with

108 vacuum distillation. While maintaining the temperature&gt; 60 ° C, 64 mL MeOH was added. The resulting suspension was heated to 70-75 ° C and aged for 1h. The suspension was cooled to 20-25 ° C over 1 h and aged at this temperature for an additional hour. The suspension was filtered and the dough was washed with 200 mL 10: 3 toluene: MeOH. The product was dried under reduced pressure at 70 ° C, giving 19.8 g (31.7 mmol, 63%) of the desired product: * H NMR (400 MHz, DMSO-dó) 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); ^l3C NMR (100 MHz, DMSO-d₆) 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 calculated for C36H45N6O4 (M + H; ESI⁺): 625.3502. Found: 625.3502. mp 190-195 ° C (decomposition).

Example A-le-4

<img file="PL2049522T3_D0123.tif" />

To a 250 mL reactor equipped with a nitrogen line and an external stirrer, 25.0 g of Example A-le-3 (40.01 mmol, 1 equiv) and 250 mL of methanol and 32.85 mL (400.1 mmol, 10 equiv) of 6M aqueous hydrogen chloride were added. The temperature was increased to 50 ° C and stirred at 50 ° C for 5h. The resulting suspension was cooled to 20-25 ° C and kept under stirring for about 18h. Filtration of the suspension gave a solid which was washed successively with 100 mL 90% methanol / water (WV) and 2x100 mL 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 external stirrer, 17.8g of raw Example A-le-4 was added followed by 72 mL of methanol. The resulting suspension was stirred at 50 ° C for 4h, cooled to 20-25 ° C and kept under stirring at 20-25 ° C for 1h. Filtration of the suspension gave 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 give 14.7 g (25.7 mmol, 82.6%) of the desired product: 1 H NMR (400 MHz, DMSO-dó) 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), 2.6-2.3 (m, 4H), 2.25-2.15 (m, 2H), 2.18-1.96 (m, 2H); ^I3C 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, cm '¹) 3429, 2627, 1636, 1567, 1493, 1428, 1028. Anal. Obi. for C26H32N6Cl4: C, 54.75; H, 5.65; Cl, 24.86; Corrected 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 (decomposition)

109

<img file="PL2049522T3_D0124.tif" />

Example 1 (IR, 1 'R) -2.2' - (4,4'-biphenyl diylbis (1H-imidazol-5,2-diyyl (2S) -2, 1-pyrrolidinyl)) bis (N, N-dimethyl-2 -oxo-l-fenyłoetanamina)

HATU (44.6 mg, 0.1 17 mmol) was added to a mixture of pyrrolidine le (22.9 mg, 0.054 mmol), diisopropylethylamine (45 pL, 0.259 mmol) and CapA (28.1 mg, 0.13 mmol) in DMF (1.5 mL), and the resulting mixture was stirred at ambient temperature for 90 minutes. The volatile component was removed in vacuo, and the residue was purified first by MCX (methanol washing; 2.0 M elution with NHfmethanol) and then by reverse phase HPLC (H2O / methanol / TFA) to provide Example 1 TFA salt as off-white foam (44.1 mg). * H 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 from NH imidazole was too wide to give a chemical shift]; LC (Condition 1): RT = 1.40 min; &gt; 98% homogeneity index; LC / MS: Anal. Calc. for [M + H]⁺ C₄₆H₅| N₈O2: 747.41; found 747.58

<img file="PL2049522T3_D0125.tif" />

Examples 2 to 24-4h were obtained as TFA salts by taking the appropriate acids instead of CapA using the same methods described for Example 1. Cap in the following table with no number are commercially available.

<td>Example</td><td>Relationship Name</td><td>0 AND</td><td>RT (LC condition); % homogeneity index; MS data</td>

<td> 2</td><td>(1R, 1'R) -2.2 '- (4,4'-biphenyldiylbis (1H-imidazol-5,2-diyl (2S) -2, 1-pyrrolidinyl)) bis (2-oxo-1 phenylethanol)</td><td> 0 ^pay HO</td><td>1.55 minutes (Condition 1); &gt; 98%; LC / MS: Anal. Calc. for [M + H]⁺C₄2H₄iN₆ABOUT₄: 693.32; found 693.46; HRMS: Anal. Calc. for [M + H]⁺ C42H41N6O4: 693.3189; found 693.3182</td>

110

<td> 3</td><td>(2S, 2'S) -1,1 '- (4,4'-biphenyldiylbis (1H-imidazol-5,2-diyl (2S) -2, 1-pyrrolidinyl)) bis (1-oxo-2-phenyl-2-propanol)</td><td>^pnAND? &lt;OH</td><td>1.77 minutes (Condition 1); &gt; 98%; LC / MS: Anal. Calc. for [M + H]⁺C₄₄H₄₅N₆ABOUT₄: 721.35; found 721.52; HRMS: Anal. Calc. for [M + H]⁺ C ^ H ^ NńO ^ t: 721.3502; found 721.3515</td>

<td> 4</td><td>(4,4'-biphenyldiylbis (1Himidazol-5,2-diyl (2S) -2, 1-pyrrolidinidiyl ((1R) -2-oxo-1 phenyl-2,1-ethanediyl)) biscarbamate dimethyl</td><td>0 Ά^hSy °^x0 Cap-4</td><td>1.64 minutes (Condition 1); &gt; 98%; LC / MS: Anal. Calc. for [M + H]⁺C₄₆H₄₇N₈ABOUT₆: 807.36; found 807.58</td>

<td> 5</td><td>(1S, 1'S) -2.2 '- (4,4'-biphenyldiylbis (1H-imidazol5,2-diyl (2S) -2, 1-pyrrolidinyl)) bis (N, N-dimethyl-2-oxo-1-phenylethanamine)</td><td>^phrS /^N\ Ent for Cap- \</td><td>1.33 minutes (Condition 1); &gt; 98%; LC / MS: Anal. Calc. for [M + H]⁺C₄₆H₅₁N₈ABOUT₂: 747.41; found 747.64; HRMS: Anal. Calc. for [M + H]⁺C₄₆H_5IN₈ABOUT₂: 747.4135; found 747.4103</td>

<td> 6</td><td>5.5 '- (4,4'-biphenyldiyl) bis (2 ((2S) -1-benzoyl-2-pyrrolidinyl) 1H-imidazole)</td><td>X</td><td>1.65 minutes (Condition 1); &gt; 98%; LC / MS: Anal. Calc. for [M + H]⁺C₄₀H₃₇N₆ABOUT₂: 633.30; found 633.51</td>

<td> 7</td><td>5.5 '- (4,4'-biphenyldiyl) bis (2 - ((2S) 1- (phenylacetyl) -2-pyrrolidinyl) 1H-imidazole)</td><td></td><td>1.71 minutes (Condition 1); &gt; 98%; LC / MS: Anal. Calc. for [M + H]⁺C₄₂H₄iN₆ABOUT₂: 661.33; found 661.53; HRMS: Anal. Calc. for [M + H]⁺ C₄₂H₄N₆ABOUT₂: 661.3291; found 661.3300</td>

111

<td> 8</td><td>5.5 '- (4,4'-biphenyldiyl) bis (2 - ((2S) 1 - ((2R) -2-methoxy-2-phenylacetyl) -2-pyrrolidinyl) 1H-imidazole)</td><td>0 C</td><td>1.63 minutes (Condition 1); &gt; 98%; LC / MS: Anal. Calc. for [M + H]⁺C₄4H45N₆ABOUT₄: 721.35; found 721.59; HRMS: Anal. Calc. for [M + H]⁺ C44H45N6O4: 721.3502; found 721.3536</td>

<td> 9</td><td>(2R, 2'R) -1,1 '- (4,4'-biphenyldiylbis (1H-imidazol5,2-diyl (2S) -2, 1-pyrrolidinyl)) bis (1-oxo-3-phenyl-2-propanol)</td><td>0 OH</td><td>1.71 minutes (Condition 1); &gt; 98%; LC / MS: Anal. Calc. for [M + H]⁺C44H45N₆ABOUT₄: 721.35; found 721.58; HRMS: Anal. Calc. for [M + H] C44H45N6O4: 721.3502; found 721.3497</td>

<td> 10</td><td>5.5 '- (4,4'-biphenyldiyl) bis (2 - ((2S) 1-propionyl-2-pyrrolidinyl) -1Himidazole)</td><td> 0</td><td>1.47 minutes (Condition 1); &gt; 98%; LC / MS: Anal. Calc. for [M + H]⁺C₃₂H₃₇N₆ABOUT₂: 537.30; found 537.40; HRMS: Anal. Calc. for [M + H]⁺ C₃₂H₃₇N₆ABOUT₂: 537.2978; found 537.2952</td>

<td> 11</td><td>5.5 '- (4,4'-biphenyldiyl) bis (2 - ((2S) 1- (cyclopropylcarbonyl) -2-pyrrolidinyl) -1H-imidazole)</td><td>Λ</td><td>1.48 minutes (Condition 1); &gt; 98%; LC / MS: Anal. Calc. for [M + H]⁺C₃₄H₃7N₆ABOUT₂: 561.30; found 561.44</td>

<td> 12</td><td>5.5 '- (4,4'-biphenyldiyl) bis (2 - ((2S) 1- (cyclopropylacetyl) -2-pyrrolidinyl) -1H-imidazole)</td><td>AA</td><td>1.57 minutes (Condition 1); &gt; 98%; LC / MS: Anal. Calc. for [M + H]⁺C₃₆H₄N₆ABOUT₂: 589.33; found 589.48; HRMS: Anal. Calc. for [M + H]⁺ C₃6H4iNóO₂: 589.3291; found</td>

112

<td></td><td></td><td></td><td> 589.3268</td>

<td> 13</td><td>5.5 '- (4,4'-biphenyldiyl) bis (2 - ((2S) 1 - ((2R) -tetrahydro-2-furanylcarbonyl) -2-pyrrolidinyl) -1H-imidazole)</td><td>X</td><td>1.44 minutes (Condition 1); &gt; 98%; LC / MS: Anal. Calc. for [M + H]⁺C36H41N6O4: 621.32; found 621.52; HRMS: Anal. Calc. for [M + H]⁺ C₃₆H₄iN6O₄: 621.3189; found 621.3191</td>

<td> 14</td><td>2,2 '- (4,4'-biphenyldiylbis (1Himidazol-5,2-diyl (2S) -2, 1-pyrrolidinyl)) bis (N, N-dimethyl-2-oxoethanamine)</td><td> 1 ⁰AND</td><td>1.27 minutes (Condition 1); &gt; 98%; LC / MS: Anal. Calc. for [M + H]⁺C34H43N8O2: 595.35; found 595.54; HRMS: Anal. Calc. for [M + H]⁺ C34H43N8O2: 595.3509; found 595.3503</td>

<td> 15</td><td>(2R, 2'R) -1,1 '- (4,4'-biphenyldiylbis (1H-imidazol5,2-diyl (2S) -2, 1-pyrrolidinyl)) bis (1-oxo-2-propanol)</td><td>0 00 OH</td><td>1.36 minutes (Condition 1); &gt; 98%; LC / MS: Anal. Calc. for [M + Hf C32H37N6O4: 569.29; found 569.44; HRMS: Anal. Calc. for [M + H]⁺ C32H37N6O4: 569.2876; found 569.2872</td>

<td> 16</td><td>(2R, 2'R) -1,1 '- (4,4'-biphenyldiylbis (1H-imidazol5,2-diyl (2S) -2, 1-pyrrolidinyl)) bis (3-methyl-1 oxo-2-butanol)</td><td>AA OH</td><td>1.51 minutes (Condition 1); &gt; 98%; LC / MS: Anal. Calc. for [M + H]⁺C36H45N6O4: 625.35; found 625.50; HRMS: Anal. Calc. for [M + Hf C36H₄₅N₆O4: 625.3502; found 625.3517</td>

113

<td> 17</td><td>5.5 '- (4,4'-biphenyldiyl) bis (2 - ((2S) 1 - ((2R) -2-phenyl-2- (1-pyrrolidinyl) acetyl) -2-pyrrolidinyl) -1H-imidazole)</td><td>0 Ά about Cap-5</td><td>1.13 minutes (Condition 1); &gt; 98%; LC / MS: Anal. Obi. for [M + H]⁺C₅oH₅5N₈0₂: 799.45; found 799.67</td>

<td> 18</td><td>4,4 '- (4,4'-biphenyldiylbis (1Himidazol-5,2-diyl (2S) -2, 1-pyrrolidinylated ((1R) -2-oxo-1 phenyl-2,1-ethanediyl)) dimorpholine</td><td>0 about Cap-6</td><td>1.11 minutes (Condition 1); &gt; 98%; LC / MS: Anal. Obi. for [M + Hf C₅₀H₅₅N₈0₄: 831.44; found 831.71</td>

<td> 19</td><td>5.5 '- (4,4'-biphenyldiyl) bis (2 - ((2S) 1 - (((3S) -3-fluoro-1-pyrrolidinyl) (phenyl) acetyl) -2-pyrrolidinyl) -1H-imidazole)</td><td>0 Ά Diastereoisomer 1 Cap-9a</td><td>1.17 minutes (Condition 1); 97%; LC / MS: Anal. Obi. for [M + H]⁺C5oH53F2N802: 835.43; found 835.51; HRMS: Anal. Obi. for [M + H]⁺ C50H₅₃F₂N₈ABOUT₂: 835.4260; found 835.4261</td>

<td> 20</td><td>5.5 '- (4,4'-biphenyldiyl) bis (2 - ((2S) 1 - (((3 S) -3-fluoro-1 pyrrolidinyl) (phenyl) acetyl) -2-pyrrolidinyl) -1H-imidazole )</td><td> 0 ^ρΆ Diastereoisomer 2- Cap-9a</td><td>1.03 minutes (Condition 1); &gt; 98%; LC / MS: Anal. Obi. for [M + H]⁺C50H53F2N8O2: 835.43; found 835.51; HRMS: Anal. Obi. for [M + H]⁺ C50H₅₃F₂N₈ABOUT₂: 835.4260; found 835.4266</td>

<td> 21</td><td>(1R, 1'R) -2,2 '- (4,4'-biphenyldiylbis (1H-imidazol5,2-diyl (2S) -2, 1-pyrrolidinyl)) bis (N, N-diethyl2-oxo-1-phenylethanamine )</td><td>0 Cap-2</td><td>1.13 minutes (Condition 1); &gt; 98%; LC / MS: Anal. Obi. for [M + H]⁺C50H59N8O2: 803.48; found 803.56; HRMS: Anal. Obi. for [M + H]⁺ C50H₅₉N₈ABOUT₂: 803.4761; found 803.4728</td>

114

<td> 22</td><td>(1R, 1'R) -2,2 '- (4,4'-biphenyldiylbis (1H-imidazol5,2-diyl (2S) -2, 1-pyrrolidinyl)) bis (N-ethyl-N-methyl-2-oxo-1-phenylethanamine )</td><td>0 Cap-3</td><td>1.10 minutes (Condition 1); &gt; 98%; LC / MS: Anal. Calc. for [M + H]⁺C48H55N8O2: 775.45; found 775.52; HRMS: Anal. Calc. for [M + H]⁺ C50H₅₉N₈ABOUT₂: 775.4448; found 775.4456</td>

<td> 23</td><td>N, N '- (4,4'-biphenyldiylbis (1Himidazol-5,2-diyl (2S) -2,1 pyrrolidinidyl ((1R) -2-oxo-1 phenyl-2,1-ethanediyl))) diformamide</td><td>ABOUT HVR 0 ABOUT</td><td>1.22 minutes (Condition 1); &gt; 98%; LC / MS: Anal. Calc. for [M + H]⁺C44H43N₈ABOUT₄: 747.34; found 747.38</td>

<td> 24</td><td>1,1 '- (4,4'-biphenyldiylbis (1Himidazol-5,2-diyl (2S) -2,1 pyrrolidinidylcarbonyl)) dicyclopropanol</td><td>OH</td><td>1.77 minutes (Condition 2); &gt; 98%; LC / MS: Anal. Calc. for [M + H]⁺C₃4H37N₆ABOUT₄: 593.29; found 593.16</td>

<td> 24-1</td><td>1,1 '- (4,4'-biphenyldiylbis (1Himidazol-5,2-diyl (2S) -2,1 pyrrolidinidyl ((1R) -2-oxo-1 phenyl-2,1-ethanediyl)) dipiperidine</td><td>0 ABOUT Cap-14</td><td>* H NMR (400 MHz, DMSO-d₆) 8 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), 6.876.85 (m, 2H), 5.51-5.48 (m, 0.5H), 5.01-4.98 (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), 2.141.82 (m, 8H), 1.47-1.31 (m, 12H); LCMS: Anal. Calc. for C.₅2H5₈N₈ABOUT₂: 826; found: 827 (M + H)⁺.</td>

115

<td> 24-2</td><td>1,1 '- (4,4'-biphenyldiylbis (1Himidazol-5,2-diyl (2S) -2, 1-pyrrolidinidiyl ((1R) -2-oxo-1 phenyl-2,1-ethanediyl))) bis ( 4-methyl-4-piperidine)</td><td>^phX 9^myh Cap-15</td><td>'HNMR (400 MHz, DMSO-d₆) 5 12.02 (brs, 1H), 11.82 (brs, 1H), 7.90-7.79 (m, 4H), 7.797.65 (m, 5H), 7.55 (br s, 2H), 7.45 (d, 7 = 7.6 Hz , 2H), 7.39-7.25 (m, 3H), 7.34 (d, 7 = 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), 4.313.96 (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), 1.351.20 (m, 5H), 1.09 (s, 2H), 1.05 (s, 4H); LCMS: Anal. Calc. for C.₅4H62N₈ABOUT₄: 886; found: 887 (M + H)⁺.</td>

<td> 24-3</td><td>(4,4'-biphenyldiylbis (1Himidazol-5,2-diyl (2S) -2,1 pyrrolidinidiyl ((1R) -1- (2-chlorophenyl) -2-oxo-2,1 ethanediyl))) dimethyl biscarbamate</td><td>NHCO₂Me</td><td>LCMS: Anal. Calc. for C₄6H44Cl2N₈ABOUT₆: 874; found: 875 (M + H)⁺.</td>

<td>24-4</td><td>N ', N "' - (4,4'-biphenyldiylbis (1Himidazol-4,2-diyl (2S) -2, 1-pyrrolidinidyl ((1R) -2-oxo-1 phenyl-2,1-ethanediyl)) bis (1,1-dimethyl urea)</td><td>NH N ° N-. / Cap-47</td><td>'HNMR (500 MHz, DMSO-d₆) δ ppm 1.892.00 (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), 2.79-284 (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 = 6.10Hz, 3H), 7.02-7.07 (m, 1H), 7.29-7.36 (m, 3H), 7.39 (t, 7 = 7.17 Hz, 4H), 7.46 (d, 7 = 7.02 Hz, 3H), 7.92</td>

116

<td></td><td></td><td></td><td>(s, 8H), 8.12 (s, 2H); HPLC XTERRA C-18 4.6 x30 mm, 0 to 100% B within 4 minutes, 1 minute stop 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. Calc. for C48H₅3N₁₀O4: 832.42; found: 833.43 (M + H)⁺; HRMS: Anal. Calc. for C48H₅3N o0₄833.4251; found: 833.4267 (M + H)⁺.</td>

<td>24-4b</td><td>N ', N "' - (4,4'-biphenyldiylbis (1Himidazol-5,2-diyl (2S) -2,1 pyrrolidinidyl ((1R) -2-oxo-1 phenyl-2,1-ethanediyl)) ) bis (1 methyl urea)</td><td>X o * n ΗΝΧ NH Cap-45</td><td>RT = 4.45 minutes (Gemini C-18 4.6 x 50mm, 0 to 100% B in 10 minutes gradient, 1 minute hold time, A = 5% acetonitrile, 95% water, 10mm Ammonium acetate, B = 95% acetonitrile, 5 % water, 10 mm Ammonium acetate); LCMS: Anal. Calc. for C.₄6H48N_l0O4 804.95; found: 805.41 (M + H)⁺; HRMS: Anal. Calc. for C46H48N10O4 805.3938; found: 805.3929 (M + H)⁺.</td>

117

<td>24-4c</td><td>N ', N "' - (4,4'-biphenyldiylbis (1H-</td><td rowspan="2">χΡ</td><td>RT = 4.20 minutes (Gemini</td>

<td></td><td>imidazol-5,2-diyl (2S) -2, l-</td><td>C-18 4.6 x 50mm, 0 to</td>

<td></td><td>pyrrolidinyl ((1 R) -2-oxo-1 -</td><td rowspan="2">o A o HNNH</td><td>100% B in 10</td>

<td></td><td>phenyl-2,1-ethanediyl))) bis (1 -</td><td>gradient minutes, 1</td>

<td></td><td>ethylurea)</td><td>( Cap-46</td><td>minute hold time, A = 5% acetonitrile, 95% water, 10mm ammonium acetate, B = 95% acetonitrile, 5% water, 10mm ammonium acetate); LCMS: Anal. Calc. for C.₄8H52N₁₀O4 833.00; found: 833.48 (M + H)⁺.</td>

<td>24-4d</td><td>N ', N "' - (4,4'-biphenyldiylbis (1H-</td><td></td><td>RT = 4.92 minutes (Gemini</td>

<td></td><td>imidazol-5,2-diyl (2S) -2, l-</td><td>AND</td><td>C-18 4.6 x 50mm, 0 to</td>

<td></td><td>pyrrolidinyl ((1 R) -2-oxo-1 -</td><td rowspan="2">NH AND Cap-48</td><td>100% B within 10 minutes</td>

<td></td><td>phenyl-2,1-ethanediyl))) bis (1 cyclopentylurea)</td><td>gradient, 1 minute stop time, A = 5% acetonitrile, 95% water, 10mm ammonium acetate, B = 95% acetonitrile, 5% water, 10mm acetate ammonium); LCMS: Anal. Calc. for C54H61N10O4 912.49; found: 913.68 (M + H)⁺; HRMS: Anal. Calc. for C54H61N10O4 913.4877; found: 913.4899 (M + H)⁺.</td>

<td>24-4</td><td>2.2 '- (4,4'-biphenyldiylbis (1H-</td><td rowspan="2"></td><td>'HNMR (500 MHz,</td>

<td></td><td>imidazol-5,2-diyl (2S) -2.1 -</td><td>DMSO-dó) δ ppm 1.97-</td>

<td></td><td>pyrrolidinyl)) bis (N-benzyl-N-</td><td rowspan="2">"b Cap-49</td><td>2.43 (m, 8H), 2.64-2.91</td>

<td></td><td>methyl-2-oksoetanamina)</td><td>(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</td>

118

<td></td><td></td><td></td><td>X 50 mm, 0 to 100% B in 10 minutes, one minute stop time, A = 90% water, 10% methanol, 0.2% phosphoric acid, B = 10% water, 90% methanol, 0.2% phosphoric acid. RT = 3.06 min; LCMS: Anal. Calc. for: C₄6H₅he₈0₂ 746.96; found: 747.41 (M + H)⁺.</td>

<td>24-4f</td><td>(2S, 2'S) -1,1 '- (4,4'-biphenyldiylbis (1H-imidazol-5,2-diyl (2S) -2, 1-pyrrolidinidiyl)) bis (N-benzyl-N-methyl-1-oxo-2-propanamine )</td><td>X Me OY X</td><td>RT = 2.95 minutes (99%); HPLC Xterra 4.6 X 50 mm, 0 to 100% B through 10 minutes, one minute stop time, A = 90% water, 10% methanol, 0.2% phosphoric acid, B = 10% water, 90% methanol, 0.2% phosphoric acid; LCMS: Anal. Calc. for: C4₈H₅₄N₈O2 775.02; found: 775.45 (M + H)⁺.</td>

<td>24-4g</td><td>1,1 '- (4,4'-biphenyldiylbis (1Himidazol-5,2-diyl (2S) -2, 1-pyrrolidinyl)) bis (N-benzylN, 3-dimethyl-1-oxo-2-butanamine)</td><td>X⁰ an N, Me \ O Cap- 50</td><td>RT = 3.86 minutes (100%); HPLC Xterra 4.6 X 50 mm, 0 to 100% B in 10 minutes, one minute stop time, A = 90% water, 10% methanol, 0.2% phosphoric acid, B = 10% water, 90% methanol, 0.2% phosphoric acid; LCMS: Anal. Calc. for: C₅2H₆₂N₈ABOUT₂ 831.13; found: 831.51 (M + H)⁺.</td>

119

<td>24-4h</td><td>1,1 '- (4,4'-biphenyldiylbis (1H-</td><td></td><td>RT = 2.86 minutes (100%);</td>

<td></td><td>imidazol-5,2-diyl (2S) -2.1 -</td><td>AND</td><td>HPLC Xterra 4.6 X 50</td>

<td></td><td>pyrrolidinyl (2-oxo-1-phenyl)</td><td rowspan="2">0-0 about</td><td>mm, 0 to 100% B within</td>

<td rowspan="3"></td><td rowspan="3">2,1-ethanediyl))) di (4-piperidinol)</td><td rowspan="3">10 minutes, one minute stop time, A = 90% water, 10%</td>

<td>AND</td>

<td>OH</td>

<td></td><td></td><td>Cap-8</td><td>methanol, 0.2% phosphoric acid, B = 10% water, 90% methanol, 0.2% phosphoric acid; LCMS: Anal. Calc. for: C52H₅₈N₈ABOUT₄ 859.09; found: 859.45 (M + H)⁺.</td>

Examples 24-5 to 24-18

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

<td> 24-5</td><td>1,1 '- (4,4'-biphenyldiylbis (1Himidazol-5,2-diyl ((2S, 4S) -4-fluoro2,1-pyrrolidinyl) ((1R) -2-oxo-1-phenyl-2,1-ethanediyl)) dipiperidates on</td><td>F f ΥααοϋΑΡ AA with l-2e-2 and Cap-1</td><td>Gemini C-18 4.6 x 50mm, 0 to 100% B in 10 minutes gradient, 1 minute hold time, A = 5% acetonitrile, 95% water, 10mm Ammonium acetate, B = 95% acetonitrile, 5% water, 10mm Acetate ammonium. (RT = 4,163 min); Nominal / LRMS Calculate For C₄6H4₈F₂N₈O2 782.93; found 783.40 (M + H)⁺; Accurate / HRMS Calculate for C₄6H49F2N₈ABOUT₂783.3946; 783.3934 (M + H)⁺.</td>

120

<td> 24-6</td><td>(1R, 1'R) -2,2 '- (4,4'-biphenyldiylbis (1Himidazol-5,2-diyl ((2S, 4S) -4-fluoro)</td><td>FF</td><td>Gemini C-18 4.6 x 50mm, 0 to 100% B in 10 minutes gradient, 1 minute</td>

<td></td><td>2,1pirolidyndiylo))) bis (N,</td><td>with 1 -2e-2 and Cap-2</td><td>retention time, A = 5% acetonitrile,</td>

<td></td><td>N-diethyl-2-oxo-</td><td></td><td>95% water, 10mm</td>

<td></td><td>fenyloetanamina)</td><td></td><td>Ammonium acetate, B = 95% acetonitrile, 5% water, 10 mm Ammonium acetate. (RT = 3.76 min); LCMS: Anal. Calc. for C.₅₀H₅₆F₂N₈ABOUT₂839.04; found: 839.49 (M + H)⁺; HRMS: Anal. Calc. for C5oH₅₇F₂N₈0₂839.4572; found: 839.4590 (M + H)⁺.</td>

<td> 24-7</td><td>(LR, l'R) -2,2'-</td><td>L Z "^-"""''¹/) aJL η h</td><td>Gemini C-18 4.6 x</td>

<td></td><td> (4,4'-</td><td>GWckoy</td><td>50mm, 0 to 100% B</td>

<td></td><td>biphenyldiylbis (1Himidazole-5.2-</td><td>ό O</td><td>within 10 minutes gradient, 1 minute</td>

<td></td><td>diyl ((2S, 4S) -4-fluoro2,1-</td><td>with l-2e-2 and Cap-14</td><td>stop time A = 5% acetonitrile,</td>

<td></td><td>pyrrolidinyl))) bis (N, N-dimethyl-2-oxo-1 phenylethanamine)</td><td></td><td>95% water, 10mm ammonium acetate, B = 95% acetonitrile, 5% water, 10mm ammonium acetate. RT = 3.99 min; LCMS: Anal. Calc. for C5₂H56F₂N₈ABOUT₂863.06; found: 863.47 (M + H)⁺; HRMS: Anal. Calc. for C.₅₂H₅₇T₂N₈ABOUT₂863.4572; found: 863.4553 (M + H)⁺.</td>

121

<td> 24-8</td><td>1,1 '- (4,4'-biphenyldiylbis (1'-imidazol-4,2-diyl ((2S) -4,4-difluoro2,1-pyrrolidinylated) ((1R) -2-oxo-1-phenyl-2,1-ethanediyl)) dipiperidates on</td><td>F0 J \ -F AND₀ ΗΝΧν / ν / W 0 0 with l-2e-3 and Cap-14</td><td>RT = 1.64 minutes, method B; LCMS: Anal. Calc. for C52H₅₄F4N₈O6: 898.43; found: 899.46 (M + H)⁺; HRMS: Anal. Calc. for C.₅2H₅₅F₄N₈O6 899.4384; found: 899.4380 (M + H)⁺.</td>

<td> 24-9</td><td> (4,4’-</td><td>^FAA^f</td><td>RT = 2.62 minutes,</td>

<td></td><td>biphenyldiylbis (1H-</td><td>Π \ = / \ = / V-NH</td><td>method C; LCMS:</td>

<td></td><td>imidazole-4,2-</td><td>° yŃH ° ° o. 0</td><td>Anal. Calc. for</td>

<td></td><td>diyl ((2S) -4,4-difluoro-</td><td> \ /</td><td>C₄6H₄2F₄N₈A6:</td>

<td></td><td> 2,1-</td><td></td><td>878.88; found:</td>

<td></td><td>pirolidyndiylo) ((R) -2-</td><td>with 1 -2e-3 and Cap-4</td><td>879.81 (M + H)⁺;</td>

<td></td><td>oxo-1-phenyl-2,1-</td><td></td><td>HRMS: Anal. Calc.</td>

<td></td><td>ethanediyl))) biskarbami</td><td></td><td>for</td>

<td></td><td>dimethyl nanate</td><td></td><td>C₄6H4₃F₄N₈ABOUT₆ 879.3</td>

<td></td><td></td><td></td><td>3242; found</td>

<td></td><td></td><td></td><td>879.3273 (M + H)⁺.</td>

<td> 24-10</td><td>l - ((R) -2 - ((2S) -2- (4-</td><td></td><td>RT = 1.54 minutes,</td>

<td></td><td>(4 '- (2 - ((2S) -4,4-</td><td></td><td>method B; LCMS:</td>

<td></td><td>difluoro-1 - ((2R) -2-</td><td rowspan="2">At 0</td><td>Anal. Calc. for</td>

<td></td><td>phenyl-2- (l-</td><td>C₅2H56F₂N₈ABOUT₆:</td>

<td></td><td>piperidinyl) acetyl) -</td><td>with l-3e and Cap-14</td><td>862.45; found:</td>

<td></td><td>2-pyrrolidinyl) -1H-</td><td></td><td>863.46 (M + H)⁺;</td>

<td></td><td>imidazol-4-yl) -4-</td><td></td><td>HRMS: Anal. Calc.</td>

<td></td><td>biphenylyl) IH-</td><td></td><td>for C.₅2H57F₂N₈O6</td>

<td></td><td>imidazol-2-yl) -l-</td><td></td><td> 863.4573;</td>

<td></td><td>pyrrolidinyl) -2-oxo-1 -</td><td></td><td>found:</td>

<td></td><td>phenylethyl) piperidine</td><td></td><td>863.4572 (M + H)⁺.</td>

<td> 24-11</td><td> (4,4'-</td><td>HO OH COA "</td><td>RT = 8.54 minutes,</td>

<td></td><td>biphenyldiylbis (1H-</td><td>¹J Try / ynATi V oi 0 Vnh X</td><td>method A; LCMS:</td>

<td></td><td>imidazole-5,2-</td><td>ΗΝ-γ oo:</td><td>Anal. Calc. for</td>

<td></td><td>diyl ((2S, 4R) -4-</td><td></td><td>C₄6H₄₆N₈ABOUT₈ 838.93;</td>

<td></td><td>hydroxy-2.1 -</td><td>from 1st and Cap-4</td><td>found: 839.41</td>

<td></td><td>pyrrolidinyl) ((1 R) -2-</td><td></td><td>(M + H)⁺; HRMS:</td>

<td></td><td>oxo-1-phenyl-2,1-</td><td></td><td>Anal. Calc. for</td>

122

<td></td><td>ethanediyl))) dimethyl nian biscuits</td><td colspan="3"></td><td>C46H47N8O8 839.9300; found: 839.3527 (M + H)⁺.</td>

<td> 24-12</td><td>(3R, 5S, 3'R, 5'S) -5,5'-</td><td>HO</td><td></td><td>OH X z- '</td><td>RT = 6.92 minutes,</td>

<td></td><td> (4,4'-</td><td>qq</td><td>H »✓&gt; —f&gt; N-ez \ _ / A //</td><td>yop</td><td>method A; LCMS:</td>

<td></td><td>biphenyldiylbis (1H-</td><td>HO ^AT</td><td></td><td>OH</td><td>Anal. Calc. for</td>

<td></td><td>imidazole-5,2-</td><td></td><td></td><td></td><td>C₄₂H4oN₆0₆ 724.81;</td>

<td></td><td>diyl)) bis (l - ((2R) -2-</td><td colspan="3">with 1-2e and mandelic acid</td><td>found: 725.43</td>

<td></td><td>hydroxy-2-</td><td></td><td></td><td></td><td>(M + H)⁺; HRMS:</td>

<td></td><td>phenylacetyl) -3-</td><td></td><td></td><td></td><td>Anal. Calc. for</td>

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

<td> 24-13</td><td>N, N '- (4,4'-</td><td>HO</td><td></td><td>OH X</td><td>RT = 3.80 minutes,</td>

<td></td><td>biphenyldiylbis (1H-</td><td>Q β</td><td>. H T y-ff W \</td><td></td><td>method D; LCMS:</td>

<td></td><td>imidazole-5,2-</td><td>HN f Y °</td><td></td><td>ohm</td><td>Anal. Calc. for</td>

<td></td><td>diyl ((2S, 4R) -4-</td><td>HN \</td><td></td><td>from^NH</td><td>C₄6H₄8Nio06</td>

<td></td><td>hydroxy-2,1-</td><td></td><td></td><td></td><td>836.95; found:</td>

<td></td><td>pyrrolidinyl) ((1 R) -2-</td><td></td><td colspan="2">with 1st and Cap-45</td><td>837.52 (M + H)⁺;</td>

<td></td><td>oxo-1-phenyl-2.1 -</td><td></td><td></td><td></td><td>HRMS: Anal. Calc.</td>

<td></td><td>ethanediyl))) bis (3 -</td><td></td><td></td><td></td><td>for C46H49N10O6</td>

<td></td><td>methylurea)</td><td></td><td></td><td></td><td>837.3836; found: 837.3809 (M + H)⁺.</td>

<td> 24-14</td><td>N ', N "' - (4,4'-</td><td rowspan="2">HO</td><td></td><td>OH X</td><td>RT = 4.39 minutes,</td>

<td></td><td>biphenyldiylbis (1H-</td><td>H z — x / = \ T yJ yZ V Ν-Χ \ / Ą //</td><td></td><td>method D; LRMS:</td>

<td></td><td>imidazole-5,2-</td><td>Hfj ⁰X</td><td></td><td>&lt;M^h</td><td>Anal. Calc. for</td>

<td></td><td>diyl ((2S, 4R) -4-</td><td>HN __</td><td></td><td> —^^NH</td><td>C48H52N10O6</td>

<td></td><td>hydroxy-2,1-</td><td></td><td></td><td></td><td>865,003; found</td>

<td></td><td>pyrrolidinyl) ((1 R) -2-</td><td colspan="2">Obtained from the 1st</td><td>and Cap-46</td><td>: 865.56 (M + H)⁺;</td>

<td></td><td>oxo-1-phenyl-2,1-</td><td></td><td></td><td></td><td>HRMS: Anal. Calc.</td>

<td></td><td>ethanediyl))) bis (l-</td><td></td><td></td><td></td><td>for C48H53N10O6</td>

<td></td><td>ethylurea)</td><td></td><td></td><td></td><td>865.4149; found: 865.4139 (M + H)⁺.</td>

123

<td> 24-15</td><td>Ν ', Ν' '- (4,4'-biphenyldiylbis (1'-imidazol-5,2-diyl ((2S, 4R) -4-hydroxy-2,1-pyrrolidinyl) ((1 R) -2-oxo-1-phenyl-2,1-ethanediyl))) bis (lcyklopentylomocznik)</td><td>HQ oA Hyo ° HN υ received</td><td>OH^hh JFS WATRA_abouts^HNH σ mana from 1st and Cap-45</td><td>RT = 4.88 minutes, method B; LRMS: Anal. Obi. for C54H60N10O6 944.13; found: 945.65 (M + H)⁺; HRMS: Anal. Obi. 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'-</td><td>HO</td><td>OH</td><td>RT = 3.66 minutes, method D; LRMS:</td>

<td></td><td>biphenyldiylbis (1H-</td><td>AND ^υ\</td><td> /^N"</td><td>Anal. Obi. for</td>

<td></td><td>imidazole-5,2-</td><td></td><td></td><td>C₄₆H₅₀N₈O4 778.39</td>

<td></td><td>diyl)) bis (1 - ((2R) -2-</td><td colspan="2">Obtained from l-2e and CapA</td><td>found: 779.39</td>

<td></td><td>(loamino dimets) -2 -</td><td></td><td></td><td>(M + H)⁺; HRMS:</td>

<td></td><td>phenylacetyl) -3-</td><td></td><td></td><td>Anal. Obi. for</td>

<td></td><td>piperidinol)</td><td></td><td></td><td>C₄6H₅₁N₈ABOUT₄779.4033; found: 779.4021 (M + H)⁺.</td>

<td> 24-17</td><td> (4,4'-</td><td>HO</td><td>OH</td><td>RT = 5.75 minutes,</td>

<td></td><td>biphenyldiylbis (1H-</td><td>Q and*</td><td>hh: / &lt;\</td><td>method D; LRMS:</td>

<td></td><td>imidazole-5,2-</td><td>HN ° A °</td><td>° / NH ° A</td><td>Anal. Obi. for</td>

<td></td><td>diyl ((2S, 4S) -4-</td><td> °\</td><td>With °</td><td>C₄₆H46N₈ABOUT₈ 838.93;</td>

<td></td><td>hydroxy-2,1-</td><td colspan="2">Obtained from 1 -2e and Caz? -4</td><td>found: 839.44</td>

<td></td><td>pirolidyndiylo) ((R) -2-</td><td></td><td></td><td>(M + H)⁺; HRMS:</td>

<td></td><td>oxo-1-phenyl-2.1 -</td><td></td><td></td><td>Anal. Obi. for</td>

<td></td><td>ethanediyl))) biskarbami</td><td></td><td></td><td>C₄6H₄₇N₈ABOUT₈</td>

<td></td><td>dimethyl nanate</td><td></td><td></td><td>839.3517 found</td>

<td></td><td></td><td></td><td></td><td>: 839.3519 (M + H)⁺.</td>

<td> 24-18</td><td>(3S, 5S, 3'S, 5'S) -5,5 '(4,4'-</td><td>HO ABOUT</td><td>OH Η H. A / = \ /^NjA ~^N AND,</td><td>RT = 4.41 minutes, method D; LRMS:</td>

<td></td><td>biphenyldiylbis (1H-</td><td>HÓ °</td><td>° OH</td><td>Anal. Obi. for</td>

<td></td><td>imidazole-5,2-</td><td>from l-2e</td><td rowspan="2">and mandelic acid</td><td>C₄₂H4oN₆0₆ 724.81;</td>

<td></td><td>diyl)) bis (1 - ((2R) -2-</td><td></td><td>found: 725.13</td>

<td></td><td>hydroxy-2fenyloacetylo) -3-pyrrolidinol)</td><td></td><td></td><td>(M + H)⁺.</td>

124

<td rowspan="2"> 24-18-1</td><td rowspan="2">(4,4'-biphenyldiylbis (1'-imidazol-5,2-diyl (1S) ι, ιetanediyl (methylmino) ((1R) -2-oxo-1-phenyl-2,1-ethanediyl)) bi dimethyl nanate</td><td colspan="2">0 " N</td><td rowspan="2">RT = 1.55 min¹; LRMS: Anal. Calc. for C44H46N8O6 782.35; found: 783.37 (M + H)⁺; HRMS: Anal. Calc. for C44H47N8O6 783.3619 found: 783.3630 (M + H)⁺.</td>

<td>ΟήΓν with l-7e and Cap-4</td><td>K * &lt;· 'O °</td>

<td> 24-18-2</td><td>(2R, 2'R) -N, N '- (4,4'-</td><td></td><td></td><td>RT = 1.16 min¹;</td>

<td></td><td>biphenyldiylbis (1Himidazol-5,2-diyl (1S) -</td><td>ΟΛ-Χ^νί⁰ ·# ^N yY</td><td></td><td>LRMS: Anal. Calc. for C.₄₄H₅oN80₂</td>

<td></td><td>1,1-ethanediyl)) bis (2-</td><td>AND</td><td></td><td>722.41; found:</td>

<td></td><td>(Dimethylamino) -N-</td><td>N &lt;</td><td>&gt; about</td><td>723.41 (M + H)⁺;</td>

<td></td><td>methyl-2-</td><td> 4</td><td rowspan="2">AND</td><td>HRMS: Anal. Calc.</td>

<td rowspan="3"></td><td rowspan="3">phenylacetamide)</td><td rowspan="3">with l-7e and Cap-l</td><td rowspan="3">for C4₄H5iN8O₂723.4135 found: 723.4152 (M + H)⁺.</td>

<td></td>

<td></td>

<td> 24-18-3</td><td>(2R, 2'R) -N, N '- (4,4'-</td><td rowspan="2">θΑχχ</td><td></td><td>RT = 1.28 min¹;</td>

<td></td><td>biphenyldiylbis (1Himidazole-5.2-</td><td></td><td>LRMS: Anal. Calc. for C5oH58Ns0₂</td>

<td></td><td>diyl (lS) -l, l-</td><td></td><td></td><td>802.47; found:</td>

<td></td><td>ethanediyl)) bis (N-</td><td></td><td>v O</td><td>803.50 (M + H)⁺;</td>

<td></td><td>methyl-2-phenyl-2- (1- -</td><td></td><td rowspan="2">N Λ ' about</td><td>HRMS: Anal. Calc.</td>

<td rowspan="3"></td><td rowspan="3">piperidinyl) acetamide)</td><td rowspan="3">with l-7e and Cap- \ 4</td><td rowspan="3">for C.₅₀H₅9N8O₂803.4761 found: 803.4778 (M + H)⁺.</td>

<td></td>

<td></td>

<td> 24-18-4</td><td>((R) -2 - ((2S) -2- (5- (4 '</td><td></td><td></td><td>RT = 1.53 min¹;</td>

<td></td><td>(2 - ((1 S) -1 - (((2R) -2-</td><td></td><td>_ νΆ</td><td>LRMS: Anal. Calc.</td>

<td></td><td>((Methoxycarbonyl) am</td><td>\. Ν "· \ / \ / \ X ~~ N</td><td>y — n 9¼</td><td>for C.₄5H4₆N₈ABOUT₆</td>

<td></td><td>ino) -2-</td><td>⁰'</td><td></td><td>794.35; found:</td>

<td></td><td>phenylacetyl) (methyl), and</td><td></td><td></td><td>795.39 (M + H)⁺;</td>

<td></td><td>mino) ethyl) -1H-</td><td>with l-5e and Cap-4</td><td></td><td>HRMS: Anal. Calc.</td>

<td></td><td>imidazol-5-yl) -4-</td><td></td><td></td><td>for C45H47N8O6</td>

<td></td><td>biphenylyl) -1H-</td><td></td><td></td><td>795.3619 found</td>

<td></td><td>imidazol-2-yl) -1-pyrrolidinyl) -2-oxo-1 phenylethyl) carbamate methyl</td><td></td><td></td><td>: 795.3616 (M + H)⁺.</td>

125

<td> 24-18-5</td><td>(2R) -2- (dimethylamino) N - ((S) -l- (5- (4 '- (2- ((2S) -l - ((2R) -2- (dimethylamino) -2fenyloacetylo) -2pirolidynylo) -lH-5-yl) -4bifenylylo ) -lH-2-yl) ethyl) -N-methyl-2fenyloacetamid</td><td>about ^N on 0¾ Obtained from l-5e and Cap-1</td><td>RT = 1.21LRMS: Anal. Calc. for C.₄5H₅he₈0₂ 734.41; found: 735.46 (M + H)⁺; HRMS: Anal. Calc. for C.₄₅H₅₁N₈ABOUT₂ 735413 5 found: 735.4136 (M + Hf.</td>

<td> 24-18-6</td><td>(2R) -N-methyl-2-</td><td>about</td><td>RT = 1.30¹; LRMS:</td>

<td></td><td>phenyl-N - ((lS) -l- (5- (4 '</td><td>Q&gt;. went A</td><td>Anal. Calc. for</td>

<td></td><td>(2 - ((2S) -l - ((2R) -2-</td><td></td><td>C₅₁H₅₈N₈ABOUT₂ 814.47;</td>

<td></td><td>phenyl-2- (l-</td><td></td><td>found: 815.48</td>

<td></td><td>piperydynylojacetylo) -</td><td>Obtained from l-5e and Cap-14</td><td>(M + H)⁺; HRMS:</td>

<td></td><td>2-pyrrolidinyl) -1H-</td><td></td><td>Anal. Calc. for</td>

<td></td><td>imidazol-5-yl) -4-</td><td></td><td>C5iH59N₈ABOUT₂</td>

<td></td><td>biphenylyl) IH-</td><td></td><td>815.4761 found</td>

<td></td><td>imidazol-2-yl) ethyl) -2-</td><td></td><td>: 815.4744 (M + H)⁺.</td>

<td></td><td>(1-piperidinyljacetam</td><td></td><td></td>

<td></td><td>id</td><td></td><td></td>

'LC conditions for 24-18-1 to 24-18-6: Phenomenex LUNA C-18 4.6 x 50 mm, 0 to 100% B in 2 minutes, 1 minute stop 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="PL2049522T3_D0126.tif" />

Examples 24-19 and 24-20 were obtained as TFA salts from 1-2e-1 and the corresponding acids using the same method described for Example 1.

<td></td><td></td><td> 0</td><td></td>

<td>Example</td><td>Union Name</td><td>"X</td><td>Data</td>

126

<td> 24-19</td><td>((17 ') - 2 - ((2S) -2- (4- (3 - (2 - ((25) 1 - ((27') - 2 ((methoxycarbonyl) amino) -2-phenylacetyl) -2-pyrrolidinyl ) 1H-imidazol-5-yl) -3-biphenylyl) -1H-imidazol-2-yl) -1-pyrrolidinyl) -2-oxo-1 phenylethyl) methyl carbamate</td><td>about^phxy ABOUT Cap-4</td><td>'H NMR (500 MHz, DMSO-dó) 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), 3.794.04 (m, 2H), 5.09-5.46 (m, 2H), 5.45-5.84 (m, 2H), 6.97- 7.49 (m, 10H), 7.617.74 (m, 4H), 7.75-7.93 (m, 4H), 8.10-8.32 (m, 4H), 14.48 (app br s, 2H); RT = 1.34 min; LC / MS: Anal. Calc. for [M + H]⁺C₄6H47N₈ABOUT₆: 807.36; found 807.40</td>

<td> 24-20</td><td>(17?) - 2 - ((25) -2- (4- (3 '- (2 - ((25) 1 - ((27?) - 2- (dimethylamino) -2-phenylacetyl) -2-pyrrolidinyl) -1H -imidazol-5-yl) -3-biphenylyl) -1H-imidazol-2-yl) -1-pyrrolidinyl) -N, N-dimethyl-2-oxo-1-phenylethanamine</td><td>^phX Cap-1</td><td>* H NMR (500 MHz, DMSO-dó) δ ppm 1.712.32 (m, 8H), 3.33-3.68 (m, 2H), 3.89-4.16 (m, 7 = 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), 9.90-10.87 (m, 2H); RT = 1.10 min; LC / MS: Anal. Calc. for [M + H]⁺C₄6H₅₁N₈ABOUT₂: 747.41; found 747.45</td>

LC conditions for 24-19 and 24-20:

Column = Phenomenex-Luna 3.0Χ 50 mm SIO

Initial% B = 0

Final% B = 100

Gradient time = 2 min

Stopping time = 3 min

Flow rate = 4 mL / min

Wavelength = 220 nm

Solvent A = 0.1% TFA in 10% methanol / 90% H2O Solvent B = 0.1% TFA in 90% methanol / 10% H₂ABOUT

127

<img file="PL2049522T3_D0127.tif" />

Examples 24-21 and 24-22 were obtained as the TFA salts of 1-4e and the corresponding carboxylic acids using the same method described for Example 1.

<td>Example</td><td>Union Name</td><td>0 "AND</td><td>Data</td>

<td> 24-21</td><td>((1 /?) - 2 - ((2 /) - 2- (4- (3- (2 ((25) -1 - ((2 /?) - 2 ((methoxycarbonyl) amino) -2-phenylacetyl) -2pirolidynylo ) -77 / -imidazol4-yl) -4-biphenylyl) -1Himidazol-2-yl) -1-pyrrolidinyl) -2-oxo-1 phenylethyl) carbamate methyl</td><td> 0 ^phgy^hSy °^x0 Cap-4</td><td>1HNMR (500 MHz, DMSO-dó) δ ppm 1.73 -2.37 (m, 8H), 3.13 (s, 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 = 1.33 min; LC / MS: Anal. Calc. for [M + H]⁺C46H47N8O6: 807.36; found 807.58</td>

<td> 24-22</td><td>(1 /) - 2 - ((2 /) - 2- (4- (3 '- (2 ((25) -1 - ((2 /) - 2 (dimethylamino) -2-phenylacetyl) -2-pyrrolidinyl) -777- imidazol4-yl) -4-biphenylyl) -1Himidazol-2-yl) -1-pyrrolidinyl) -A (A-dimethyl-2-oxo-1-phenylethanamine</td><td>^phvA /AND Cap-1</td><td>'HNMR (500 MHz, DMSO-d₆) δ ppm 1.84-2.32 (m, 8H), 2.92-3.10 (m, 2H), 3.92-4.08 (m, 2H), 4.43 (app br s, 12H), 5.165.37 (m, 2H), 5.39- 5.58 (m, 2H), 7.16-8.24 (m, 20H), 9.60-10.46 (m, 2H); RT = 1.08 min; LC / MS: Anal. Calc. for [M + H]⁺</td>

128

C46H51N8O2: 747.41; found 747.45

LC conditions for 24-21 and 24-22:

= Phenomenex-Luna 3.0Χ 50 mm SIO = 0 = 100 = 2 min = 3 min

Column Initial% B Final% B Gradient Time Stop Time

Flow rate = 4 mL / min Wavelength = 220 nm

Solvent A Solvent B

0.1% TFA in 10% methanol / 90% H₂About 0.1% TFA in 90% methanol / 10% H₂About Example 24-23

<img file="PL2049522T3_D0128.tif" />

((S) -l - (((2S) -2- (5- (4 '- (2 - ((2S) -l - ((2S) -2 - ((methoxycarbonyl) amino) -3-methylbutanoyl) Methyl -2-pyrrolidinyl) -1H-imidazol-5-yl) -4-biphenyl) -1H-imidazol-2-yl) -1-pyrrolidinyl) carbonyl) 2-methylpropyl) carbamate

To a 50 mL flask equipped with a stirrer was successively added 2.5 mL acetonitrile, 0.344 g (2.25 mmol, 2.5 equiv.) Hydroxybenzotriazole hydrate, 0.374 g (2.13 mmol, 2.4 equiv.) N- (methoxycarbonyl) -L-valine, 0.400 g (2.09 mmol, 2.4 eq. 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride and an additional 2.5 mL of acetonitrile. The resulting solution was stirred at 20 ° C for 1 hour and 0.501 g (0.88 mmol, 1 eq.) Of Example A-le-4 was added. The suspension was cooled to about 0 ° C and 0.45 g (3.48 mmol, 4 equiv.) Diisopropylethylamine was added over 30 minutes keeping the temperature below 10 ° C. The solution was slowly warmed to 15 ° C over 3 hours and kept at 15 ° C for 16 hours. The temperature was increased to 20 ° C and stirred for 3.25 hours. 3.3 g 13% by weight was added to the obtained solution. aqueous NaCl and heated to 50 ° C for 1 hour. After cooling to 20 ° C, 2.5 mL isopropyl acetate was added. The rich organic phase was washed with 2 x 6.9 g 0.5 N NaOH solution containing 13 wt. NaCl followed by 3.3 g 13 wt. aqueous NaCl. The mixture was exchanged for isopropyl acetate by vacuum distillation to a target volume of 10 mL. The resulting cloudy solution was cooled to 20 ° C and filtered through a 0.45 pm filter. In a clear solution then

129 the solvent was exchanged for ethanol by vacuum distillation with a target volume of 3 mL. 1.67 mL (2.02 mmol, 2.3 equiv) 1.21 M HCl in ethanol was added. The mixture was then stirred at 25 ° C for 15 hours. The resulting suspension was filtered and the wet cake was washed with 2.5 mL 2: 1 acetone. Ethanol. The solids were dried in a vacuum dryer at 50 ° C to give 0.550 g (0.68 mmol, 77%) of the desired product.

Recrystallization of Example 24-23

The solution of Example 24-23 obtained above was obtained by dissolving 0.520 g of the above product in 3.65 mL of methanol. To the solution, 0.078 g of Cuno Zeta type 3 loose carbon were then added and allowed to stir for 0.25 hours. The mixture was then filtered and washed with 6 mL methanol. The product-rich solution was concentrated 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 acetonretanol and dried in a vacuum oven at 70 ° C to give 0.406 g (57.0%) of the desired product in the form of white crystals: 1 H NMR (400 MHz, DMSO-d6, 80 ° C) : 8.02 (d, 3 = 8.34 Hz, 4 H), 7.97 (s, 2 H), 7.86 (d, 3 = 8.34 Hz, 4 H), 6.75 (s, 2 H), 5.27 (t, 3 = 6.44 Hz , 2 H), 4.17 (t, 3 = 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, 3 = 6.57 Hz, 6 H), 0.79 (d, 3 = 6.32 Hz, 6 H) ; ^l3C 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 (clean, cm '¹): 3385, 2971, 2873, 2669, 1731, 1650. Anal. Calc. for C256feHg: 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 (decomposition). The characteristic positions of the diffraction peaks (degrees 20 + - 0.1) @ RT, based on the high quality formula collected using a diffractometer (CuKa) with a rotating capillary calibrated with NIST, other relevant standards 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 (1H-imidazol-5,2-diyyl (2S) -2, 1-pyrrolidinidyl ((1R) -2-oxo-1-phenyl-2,1-ethanediyl) )) diacetamid

<img file="PL2049522T3_D0129.tif" />

Example 25 Stage a:

(4,4'-biphenyldiylbis (1H-imidazol-5,2-diyl (2S) -2, 1-pyrrolidinidiyl ((1R) -2-oxo-1-phenyl 2,1-ethanediyl)) di-tert biscarbamate -butyl and

Example 25 Step b:

130

<img file="PL2049522T3_D0130.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 reverse phase HPLC (H₂O / methanol / TFA). The HPLC eluate was neutralized with an excess of 2.0 M / NH₃ in CH₃OH and the volatile component were removed in vacuo. The residue was carefully partitioned between CH2Cl2 and saturated NaHCO₃. The aqueous phase was extracted with more CH2Cl2 (2x). The combined organic phases were dried (MgSO₄), filtered and concentrated in vacuo to provide 25a as a semi-solid oil film (78.8 mg). LC (Condition 1): RT = 1.99 min; &gt; 98% homogeneity index. LC / MS: Anal. Calc. for [M + H]⁺ C₅2H59N₈ABOUT₆: 891.46; found 891.55.

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

Example 25

N, N '- (4,4^,biphenyldiylbis (1H-imidazol-5,2-diyl (2S) -2, 1-pyrrolidinidyl ((1R) -2-oxo-1-phenyl-2,1-ethanediyl))) diacetamide

Acetic anhydride (20 pL, 0.21 mmol) was added to the DMF solution (1.5 mL) 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 2 M) and stirred for an additional 1.5 hours. The volatile component was removed in vacuo and the residue was purified by reverse phase HPLC (H₂O / methanol / TFA) to provide the TFA salt of Example 25 as a white foam (28.1 mg). LC (Condition 1): RT = 1.61 min; &gt; 98% homogeneity index; LC / MS: Anal. Calc. for [M + H]⁺ C46H47N8O4: 775.37; found 775.40; HRMS: Anal. Calc. for [M + H]⁺ C₄₆H₄₇N8O₄: 775.3720; found 775.3723

Example 25-1 to 25-5

<img file="PL2049522T3_D0131.tif" />

Examples 25-1 to 25-5 were prepared from 25b and the corresponding carboxylic acid using standard amide-forming conditions similar to those described for

131 receiving the example of Izie. Examples 25-6 to 25-8 were obtained from 25b and the corresponding carbamoyl chloride or isocyanate.

<td>Number example</td><td>Union Name</td><td>R</td><td>RT (LC condition); % homogeneity index; MS data</td>

<td> 25-1</td><td>(2R, 2'R) -N, N '- (4,4-biphenyldiylbis (1H-imidazol5,2-diyl (2S) -2, 1-pyrrolidinidiyl ((1R) -2-oxo-1 phenyl-2, letanediyl) )) d ^ tetrahydro-2furanokarboksamid</td><td></td><td>RT = 5.68 minutes; HPLC Xterra 4.6 X 50 mm, 0 to 100% B in 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. Calc. for: C₅2H54N₈ABOUT₆: 887.06; found: 887.58 (M + H)⁺</td>

<td> 25-2</td><td>N, N '- (4,4'-biphenyldiylbis (1Himidazol-5,2-diyl (2S) -2, 1-pyrrolidinylated ((1R) -2-oxo-1 phenyl-2,1-ethanediyl))) bis ( 1 methyl-1H-imidazo 1-5 carboxamide)</td><td>oh N \</td><td>RT = 3.54 minutes; HPLC Xterra 4.6 X 50 mm, 0 to 100% B in 10 minutes, one minute stop time, A = 90% water, 10% methanol, 0.2% phosphoric acid, B = 10% water, 90% methanol, 0.2% phosphoric acid ; LCMS: Anal. Calc. for: C₅2H5oNi₂0₄: 907.06_; found: 907.42 (M + H)⁺</td>

<td> 25-3</td><td>(2S, 2'S) -N, N '- (4,4'-biphenyldiylbis (1H-imidazol5,2-diyl (2S) -2, 1-pyrrolidinidiyl ((1R) -2-oxo-1 phenyl-2,1 - ethanediyl))) bis (1 methyl-2-pyrrolidinecarboxamide)</td><td>CVI N \</td><td>RT = 3.1 minutes; HPLC Xterra 4.6 X 50 mm, 0 to 100% B in 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. Calc. for: C₅4H6oN₁₀04 913.14; found: 913.54 (M + H)⁺</td>

132

<td> 25-4</td><td>N, N '- (4,4'-biphenyldiylbis (1-imidazol-5,2-diyl (2S) -2, 1-pyrrolidinylated ((1 R) -2-oxo-1 phenyl-2,1-ethanediyl)) bis (2- (3-pyridinyl) acetamide)</td><td>AND</td><td>RT = 3.37 minutes; HPLC Xterra 4.6 X 50 mm, 0 to 100% B in 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. Calc. for: C56H52N10O4 929.10 Found: 929.42 (M + H)⁺</td>

<td> 25-5</td><td>N, N '- (4,4'-biphenyldiylbis (1Himidazol-5,2-diyl (2S) -2, 1-pyrrolidinidyl ((1R) -2-oxo-1 phenyl-2,1-ethanediyl))) bis ( 2- (dimethylamino) acetamide) (name not preferred)</td><td>_ / N s</td><td>RT = 7.07 minutes; HPLC Xterra 4.6 X 50 mm, 0 to 100% B in 10 minutes, one minute stop time, A = 90% water, 10% methanol, 0.2% phosphoric acid, B = 10% water, 90% methanol, 0.2% phosphoric acid ; LCMS: Anal. Calc. for: C5oH₅₆Nio0₄861.07 Found: 859.69 (M + H)⁺</td>

<td> 25-6</td><td>N, N '- (4,4'-biphenyldiylbis (1Himidazol-5,2-diyl (2S) -2,1 pyrrolidinidyl ((1R) -2-oxo-1 phenyl-2,1-ethanediyl)) di (4morfolinokarboksamid)</td><td>ΰ N 1 «/ UW</td><td>* H NMR (500 MHz, DMSOd₆) pmpm 1.86-2.18 (m, 6H), 2.23-2.39 (m, 2H), 3.20-3.40 (m, 8H), 3.40-3.61 (m, 8H), 3.90-4.19 (m, 4H), 5.27 (dd, 7 = 8.09.3.51 Hz, 2H), 5.375.63 (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 in 10 minutes, one minute hold time, A = 90% water, 10% methanol, 0.2% phosphoric acid, B = 10% water, 90% methanol,</td>

133

<td></td><td></td><td></td><td>0.2% phosphoric acid RT = 6.01 minutes; LCMS: Anal. Calc. for: C52H56N10O6 917.09; found: 917.72 (M + H)⁺</td>

<td> 25-7</td><td>N, N '- (4,4'-biphenyldiylbis (1Himidazol-5,2-diyl (2S) -2,1 pyrrolidinidyl ((1R) -2-oxo-1 phenyl-2,1-ethanediyl)) bis (4-methyl-1piperazynekarboksamid)</td><td>about N 1 EOU</td><td>RT = 3.74 minutes; HPLC Xterra 4.6 X 50 mm, 0 to 100% B in 10 minutes, one minute stop time, A = 90% water, 10% methanol, 0.2% phosphoric acid, B = 10% water, 90% methanol, 0.2% phosphoric acid ; LCMS: Anal. Calc. for: C54H62N12O4 943.17; found: 943.84 (M + H)⁺</td>

<td> 25-8</td><td>N, N "- (4,4'-biphenyldiylbis (1Himidazol-5,2-diyl (2S) -2,1 pyrrolidinylated ((1R) -2-oxo-1 phenyl-2,1-ethanediyl)) bis (3- (3-pyridinyl) urea)</td><td>/ = N Q HN-</td><td>1 H NMR (500 MHz, DMSOd₆) δ ppm 1.79-2.17 (m, 6H), 2.29 (d, J = 9.11 Hz, 2H), 3.06-3.39 (m, 2H), 3.72-4.14 (m, 2H), 5.27 (dd, 7 = 8.24. 2.75 Hz, 2H), 5.66 (d, 7 = 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), 8.61-8.97 (m, 2H), 9.38 (s, 2H), 14.51 (s, 2H); HPLC Xterra 4.6 X 50 mm, 0 to 100% B in 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. Calc. for: C54H50N12O4 931.08; found: 931.78 (M + H)⁺.</td>

Example 26

134 ((R) -l - (((2S) -2- (5- (4 '- (2 - ((2S) -l - ((2R) -2 - ((methoxycarbonyl) amino) -3-methylbutanoyl) Methyl -2-pyrrolidinyl) -1H-imidazol-5-yl) -4-biphenyl) -1H-imidazol-2-yl) 1-pyrrolidinyl) carbonyl) -2-methylpropyl) carbamate

<img file="PL2049522T3_D0132.tif" />

(2R, 2'R) -1.1 '- (4,4'-biphenyldiylbis (1H-imidazol-5,2-diyl (2S) -2, 1-pyrrolidinyl)) bis (3-methyl-1-oxo-2 -butanamina)

<img file="PL2049522T3_D0133.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 ((1R) -1 - (((2S) -2- (5- (4 '- (2 - ((2S) -1 - ((2R) -2 - ((methoxycarbonyl) amino) -3-methylbutanoyl) Methyl -2-pyrrolidinyl) -1H-imidazol-5-yl) -4-biphenyl) -1H-imidazol-2-yl) -1-pyrrolidinyl) carbonyl) -2-methylpropyl) carbamate

Methyl chloroformate (18 pL, 0.23 mmol) was added to a solution of THF (1.5 mL) of diamine 26a (30 mg, 0.048 mmol) and triethylamine (30 pL, 0.22 mmol), and the reaction mixture was stirred at ambient conditions for 3 hours. Volatile components were removed in vacuo, and the residue treated with NlL / methanol (2 mL 2 M) and stirred at ambient conditions for 15 minutes. All volatiles were 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 (Condition2): RT = 2.00 min; &gt; 98% homogeneity index; LC / MS: Anal. Obi. for [M + H]⁺ C4oH5iN806: 739.39; found 739.67; HRMS: Anal. Obi. for [M + H]⁺ C4oH₅iN₈0₆: 739.3932; found 739.3966.

Example 27

N - ((R) -l - (((2S) -2- (5- (4 '- (2 - ((2S) -l - ((2R) -2-acetamido-3-methylbutanoyl) -2- pyrrolidinyl) 1H-imidazol-5-yl) -4-biphenylyl) -1H-imidazol-2-yl) -1-pyrrolidinyl) carbonyl) -2-methylpropyl) acetamide

135

<img file="PL2049522T3_D0134.tif" />

Diamine 26a was converted to Example 27 (TFA salt) according to the method described in the preparation of Example 25. LC (Condition 2): RT = 1.93min; &gt; 98% homogeneity index; LC / MS: Anal. Calc. for [M + Hf C₄oH₅iN₈0₄: 707.40; found 707.59; HRMS: Anal. Calc. for [M + Hf C₄oH5iN₈0₄: 707.4033; found 707.4054.

Example 28 ((1R) -2-oxo-1-phenyl-2 - ((2S) -2- (5- (4 '- (2 - ((2S) -1- (phenylacetyl) -2-pyrrolidinyl) - 1-Himidazol-5-yl) -4-biphenylyl) -1H-imidazol-2-yl) -1-pyrrolidinyl) ethyl) carbamate methyl

<img file="PL2049522T3_D0135.tif" />

<img file="PL2049522T3_D0136.tif" />

HATU (19.868g, 52.25 mmol) was added to a heterogeneous mixture of N-Cbz-Lproline (12,436 g, 49.89 mmol) and 2-amino-1- (4-bromophenyl) ethanone HCl salt (12.157 g,

48.53 mmol) in DMF (156 mL). The mixture was lowered into an ice-water bath, and immediately N, N-diisopropylethylamine (27 mL, 155 mmol) was added dropwise over 13 minutes. After the base addition was complete, 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 obtained crude solid and stirred for about 1 hour. The off-white solid was filtered and washed extensively with water, and dried in vacuo to provide ketoamide 28a as a white solid (20.68 g). 1 H 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 (Condition 1): RT = 1.65 min; 98% homogeneity index; LC / MS: Anal. Calc. for [M + Hf Ο₂ιΗ22ΒγΝ2Ο₄: 445.08; found 445.31.

Example 28, Step b

<img file="PL2049522T3_D0137.tif" />

28b

136

Ketoamide 28a (10.723g, 24.08 mmol) was converted to 28b according to the procedure described for the synthesis of carbamate 1b, with the proviso that the crude material was purified by flash chromatography (sample was applied with elution solvent; 50% ethyl acetate / hexanes). Bromide 28b was recovered as an off-white foam (7.622 g). * H NMR (DMSO-dó, δ = 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 (Condition 1): RT = 1.42 min; &gt; 95% homogeneity index; LC / MS: Anal. Calc. for [M + H]⁺ C2iH2iBrN3O2: 426.08; found 426.31; HRMS: Anal. Calc. for [M + H]⁺ C2iH2iBrN₃ABOUT₂: 426.0817; found: 426.0829. Optical purity 28b was evaluated using the following chiral HPLC methods and 99% ee 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 (2S, 2 'S) -2,2' - (4,4'-biphenyldiylbis (1H-imidazol-5,2-diyl)) di-1-pyrrolidinecarboxylate tert-butyl benzyl

<img file="PL2049522T3_D0138.tif" />

Pd (Ph₃Q)₄ (711.4 mg, 0.616 mmol) was added to the mixture of boronic ester lc (7.582 g, ~ 17 mmol), 28b bromide (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 flushed with N₂ and heated in 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 extracted with CH₂C1₂. The combined organic phases were dried (MgSO₄), filtered and concentrated in vacuo. The resulting material was subjected to flash chromatography (the sample was applied as a silica gel mesh; ethyl acetate was used as the eluent) to provide biphenyl 28c as an off-white foam containing Ph₃PO (7.5 g). * H NMR (DMSO-dó, δ = 2.5 ppm, 400 MHz): δ 12.24-12.19 (m, 0.36H), 12.00-11.82 (m, 1.64H), 7.856.98 (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 (Condition): RT = 1.41 minutes; LC / MS: Anal. Calc. for [M + H]⁺ C39H43N6O4: 659.34; found 659.52; HRMS: Anal. Calc. for [M + H]⁺ C39H4₃N₆ABOUT₄: 659.3346; found 659.3374.

Example 28, Step d

137 (2S) -2- (5- (4 '- (2 - ((2S) -2-pyrrolidinyl) -1H-imidazol-5-yl) -4-biphenyl) -1H-imidazol2-yl) -1-pyrrolidinecarboxylate tert-butyl

<img file="PL2049522T3_D0139.tif" />

K2CO3 (187.8 mg, 1.36 mmol) was added to the mixture of catalyst (10% Pd / C; 205.3 mg), carbamate 28c (1.018 g, ~ 1.5 mmol), methanol (20 mL) and 3 drops of water from the pipette. Balloon with H.₂ attached and the mixture stirred for 6 hours. Then additional catalyst (10% Pd / C, 100.8 mg) and K₂WHAT₃ (101.8 mg, 0.738 mmol) was added and stirring continued for 3.5 hours. In the hydrogenation process, balloon H₂ changed three times at intervals. The reaction mixture was filtered through a plug of diatomaceous earth (Celite 521), and the filtrate was concentrated in vacuo. The resulting crude material was flash chromatographed using a short column (sample applied as a silica gel mesh; 0-20% methanol / CH₂Cl2 was used as the eluent) to provide 28d as a light yellow foam (605.6 mg). * H NMR (DMSO-dó, 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, 3 = 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), 2.301 .69 (m, 8H), 1.41 / 1.16 (two br s, 9H). Note: the NH pyrrolidine signal appears to overlap with signals of the region of 3.6-3.2 ppm; LC (Condition 1): RT = 1.21 min; &gt; 95% homogeneity index; LC / MS: Anal. Calc. for [M + H]⁺ C31H37N6O2: 525.30; found 525.40.

Example 28, Step ef Example 28 step e (2S) -2- (5- (4 '- (2 - ((2S) -1 - ((2R) -2 - ((methoxycarbonyl) amino) -2-phenylacetyl) -2-pyrrolidinyl) -! H-imidazol-5-yl) -4-biphenyl) -I H-imidazol-2-yl) -1-tert-butyl pyrrolidinecarboxylate

Example 28, Step f ((1R) -2-oxo-1-phenyl-2 - ((2S) -2- (5- (4 '- (2 - ((2S) -2-pyrrolidinyl) -1H-imidazole Methyl -5-yl) -4-biphenylyl) -1H-imidazol-2-yl) -1-pyrrolidinyl) ethyl) carbamate

<img file="PL2049522T3_D0140.tif" />

Step e: HATU (316.6 mg, 0.833 mmol) was added to the 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 mixture the reaction mixture was stirred for 45 minutes. The volatile component was removed in vacuo, and the residue was partitioned between CH2Cl2 (50 mL) and an aqueous medium (20 mL H₂O + 1 mL saturated NaHCO solution₃). The aqueous phase was extracted again with CH2Cl2, and

138 the combined organic phases were dried (MgSO 4), 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 (Condition 1): RT = 1.68min; 91% homogeneity index; LC / MS: Anal. Calc. for [M + H]⁺ C41H46N7O5: 716.35; found 716.53.

Step f: Carbamate 28e was converted to amine 28f using the procedure described in the conversion of ld to le. LC (Condition 1): RT = 1.49min; &gt; 98% homogeneity index. LC / MS: Anal. Calc. for [M + H]⁺ C36H38N7O3: 616.30; found 616.37; HRMS: Anal. Calc. for [M + H]⁺ C36H₃₈N₇ABOUT₃: 616.3036; found 616.3046.

Example 28 ((1R) -2-oxo-1-phenyl-2 - ((2S) -2- (5- (4 '- (2 - ((2S) -1- (phenylacetyl) -2-pyrrolidinyl) - Methyl 1Himidazol-5-yl) -4-biphenyl) -1H-imidazol-2-yl) -1-pyrrolidinyl) ethyl) carbamate

<img file="PL2049522T3_D0141.tif" />

Amine 28f was converted to the TFA salt of Example 28 by using the last step in the synthesis of Example 1. 'H NMR (DMSO-dó, 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 signal for OCH₃ at 3.54 and 3.53), 2.451.72 (m, 8H). LC (Condition 1): RT = 1.66 minutes,&gt; 98% homogeneity index; LC / MS: Anal. Calc. for [M + H]⁺ C44H44N704: 734.35; found 734.48; HRMS: Anal. Calc. for [M + H]⁺ C44H44N7O4: 734.3455; 734.3455.

Example 28-1 to 28-4

<img file="PL2049522T3_D0142.tif" />

Examples 28-1 to 28-4 (R groups shown in the table below) were obtained in a similar manner to Example 28 via intermediate 28d.

Example 28-1 (1R) -N, N-dimethyl-2-oxo-1-phenyl-2 - ((2S) -2- (5- (4 '- (2 - ((2S) -1 - (( 2R) -2-phenyl-2- (lpiperydynylo) acetyl) -2-pyrrolidinyl) -lH-imidazol-5-yl) -4-biphenylyl) -lH-imidazol-2-yl) -l-pyrrolidinyl) ethanamine as starting materials

CapA was added, Boc carbamate was removed with TFA or HCl, and Cap-14 was added.

Example 28-2

139 l - ((R) -2-oxo-l-phenyl-2 - ((2S) -2- (5- (4 '- (2 - ((2S) -l - ((2R) -tetrahydro-2- furanylcarbonyl) -2pirolidynyło) -lH-imidazol-5-yl) -4-biphenylyl) -lH-imidazol-2-yl) -Ipirolidynylo) ethyl) piperidine

Tetrahydrofuran acid was added, Boc carbamate was removed with TFA or HCl, and Cap-14 was added.

Example 28-3 ((1R) -1- (2-chloropheryl) -2-oxo-2 - ((2S) -2- (5- (4 '- (2 - ((2S) -1 - ((2R ) -2-phenyl-2- (1-piperidinyl) acetyl) -2-pyrrolidinyl) -1H-imidazol-5-yl) -4-biphenylyl) -1H-imidazol-2-yl) -1-pyrrolidinyl) ethyl) carbamate at

Cap-40 was added, Boc carbamate was removed with TFA or HCl, and Cap-14 was added.

Example 28-4 (1R) -1- (2-chlorophenyl) -N, N-dimethyl-2-oxo-2 - ((2S) -2- (5- (4 '- (2 - ((2S) - l - ((2R) -2-phenyl-2- (lpiperydynylo) acetyl) -2-pyrrolidinyl) -lH-imidazol-5-yl) -4-biphenylyl) -lH-imidazol-2-yl) -l-pyrrolidinyl) ethanamine as starting materials

Cap-39 was added, Boc carbamate was removed with TFA or HCl, and Cap-14 was added.

Example 28-5 (1R) -1- (2-fluorophenyl) -N, N-dimethyl-2-oxo-2 - ((2S) -2- (5- (4 '- (2 - ((2S) - l - ((2R) -2-phenyl-2- (lpiperydynyło) acetyl) -2-pyrrolidinyl) -lH-imidazol-5-yl) -4-biphenylyl) -lH-imidazol-2-yl) -l-pyrrolidinyl) ethanamine as starting materials

Cap-3% was added, Boc carbamate was removed with TFA or HCl, and Cap-14 was added,

<td>Example</td><td>Union 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) -1 ((2R) -2- phenyl-1- (1-piperidinyl) acetyl) -2-pyrrolidinyl) -1H-imidazol-5-yl) -4-biphenyl) -1H-imidazol-2-yl) -1-pyrrolidinyl) ethanamine</td><td>ABOUT AND-</td><td>LCMS: Anal. Calc. for C49H₅4N₈ABOUT₂: 786; found: 787 (M + H)⁺.</td>

<td> 28-2</td><td>1 - ((1 R) -2-oxo-1-phenyl-2 - ((2S) -2 (5- (4 '- (2 - ((2S) -1 - ((2R) -tetrahydro-2-furanylcarbonyl) -2-pyrrolidinyl) 1H-imidazol-5-yl) -4-biphenylyl) 1H-imidazol-2-yl) -1-pyrrolidinyl) ethyl) piperidine</td><td>ck</td><td>LCMS: Anal. Calc. for C44H49N7O3: 723; found: 724 (M + H)⁺.</td>

140

<td rowspan="7"> 28-3</td><td rowspan="7">((1R) -1- (2-chlorophenyl) -2-oxo-2 ((2S) -2- (5- (4 '- (2 - ((2S) -1 - ((2R) -2-phenyl-2 - (1-piperidinyl) acetyl) 2-pyrrolidinyl) -1H-imidazol-5-yl) 4-biphenyl) -1H-imidazol-2-yl) -1-pyrrolidinyl) ethyl) carbamate methyl</td><td>Y \ /^Cabout</td><td rowspan="7">LCMS: Anal. Calc. for C.₄9H5iClN₈ABOUT₄: 850; found: 851 (M + H)⁺.</td>

<td></td>

<td></td>

<td>t \ ABOUT</td>

<td></td>

<td></td>

<td></td>

<td> 28-4</td><td>(1R) -1- (2-chlorophenyl) -N, N-dimethyl-2-oxo-2 - ((2S) -2- (5- (4 '- (2 ((2 S) -1 - ((2R) -2-phenyl-2- (1 piperidinyl) acetyl) -2-pyrrolidinyl) -1H-imidazol-5-yl) -4-biphenyl) -1H-imidazol-2-yl) -1-pyrrolidinyl) ethanamine</td><td>ca / V</td><td>LCMS: Anal. Calc. for C.₄9H₅3C1N₈ABOUT₂: 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) -1 - ((2R) -2-phenyl-2- (1 piperidinyl) acetyl) -2-pyrrolidinyl) -1H-imidazol-5-yl) -4-biphenyl) -1H-imidazol-2-yl) -1-pyrrolidinyl) ethanamine</td><td>ca /AND</td><td>LCMS: Anal. Calc. for C.₄9H₅₃FN₈ABOUT₂: 804; found: 805 (M + H)⁺.</td>

Example 29 ((1R) -2 - ((2S) -2- (5- (4^,- (2 - ((2S) -l - ((4-methyl-l-piperazinyl) carbonyl) -2-pyrrolidinyl) -lH-5-yl) -4-biphenylyl) -lH-imidazol-2-yl) - methyl 1-pyrrolidinyl) -2-oxo-1-phenylethyl) carbamate

<img file="PL2049522T3_D0143.tif" />

4-methylpiperazine-1-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 reverse phase HPLC (H2O / methanol / TFA) to provide the TFA salt of Example 29 as a pale yellow foam (29.3 mg). LC (Condition 2): RT = 1.82 minutes,&gt; 98% homogeneity index; LC / MS: Anal. Calc. for [M + H]⁺C42H48N9O4: 742.38; found 742.49.

Example 30

141 ((R) -2 - ((2S) -2- (5- (4 '- (2 - ((2S) -l-glycylo-2-pyrrolidinyl) -lH-imidazol-5-yl) -bifenylylo) - Methyl 1Himidazol-2-yl) -1-pyrrolidinyl) -2-oxo-1-phenylethyl) carbamate

<img file="PL2049522T3_D0144.tif" />

((R) -2 - ((2S) -2- (5- (4 '- (2 - ((2S) -l- (N- (tert-butoxycarbonyl) glycylo) -2-pyrrolidinyl) -lH-5 methyl-1-yl) -4-biphenylyl) -1H-imidazol-2-yl) -1-pyrrolidinyl) -2-oxo-1-phenylethyl) carbamate

<img file="PL2049522T3_D0145.tif" />

Carbamate 30a was obtained from pyrrolidine 28f and Boc-Glycine using the procedure described for the preparation of 25a from le. LC (Condition T): RT = 2.12 minutes,&gt; 98% homogeneity index; LC / MS: Anal. Calc. for [M + H]⁺ C43H49N8O6: 773.38; found 773.46

Example 30 ((1R) -2 - ((2S) -2- (5- (4 '- (2 - ((2S) -1-glycyl-2-pyrrolidinyl) -1H-imidazol-5-yl) -4 methyl-biphenylyl) 1H-imidazole-2-yl) -1-pyrrolidinyl) -2-oxo-1-phenylethyl) carbamate

Carbamate 30a was converted to Example 30 according to the procedure described for the preparation of le from 1d. LC (Condition 2): RT = 1.81 minutes,&gt; 98% homogeneity index; LC / MS: Anal. Calc. for [M + H]⁺ C38H41N8O4: 673.33; found 673.43 HRMS: Anal. Calc. for [M + H]⁺ C38H41N8O4: 673.3251; found 673.3262

Example 30-1 ((1S) -2 - ((2S) -2- (5- (4 '- (2 - ((2S) -1 - ((2R) -2- (diethylamino) -2-phenylacetyl) Methyl -2-pyrrolidinyl) -1H-imidazol-5-yl) -4-biphenylyl) -1H-imidazol-2-yl) -1-pyrrolidinyl) -1-methyl-2-oxoethyl) carbamate

<img file="PL2049522T3_D0146.tif" />

142

Example 30-1 was prepared in three steps from Example 28d. Step one: Attach Cap-2 using the procedure describing the synthesis of 28e from 28d. Step two: Hydrolysis of Boc carbamate using the procedure describing the synthesis of 28f from 28e. Step three: Attach Cap-52 using the procedure describing the synthesis of 28e from 28d. RT = 1.70 min (Condition 1b); &gt; 95% homogeneity index. LC / MS: Anal. Calc. for [M + H]⁺ C43H51N8O4: 743.40; found, 743.50. HRMS: Anal. Calc. for [M + H]⁺ C₄₃H_5IN8O4: 743.4033; found, 743.4053

By replacing the corresponding acid chloride or carboxylic acid in Example 29 or 30, the following compounds (Example 31 to 84-87) were obtained as the TFA salts.

<img file="PL2049522T3_D0147.tif" />

step b: the same procedure as in converting Example 1d to le step c: As in the last step of Example 1 using 1.1 eq. corresponding carboxylic acid and HATU

<td>Example</td><td>Union Name</td><td>ABOUT</td><td>Retention time (LC conditions); homogeneity index MS data</td>

<td> 31</td><td>((1R) -2 - ((2S) -2- (5- (4 '- (2 - ((2S) 1-acetyl-2-pyrrolidinyl) -1Himidazol-5-yl) -4-biphenyl) 1H -imidazol-2-yl) -1-pyrrolidinyl) -2-oxo-1 phenylethyl) carbamate</td><td>ABOUT</td><td>1.54 minutes (Condition 1); &gt; 98%; LC / MS: Anal. Calc. for [M + H]⁺ C38H4oN704: 658.31; found 658.42; HRMS: Anal. Calc. for [M + H]⁺ C38H₄₀N₇ABOUT₄: 658.3142; found 658.3135</td>

<td> 32</td><td>((1 R) -2-oxo-1-phenyl-2 - ((2S) 2- (5- (4 '- (2 - ((2S) -1-propionyl-2-pyrrolidinyl) -1H-imidazol-5-yl) -4-biphenylyl) -1H-imidazol2-yl) -1-pyrrolidinyl) ethyl) carbamate methyl</td><td>about -AND</td><td>1.57 minutes (Condition 1); &gt; 98%; LC / MS: Anal. Calc. for [M + H]⁺ C39H42N7O4: 672.33; found 672.46; HRMS: Anal. Calc. for [M + H]⁺C39H₄₂N₇ABOUT₄: 672.3298; found 672.3299</td>

143

<td> 33</td><td>((1R) -2 - ((2S) -2- (5- (4 '- (2 - ((2S) 1- (cyclopropylcarbonyl) -2-pyrrolidinyl) -1H-imidazol-5-yl) -4-biphenyl) - Methyl 1H-imidazol2-yl) -1-pyrrolidinyl) -2-oxo-1 phenylethyl) carbamate</td><td>Λ</td><td>1.59 minutes (Condition 1); &gt; 98%; LC / MS: Anal. Obi. for [M + H]⁺ C40H42N7O4: 684.33; found 684.44; HRMS: Anal. Obi. for [M + H]⁺ C40H42N7O4: 684.3298; found 684.3324</td>

<td> 34</td><td>((1R) -2 - ((2S) -2- (5- (4 '- (2 - ((2S) 1- (cyclopropylacetyl) -2-pyrrolidinyl) -1H-imidazol-5-yl) -4-biphenyl) - Methyl 1H-imidazol2-yl) -1-pyrrolidinyl) -2-oxo-1 phenylethyl) carbamate</td><td>AND</td><td>1.61 minutes (Condition 1); &gt; 98%; LC / MS: Anal. Obi. for [M + H]⁺ C40H42N7O4: 698.35; found 698.48; HRMS: Anal. Obi. for [M + H]⁺ C40H42N7O4: 698.3455; found 698.3489</td>

<td> 35</td><td>((1R) -2 - ((2S) -2- (5- (4 '- (2 - ((2S) 1 - ((2R) -2-hydroxypropane 1) 2-pyrrolidinyl) -1H-imidazol- Methyl 5-yl) -4-biphenylyl) -1H-imidazol2-yl) -1-pyrrolidinyl) -2-oxo-1 phenylethyl) carbamate</td><td>about V HO</td><td>1.54 minutes (Condition 1); &gt; 98%; LC / MS: Anal. Obi. for [M + H]⁺ C39H42N7O5: 688.33; found 688.47</td>

<td> 36</td><td>((1 R) -2-oxo-1-phenyl-2 - ((2S) 2- (5- (4 '- (2 - ((2S) -1 - ((2R) tetrahydro-2-furanylcarbonyl) -2-pyrrolidinyl ) -1 H-imidazol-5-yl) -4-biphenylyl) -1 H-imidazol-2-yl) -1-pyrrolidinyl) ethyl) carbamate methyl</td><td>P</td><td>1.59 minutes (Condition 1); &gt; 98%; LC / MS: Anal. Obi. for [M + H]⁺ C41H44N7O5: 714.34; found 714.49; HRMS: Anal. Obi. for [M + H]⁺ C₄₁H₄₄N₇ABOUT₅: 714.3404; found 714.3430</td>

<td> 37</td><td>((1R) -2 - ((2S) -2- (5- (4 '- (2 - ((2S) 1- (N, N-dimethylglycyl) -2-pyrrolidinyl) -1H-imidazol-5-yl) -4 methyl-biphenylyl) -1H-imidazol2-yl) -1-pyrrolidinyl) -2-oxo-1 phenylethyl) carbamate</td><td> 1 °</td><td>1.48 minutes (Condition 1); &gt; 98%; LC / MS: Anal. Obi. for [M + H]⁺ C4oH45N804: 701.36; found 701.49; HRMS: Anal. Obi. for [M + H]⁺ C40H₄₅N₈ABOUT₄: 701.3564; found 701.3553</td>

144

<td> 38</td><td>((1R) -2 - ((2S) -2- (5- (4 '- (2 - ((2S) 1 - ((2S) -2- (dimethylamino) -2-phenylacetyl) -2-pyrrolidinyl) 1H -imidazol-5-yl) -4-biphenylyl) -1H-imidazol-2-yl) 1-pyrrolidinyl) -2-oxo-1 phenylethyl) carbamate</td><td>Me O me-^{N /}'- ^ V ph Cap-l</td><td>1.20 minutes (Condition 1); &gt; 98%; LC / MS: Anal. Calc. for [M + H]⁺ C46H49N8O4: 777.39; found 777.61; HRMS: Anal. Calc. for [M + H]⁺ C46H49N₈ABOUT₄: 777.3877; found 777.3909</td>

<td> 39</td><td>((1R) -2 - ((2S) -2- (5- (4 '- (2 - ((2S) 1- (4-morpholinylacetyl) -2-pyrrolidinyl) -1H-imidazol-5-yl) -4- methyl biphenylyl) -1H-imidazol2-yl) -1-pyrrolidinyl) -2-oxo-1 phenylethyl) carbamate</td><td>ABOUT</td><td>1.79 minutes (Condition 2); &gt; 98%; LC / MS: Anal. Calc. for [M + H] C₄2H₄7N₈O5: 743.37; found 743.49; HRMS: Anal. 743.3672Obl. for [M + H]⁺C₄2H47N8O₅: 743.3669; found 743.3672</td>

<td> 40</td><td>(2 - ((2S) -2- (5- (4 '- (2 - ((2S) -1 ((2R) -2 ((methoxycarbonyl) amino) -2-phenylacetyl) -2-pyrrolidinyl) 1H-imidazole Methyl -5-yl) -4-biphenyl) -1 H-imidazol-2-yl) 1-pyrrolidinyl) -2-oxoethyl) carbamate</td><td>h U ABOUT</td><td>1.92 minutes (Condition 2); &gt; 98%; LC / MS: Anal. Calc. for [M + H]⁺ C₄oH₄3N₈0₆: 731.33; found 731.42; HRMS: Anal. Calc. for [M + H]⁺ C40H43N8O6: 731.3306; found 731.3333</td>

<td> 41</td><td>((1R) -2 - ((2S) -2- (5- (4 '- (2 - ((2S) 1- (N-acetylglycyl) -2-pyrrolidinyl) -1H-imidazol-5-yl) -4-biphenylyl ) -1-H-imidazol2-yl) -1-pyrrolidinyl) -2-oxo-1 phenylethyl) carbamate</td><td>II ⁰ 0</td><td>1.86 minutes (Condition 2); &gt; 98%; LC / MS: Anal. Calc. for [M + H]⁺ C4oH43N805: 715.34; found 715.49; HRMS: Anal. Calc. for [M + H]⁺ C4oH43N₈0₅: 715.3356; found 715.3369</td>

<td> 42</td><td>((1R) -2 - ((2S) -2- (5- (4 '- (2 - ((2S) 1 - ((2R) -2- (dimethylamino) -2-phenylacetyl) -2-pyrrolidinyl) 1H -imidazol-5-yl) -4-biphenylyl) -1H-imidazol-2-yl) 1-pyrrolidinyl) -2-oxo-1 phenylethyl) methyl carbamate</td><td>OJL_FROM</td><td>1.85 minutes (Condition 2); &gt; 98%; LC / MS: Anal. Calc. for [M + H]⁺ C46H₄9N₈ABOUT₄: 777.39; found 777.56</td>

145

<td> 43</td><td>((1 R) -2 - ((2S) -2- (5- (4 '- (2 - ((2S) 1 - ((2R) -2-hydroxy-2-phenylacetyl) -2-pyrrolidinyl) 1H- methyl imidazol-5-yl) -4-biphenyl) -1H-imidazol-2-yl) 1-pyrrolidinyl) -2-oxo-1 phenylethyl) carbamate</td><td>OH</td><td>1.96 minutes (Condition 2); &gt; 98%; LC / MS: Anal. Calc. for [M + H]⁺ C44H44N7O5: 750.34; found 750.51; HRMS: Anal. Calc. for [M + H]⁺ C44H44N7O5: 750.3404; found 750.3437</td>

<td> 44</td><td>((1R) -2 - ((2S) -2- (5- (4 '- (2 - ((2S) 1- ((1-methyl-4-piperidinyl) carbonyl) -2-pyrrolidinyl) -1H-imidazol-5-yl Methyl) -4-biphenylyl) -1H-imidazol2-yl) -1-pyrrolidinyl) -2-oxo-1 phenylethyl) carbamate</td><td>X</td><td>1.78 minutes (Condition 2); &gt; 98%; LC / MS: Anal. Calc. for [M + H]⁺ C₄3H₄9N₈ABOUT₄: 741.39; found 741.55; HRMS: Anal. Calc. for [M + H] C₄₃H49N₈ABOUT₄: 741.3877; found 741.3893</td>

<td> 45</td><td>((1 R) -2-oxo-1-phenyl-2 - ((2S) 2- (5- (4 '- (2 - ((2S) -1- (tetrahydro2H-pyran-4-ylcarbonyl) -2-pyrrolidinyl ) -1 H-imidazol-5-yl) -4-biphenylyl) -1 H-imidazol-2-yl) -1-pyrrolidinyl) ethyl) carbamate methyl</td><td>X</td><td>1.87 minutes (Condition 2); &gt; 98%; LC / MS: Anal. Calc. for [M + H]⁺ C42H46N7O5: 728.36; found 728.52; HRMS: Anal. Calc. for [M + H]⁺ C42H46N₇ABOUT₅: 728.3560; found 728.3587</td>

<td> 46</td><td>((1 R) -2-oxo-1-phenyl-2 - ((2S) 2- (5- (4 '- (2 - ((2S) -1- (2-pyridinylacetyl) -2-pyrrolidinyl) -1H-imidazole -5-yl) -4-biphenylyl) -1H-imidazol-2-yl) -1-pyrrolidinyl) ethyl) carbamate methyl</td><td></td><td>1.80 minutes (Condition 2); &gt; 98%; LC / MS: Anal. Calc. for [M + H]⁺ C43H43N8O4: 735.34; found 735.51; HRMS: Anal. Calc. for [M + H]⁺ C43H₄3N₈ABOUT₄: 735.3407; found 735.3416</td>

<td> 47</td><td>((1 R) -2-oxo-1-phenyl-2 - ((2S) 2- (5- (4 '- (2 - ((2S) -1- (3-pyridinylacetyl) -2-pyrrolidinyl) -1H-imidazole -5-yl) -4-biphenylyl) -1H-imidazol-2-yl) -1-pyrrolidinyl) ethyl) carbamate methyl</td><td>Cla_from</td><td>1.76 minutes (Condition 2); &gt; 98%; LC / MS: Anal. Calc. for [M + H]⁺ C₄3H43N₈ABOUT₄: 735.34; found 735.52</td>

146

<td> 48</td><td>((1 R) -2-oxo-1-phenyl-2 - ((2S) 2- (5- (4 '- (2 - ((2S) -1- (4-pyridinylacetyl) -2-pyrrolidinyl) -1H-imidazole -5-yl) -4-biphenylyl) -1H-imidazol-2-yl) -1-pyrrolidinyl) ethyl) carbamate methyl</td><td>OJL,</td><td>Χ.ΊΊ minutes (Condition 2); &gt; 98%; LC / MS: Anal. Calc. for [M + H]⁺ C43H43N8O4: 735.34; found 735.50; HRMS: Anal. Calc. for [M + H]⁺ C43H₄₃N8O₄: 735.3407; found 735.3405</td>

<td> 49</td><td>((1R) -2 - ((2S) -2- (5- (4 '- (2 - ((2S) 1 - ((1-methyl-1H-imidazol-5-yl) carbonyl) -2-pyrrolidinyl) methyl 1H-imidazol-5-yl) -4-biphenylyl) -1H-imidazol-2-yl) 1-pyrrolidinyl) -2-oxo-1 phenylethyl) carbamate</td><td>βγ Μ</td><td>1.77 minutes (Condition 2); &gt; 98%; LC / MS: Anal. Calc. for [M + H]⁺ C4, H42N9O4: 724.34; found 724.51; HRMS: Anal. Calc. for [M + H]⁺ C41H₄₂N₉ABOUT₄: 724.3360; found 724.3380</td>

<td> 50</td><td>((1R) -2 - ((2S) -2- (5- (4 '- (2 - ((2S) 1- (dimethylcarbamoyl) -2-pyrrolidinyl) -1H-imidazol-5-yl) -4-biphenyl) - Methyl 1H-imidazol2-yl) -1-pyrrolidinyl) -2-oxo-1 phenylethyl) carbamate</td><td>about Ra / 1</td><td>1.91 minutes (Condition 2); &gt; 98%; LC / MS: Anal. Calc. for [M + H]⁺ C39H43N8O4: 687.34; found 687.49; HRMS: Anal. Calc. for [M + H]⁺ C39H4₃N₈ABOUT₄: 687.3407; found 687.3414</td>

<td> 51</td><td>((1R) -2 - ((2S) -2- (5- (4 '- (2 - ((2S) 1- (1-methyl-D-prolyl) -2-pyrrolidinyl) -1H-imidazol-5-yl) Methyl-4-biphenylyl) -1H-imidazol2-yl) -1-pyrrolidinyl) -2-oxo-1 phenylethyl) carbamate</td><td> \ ⁰AND Cap-10</td><td>1.79 minutes (Condition 2); &gt; 98%; LC / MS: Anal. Calc. for [M + H]⁺ C₄₂H47N8O₄: 727.37; found 727.34; HRMS: Anal. Calc. for [M + H] C42H47N8O4: 727.3720; found 727.3719</td>

<td> 52</td><td>((1R) -2 - ((2S) -2- (5- (4 '- (2 - ((2S) 1- (1-methyl-L-prolyl) -2-pyrrolidinyl) -1H-imidazol-5-yl) Methyl-4-biphenylyl) -1H-imidazol2-yl) -1-pyrrolidinyl) -2-oxo-1 phenylethyl) carbamate</td><td> \ ⁰X Cap-10 enantiomer</td><td>1.77 minutes (Condition 2); &gt; 98%; LC / MS: Anal. Calc. for [M + H]⁺ C42H47N8O4: 727.37; found 727.33; HRMS: Anal. Calc. for [M + H]⁺ C42H47N8O4: 727.3720; found 727.3738</td>

147

<td> 53</td><td>((1R) -2 - ((2S) -2- (5- (4 '- (2 - ((2S) 1- (N-acetyl-D-alanyl) -2-pyrrolidinyl) -1H-imidazol-5-yl) Methyl-4-biphenylyl) -1H-imidazol2-yl) -1-pyrrolidinyl) -2-oxo-1 phenylethyl) carbamate</td><td>ΎΫ7 0 ¹</td><td>1.92 minutes (Condition 2); &gt; 98%; LC / MS: Anal. Calc. for [M + H]⁺ C_4IH4₅N8O₅: 729.35; found 729.33; HRMS: Anal. Calc. for [M + H]⁺ C41H45N8O5: 729.3513; found 729.3530</td>

<td> 54</td><td>((1R) -2 - ((2S) -2- (5- (4 '- (2 - ((2S) 1- (N-acetyl-L-alanyl) -2-pyrrolidinyl) -1H-imidazol-5-yl) Methyl-4-biphenylyl) -1H-imidazol2-yl) -1-pyrrolidinyl) -2-oxo-1 phenylethyl) carbamate</td><td>h U about</td><td>1.87 minutes (Condition 2); &gt; 98%; LC / MS: Anal. Calc. for [M + H]⁺ C41H45N8O5: 729.35; found 729.33</td>

<td> 55</td><td>((1R) -2 - ((2S) -2- (5- (4 '- (2 - ((2S) 1- (methoxyacetyl) -2-pyrrolidinyl) -1H-imidazol-5-yl) -4-biphenyl) - Methyl 1 H-imidazol-2-yl) -1-pyrrolidinyl) -2-oxo-1 phenylethyl) carbamate</td><td>about / ^ O</td><td>1.89 minutes (Condition 2); &gt; 98%; LC / MS: Anal. Calc. for [M + H]⁺ C39H42N7O5: 688.32; found 688.28; HRMS: Anal. Calc. for [M + H]⁺ C3₉H₄2N₇ABOUT₅: 688.3247; found 688.3231</td>

<td> 56</td><td>((1R) -2 - ((2S) -2- (5- (4 '- (2 - ((2S) 1 - ((2R) -2-hydroxybutanoyl) -2-pyrrolidinyl) -1H-imidazol-5-yl) Methyl-4-biphenylyl) -1H-imidazol2-yl) -1-pyrrolidinyl) -2-oxo-1 phenylethyl) carbamate</td><td>0 X ? H</td><td>1.91 minutes (Condition 2); &gt; 98%; LC / MS: Anal. Calc. for [M + H]⁺ C40H44N7O5: 702.34; found 702.30; HRMS: Anal. Calc. for [M + H]⁺ C40H44N7O5: 702.3404; found 702.3393</td>

<td> 57</td><td>((1R) -2 - ((2S) -2- (5- (4 '- (2 - ((2S) 1- ((4-methyl-1-piperazinyl) acetyl) -2-pyrrolidinyl) -1H-imidazol-5-yl) Methyl-4-biphenylyl) -1H-imidazol2-yl) -1-pyrrolidinyl) -2-oxo-1 phenylethyl) carbamate</td><td>about</td><td>1.80 minutes (Condition 2); &gt; 98%; LC / MS: Anal. Calc. for [M + H]⁺ C43H50N9O4: 756.40; found 756.36; HRMS: Anal. Calc. for [M + H]⁺ C43H50N9O4: 756.3986; found 756.3965</td>

148

<td> 58</td><td>((1 R) -2-oxo-1-phenyl-2 - ((2S) 2- (5- (4 '- (2 - ((2S) -1- (1-pyrrolidinylacetyl) -2-pyrrolidinyl) -1H-imidazole -5-yl) -4-biphenylyl) -1H-imidazol-2-yl) -1-pyrrolidinyl) ethyl) carbamate methyl</td><td> /—\ °</td><td>1.82 minutes (Condition 2); &gt; 98%; LC / MS: Anal. Calc. for [M + H]⁺ C42H47N8O4: 727.37; found 727.33; HRMS: Anal. Calc. for [M + H]⁺ C42H₄₇N₈ABOUT₄: 727.3720; found 727.3696</td>

<td> 59</td><td>((1 R) -2-oxo-1-phenyl-2 - ((2S) 2- (5- (4 '- (2 - ((2S) -1 - ((2S) lcarbonyl tetrahydro-2-furans) 2-pyrrolidinyl) -1H-imidazol-5-yl) -4-biphenylyl) -1H-imidazol2-yl) -1-pyrrolidinyl) ethyl) carbamate methyl</td><td>AND</td><td>1.94 minutes (Condition 2); &gt; 98%; LC / MS: Anal. Calc. for [M + H]⁺ C41H43N7O5: 714.34; found 714.24</td>

<td> 60</td><td>((1R) -2 - ((2S) -2- (5- (4 '- (2 - ((2S) 1- (((hydroxycyclopropyl) carbonyl) -2-pyrrolidinyl) -1H-imidazol-5-yl) Methyl-4-biphenylyl) -1-Himidazol-2-yl) -1-pyrrolidinyl) 2-oxo-1-phenylethyl) carbamate</td><td>AND</td><td>1.93 minutes (Condition 2); &gt; 98%; LC / MS: Anal. Calc. for [M + H]⁺ C4oH42N705: 700.32; found 700.23; HRMS: Anal. Calc. for [M + H]⁺ C4oH42N70₅: 700.3247; found 700.3265</td>

<td> 61</td><td>((1 R) -2 - ((2S) -2- (5- (4 '- (2 - ((2S) 1- (1H-imidazol-5-ylacetyl) -2-pyrrolidinyl) -1H-imidazol- Methyl 5-yl) -4-biphenyl) -1H-imidazol2-yl) -1-pyrrolidinyl) -2-oxo-1 phenylethyl) carbamate</td><td>, f ~ NH O 'Ά,</td><td>1.84 minutes (Condition 2); &gt; 98%; LC / MS: Anal. Calc. for [M + H]⁺ C4iH42N9O4: 724.34; found 724.21; HRMS: Anal. Calc. for [M + H]⁺ C4iH42N₉ABOUT₄: 724.3360; found 724.3365</td>

<td> 62</td><td>((1 R) -2 - ((2S) -2- (5- (4 '- (2 - ((2S) 1 - ((1-methyl-1H-imidazol-4-yl) acetyl) -2-pyrrolidinyl ) -1-Himidazol-5-yl) -4-biphenylyl) 1H-imidazol-2-yl) -1-pyrrolidinyl) -2-oxo-1 phenylethyl) methyl carbamate</td><td>/ = NO</td><td>1.85 minutes (Condition 2); &gt; 98%; LC / MS: Anal. Calc. for [M + H] C4₂H₄4N₉ABOUT₄: 738.35; found 738.22; HRMS: Anal. Calc. for [M + H] C₄₂H₄4N₉O4: 738.3516; found 738.3539</td>

149

<td> 63</td><td>((1R) -2 - ((2S) -2- (5- (4 '- (2 - ((2S) 1- (1H-imidazol-2-ylcarbonyl) 2-pyrrolidinyl) -1H-imidazol- Methyl 5-yl) -4-biphenylyl) -1H-imidazol2-yl) -1-pyrrolidinyl) -2-oxo-1 phenylethyl) carbamate</td><td></td><td>1.95 minutes (Condition 2); &gt; 98%; LC / MS: Anal. Obi. for [M + H]⁺ C40H41N9O4: 710.32; found 710.17</td>

<td> 64</td><td>((1R) -2 - ((2S) -2- (5- (4 '- (2 - ((2S) 1- ((4-hydroxy-1-piperidinyl) (phenyl) acetyl) 2-pyrrolidinyl) -1H -imidazol-5-yl) -4-biphenylyl) -1H-imidazol-2-yl) -1-pyrrolidinyl) -2-oxo-1 phenylethyl) carbamate</td><td>Q OH Cap-8 Single diastreoizomer</td><td>1.92 minutes (Condition 2); &gt; 98%; LC / MS: Anal. Obi. for [M + H]⁺ C49H53N8O5: 833.41; found 833.32; HRMS: Anal. Obi. for [M + H]⁺ C₄₉H₅₃N₈ABOUT₅: 833.4139; found 833.4163</td>

<td> 65</td><td>((1 R) -2-oxo-1-phenyl-2 - ((2S) 2- (5- (4 '- (2 - ((2S) -1- (1H-tetrazol-5-lacetyl) -2 pyrrolidinyl) 1H-imidazol-5-yl) -4-biphenyl) -1H-imidazol-2-yl) 1-pyrrolidinyl) ethyl) carbamate methyl</td><td>nn 0 ΥΛ</td><td>1.92 minutes (Condition 2); &gt; 98%; LC / MS: Anal. Obi. for [M + H]⁺C39H4oNii04: 726.33; found 726.22; HRMS: Anal. Obi. for [M + H]⁺ C39H₄oNii0₄: 726.3265; found 726.3290</td>

<td> 67</td><td>((1 R) -2-oxo-1-phenyl-2 - ((2S) 2- (5- (4 '- (2 - ((2S) -1- (2-pyridinylcarbonyl) -2-pyrrolidinyl) -1H-imidazol- 5-yl) -4-biphenylyl) -1H-imidazol-2-yl) -1-pyrrolidinyl) ethyl) carbamate methyl</td><td></td><td>2.03 minutes (Condition 2); &gt; 98%; LC / MS: Anal. Obi. for [M + H]⁺ C₄2H₄iN₈ABOUT₄: 721.33; found 721.31; HRMS: Anal. Obi. for [M + H] C₄2H₄iN₈ABOUT₄: 721.3251; found 721.3247</td>

<td> 68</td><td>((1 R) -2-oxo-1-phenyl-2 - ((2S) 2- (5- (4 '- (2 - ((2S) -1- (3-pyridinylcarbonyl) -2-pyrrolidinyl) -1H-imidazole -5-yl) -4-biphenylyl) -1H-imidazol-2-yl) -1-pyrrolidinyl) ethyl) carbamate methyl</td><td></td><td>1.91 minutes (Condition 2); &gt; 98%; LC / MS: Anal. Obi. for [M + H]⁺ C42H4iN8O4: 721.33; found 721.31; HRMS: Anal. Obi. for [M + H]⁺ C42H₄₁N₈ABOUT₄: 721.3251; found 721.3226</td>

150

<td> 69</td><td>((1R) -2 - ((2S) -2- (5- (4 '- (2 - ((2S) 1-isonicotinoyl-2-pyrrolidinyl) -1H-imidazol-5-yl) -4-biphenyl) -1 H -imidazol2-yl) -1-pyrrolidinyl) -2-oxo-1 phenylethyl) carbamate</td><td>AND</td><td>1.89 minutes (Condition 2); &gt; 98%; LC / MS: Anal. Calc. for [M + H]⁺ C42H41N8O4: 721.33; found 721.29; HRMS: Anal. Calc. for [M + H]⁺ C₄2H₄iN₈ABOUT₄·. 721.3251; found 721.3251</td>

<td> 70</td><td>((1R) -2 - ((2S) -2- (5- (4 '- (2 - ((2S) 1 - ((4R) -4-fluoro-1-methyl-Lprolyl) -2-pyrrolidinyl) Methyl -1Himidazol-5-yl) -4-biphenyl) 1H-imidazol-2-yl) -1-pyrrolidinyl) -2-oxo-1 phenylethyl) methyl carbamate</td><td>AND F Cap-11</td><td>1.84 minutes (Condition 2); &gt; 98%; LC / MS: Anal. Calc. for [M + H]⁺ C42H46FN8O4: 745.36; found 745.27; HRMS: Anal. Calc. for [M + H]⁺ C42H₄6FN₈ABOUT₄: 745.3626; found 745.3658</td>

<td> 71</td><td>((1R) -2 - ((2S) -2- (5- (4 '- (2 - ((2S) 1- (1,3-oxazol-2-ylcarbonyl) 2-pyrrolidinyl) -1H-imidazole Methyl-5-yl) -4-biphenylyl) -1H-imidazol2-yl) -1-pyrrolidinyl) -2-oxo-1 phenylethyl) carbamate</td><td>AND</td><td>1.97 minutes (Condition 2); &gt; 98%; LC / MS: Anal. Calc. for [M + H]⁺ C₄oH₃₉N₈0₅: 711.30; found 711.27</td>

<td> 72</td><td>((1R) -2 - ((2S) -2- (5- (4 '- (2 - ((2S) 1- (1,3-oxazol-5-ylcarbonyl) 2-pyrrolidinyl) -1H-imidazol- Methyl 5-yl) -4-biphenyl) -1H-imidazol2-yl) -1-pyrrolidinyl) -2-oxo-1 phenylethyl) carbamate</td><td>AND</td><td>1.95 minutes (Condition 2); &gt; 98%; LC / MS: Anal. Calc. for [M + H]⁺ C₄oH₃9N₈0₅: 711.30; found 711.27; HRMS: Anal. Calc. for [M + H]⁺ C4oH₃₉N₈0₅: 711.3043; found 711.3078</td>

<td> 73</td><td>((1R) -2 - ((2S) -2- (5- (4 '- (2 - ((2S) 1 ((dimethylamino) (oxo) acetyl) 2-pyrrolidinyl) -1H-imidazol-5-yl) Methyl-4-biphenylyl) -1H-imidazol2-yl) -1-pyrrolidinyl) -2-oxo-1 phenylethyl) carbamate</td><td> 0</td><td>1.92 minutes (Condition 2); &gt; 98%; LC / MS: Anal. Calc. for [M + H]⁺ C₄oH₄₃N₈0₅: 715.34; found 715.40</td>

151

<td> 74</td><td>((1 R) -2-oxo-1-phenyl-2 - ((2S) 2- (5- (4 '- (2 - ((2S) -1- (tetrahydro-3-furanylcarbonyl) -2-pyrrolidinyl) -1H -imidazol-5-yl) -4-biphenylyl) -1H-imidazol-2-yl) -1-pyrrolidinyl) ethyl) carbamate methyl</td><td>AND</td><td>1.91 minutes (Condition 2); &gt; 98%; LC / MS: Anal. Calc. for [M + H]⁺ C41H44N7O5: 714.34; found 714.39; HRMS: Anal. Calc. for [M + Hf C41H44N7O5: 714.3404; found 714.3433</td>

<td> 75</td><td>((1R) -2 - ((2S) -2- (5- (4 '- (2 - ((2S) 1 - (N- (methoxycarbonyl) -Lalanyl) -2-pyrrolidinyl) -1Himidazol-5-yl Methyl) -4-biphenylyl) 1H-imidazol-2-yl) -1-pyrrolidinyl) -2-oxo-1 phenylethyl) carbamate</td><td>H? 0 ^ΞCap-12</td><td>1.94 minutes (Condition 2); &gt; 98%; LC / MS: Anal. Calc. for [M + H]⁺ C4iH45N8O6: 745.35 found 745.34; HRMS: Anal. Calc. for [M + H]⁺ C4iH₄5N₈ABOUT₆: 745.3462; found 745.3486</td>

<td> 76</td><td>((1R) -2 - ((2S) -2- (5- (4 '- (2 - ((2S) 1- (N, N-dimethyl-L-alanyl) -2-pyrrolidinyl) -1H-imidazol-5-yl ) -4-biphenylyl) -1H-imidazol 2-yl) -1-pyrrolidinyl) -2-oxo-1 phenylethyl) carbamate</td><td> 1 °</td><td>1.80 minutes (Condition 2); &gt; 98%; LC / MS: Anal. Calc. for [M + H]⁺ C4iH47N8O4 715.37; found 715.35; HRMS: Anal. Calc. for [M + H]⁺ C4iH4₇N₈ABOUT₄715.3720; found 715.3737</td>

<td> 77</td><td>(2S) -2- (5- (4 '- (2 - ((2S) -1 - ((2R) -2 ((methoxycarbonyl) amino) -2-phenylacetyl) -2-pyrrolidinyl) 1H-imidazol-5- yl) -4-biphenylyl) -1H-imidazol-2-yl) methyl 1-pyrrolidinecarboxylate</td><td>0 ay</td><td>1.97 minutes (Condition 2); &gt; 98%; LC / MS: Anal. Calc. for [M + H]⁺ C38H40N7O5: 674.31; found 674.66; HRMS: Anal. Calc. for [M + H]⁺ C3₈H₄he₇05: 674.3091; found 674.3110</td>

<td> 78</td><td>((1R) -2 - ((2S) -2- (5- (4 '- (2 - ((2S) 1- (4-morpholinylcarbonyl) -2-pyrrolidinyl) -1H-imidazol-5-yl) -4-biphenyl ) -1-H-imidazol2-yl) -1-pyrrolidinyl) -2-oxo-1 phenylethyl) carbamate</td><td>ABOUT cA</td><td>1.95 minutes (Condition 2); &gt; 98%; LC / MS: Anal. Calc. for [M + H]⁺ C4iH45N8O5: 729.35; found 729.40; HRMS: Anal. Calc. for [M + H]⁺ C4 | H₄5N₈O5: 729.3513; found 729.3502</td>

152

<td rowspan="2"> 79</td><td rowspan="2">((1R) -2 - ((2S) -2- (5- (4 '- (2 - ((2S) 1 - ((4S) -4-fluoro-L-prolyl) -2-pyrrolidinyl) -1H- methyl imidazol-5-yl) -4-biphenyl) -1H-imidazol-2-yl) -1-pyrrolidinyl) -2-oxo-1 phenylethyl) carbamate</td><td colspan="2">H and?</td><td rowspan="2">1.80 minutes (Condition 2); &gt; 98%; LC / MS: Anal. Calc. for [M + H]⁺ C₄iH44FN₈ABOUT₄: 731.84; found 731.26</td>

<td>N___ ABOUT F</td><td></td>

<td> 80</td><td>((1 R) -2-oxo-1-phenyl-2 - ((2S) 2- (5- (4 '- (2 - ((2S) -1 -L-prolyl-2-pyrrolidinyl) -1H-imidazole -5-yl) -4-biphenylyl) -1H-imidazol-2-yl) -1-pyrrolidinyl) ethyl) carbamate methyl</td><td colspan="2">X</td><td>1.84 minutes (Condition 2); &gt; 98%; LC / MS: Anal. Calc. for [M + H]⁺ C₄H₄5N₈ABOUT₄: 713.36; found 713.36; HRMS: Anal. Calc. for [M + H] C₄ iH4₅N₈ABOUT₄: 713.3564; found 713.3563</td>

<td> 81</td><td>((1R) -2 - ((2S) -2- (5- (4 '- (2 - ((2S) 1- (4,4-difluoro-L-prolyl) -2-pyrrolidinyl) -1H-imidazol- Methyl 5-yl) -4-biphenyl) -1H-imidazol2-yl) -1-pyrrolidinyl) -2-oxo-1 phenylethyl) carbamate</td><td colspan="2">H and X F</td><td>1.88 minutes (Condition 2); &gt; 98%; LC / MS: Anal. Calc. for [M + H]⁺ C4iH43F2N8O4: 749.34; found 749.31; HRMS: Anal. Calc. for [M + H]⁺ C4iH43F₂N₈ABOUT₄: 749.3375; found 749.3390</td>

<td> 82</td><td>((1R) -2 - ((2S) -2- (5- (4 '- (2 - ((2S) 1 - ((4R) -4-fluoro-L-prolyl) -2-pyrrolidinyl) -1H- methyl imidazol-5-yl) -4-biphenylyl) -1H-imidazol2-yl) -1-pyrrolidinyl) -2-oxo-1 phenylethyl) carbamate</td><td colspan="2">X F</td><td>1.83 minutes (Condition 2); &gt; 98%; LC / MS: Anal. Calc. for [M + H]⁺ C4iH44FN8O4: 731.35; found 731.37; HRMS: Anal. Calc. for [M + H]⁺ C4iH₄₄FN₈ABOUT₄: 731.3470; found 731.3502</td>

<td> 83</td><td>((R) -2 - ((2S) -2- (5- (4 '- (2 - ((2S) l - ((lS, 3S, 5S) -2-aza [3.1.0] hex-3ylokarbonylo) - 2-pyrrolidinyl) 1H-imidazol-5-yl) -4-biphenylyl) -1H-imidazol-2-yl) 1-pyrrolidinyl) -2-oxo-1 phenylethyl) methylcarbamate</td><td colspan="2">X Si "</td><td>1.82 minutes (Condition 2); &gt; 98%; LC / MS: Anal. Calc. for [M + H]⁺ C42H45N8O4: 725.36; found 725.39; HRMS: Anal. Calc. for [M + H]⁺ C42H45N₈ABOUT₄: 725.3564; found 725.3574</td>

153

<td> 84</td><td>((1R) -2 - ((2S) -2- (5- (4 '- (2 - ((2S) 1 -L-alanyl-2-pyrrolidinyl) -1Himidazol-5-yl) -4-biphenyl)) Methyl 1H-imidazol-2-yl) -1-pyrrolidinyl) -2-oxo-1 phenylethyl) carbamate</td><td>about</td><td>1.82 minutes (Condition 2); &gt; 98%; LC / MS: Anal. Calc. for [M + H]⁺ C39H43N8O4: 687.34; found 687.32; HRMS: Anal. Calc. for [M + H]⁺ C39H43N8O4: 687.3407; found 687.3435</td>

<td> 84-1</td><td>((1 R) -2-oxo-1-phenyl-2 - ((2S) 2- (5- (4 '- (2 - ((2S) -1 - ((2R) -2-phenyl-2- (1 piperidinyl) acetyl) -2-pyrrolidinyl) -1H-imidazol-5-yl) -4-biphenyl) -1H-imidazol-2-yl) -1-pyrrolidinyl) ethyl) carbamate methyl</td><td> 0 ^phMO Cap-14</td><td>* H NMR (400 MHz, CD3OD) δ 7.90-7.85 (m, 9H), 7.81-7.79 (m, 1H), 7.63-7.57 (m, 5H), 7.457.32 (m, 6H), 5.51 (s, 1H), 5.45 (s, 1H), 5.33-59 (m, 2H), 4.06-4.01 (m, 2H), 3.63 (d, J = 4.04 Hz, 3H), 3.59-3.50 (m, 2H), 3.193 .12 (m, 1H), 3.07-3.01 (m, 1H), 2.93-2.76 (m, 2H), 2.57- 2.51 (m, 1H), 2.402.31 (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. Calc. for C49H52N8O4: 816; found: 817 (M + H)⁺.</td>

<td> 84-2</td><td>((1R) -2 - ((2S) -2- (5- (4 '- (2 - ((2S) 1 - ((2S) -2- (2-fluorophenyl) -2-hydroxypropanoyl) -2-pyrrolidinyl) - methyl 1H-imidazol-5-yl) -4-biphenyl) -1H-imidazol-2-yl) -1-pyrrolidinyl) -2-oxo-1 phenylethyl) carbamate</td><td>M OH</td><td>'HNMR (400 MHz, CD3OD) δ 7.89-7.85 (m, 8H), 7.81-7.73 (2H), 7.677.65 (m, 1H), 7.45- 7.26 (m, 7H), 7.13-7.08 (m, 1H), 6.94-6.89 ( m, 0.5H), 6.72-6.67 (0.5H), 6.09-6.07 (m, 0.4H), 5.51 (s, 1H), 5.32-5.25 (m, 1.6H), 4.083.95 (m, 2H), 3.85-3.79 (1H), 3.64-3.63 (m, 3H), 3.56-3.349 (1H), 3.09-3.03 (m, 1H), 2.59-2.50 (m, 1H), 2.42-2.33 (m, 2H )</td>

154

<td></td><td></td><td></td><td>2.21-2.00 (m, 6H), 1.821.74 (m, 1H), 1.66 (d, J = 4.55 Hz, 3H); LCMS: Anal. Calc. for C45H46LN7O3: 781; found: 782 (M + H)⁺.</td>

<td> 84-3</td><td>((1 R) -2-oxo-2 - ((2S) -2- (5- (4 '(2 - ((2S) -1- (5-oxo-D-prolyl) -2-pyrrolidinyl) -1H- methyl imidazol-5-yl) -4-biphenyl) -1H-imidazol-2-yl) -1-pyrrolidinyl) -1-phenylethyl) carbamate</td><td>X about</td><td>LCMS: Anal. Calc. for C.₄₁H₄2N₈ABOUT₅: 726; found: 727 (M + H)⁺.</td>

<td> 84-4</td><td>((1R) -2 - ((2S) -2- (5- (4 '- (2 - ((2S) 1 - ((2R) -2- (4-hydroxy-4-methyl-1-piperidinyl) -2-phenylacetyl ) -2-pyrrolidinyl) 1H-imidazol-5-yl) -4-biphenylyl) -1H-imidazol-2-yl) 1-pyrrolidinyl) -2-oxo-1 phenylethyl) methylcarbamate</td><td>OH yr Cap-15</td><td>LCMS: Anal. Calc. for C.₅oH₅4N₈0₅: 846; found: 847 (M + H)⁺.</td>

<td> 84-5</td><td>(4R) -4 - (((2S) -2- (5- (4 '- (2 - ((2S) l - ((2R) -2- ((methoxycarbonyl) amino) -2fenyloacetylo) -2-pyrrolidinyl) 1H-imidazol-5-yl) -4-biphenylyl) -1H-imidazol-2-yl) 1-pyrrolidinyl) carbonyl) -1,3-thiazolidine-3-carboxylate tert-butyl</td><td>Yo SC Boc</td><td>LCMS: Anal. Calc. for C.₄5H₅he₈0₆S: 830; found: 831 (M + H)⁺.</td>

<td> 84-6</td><td>((1 R) -2 - ((2S) -2- (5- (4 '- (2 - ((2S) 1- ((1- ((tert-butoxycarbonyl) amino) cyclopentyl) carbonyl) -2-pyrrolidinyl) - Methyl 1-H-imidazol-5-yl) -4-biphenylyl) -1 H-imidazol-2-yl) -1-pyrrolidinyl) -2-oxo-1 phenylethyl) carbamate</td><td>loaf</td><td>LCMS: Anal. Calc. for C.₄₇H₅4FN₈ABOUT₆: 826; found: 827 (M + H)⁺.</td>

155

<td> 84-7</td><td>((1R) -2 - ((2S) -2- (5- (4 '- (2 - ((2S) 1- (N-benzoylglycyl) -2-pyrrolidinyl) -1H-imidazol-5-yl) -4-biphenylyl ) -1-H-imidazol2-yl) -1-pyrrolidinyl) -2-oxo-1 phenylethyl) carbamate</td><td>Ph H horsepower oo</td><td>LCMS: Anal. Obi. for C45H₄4FN₈ABOUT₅: 776; found: 777 (M + H)⁺.</td>

<td> 84-8</td><td>((1 R) -2 - ((2S) -2- (5- (4 '- (2 - ((2 S) 1- (4- (4-methyl-1-piperazinyl) benzoyl) -2-pyrrolidinyl) -1H -imidazol-5-yl) -4-biphenylyl) -1H-imidazol2-yl) -1-pyrrolidinyl) -2-oxo-1 phenylethyl) carbamate</td><td></td><td>LCMS: Anal. Obi. for C.₄₈H5iN₉ABOUT₄: 817; found: 818 (M + H)⁺.</td>

<td> 84-9</td><td>((1 R) -2-oxo-1-phenyl-2 - ((2S) 2- (5- (4 '- (2 - ((2S) -1 - ((5-phenyl-2-thienyl) carbonyl) - 2-pyrrolidinyl) -1H-imidazol-5-yl) -4-biphenylyl) -1H-imidazol2-yl) -1-pyrrolidinyl) ethyl) carbamate methyl</td><td>V ph</td><td>LCMS: Anal. Obi. for C.₄₇H₄₃N₇ABOUT₄S: 801; found: 802 (M + H)⁺.</td>

<td> 84-10</td><td>((1 R) -2-oxo-1-phenyl-2 - ((2 S) 2- (5- (4 '- (2 - ((2S) -1 - ((4-phenylol, 2,3- thiadiazol-5-yl) carbonyl) 2-pyrrolidinyl) -1H-imidazol-5-yl) -4-biphenyl) -1H-imidazol2-yl) -1-pyrrolidinyl) ethyl) carbamate methyl</td><td>ph IN_aboutNs °</td><td>LCMS: Anal. Obi. for C45H41N9O4S: 803; found: 804 (M + H)⁺.</td>

<td> 84-11</td><td>((1 R) -2-oxo-1-phenyl-2 - ((2S) 2- (5- (4 '- (2 - ((2S) -1 - ((2-phenyl-1,3-thiazol-4 -yl) carbonyl) -2-pyrrolidinyl) -1H-imidazol-5-yl) -4-biphenylyl) -1H-imidazol2-yl) -1-pyrrolidinyl) ethyl) carbamate methyl</td><td>2 CL</td><td>LCMS: Anal. Obi. for C.₄óH42N₈ABOUT₄S: 802; found: 803 (M + H)⁺.</td>

156

<td> 84-12</td><td>4 - (((2S) -2- (5- (4 '- (2 - ((2S) -1 ((2R) -2 ((methoxycarbonyl) amino) -2-phenylacetyl) -2-pyrrolidinyl) 1H-imidazole -5-yl) -4-biphenylyl) -1H-imidazol-2-yl) 1-pyrrolidinyl) carbonyl) -4-methyl-1-tert-butylpiperidine carboxylate</td><td>Boc. AND</td><td>LCMS: Anal. Calc. for C.₄₈H56N₈ABOUT₆: 840; found: 841 (M + H)⁺.</td>

<td> 84-13</td><td>((1R) -2 - ((2S) -2- (5- (4 '- (2 - ((2S) 1- (4- (dimethylamino) butanoyl) 2-pyrrolidinyl) -1H-imidazol-5-yl) Methyl-4-biphenylyl) -1H-imidazol2-yl) -1-pyrrolidinyl) -2-oxo-1 phenylethyl) carbamate</td><td>--N \</td><td>LCMS: Anal. Calc. for C.₄₂H₄₈N₈ABOUT₄: 728; found: 729 (M + H)⁺.</td>

<td> 84-14</td><td>((1R) -2 - ((2S) -2- (5- (4 '- (2 - ((2S) 1- ((3-hydroxyphenyl) acetyl) 2-pyrrolidinyl) -1H-imidazol-5-yl Methyl) -4-biphenylyl) -1H-imidazol2-yl) -1-pyrrolidinyl) -2-oxo-1 phenylethyl) carbamate</td><td>X OH</td><td>LCMS: Anal. Calc. for C44H₄₃N₇ABOUT₅: 749; found: 750 (M + H)⁺.</td>

<td> 84-15</td><td>((1R) -2 - ((2S) -2- (5- (4 '- (2 - ((2S) 1- (N, N-dimethyl-beta-alanyl) 2-pyrrolidinyl) -1H-imidazol- Methyl 5-yl) -4-biphenyl) -1H-imidazol2-yl) -1-pyrrolidinyl) -2-oxo-1 phenylethyl) carbamate</td><td>0 N /</td><td>LCMS: Anal. Calc. for C.₄| H₄6N₈ABOUT₄: 714; found: 715 (M + H)⁺.</td>

<td> 84-16</td><td>((1R) -2 - ((2S) -2- (5- (4 '- (2 - ((2S) 1- (4 (hydroxymethyl) benzoyl) -2-pyrrolidinyl) -1H-imidazol-5-yl) -4 methyl-biphenylyl) -1H-imidazol2-yl) -1-pyrrolidinyl) -2-oxo-1 phenylethyl) carbamate</td><td>^ΗΟ00Λ</td><td>LCMS: Anal. Calc. for C₄₄H₄3N7O5: 749; found: 750 (M + H)⁺.</td>

<td> 84-17</td><td>((1R) -2 - ((2S) -2- (5- (4 '- (2 - ((2S) 1 - (((3R) -1-benzyl-3-pyrrolidinyl) carbonyl) -2-pyrrolidinyl) - 1H-imidazol-5-yl) -4-biphenylyl) -1H-imidazol-</td><td>\&gt; "Ζ</td><td>LCMS: Anal. Calc. for C.₄₈H5oN₈0₄: 802; found: 803 (M + H)⁺.</td>

157

<td></td><td>Methyl 2-yl) -1-pyrrolidinyl) -2-oxo-1 phenylethyl) carbamate</td><td></td><td></td>

<td> 84-18</td><td>(2S) -2- (2 - ((2S) -2- (5- (4 '- (2- ((2S) -l - ((2R) -2- ((methoxycarbonyl) amino) -2fenyloacetylo) -2- pyrrolidinyl) 1H-imidazol-5-yl) -4-biphenylyl) -1H-imidazol-2-yl) 1-pyrrolidinyl) -2-oxoethyl) -1-tert-butyl pyrrolidinecarboxylate</td><td>'Μ / ν 1 N-Boc</td><td>LCMS: Anal. Calc. for C47H54N8O6: 826; found: 827 (M + H)⁺.</td>

<td> 84-19</td><td>((1R) -2 - ((2S) -2- (5- (4 '- (2 - ((2S) 1 - ((5-methyl-1H-pyrazol-3-yl) acetyl) -2-pyrrolidinyl) Methyl -1Himidazol-5-yl) -4-biphenyl) 1H-imidazol-2-yl) -1-pyrrolidinyl) -2-oxo-1 phenylethyl) methyl carbamate</td><td>AND HNA</td><td>LCMS: Anal. Calc. for C42H43N9O4: 737; found: 738 (M + H)⁺.</td>

<td> 84-20</td><td>((1R) -2 - ((2S) -2- (5- (4 '- (2 - ((2S) 1 - (((3S) -7-hydroxy-1,2,3,4-tetrahydro-3-isoquinolinyl ) carbonyl) -2-pyrrolidinyl) -1H-imidazol-5-yl) -4-biphenyl) -1H-imidazol2-yl) -1-pyrrolidinyl) -2-oxo-1 phenylethyl) methyl carbamate</td><td>\ - NH v</td><td>LCMS: Anal. Calc. for C46H46N8O5: 790; found: 791 (M + H)⁺.</td>

<td> 84-21</td><td>(2R) -2 - (((2S) -2- (5- (4 '- (2 - ((2S) l - ((2R) -2- ((methoxycarbonyl) amino) -2fenyloacetylo) -2-pyrrolidinyl) 1H-imidazol-5-yl) -4-biphenylyl) -1H-imidazol-2-yl) 1-pyrrolidinyl) carbonyl) -1-tert-butyl piperidinecarboxylate</td><td>CA Boc</td><td>LCMS: Anal. Calc. for C.₄₇H54N₈ABOUT₆: 826; found: 827 (M + H)⁺.</td>

<td> 84-22</td><td>((1 R) -2-oxo-1-phenyl-2 - ((2S) 2- (5- (4 '- (2 - ((2S) -1 - ((5-phenyl-4-oxazolyl) carbonyl) - 2-pyrrolidinyl) -1H-imidazol-5-yl) -4-biphenylyl) -1H-imidazol-</td><td>ph</td><td>LCMS: Anal. Calc. for C.₄6H₄2N₈ABOUT₅: 786; found: 787 (M + H)⁺.</td>

158

<td></td><td>2-yl) -l-pyrrolidinyl) ethyl) carbamate methyl</td><td></td><td></td>

<td> 84-23</td><td>((1R) -2 - ((2S) -2- (5- (4 '- (2 - ((2S) 1 - (((1R, 3S) -3 - ((tert-butoxycarbonyl) amino) cyclopropyl) carbonyl ) -2-pyrrolidinyl) -1H-imidazol-5-yl) 4-biphenylyl) -1H-imidazol-2-yl) -1-pyrrolidinyl) -2-oxo-1 phenylethyl) methyl carbamate</td><td></td><td>LCMS: Anal. Calc. for C4₇H₅₄N₈ABOUT₆: 826; found: 827 (M + H)⁺.</td>

<td> 84-24</td><td>((1 R) -2-oxo-1-phenyl-2 - ((2S) 2- (5- (4 '- (2 - ((2S) -1- (3- (piperidinyl) propanoyl) -2-pyrrolidinyl ) -1 H-imidazol-5-yl) -4-biphenylyl) -1 H-imidazol-2-yl) -1-pyrrolidinyl) ethyl) carbamate methyl</td><td>χ Ό</td><td>LCMS: Anal. Calc. for C44H50N8O4: 754; found: 755 (M + H)⁺.</td>

<td> 84-25</td><td>((1R) -2 - ((2S) -2- (5- (4 '- (2 - ((2S) 1- (2-benzoyl-benzoyl) -2-pyrrolidinyl) -1H-imidazol-5-yl) -4-biphenyl ) -1-H-imidazol2-yl) -1-pyrrolidinyl) -2-oxo-1 phenylethyl) carbamate</td><td>Q / ° ph</td><td>LCMS: Anal. Calc. for C.₅₀H₄₅N₇ABOUT₅: 823; found: 824 (M + H)⁺.</td>

<td> 84-26</td><td>((1R) -2 - ((2S) -2- (5- (4 '- (2 - ((2S) 1 - ((2-methoxyphenoxy) acetyl) 2-pyrrolidinyl) -1H-imidazol-5-yl) Methyl-4-biphenylyl) -1H-imidazol2-yl) -1-pyrrolidinyl) -2-oxo-1 phenylethyl) carbamate</td><td>Y Meo</td><td>LCMS: Anal. Calc. for C.₄5H4₅N₇ABOUT₆: 779; found: 780 (M + H)⁺.</td>

<td> 84-27</td><td>3 - (((2S) -2- (5- (4 '- (2 - ((2S) -l ((2R) -2- ((methoxycarbonyl) amino) -2fenyloacetylo) -2-pyrrolidinyl) -lH-imidazol- 5-yl) -4-biphenylyl) -1H-imidazol-2-yl) 1-pyrrolidinyl) carbonyl) -1-tert-butyl azetidinecarboxylate</td><td>Boc "ⁿAT 9</td><td>LCMS: Anal. Calc. for C45H50N8O6: 798; found: 799 (M + H)⁺.</td>

159

<td> 84-28</td><td>((1R) -2 - ((2S) -2- (5- (4 '- (2 - ((2S) 1 - (((3S) -1-benzyl-3-pyrrolidinyl) carbonyl) -2-pyrrolidinyl) -1 Methyl H-imidazol-5-yl) -4-biphenyl) -1H-imidazol-2-yl) -1-pyrrolidinyl) -2-oxo-1 phenylethyl) carbamate</td><td>ph "oA</td><td>LCMS: Anal. Calc. for C48H50N8O4: 802; found: 803 (M + H)⁺.</td>

<td> 84-29</td><td>((1 R) -2-oxo-1-phenyl-2 - ((2S) 2- (5- (4 '- (2 - ((2S) -1- (3- (1-pyrrolidinyl) benzoyl) -2-pyrrolidinyl) -1 H-imidazol-5-yl) -4-biphenylyl) -1 H-imidazol-2-yl) -1-pyrrolidinyl) ethyl) carbamate methyl</td><td> 0</td><td>LCMS: Anal. Calc. for C47H48N8O4: 788; found: 789 (M + H)⁺.</td>

<td> 84-30</td><td>((1R) -2 - ((2S) -2- (5- (4 '- (2 - ((2S) 1- (2 - ((tert-butoxycarbonyl) amino) benzoyl) -2-pyrrolidinyl) -1Himidazol- Methyl 5-yl) -4-biphenyl) 1H-imidazol-2-yl) -1-pyrrolidinyl) -2-oxo-1 phenylethyl) carbamate</td><td>QA NHBoc</td><td>LCMS: Anal. Calc. for C48H50N8O6: 834; found: 835 (M + H)⁺.</td>

<td> 84-31</td><td>(3R) -3 - (((2S) -2- (5- (4 '- (2 - ((2S) l - ((2R) -2- ((methoxycarbonyl) amino) -2fenyloacetylo) -2-pyrrolidinyl) 1H-imidazol-5-yl) -4-biphenylyl) -1H-imidazol-2-yl) 1-pyrrolidinyl) carbonyl) -1-tert-butyl piperidinecarboxylate</td><td>"X X Boc</td><td>LCMS: Anal. Calc. for C.₄7H₅₄N₈ABOUT₆: 826; found: 827 (M + H)⁺.</td>

<td> 84-32</td><td>((1R) -2-oxo-1-phenyl-2 - ((2S) 2- (5- (4 '- (2 - ((2S) -1 - ((1 (trifluoromethyl) cyclopropyl) carbonyl) - Methyl 2-pyrrolidinyl) -1-imidazol-5-yl) -4-biphenyl) 1H-imidazol-2-yl) -1-pyrrolidinyl) ethyl) carbamate methyl</td><td>AND f₃c</td><td>LCMS: Anal. Calc. for C41H40F3N7O4: 751; found: 752 (M + H)⁺.</td>

160

<td> 84-33</td><td>((1 R) -2 - ((2S) -2- (5- (4 '- (2 - ((2S) 1- (4- (dimethylamino) benzoyl) 2-pyrrolidinyl) -1H-imidazol-5-yl) Methyl-4-biphenyls) -1H-imidazol2-yl) -1-pyrrolidinyl) -2-oxo-1 phenylethyl) carbamate</td><td>Yoa,</td><td>LCMS: Anal. Calc. for C.₄5H₄6N₈ABOUT₄: 762; found: 763 (M + H)⁺.</td>

<td> 84-34</td><td>((1R) -2 - ((2S) -2- (5- (4 '- (2 - ((2S) 1- (3-benzoylbenzoyl) -2-pyrrolidinyl) -1H-imidazol-5-yl) -4-biphenyl ) -1-H-imidazol2-yl) -1-pyrrolidinyl) -2-oxo-1 phenylethyl) methylcarbamate</td><td>ph</td><td>LCMS: Anal. Calc. for C50H45N7O5: 823; found: 824 (M + H)⁺.</td>

<td> 84-35</td><td>((1R) -2 - ((2S) -2- (5- (4 '- (2 - ((2S) 1 - ((cis-4 - ((tert-butoxycarbonyl) amino) cycloexyl) carbonyl) -2-pyrrolidinyl) -1 H-imidazol-5-yl) -4-biphenylyl) -1 H-imidazol-2-yl) -1-pyrrolidinyl) -2-oxo-1 phenylethyl) methyl carbamate</td><td>fM loaf¹''\__/ ABOUT</td><td>LCMS: Anal. Calc. for C.₄₈H₅6N₈ABOUT₆: 840; found: 841 (M + H)⁺.</td>

<td> 84-36</td><td>4 - (((2S) -2- (5- (4 '- (2 - ((2S) -1 ((2R) -2 ((methoxycarbonyl) amino) -2-phenylacetyl) -2-pyrrolidinyl) 1H-imidazole -5-yl) -4-biphenylyl) -1H-imidazol-2-yl) 1-pyrrolidinyl) carbonyl) -1-tert-butyl piperidinecarboxylate</td><td>BcA ^ / °</td><td>LCMS: Anal. Calc. for C.₄7H54N₈ABOUT₆: 826; found: 827 (M + H)⁺.</td>

<td> 84-37</td><td>((1R) -2 - ((2S) -2- (5- (4 '- (2 - ((2S) 1- ((cis-4 - ((tert-butoxycarbonyl) amino) cycloxyl) carbonyl) -2-pyrrolidinyl) methyl -1H-imidazol-5-yl) -4-biphenylyl) -1H-imidazol2-yl) -1-pyrrolidinyl) -2-oxo-1 phenylethyl) methyl carbamate</td><td>BocHN ' ^X°</td><td>LCMS: Anal. Calc. for C.₄₈Hj6N₈O6: 840; found: 841 (M + H)⁺.</td>

161

<td> 84-38</td><td>((1 R) -2 - ((2S) -2- (5- (4 '- (2 - ((2S) 1- (diphenylacetyl) -2-pyrrolidinyl) -1H-imidazol-5-yl) -4-biphenyl)) Methyl -1H-imidazol2-yl) -1-pyrrolidinyl) -2-oxo-1 phenylethyl) carbamate</td><td> ‘^/V_vv. ^phX Pif °</td><td>LCMS: Anal. Calc. for C50H47N7O4: 809; found: 810 (M + H)⁺.</td>

<td> 84-39</td><td>((1 R) -2-oxo-2 - ((2S) -2- (5- (4 (2 - ((2S) -1- (4-oxopentanoyl) -2-pyrrolidinyl) -1H-imidazol-5-yl) Methyl-4-biphenylyl) -1H-imidazol2-yl) -1-pyrrolidinyl) -1-phenylethyl) carbamate</td><td></td><td>LCMS: Anal. Calc. for C41H43N7O5: 713; found: 714 (M + H)⁺.</td>

<td> 84-40</td><td>((1R) -2 - ((2S) -2- (5- (4 '- (2 - ((2S) 1- (2-fluorobenzoyl) -2-pyrrolidinyl) -1H-imidazol-5-yl) -4-biphenylyl ) -1-H-imidazol2-yl) -1-pyrrolidinyl) -2-oxo-1 phenylethyl) carbamate</td><td>F</td><td>LCMS: Anal. Calc. for C43H₄ofn₇0₄: 737; found: 738 (M + H)⁺.</td>

<td> 84-41</td><td>((1R) -2 - ((2S) -2- (5- (4 '- (2 - ((2S) 1- (2-biphenylylcarbonyl) -2-pyrrolidinyl) -1H-imidazol-5-yl) -4-biphenyl)) Methyl -1H-imidazol2-yl) -1-pyrrolidinyl) -2-oxo-1 phenylethyl) carbamate</td><td>"X X ph</td><td>LCMS: Anal. Calc. for C49H45N7O4: 795; found: 796 (M + H)⁺.</td>

<td> 84-42</td><td>((1R) -2 - ((2S) -2- (5- (4 '- (2 - ((2S) 1- (2-benzylbenzoyl) -2-pyrrolidinyl) -1H-imidazol-5-yl) -4-biphenylyl ) -1-H-imidazol2-yl) -1-pyrrolidinyl) -2-oxo-1 phenylethyl) carbamate</td><td>&lt;Xo ph</td><td>LCMS: Anal. Calc. for C50H47N7O4: 809; found: 810 (M + H)⁺.</td>

<td> 84-43</td><td>((R) -2 - ((2S) -2- (5- (4 '- (2 - ((2S) l - ((2E) -3- (4- (dimethylamino) phenyl) -2propenoilo) -2- pyrrolidinyl) -1-imidazol-5-yl) -4-biphenylyl) 1H-imidazol-2-yl) -1 pyrrolidinyl) -2-oxo-1 phenylethyl) methyl carbamate</td><td>X</td><td>LCMS: Anal. Calc. for C47H48N8O4: 788; found: 789 (M + H)⁺.</td>

162

<td> 84-44</td><td>((1 R) -2-oxo-1-phenyl-2 - ((2S) 2- (5- (4 '- (2 - ((2S) -1- (1,3-thiazol-4-ylcarbonyl) -2 pyrrolidinyl) -lH-imidazol-5-yl) -4bifenylylo) -lH-imidazol-2-yl) 1pirolidynylo) ethyl) carbamate methyl</td><td>^s0A AND ^AT</td><td>LCMS: Anal. Obi. for C.₄₀H₃₈N₈ABOUT₄S: 726; found: 727 (M + H)⁺.</td>

<td> 84-45</td><td>((1 R) -2 - ((2S) -2- (5- (4 '- (2 - ((2S) 1 - ((((1 R, 2S, 5R) -2-isopropyl-5-methylcyclohexyl) oxy ) acetyl) -2-pyrrolidinyl) -1H-imidazol-5-yl) -4-biphenyl) -1H-midazol-2-yl) -1-pyrrolidinyl) 2-oxo-1-ethyl-ethyl) -carbamate</td><td>oA AND.....</td><td>LCMS: Anal. Obi. for C.₄₈H₅₇N₇ABOUT₅: 811; found: 812 (M + H)⁺.</td>

<td> 84-46</td><td>((1R) -2 - ((2S) -2- (5- (4 '- (2 - ((2S) 1 - ((dimethylamino) (2-thienyl) acetyl) -2-pyrrolidinyl) 1H-imidazol-5- methyl) -4-biphenylyl) -1H-imidazol-2-yl) 1-pyrrolidinyl) -2-oxo-1 phenylethyl) carbamate</td><td>₀9 / NMe₂Cap AT</td><td>LCMS: Anal. Obi. for C44H46N8O4S: 782; found: 782 (M + H)⁺.</td>

<td> 84-47</td><td>((1R) -2 - ((2S) -2- (5- (4 '- (2 - ((2S) 1 - ((dimethylamino) (3-thienyl) acetyl) -2-pyrrolidinyl) 1H-imidazol-5 methyl-yl) -4-biphenylyl) -1H-imidazol-2-yl) 1-pyrrolidinyl) -2-oxo-1-phenylethyl) carbamate</td><td>P Ρ ' ^ΝΜθ2 Cap-3 3</td><td>LCMS: Anal. Obi. for C.₄₄H₄₆N₈ABOUT₄S: 782; found: 782 (M + H)⁺.</td>

<td> 84-48</td><td>((1R) -2 - ((2S) -2- (5- (4 '- (2 - ((2S) 1 - ((dimethylamino) (2-methyl-1,3-thiazol-4-yl) acetyl) - 2-pyrrolidinyl) -1H-imidazol-5-yl) -4-biphenylyl) -1H-imidazol2-yl) -1-pyrrolidinyl) -2-oxo-1 phenylethyl) methyl carbamate</td><td>F. V A NMe₂CapA 1</td><td>LCMS: Anal. Obi. for C.₄₄H₄₇N₉ABOUT₄S: 797; found: 798 (M + H)⁺.</td>

163

<td rowspan="7"> 84-49</td><td rowspan="7">((1R) -2 - ((2S) -2- (5- (4 '- (2 - ((2S) 1- (1,2-benzisoxazol-3-yl (dimethylamino) acetyl) -2-pyrrolidinyl) -1H -imidazol-5-yl) -4-biphenylyl) -1H-imidazol2-yl) -1-pyrrolidinyl) -2-oxo-1 phenylethyl) carbamate</td><td rowspan="7">NMe₂Cop-34</td><td>LCMS: Anal. Calc. for</td>

<td>C47H47N9O5: 817;</td>

<td>found: 818 (M + H)⁺.</td>

<td></td>

<td></td>

<td></td>

<td></td>

<td> 84-50</td><td>((R) -2 - ((2S) -2- (5- (4 '- (2 - ((2S) -</td><td></td><td>LCMS: Anal. Calc. for</td>

<td></td><td>1 - (1-benzothiophen-3 -</td><td>Ω /</td><td>C₄₈H₄₈N₈ABOUT₄S: 832;</td>

<td></td><td>methyl (dimethylamino) acetyl) -2-pyrrolidinyl) -1H-imidazol-5-yl) -4-biphenyl) -1H-imidazol2-yl) -1-pyrrolidinyl) -2-oxo-1-phenylethyl) carbamate methyl</td><td>NMe₂Cap-35</td><td>found: 833 (M + H)⁺.</td>

<td> 84-51</td><td>((R) -2 - ((2S) -2- (5- (4 '- (2 - ((2S) -</td><td></td><td>LCMS: Anal. Calc. for</td>

<td></td><td>1 - ((dimethylamino) (1-naphthy 1) acetyl) -2-pyrrolidinyl) -1Himidazol-5-yl) -4-biphenyl yl) 1H-imidazol-2-yl) -1-pyrrolidinyl) -2-oxo Methyl phenylethyl) carbamate</td><td>NMe₂Cap-23</td><td>C5oH5oN₈0₄: 826; found: 827 (M + H)⁺.</td>

<td> 84-52</td><td>((R) -2 - ((2S) -2- (5- (4 '- (2 - ((2S) -</td><td></td><td>LCMS: Anal. Calc. for</td>

<td></td><td>1 - ((dimethylamino) (3-</td><td rowspan="2">1 'NMe₂Cap-37</td><td>C49H49N9O4: 827;</td>

<td></td><td>quinolinyl) acetyl) -2-pyrrolidinyl) -1H-imidazol-5-yl) -4-biphenyl) -1H-imidazol2-yl) -1-pyrrolidinyl) -2-oxo-1 phenylethyl) methyl carbamate</td><td>found: 828 (M + H)⁺.</td>

<td> 84-53</td><td>((R) -2 - ((2S) -2- (5- (4 '- (2 - ((2S) -</td><td rowspan="3">uL X J ^K NMe₂Cap-36</td><td>LCMS: Anal. Calc. for</td>

<td></td><td>1 - ((dimethylamino) (2-methyl-</td><td>C₄₈H₄9N9O₄S: 847;</td>

<td></td><td>1,3-benzothiazol-5-yl) acetyl) -2-pyrrolidinyl) -1H-imidazol-5-yl) -4-biphenyl) -1H-imidazol2-yl) -1-pyrrolidinyl) -2-oxo-1 phenylethyl) carbamate methyl</td><td>found: 848 (M + H)⁺.</td>

164

<td> 84-54</td><td>((1R) -2 - ((2S) -2- (5- (4 '- (2 - ((2S) 1 - ((dimethylamino) (3- (trifluoromethyl) phenyl) acetyl) 2-pyrrolidinyl) -1H -imidazol-5-yl) -4-biphenylyl) -1H-imidazol2-yl) -1-pyrrolidinyl) -2-oxo-1 phenylethyl) carbamate</td><td>•AND ^ΝΜθ2 Cap-24</td><td>LCMS: Anal. Calc. for C47H47F3N8O4: 844; found: 845 (M + H)⁺.</td>

<td> 84-55</td><td>((1R) -2 - ((2S) -2- (5- (4 '- (2 - ((2S) 1- ((dimethylamino) (2 (trifluoromethyl) phenyl) acetyl) 2-pyrrolidinyl) -1H -imidazol-5-yl) -4-biphenylyl) -1H-imidazol2-yl) -1-pyrrolidinyl) -2-oxo-1 phenylethyl) carbamate</td><td>/ NMe₂Cap-25</td><td>LCMS: Anal. Calc. for C47H47F3N8O4: 844; found: 845 (M + H)⁺.</td>

<td> 84-56</td><td>((1R) -2 - ((2S) -2- (5- (4 '- (2 - ((2S) 1 - ((2-chlorophenyl) (dimethylamino) acetyl) -2-pyrrolidinyl) -1Himidazol-5-yl Methyl) -4-biphenylyl) 1H-imidazol-2-yl) -1-pyrrolidinyl) -2-oxo-1 phenylethyl) carbamate</td><td>AND Cap-29</td><td>LCMS: Anal. Calc. for C46H47CIN8O4: 810; found: 811 (M + H)⁺.</td>

<td> 84-57</td><td>((1R) -2 - ((2S) -2- (5- (4 '- (2 - ((2S) 1 - ((3-chlorophenyl) (dimethylamino) acetyl) -2-pyrrolidinyl) -1Himidazol-5-yl Methyl) -4-biphenylyl) 1H-imidazol-2-yl) -1-pyrrolidinyl) -2-oxo-1 phenylethyl) carbamate</td><td>gr^clA NMe₂Cap-2%</td><td>LCMS: Anal. Calc. for C46H47CIN8O4: 810; found: 811 (M + H)⁺.</td>

<td> 84-58</td><td>((1R) -2 - ((2S) -2- (5- (4 '- (2 - ((2S) 1 - ((4-chlorophenyl) (dimethylamino) acetyl) -2-pyrrolidinyl) -1Himidazol-5-yl Methyl) -4-biphenylyl) 1H-imidazol-2-yl) -1-pyrrolidinyl) -2-oxo-1 phenylethyl) carbamate</td><td>cl AND NMe₂~ υν ²Cap-39</td><td>LCMS: Anal. Calc. for C46H47CIN8O4: 810; found: 811 (M + H)⁺.</td>

165

<td> 84-59</td><td>((1R) -2 - ((2S) -2- (5- (4 '- (2 - ((2S) 1- ((dimethylamino) (2-fluorophenyl) acetyl) -2-pyrrolidinyl) -1H-imidazol-5-yl Methyl) -4-biphenylyl) -1H-imidazol2-yl) -1-pyrrolidinyl) -2-oxo-1 phenylethyl) carbamate</td><td>NMe₂Cap-26</td><td>LCMS: Anal. Calc. for C.₄6H47FN₈ABOUT₄: 794; found: 795 (M + H)⁺.</td>

<td> 84-60</td><td>((1R) -2 - ((2S) -2- (5- (4 '- (2 - ((2S) 1 - ((dimethylamino) (3-fluorophenyl) acetyl) -2-pyrrolidinyl) -1H-imidazol-5-yl) Methyl-4-biphenylyl) -1H-imidazol2-yl) -1-pyrrolidinyl) -2-oxo-1 phenylethyl) carbamate</td><td>AND 4L ^NM®²Cap-21</td><td>LCMS: Anal. Calc. for C.₄₆H47FN₈ABOUT₄: 794; found: 795 (M + H)⁺.</td>

<td> 84-61</td><td>((1R) -2 - ((2S) -2- (5- (4 '- (2 - ((2S) 1- ((dimethylamino) (2-pyridinyl) acetyl) -2-pyrrolidinyl) -1H-imidazol-5-yl) Methyl-4-biphenylyl) -1H-imidazol2-yl) -1-pyrrolidinyl) -2-oxo-1 phenylethyl) carbamate</td><td>yf X NMe₂Cap-29</td><td>LCMS: Anal. Calc. for C45H47N9O4: 777; found: 778 (M + H)⁺.</td>

<td> 84-62</td><td>((1R) -2 - ((2S) -2- (4- (4 '- (2 - ((2S) 1 - ((dimethylamino) (3-pyridinyl) acetyl) -2-pyrrolidinyl) -1H-imidazol-5-yl) - Methyl 4-biphenylyl) -1H-imidazol2-yl) -1-pyrrolidinyl) -2-oxo-1 phenylethyl) carbamate</td><td>K A NMe₂Cap-19</td><td>LCMS: Anal. Calc. for C45H47N9O4: 777; found: 778 (M + H)⁺.</td>

<td> 84-63</td><td>((1R) -2 - ((2S) -2- (5- (4 '- (2 - ((2S) 1 - ((4-methoxyphenyl) acetyl) -2-pyrrolidinyl) -1H-imidazol-5-yl) -4 methyl-biphenylyl) -1H-imidazol2-yl) -1-pyrrolidinyl) -2-oxo-1 phenylethyl) carbamate</td><td>OMe</td><td>LCMS: Anal. Calc. for C45H45N7O5: 763; found: 764 (M + H)⁺.</td>

<td> 84-64</td><td>((1R) -2 - ((2S) -2- (5- (4 '- (2 - ((2S) 1- ((3-methoxyphenyl) acetyl) -2-pyrrolidinyl) -1H-imidazol-5-yl) -4 -biphenylyl) -1H-imidazol2-yl) -1-pyrrolidinyl) -2-oxo-1 -</td><td>V</td><td>LCMS: Anal. Calc. for C45H45N7O5: 763; found: 764 (M + H)⁺.</td>

166

<td></td><td>methyl phenylethyl) carbamate</td><td></td><td></td>

<td> 84-65</td><td>((1R) -2 - ((2S) -2- (5- (4 '- (2 - ((2S) 1 - ((2-methoxyphenyl) acetyl) -2-pyrrolidinyl) -1H-imidazol-5-yl) -4 methyl-biphenylyl) -1H-imidazol2-yl) -1-pyrrolidinyl) -2-oxo-1 phenylethyl) carbamate</td><td>Q Ck / OMe AND</td><td>LCMS: Anal. Calc. for C₄5H4₅N₇ABOUT₅: 763; found: 764 (M + H)⁺.</td>

<td> 84-66</td><td>((1R) -2 - ((2S) -2- (5- (4 '- (2 - ((2S) 1 - ((2-chlorophenyl) acetyl) -2-pyrrolidinyl) -1H-imidazol-5-yl) - Methyl 4-biphenylyl) -1H-imidazol2-yl) -1-pyrrolidinyl) -2-oxo-1 phenylethyl) carbamate</td><td>AND AND</td><td>LCMS: Anal. Calc. for C44H42CIN7O4: 767; found: 768 (M + H)⁺.</td>

<td> 84-67</td><td>((1R) -2 - ((2S) -2- (5- (4 '- (2 - ((2S) 1- ((3-chlorophenyl) acetyl) -2-pyrrolidinyl) -1H-imidazol-5-yl) - Methyl 4-biphenylyl) -1H-imidazol2-yl) -1-pyrrolidinyl) -2-oxo-1 phenylethyl) carbamate</td><td>θ ' " AND</td><td>LCMS: Anal. Calc. for C44H42CIN7O4: 767; found: 768 (M + H)⁺.</td>

<td> 84-68</td><td>((1R) -2 - ((2S) -2- (5- (4 '- (2 - ((2S) 1 - ((4-chlorophenyl) acetyl) -2-pyrrolidinyl) -1H-imidazol-5-yl) Methyl-4-biphenylyl) -1H-imidazol2-yl) -1-pyrrolidinyl) -2-oxo-1 phenylethyl) carbamate</td><td>cl k</td><td>LCMS: Anal. Calc. for C44H42CIN7O4: 767; found: 768 (M + H)⁺.</td>

<td> 84-69</td><td>((1R) -2 - ((2S) -2- (5- (4 '- (2 - ((2S) 1 - ((2-methylphenyl) acetyl) -2-pyrrolidinyl) -1H-imidazol-5-yl) - Methyl 4-biphenylyl) -1H-imidazol2-yl) -1-pyrrolidinyl) -2-oxo-1 phenylethyl) carbamate</td><td>k</td><td>LCMS: Anal. Calc. for C.₄₅H45N₇O4: 747; found: 748 (M + H)⁺.</td>

<td> 84-70</td><td>((1R) -2 - ((2S) -2- (5- (4 '- (2 - ((2S) 1 - ((4-methylphenyl) acetyl) -2-pyrrolidinyl) -1H-imidazol-5-yl) - Methyl 4-biphenylyl) -1H-imidazol2-yl) -1-pyrrolidinyl) -2-oxo-1 phenylethyl) carbamate</td><td>k</td><td>LCMS: Anal. Calc. for C45H45N7O4: 747; found: 748 (M + H)⁺.</td>

167

<td> 84-71</td><td>((1 R) -2 - ((2S) -2- (5- (4 '- (2 - ((2S) 1- ((3-methylphenyl) acetyl) -2-pyrrolidinyl) -1H-imidazol-5-yl) Methyl-4-biphenylyl) -1H-imidazol2-yl) -1-pyrrolidinyl) -2-oxo-1 phenylethyl) carbamate</td><td></td><td>LCMS: Anal. Calc. for C.₄₅H45N₇ABOUT₄: 747; found: 748 (M + H)⁺.</td>

<td> 84-72</td><td>((1R) -2 - ((2S) -2- (5- (4 '- (2 - ((2S) 1 - ((2-methyl-1,3-thiazol-4-yl) acetyl) -2-pyrrolidinyl ) -1-Himidazol-5-yl) -4-biphenylyl) 1H-imidazol-2-yl) -1-pyrrolidinyl) -2-oxo-1 phenylethyl) methyl carbamate</td><td>AND</td><td>LCMS: Anal. Calc. for C42H₄₂N₈ABOUT₄S: 754; found: 755 (M + H)⁺.</td>

<td> 84-73</td><td>((1 R) -2-oxo-1-phenyl-2 - ((2S) 2- (5- (4 '- (2 - ((2S) -1- (3-thienylacetyl) -2-pyrrolidinyl) 1H- imidazol-5-yl) -4-biphenylyl) -1H-imidazol-2-yl) 1-pyrrolidinyl) ethyl) carbamate methyl</td><td>AND</td><td>LCMS: Anal. Calc. for C42H41N-7O4S: 739; found: 740 (M + H)⁺.</td>

<td> 84-74</td><td>((1R) -2 - ((2S) -2- (5- (4 '- (2 - ((2S) 1- ((3-methyl-5 isoxazolyl) acetyl) -2-pyrrolidinyl) -1H-imidazol- Methyl 5-yl) -4-biphenylyl) -1H-imidazol2-yl) -1-pyrrolidinyl) -2-oxo-1 phenylethyl) carbamate</td><td>Y at,</td><td>LCMS: Anal. Calc. for C42H42N8O5: 738; found: 739 (M + H)⁺.</td>

<td> 84-75</td><td>((1R) -2 - ((2S) -2- (5- (4 '- (2 - ((2S) 1- (cyclohexylacetyl) -2-pyrrolidinyl) -1H-imidazol-5-yl) -4-biphenyl) - Methyl 1H-imidazol2-yl) -1-pyrrolidinyl) -2-oxo-1 phenylethyl) carbamate</td><td>Y</td><td>LCMS: Anal. Calc. for C₄4H49N₇ABOUT₄: 739; found: 740 (M + H)⁺.</td>

<td> 84-76</td><td>((1 R) -2-oxo-1-phenyl-2 - ((2S) 2- (5- (4 '- (2 - ((2S) -1 - ((2R) -2-phenylpropanoyl) -2-pyrrolidinyl) - 1H-imidazol-5-yl) -4-biphenylyl) -1H-imidazol-2-yl) -1-</td><td>"and?</td><td>LCMS: Anal. Calc. for C45H₄₅N₇ABOUT₄: 747; found: 748 (M + H)⁺.</td>

168

<td></td><td>pyrrolidinyl) ethyl) carbamate methyl</td><td></td><td></td>

<td> 84-77</td><td>((1 R) -2-oxo-1-phenyl-2 - ((2S) 2- (5- (4 '- (2 - ((2S) -1 - ((1-phenylcyclopropyl) carbonyl) 2-pyrrolidinyl) - 1H-imidazol-5-yl) -4-biphenylyl) -1H-imidazol-2-yl) -1-pyrrolidinyl) ethyl) carbamate methyl</td><td>X</td><td>LCMS: Anal. Calc. for C46H₄₅N₇ABOUT₄: 759; found: 760 (M + H)⁺.</td>

<td> 84-78</td><td>((1R) -2 - ((2S) -2- (5- (4 '- (2 - ((2S) 1 - ((1- (4-chlorophenyl) cyclopropyl) carbonyl) -2-pyrrolidinyl) -1Himidazol- Methyl 5-yl) -4-biphenyl) 1H-imidazol-2-yl) -1-pyrrolidinyl) -2-oxo-1 phenylethyl) carbamate</td><td>cl -5 X</td><td>LCMS: Anal. Calc. for C.₄6H44C1N₇ABOUT₄: 793; found: 794 (M + H)⁺.</td>

<td> 84-79</td><td>((1R) -2 - ((2S) -2- (5- (4 '- (2 - ((2S) 1- (2- (4-chlorophenyl) -2-methylpropanoyl) -2-pyrrolidinyl) -1H-imidazol- Methyl 5-yl) -4-biphenylyl) -1H-imidazol2-yl) -1-pyrrolidinyl) -2-oxo-1 phenylethyl) carbamate</td><td>cl P X</td><td>LCMS: Anal. Calc. for C46H46CIN7O4: 795; found: 796 (M + H)⁺.</td>

<td> 84-80</td><td>((1R) -2 - ((2S) -2- (5- (4 '- (2 - ((2S) 1 - ((2R) -2-methoxy-2-phenylacetyl) -2-pyrrolidinyl) -1H-imidazol- Methyl 5-yl) -4-biphenyl) -1H-imidazol-2-yl) 1-pyrrolidinyl) -2-oxo-1 phenylethyl) carbamate</td><td>/ OMe '^/vv_V.</td><td>LCMS: Anal. Calc. for C4₅H₄₅N₇ABOUT₅: 763; found: 764 (M + H)⁺.</td>

<td> 84-81</td><td>((1 R) -2-oxo-1-phenyl-2 - ((2S) 2- (5- (4 '- (2 - ((2S) -1 - ((2S) -3,3,3-trifluoro) 2-methoxy-2-phenylpropanoyl) -2-pyrrolidinyl) -1H-imidazol-5-yl) -4-biphenylyl) -1H-imidazol2-yl) -1-pyrrolidinyl) ethyl) carbamate</td><td>Ox lomé "/ \ F₃X ^J</td><td>LCMS: Anal. Calc. for C46H44F3N7O5: 831; found: 832 (M + H)⁺.</td>

169

<td></td><td>methyl</td><td></td><td></td>

<td> 84-82</td><td>(1R) -2 - ((2S) -2- (5- (4 '- (2 ((2S) -1 - ((2R) -2 ((methoxycarbonyl) amino) -2-phenylacetyl) -2-pyrrolidinyl) acetate 1H-imidazol-5-yl) -4-biphenylyl) -1H-imidazol-2-yl) 1-pyrrolidinyl) -2-oxo-1 phenylethyl</td><td>AND-/ about</td><td>LCMS: Anal. Obi. for C.₄₆H₄₅N₇ABOUT₆: 791; found: 792 (M + H)⁺.</td>

<td> 84-83</td><td>(1S) -2 - ((2S) -2- (5- (4 '- (2 ((2S) -1 - ((2R) -2 ((methoxycarbonyl) amino) -2-phenylacetyl) -2-pyrrolidinyl) acetate 1H-imidazol-5-yl) -4-phenyl-yl) -1H-imidazol-2-yl) 1-pyrrolidinyl) -2-oxo-1 phenylethyl</td><td>0. / about</td><td>LCMS: Anal. Obi. for C.₄₆H₄₅N₇ABOUT₆: 791; found: 792 (M + H)⁺.</td>

<td> 84-84</td><td>((1R) -2 - ((2S) -2- (5- (4 '- (2 - ((2S) 1- ((2- (4-morpholinylmethyl) phenyl) acetyl) -2-pyrrolidinyl) -1H methyl-imidazol-5-yl) -4-biphenylyl) -1-Himidazol-2-yl) -1-pyrrolidinyl) 2-oxo-1-phenylethyl) -carbamate</td><td>, 3 "Q Cap-4l</td><td>LCMS: Anal. Obi. for C.₄₉H₅₂N₈ABOUT₅: 832; found: 833 (M + H)⁺.</td>

<td> 84-85</td><td>((1 R) -2-oxo-1-phenyl-2 - ((2S) 2- (5- (4 '- (2 - ((2S) -1 - ((2- (1-piperidinylmethyl) phenyl) acetyl ) -2-pyrrolidinyl) -1-imidazol-5-yl) -4-biphenylyl) 1H-imidazol-2-yl) -1-pyrrolidinyl) ethyl) carbamate methyl</td><td>V about Cap-42</td><td>LCMS: Anal. Obi. for C5oH5₄N₈0₄: 830; found: 831 (M + H)⁺.</td>

<td> 84-86</td><td>((1 R) -2-oxo-1-phenyl-2 - ((2S) 2- (5- (4 '- (2 - ((2S) -1 - ((2- (1-pyrrolidinylmethyl) phenyl) ace rear) -2-pyrrolidinyl) -1-Himidazol-5-yl) -4-biphenyl) 1H-imidazol-2-yl) -1-pyrrolidinyl) ethyl) carbamate</td><td>c about Cap-43</td><td>LCMS: Anal. Obi. for C.₄₉H₅₂N₈ABOUT₄: 816; found: 816 (M + H)⁺.</td>

170

<td></td><td>methyl</td><td></td><td></td>

<td> 84-87</td><td>((1R) -2 - ((2S) -2- (5- (4 '- (2 - ((2S) 1 - ((2 ((dimethylamino) methyl) phenyl) acetyl) -2-pyrrolidinyl) - 1-Himidazol-5-yl) -4-biphenylyl) 1H-imidazol-2-yl) -1-pyrrolidinyl) -2-oxo-1 phenylethyl) methyl carbamate</td><td>FRs / /AND Ά ^Me Me Cap-44</td><td>LCMS: Anal. Calc. for C.₄₇H₅₀N₈ABOUT₄: 790; found: 791 (M + H)⁺.</td>

1) stage a

2) etab b

3) stage c

<img file="PL2049522T3_D0148.tif" />

Example 28d step a: Cap with cap 1 as in Example 28 step b: Same procedure as for converting Example 1d to le step c: As in the last step of Example 1 using 1.1 eq. corresponding carboxylic acid and HATU

<td>Example</td><td>Union Name</td><td>Λ</td><td>Retention time (LC conditions); homogeneity index Data MS</td>

<td> 85</td><td>(1 R) -N, N-dimethyl-2-oxo-1 phenyl-2 - ((2S) -2- (5- (4 '- (2 - ((2S) 1- (3-pyridinylacetyl) -2-pyrrolidinyl ) -1 H-imidazol-5-yl) -4-biphenylyl) -1 H-imidazol-2-yl) -1-pyrrolidinyl) ethanamine</td><td></td><td>1.64 minutes (War. 2); &gt; 98%; LC / MS: Anal. Calc. for [M + H]⁺ C₄₃H₄₅N₈ABOUT₂: 705.37; found 705.43; HRMS: Anal. Calc. for [M + H]⁺ C₄₃H₄₅N₈ABOUT₂: 705.3665; found 705.3675</td>

<td> 86</td><td>(1 R) -N, N-dimethyl-2-oxo-1 phenyl-2 - ((2S) -2- (5- (4 '- (2 - ((2S) 1 - ((2R) -tetrahydro- 2-furanylcarbonyl) -2-pyrrolidinyl) -1H-imidazol-5-yl) -4-biphenylyl) -1H-imidazol2-yl) -1-pyrrolidinyl) ethanamine</td><td>AND</td><td>1.73 minutes (War. 2); &gt; 98%; LC / MS: Anal. Calc. for [M + H]⁺ C₄H₄₆N₇A3: 684.37; found 684.44; HRMS: Anal. Calc. for [M + H]⁺C₄H₄₆N₇ABOUT₃: 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- 2-furanylcarbonyl) -2-</td><td>AND</td><td>1.12 minutes (War. 2); &gt; 98%; LC / MS: Anal. Calc. for [M + H]⁺ C₄H₄₆N₇ABOUT₃: 684.37; found 684.68;</td>

171

<td></td><td>pyrrolidinyl) -1H-imidazol-5-yl) -4-biphenylyl) -1H-imidazol2-yl) -1-pyrrolidinyl) ethanamine</td><td></td><td>HRMS: Anal. Calc. for [M + H]⁺ C₄H₄6N₇ABOUT₃: 684.3662; found 684.3692</td>

<td> 88</td><td>(1R) -N, N-dimethyl-2 - ((2S) -2 (5- (4 '- (2 - ((2S) -1 - ((1-methyl-1Himidazol-4-yl) acetyl) - 2-pyrrolidinyl) -1H-imidazol-5-yl) -4-biphenylyl) -1H-imidazol2-yl) -1-pyrrolidinyl) -2-oxo-1 phenylethanamine</td><td>AN O</td><td>1.66 minutes (War. 2); &gt; 98%; LC / MS: Anal. Calc. for [M + H]⁺ C₄₂H₄₆N₉ABOUT₂: 708.38; found 708.36</td>

<td> 89</td><td>(R) -N, N-dimethyl-2 - ((2S) -2- (5- (4 '- (2 - ((2S) -l - ((2R) -2- (4-morpholinyl) -2-phenylacetyl) -2-pyrrolidinyl) -1H-imidazol-5-yl) -4-biphenylyl) -1H-imidazol2-yl) -1-pyrrolidinyl) -2-oxo-1 phenylethanamine</td><td>X Cap-6</td><td>1.70 minutes (War. 2); &gt; 98%; LC / MS: Anal. Calc. for [M + H]⁺ C₄oH45N₈0₄: 701.36; found 701.34; HRMS: Anal. Calc. for [M + H]⁺ C40H45N8O4: 701.3564; found 701.3576</td>

<td> 90</td><td>(1 R) -N, N-dimethyl-2-oxo-1 phenyl-2 - ((2S) -2- (5- (4 '- (2 - ((2S) 1- ((2R) -2- phenyl-2- (1-pyrrolidinyl) acetyl) -2-pyrrolidinyl) -1H-imidazol-5-yl) -4-biphenyl) -1H-imidazol2-yl) -1-pyrrolidinyl) ethanamine</td><td>Æ? Cap-5</td><td>1.80 minutes (War. 2); &gt; 98%; LC / MS: Anal. Calc. for [M + H]⁺ C₄8H₅₃N8O₂: 113A3 ', found 773.42; HRMS: Anal. Calc. for [M + H]⁺ C₄8H₅₃N₆ABOUT₂: 773.4291; found 773.4309</td>

<td> 91</td><td>(2 - ((2S) -2- (5- (4 '- (2 - ((2S) -1 ((2R) -2- (dimethylamino) -2-phenylacetyl) -2-pyrrolidinyl) 1H-imidazol-5 -yl) -4-biphenyls lyl) -1H-imidazol-2-yl) 1-pyrrolidinyl) -2-oxoethyl) carbamate</td><td> 0</td><td>1.66 minutes (War. 2); &gt; 98%; LC / MS: Anal. Calc. for [M + H]⁺ C₄₂H₄6N₉ABOUT₂: 708.38; found 708.36; HRMS: Anal. Calc. for [M + H]⁺ C₄₂H₄₆N₉ABOUT₂: 708.3744; found 708.3770</td>

<td> 92</td><td>((1S) -2 - ((2S) -2- (5- (4 '- (2 - ((2S) 1 - ((2R) -2- (dimethylamino) -2-phenylacetyl) -2-pyrrolidinyl) 1H -imidazol-5-yl) -4-biphenylyl) -1H-imidazol-2-yl) -</td><td>\ about £ ° A ZI 0</td><td>1.73 minutes (War. 2); &gt; 98%; LC / MS: Anal. Calc. for [M + H]⁺ C41H47N8O4: 715.37; found 715.41; HRMS: Anal. Calc. for</td>

172

<td></td><td>Methyl 1-pyrrolidinyl) -1-methyl-2 oxoethyl) carbamate</td><td></td><td>[M + H]⁺ C₄iH47N₈ABOUT₄: 715.3720; found 715.3729</td>

<td> 93</td><td>(1 R) -N, N-dimethyl-2 - ((2S) -2 (5- (4 '- (2 - ((2S) -1- (4-morpholinylcarbonyl) -2-pyrrolidinyl) -1H-imidazol-5-yl) -4-biphenylyl) -1H-imidazol2-yl) -1-pyrrolidinyl) -2-oxo-1 phenylethanamine</td><td>ABOUT AND</td><td>1.76 minutes (War. 2); &gt; 98%; LC / MS: Anal. Calc. for [M + H]⁺ C₄H₄7N₈ABOUT₃: 699.38; found 699.45; HRMS: Anal. Calc. for [M + H]⁺ C₄₁H₄₇N₈ABOUT₃: 699.3771; found 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-pyrrolidine lcarbonyl) - 2-pyrrolidinyl) -1H-imidazol-5-yl) -4-biphenylyl) -1H-imidazol2- and lo) -1-pyrrolidinyl) ethanamine</td><td>X</td><td>1.86 minutes (War. 2); &gt; 98%; LC / MS: Anal. Calc. for [M + H]⁺ C₄| H₄7N₈ABOUT₂: 683.38; found 683.46; HRMS: Anal. Calc. for [M + H]⁺ C₄H₄7N₈ABOUT₂: 683.3822; found 683.3835</td>

<td> 94-1</td><td>(2S) -1 - ((2S) -2- (5- (4 '- (2 - ((2S) -1 ((2R) -2- (dimethylamino) -2-phenylacetyl) -2-pyrrolidinyl) 1H- imidazol-5-yl) -4-biphenyl) -1H-imidazol-2-yl) 1-pyrrolidinyl) -2- (2-fluorophenyl) -1-oxo-2-propanol</td><td> 9 ^0H</td><td>'HNMR (400 MHz, CD₃OD) δ 7.90-7.84 (m, 9H), 7.79-7.73 (m, 2H), 7.67-7.65 (m, 1H), 7.637.52 (m, 5H), 7.39-7.36 (m, 1H), 7.30-7.26 (m, 1H), 7.13- 7.08 (m, 1H), 6.936.88 (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), 3.843.73 (m, 1H), 3.69-3.55 (m, 1H), 3.21-3.04 (m, 2H), 2.79 (br s, 6H), 2.39- 2.33 (m, 2H), 2.21-1.93 (m, 5H), 1.65 (d, 7 = 4.55 Hz, 3H) .; LCMS: Anal. Calc. for C.₄5H46FN₇ABOUT₃: 751; found: 752 (M + H)⁺.</td>

173

<td> 94-2</td><td>(5R) -5 - (((2S) -2- (5- (4 '- (2 - ((2S) 1 - ((2R) -2- (dimethylamino) -2-phenylacetyl) -2-pyrrolidinyl) 1H -imidazol-5-yl) -4-biphenylyl) -1H-imidazol-2-yl) 1-pyrrolidinyl) carbonyl) -2-pyrrolidinone</td><td>about</td><td>LCMS: Anal. Calc. for C.₄₁H44N₈ABOUT₃: 696; found: 697 (M + H)⁺.</td>

<td> 94-3</td><td>1- ((1R) -2 - ((2S) -2- (5- (4 '- (2 ((2S) -1 - ((2R) - (dimethylamino) 2-phenylacetyl) -2-pyrrolidinyl) -1H- imidazol-5-yl) -4-biphenylyl) -1H-imidazol-2-yl) -1-pyrrolidinyl) -2-oxo-1 phenylethyl) -4-methyl-4-piperidinol</td><td>OH AND AND Cap-15</td><td>LCMS: Anal. Calc. for C.₅oH₅₆N₈0₃: 816; found: 817 (M + H)⁺.</td>

<td> 94-4</td><td>(4R) -4 - (((2S) -2- (5- (4 '- (2 - ((2S) 1 - ((2R) -2- (dimethylamino) -2-phenylacetyl) -2-pyrrolidinyl) 1H -imidazol-5-yl) -4-biphenylyl) -1H-imidazol-2-yl) 1-pyrrolidinyl) carbonyl) -1,3-thiazolidine-3-carboxylate tert-butyl</td><td>cA '-N ^atBoc</td><td>LCMS: Anal. Calc. for C.₄5H52N₈ABOUT₄S: 800; found: 801 (M + H)⁺.</td>

<td> 94-5</td><td>(1 - (((2S) -2- (5- (4 '- (2 - ((2S) -1 ((2R) -2- (dimethylamino) -2-phenylacetyl) -2-pyrrolidinyl) 1H-imidazol- 5-yl) -4-biphenyl) -1H-imidazol-2-yl) 1-pyrrolidinyl) carbonyl) cyclopropyl) tert-butyl carbamate</td><td>AND loaf</td><td>LCMS: Anal. Calc. for C.₄7H₅₆FN₈ABOUT₄: 796; found: 797 (M + H)⁺.</td>

<td> 94-6</td><td>N- (2 - ((2S) -2- (5- (4 '- (2 - ((2S) -1 ((2R) -2- (dimethylamino) -2-phenylacetyl) -2-pyrrolidinyl) 1H-imidazole -5-yl) -4-biphenylyl) -1H-imidazol-2-yl) 1-pyrrolidinyl) -2-oxoethyl) benzamide</td><td> 0 \&gt;</td><td>LCMS: Anal. Calc. for C₄₅H46FN₈ABOUT₃: 746; found: 747 (M + H)⁺.</td>

174

<td> 94-7</td><td>(1 R) -N, N-dimethyl-2 - ((2S) -2 (5- (4 '- (2 - ((2S) -1 - (4- (4-methyl-1 piperazinyl) benzoyl) - 2-pyrrolidinyl) -1H-imidazol-5-yl) -4-biphenylyl) -1H-imidazol2-yl) -1-pyrrolidinyl) -2-oxo-1 phenylethanamine</td><td>MeN _χ__y + ====⁷</td><td>LCMS: Anal. Calc. 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-2-thienes lo) carbonyls) -2) pyrrolidinyl) -1H-imidazol-5-yl) -4-biphenyl) -1H-imidazol2-yl) -1-pyrrolidinyl) ethanamine</td><td>Y CL</td><td>LCMS: Anal. Calc. for C.₄₇H45N₇ABOUT₂S: 771; found: 772 (M + H)⁺.</td>

<td> 94-9</td><td>(1R) -N, N-dimethyl-2 - ((2S) -2 (5- (4 '- (2 - ((2S) -1- (4- (4-morpholinyl) benzoyl) -2-pyrrolidinyl) -1 H- imidazol-5-yl) -4-biphenylyl) -1H-imidazol-2-yl) -1-pyrrolidinyl) -2-oxo-1 phenylethanamine</td><td></td><td>LCMS: Anal. Calc. for C4M0N8O3: 774; found: 775 (M + H)⁺.</td>

<td> 94-10</td><td>(1 R) -N, N-dimethyl-2-oxo-1 phenyl-2 - ((2S) -2- (5- (4 '- (2 - ((2S) 1 - ((4-phenyl-1 , 2,3-thiadiazol-5-yl) carbonyl) -2-pyrrolidinyl) 1H-imidazol-5-yl) -4-biphenyl) -1H-imidazol-2-yl) 1-pyrrolidinyl) ethanamine</td><td>ph Χζ Ns °</td><td>LCMS: Anal. Calc. 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) carbonyl) -2-pyrrolidinyl) 1H-imidazol-5-yl) -4-biphenyl) -1H-imidazol-2-yl) 1-pyrrolidinyl) ethanamine</td><td>CL</td><td>LCMS: Anal. Calc. for C46H44N8O2S: 772; found: 773 (M + H)⁺.</td>

<td> 94-12</td><td>4 - (((2S) -2- (5- (4 '- (2 - ((2S) -1 ((2R) -2- (dimethylamino) -2-phenylacetyl) -2-pyrrolidinyl) 1H-imidazol-5 -yl) -4-biphenylyl) -! H-imidazol-2-yl) -</td><td>Because &lt;\ AND</td><td>LCMS: Anal. Calc. for C48H₅₈N8O₄: 810; found: 811 (M + H)⁺.</td>

175

<td></td><td>Tert-butyl 1-pyrrolidinyl) carbonyl) -4-methyl-1-piperidinecarboxylate</td><td></td><td></td>

<td> 94-13</td><td>3- (2 - ((2S) -2- (5- (4 '- (2 - ((2S) -1 ((2R) -2- (dimethylamino) -2-phenylacetyl) -2-pyrrolidinyl) 1H-imidazole -5 - yl) -4-biphenylyl) -1H-imidazol-2-yl) 1-pyrrolidinyl) -2-oxoethyl) phenol</td><td>Λ OH</td><td>LCMS: Anal. Obi. for C44H45N7O3: 719; found: 720 (M + H)⁺.</td>

<td> 94-14</td><td>3 - ((2S) -2- (5- (4 '- (2 - ((2S) -1 ((2R) -2- (dimethylamino) -2-phenylacetyl) -2-pyrrolidinyl) 1H-imidazol-5- yl) -4-biphenylyl) -1H-imidazol-2-yl) 1-pyrrolidinyl) -N, N-dimethyl-3-oxo-1-propanamine</td><td>&lt;svw about N /</td><td>LCMS: Anal. Obi. for C.₄₁H₄₈N₈ABOUT₂: 684; found: 685 (M + H)⁺.</td>

<td> 94-15</td><td>(4 - (((2S) -2- (5- (4 '- (2 - ((2S) -1 ((2R) -2- (dimethylamino) -2-phenylacetyl) -2-pyrrolidinyl) 1H-imidazol- 5-yl) -4-biphenylyl) -1H-imidazol-2-yl) 1-pyrrolidinyl) carbonyl) phenyl) methanol</td><td>^H0VH</td><td>LCMS: Anal. Obi. for C44H45N7O4: 719; found: 720 (M + H)⁺.</td>

<td> 94-16</td><td>(1 R) -2 - ((2S) -2- (5- (4 '- (2 - ((2S) -1 (1H-indol-3-ylcarbonyl) -2-pyrrolidinyl) -1H-imidazol-5-yl ) -4-biphenylyl) -1H-imidazol2-yl) -1-pyrrolidinyl) -N, N-dimethyl-2-oxo-1 phenylethanamine</td><td>AND</td><td>LCMS: Anal. Obi. for C.₄₅H₄₄N₈ABOUT₂: 728; found: 729 (M + H)⁺.</td>

<td> 94-17</td><td>(1 R) -2 - ((2S) -2- (5- (4 '- (2 - ((2S) -1 (((3R) -1-benzyl-3-pyrrolidinyl) carbonyl) -2-pyrrolidinyl) -1H -imidazol-5-yl) -4-biphenylyl) -1H-imidazol-2-yl) -1-pyrrolidinyl) -N, N-dimethyl-2-oxo-1 -</td><td>^ph _Ύ</td><td>LCMS: Anal. Obi. for C.₄₈H₅₂N₈ABOUT₂: 772; found: 773 (M + H)⁺.</td>

176

<td></td><td>fenyloetanamina</td><td></td><td></td>

<td> 94-18</td><td>(2S) -2- (2 - ((2S) -2- (5- (4 '- (2- ((2S) -l - ((2R) -2- (dimethylamino) -2fenyloacetylo) -2-pyrrolidinyl) 1 H-imidazol-5-yl) -4-biphenylyl) -1 H-imidazol-2-yl) 1-pyrrolidinyl) -2-oxoethyl) -1-tert-butyl pyrrolidinecarboxylate</td><td>di</td><td>LCMS: Anal. Calc. for C47H56N8O4: 796; found: 797 (M + H)⁺.</td>

<td> 94-19</td><td>(1R) -N, N-dimethyl-2 - ((2S) -2 (5- (4 '- (2 - ((2S) -1 - ((5-methyl1H-pyrazol-3-yl) acetyl) -2-pyrrolidinyl) -1H-imidazol-5-yl) -4-biphenylyl) -1H-imidazol2-yl) -1-pyrrolidinyl) -2-oxo-1 phenylethanamine</td><td>ΗΝΧ</td><td>LCMS: Anal. Calc. for C42H45N9O2: 707; found: 708 (M + H)⁺.</td>

<td> 94-20</td><td>(2R) -2 - (((2S) -2- (5- (4 '- (2 - ((2S) 1 - ((2R) -2- (dimethylamino) -2-phenylacetyl) -2-pyrrolidinyl) 1H -imidazol-5-yl) -4-biphenylyl) -1H-imidazol-2-yl) 1-pyrrolidinyl) carbonyl) -1-tert-butyl piperidinecarboxylate</td><td>+ c Boc</td><td>LCMS: Anal. Calc. for C.₄7H₅6N8O₄: 796; found: 797 (M + H)⁺.</td>

<td> 94-21</td><td>((1S, 3R) -3 - (((2S) -2- (5 - (4 '- (2 ((2S) -1 - ((2R) -2 (dimethylamino) -2-phenylacetyl) -2-pyrrolidinyl) 1H-imidazol-5-yl) -4-biphenylyl) -1H-imidazol-2-yl) 1-pyrrolidinyl) carbonyl) cyclopropyl) tert-butyl carbamate</td><td></td><td>LCMS: Anal. Calc. 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) -1H-imidazol-5-yl) -4-biphenylyl) -1H-imidazol-</td><td>AND about</td><td>LCMS: Anal. Calc. for C44H52N8O2: 724; found: 725 (M + H)⁺.</td>

ΥΠ

<td></td><td>2-yl) -1-pyrrolidinyl) ethanamine</td><td></td><td></td>

<td> 94-23</td><td>(2 - (((2S) -2- (5- (4 '- (2 - ((2S) -1 ((2R) -2- (dimethylamino) -2-phenylacetyl) -2-pyrrolidinyl) 1H-imidazol- 5-yl) -4-biphenylyl) -1H-imidazol-2-yl) 1-pyrrolidinyl) carbonyl) phenyl) (f phenyl) -methanone</td><td>AND ph</td><td>LCMS: Anal. Calc. for C5oH₄₇N₇0₃: 793; found: 794 (M + H)⁺.</td>

<td> 94-24</td><td>(1 R) -2 - ((2S) -2- (5- (4 '- (2 - ((2S) -1 ((2-methoxy-phenoxy) acetyl) -2-pyrrolidinyl) -1H-imidazol-5 yl) -4-biphenylyl) -1H-imidazol2-yl) -1-pyrrolidinyl) -N, N-dimethyl-2-oxo-1 phenylethanamine</td><td> 0 ^Me° \₌AND</td><td>LCMS: Anal. Calc. for C.₄₅H₄₇N₇ABOUT₄: 749; found: 750 (M + H)⁺.</td>

<td> 94-25</td><td>3 - (((2S) -2- (5- (4 '- (2 - ((2S) -1 ((2R) -2- (dimethylamino) -2-phenylacetyl) -2-pyrrolidinyl) 1H-imidazol-5 -yl) -4-biphenylyl) -1H-imidazol-2-yl) 1-pyrrolidinyl) carbonyl) -1-tert-butyl azetidinecarboxylate</td><td></td><td>LCMS: Anal. Calc. for C.₄₅H₅₂N₈ABOUT₄: 768; found: 769 (M + H)⁺.</td>

<td> 94-26</td><td>(1 R) -2 - ((2S) -2- (5- (4 '- (2 - ((2S) -1 (((3S) -1-benzyl-3 pyrrolidinyl) carbonyl) -2-pyrrolidinyl) - 1 H-imidazol-5-yl) -4-biphenylyl) -1 H-imidazol-2-yl) -1-pyrrolidinyl) -N, N-dimethyl-2-oxo-1 phenylethanamine</td><td>Vo</td><td>LCMS: Anal. Calc. for C.₄₈H₅₂N₈ABOUT₂: 772; found: 773 (M + H)⁺.</td>

<td> 94-27</td><td>(1 R) -N, N-dimethyl-2-oxo-1 phenyl-2 - ((2S) -2- (5- (4 '- (2 - ((2S) 1- (3- (1-pyrrolidinyl) ) benzoyl) 2-pyrrolidinyl) -1H-imidazol-5-yl) -4-biphenylyl) -1H-imidazol2-yl) -1-pyrrolidinyl) ethanamine</td><td>AND 0</td><td>LCMS: Anal. Calc. for C.₄₇H₅₀N₈ABOUT₂: 758; found: 759 (M + H)⁺.</td>

178

<td> 94-28</td><td>(2 - (((2S) -2- (5- (4 '- (2 - ((2S) -1 ((2R) -2- (dimethylamino) -2-phenylacetyl) -2-pyrrolidinyl) 1H-imidazol- 5-yl) -4-biphenylyl) -1H-imidazol-2-yl) 1-pyrrolidinyl) carbonyl) phenyl) tert-butyl carbamate</td><td>months ° NHBoc</td><td>LCMS: Anal. Calc. for C.₄₈H₅₂N₈ABOUT₄: 804; found: 805 (M + H)⁺.</td>

<td> 94-29</td><td>(3R) -3 - (((2S) -2- (5- (4 '- (2 - ((2S) 1 - ((2R) -2- (dimethylamino) -2-phenylacetyl) -2-pyrrolidinyl) 1H -imidazol-5-yl) -4-biphenylyl) -1H-imidazol-2-yl) 1-pyrrolidinyl) carbonyl) -1-tert-butyl piperidinecarboxylate</td><td>X X. Ν ''⁷Boc</td><td>LCMS: Anal. Calc. for C47H₅₆N₈ABOUT₄: 796; found: 797 (M + H)⁺.</td>

<td> 94-30</td><td>(1 R) -N, N-dimethyl-2-oxo-1 phenyl-2 - ((2S) -2- (5- (4 '- (2 - ((2S) and - ((i (trifluoromethyl) cyclopropyl ) carbonyl) -2-pyrrolidinyl) -1H-imidazol-5-yl) -4-biphenyl) 1H-imidazol-2-yl) -1-pyrrolidinyl) ethanamine</td><td>LA f₃c</td><td>LCMS: Anal. Calc. for C4₁H₄₂F₃N₇ABOUT₂: 721; found: 722 (M + H)⁺.</td>

<td> 94-31</td><td>4 - (((2S) -2- (5- (4 '- (2 - ((2S) -l ((2R) -2- (dimethylamino) -2fenyloacetylo) -2-pyrrolidinyl) -lH-imidazol-5- yl) -4-biphenylyl) -1H-imidazol-2-yl) 1-pyrrolidinyl) carbonyl) -N, N-dimethylaniline</td><td>&gt; Χ.</td><td>LCMS: Anal. Calc. for C.₄₅H₄₈N₈ABOUT₂: 732; found: 733 (M + H)⁺.</td>

<td> 94-32</td><td>(3 - (((2S) -2- (5- (4 '- (2 - ((2S) -1 ((2R) -2- (dimethylamino) -2-phenylacetyl) -2-pyrrolidinyl) 1H-imidazol- 5-yl) -4-biphenylyl) -1H-imidazol-2-yl) 1-pyrrolidinyl) carbonyl) phenyl) (f phenyl) -methanone</td><td>'' '' WX ph</td><td>LCMS: Anal. Calc. for C.₅₀H₄₇N₇ABOUT₃: 793; found: 794 (M + H)⁺.</td>

179

<td> 94-33</td><td>(cis-4 - (((2S) -2- (5- (4 '- (2 - ((2S) -1 ((2R) -2- (dimethylamino) -2-phenylacetyl) -2-pyrrolidinyl) 1H- imidazol-5-yl) -4-biphenylyl) -1H-imidazol-2-yl) 1-pyrrolidinyl) carbonyl) cyclohexyl) tert-butyl carbamate</td><td></td><td>LCMS: Anal. Calc. for C₄8H5₈N₈ABOUT₄: 810; found: 811 (M + H)⁺.</td>

<td> 94-34</td><td>4 - (((2S) -2- (5- (4 '- (2 - ((2S) -1 ((2R) -2- (dimethylamino) -2-phenylacetyl) -2-pyrrolidinyl) 1H-imidazol-5 -yl) -4-biphenylyl) -1H-imidazol-2-yl) 1-pyrrolidinyl) carbonyl) -1-tert-butyl piperidinecarboxylate</td><td>"νυν Boc-N-Y</td><td>LCMS: Anal. Calc. for C47H56N8O4: 796; found: 797 (M + H)⁺.</td>

<td> 94-35</td><td>(cis-4 - (((2S) -2- (5- (4 '- (2 - ((2S) -1 ((2R) -2- (dimethylamino) -2-phenylacetyl) -2-pyrrolidinyl) 1H- imidazol-5-yl) -4-biphenylyl) -1H-imidazol-2-yl) 1-pyrrolidinyl) carbonyl) cyclohexyl) tert-butyl carbamate</td><td>"VVV BocHN ^ AJ Y</td><td>LCMS: Anal. Calc. for C.₄₈H₅₈N₈ABOUT₄: 810; found: 811 (M + H)⁺.</td>

<td> 94-36</td><td>(1 R) -2 - ((2S) -2- (5- (4 '- (2 - ((2S) -1 (diphenylacetyl) -2-pyrrolidinyl) -1H-imidazol-5-yl) -4-biphenyl) - 1H-imidazol2-yl) -1-pyrrolidinyl) -N, N-dimethyl-2-oxo-1 phenylethanamine</td><td>AND</td><td>LCMS: Anal. Calc. for C5oH49N₇0₂: 779; found: 780 (M + H)⁺.</td>

<td> 94-37</td><td>5 - ((2S) -2- (5- (4 '- (2 - ((2S) -1 ((2R) -2- (dimethylamino) -2-phenylacetyl) -2-pyrrolidinyl) 1H-imidazol-5- yl) -4-biphenylyl) -1H-imidazol-2-yl) 1-pyrrolidinyl) -5-oxo-2-pentanone</td><td>JVW 0</td><td>LCMS: Anal. Calc. for C.₄₁H₄₅N₇ABOUT₃: 683; found: 684 (M + H)⁺.</td>

180

<td> 94-38</td><td>(1 R) -2 - ((2S) -2- (5- (4 '- (2 - ((2S) -1 (2-fluorobenzoyl) -2-pyrrolidinyl) -1H-imidazol-5-yl) -4-biphenylyl ) -1 H-imidazol2-yl) -1-pyrrolidinyl) -N, N-dimethyl-2-oxo-1 phenylethanamine</td><td>AND F</td><td>LCMS: Anal. Calc. for C43H42FN7O2: 707; found: 708 (M + H)⁺.</td>

<td> 94-39</td><td>(1 R) -2 - ((2S) -2- (5- (4 '- (2 - ((2S) -1 (2-biphenylcarbonyl) -2-pyrrolidinyl) -1H-imidazol-5-yl) -4-biphenyl ) -1 H-imidazol2-yl) -1-pyrrolidinyl) -N, N-dimethyl-2-oxo-1 phenylethanamine</td><td>ph</td><td>LCMS: Anal. Calc. for C49H47N7O2: 765; found: 766 (M + H)⁺.</td>

<td> 94-40</td><td>(1 R) -2 - ((2S) -2- (5- (4 '- (2 - ((2S) -1 (2-benzylbenzoyl) -2-pyrrolidinyl) -1H-imidazol-5-yl) -4-biphenyl)) -1 H-imidazol-2-yl) -1-pyrrolidinyl) -N, N-dimethyl-2-oxo-1 phenylethanamine</td><td>"Vbv ph</td><td>LCMS: Anal. Calc. for C50H49N7O2: 779; found: 780 (M + H)⁺.</td>

<td> 94-41</td><td>4 - ((1E) -3 - ((2S) -2- (5- (4- (2 ((2S) -1 - ((2R) -2 (dimethylamino) -2-phenylacetyl) -2-pyrrolidinyl) 1 H-imidazol-5-yl) -4-biphenylyl) -1H-imidazol-2-yl) 1-pyrrolidinyl) -3-oxo-1 propen-1-yl) -N, N-dimethylaniline</td><td></td><td>LCMS: Anal. Calc. for C.₄7H₅he₈0₂: 758; found: 759 (M + H)⁺.</td>

<td> 94-42</td><td>(1 R) -N, N-dimethyl-2-oxo-1 phenyl-2 - ((2S) -2- (5- (4 '- (2 - ((2S) 1 - (1,3-thiazol- 4-ylcarbonyl) -2-pyrrolidinyl) -1H-imidazol-5-yl) -4-biphenylyl) -1H-imidazol2-yl) -1-pyrrolidinyl) ethanamine</td><td>Ά sG-Z Oh</td><td>LCMS: Anal. Calc. for C4oH₄he₈0₂S: 696; found: 697 (M + H)⁺.</td>

<td> 94-43</td><td>(1 R) -2 - ((2S) -2- (5- (4 '- (2 - ((2S) -1 (((1R, 2S, 5R) -2-isopropyl-5-methylcyclohexyl) oxy) acetyl o) -2-pyrrolidinyl) -1H-imidazol-</td><td>□ A .....</td><td>LCMS: Anal. Calc. for C.₄₈H59N₇O3: 781; found: 782 (M + H)⁺.</td>

181

<td></td><td>5-yl) -4-biphenylyl) -1Himidazol-2-yl) -1-pyrrolidinyl) N, N-dimethyl-2-oxo-1 phenylethanamine</td><td></td><td></td>

<td> 94-44</td><td>1- (6-chloro-3-pyridinyl) -2 ((2S) -2- (5- (4 '- (2 - ((2S) -1 - ((2R) 2- (dimethylamino) -2-phenylacetyl) - 2-pyrrolidinyl) 1H-imidazol-5-yl) -4-biphenylyl) -1H-imidazol-2-yl) 1-pyrrolidinyl) -N, N-dimethyl-2-oxoethanamine</td><td>/ "&gt; V X cl Cap-21</td><td>LCMS: Anal. Calc. for C45H48CIN9O2: 781; found: 782 (M + H)⁺.</td>

<td> 94-45</td><td>2 - ((2S) -2- (5- (4 '- (2 - ((2S) -1 ((2R) -2- (dimethylamino) -2-phenylacetyl) -2-pyrrolidinyl) 1H-imidazol-5- yl) -4-biphenylyl) -1H-imidazol-2-yl) 1-pyrrolidinyl) -N, N-dimethyl-2-oxo-1- (3-pyridinyl) ethanamine</td><td>/ k Cap-19</td><td>LCMS: Anal. Calc. for C45H49N9O2: 747; found: 748 (M + H)⁺.</td>

<td> 94-46</td><td>2 - ((2S) -2- (5- (4 '- (2 - ((2S) -1 ((2R) -2- (dimethylamino) -2-phenylacetyl) -2-pyrrolidinyl) 1H-imidazol-5- yl) -4-biphenylyl) -1H-imidazol-2-yl) 1-pyrrolidinyl) -N, N-dimethyl-2-oxo-1- (2-pyridinyl) ethanamine</td><td>/ / / Ό on Cap-20</td><td>LCMS: Anal. Calc. 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) 1- (2-thienylacetyl) -2-pyrrolidinyl) ) -1 H-imidazol-5-yl) -4-biphenylyl) -1 H-Imidazol-2-yl) -1-pyrrolidinyl) ethanamine</td><td>ά⁴</td><td>LCMS: Anal. Calc. for C.₄₂H₄₃N₇ABOUT₂S: 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) 1- (3-thienylacetyl) -2-pyrrolidinyl) ) -1 H-imidazol-5-yl) -4-biphenylyl) -1 H-Imidazol-2-yl) -1-pyrrolidinyl) ethanamine</td><td>cC AND</td><td>LCMS: Anal. Calc. for C.₄2H₄₃N₇ABOUT₂S: 709; found: 710 (M + H)⁺.</td>

182

<td> 94-49</td><td>(1 R) -N, N-dimethyl-2 - ((2S) -2 (5- (4 '- (2 - ((2S) -1- (1-naphthylacetyl) -2-pyrrolidinyl) 1H-imidazol-5 -yl) -4-biphenylyl) -1H-imidazol-2-yl) 1-pyrrolidinyl) -2-oxo-1 phenylethanamine</td><td></td><td>LCMS: Anal. Obi. for C.₄₈H₄₇N₇ABOUT₂: 753; found: 754 (M + H)⁺.</td>

<td> 94-50</td><td>(1 R) -2 - ((2S) -2- (5- (4 '- (2 - ((2S) -1 (1H-imidazol-5-ylacetyl) -2-pyrrolidinyl) -1H-imidazol-5-yl) -4-biphenylyl) -1H-imidazol2-yl) -1-pyrrolidinyl) -N, N-dimethyl-2-oxo-1 phenylethanamine</td><td>P N ^ /</td><td>LCMS: Anal. Obi. for C.₄H₄₃N₉ABOUT₂: 693; found: 694 (M + H)⁺.</td>

<td> 94-51</td><td>(1 R) -2 - ((2S) -2- (5- (4 '- (2 - ((2S) -1 ((2-fluorophenyl) acetyl) -2-pyrrolidinyl) -1H-imidazol-5-yl) - 4-biphenylyl) -1H-imidazol2-yl) -1-pyrrolidinyl) -N, N-dimethyl-2-oxo-1 phenylethanamine</td><td>AND</td><td>LCMS: Anal. Obi. for C.₄₄H₄₄FN₇ABOUT₂: 721; found: 722 (M + H)⁺.</td>

<td> 94-52</td><td>(1 R) -2 - ((2S) -2- (5- (4 '- (2 - ((2S) -1 ((3-fluorophenyl) acetyl) -2-pyrrolidinyl) -1H-imidazol-5-yl) -4-biphenylyl) -1H-imidazol2- and 1o) -1-pyrrolidinyl) -N, N dimethyl-2-oxo-1 phenylethanamine</td><td>AND F</td><td>LCMS: Anal. Obi. for C.₄₄H₄₄FN₇ABOUT₂: 721; found: 722 (M + H)⁺.</td>

<td> 94-53</td><td>(1R) -2 - ((2S) -2- (5- (4 '- (2 - ((2S) -1 ((4-fluorophenyl) acetyl) -2-pyrrolidinyl) -1H-imidazol-5-yl) -4 -biphenylyl) -1H-imidazol2-yl) -1-pyrrolidinyl) -N, N-dimethyl-2-oxo-1 phenylethanamine</td><td>3 F</td><td>LCMS: Anal. Obi. for C.₄₄H₄₄FN₇ABOUT₂: 721; found: 722 (M + H)⁺.</td>

<td> 94-54</td><td>(1 R) -2 - ((2S) -2- (5- (4 '- (2 - ((2S) -1 (1-benzothiophen-3-ylacetyl) -2-pyrrolidinyl) -1H-imidazol-5-yl ) -4-biphenylyl) -1H-imidazol2-yl) -1-pyrrolidinyl) -N, N-</td><td>---/AND) about</td><td>LCMS: Anal. Obi. for C.₄₆H₄₅N₇ABOUT₂S: 759; found: 760 (M + H)⁺.</td>

183

<td></td><td>dimethyl-2-oxo-1 phenylethanamine</td><td></td><td></td>

<td> 94-55</td><td>(1 R) -2 - ((2S) -2- (5- (4 '- (2 - ((2S) -1 (1,2-benzisoxazol-3-ylacetyl) -2-pyrrolidinyl) -1Himidazol-5- yl) -4-biphenylyl) 1H-imidazol-2-yl) -1-pyrrolidinyl) -N, N-dimethyl-2-oxo-1-phenylethanamine</td><td></td><td>LCMS: Anal. Calc. for C45H44N8O3: 744; found: 745 (M + H)⁺.</td>

<td> 94-56</td><td>(1R) -2 - ((2S) -2- (5- (4 '- (2 - ((2S) -1 (1H-indol-3-ylacetyl) -2-pyrrolidinyl) -1H-imidazol-5-yl) -4-biphenylyl) -1H-imidazol2-yl) -1-pyrrolidinyl) -N, N-dimethyl-2-oxo-1 phenylethanamine</td><td>γ-ν σΧ H</td><td>LCMS: Anal. Calc. for C46H46N8O2: 742; found: 743 (M + H)⁺.</td>

<img file="PL2049522T3_D0149.tif" />

step b: the same procedure as in converting Example 1d to le step c: As in the last step of Example 1 using 1.1 eq. corresponding carboxylic acid and HATU

<td>Example</td><td>Union Name</td><td>0 rA /</td><td>Retention time (LC conditions); homogeneity index MS data</td>

<td> 95</td><td>2 - ((2S) -1 - ((2R) -2-phenyl-2- (1 pyrrolidinyl) acetyl) -2-pyrrolidinyl) -5- (4 '- (2 - ((2S) -1 ((2S) - tetrahydro-2-furanylcarbonyl) -2-pyrrolidinyl) -1H-imidazol-5-yl) -4-biphenylyl) -1H-imidazole</td><td>X</td><td>1.16 minutes (War. 1); &gt; 98%; LC / MS: Anal. Calc. for [M + H]⁺C₄₃H₄₈N₇ABOUT₃: 710.38; found 710.60</td>

184

<td> 96</td><td>4 - ((1 R) -2-oxo-1-phenyl-2 ((2S) -2- (5- (4 '- (2 - ((2S) -1 - ((2R) 2-phenyl-2 - (1-pyrrolidinyl) acetyl) -2-pyrrolidinyl) -1H-imidazol-5-yl) -4-biphenyl) -1H-imidazol2-yl) -1-pyrrolidinyl) ethyl) morpholine</td><td>οχ about about Cap-6</td><td>1.82 minutes (War. 1); &gt; 98%; LC / MS: Anal. Calc. for [M + Hf C₅₀H55N₈ABOUT₃: 815.44; found 815.45; HRMS: Anal. Calc. for [M + Hf C50H55N8O3: 815.4397; found 815.4395</td>

<td> 97</td><td>1- (2-oxo-1-phenyl-2 - ((2S) -2- (5 - (4 '- (2 - ((2S) -1 - ((2R) -2-phenyl-2 (1 - pyrrolidinyl) acetyl) -2-pyrrolidinyl) -1H-imidazol-5-yl) -4-biphenyl) -1H-imidazol2-yl) -1-pyrrolidinyl) ethyl) -4-piperidinol</td><td>Q OH Single diastereoisomer Cap-8</td><td>1.79 minutes (War. 2); &gt; 98%; LC / MS: Anal. Calc. for [M + Hf C₅H₅₇N8O₃: 829.46; found 829.43; HRMS: Anal. Calc. for [M + Hf C₅₁H57N₈ABOUT₃: 829.4554; found 829.4585</td>

<td> 98</td><td>1-methyl-4- (2-oxo-1-phenyl-2 ((2S) -2- (5- (4 '- (2 - ((2S) -1 - ((2R) 2-phenyl-2- (1-pyrrolidinyl) acetyl) -2-pyrrolidinyl) -1H-imidazol-5-yl) -4-biphenyl) -1H-imidazol2-yl) -1-pyrrolidinyl) ethyl) piperazine</td><td>θΛ 0 1 Single diastereoisomer Cap-YLC</td><td>1.84 minutes (War. 2); &gt; 98%; LC / MS: Anal. Calc. for [M + Hf C₅₁H₅8N₉ABOUT₂: 828.47; found 828.45; HRMS: Anal. Calc. for [M + Hf 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) 1- ((2R) -2- phenyl-2- (1-pyrrolidinyl) acetyl) -2-pyrrolidinyl) -1H-imidazol-5-yl) -4-biphenyl) -1H-imidazol2-yl) -1-pyrrolidinyl) ethanamine</td><td>Coy AND Cap-2</td><td>1.86 minutes (War. 2); &gt; 98%; LC / MS: Anal. Calc. for [M + H] C50H57N8O2: 801.46; found 801.44; HRMS: Anal. Calc. for [M + Hf C50H57N8O2: 801.4604; found 801.4595</td>

185

<td> 100</td><td>((1 R) -2-oxo-1-phenyl-2 - ((2S) 2- (5- (4 '- (2 - ((2S) -1 - ((2R) -2-phenyl-2- (1-pyrrolidinyl) ) acetyl) -2-pyrrolidinyl) -1H-imidazol-5-yl) -4-biphenyl) -1H-imidazol-2-yl) -1-pyrrolidinyl) ethyl) carbamate methyl</td><td>οχ HVR ^ O ° \ Cap-4</td><td>1.93 minutes (War. 2); LC / MS: Anal. Calc. for [M + H]⁺C48H51N8O4: 803.40; found 803.47; HRMS: Anal. Calc. for [M + H]⁺C48H₅iN₈ABOUT₄: 803.4033; found 803.4058</td>

<td> 101</td><td>((1S) -1-methyl-2-oxo-2 - ((2S) 2- (5- (4- (2 - ((2S) -1 - ((2R) -2-phenyl-2- (1-pyrrolidinyl) acetyl ) -2-pyrrolidinyl) -1H-imidazol-5-yl) -4-biphenylyl) -1H-imidazol2-yl) -1-pyrrolidinyl) ethyl) carbamate methyl</td><td>\ ABOUT ? ^{O =}^ &gt; § ZI 0 .....</td><td>1.80 minutes (War. 2); LC / MS: Anal. Calc. for [M + H]⁺· C43H49N8O4. 741.39; found 741.33; HRMS: Anal. Calc. for [M + H]⁺C43H₄9N₈ABOUT₄: 741.3877; found 741.3900</td>

<td> 102</td><td>(2-oxo-2 - ((2S) -2- (5- (4 '- (2 ((2S) -1 - ((2R) -2-phenyl-2- (1 pyrrolidinyl) acetyl) -2-pyrrolidinyl) -1 H-imidazol-5-yl) -4-biphenylyl) -1 H-imidazol-2-yl) -1 pyrrolidinyl) ethyl) carbamate methyl</td><td>^H at 0</td><td>1.80 minutes (War. 2); LC / MS: Anal. Calc. for [M + H]⁺C42H47N8O4: 727.37; found 727.24; HRMS: Anal. Calc. for [M + H]⁺C42H₄7N₈ABOUT₄: 727.3720; found 727.3743</td>

<td> 103</td><td>(2S) -N, N-dimethyl-1-oxo-1 ((2S) -2- (5- (4 '- (2 - ((2S) -1 - ((2R) 2-phenyl-2- ( pyrrolidinyl) acetyl) -2-pyrrolidinyl) -1H-imidazol-5-yl) -4-biphenylyl) -1H-imidazol2-yl) -1-pyrrolidinyl) -2-propanamine</td><td>1 ° / ΝχΧγ Cap-13</td><td>1.69 minutes (War. 2); LC / MS: Anal. Calc. for [M + H]⁺C43H5, N8O2: 711.41; found 711.37; HRMS: Anal. Calc. for [M + H]⁺C43H5iN₈O2: 711.4135; found 711.4154</td>

186

Example 28d

<img file="PL2049522T3_D0150.tif" />

step a: Cap with (R) -2-tetrahydrofuran acid as in Example 28 step b: the same procedure as in converting Example 1d to le step c: As in the last step of Example 1 using 1.1 eq. corresponding carboxylic acid and HATU

<td> 103-1</td><td>1- (2-oxo-1-phenyl-2 - ((2S) -2 (5- (4 '- (2 - ((2S) -1 - ((2R) -</td><td>c</td><td>A) Fr.</td><td>RT = 4.80 minutes; HPLC Xterra 4.6 X 50</td>

<td></td><td>tetrahydro-2-</td><td></td><td></td><td>mm, 0 to 100% B in</td>

<td></td><td>furanylcarbonyl) -2-</td><td></td><td>ph</td><td>within 10 minutes, one</td>

<td></td><td>pyrrolidinyl) -1H-imidazol-4-</td><td></td><td></td><td>minute time</td>

<td></td><td>yl) -4-biphenylyl) -1H-</td><td colspan="2">Diastereomer 1</td><td>stops, A = 90%</td>

<td></td><td>imidazol-2-yl) -l-</td><td></td><td rowspan="2">Cap-l7d</td><td>water, 10% methanol,</td>

<td></td><td>pyrrolidinyl) ethyl) -4-</td><td></td><td>0.2% acid</td>

<td></td><td>phenylpiperidine</td><td></td><td></td><td>phosphoric, B = 10% water, 90% methanol, 0.2% phosphoric acid; LCMS: Anal. Calc. for: C50H53N7O3 800.03 Found: 800.49 (M + H)⁺</td>

<td> 103-2</td><td>1- (2-oxo-1-phenyl-2 - ((2S) -2-</td><td></td><td> |1</td><td>RT = 4.59 minutes;</td>

<td></td><td>(5- (4 '- (2 - ((2S) -l - ((2R) -</td><td>AND</td><td>ii?</td><td>HPLC Xterra 4.6 X 50</td>

<td></td><td>tetrahydro-2-</td><td></td><td rowspan="2">ΑΝγγ ph</td><td>mm, 0 to 100% B in</td>

<td></td><td>furanylcarbonyl) -2-</td><td></td><td>within 10 minutes, one</td>

<td></td><td>pyrrolidinyl) -1H-imidazol-4-</td><td></td><td></td><td>minute time</td>

<td></td><td>yl) -4-biphenylyl) -1H-</td><td colspan="2">Diastereomer 2</td><td>stops, A = 90%</td>

<td></td><td>imidazol-2-yl) -l-</td><td></td><td rowspan="2">Cap-17d</td><td>water, 10% methanol,</td>

<td></td><td>pyrrolidinyl) ethyl) -4-</td><td></td><td>0.2% acid</td>

<td></td><td>phenylpiperidine</td><td></td><td></td><td>phosphoric, B = 10% water, 90% methanol, 0.2% phosphoric acid; LCMS: Anal. Calc. for: C50H53N7O3 800.03 Found: 800.48 (M + H)⁺</td>

187

<td> 103-3</td><td>1-methyl-4- (2-oxo-1-phenyl2 - ((2S) -2- (5- (4 '- (2 - ((2S) -1 ((2R) -tetrahydro-2-furanylcarbonyl) -2-pyrrolidinyl) -1 H-imidazol-4-yl) -4-biphenylyl) -1 H-imidazol-2-yl) -1-pyrrolidinyl) ethyl) piperazine</td><td>AA ° Oya ph Diastereomer 1 Cap-17c</td><td>RT = 3.36; HPLC Xterra 4.6 X 50 mm, 0 to 100% B in 10 minutes, one minute stop time, A = 90% water, 10% methanol, 0.2% phosphoric acid, B = 10% water, 90% methanol, 0.2% phosphoric acid ; LCMS: Anal. Calc. for: C₄4H₅₀N₈ABOUT₃ 738.94 Found: 739.49 (M + H)⁺</td>

<td> 103-4</td><td>1-methyl-4- (2-oxo-1-phenyl2 - ((2S) -2- (5- (4 '- (2 - ((2S) -1 ((2R) - tetrahydro-2-furanylcarbonyl) -2-pyrrolidinyl) -1 H-imidazol-4-yl) -4-biphenylyl) -1 H-imidazol-2-yl) -1-pyrrolidinyl) ethyl) piperazine</td><td>AA ° ph Diastereomer 2 Cap-17c</td><td>RT = 3.47 minutes; HPLC Xterra 4.6 X 50 mm, 0 to 100% B in 10 minutes, one minute hold time, A = 90% water, 10% methanol, 0.2% phosphoric acid, B = 10% water, 90% methanol, 0.2% acid phosphoric acid; LCMS: Anal. Calc. for: C44H5oN₈0₃ 738.94 Found: 739.51 (M + H)⁺</td>

<td> 103-5</td><td>4- (2-oxo-1-phenyl-2 - ((2S) -2 (5- (4 '- (2 - ((2S) -1 - ((2R) tetrahydro-2-furanylcarbonyl) -2-pyrrolidinyl) -1H -imidazol-4-yl) -4-biphenylyl) -1-Himidazol-2-yl) -1-pyrrolidinyl) ethyl) -1 piperazinecarboxylate benzyl</td><td>cA Diastereomer 1 Cap-Yla</td><td>RT = 5.00 minutes; HPLC Xterra 4.6 X 50 mm, 0 to 100% B in 10 minutes, one minute hold time, A = 90% water, 10% methanol, 0.2% phosphoric acid, B = 10% water, 90% methanol,</td>

188

<td></td><td></td><td></td><td>0.2% phosphoric acid; LCMS: Anal. Calc. for: C_5IH54N₈ABOUT₅ 859.05 Found: 859.51 (M + H)⁺</td>

<td> 103-6</td><td>4- (2-oxo-1-phenyl-2 - ((2 S) -2 (5- (4 '- (2 - ((2S) -1 - ((2R) tetrahydro-2-furanylcarbonyl) -2-pyrrolidinyl) -1 H-imidazol-4-yl) -4-biphenylyl) -1-Himidazol-2-yl) -1-pyrrolidinyl) ethyl) -1 piperazinecarboxylate benzyl</td><td>Diastereomer 2 Ca /? - 17a</td><td>RT = 5.10 minutes; HPLC Xterra 4.6 X 50 mm, 0 to 100% B in 10 minutes, one minute hold time, A = 90% water, 10% methanol, 0.2% phosphoric acid, B = 10% water, 90% methanol, 0.2% acid phosphoric acid; LCMS: Anal. Calc. for: C₅H₅4N₈ABOUT₅ 859.05 Found: 859.49 (M + H)⁺</td>

<td> 103-7</td><td>1- (2-oxo-1-phenyl-2 - ((2S) -2 (5- (4 '- (2 - ((2S) -1 - ((2R) tetrahydro-2-furanylcarbonyl) -2-pyrrolidinyl) -1H -imidazol-4-yl) -4-biphenylyl) -1H-imidazol-2-yl) -l-pyrrolidinyl) ethyl) piperazine</td><td>HN ^ and ΑγΑ / ph Obtained by hydrogenolysis 103-5</td><td>RT = 3.61 minutes; HPLC Xterra 4.6 X 50 mm, 0 to 100% B in 10 minutes, one minute hold time, A = 90% water, 10% methanol, 0.2% phosphoric acid, B = 10% water, 90% methanol, 0.2% acid phosphoric acid; LCMS: Anal. Calc. for: C₄3H₄₈N₈ABOUT₃ 724.91 Found: 725.47 (M + H)⁺</td>

189

<td> 103-8</td><td>4- (2-oxo-1-phenyl-2 - ((2S) -2 (5- (4 '- (2 - ((2S) -1 - ((2R) tetrahydro-2-furanylcarbonyl) -2-pyrrolidinyl) -1H -imidazol-4-yl) -4-biphenylyl) -1H-imidazol-2-yl) -l-pyrrolidinyl) ethyl) -2piperazynon</td><td>about QP ---^Ν· ΓΑ / ph Cap-I7b</td><td>RT = 3.97; HPLC Xterra 4.6 X 50 mm, 0 to 100% B in 10 minutes, one minute stop time, A = 90% water, 10% methanol, 0.2% phosphoric acid, B = 10% water, 90% methanol, 0.2% phosphoric acid ; LCMS: Anal. Obi. for: C₄₃H₄₆N₈ABOUT₄ 738.90 Found: 739.56 (M + H)⁺</td>

<td> 103-9</td><td>1-methyl-3 - ((1 R) -2-oxo-1 phenyl-2 - ((2S) -2- (4- (4 '- (2 ((2S) -1 - ((2R) -tetrahydro -2-furanylcarbonyl) -2-pyrrolidinyl) -1H-imidazol-4-yl) -4-biphenylyl) -1H-imidazol-2-yl) -1-pyrrolidinyl) ethyl) urea</td><td>p 0 *, 0 ΗΝ- ~ γ HN ^ Cap-45 was used</td><td>HPLC XTERRA C-18 4.6 x 30 mm, 0 to 100% B in 4 minutes, 1 minute stop time, A = 90% water, 10% methanol, 0.2% H₃AFTER₄, B = 10% water, 90% methanol, 0.2% H₃AFTER₄, RT = 1.81 minutes, 96% homogeneity index .; LCMS: Anal. Obi. for C.₄| H₄₄N₈ABOUT₄: 712.84; found: 713.37 (M + H)⁺; HRMS: Anal. Obi. for C₄H₄₅N₈ABOUT₄713.3564; found: 713.3564 (M + H)⁺.</td>

<td> 103-10</td><td>1-ethyl-3 - ((1R) -2-oxo -1-phenyl-2 - ((2S) -2- (4- (4 '- (2 ((2S) -1 - ((2R) -tetrahydro-2-furanylcarbonyl) ) -2-pyrrolidinyl) -1H-imidazol-4-yl) -4-biphenylyl) -1Himidazol-2-yl) -1-</td><td>p About ».0 HNyŻ HN Cap-46 was used</td><td>HPLC XTERRA C-18 4.6 x 30 mm, 0 to 100% B in 2 minutes, 1 minute stop time, A = 90% water, 10% methanol, 0.2% H₃AFTER₄, B = 10%</td>

190

<td></td><td>pyrrolidinyl) ethyl) urea</td><td></td><td>water, 90% methanol, 0.2% H3PO4, RT = 1.88 minutes, 95% homogeneity index; LCMS: Anal. Calc. for C.₄₂H₄₆N₈ABOUT₄: 726.87; found: 727.71 (M + H)⁺; HRMS: Anal. Calc. for C.₄2H₄₇N₈ABOUT₄727.3720; found: 727.3695 (M + H)⁺.</td>

<td> 103-11</td><td>1-cyclopentyl-3 - ((1 R) -2-oxo-1-phenyl-2 - ((2S) -2- (4- (4 '(2 - ((2S) -1 - ((2R) -tetrahydro- 2-furanylcarbonyl) -2-pyrrolidinyl) -1H-imidazol-4-yl) -4-biphenylyl) -1H-imidazol-2-yl) -1-pyrrolidinyl) ethyl) urea</td><td>«Λ / W \ \ l γ HN A9 Cap-48 was used</td><td>HPLC XTERRA C-18 4.6 x 30 mm, 0 to 100% B in 2 minutes, 1 minute stop time, A = 90% water, 10% methanol, 0.2% H₃AFTER₄, B = 10% water, 90% methanol, 0.2% H₃AFTER₄, RT = 2.11 minutes, 96% homogeneity index; LCMS: Anal. Calc. for C.₄₅H₅he₈0₄: 766.93; found: 767.45 (M + H)⁺; HRMS: Anal. Calc. for C.₄₅H₅iN₈ABOUT₄767.4033; 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 ((2 S) -1 - ((2R) -tetrahydro-2-furanylcarbonyl) -2-pyrrolidinyl) -1H-imidazol-4-yl) -4-biphenyl) -1H-imidazol-2-yl) -1-pyrrolidinyl) ethyl) urea</td><td>from^NCap-47 was used</td><td>HPLC XTERRA C-18 4.6 x 30 mm, 0 to 100% B in 2 minutes, 1 minute stop time, A = 90% water, 10% methanol, 0.2% H₃AFTER₄, B = 10% water, 90% methanol, 0.2% H₃AFTER₄, RT = 1.87 minutes, 97% homogeneity index; LCMS: Anal. Calc. for</td>

191

<td></td><td></td><td></td><td>C₄2H46N₈ABOUT₄: 726.87; found: 727.38 (M + H)⁺; HRMS: Anal. Obi. for C.₄2H47N₈ABOUT₄727.3720; found: 727.3723 (M + H)⁺.</td>

Example 28d

1) stage a

2) etab b

3) stage c

<img file="PL2049522T3_D0151.tif" />

step a: Cap with (S) -2-tetrahydrofuran acid as in Example 28 step b: the same procedure as for converting Example Id to le step c: As in the last step of Example 1 using 1.1 eq. corresponding carboxylic acid and HATU

<td>Example</td><td>Union Name</td><td>0 fa/</td><td>Retention time (LC conditions); index homogeneity MS data</td>

<td> 104</td><td>1-methyl-4- (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-2-yl) -1-pyrrolidinyl) ethyl) piperazine</td><td>ph Single diastereoisomer Cap-l 7c</td><td>1.12 minutes (War. 1); &gt; 98%; LC / MS: Anal. Calc. for [M + H] C₄4H₅iN₈ABOUT₃: 739.41; found 739.63; HRMS: Anal. Calc. for [M + H]⁺C₄₄H5iN₈A3: 739.4084; found 739.4054</td>

<td> 105</td><td>4 - ((1 R) -2-oxo-1-phenyl-2 ((2S) -2- (5- (4 '- (2 - ((2S) -1 - ((2S) tetrahydro-2-furanylcarbonyl) - 2-pyrrolidinyl) -1H-imidazol-5-yl) -4-biphenylyl) -1H-imidazol2-yl) -1-pyrrolidinyl) ethyl) morpholine</td><td>about ph Cap-6</td><td>1.13 minutes (War. 1); &gt; 98%; LC / MS: Anal. Calc. for [M + H]⁺C₄3H4₈N7O₄: 726.38; found 726.63; HRMS: Anal. Calc. for [M + H]⁺C43H₄₈N7O₄:</td>

192

<td></td><td></td><td></td><td>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) 1 - ((2S) -tetrahydro- 2-furanylcarbonyl) -2-pyrrolidinyl) -1H-imidazol-5-yl) -4-biphenyl) -1H-imidazol-2-yl) -1-pyrrolidinyl) ethanamine</td><td>Oh ph Cap-2</td><td>1.12 minutes (War. 1); 97%; LC / MS: Anal. Calc. for [M + Hf C43H50N7O3: 712.40; found 712.45; HRMS: Anal. Calc. for [M + Hf C43H50N7O3: 712.3975; found 712.3998</td>

<td> 107</td><td>(1R) -N-ethyl-N-methyl-2-oxo1-phenyl-2 - ((2S) -2- (5- (4 '- (2 ((2S) -1 - ((2S) -tetrahydro- 2-furanylcarbonyl) -2-pyrrolidinyl) -1H-imidazol-5-yl) -4-biphenyl) -1H-imidazol2-yl) -1-pyrrolidinyl) ethanamine</td><td>A 0 &gt; X ph Cap-3</td><td>1.10 minutes (War. 1); &gt; 98%; LC / MS: Anal. Calc. for [M + Hf C42H48N7O3: 698.38; found 698.45; HRMS: Anal. Calc. for [M + H] C42H48N7O3: 698.3819; 698.3823</td>

Example 28d

<img file="PL2049522T3_D0152.tif" />

step a: Cap with cap-14 as in Example 28 step b: the same procedure as in converting Example 1d to le step c: As in the last step of Example 1 using 1.1 eq. corresponding carboxylic acid and HATU

<td>Number example</td><td>Union Name</td><td>Structure</td><td>Data</td>

<td>Example 107-1</td><td>(1S) -2-oxo-1-phenyl-2 ((2S) -2- (5- (4 '- (2 ((2S) -1 - ((2R) -2-phenyl-2- (1-piperidinyl) acetate acetate</td><td>ó 0</td><td>'HNMR (400 MHz, CDCI3) δ 7.63-7.85 (m, 8H), 7.48- 7.54 (m, 2H), 7.26- 7.46 (m, 7H), 6.947.17 (m, 3H), 6.22 and 6.18 (s , 1H, rotamers, 1: 1),</td>

193

<td></td><td>yl) -2-pyrrolidinyl) -1H-imidazol-5-yl) -4-biphenyl-1H-imidazol-2-yl) -1-pyrrolidinyl) ethyl</td><td></td><td>5.99 and 5.68 (s, 1H, rotamers, 1: 1), 5.61 and 5.54 (d, J = 7.8 Hz, 1H, rotamers, 1: 1), 5.20-53 and 5.10-5.13 (m, 1H, rotamers, 1: 1), 4.46 and 4.43 (s, 1H, rotamers, 1: 1), 3.97-4.06 (m, 1H), 3.893.93 and 3.78-3.84 (m, 1H, rotamers, 1: 1), 3.63- 3.72 and 3.46-3.60 (m, 1H, 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), 1.98 (m, 1H), 1.82-1.90 (m, 1H), 1.58 (br s, 4H), 1.45 (br s, 2H); LCMS: Anal. Calc. for C49H51N7O4: 801; found: 802 (M + H)⁺.</td>

<td>Example 107-2</td><td>4-methyl-1 - ((1 R) 2-oxo-1-phenyl2 - ((2S) -2- (5- (4 '(2 - ((2S) -1 - ((2R) 2-phenyl- 2- (lpiperydynylo) acetamide yl) -2pirolidynylo) -lH-5-yl) -4bifenylylo) -lH-2-yl) -l-pyrrolidinyl) ethyl ) -4-piperidinol</td><td>OH oh</td><td>LCMS: Anal. Calc. for C.₅₃H₆he₈0₃: 856; found: 857 (M + H)⁺.</td>

<td>Example 107-3</td><td>1- ((1R) -2 - ((2S) 2- (5- (4 '- (2 - ((2S) 1- (2-fluorobenzoyl) 2-pyrrolidinyl) 1H-imidazol-5-</td><td>^F ABOUT</td><td>LCMS: Anal. Calc. for C.₄6H56FN₇ABOUT₂: 747; found: 748 (M + H)⁺.</td>

194

<td></td><td>yl) -4bifenylylo) -lH-2-yl) -l-pyrrolidinyl) -2-oxo-1phenylethyl) piper ethylpyridin</td><td></td><td></td>

<td>Example 107-4</td><td>N, N-dimethyl-4 (((2S) -2- (5- (4 '(2 - ((2S) -l - ((2R) -2-phenyl-2- (lpiperydynylo) acetamide yl) -2pirolidynylo) -lH-5-yl) -4bifenylylo) -lH-2-yl) -l-pyrrolidinyl) notch onyl) aniline</td><td>' about</td><td>LCMS: Anal. Calc. for C48H52N8O2: 772; found: 773 (M + H)⁺.</td>

<td>Example 107-5</td><td>5-oxo-5 - ((2S) -2- (5- (4 '- (2 - ((2S) -l ((2R) -2-phenyl-2- (1-piperidinyl) acetamide yl) -2irolidynylo) -lH-5-yl) -4bifenylylo) -lH-2-yl) -l-pyrrolidinyl) -2pentanon</td><td></td><td>LCMS: Anal. Calc. for C44H49N7O3: 723; found: 724 (M + H)⁺.</td>

<td>Example 107-6</td><td>1- ((1R) -2 - ((2S) 2- (5- (4 '- (2 - ((2S) 1 (diphenylacetyl) 2-pyrrolidinyl) 1H-imidazol-5-yl) -4-biphenyl)) 1H-imidazol-2-yl) -1-pyrrolidinyl) -2-</td><td>^ph 0</td><td>LCMS: Anal. Calc. for C53H53N7O2: 819; found: 820 (M + H)⁺.</td>

195

<td></td><td>oxo-1phenylethyl) piper ethylpyridin</td><td></td><td></td>

<td>Example 107-7</td><td>l- (3-oxo-3- ((2S) -2- (5- (4 '- (2- ((2S) -l - ((2R) -2fenylo-2- (lpiperydynylo) acetamide yl) -2pirolidynylo) -lH-5-yl) -4bifenylylo) -lH-2-yl) -l-pyrrolidinyl) -prop yl) piperidine</td><td>oo</td><td>LCMS: Anal. Calc. for C.₄7H₅₆N₈ABOUT₂: 764; found: 765 (M + H)⁺.</td>

<td>Example 107-8</td><td>1- ((1R) -2 - ((2S) 2- (5- (4 '- (2 - ((2S) 1 - ((2-methoxyphenoxy) a cetyl) -2pirolidynylo) -lH-5-yl) -4bifenylylo) -lH-2-yl) -l-pyrrolidinyl) -2-oxo-1phenylethyl) piper ethylpyridin</td><td>Jo Fr</td><td>LCMS: Anal. Calc. for C4₈H₅₁N₇ABOUT₄: 789; found: 790 (M + H)⁺.</td>

<td>Example 107-9</td><td>4 - (((2S) -2- (5- (4 '(2 - ((2S) -l - ((2R) -2-phenyl-2- (lpiperydynylo) acetamide yl) -2pirolidynylo) -1H-imidazol-5-yl) -4bifenylylo) -lH-2-yl) -l-pyrrolidinyl) notch onyl) -lpiperydynokarbok tert-butyl silane</td><td></td><td>LCMS: Anal. Calc. for C5oH6oN₈0₄: 836; found: 837 (M + H)⁺.</td>

196

<td>Example 107-10</td><td>4- (4 - (((2S) -2- (5- (4 '- (2 - ((2S) -l ((2R) -2-phenyl-2 (ipiperydynylo) acetamide yl) -2płrolidynylo) -lH-5-yl) -4bifenylylo) -lH-2-yl) -l-pyrrolidinyl) notch ) phenyl) mor Folin</td><td></td><td>LCMS: Anal. Obi. for C.₅₀H₅₄N₈ABOUT₃: 814; found: 815 (M + H)⁺.</td>

<td>Example 107-11</td><td>l - ((R) -2-oxo-lfenylo-2 - ((2S) -2- (5- (4 '- (2 - ((2S) -l (l, 3-thiazol-4ilokarbonylo) -2pirolidynylo) - imidazol-5-yl) -4bifenylylo) -lH-2-yl) -l-pyrrolidinyl) ethyl ) piperidine</td><td></td><td>LCMS: Anal. Obi. for C.₄₃H₄₄N₈ABOUT₂S: 736; found: 737 (M + H)⁺.</td>

<td>Example 107-12</td><td>3 - (((2S) -2- (5- (4 '(2 - ((2S) -l - ((2R) -2-phenyl-2- (lpiperydynylo) acetamide yl) -2-pyrrolidinyl) -1H-imidazol-5-yl) -4-biphenyl-1H-imidazol-2-yl) -1-pyrrolidinyl) carbonyl) -lazetidinecarboxyl tert-butyl carboxylate</td><td></td><td>LCMS: Anal. Obi. for C₄₈H5óN₈ABOUT₄: 808; found: 809 (M + H)⁺.</td>

<td>Example 107-13</td><td>(Cis-4 - (((2S) -2- (5- (4 '- (2 - ((2S) -l ((2R) -2-phenyl-2 (i-</td><td>ABOUT</td><td>LCMS: Anal. Obi. for C.₅H₆₂N₈ABOUT₄: 850; found: 851 (M + H)⁺.</td>

197

<td></td><td>piperidinyl) acetamide yl) -2pirolidynylo) -1H-imidazol-5-yl) -4bifenylylo) -lH-2-yl) -l-pyrrolidinyl) notch onyl) cyclohexylamine phenyl) carbamate tert-butyl</td><td></td><td></td>

<td>Example 107-14</td><td>4-methyl-4- (((2S) -2- (5- (4 '- (2- ((2S) -l - ((2R) -2fenylo-2- (lpiperydynylo) acetamide yl) -2-pyrrolidinyl) -1H-imidazol-5-yl) -4-biphenyl) -1H-imidazol-2-yl) -1-pyrrolidinyl) carbonyl) -1-piperidinecarbocarbyl tert-butyl silane</td><td>Boc_K \ 1 Η H] / ('' 'Χ</td><td>LCMS: Anal. Calc. for C.₅₁H₆₂N₈ABOUT₄: 850; found: 851 (M + H)⁺.</td>

<td>Example 107-15</td><td>l - ((R) -2-oxo-lfenylo-2 - ((2S) -2- (5- (4 '- (2 - ((2S) -l ((i (trifluoromethyl) c yklopropylo) notch ethanesulfonyl) -2pirolidynylo) -lH-5-yl) -4bifenylylo) -lH-2-yl) -l-pyrrolidinyl) ethyl ) piperidine</td><td>^F‘^c /0</td><td>LCMS: Anal. Calc. for C₄₄H₄6F3N7O₂: 761; found: 762 (M + H)⁺.</td>

<td>Example 107-16</td><td>1- ((1R) -2 - ((2S) 2- (5- (4 '- (2 - ((2S) 1 - ((5-methyl-1H-pyrazol-3-</td><td>HN ^ O</td><td>LCMS: Anal. Calc. for C.₄₅H₄9N₉ABOUT₂: 747; found: 748 (M + H)⁺.</td>

198

<td></td><td>yl) acetyl) -2pirolidynylo) -1H-imidazol-5-yl) -4bifenylylo) -lH-2-yl) -l-pyrrolidinyl) -2-oxo-1phenylethyl) piper ethylpyridin</td><td></td><td></td>

<td>Example 107-17</td><td>1- ((1R) -2 - ((2S) 2- (5- (4 '- (2 - ((2S) 1 - (((3R) -1-benzyl-3-pyrrolidinyl) carbonyl) -2-pyrrolidinyl) -1Himidazol- 5-yl) -4-biphenylyl) -1-Himidazol-2-yl) -1-pyrrolidinyl) -2-oxo-1-phenylethyl) piper ethylpyridin</td><td></td><td>LCMS: Anal. Calc. for C.₅₁H₅₆N₈ABOUT₂: 812; found: 813 (M + H)⁺.</td>

<td>Example 107-18</td><td>1- ((1R) -2 - ((2S) 2- (5- (4 '- (2 - ((2S) 1 - (((3S) -1-benzyl-3-pyrrolidinyl) carbonyl) -2-pyrrolidinyl) -1Himidazol- 5-yl) -4bifenylylo) -lH-2-yl) -l-pyrrolidinyl) -2-oxo-1phenylethyl) piper ethylpyridin</td><td></td><td>LCMS: Anal. Calc. for C.₅H₅₆N₈ABOUT₂: 812; found: 813 (M + H)⁺.</td>

<td>Example 107-19</td><td>1- ((1R) -2 - ((2S) 2- (5- (4 '- (2 - ((2S) 1 - ((2R) -2-methoxy-2-</td><td>Oh</td><td>LCMS: Anal. Calc. for C₄₈H₅₁N₇ABOUT₃: 773; found: 774 (M + H)⁺.</td>

199

<td></td><td>phenylacetyl) -2pirolidynylo) -1H-imidazol-5-yl) -4bifenylylo) -lH-2-yl) -l-pyrrolidinyl) -2-oxo-1phenylethyl) piper ethylpyridin</td><td></td><td></td>

<td>Example 107-20</td><td>1- ((1R) -2 - ((2S) (5- (4 '- (2 - ((2S) -1 ((2S) -2-ethoxy-2-phenylacetyl) -2-pyrrolidinyl) -1Himidazol-5-yl) -4bifenylylo) -lH-2-yl) -l-pyrrolidinyl) -2-oxo-1phenylethyl) piper ethylpyridin</td><td></td><td>LCMS: Anal. Calc. for C48H51N7O3: 773; found: 774 (M + H)⁺.</td>

<td>Example 107-21</td><td>(1R) -2-oxo-1-phenyl-2 ((2S) -2- (5- (4 '- (2 ((2S) -1 - ((2R) -2-phenyl-2- (1-piperidinyl) acetate acetate yl) -2pirolidynylo) -lH-5-yl) -4bifenylylo) -lH-2-yl) -l-pyrrolidinyl) ethyl</td><td>ΧόΧλΡ</td><td>LCMS: Anal. Calc. for C49H51N7O4: 801; found: 802 (M + H)⁺.</td>

<td>Example 107-22</td><td>l - ((R) -2-oxo-lfenylo-2 - ((2S) -2- (5- (4 '- (2 - ((2S) -l ((ifenylocykloprop yl) carbonyl) -2pirolidynylo) -lH-5-yl) -4-</td><td>At 0</td><td>LCMS: Anal. Calc. for C.₄9H₅N₇O2: 769; found: 770 (M + H)⁺.</td>

200

<td></td><td>biphenylyl) -lH-2-yl) -l-pyrrolidinyl) ethyl ) piperidine</td><td></td><td></td>

<td>Example 107-23</td><td>N, N-dimethyl-l (2- (2-Oxo-2- ((2S) -2- (5- (4 '- (2- ((2S) -l - ((2R) -2fenylo-2- (lpiperydynylo ) acetamide yl) -2pirolidynylo) -lH-5-yl) -4bifenylylo) -lH-2-yl) -l-pyrrolidinyl) ethyl ) Phenyl) metanami on</td><td></td><td>LCMS: Anal. Calc. for C50H56N8O2: 800; found: 801 (M + H)⁺.</td>

<td>Example 107-24</td><td>1- ((1R) -2 - ((2S) 2- (5- (4 '- (2 - ((2S) 1 - ((3-methyl-5-oxoxazolyl) acetyl) -2-pyrrolidinyl) -1Himidazol-5- yl) -4bifenylylo) -lH-2-yl) -l-pyrrolidinyl) -2-oxo-1phenylethyl) piper ethylpyridin</td><td>ΥϊΜΜΚϊΧ</td><td>LCMS: Anal. Calc. for C.₄₅H₄₈N₈ABOUT₃: 748; found: 749 (M + H)⁺.</td>

<td>Example 107-25</td><td>l - ((R) -2 - ((2S) (5- (4 '- (2 - ((2S) -l ((2-methyl-l, 3-thiazol-4-yl) acetyl) -2pirolidynylo) -1H-imidazol-5 yl) -4bifenylylo) -lH-2-yl) -l-pyrrolidinyl) -2-</td><td>ABOUT</td><td>LCMS: Anal. Calc. for C.₄₅H₄₈N₈O2S: 764; found: 765 (M + H)⁺.</td>

201

<td></td><td>oxo-1phenylethyl) piper ethylpyridin</td><td></td><td></td>

<td>Example 107-26</td><td>4- (2- (2-Oxo-2- ((2S) -2- (5- (4 '- (2- ((2S) -l - ((2R) -2fenylo-2- (lpiperydynylo) acetamide yl) -2pirolidynylo) -lH-5-yl) -4bifenylylo) -lH-2-yl) -l-pyrrolidinyl) ethyl ) Benzyl) -morpholin and</td><td>At 0</td><td>LCMS: Anal. Calc. for C.₅₂H₅₈N₈ABOUT₃: 842; found: 843 (M + H)⁺.</td>

<td>Example 107-27</td><td>1- ((1R) -2-oxo-1-phenyl-2 - ((2S) -2 (5- (4 '- (2 - ((2S) -1 ((2- (1-pyrrolidinylmethyl) ) phenyl) acetyl) 2-pyrrolidinyl) 1H-imidazol-5-yl) -4-biphenyl) 1H-imidazol-2-yl) -1-pyrrolidinyl) ethyl ) piperidine</td><td>OO</td><td>LCMS: Anal. Calc. for C.₅2H₅₈N₈ABOUT₂: 826; found: 827 (M + H)⁺.</td>

<td>Example 107-28</td><td>1- ((1R) -2 - ((2S) 2- (5- (4 '- (2 - ((2S) 1 - ((2-fluorophenyl) acet yl) -2pirolidynylo) -1H-imidazol-5-yl) -4bifenylylo) -1H-imidazol-2-yl) -l-pyrrolidinyl) -2-oxo-1phenylethyl) piper</td><td></td><td>LCMS: Anal. Calc. for C₄7H₄₈FN₇O2: 800; found: 801 (M + H)⁺.</td>

202

<td></td><td>ethylpyridin</td><td></td><td></td>

<td>Example 107-29</td><td>1- ((1R) -2 - ((2S) 2- (5- (4 '- (2 - ((2S) 1-acetyl-2-pyrrolidinyl) -1Himidazol-5-yl) -4-biphenyl) -1Himidazol-2- yl) -l-pyrrolidinyl) -2-oxo-1phenylethyl) piper ethylpyridin</td><td></td><td>LCMS: Anal. Calc. for C.₄H₄₅FN₇ABOUT₂: 667; found: 668 (M + H)⁺.</td>

<td>Example 107-30</td><td>l - ((R) -2-oxo-lfenylo-2 - ((2S) -2- (5- (4 '- (2 - ((2S) -l (2tienyloacetylo) -2pirolidynylo) -lH-5-yl) -4bifenylylo) -lH-2-yl) -l-pyrrolidinyl) ethyl ) piperidine</td><td>OO</td><td>LCMS: Anal. Calc. for C.₄₅H₄₇N₇ABOUT₂S: 749; found: 750 (M + H)⁺.</td>

Example 107-31 to 107-34

<img file="PL2049522T3_D0153.tif" />

Examples 107-31 to 107-34 were obtained in a similar manner to Example 28. Cop-38 was attached to intermediate 28d, Boc carbamate was removed by TFA or HCl and the corresponding carboxylic acid coupled.

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

<td>Example 107-31</td><td>(R) -2 - ((2S) -2- (5- (4 '- (2- ((2S) -l - ((2R) -2- (dimethylamino) -2- (2-fluorophenyl) acetyl) -2pirolidynylo) - 1-Himidazol-5-yl) -4-biphenylyl) -1H-imidazol-2-yl) -1-pyrrolidinyl) -</td><td>ABOUT 5-ΧΧ XX) X) X^N Ν ° *</td><td>LCMS: Anal. Calc. for C₄₆H₄₉FN₈ABOUT₂: 764; found: 765 (M + H)⁺.</td>

203

<td></td><td>N, N-dimethyl-2-oxo-1 phenylethanamine</td><td></td><td></td>

<td>Example 107-32</td><td>(1R) -1- (2-fluorophenyl) -2 ((2S) -2- (5- (4 '- (2 - ((2S) -1 ((2R) -2-methoxy-2-phenylacetyl) -2-pyrrolidinyl) -1Himidazol-5-yl) -4-biphenylyl) -1H-imidazol2-yl) -1-pyrrolidinyl) N, N-dimethyl-2-oxoethanamine</td><td>ABOUT Ge^0M'</td><td>LCMS: Anal. Calc. for C45H46FN7O3: 751; found: 752 (M + H)⁺.</td>

<td>Example 107-33</td><td>(1R) -2 - ((2S) -2- (5 (4 '- (2 - ((2S) -1 - ((2R) -2 (dimethylamino) -2- (2-fluorophenyl) acetyl) -2-pyrrolidinyl) acetate -1Himidazol-5-yl) -4-biphenylyl) -1H-imidazol2-yl) -1-pyrrolidinyl) -2-oxo-1-phenylethyl</td><td>'* ΘΑ "</td><td>LCMS: Anal. Calc. for C46H46FN7O4: 779; found: 780 (M + H)⁺.</td>

<td>Example 107-34</td><td>(1R) -1- (2-fluoro-phenyl) N, N-dimethyl-2-oxo-2 ((2S) -2- (5- (4 '- (2 - ((2S) -1 ((ifenylcyclopropyl) carbon) nyl) -2-pyrrolidinyl) -1-Himidazol-5-yl) -4-biphenylyl) -1H-imidazol-2-yl) -1-pyrrolidinyl) ethanamine</td><td>ΓΗΚΚλ X &lt;Xh ^J</td><td>LCMS: Anal. Calc. for C46H46FN7O2: 747; found: 748 (M + H)⁺.</td>

<img file="PL2049522T3_D0154.tif" />

Examples 107-35 to 107-38 were prepared in a similar manner to Example 28. Cap-39 was attached to intermediate 28d, Boc carbamate was removed with TFA or HCl and the corresponding carboxylic acid was coupled.

204

<td>Example</td><td>Union 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) -2-pyrrolidinyl) ) -1Himidazol-5-yl) -4-biphenylyl) -1H-imidazolyl) -1-pyrrolidinyl) N, N-dimethyl-2-oxoethanamine</td><td></td><td>LCMS: Anal. Obi. for C.₄₆H₄₉C1N₈ABOUT₂: 780; found: 781 (M + H)⁺.</td>

<td>Example 107-36</td><td>((R) -2 - ((2S) -2- (5- (4 '- (2- ((2S) -l - ((2R) -2- (2-chlorophenyl) -2- (dimethylamino) acetyl) -2-pyrrolidinyl ) -1-Himidazol-5-yl) -4-biphenylyl) -1 H-imidazol-2-yl) -1-pyrrolidinyl) -2-oxo-1-phenylethyl) carbamate methyl</td><td> _ 9</td><td>LCMS: Anal. Obi. for C.₄₆H₄₇C1N₈ABOUT₄: 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-2-phenylacetyl) -2-pyrrolidinyl) -1Himidazol-5-yl) -4-biphenylyl) -1H-imidazolyl) -1-pyrrolidinyl) N, N-dimethyl-2-oxoethanamine</td><td></td><td>LCMS: Anal. Obi. for C.₄₅H₄₆CIN₇ABOUT₃: 767; found: 768 (M + H)⁺.</td>

<td>Example 107-38</td><td>(1R) -1- (2-chlorophenyl) N, N-dimethyl-2-oxo-2 ((2S) -2- (5- (4- (2 - ((2S) -1 ((2R) -tetrahydro -2furanylokarbonylo) -2pirolidynylo) -lH-5-yl) -4-</td><td>ικΧΧϊ</td><td>LCMS: Anal. Obi. for C.₄H₄₄C1N₇ABOUT₃: 717; found: 718 (M + H)⁺.</td>

205

<td></td><td>biphenylyl) -1H-imidazol2-yl) -1-pyrrolidinyl) ethanamine</td><td></td><td></td>

<img file="PL2049522T3_D0155.tif" />

Examples 107-39 to 107-44 were prepared in a similar manner to example 28. Cap-40 was attached to intermediate 28d, Boc carbamate was removed by TFA or HCl and the corresponding carboxylic acid was coupled.

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

<td>Example 107-39</td><td>((1R) -1- (2-chloro-phenyl) -2-oxo-2 - ((2S) -2- (5- (4 '- (2 - ((2S) 1 - ((2R) -tetrahydro-2-furanylcarbonyl) Methyl -2-pyrrolidinyl) -1H-imidazol-5-yl) -4-biphenyl) -1H-imidazol-2-yl) -1-pyrrolidinyl) ethyl) carbamate methyl</td><td>η "h Jo</td><td>'HNMR (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), 5.155.18 (m, 1H), 4.67- 4.70 and 4.39-4.42 (m, 1H, rotamers, 1: 1), 3.92-3.98 (m, 1H), 3.853.90 (m, 1H), 3.69-3.84 (m, 2H), 3.64 and 3.63 (s, 3H, rotamers, 1: 1),</td>

206

<td></td><td></td><td></td><td>3.53-3.59 (m, 1H), 2.35- 2.46 (m, 1H), 2.212.29 (m, 2H), 2.06-2.17 (m, 3H), 1.84-2.01 (m, 4H), 1.661.76 and 1.41-1.47 (m, 1H , rotamers, 1: 1); LCMS: Anal. Calc. for C₄₁H₄₂C1N₇ABOUT₅: 747; found: 748 (M + Hf.</td>

<td>Example 107-40</td><td>((1R) -1- (2-chlorophenyl) -2 ((2S) -2- (5- (4 '- (2 - ((2S) -1 ((2R) -2- (dimethylamino) -2-phenylacetyl) -2-pyrrolidinyl) 1H-imidazol-5-yl) -4-biphenylyl) -1H-imidazol-2-yl) -1-pyrrolidinyl) -2-oxoethyl) carbamate methyl</td><td></td><td>LCMS: Anal. Calc. for C.₄₆H₄7C1N₈ABOUT₄: 810; found: 811 (M + Hf.</td>

<td>Example 107-41</td><td>((1R) -2 - ((2S) -2- (5- (4 '- (2 ((2S) -1 - ((2R) -2- (2-chlorophenyl) -2 ((methoxycarbonyl) amino) a cetyl ) -2-pyrrolidinyl) -1-imidazol-5-yl) -4-biphenylyl) 1H-imidazol-2-yl) -1-pyrrolidinyl) -2-oxo-1 phenylethyl) methyl carbamate</td><td>IMeO, CHN ' n- ,. / -ά χ X N_K W) N Ύ Η "γ.</td><td>LCMS: Anal. Calc. for C.₄₆H₄₅C1N₈ABOUT₆: 840; found: 841 (M + Hf.</td>

<td>Example 107-42</td><td>((1R) -1- (2-chlorophenyl) -2 ((2S) -2- (5- (4 '- (2 - ((2S) -1 ((2R) -2- (4-hydroxy-4 -methyl1-piperidinyl) -2-phenylacetyl) -2-pyrrolidinyl) 1H-imidazol-5-yl) -4-biphenyl) -1H-imidazol-2-yl) -1-pyrrolidinyl) -2-</td><td>Meo₂CHN ^ 'X Ύ ^s AND ⁼ -Yr^N· .. * ./ x-^; k —χ</td><td>LCMS: Anal. Calc. for C₅oH₅₃C1N₈0₅: 880; found: 881 (M + Hf.</td>

207

<td></td><td>methyl oxoethyl) carbamate</td><td></td><td></td>

<td>Example 107-43</td><td>((1R) -1- (2-chloro-phenyl) -2 ((2S) -2- (5- (4 '- (2 - ((2S) -1 ((2R) -2-methoxy-2-phenylacetyl) - 2-pyrrolidinyl) 1H-imidazol-5-yl) -4-biphenylyl) -1H-imidazol-2-yl) -1-pyrrolidinyl) -2-oxoethyl) carbamate methyl</td><td>MeOCHN AU⁰ ~ Γ » -'Ά ń \ _ / F 7 _N_Jf _N OMe AND⁵ About "» About</td><td>LCMS: Anal. Calc. for C.₄₅H₄₄C1N₇ABOUT₅: 797; found: 798 (M + H)⁺.</td>

<td>Example 107-44</td><td>((1R) -1- (2-chlorophenyl) -2 ((2S) -2- (5- (4 '- (2 - ((2S) -1 ((2R) -2- (2-chlorophenyl) - Methyl 2 (dimethylamino) acetyl) -2-pyrrolidinyl) -1H-imidazol-5-yl) -4-biphenyl) -1H-imidazol-2-yl) -1-pyrrolidinyl) -2-oxoethyl) carbamate</td><td></td><td>LCMS: Anal. Calc. for C.₄₆H46C1₂N₈ABOUT₄: 844; found: 845 (M + H)⁺.</td>

Example 108 ((1 R) -2 - ((2S) -2- (5- (4 '- (2 - ((2S) -1- (ethylcarbamoyl) -2-pyrrolidinyl) -1H-imidazol-5-yl) -4-biphenylyl) -lH-imidazol-2-yl) -l-pyrrolidinyl) -2-oxo-l-phenylethyl) karbamiman

<img file="PL2049522T3_D0156.tif" />

Ethyl isocyanate (5 pL, 0.063 mmol) was added to the methanol solution (1.0 mL) 28f (30 mg, 0.049 mmol) and stirred at ambient conditions 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 volatiles were removed in vacuo. The resulting material was purified by 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 (Condition 2); &gt; 98% homogeneity index; LC / MS: Anal. Calc. for [M + H]⁺ Ο39Η43Ν8Ο4: 687.34; found 687.53; HRMS: Anal. Calc. for [M + H]⁺ C39H4₃N₈ABOUT₄: 687.3407; found 687.3417.

Example 109 (2S, 2'S) -2.2 '- (4,4'-biphenyldiylbis (1H-imidazol-5,2-diyyl)) dibenzyl di (1-pyrrolidinecarboxylate)

208

<img file="PL2049522T3_D0157.tif" />

Example 109, Step a (2S) -2- (5- (4 '- (2 - ((2S) -2-pyrrolidinyl) -1H-imidazol-5-yl) -4-biphenyl) -1H-imidazol-2 benzyl-yl) -1-pyrrolidine carboxylate

<img file="PL2049522T3_D0158.tif" />

Boc-protected 28c, using the procedure described for the synthesis of pyrrolidine le from ld carbamate, provided 109a. RT = 1.92 minutes (Condition 2); &gt; 98% homogeneity index; LC / MS: Anal. Calc. for. C34H35N6O2: 559.28; found 559.44

Example 109 (2S, 2 'S) -2,2' - (4,4'-biphenyldiylbis (1H-imidazol-5,2-diyl)) di (1-pyrrolidine carboxylate)

<img file="PL2049522T3_D0159.tif" />

Benzyl chloroformate (10.5 pL, 0.0736 mmol) was added to a solution of THF (2.0 mL) 109a (37.1 mg, 0.664 mmol) and triethylamine (15 µL, 0.107 mmol) and stirred at 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 was purified by reverse phase HPLC (H2O / methanol / TFA) to provide the TFA salt of Example 109 as an off-white foam (37.9 mg). LC (Condition 2): RT =

2.25 min; &gt; 98% homogeneity index; LC / MS: Anal. Calc. for [M + H]⁺ C42H41N6O4: 693.32; found 693.59; HRMS: Anal. Calc. for [M + H]⁺ C42H41N6O4: 693.3189; found 693.3220.

Example 110 (2R) -N - ((1R) -2-oxo-1-phenyl-2 - ((2S) -2- (5- (4 '- (2 - ((2S) -1 - ((2S ) -tetrahydro-2-furanylcarbonyl) -2-pyrrolidinyl) -1H-imidazol-5-yl) -4-biphenyl) -1H-imidazol-2-yl) -1-pyrrolidinyl) ethyl) tetrahydro-2-furancarboxamide

<img file="PL2049522T3_D0160.tif" />

Example 110, Step a

209 (R) -2-oxo-l-phenyl-2 - ((2S) -2- (5- (4 '- (2 - ((2S) -l - ((2S) -tetrahydro-2-furanylcarbonyl) - 2-pyrrolidinyl) -1H-imidazol-5-yl) -4-biphenylyl) -1H-imidazol-2-yl) -1-pyrrolidinyl) ethanamine

<img file="PL2049522T3_D0161.tif" />

Amine 10a was synthesized starting from 28d and (S) -tetrahydrofuran-2-carboxylic acid by using sequentially the procedures described in preparation 28f (from 28d) and 25b (from le). LC (Condition 1): RT = 1.13 min; &gt; 98% homogeneity index; LC / MS: Anal. Calc. for [M + H]⁺C39H42N7O3: 656.34; found 656.49; HRMS: Anal. Calc. for [M + H]⁺ C39H42N7O3: 656.3349; found 656.3377.

Example 110 (2R) -N - ((1R) -2-oxo-1-phenyl-2 - ((2S) -2- (5- (4 '- (2 - ((2S) -1 - ((2S ) -tetrahydro-2-furanylcarbonyl) -2-pyrrolidinyl) -1H-imidazol-5-yl) -4-biphenyl) -1H-imidazol-2-yl) -1-pyrrolidinyl) ethyl) tetrahydro-2-furancarboxamide

<img file="PL2049522T3_D0162.tif" />

Example 110 (TFA salt) was prepared from Example 10a and (S) -tetrahydrofuran-2-carboxylic acid using the conditions described for the synthesis of Example 1 from amine le. LC (Condition 1): RT = 1.28 min; &gt; 98% homogeneity index; LC / MS: Anal. Calc. for [M + H]⁺C44H48N7O5: 754.37; found 754.60; HRMS: Anal. Calc. for [M + H]⁺ C44H48N7O₅: 754.3717; found 754.3690.

Example 111

N - ((R) -2-oxo-l-phenyl-2 - ((2S) -2- (5- (4 '- (2 - ((2S) -l - ((2S) -tetrahydro-2- furanylcarbonyl) -2pirolidynylo) -lH-imidazol-5-yl) -4-biphenylyl) -lH-imidazol-2-yl) -l-pyrrolidinyl) ethyl) -4morfolinokarboksamid

<img file="PL2049522T3_D0163.tif" />

Example 111 (TFA salt) was prepared from amine 10a and morpholine-4-carbonyl chloride using the procedure described for the synthesis of Example 29 from amine 28f. LC (Condition 1): RT = 1.28 min; &gt; 98% homogeneity index; LC / MS: Anal. Calc. for [M + H]⁺ 04₄Η₄₉Ν₈05: 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.

210

<img file="PL2049522T3_D0164.tif" />

<td>Example</td><td>Union Name</td><td>about X</td><td>Retention time (LC conditions); homogeneity index Data MS</td>

<td> 112</td><td>(2S) -N - ((R) -2-oxo-lfenylo-2 - ((2S) -2- (5- (4 '- (2- ((2S) -l - ((2S) -tetrahydro-2-furanylcarbonyl ) -2-pyrrolidinyl) -1H-imidazol-5-yl) -4-biphenylyl) -1Himidazol-2-yl) -1-pyrrolidinyl) ethyl) tetrahydro-2-furancarboxamide</td><td>X</td><td>1.28 minutes (War. 1); &gt; 98%; LC / MS: Anal. Calc. for [M + H]⁺ C44H48N7O5: 754.37; found 754.59; HRMS: Anal. Calc. for [M + H]⁺C₄₄H₄₈N₇ABOUT₅: 754.3717; found 754.3731</td>

<td> 113</td><td>1-methyl-N - ((1 R) -2-oxo-phenyl-2 - ((2S) -2- (5- (4 '(2 - ((2S) -1 - ((2S) tetrahydro-2-furanylcarbonyl) ) -2-pyrrolidinyl) -1H-imidazol-5-yl) -4-biphenylyl) -1H-imidazol-2-yl) -1-pyrrolidinyl) ethyl) -Lprolinamide</td><td></td><td>1.14 minutes (War. 1); &gt; 98%; LC / MS: Anal. Calc. for [M + H]⁺ C₄₄H₅₁N₈ABOUT₄: 767.40; found 767.68; HRMS: Anal. Calc. for [M + H]⁺C₄₄H₅iN₈ABOUT₄: 767.4033; found 767.4035</td>

<td> 114</td><td>1-methyl-N - ((1R) -2-oxo-1 phenyl-2 - ((2S) -2- (5- (4 '- (2 ((2S) -1 - ((2S) -tetrahydro- 2-furanylcarbonyl) -2-pyrrolidinyl) -1H-imidazol-5-yl) -4-biphenyl) -1H-imidazol-2-yl) -1-pyrrolidinyl) ethyl) -4-piperidinecarboxamide</td><td>X</td><td>1.12 minutes (War. 1); &gt; 98%; LC / MS: Anal. Calc. for [M + H]⁺ C₄₆H₅₃N₈ABOUT₄: 781.42; found 781.67; HRMS: Anal. Calc. for [M + H]⁺C₄₆H₅₃N₈0₄: 781.4190; found 781.4195</td>

<td> 115</td><td>N - ((1 R) -2-oxo-1-phenyl-2 ((2S) -2- (5- (4 '- (2 - ((2S) -1 ((2S) -tetrahydro-2-</td><td> 0</td><td>1.24 minutes (War. 1); &gt; 98%; LC / MS: Anal. Calc. for [M + H]⁺ C₄₅H₅he₇0₅:</td>

211

<td></td><td>furanylcarbonyl) -2-pyrrolidinyl) -1H-imidazol-5-yl) -4-biphenylyl) -1H-imidazol-2-yl) -1-pyrrolidinyl) ethyl) tetrahydride ro-2H-pyran-4karboksamid</td><td></td><td>768.39; found 768.66; HRMS: Anal. Calc. for [M + H]⁺C45H50N7O5: 768.3873; found 768.3897</td>

<td> 116</td><td>(4R) -4-fluoro-1-methyl-N ((1R) -2-oxo-1-phenyl-2 ((2S) -2- (5- (4 '- (2 - ((2S) - 1 ((2S) -tetrahydro-2-furanylcarbonyl) -2-pyrrolidinyl) -1H-imidazol5-yl) -4-biphenylyl) -1Hididazol-2-yl) -1-pyrrolidinyl) ethyl) -Lprolinamide</td><td>F Cap-11</td><td>1.16 minutes (War. 1); &gt; 98%; LC / MS: Anal. Calc. for [M + H]⁺ C45H₅ofn₈0₄: 785.39; found 785.63, HRMS: Anal. Calc. for [M + H]⁺C45H₅ofn₈0₄: 785.3939; found: 785.3940</td>

<td> 117</td><td>4-methyl-N - ((1 R) -2-oxol-phenyl-2 - ((2S) -2- (5- (4 '(2 - ((2S) -1 - ((2S) tetrahydro-2-furanylcarbonyl) ) -2-pyrrolidinyl) -1H-imidazol-5-yl) -4-biphenylyl) -1H-imidazol-2-yl) -1-pyrrolidinyl-ethyl) -1-piperazinecarboxamide</td><td>\ ABOUT</td><td>1.15 minutes (War. 1); 97.6%; LC / MS: Anal. Calc. for [M + H]⁺C45H₅₂N₉ABOUT₄: 782.41; found 782.64; HRMS: Anal. Calc. for [M + H]⁺ C₄₅H₅₂N₉ABOUT₄: 782.4142; found 782.4161</td>

<img file="PL2049522T3_D0165.tif" />

Examples 118 to 120-9 were prepared as described in the preparation of Example 11a replacing (R) -tetrahydrofurylcarboxylic acid and the corresponding carboxylic acid, acid chloride, carbamoyl chloride or isocyanate.

<td>Example</td><td>Union Name</td><td>ABOUT rK</td><td>Retention time (LC conditions); homogeneity index; MS data</td>

212

<td> 118</td><td>Ν - ((1 R) -2-oxo-1-phenyl-2 ((2S) -2- (5- (4 '- (2 - ((2S) -1 ((2R) -tetrahydro-2-furanylcarbonyl) - 2-pyrrolidinyl) -1H-imidazol-5-yl) -4-biphenylyl) -1H-imidazol-2-yl) -1-pyrrolidinyl) ethyl) acetamide</td><td>ABOUT AND</td><td>1.89 minutes (War. 2); &gt; 98%; LC / MS: Anal. Obi. for [M + H]⁺C41H44N7O4: 698.35; found 698.25; HRMS: Anal. Obi. for [M + H]⁺ C41H44N7O4: 698.3455; found 698.3474</td>

<td> 119</td><td>(2R) -N - ((1 R) -2-oxo-1-phenyl2 - ((2S) -2- (5- (4 '- (2 - ((2S) -1 ((2R) -tetrahydro- 2-furanylcarbonyl) -2-pyrrolidinyl) -1H-imidazol-5-yl) -4-biphenyl) -1H-imidazol-2-yl) -1-pyrrolidinyl) ethyl) tetrahydro-2-furancarboxamide</td><td></td><td>1.99 minutes (War. 2); &gt; 98%; LC / MS: Anal. Obi. for [M + H]⁺C44H48N7O5: 754.37; found 754.28; HRMS: Anal. Obi. for [M + H]⁺ C44H48N7O5: 754.3717; found 754.3705</td>

<td> 120</td><td>N - ((1 R) -2-oxo-1-phenyl-2 ((2S) -2- (5- (4 '- (2 - ((2S) -1 ((2R) -tetrahydro-2-furanylcarbonyl) - 2-pyrrolidinyl) -1H-imidazol-5-yl) -4-biphenylyl) -1H-imidazol-2-yl) -1-pyrrolidinyl) ethyl) -4-morpholinecarboxamide</td><td>about AND oh</td><td>2.00 minutes (War. 2); &gt; 98%; LC / MS: Anal. Obi. for [M + H]⁺C44H49N8O5: 769.38; found 769.32</td>

<td> 120-5</td><td>1-methyl-N - ((1 R) -2-oxo-1 phenyl-2 - ((2S) -2- (5- (4 '- (2 ((2 S) -1 - ((2R) - tetrahydro-2-furanylcarbonyl) -2-pyrrolidinyl) -1H-imidazol-4-yl) -4-biphenyl) -1H-imidazol-2-yl) -1-pyrrolidinyl) ethyl) -1H-imidazol-5-carboxamide</td><td>\ s IX Kj.</td><td>RT = 4.02 (97%); HPLC XTERRA C-18 4.6 x 30 mm, 0 to 100% B in 2 minutes, one minute stop 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. Obi. for: C44H45N9O4 763.91; Found: 764.52 (M + H)⁺</td>

<td> 120-6</td><td>1-methyl-N - ((1 R) -2-oxo-1 phenyl-2 - ((2S) -2- (5- (4 '- (2 ((2S) -1 - ((2R) -tetrahydro -2-</td><td> \</td><td>RT = 3.68 (99%); HPLC XTERRA C-18 4.6 x 30 mm, 0 to 100% B in 2 minutes, 1</td>

213

<td></td><td>furanylcarbonyl) -2-pyrrolidinyl) -1H-imidazol-4-yl) -4-biphenylyl) -1Himidazol-2-yl) -1-pyrrolidinyl) ethyl) -Lprolinamide</td><td></td><td>minute stop time, A = 90% water, 10% methanol, 0.2% H3PO4, B = 10% water, 90% methanol, 0.2% H3PO4, RT = 1.87 minutes, 91% homogeneity index; LCMS: Anal. Calc. for: C₄5H₅he₈0₄ 766.95; Found: 767.47 (M + H)⁺</td>

<td> 120-7</td><td>N - ((1 R) -2-oxo-1-phenyl-2 ((2S) -2- (5- (4 '- (2 - ((2S) -1 ((2R) -tetrahydro-2-furanylcarbonyl) - 2-pyrrolidinyl) -1H-imidazol-4-yl) -4-biphenylyl) -1H-imidazol-2-yl) -1-pyrrolidinyl) ethyl) -2- (3-pyridinyl) acetamide</td><td></td><td>RT = 3.81 (99%); HPLC TERRA C-18 4.6 x 30 mm, 0 is 100% o B within 2 minutes, 1 minute stop 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. Calc. for: C46H₄₆N₈O4 774.93; Found: 775.47 (M + H)⁺</td>

<td> 120-8</td><td>N²N²-dimethyl-N - ((1R) -2-oxo-1-phenyl-2 - ((2S) -2- (5- (4 '(2 - ((2S) -1 - ((2R) -tetrahydro-2-furanylcarbonyl) ) -2-pyrrolidinyl) -1H-imidazol-4-yl) -4-biphenylyl) -1Himidazol-2-yl) -1-pyrrolidinyl) ethyl) glycinamide</td><td>Y /^Nx</td><td>1 H NMR (500 MHz, DMSO-d₆) δ ppm 1.71-2.44 (m, 12H), 2.652.89 (m, 6H), 3.04-3.21 (m, 7 = 8.55 Hz, 1H), 3.46-3.68 (m, 1H), 3.64-4.07 (m, 6H), 4.64 (dd, 7 = 8.09, 5.34 Hz, 1H), 5.095.30 (m, 2H), 5.66-5.86 (m, 1H), 7.32-7.49 (m, 4H), 7.82- 8.22 (m, 10H), 9.15-9.38 (m, 1H), 9.68 (s, 1H), 14.60 (s, 2H); HPLC Xterra 4.6 X 50 mm, 0 to 100% B in 10 minutes, one minute hold time, A = 90% water, 10% methanol, 0.2% phosphoric acid, B = 10% water, 90% methanol, 0.2% acid phosphoric, RT = 3.61 min; LCMS: Anal. Calc. for: C52H56N10O6 740.91; Found: 741.48 (M + H)⁺.</td>

214

<td> 120-9</td><td>1 - ((1 R) -2-oxo-1-phenyl-2 ((2S) -2- (5- (4 '- (2 - ((2S) -1 ((2R) -tetrahydro-2-furanylcarbonyl) - 2-pyrrolidinyl) -1H-imidazol-4-yl) -4-biphenylyl) -1Himidazol-2-yl) -1-pyrrolidinyl) ethyl) -3- (3-pyridinyl) urea</td><td>^ NH about</td><td>1 H NMR (500 MHz, DMSO-d_about) δ ppm 1.64-2.40 (m, 12H), 3.113.27 (m, 1H), 3.51-3.65 (m, 1H), 3.80 (dd, J = 18.46, 6.87 Hz, 3H), 3.96- 4.11 (m, 1H), 4.64 (dd, 7 = 7.78, 5.34 Hz, IH), 5.135.23 (m, IH), 5.21-5.35 (m, IH), 5.66 (d, J = 7.02 Hz, IH), 7.297.57 (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 in 10 minutes, one minute hold time, A = 90% water, 10% methanol, 0.2% phosphoric acid, B = 10% water, 90% methanol, 0.2% acid phosphoric, RT = 3.83 min; LCMS: Anal. Calc. for: C45H45N9O4 775.92; Found: 776.53 (M + H)⁺.</td>

Example 121 (1R, 1 'R) -2.2' - ((2,2'-dimethyl-4,4^,biphenyldiyl) bis (1H-imidazol-5,2-diyl (2S) -2, 1-pyrrolidinidiyl)) bis (N, N-dimethyl-2-oxo-1-phenylethanamine)

<img file="PL2049522T3_D0166.tif" />

<img file="PL2049522T3_D0167.tif" />

<img file="PL2049522T3_D0168.tif" />

PdChCPhsPf (257 mg, 0.367 mmol) was added to the dioxane (45 mL) solution of 1-bromo-4-iodo-2-methylbenzene (3.01 g, 10.13 mmol) and tri-n-butyl (1-ethoxyvinyl) stannan (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 portions over 7 minutes. After about 25 minutes of stirring, the volatile component was removed in vacuo, and the residue was partitioned between CH2Cl2 and water. layer

215 aqueous was extracted with CH 2 Cl 2, and the combined organic phases were dried (MgSO₄), filtered and concentrated in vacuo. The resulting crude material was purified by gravity chromatography (silica gel; 4% ethyl acetate / hexanes) to provide 12la bromide as a brown-yellow solid (2,699 g); The sample is contaminated and contains, among others, impurities derived from stannan. * H NMR (CDCl3, δ = 7.24, 400 MHz): 7.83 (s, 1H), 7.63 (s, 2H), 4.30 (s, 2H), 2.46 (s, 3H).

CH3CN solution (15 mL) 121a (2.69 g, &lt;9.21 mmol) was added dropwise over 3 minutes to the CH solution₃CN (30 mL) (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 flash chromatography (silica gel; 15-20% ethyl acetate / hexanes) to provide 121 b as a colorless viscous oil (2.74g). 1 H 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 (Condition 1): RT = 1.91 min; &gt; 95% homogeneity index; LC / MS: Anal. Calc. for [M + Na]⁺ Ci9H₂₄BrNNaO5 448.07; found 448.10.

Additional keto-esters can be obtained in an analogous manner.

LC conditions: Condition 1: Phenomenex LUNA C-18 4.6 x 50 mm, 0 to 100% B in 3 minutes, 1 minute stop 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 in 2 minutes, 1 minute stop 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>o</td><td>RT = 2.15 minutes (condition 2, 98%); LRMS: Anal. Calc. for C,₇H₂₂WELL₅ 399.07; found: 400.10 (M + H)⁺.</td>

<td>121b-2</td><td>ΌΧ ' About Ł</td><td>RT = 2.78 minutes (condition 1, &gt; 90%); LRMS: Anal. Calc. for C.₂oH₂about³⁷BrNOj 435.05 found: 458.02 (M + Na)⁺.</td>

Example 121, Step c

<img file="PL2049522T3_D0169.tif" />

121c

216

A mixture of ketoester 121b (1.445 g, 3.39 mmol) and NH4OAC (2.93 g, 38.0 mmol) in xylenes (18 mL) was heated in the microwave at 140 ° C for 80 minutes. The volatile component was removed in vacuo, and the residue was carefully partitioned between CH2Cl2 and water, where enough NaHCO solution was added₃ to neutralize the aqueous medium. The aqueous phase was extracted with CH 2 Cl 2, and the combined organic phases were dried (MgSO₄), filtered and concentrated in vacuo. The crude product was purified by flash chromatography (silica gel, 40% ethyl acetate / hexanes) to provide imidazole 12lc as an off-white solid (1.087 g). * H NMR (DMSO-d₆, δ = 2.50, 400 MHz): 12.15 / 11.91 / 11.84 (br s, 1H), 7.727.24 (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 (Condition 1): RT = 1.91 min; &gt; 98% homogeneity index; LC / MS: Anal. Calc. for [M + H]⁺ these₉H2₃BrN₃O2 405.96; found 406.11.

Example 121, Step d

<img file="PL2049522T3_D0170.tif" />

PdCl2dppf CH2Cl2 (50.1 mg, 0.061 mmol) was added to a pressure tube containing a mixture of 12lc bromide (538.3 mg, 1.325 mmol), bis (pinacolano) diborane (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 CH 2 Cl 2 and water, where enough NaHCO solution was added₃ to make the pH of the aqueous medium neutral. The aqueous phase was extracted with CH 2 Cl 2, and the combined organic phases were dried (MgSO₄), filtered and concentrated in vacuo. The resulting material was purified using a Biotage system (silica gel, 40-50% ethyl acetate / hexanes) to provide 121d boronate as a white foam (580 mg). According to * H NMR the sample contains pinacol residue in a product / pinacol ratio -3.^fH NMR (DMSO-d6, δ = 2.50, 400 MHz): δ 12.16 / 11.91 / 11.83 (br s, 1H), 7.637.25 (m, 4H), 4.78 (m, 1H), 3.53 (m, 1H) , 3.39-3.32 (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 (Condition 1): RT = 1.62 min; LC / MS: Anal. Calc. for [M + H]⁺ C25H₃₇BN₃ABOUT₄ 454.29; found 454.15

Example 121, Step ei

<img file="PL2049522T3_D0171.tif" />

217

Carbamate 121e was prepared from bromide 121c and boronate 121d according to the production of 1d dimer; LC (Condition 1): RT = 1.43 min; LC / MS: Anal. Calc. for [M + H]⁺C38H49N6O4 653.38; found 653.65.

Deprotection of carbamate 121e, according to the production of pyrrolidine le, gave 121 f as an off-white foam. * H NMR (DMSO-d₆, δ = 2.50, 400 MHz): 11.79 (br s, 2H), 7.66 (s, 2H),

7.57 (d, 7 = 7.8, 2H), 7.41 (brs, 2H), 7.02 (d, 7 = 7.8, 2H), 4.15 (appt, 7 = 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 NH pyrrolidine appear in the region

2.8-3.2 ppm, the actual range of their chemical shift cannot be determined. LC (Condition 1): RT = 1.03 min; LC / MS: Anal. Calc. for [M + H]⁺ C₂₈H₃₃N₆ 453.28; found

453.53

<img file="PL2049522T3_D0172.tif" />

Example 121 (1R, 1 'R) -2,2' - ((2,2'-dimethyl-4,4'-biphenyldiyl) bis (1H-imidazol-5,2-diyl (2S) -2, 1-pyrrolidinylated) )) bis (N, N-dimethyl-2-oxo-l-fenyloetanamina)

Example 121 (TFA salt) was synthesized from 121 f according to the preparation of Example 1 from le; LC (Condition 1): RT = 1.14 min; &gt; 98% homogeneity index; LC / MS: Anal. Calc. for [M + H]⁺ C48H55N8O2 775.45; 775.75; HRMS: Anal. Calc. for [M + H]⁺ C48H₅₅N₈ABOUT₂ 775.4448; found 775.4473

Example 122 ((2,2'-dimethyl-4,4'-biphenyldiyl) bis (1H-imidazol-5,2-diyl (2S) -2, 1-pyrrolidinidiyl ((1R) -2-oxo-1-phenyl- 2,1-ethanediyl))) dimethyl biscarbamate

<img file="PL2049522T3_D0173.tif" />

Example 122 (TFA salt) was prepared from pyrrolidine 12If and Cap-4 using the procedure described for the preparation of Example 1 from pyrrolidine le. LC (Condition 1): RT = 1.35 min; &gt; 98% homogeneity index; HRMS: Anal. Calc. for [M + H]⁺ C4₈H5iN₈0e 835.3932; found 835.3954

Example 123-125

218

<img file="PL2049522T3_D0174.tif" />

Example 123-125 was prepared starting from lc boronate and 121c bromide using the methods described in Example 1, step d, Example 1, step e, and in the step describing

<td>final</td><td colspan="3">preparation of Example 1.</td>

<td>Example</td><td>Union Name</td><td>ABOUT AND</td><td>RT (LC-Cond.); % homogeneity index; MS data</td>

<td> 123</td><td>(1R, 1 'R) -2,2' - ((2-methyl-4,4'-biphenyldiyl) bis (1Himidazol-5,2-diyl (2S) -2,1 pyrrolidinidiyl)) bis (N, N-dimethyl -2-oxo-1 phenylethanamine)</td><td>about ρι, ΜΧ / X Cap-l</td><td>1.12 minutes (War. 1); &gt; 98%; LC / MS: Anal. Calc. for [M + H]⁺C₄₇H₅₃N₈ABOUT₂: 761.43; found 761.49; HRMS: Anal. Calc. for [M + H]⁺C₄₇H53N₈ABOUT₂: 761.4291; found 761.4311</td>

<td> 124</td><td>((2-methyl-4,4'-biphenyldiyl) bis (1Himidazol-5,2-diyl (2S) -2,1 pyrrolidinidyl ((1R) -2-oxo-1 phenyl-2,1-ethanediyl)) biscarbamate dimethyl</td><td>ABOUT AY ABOUT Cap-4</td><td>1.34 minutes (War. 1); &gt; 98%; LC / MS: Anal. Calc. for [M + H] C₄7H₄₉N₈ABOUT₆: 821.38; found 821.45; HRMS: Anal. Calc. for [M + H]⁺C₄₇H₄₉N₈ABOUT₆: 821.3775; found 821.3785</td>

<td> 125</td><td>(1R, 1 'R) -2,2' - ((2-methyl-4,4'-biphenyldiyl) bis (1Himidazol-5,2-diyl (2S) - 2,1 pyrrolidinidiyl)) bis (2-oxo- 1 phenylethanol)</td><td>0 Ά ? H</td><td>1.23 minutes (War. 1); &gt; 98%; LC / MS: Anal. Calc. for [M + H]⁺ C₄₃H₄₃N₆ABOUT₄: 707.34; found 707.38; HRMS: Anal. Calc. for [M + H]⁺C₄₃H₄₃N₆ABOUT₄: 707.3346; found 707.3356</td>

219

Examples 126-128

<img file="PL2049522T3_D0175.tif" />

Example 126-128 was prepared starting from bromide 28b and boronate 121d using

<td colspan="2">the methods described in Example 28 vol</td><td colspan="2">hare from stage c.</td>

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

<td> 126</td><td>((R) -2 - ((2S) -2- (5- (4 '- (2- ((2S) -l - ((2R) -2- (dimethylamino) -2fenyloacetylo) -2pirolidynylo) -1H-imidazol-5- yl) -2'-methyl 4-biphenylyl) -1Himidazol-2-yl) -1-pyrrolidinyl) -2-oxo-1 phenylethyl) carbamate methyl</td><td> 0 ^p&gt;X from". Cap-l</td><td>1,22min (War. 1); &gt; 98%; LC / MS: Anal. Calc. for [M + H]⁺ C₄₇H₅₁N₈ABOUT₄: 791.40; found 791.70; HRMS: Anal. Calc. for [M + H]⁺C₄₇H₅iN₈ABOUT₄: 791.4033; found 791.4061</td>

<td> 127</td><td>((R) -2 - ((2S) -2- (5- (2'-methyl-4 '- (2 - ((2S) -l- (3pirydynyloacetylo) -2pirolidynylo) -lH-5-yl) -4bifenylylo ) -1 H-imidazol2-yl) -1-pyrrolidinyl) -2-oxo-1-phenylethylcarbamate methyl</td><td>«OA</td><td>1.19 minutes (War. 1); &gt; 98%; LC / MS: Anal. Calc. for [M + H]⁺ C₄₄H₄₅N₈ABOUT₄: 749.36; found 749.62; HRMS: Anal. Calc. for [M + H]⁺C₄₄H₄₅N₈ABOUT₄: 749.3564; found 749.3592</td>

<td> 128</td><td>((R) -2 - ((2S) -2- (5- (2-methyl-4 '- (2 - ((2S) -l ((2S) -tetrahydro-2-furanylcarbonyl) -2pirolidynylo) -lH-5-yl ) -4-biphenylyl) -1H-imidazol2-yl) -1-pyrrolidinyl) -2-</td><td>X</td><td>1.27 minutes (War. 1); &gt; 98%; LC / MS: Anal. Calc. for [M + H]⁺ C₄₂H₄₆N₇ABOUT₅: 728.36; found 728.59; HRMS: Anal. Calc. for [M + H]⁺C₄₂H₄₆N₇ABOUT₅: 728.3560; found 728.3593</td>

220 methyl oxo-1-phenylethyl) carbamate

Example 129 ((1R) -2 - ((2S) -2- (5- (4 '- (2 - ((2S) -1 - ((2R) -2- (dimethylamino) -2-phenylacetyl) -2-pyrrolidinyl) ) -1H-imidazol-5-yl) -2,2'-dimethyl-4-biphenylyl) -1H-imidazol-2-yl) -1-pyrrolidinyl) -2-oxo-1-phenylethyl) methyl carbamate

<img file="PL2049522T3_D0176.tif" />

<img file="PL2049522T3_D0177.tif" />

HATU (104.3 mg, 0.274 mmol) was added to a mixture of 12I, CapA (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 (HzO / methanol / TFA) and converted into the free base using an MCX column (methanol washing; 2.0 M NH 3 / methanol) to provide 129a (89.9 mg). LC (Condition 1): RT = 1.22 min; 95% homogeneity index; LC / MS: Anal. Obi. for [M + H]⁺ C38H42N7O3 644.34; found 644.55.

Example 129 ((1R) -2 - ((2S) -2- (5- (4 '- (2 - ((2S) -1 - ((2R) -2- (dimethylammo) -2-phenylacetyl) -2 pyrrolidinyl) 1H-imidazol-5-yl) -2,2'-dimethyl-4-biphenyl) -1H-imidazol-2-yl) -1-pyrrolidinyl) -2-oxo-1-phenylethyl) carbamate

<img file="PL2049522T3_D0178.tif" />

Example 129 (TFA salt) was obtained with 129a by the method used to convert Example 1a to Example 1. LC (Condition 1): RT = 1.27 min; 97% homogeneity index; LC / MS: Anal. Obi. for [M + H]⁺ C48H53N8O4 805.42; found 805.61.

Example 130 (1R, 1 R) -2.2 '- ((2- (trifluoromethyl) -4,4'-biphenyldiyl) bis (1H-imidazol-5,2-diyl (2S) -2,1221 pyrrolidinyl)) bis (N, N-dimethyl-2-oxo-l-fenyloetanamina)

<img file="PL2049522T3_D0179.tif" />

<img file="PL2049522T3_D0180.tif" />

130a

Glyoxal (2.0 mL 40% in water) was added dropwise over 11 minutes to a methanolic NH solution₄OH (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 flash chromatography (silica gel, ethyl acetate) and then recrystallized (ethyl acetate at room temperature) to provide imidazole 130a as a white fluffy solid (4.43 g). * H NMR (DMSO-d6, δ = 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 (Condition 1): RT = 0.87 min; &gt; 95% homogeneity index; LC / MS: Anal. Calc. for [M + H]⁺ C12H20N3O2 238.16; found 238.22. Imidazole 130a had 98.9% ee when analyzed under the chiral HPLC conditions listed below. Column: Chiralpak AD, 10 um, 4.6 x 50 mm

Solvent: 1.7% ethanol / heptane (isocratic)

Flow rate: 1 mL / min

Wavelength: 220 or 256 nm

Relative retention time: 3.25min (R), 5.78 minutes (5)

Example 130, Step b

<img file="PL2049522T3_D0181.tif" />

130b

N-Bromosuccinimide (838.4 mg, 4.71 mmol) was added in portions, over 15 minutes, to a cooled (ice / water) CH2Cl2 (20 mL) solution of imidazole 130a (1.0689 g, 4.504 mmol) and stirred at a similar temperature for 75 minutes. The volatile component was removed in vacuo. The crude material was purified by reverse phase HPLC (H₂O / methanol / TFA) to separate bromide 130b from its dibromo-analog and unused starting material. The HPLC eluate was neutralized with excess Naf / methanol and the volatile component was removed in vacuo. The residue was partitioned between CH 2 Cl 2 and water, and the aqueous layer was extracted with water. The combined organic phases were dried (MgSO₄), filtered and concentrated in vacuo to provide 130b as a white solid (374 mg). * H NMR (DMSO-dó, δ = 2.50, 400 MHz): 12.12 (br s, 1H), 7.10 (m, 1H), 4.70 (m, 1H), 3.31 (m, IH; superimposed with

222 water signal), 2.25-1.73 (m, 4H), 1.39 / 1.17 (s, 3.8H + 5.2H). LC (Condition 1): RT = 1.10 min; &gt; 95% homogeneity index; LC / MS: Anal. Calc. for [M + H]⁺ Οι₂Ηι9ΒγΝ₃Ο2 316.07; found 316.10.

<img file="PL2049522T3_D0182.tif" />

Pd (Ph3P) 4 (78.5 mg, 0.0679 mmol) was added to the bromide mixture 130b (545 mg, 1.724 mmol), 2- (4-chloro-3- (trifluoromethyl) phenyl-4,4,5,5-tetramethyl-1 , 3.2-dioxaborolate (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 in an oil bath at 80 ° C for 27 hours, and then the volatile component was removed in vacuo. The residue was partitioned between CH2Cl2 and water, and the organic layer was dried (MgSO₄), filtered and concentrated in vacuo. The resulting crude material was purified by Biotage (silica gel, 40-50% ethyl acetate / hexanes) followed by reverse phase HPLC (water / methanol / TFA). The HPLC eluate was treated with excess NH3 / methanol and concentrated. The residue was partitioned between water and CH 2 Cl 2, and the organic layer was dried (MgSO₄), filtered and concentrated in vacuo to provide 130c as a white foam (317.4 mg). * H NMR (DMSO-d₆, δ = 2.50, 400 MHz): 12.36 / 12.09 / 12.03 (br s, 1H), 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, 1H), 7.66 (d, J = 8.3, 0.93H), 7.46 (m, 0.07H), 4.80 (m, 1H), 3.53 ( m, 1H),

3.36 (m, 1H), 2.30-1.77 (m, 4h), 1.40 / 1.15 (s, 3.8H + 5.2H). LC (Condition 1): RT = 1.52 min; &gt; 95% homogeneity index; LC / MS: Anal. Calc. for [M + H]⁺ C19H22CIF3N3O2 416.14; found 416.17.

<img file="PL2049522T3_D0183.tif" />

Pd [P (t-Bu) 3]₂ (48 mg, 0.094 mmol) was added to a mixture of 130c chloride (245 mg, 0.589 mmol), le boronate (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 aqueous layer was extracted with CH 2 Cl 2 (2x), and the combined organic phases were dried (MgSO₄), filtered and concentrated in vacuo. The resulting material was purified by Biotage (silica gel, ethyl acetate) to provide carbamate 130d as an off-white foam (297 mg). LC (Condition 1): RT = 1.44 min; &gt; 95% homogeneity index; LC / MS: Anal. Calc. for [M + H]⁺ C37H44F3N6O4 693.34; found 693.34.

223

Deprotection of 13Od, which was carried out in accordance with the production of pyrrolidine le, gave 130e as a pale yellow foam. * H NMR (DMSO-dć, δ = 2.50, 400 MHz): 11.88 (br s, 2H), 8.16 (d, J = 1.5, IH), 8.02 (d, J = 7.8, IH), 7.78 (d, J = 8.1, 2H), 7.66 (br s, IH), 7.48 (br s, IH), 7.37 (d, 7 = 8.1, IH), 7.28 (d, J = 8.3, 2H), 4.18 (m, 2H ), 2.99-2.93 (m, 2H), 2.89-2.83 (m, 2H), 2.1 1-2.01 (m, 2H), 1.94-1.85 (m, 2H), 1.82-1.67 (m, 4H). Note: although the broad signals corresponding to NH pyrrolidine appear in the 2.8-3.2 ppm region, the actual range of their chemical shift cannot be determined. LC (Condition 1): RT = 1.12 min; &gt; 95% homogeneity index; LC / MS: Anal. Calc. for [M + H]⁺ C27H2₈F3N₆ 493.23; found 493.14.

Example 130 (1R, 1 'R) -2,2' - ((2- (trifluoromethyl) -4,4'-biphenyldiyl) bis (1H-imidazole-5,2-diyl (2S) -2,1-pyrrolidinidiyl) ) bis (N, N-dimethyl-2-oxo-l-fenyloetanamina)

<img file="PL2049522T3_D0184.tif" />

Example 130 (TFA salt) was prepared from 130e and Cap-1 according to the preparation of Example 1 from pyrrolidine le. LC (Condition 1): RT = 1.17 min; &gt; 98% homogeneity index; LC / MS: Anal. Calc. for [M + H]⁺ C47H50F3N8O2 815.40; found 815.44; HRMS: Anal. Calc. for [M + H]⁺ C47H50F3N8O2 815.4009; found 815.4013

Example 131

5,5 '- (2- (trifluoromethyl) -4,4'-bifenyldiyło) bis (2 - ((2S) -l - ((2R) -2-phenyl-2- (pyrrolidinyl) acetyl) -2-pyrrolidinyl ) -l H-imidazole)

<img file="PL2049522T3_D0185.tif" />

Example 131 (TFA salt) was synthesized with 130e and Cap-5 according to the preparation of Example 130.

LC (Condition 1): RT = 1.19 min; &gt; 98% homogeneity index

LC / MS: Anal. Calc. for [M + H]⁺ C₅H₅4F₃N8O2 867.43; found 867.51

HRMS: Anal. Calc. for [M + H]⁺ C51H54F3N8O2 867.4322; found 867.4315

224

Example 1-6e

1) stage a

2) etab b

3) stage c stage a: stage b stage c:

Example 131.1-1 to 131.1-2

<img file="PL2049522T3_D0186.tif" />

Cap-4 coupling to IIATU as in Example 28 step ej Removal of the Cbz group by II₂, Pd / C Attach the appropriate cap

<img file="PL2049522T3_D0187.tif" />

Examples 131.1-1 to 131.1-2 were obtained in a similar manner to Example 28 by the intermediation of intermediate 1-6e after addition of Cap-4.

Example 131.1-1 ((1R) -2 - (((1S) -1- (5- (4 '- (2 - ((2S) -1 - ((2R) -2- (dimethylamino) -2-phenylacetyl ) -2-pyrrolidinyl) 1H-imidazol-5-yl) -4-biphenylyl) -1H-imidazol-2-yl) ethyl) (methyl) ammo) -2-oxo-1-phenylethyl) methyl carbamate

<img file="PL2049522T3_D0188.tif" />

Cap-1 was added after removal of Cbz carbamate from 1-6e with Pd / C / I J.

LCMS conditions: Phenomenex LUNA C-18 4.6 x 50 mm, 0 to 100% B in 3 minutes, 1 minute stop time, A = 90% water, 10% methanol, 0.1% TFA, B = 10% water, 90% methanol, 0.1% TFA, 220nm, 5 pL injection volume. tR = 1.42 min

LRMS: Anal. Calc. for CąsHągNgOą 765.39; found: 765.38 (M + H)⁺.

HRMS: Anal. Calc. for CąsHąęNsOąObl. 765.3877 found: 765.3905 (M + H)⁺.

Example 131.1-2 ((1R) -2- (methyl ((1S) -1- (5- (4 '- (2 - ((2S) -1 - ((2R) -2-phenyl-2- (1 -piperidinyl) acetyl) -2-pyrrolidinyl) -1H-imidazol-5-yl) -4-biphenylyl) -1H-imidazol-2-yl) ethyl) amino) -2-oxo-1-ethyl-ethyl) -carbamate

<img file="PL2049522T3_D0189.tif" />

Cap-14 was added after removal of Cbz carbamate from 1-6e with Pd / C / H₂.

225

LCMS conditions: Phenomenex LUNA C-18 4.6 x 50 mm, 0 to 100% B in 3 minutes, 1 minute stop 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 (&gt; 95%)

LRMS: Anal. Calc. for C.₄₈H₅2N8O₄ 805.42; found: 805.41 (M + H)⁺.

HRMS: Anal. Calc. for C.₄₈H₅₂N₈ABOUT₄ Calc. 805.4190 found: 805.4214 (M + H)⁺.

Example 131.2 (2R) -2- (dimethylamino) -N-methyl-2-phenyl-N - ((1S) -1- (5- (4 '- (2 - ((2S) -1 - ((2R) -2-phenyl-2- (1-piperidinyl) acetyl) -2-pyrrolidinyl) -1E-imidazol-5-yl) -4-biphenylyl) -1H-imidazole-2-yl) ethyl) acetamide

Example 131. 2 was prepared in a similar manner to Example 131.1-1 and Example 131.1-2 through the intermediation of intermediate 1-6e after addition of CapA. Cap-14 was added after removal of Cbz carbamate with Pd / C / H2.

LCMS conditions: Phenomenex LUNA C-18 4.6 x 50 mm, 0 to 100% B in 3 minutes, 1 minute stop time, A = 90% water, 10% methanol, 0.1% TFA, B = 10% water, 90% methanol, 0.1% TFA, 220nm, 5 pL injection volume. t_R = 1.28 min

LRMS: Anal. Calc. for C.₄₈H5₄N₈ABOUT₂ 775.44; found: 775.45 (M + H)⁺.

HRMS: Anal. Calc. for C.₄₈H5₄N₈ABOUT₂ Calc. 775.4448 found: 775.4460 (M + H)⁺.

Example 132 (1R) -2 - ((2S) -2- (5- (6- (4- (2 - ((2S) -1 - ((2R) -2- (dimethylamino) -2-phenylacetyl) - 2-pyrrolidinyl) -lH-imidazol-5-yl) phenyl) -3-pyridinyl) -lH-imidazol-2-yl) -l-pyrrolidinyl) -N, N-dimethyl-2-oxo-1-fenyloetanamina

Example 132, Step ab

br

br

132

br

132b

Boc

CH2Cl2 solution (10 mL) Br₂ (7.63 g, 47.74 mmol) was added dropwise over 5 min to cooled (ice / water) CH2Cl2 (105 mL) solution of 1- (6-bromopyridin-3-yl) ethanone (9.496 g, 47.47 mmol) and 48% HBr ( 0.4 mL). The cooling bath was removed 40 min later, and

226 stirring was continued at ambient temperature for about 66 hr. The solid cake formed was filtered, washed with CH 2 Cl 2 and dried in vacuo to give an impure 132 as off-white solid (15.94 g).

Boc-L-proline (9.70 g, 45.06 mmol) was added in one portion to a heterogeneous mixture of crude 132a (15.4 g) and CH3CN (150 mL), followed by the dropwise addition of Et₃N (13.0 mL, 93.2 mmol) within 6 min. The reaction mixture was stirred for 50 min, the volatile component was removed in vacuo and the residue partitioned between CH₂C1₂ and water. CH layer₂C1₂dried (MgSO₄), filtered and concentrated in vacuo, and the resulting material was purified by flash chromatography (silica gel; sample was eluted with solvent; 25% EtOAc / hexanes) to give 132b as a very viscous yellow oil (11.44g). * H 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), 5.65-5.46 (m, 2H) , 4.36-4.31 (m, 1H), 3.41-3.29 (m, 2H), 2.36-2.22 (m, 1H), 2.14-2.07 (m, 1H), 1.93-1.83 (m, 2H), 1.40 &amp; 1.36 ( two s, 9H). LC (Condition 1): RT = 2.01 min; &gt; 90% homogeneity index

LC / MS: Anal. Calc. for [M + Na]⁺ Ci7H₂iNaBrN₂O5: 435.05; found 435.15

HRMS: Anal. Calc. for [M + H]⁺ CnlfeBr ^ Os: 413.0712; found 413.0717

<img file="PL2049522T3_D0190.tif" />

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 in the microwave at 140 ° C for 90 min. The volatile component was removed in vacuo and the residue partitioned between CH₂C1₂ and water, where enough NaHCO solution was added₃ to neutralize the aqueous medium. The aqueous phase was extracted with CH₂C1₂, and the combined organic phases were dried (MgSO₄), filtered and concentrated in vacuo. The resulting crude material was purified by Biotage (silica gel; 50% EtOAc / hexanes) to give imidazole 132c as an off-white foam (1.025 g). * H NMR (DMSO, δ = 2.5 ppm, 400 MHz): 12.33 / 12.09 / 12.02 (br m, 1H), 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, 1H), 7.69 / 7.67 (br m, 1H), 7.58 / 7.43 (d for the first peak, J = 8.3, 1H), 4.80 (m, 1H), 3.53 ( m, 1H), 3.36 (m, 1H), 2.33-2.11 (m, 1H), 2.04-1.79 (m, 3H), 1.39 / 1.15 (app br s, 3.9H + 5.1H).

LC (Condition 1): RT = 1.52 min; &gt; 98% homogeneity index

LC / MS: Anal. Calc. for [M + H]⁺ C₁₇H₂₂BrN₄ABOUT₂: 393.09; found 393.19

HRMS: Anal. Calc. for [M + H]⁺ these₇H₂₂BrN₄ABOUT₂: 393.0926; found 393.0909

227

<img file="PL2049522T3_D0191.tif" />

Pd (Ph.3P) 4 (115.1 mg, 0.10 mmol) was added to a mixture of 132c bromide (992mg, 2.52 mmol), le boronate (1.207 g, 2.747 mmol), NaHCOA (698.8 mg, 8.318 mmol) in 1,2-dimethoxyethane (18 mL) and water (4 mL). The reaction mixture was flushed with nitrogen, heated in an oil bath at 90 ° C for 37 hours. and allowed to cool to ambient temperature. The resulting suspension was filtered and washed with water followed by 1,2-dimethoxyethane, and dried in vacuo. Silica gel mesh was obtained from the crude solid and subjected to flash chromatography (silica gel; EtOAc) to give carbamate 132d as a white solid which yellowed slightly upon standing at ambient conditions (1.124g). 1 H NMR showed that the sample contained a residue of MeOH in a product / MeOH 1.3 molar ratio.

LC (Condition 1): RT = 1.71 min; &gt; 98% homogeneity index

LC / MS: Anal. Calc. for [M + H]⁺ C35H44N7O4: 626.35; found 626.64

HRMS: Anal. Calc. for [M + H]⁺ C35H44N7O4: 626.3455; 626.3479

Carbamate 132d (217 mg) was treated with 25% TFA / CH 2 Cl 2 (3.6 mL) and stirred at ambient conditions for 6 hr. The volatile component was removed in vacuo, and the resulting material was converted into the free base column with an MCX column (MeOH wash; elution with 2.0 M NH3 / MeOII) giving 132e as a dull yellow foam which solidified gradually on standing (150.5 mg; mass is above theoretical) .^!H NMR (DMSO, δ =

2.5 ppm; 400 MHz): 11.89 (very wide, 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: no convertible hydrogen pyrrolidine atoms observed]

LC (Condition 1): RT = 1.21min; &gt; 98% homogeneity index

LC / MS: Anal. Calc. for [M + FI]⁺ C₂₅H28N₇: 426.24; found 426.40

HRMS: Anal. Calc. for [M + H]⁺ C25H28N7: 426.2406; found 426.2425

Example 132 (1R) -2 - ((2S) -2- (5- (6- (4- (2 - ((2S) -1 - ((2R) -2- (dimethylamino) -2-phenylacetyl) - 2-pyrrolidinyl) -lH-imidazol-5-yl) phenyl) -3-pyridinyl) -lH-imidazol-2-yl) -l-pyrrolidinyl) -N, N-dimethyl-2 228

<img file="PL2049522T3_D0192.tif" />

HATU (41.4 mg, 0.109 mmol) was added to the mixture of pyrrolidine 132e (23.1 mg, 0.054 mmol), (z-Pr)₂EtN (40 pL, 0.23 mmol) and CapA (25.3 mg, 0.117 mmol) in DMF (1.5 mL) and the mixture was stirred at ambient temperature for 1 h. The volatile component was removed in vacuo, and the residue was purified first by MCX (MeOH wash; elution with 2.0 Μ ΝΗβ / ΜεΟΗ) and then by reverse phase HPLC (H2O / MeOH / TFA) to give Example 132 TFA salt as a yellow foam (39.2 mg ).

LC (Condition 1): RT = 1.37min; &gt; 98% homogeneity index

LC / MS: Anal. Obi. for [M + H]⁺ C45H50N9O2: 748.41; found 748.53

HRMS: Anal. Obi. for [M + H]⁺ C45H50N9O2: 748.4087; found 748.4090

Example 133-135 was obtained as the TFA salts of 132e using the same preparation method as Example 132 and the appropriate reagents.

<img file="PL2049522T3_D0193.tif" />

<td>Example</td><td>Union Name</td><td>ABOUT AND</td><td>RT (LC-Cond.); % homogeneity index; MS data</td>

<td> 133</td><td>(R) -2 - ((2S) -2- (5- (6- (4- (2- ((2S) -l - ((2R) -2-hydroxy-2fenyloacetylo) -2pirolidynylo) -lH-imidazol- 5-yl) phenyl) -3-pyridinyl) 1H-imidazol-2-yl) -1-pyrrolidinyl) -2-oxo-1 phenylethanol</td><td>ABOUT^ph AND HO</td><td>1.49 min (War. 1); &gt; 98% LC / MS: Anal. Obi. for [M + H]⁺ C4iH₄he₇0₄: 694.31; found 694.42 HRMS: Anal. Obi. for [M + H]⁺ C_4IH₄he₇0₄: 694.3142, found: 694.3164</td>

229

<td> 134</td><td>((R) -2 - ((2S) -2- (5- (6- (4- (2- ((2S) -l - ((2R) -2- ((methoxycarbonyl) amino) -2-phenylacetyl) -2pirolidynylo ) -1-H-imidazol-5-yl) phenyl) -3-pyridinyl) 1H-imidazol-2-yl) -1-pyrrolidinyl) -2-oxo-1 phenylethyl) methylcarbamate</td><td>ABOUT ABOUT CAPA</td><td>1.60 min (War. 1); &gt; 98% LC / MS: Anal. Calc. for [M + H]⁺ C₄₅H₄₆N₉ABOUT₆: 808.36; found 808.51 HRMS: Anal. Calc. for [M + H]⁺ C₄₅H₄₆N₉ABOUT₆: 808.3571; found 808.3576</td>

<td> 135</td><td>5- (2 - ((2S) -1 - ((2R) -2-methoxy-2-phenylacetyl) -2-pyrrolidinyl) -1H-imidazol-5-yl) -2- (4- (2 - ((2S) -1 - ((2R) -2-methoxy-2-phenylacetate) -2-pyrrolidinyl) -1H-imidazol-5-yl) phenyl) pyridine</td><td>ABOUT^ph&gt; A / K</td><td>1.60 min (War. 1); &gt; 98% LC / MS: Anal. Calc. for [M + H]⁺ C₄₃H44N₇ABOUT₄: 722.35; found 722.40 HRMS: Anal. Calc. for [M + H]⁺ C₄₃H₄₄N₇ABOUT₄: 722.3455; found 722.3464</td>

Example 136 (1R) -2 - ((2S) -2- (5- (6- (4- (2 - ((2S) -1 - ((2R) -2- (dimethylamino) -2-phenylacetyl) - 2-pyrrolidinyl) 1H-imidazol-5-yl) -2-methylphenyl) -3-pyridinyl) -1H-imidazol-2-yl) -1-pyrrolidinyl) -N, N-dimethyl-2-oxo-1-phenylethanamine

<img file="PL2049522T3_D0194.tif" />

Example 136, Step a and b

<img file="PL2049522T3_D0195.tif" />

<img file="PL2049522T3_D0196.tif" />

PdCl₂(Ph₃Q)₂ (257 mg, 0.367 mmol) was added to the dioxane (45 mL) solution of 1-bromo-4-iodo-2-methylbenzene (3.01 g, 10.13 mmol) and tri-n-butyl (1-ethoxyvinyl) 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 portions over 7 min. About 25 min 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 phases were dried (MgSO₄), filtered and concentrated in vacuo. The resulting crude material was purified by gravity chromatography (gel

230 silica; 4% EtOAc / hexanes) to give bromide 136a as a brown-yellow solid (2.699 g); The sample is contaminated and contains, among others, impurities derived from stannan. '' NMR (CDCl₃, δ = 124, 400 MHz): 7.83 (s, IH), 7.63 (s, 2H), 4.30 (s, 2H), 2.46 (s, 3H).

CH3CN (15 mL) solution 136a (2.69 g, &lt;9.21 mmol) was added dropwise within 3 min to a solution of CH3CN (30 mL) (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 CH2Cl2, and the organic phase was dried (MgSO₄), filtered and concentrated in vacuo. The resulting crude material was purified by flash chromatography (silica gel; 15-20% EtOAc / hexanes) to give 136b as a colorless viscous oil (2.74g).^]1 H 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), 2.33-2.08 (m, 2H),

1.93-1.83 (m, 2H), 1.40 / 1.36 (s, 9H). LC (Condition 1): RT = 1.91 min; &gt; 95% homogeneity index

LC / MS: Anal. Calc. for [M + Naf Ci₉H₂₄BrNNaO5 448.07; found 448.10

Example 136, Step c

<img file="PL2049522T3_D0197.tif" />

A mixture of ketoester 136b (1.445 g, 3.39 mmol) and NH₄OAc (2.93 g, 38.0 mmol) in xylenes (18 mL) was heated in the microwave at 140 ° C for 80 min. The volatile component was removed in vacuo, and the residue was carefully partitioned between CH2Cl2 and water, where enough NaHCCL solution was added to neutralize the aqueous medium. The aqueous phase was extracted with CH 2 Cl 2, and the combined organic phases were dried (MgSO₄), filtered and concentrated in vacuo. The crude mixture was purified by flash chromatography (silica gel, 40% EtOAc / hexanes) to give imidazole 136c as an off-white solid (1.087 g). 1 H NMR (DMSO-d₆, δ = 2.50, 400 MHz): 12.15 / 11.91 / 11.84 (br s, 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 (Condition 1): RT = 1.91 min; &gt; 98% homogeneity index

LC / MS: Anal. Calc. for [M + Hf Ci ^ sBrNsOz 405.96; found 406.11

<img file="PL2049522T3_D0198.tif" />

PdCl₂dppf.CH2Cl₂ (50.1 mg, 0.061 mmol) was added to a pressure tube containing a mixture of 136c bromide (538.3 mg, 1.325 mmol), bis (pinacolano) diborane

231 (666.6 mg, 2,625 mmol), KOAc (365.8 mg, 3,727 mmol) and DMF (10 mL). The reaction mixture was purged with N₂ and heated at 80 ° C for 24.5 hours. The volatile component was removed in vacuo and the residue was partitioned between CH 2 Cl 2 and water, where enough NaHCO solution was added₃ to make the pH of the aqueous medium neutral. The aqueous phase was extracted with CH₂C1₂, and the combined organic phases were dried (MgSO₄), filtered and concentrated in vacuo. The resulting material was purified using a Biotage system (silica gel, 40-50% EtOAc / hexanes) to give 136d boronate as a white foam (580 mg). According to 'H NMR, the sample contains pinacol residue in a product / pinacol ratio ~ 3. * H NMR (DMSO-dó, δ = 2.50, 400 MHz): 12.16 / 11.91 / 11.83 (br s, 1H), 7.63-7.25 (m, 4H),

4.78 (m, 1H), 3.53 (m, 1H), 3.39-3.32 (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 (Condition 1): RT = 1.62 min LC / MS: Anal. Calc. for [M + H]⁺ C₂₅H₃₇BN₃ABOUT₄ 454.29; found 454.15

<img file="PL2049522T3_D0199.tif" />

Biaryl 136e was prepared from bromide 132c and boronate 136d according to the coupling conditions described for the preparation of biaryl 132d. LC (Condition la): RT = 1.32 min; &gt; 90% homogeneity index LC / MS: Anal. Calc. for [M + H]⁺ C₃OH₄₅N₇ABOUT₄ 640.36; found 640.66. Deprotection of biaryl 136e was performed according to the preparation of pyrrolidine 132e to give 136f as a light yellow foam. 'H NMR (DMSO-dó, δ = 2.50, 400 MHz): 11.88 (br s, 2H), 9.02 (d, 7 = 2, 1H), 8.12 (dd, 7 = 8.4, 2.3, 1H), 7.67 ( s, 1H), 7.64-7.62 (m, 2H), 7.50 (d, 7 = 8.3, 1H), 7.46 (br s, 1H), 7.40 (d, 7 = 7.8, 1H), 4.21-4.14 (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 NH pyrrolidine appears in 3.22-2.80 and is too wide to assign a chemical shift.]

LC (Condition 1): RT = 0.84 min

LC / MS: Anal. Calc. for [M + H]⁺ C₂₆H₃₀N₇ 440.26; found 440.50

Example 136 (1R) -2 - ((2S) -2- (5- (6- (4- (2 - ((2S) -1 - ((2R) -2- (dimethylamino) -2-phenylacetyl) - 2-pyrrolidinyl) -lH-imidazol-5-yl) -2-methylphenyl) -3-pyridinyl) -lH-imidazol-2-yl) -l-pyrrolidinyl) -N, N-dimethyl-2-oxo-l-fenyloetanamina

<img file="PL2049522T3_D0200.tif" />

\\

N

232

Example 136 (TFA salt) was synthesized from 136f according to the preparation of Example 132 from 132e.

1.05 min (Condition 1); &gt; 98%

LC / MS: Anal. Obi. for [M + H]⁺ C₄6H₅2N9O₂: 762.42, found: 762.77

HRMS: Anal. Obi. for [M + H]⁺ C46H52N9O2: 762.4244; found 762.4243

Example 138 ((1R) -2 - ((2S) -2- (5- (6- (4- (2 - ((2S) -1 - ((2R) -2 - ((methoxycarbonyl) amino) -2 -phenylacetyl) -2-pyrrolidinyl) -1H-imidazol-5-yl) -2-methylphenyl) -3-pyridinyl) -1H-imidazol-2-yl) -1-pyrrolidinyl) -2-oxo-1-phenylethyl) methyl carbamate

<img file="PL2049522T3_D0201.tif" />

Example 138 was similarly obtained from pyrrolidine 136f and CapA.

1.60 min (Condition 1); &gt; 98%

LC / MS: Anal. Obi. for [M + H]⁺ C46H48N9O6: 822.37; found 822.74

HRMS: Anal. Obi. for [M + H]⁺ C₄6H4₈N₉ABOUT₆: 822.3728; found 822.3760

Example 139

N - ((R) -2 - ((2S) -2- (5- (6- (4- (2 - ((2S) -l - ((2R) -2-acetamido-2-phenylacetyl) -2 pyrrolidinyl) -lH-imidazol-5-yl) phenyl) -3-pyridinyl) -lH-imidazol-2-yl) -l-pyrrolidinyl) -2-oxo-lfenyloetylo) -acetamide

<img file="PL2049522T3_D0202.tif" />

Example 139, Step a

<img file="PL2049522T3_D0203.tif" />

HATU (99.8 mg, 0.262 mmol) was added to a mixture of 132e (54.1 mg, 0.127 mmol), (7?) -2 - (/ - butoxycarbonylamino) -2-phenylacetic acid (98.5 mg, 0.392 mmol) and / -P ^ EtN (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 reverse phase HPLC

233 (JfiO / MeOH / TFA), where the HPLC eluate was treated with an excess of 2.0 N NH₃/ MeOH, before removing the volatile component in vacuo. The resulting material was partitioned between CH2Cl2 and water, and the aqueous phase was extracted with CH2Cl2 (2x). The combined organic phases were dried (MgSO₄), filtered and concentrated in vacuo. Carbamate 139a was obtained as a white foam film (82.3 mg).

LC (Condition 1): RT = 1.97 min; &gt; 95% homogeneity index.

LC / MS: Anal. Calc. for [M + H]⁺ C51H58N9O6: 892.45; found 892.72

<img file="PL2049522T3_D0204.tif" />

Carbamate 139a was deprotected to amine 139b using the procedure described for the preparation of pyrrolidine 132e from 132d.

LC (Condition 1): RT = 1.37 min; &gt; 95% homogeneity index

LC / MS: Anal. Calc. for [M + H]⁺ C41H42N9O2: 692.35; found 692.32

Example 139

N - ((R) -2 - ((2S) -2- (5- (6- (4- (2 - ((2S) -l - ((2R) -2-acetamido-2-phenylacetyl) -2 pyrrolidinyl) -lH-imidazol-5-yl) phenyl) -3-pyridinyl) -lH-imidazol-2-yl) -l-pyrrolidinyl) -2-oxo-

<img file="PL2049522T3_D0205.tif" />

Acetic anhydride (20 pL, 0.212 mmol) was added to the DMF solution (1.5 mL) 139b (31.2 mg, 0.045 mmol) and the reaction mixture was stirred for 1 h. NH₃/ MeOH (1.0 mL 2N) was added to the reaction mixture and stirring was continued for 100 min. The volatile component was removed in vacuo and the resulting crude material was purified by reverse phase HPLC (H2O / MeOH / TFA) to give the TFA salt of Example 139 as a pale yellow solid (24.1 mg). LC (Condition 1): RT = 1.53 min; &gt; 98% LC / MS homogeneity index: Anal. Calc. for [M + H]⁺ ¢ 45 ^^ 04: 776.37; found 776.38

HRMS: Anal. Calc. for [M + H]⁺ C45H46N9O4: 776.3673; found 776.3680

Example 140 ((1R) -2 - ((2S) -2- (5- (4- (5- (2 - ((2S) -1 - ((2R) -2- (dimethylamino) -2-phenylacetyl) Methyl -2-pyrrolidinyl) -1H-imidazol-5-yl) -2-pyridinyl) phenyl) -1H-imidazol-2-yl) -1-pyrrolidinyl) -2-oxo-1-phenylethyl) methyl carbamate

234

<img file="PL2049522T3_D0206.tif" />

<img file="PL2049522T3_D0207.tif" />

HATU (19.868g, 52.25 mmol) was added to a heterogeneous mixture of N-Cbz-Lproline (12,436 g, 49.89 mmol) and 2-amino-1- (4-bromophenyl) ethanone HCl salt (12.157 g,

48.53 mmol) in DMF (156 mL). The mixture was left in an ice-water bath, and immediately N, N-diisopropylethylamine (27 mL, 155 mmol) was added dropwise thereto over 13 min. When done addition of the base was complete, 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 obtained crude solid product and stirred for about 1 h. The off-white solid was filtered and washed extensively with water, and dried in vacuo to give ketoamide 140a as a white solid (20.68 g). 'H NMR (DMSO-dó, δ = 2.5 ppm, 400 MHz): 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), 4.334.26 (m, 1H), 3.53-3.36 (m, 2H), 2.23-2.05 (m, 1H), 1.94-1.78 (m, 3H).

LC (Condition 1): RT = 1.65 min; 98% homogeneity index

LC / MS: Anal. Calc. for [M + H]⁺ C₂₁H₂₂BrN₂ABOUT₄: 445.08; found 445.31

<img file="PL2049522T3_D0208.tif" />

Ketoamide 140a (10.723g, 24.08 mmol) was converted to 140b according to the procedure described for the synthesis of carbamate 132c, with the proviso that the crude material was purified by flash chromatography (silica gel; 50% EtOAc / hexanes). Bromide 140b was recovered as an off-white foam (7.622 g). * H NMR (DMSO-dó, 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 (Condition 1): RT = 1.42 min; &gt; 95% LC / MS homogeneity index: Anal. Calc. for [M + H]⁺ C₂H₂| BrN₃ABOUT₂: 426.08; found 426.31

HRMS: Anal. Calc. for [M + H]⁺ C₂H₂, BrN₃ABOUT₂: 426.0817; found: 426.0829

Optical purity 140b was evaluated using the following chiral HPLC methods, and 99% ee observed.

Column: Chiralpak AD, 10 um, 4.6 x 50 mm

235

Solvent: 20% ethanol / heptane (isocratic) Flow rate: 1 ml / min Wave length: 254 nm

Relative retention time: 1.82 min (/?), 5.23 min (5)

<img file="PL2049522T3_D0209.tif" />

Pd (Ph3P) 4 (208 mg, 0.180 mmol) was added to a pressure tube containing a mixture of 140b bromide (1.80 g, 4.22 mmol), bis (pinacolano) diborane (2.146 g, 8.45 mmol), KO Ac (1.8 g, 11.0 mmol) and 1,4-dioxane (34 mL). The reaction flask was flushed with nitrogen, sealed and heated in an oil bath at 80 ° C for 23 hours. The volatile component was removed in vacuo, and the residue was carefully partitioned between CH2Cl2 (70 mL) and an aqueous medium (22 mL water + 5 mL saturated NaHCCR solution). The aqueous layer was extracted with CH 2 Cl 2, and the combined organic phases were dried (MgSO₄), filtered and concentrated in vacuo. The oily residue was crystallized from EtOAc / hexanes to give 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 / CRCk) to give an additional 140c as an off-white solid containing residual pinacol (772 mg).

LC (Condition 1): RT = 1.95 min

LC / MS: Anal. Calc. for [M + H]⁺ C27H33BN₃ABOUT₄: 474.26; found 474.31

<img file="PL2049522T3_D0210.tif" />

Aryl bromide 132c was coupled to boronate 140c to give 140d using the same procedure described for the synthesis of biaryl 132d. The sample contains the desbromo 132c version as impurity. Proceed to the next step without further purification.

LC (Condition 1): RT = 1.72 min; -85% homogeneity index

LC / MS: Anal. Calc. 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 hydrogen balloon for -160 hr, where hydrogen supply was periodically topped up as needed. The reaction mixture was filtered through a diatomaceous earth layer (Celite®), and the filtrate

236 evaporated in vacuo to give crude 140e as a yellowish brown foam (911 mg). Proceed to the next step without further purification.

LC (Condition 1): RT = 1.53 min

LC / MS: Anal. Calc. for [M + H]⁺ C30H36N7O2: 526.29; found 526.23

Example 140, Step fg

<img file="PL2049522T3_D0211.tif" />

Pyrrolidine 140g was prepared from 140e and Cap-4, via 140f carbamate, sequentially using amide formation and Boc-protected protocols used in the synthesis of Example 132.

LC (Condition 1): RT = 1.09 min; -94% homogeneity index

LC / MS: Anal. Calc. for [M + H]⁺ C35H37N8O3: 617.30; found 617.38

Example 140 ((1R) -2 - ((2S) -2- (5- (4- (5- (2 - ((2S) -1 - ((2R) -2- (dimethylamino) -2-phenylacetyl) -2-pyrrolidinyl) -1 H -imidazol-5-yl) -2-pyridinyl) phenyl) -1H-imidazol-2-yl) -1-pyrrolidinyl) -2-oxo-1-phenylethyl) methyl carbamate

<img file="PL2049522T3_D0212.tif" />

The Example 140 TFA salt was synthesized from pyrrolidine 140g and Cap-1 using the procedure described for the preparation of Example 132 from intermediate 132e.

1.15 min (Condition 1); &gt; 98% homogeneity index

LC / MS: Anal. Calc. for [M + H]⁺ C45H40N7O4: 778.38; found 778.48

HRMS: Anal. Calc. for [M + H]⁺ C45H40N7O4: 778.3829; found 778.3849

The TFA salt of Example 141-143 was synthesized from intermediate 140g and the appropriate reagents in a similar manner.

237

Example 141-143

<img file="PL2049522T3_D0213.tif" />

<td>Example</td><td>Union Name</td><td>Λ</td><td>RT (LC-Cond.); % homogeneity index; MS data</td>

<td> 141</td><td>((1 R) -2-oxo-1-phenyl-2 - ((2S) 2- (5- (4- (5- (2 - ((2S) -1 - ((2R) tetrahydro-2-furanylcarbonyl) - Methyl 2-pyrrolidinyl) -1H-imidazol-5-yl) -2-pyridinyl) phenyl) -1H-imidazol-2-yl) -1-pyrrolidinyl) ethyl) carbamate</td><td></td><td>1.15 min (War. 1); &gt; 98% LC / MS: Anal. Calc. for [M + H]⁺ C₄₀H₄₃N₈ABOUT₅: 715.34; found 715.44 HRMS: Anal. Calc. for [M + H]⁺ C₄₀H₄₃N₈ABOUT₅: 715.3356; found 715.3381</td>

<td> 142</td><td>((1R) -2 - ((2S) -2- (5- (4- (5- (2 ((2S) -1 - ((1-methyl-4-piperidinyl) carbonyl) -2-pyrrolidinyl) -1H-imidazole Methyl 5-yl) -2-pyridinyl) phenyl) -1-Himidazol-2-yl) -1-pyrrolidinyl) 2-oxo-1-phenylethyl) carbamate</td><td>cA</td><td>1.07 min (War. 1); &gt; 98% LC / MS: Anal. Calc. for [M + H]⁺ C₄₂H₄₈N₉ABOUT₄: 742.38; found 742.48 HRMS: Anal. Calc. for [M + H]⁺ C₄₂H₄₈N₉ABOUT₄: 742.3829; found 742.3859</td>

<td> 143</td><td>((1 R) -2-oxo-1-phenyl-2 - ((2S) 2- (5- (4- (5- (2 - ((2S) -1- (3-pyridinylacetyl) -2-pyrrolidinyl) -1H -imidazol-5-yl) -2-pyridinyl) phenyl) -1-imidazol-2-yl) -1-pyrrolidinyl) ethyl) carbamate methyl</td><td></td><td>1.09 min (War. 1); &gt; 98% LC / MS: Anal. Calc. for [M + H]⁺ C₄₂H₄₂N₉ABOUT₄: 736.34; found 736.44 HRMS: Anal. Calc. for [M + H]⁺ C₄₂H₄₂N₉ABOUT₄:</td>

238

736.3360; 736.3344

Example 144 ((1R) -2 - ((2S) -2- (5- (4- (5- (2 - ((2S) -1- (4-morpholinylcarbonyl) -2-pyrrolidinyl) -1H-imidazole Methyl) -2-pyridinyl) phenyl) -1H-imidazol-2-yl) -1-pyrrolidinyl) -2-oxo-1-phenylethyl) methyl carbamate

<img file="PL2049522T3_D0214.tif" />

A solution of DMF (1.5 mL) morpholine-4-carbonyl chloride (8.5 mg, 0.057 mmol) was added to a mixture of P 2 EtN (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 reverse phase HPLC (H2O / MeOH / TFA) to give the TFA salt of Example 144 as a yellow foam (34.6 mg).

1.17 min (Condition 1); &gt; 98%

LC / MS: Anal. Calc. for [M + H]⁺ C40H44N9O5: 730.35; found 730.42

HRMS: Anal. Calc. for [M + H]⁺ C40H44N9O5: 730.3465; found 730.3477

Example 145 (2,2'-bipyridin-5,5'-diylbis (1H-imidazol-5,2-diyl (2S) -2, 1-pyrrolidinidyl ((1R) -2-oxo-1-phenyl-2,1 -ethanediyl))) dimethyl biscarbamate

<img file="PL2049522T3_D0215.tif" />

Pd (Ph3P)₄ (9.6 mg, 0.008 mmol) and LiCl (28 mg, 0.67 mmol) were added to a mixture of aryl bromide 132c (98.7 mg, 0.251 mmol) and hexamethyldicine (51.6 mg, 0.158 mmol) and heated at 80 ° C for ~ 3 days. The volatile component was removed in vacuo and the resulting crude material was purified by flash chromatography (silica gel; 0-10% MeOH / EtOAc) followed by reverse phase HPLC (H2O / MeOH / TFA). The HPLC eluate was neutralized with an excess of 2.0 N NH3 / MeOH, and the volatile component was removed in vacuo.

239

The residue was partitioned between CH2Cl2 and water, and the aqueous phase was washed with CH2Cl2 (2x). The combined organic phases were dried (MgSOJ, filtered and concentrated in vacuo to give carbamate 145a as an oil film (8.7 mg). LC (Condition 1): RT = 1.68 min;&gt; 98% homogeneity index LC / MS: Anal. Calcd for [M + H]⁺ C34H43N8O4: 627.34; found 627.47

Carbamate 145a was converted to pyrrolidine 145b according to the preparation 132e from 132d. * H 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, / = 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: no NH pyrrolidine signal observed].

LC (Condition 1): RT = 1.17 min; &gt; 98% homogeneity index

LC / MS: Anal. Obi. for [M + H]⁺ C24H27N8: 427.24; found 427.13

Example 145 (2,2'-bipyridin-5,5'-diylbis (1H-imidazol-5,2-diyl (2S) -2, 1-pyrrolidinidiyl ((1R) -2-oxo-1-phenyl-2,1 -ethanediyl))) dimethyl biscarbamate

<img file="PL2049522T3_D0216.tif" />

Example 145 (TFA salt) was synthesized from 145b according to the preparation of Example 132 from 132e.

LC (Condition 1): RT = 1.63 min; 98% homogeneity index

LC / MS: Anal. Obi. for [M + H]⁺ C₄4H4₅Nio06: 809.35; found 809.40

Example 146 (1R) -2 - ((2S) -2- (5- (5- (4- (2 - ((2S) -1 - ((2R) -2- (dimethylamino) -2-phenylacetyl) - 2-pyrrolidinyl) -lH-imidazol-5-yl) phenyl) -2-pyridinyl) -lH-imidazol-2-yl) -l-pyrrolidinyl) -N, N-dimethyl-2-

<img file="PL2049522T3_D0217.tif" />

n-BuLi (12.0 mL 2.5M / hexanes, 30 mmol) was added dropwise over 15 min to chilled (-78 ° C) toluene (300 mL) semi-solution of 2,5-dibromopyridine (6,040 g,

25.5 mmol), and stirred for 2.5 hr. T240 butyl 2- (methoxy (methyl) amino) -2-oxoethylcarbamate (2.809 g, 12.87 mmol) was added in portions over 7 min, and stirring continued for 1.5 hr at -78 ° C. The -78 ° C bath was replaced by the -60 ° C bath, which was allowed to warm to -15 ° C over 2.5 hr. The reaction was quenched with a saturated NH solution₄C1 (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 give a red-brown semi-solid which was washed with hexanes to remove colored residues. Pyridine 146a was recovered as an gray solid (842 mg). 'H 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, J = 5.8, 2H), 1.40 / 1.28 (two app s, 7.83H + 1.17H). LC (Condition 1): RT = 2.00 min; &gt; 95% LC / MS homogeneity index: Anal. Calc. for [M + Na]⁺ these₂hi₅BrNaN₂ABOUT₃: 337.02; found 337.13

Example 146, Step b .N

NH₂

146b

48% HBr (1.0 mL) was added dropwise 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 give the HBr salt of amine 146b as an off-white solid (672.4 mg; exact molar equivalent of HBr salt not determined). * H NMR (DMSO, δ = 2.5 ppm; 400 MHz): 8.95 (d, J = 2.3, 1H), 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 (Condition 1): RT = 0.53 min

LC / MS: Anal. Calc. for [M + H]⁺ C₇H₈BrN₂A: 214.98; found 215.00

<img file="PL2049522T3_D0218.tif" />

with PR₂EtN (2.3 mL, 13.2 mmol) was added dropwise over 15 min to a heterogeneous 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 hour. The volatile component was removed in vacuo and the residue was partitioned between EtOAc (40 mL) and aqueous medium (20 mL water + 1 mL saturated NaHCO solution)₃). The aqueous layer was washed with EtOAc (20 mL), and the combined organic phases were dried (MgSO₄), filtered and concentrated in vacuo. The resulting crude material was purified by flash chromatography (silica gel; 40-50% EtOAc / hexanes) to give ketoamide 146c as a slightly yellow foam (1.465g). 'H NMR (DMSO, δ = 2.5 ppm; 400 MHz): 8.90 (d, 7 = 2.3, 1H), 8.30 (dd, J = 8.5,

2.4, 1H), 8.01-8.07 (m, 1H), 7.90 (d, 7 = 8.3, 1H), 4.6 (m, 1H), 4.64 (dd, 7 = 19.1, 5.5, 1H);

241

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 (Condition 1): RT = 1.91 min

LC / MS: Anal. Calc. for [M + Na]⁺ C ^ BrNsNaO are: 434.07; found 433.96.

<img file="PL2049522T3_D0219.tif" />

A mixture of ketoamide 146c (782.2 mg, 1.897 mmol) and NH₄OAc (800 mg, 10.4 mmol) in xylenes was heated with microwaves (140 ° C) for 90 min. The volatile component was removed in vacuo and the residue was carefully partitioned between CH2Cl2 and water where sufficient NaHCO solution was added₃ to neutralize him. The aqueous phase was extracted with CH₂C1₂ (2x), and the combined organic phases were dried (MgSO₄), filtered and concentrated in vacuo. The resulting crude material was purified by flash chromatography (silica gel; 50% CH₂cl₂/ EtOAc) to give imidazole Mód as an off-white solid (552.8 mg). * H NMR (DMSO, δ = 2.5 ppm; 400 MHz): 12.49 / 12.39 / 12.15 / 12.06 (br s, 1H), 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, 1H), 4.93-4.72 (m, 1H), 3.53 (m, 1H), 3.41-3.32 (m, 1H), 2.331.77 (m, 4H), 1.39 / 1.14 ( app br s, 3.7H + 5.3H). LC (Condition 1): RT = 1.67 min; &gt; 95% homogeneity index

LC / MS: Anal. Calc. for [M + Na]⁺ these₇H₂, BrN₄NaO₂: 415.08; found 415.12

Example 146, Step e

<img file="PL2049522T3_D0220.tif" />

^1&lt; 146e (Ri = H, R₂ = SEM) or (Ri = SEM, R₂ = H)

NaH (60%; 11.6 mg, 0.29 mmol) was added in one portion to a heterogeneous mixture of imidazole Mód (80 mg, 0.203 mmol) and DMF (1.5 mL), and stirred at ambient conditions for 30 min. SEM-C1 (40 pL, 0.226 mmol) was added dropwise within 2 min to the above reaction mixture, and stirring was continued for 14 hr. The volatile component was removed in vacuo and the residue partitioned between water and CH₂C1₂. The aqueous layer was extracted with CH₂C1₂, and the combined organic phases were dried (MgSO₄), filtered and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel; 20% EtOAc / hexanes) to give 146e as a colorless viscous oil (87.5 mg). The exact regiochemistry of 146e has not been established. '' NMR (CDCl₃, δ = 7.4 ppm; 400 MHz): 8.53 (d, J = 2.2, 1H), 7.90-7.72 (m, 2H), 7.52 (s, 1H), 5.87 (m, 0.46H), 5.41 (m, 0.54H), 5.16 (d , J =

242

10.8, ΙΗ), 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 (Condition 1): RT = 2.1 min LC / MS: Anal. Calc. for [M + H]⁺ C2₃H₃6BrN4O₃Si: 523.17; found 523.24

<img file="PL2049522T3_D0221.tif" />

Pd (Ph3P) 4 (24.4 mg, 0.021 mmol) was added to a mixture of imidazole 146e (280 mg, 0.535 mmol), lc (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 purged with nitrogen, heated in an oil bath at 80 ° C for -24 hr and then the volatile component was removed in vacuo. The residue was partitioned between CH2Cl2 and water, and the organic phase was dried (MgSCC), filtered and concentrated in vacuo. The crude material was purified by Biotage (silica gel; 75-100% EtOAc / hexanes) followed by reverse phase HPLC (H2O / MeOH / TFA). The HPLC eluate was neutralized with 2M NH3 / MeOH and evaporated in vacuo, and the residue was partitioned between water and CH2Cl2. The organic layer was dried (MgSO4), filtered and concentrated in vacuo to give 146f as a white foam (162 mg). LC (Condition 1): RT = 2.1 min LC / MS: Anal. Calc. for [M + Hf C41H58N7O5S1: 756.43; found 756.55

<img file="PL2049522T3_D0222.tif" />

Carbamate 146f (208 mg, 0.275 mmol) was treated with 25% TFA / CH2Cl2 (4.0 mL) and stirred at ambient temperature for 10 br. The volatile component was removed in vacuo and the residue was first converted into the free base by MCX (MeOH wash; elution with 2.0 M NH₃/ MeOH) and then purified by reverse phase HPLC (H₂O / MeOH / TFA) and the resulting material was again converted into the free base (MCX) to give pyrrolidine 146g as an oil film (53.7 mg). 'H NMR (DMSO, δ = 2.5 ppm; 400 MHz): 1.88 (app br s, 2H), 8.83 (d, J = 2.1, IH), 8.07 (dd, 7 = 8.3 / 2.3, IHO, 7.87 (d , 7 = 8.5, IH), 7.84 (d, 7 = 8.3, 2H), 7.71 (d, 7 = 8.3, 2H),

7.55 (s, IH), 7.50 (br s, IH), 4.18 (m, 2H), 3.00- 2.94 (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 (Condition 1): RT = 0.95 min; &gt; 98% homogeneity index

LC / MS: Anal. Calc. for [M + Hf C25H28N7: 426.24; found 426.27

243

Example 146 (1R) -2 - ((2S) -2- (5- (5- (4- (2 - ((2S) -1 - ((2R) -2- (dimethylamino) -2-phenylacetyl) - 2-pyrrolidinyl) 1H-imidazol-5-yl) phenyl) -2-pyridinyl) -1H-imidazol-2-yl) -1-pyrrolidinyl) -N, N-dimethyl-2

<img file="PL2049522T3_D0223.tif" />

Example 146 (TFA salt) was synthesized from pyrrolidine 146g according to the preparation of Example 132 from intermediate 132e.

LC (Condition 1): RT = 1.42 min; 96.5% LC / MS homogeneity index: Anal. Calc. for [M + H]⁺ C45H50N9O2: 748.41; found 748.57 HRMS: Anal. Calc. for [M + H]⁺ C₄₅H₅he₉02: 748.4087; found 748.4100

Example 147 ((1R) -2 - ((2S) -2- (5- (5- (4- (2 - ((2S) -1 - ((2R) -2 - ((methoxycarbonyl) ammo) -2 -phenylacetyl) -2-pyrrolidinyl) -1H-imidazol-5-yl) phenyl) -2-pyridinyl) -1H-imidazol-2-yl) -1-pyrrolidinyl) -2-oxo-1-phenylethyl) methyl carbamate

<img file="PL2049522T3_D0224.tif" />

The TFA salt of Example 147 was similarly obtained from intermediate 146g by using Cap-4.

LC (Condition 1): RT = 1.66 min; 95% homogeneity index

LC / MS: Anal. Calc. for [M + H]⁺ C45H46N9O6: 808.36; found 808.55 Example 148 (1R, 1 R) -2.2 '- (4,4'-biphenyldiylbis (1H-imidazol-5,2-diyl (4R) -1,3-thiazolidin-4,3-diyl)) bis (N, N-dimethyl-2-oxo-l-fenyloetanamma)

<img file="PL2049522T3_D0225.tif" />

244

Example 148, Step a

<img file="PL2049522T3_D0226.tif" />

A solution of bromine (1.3mL, 25.0 mmol) in 15mL glacial acetic acid was added dropwise to a solution of 4-4'-diacetylbiphenyl (3.0g, 12.5mmol) in 40 mL acetic acid at 50 ° C. After the addition, the mixture was stirred at room temperature overnight. The product precipitate was filtered and recrystallized from chloroform to give 1,1 '- (biphenyl-4,4-diyl) bis (2-bromoethanone) (3.84g, 77.5%) as a white solid.

'H 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)

Nominalna / LRMS - Anal. Calc. for 369.07 found; (M + H)⁺ - 397.33, (MH) '- 395.14

Example 148, Step b

<img file="PL2049522T3_D0227.tif" />

.2HCI

Sodium diformylamide (3.66g, 38.5mmol) was added to a suspension of 1,1 '(biphenyl-4,4'diyl) bis (2-bromoethanone) (6.1g, 15.4mmol) in 85mL acetonitrile. The mixture was refluxed for 4 hours and concentrated under reduced pressure. The residue was suspended in 300 mL of 5% HCl in ethanol and heated under reflux for 3.5 hours. The reaction was cooled to room temperature and placed in the freezer for 1 hour. The precipitate was collected, washed with 200 mL 1: 1 ethanol / ether and then 200mL pentane, and dried under reduced pressure to give 1,1 '- (biphenyl-4,4'diyl) bis (2-aminoethanone) dihydrochloride (4.85g, 92 %). Continued without further purification.

1 H 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 in 4 minutes gradient, 1 minute stop time, A = 10% methanol 90% water 0.1% TFA, B = 90% methanol 10% water 0.1% TFA, tR = 0.44 minutes, Anal. Calc. for C16H16N2O2 268.31 found; 269.09 (M + H)⁺ .

Example 148, Step c

<img file="PL2049522T3_D0228.tif" />

To a mixed solution of 1,1 '(biphenyl-4,4'-diyl) bis (2-aminoethanone) dihydrochloride (0.7g, 2.1mmol), N- (tert-butoxycarbonyl) -L-thioproline (0.96g, 4.2mmol) and HATU (1.68g, 4.4mmol) in 14mL DMF added diisopropylethylamine (1.5mL, 8.4mmol)

245 dropwise within 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 / chloroform and water. The aqueous phase was washed once with 20% methanol / chloroform. The combined organic phases were washed with brine, dried (MgSO₄), filtered and concentrated under reduced pressure. The crude product was chromatographed on silica gel eluting with a gradient of 10-50% ethyl acetate / CH₂cl₂ to give (4S, 4'S) -4,4 '- (2,2' - (biphenyl-4,4'-diyl) bis (2-oxoethane-2,1-diyl)) bis (azanediyl) bis (oxomethylene) dithiazolidine- Tert-butyl 3-carboxylate (0.39g, 27%) as an orange foam.

* H NMR (400 MHz, DMSO-d₆) δ ppm 8.38 (2 H, s) 8.12 (4 H, d, 7 = 8.56 Hz) 7.94 (4 H, d, 7 = 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 a 4-minute gradient, 1 minute hold time, A = 10% methanol 90% water 0.1% TFA, B = 90% methanol 10% water 0.1% TFA, tR = 3.69 minutes, Anal. Calc. for C.₃₄H₄₂N₄ABOUT₈S₂ 698.85 found; 699.12 (M + H)⁺ .

<img file="PL2049522T3_D0229.tif" />

(4S, 4'S) -4,4 '- (5,5' - (biphenyl-4,4'-diyl) bis (1H-imidazol-5,2-diyl)) tert-butyl 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 eluting with a 1-6% methanol / CH 2 gradient to give (4S, 4'S) -4,4 '- (5,5' - (biphenyl-4,4'-diyl) bis ( tert-butyl dithiazolidine-3-carboxylate 1H-imidazol-5,2-diyl)) (0.15g, 41%) as a yellow solid.

1 H NMR (500 MHz, DMSO-d₆) δ ppm 12.02 (2H, s) 7.70 - 7.88 (10H, m) 5.28 - 5.37 (2H, m) 4.68 (2H, d, 7 = 9.16 Hz) 4.47 - 4.55 (2H, m) 3.46 (2 H, s) 3.23 (2 H, s) 1.26 - 1.43 (18 H, m)

LCMS - LUNA C-18 3.0 x 50mm, 0 to 100% B in 3.0 minutes gradient, 1 minute hold time, A = 5% acetonitrile, 95% water, 10mm Ammonium acetate, B = 95% acetonitrile, 5% water, 10 mm Ammonium acetate, tR = 1.96 min., Anal. Calc. for C.₃₄H₄oN60₄S₂ 660.85 found; 661.30 (M + H)⁺, 659.34 (MH) '

Example 148, Step e

246

<img file="PL2049522T3_D0230.tif" />

To a solution of (4S, 4'S) -4,4 '- (5,5' - (biphenyl-4,4'-diyl) bis (1H-imidazol-5,2-diyl)) tert-butyl dithiazolidine-3-carboxylate in 1mL dioxane, 0.3mL of a 4.0 M HCl solution in dioxane was added. The reaction was stirred for 3 hours at room temperature and concentrated under reduced pressure. The resulting beige solid was dried under reduced pressure to obtain 4,4'-bis (2 - (((S) -thiazolidin-4-yl) -1H-imidazol-5-yl) biphenyl tetrachlorohydrochloride (0.12g, 100%) as a yellow body Constant.

1 H 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 a 4 minute gradient, 1 minute hold time, A = 5% acetonitrile, 95% water, 10mm Ammonium acetate, B = 95% acetonitrile, 5% water, 10 mm Ammonium acetate, vol_R = 1.70 min., Anal. Calc. for C24H24N6S2

460.62 found; 461.16 (M + H)⁺, 459.31 (MH) '

Example 148 (1R, 1R) -2.2 ^,- (4,4'-bifenyłodiyłobis (lH-imidazol-5,2-diyl (4R) -l, 3-thiazolidin-4,3diylo)) bis (N, N-dimethyl-2-oxo-l-fenyloetanamina)

<img file="PL2049522T3_D0231.tif" />

To a mixed solution of (4,4'-bis (2 - ((S) -thiazolidin-4-yl) -1H-imidazoI-5-yl) biphenyl tetrachloride hydrochloride (0.028g, 0.046mmol), (R) -2- (dimethylamino acid) ) -2-phenylacetic (CapA, 0.017g, 0.0.10 mmol) and HATU (0.039g, O. 10 mmol) in 2mL DMF was added diisopropylethylamine (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 (1H-imidazol-5,2-diyl)) bis (thiazolidin-4,3-diyl)) bis (2- (dimethylamino) -2-phenylethanone), TFA salt (0.012g, 21%) * H NMR (500 MHz, DMSO-d₆) δ ppm 7.59 - 7.91 (20 H, m) 5.62 (2 H, dd, 7 = 6.56, 2.59 Hz)

4.99 (2 H, d, 7 = 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 in 7.0 minutes gradient, 1 minute hold time, A = 5% acetonitrile, 95% water, 10mm Ammonium acetate, B = 95% acetonitrile, 5% water, 10 mm Ammonium acetate mobile phase t_R = 3.128 min.

Nominal / LRMS - Calculate for C44H46N8O2S2 783.03; found 783.28 (M + H)⁺

247

Accurate / HRMS - Obi. for C.₄4H47N₈ABOUT₂S₂ 783.3263; 783.3246 (M + H)⁺

Examples 149 and 150 were prepared in a similar manner as described for the preparation of Example 148.

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

<td>Example 149</td><td>(4,4'-biphenyldiylbis (1Himidazol-5,2-diyl (4R) -1,3-thiazolidine-4,3-diyl ((1R) 2-oxo-1-phenyl-2,1-ethanediyl)) dimethyl biscarbamate</td><td>^ AOOA⁰γ T from 148e and CapA</td><td>t_R = 3.36 min (LCMS - Luna C18 3.0 x 50mm, 0 to 100% B in 7.0 minutes gradient, 1 minute stop time, A = 5% acetonitrile, 95% water, 10 mm ammonium acetate, B = 95% acetonitrile, 5% water, 10mm ammonium acetate) LRMS: Anal. Obi. for C.₄4H4₂N₈ABOUT₆S2 842.99 found: 843.25 (M + H)⁺HRMS: Anal. Obi. for C.₄₄H₄3N₈ABOUT₆S₂843.2747 found: 843.2724 (M + H)⁺</td>

<td>Example 150</td><td>(4R, 4'R) -4,4 '- (4,4'-biphenyldiylbis (1Himidazol-5,2-diyl)) bis (3 ((2R) -tetrahydro-2-furanylcarbonyl) -1,3-thiazolidine)</td><td>from 148e and tetrahydrofuran acid</td><td>tR = 4.32 min (HPLC - X- Terra C-18 4.6 x 50mm, 0 to 100% B in 10.0 minutes gradient, 1 minute hold time, A = 10% methanol 90% water 0.1% TFA, B = 90% methanol 10% 0.1% TFA) LRMS: Anal. Obi. for C34H36N6O4S2</td>

248

656.83 found:

657.32 (M + Hf

Example 151 (1R, 1'R) -2.2 '- (4,4'-biphenyldiylbis ((1-methyl-1H-imidazol-4,2-diyl) (2S) -2.1 pyrrolidinyl)) bis ( N, N-dimethyl-2-oxo-l-fenyloetanamina)

<img file="PL2049522T3_D0232.tif" />

<img file="PL2049522T3_D0233.tif" />

For a mixed solution of 1d, (2S, 2'S) -2,2 '- (4,4' - (biphenyl-4,4'-diyl) bis (1H-imidazol4,2-diyl)) tert- dipyrrolidine-1-carboxylate butyl (100 mg, 0.16 mmol) and iodomethane (40 pL, 0.16 mmol) in CH2Cl2 (2 mL) sodium hydride (40%) (21.2 mg, 0.352 mmol) was added. After five hours at ambient temperature, it was concentrated under reduced pressure. Crude reaction product 15a, (2S, 2'S) -2,2 '- (4,4' - (biphenyl-4,4'-diyl) bis (1-methyl-1-Himidazol-4,2-diyl)) dipyrrolidine tert-butyl 1-carboxylate (~ 90 mg) was carried on to the next step without further purification (purity - 85%) LCMS: Anal. Calc. for: C38H48N₆ABOUT₄ 652.83; found: 653.51 (M + Hf. It should be noted that many methylation isomers are possible in this reaction and we have not attempted to attribute them.

Example 151, Step b

<img file="PL2049522T3_D0234.tif" />

151 a, (2S, 2'S) -2,2 '- (4,4' - (biphenyl-4,4'-diyl) bis (1-methyl-1H-imidazol-4,2-diyl)) dipyrrolidine-1-carboxylate tert-butyl (100 mg, 0.153 mmol) was treated with 4 M HCl / dioxane (20 mL). After three hours at ambient temperature, it was concentrated under

249 reduced pressure. Crude reaction product, 4,4'-bis (1-methyl-2 - ((S) -pyrrolidin-2-yl) -1H-imidazol-4-yl) biphenyl (-110 mg, HCl salt) was carried to the next step without further purification (purity - 85%) LCMS: Anal. Calc. for: C28H32N6 452.59; found: 453.38 (M + H)⁺. Many imidazole isomers were present and all were used further.

Example 151

HATU (58.9 mg, 0.150 mmol) was added to a mixture of 15lb, 4,4'-bis (1-methyl-2 - ((S) pyrrolidin-2-yl) -1H-imidazol-4-yl) biphenyl (45.0 mg, 0.075 mmol), (z-Pr ^ EtN (78 pL, 0.451 mmol) and CapA, (R) -2- (dimethylamino) -2-phenylacetic acid (0.026 mg 0.150mmol) in DMF (1.0 mL). The resulting mixture was stirred at ambient temperature until coupling was not complete as determined by LC / MS. Preparative reverse phase HPLC (Waters-Sunfire 30 X 100mm S5, detection at 220 nm, flow rate 30 mL / min, 0 to 90% B in 14 min; A = 90% water, 10% ACN, 0.1% TFA, B = 10% water, 90% ACN, 0.1% TFA) to provide two isomers 151, (2R, 2'R) -1.1 '- ((2S, 2'S) -2.2' - (4, 4 '- (biphenyl-4,4'-diyl) bis (1-methyl-1H-imidazol-4,2-diyl)) bis (pyrrolidin-2,1-diyl)) bis (2- (dimethylamino) -2- phenylethanone), TFA salts.

Isomer 1: (1R, 1'R) -2,2 '- (4,4'-biphenyldiylbis ((1-methyl-1H-imidazol-4,2-diyl) (2S) 2,1-pyrrolidinyl)) bis (N, N-dimethyl-2-oxo-1-phenylethanamine) (8 mg, 8.6%) as a colorless wax.

* H NMR (500 MHz, DMSO-d₆) δ 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 in 10 minutes, one minute hold time, A = 90% water, 10% methanol, 0.2% phosphoric acid, B = 10% water, 90% methanol, 0.2% acid phosphoric, RT = 2.74 min, 98%.

LCMS: Anal. Calc. for: C48H54N8O2 775.02; found: 775.50 (M + H)⁺.

Isomer 2: (1R, 1 R) -2,2 '- (4,4'-biphenyldiylbis ((1-methyl-1H-imidazol-4,2-diyl) (2S) -2, 1-pyrrolidinyl)) bis (N , N-dimethyl-2-oxo-1-phenylethanamine) (10.2 mg, 11%) as a colorless wax.

1 H 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, 2H) 7.52 - 7.91 (m, 20H).

HPLC Xterra 4.6 X 50 mm, 0 to 100% B in 10 minutes, one minute hold time, A = 90% water, 10% methanol, 0.2% phosphoric acid, B = 10% water, 90% methanol, 0.2% acid phosphoric, RT = 2.75 min, 90%.

LCMS: Anal. Calc. for: C₄8H₅₄N8O₂ 775.02; found: 775.52 (M + H)⁺.

Example 152

250

<img file="PL2049522T3_D0235.tif" />

Example 152 al step a. 2-Chloro-5- (1-ethoxyvinyl) pyrimidine

<img file="PL2049522T3_D0236.tif" />

To a solution of 5-bromo-2-chloropyrimidine (12.5 g, 64.62 mmol) in dry DMF (175 mL) under N2 was added tributyl (1-ethoxyvinyl) tin (21.8 mL, 64.62 mmol) and dichlorobis (triphenylphosphine) palladium (II) ( 2.27 g, 3.23 mmol). The mixture was heated at 100 ° C for 3h and then allowed to stir at room temperature for 16 hours. The mixture was then diluted with ether (200 mL) and treated with an aqueous KF solution (55 g potassium fluoride in 33 mL water). The biphasic mixture was stirred vigorously for 1 h at room temperature and filtered through diatomaceous earth (Celite®). The filtrate was washed with saturated NaHCO solution₃ and brine, before being dried (FASCL). 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) gave the title compound in forms of a white crystalline solid (18.2 g, 73%).

* H NMR (500 MHz, DMSO-d₆) δ 8.97 (s, 2H), 5.08 (d, 7 = 3.7 Hz, 1H), 4.56 (d, 7 = 3.4 Hz, 1H), 3.94 (q, 7 = 7.0 Hz, 2H), 1.35 (t, 7 = 7.0 Hz, 3H) ..

LCMS Phenomenex LUNA C-18 4.6 x 50 mm, 0 to 100% B in 3 minutes, 1 minute stop 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. Calc. for CsIIioClAO 185.05; found: 185.04 (M + H)⁺.

HRMS: Anal. Calc. for C.₈H₁₀CLN₂At 185.0482; found: 185.0490 (M + H)⁺.

The same method was used to prepare Examples 152a-2 and 152a-3:

LC conditions: Condition 1: Phenomenex LUNA C-18 4.6 x 50 mm, 0 to 100% B in 3 minutes, 1 minute stop 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 in 2 minutes, 1 minute stop time, A = 90% water, 10% methanol, 0.1% TFA, B = 10% water, 90% methanol, 0.1% TFA, 220nm, 5 pL injection volume.

251

<td>Example 152a-2</td><td>^theseyx N with dichloropyridazine</td><td>tR = 2.24 min 96.4%, condition 1 LRMS: Anal. Calc. for C.₈hi₀C1N₂ABOUT 185.05; found: 185.06 (M + H)⁺. HRMS: Anal. Calc. for C.₈hi₀C1N₂At 185.0482; found: 185.0476 (M + H)⁺.</td>

<td></td><td></td><td>tR = 2.82 min (52.1%, not applicable)</td>

<td rowspan="2">Example 152a-3</td><td>r</td><td>separate with 2,5-dibrompirazine (vol_R = 1.99 min, 43.2%)); condition 1</td>

<td rowspan="2">with dibromopyrazine</td><td rowspan="2">LRMS: Anal. Calc. for C.₈H_l0BrN₂ABOUT 229.00; found: 228.93 (M + H)⁺.</td>

<td></td>

Example 152d-1 to 152d-6 Example 152b-1, step b.

(Tert-butyl pyrrolidine-l-carboxylate (S) -2- (5- (2-chloropyrimidin-5-yl) -1H-imidazol-2-yl) or (S) -2- [5] tert-butyl ester - (2-Chloro-pyrimidin-5-yl) -1H-imidazol-2-yl] pyrrolidine-1-carboxylic acid

<img file="PL2049522T3_D0237.tif" />

NBS (16.1 g, 90.7 mmol) was added in one portion to a mixed solution of 2-chloro-5- (letoxvinyl) pyrimidine (152a-1, 18.2 g, 98.6 mmol) in THF (267 mL) and H₂O (88 mL) at 0 ° C under N₂. The mixture was stirred for 1 h at 0 ° C and then diluted with more H₂O and extracted with ethyl acetate (2x). The combined extracts were washed with saturated NaHCO solution₃ and brine, and then dried (Na₂SO₄), filtered and the solvents were evaporated. LCMS Phenomenex LUNA C-18 4.6 x 50 mm, 0 to 100% B in 3 minutes, 1 minute stop time, A = 90% water, 10% methanol, 0.1% TFA, B = 10% water, 90% methanol, 0.1% TFA, RT = 1.52 min (asymmetrical peak). LCMS: Anal. Calc. for C.₆hi₄BrClN₂At 235.92; found: 236.85 (M + H)⁺.

Example I52c-1, step c.

Half of the crude solid (2-bromo-1- (2-chloropyrimidin-5-yl) ethanone, ~ 14.5g) was dissolved in anhydrous acetonitrile (150 mL) and treated directly with N-Boc-Lproline (9.76 g, 45.35 mmol) and diisopropylethylamine (7.9 mL, 45.35 mmol). After stirring 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, saturated NaHCO solution₃ and brine, and then dried (Na₂SO₄), filtered and concentrated. LCMS Phenomenex LUNA C-18 4.6 x 50 mm, 0 to 100% B in 3 minutes, 1 minute stop time, A = 90% water, 10% methanol, 0.1% TFA, B = 10% water, 90% methanol, 0.1% TFA, RT = 2.66 min.

252

The same method was used to prepare Examples 152c to 152c-6. LC conditions: Condition 1: Phenomenex LUNA C-18 4.6 x 50 mm, 0 to 100% B in 3 minutes, 1 minute stop 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 in 2 minutes, 1 minute stop time, A = 90% water, 10% methanol, 0.1% TFA, B = 10% water, 90% methanol, 0.1% TFA, 220nm, 5 pL injection volume.

<td>Example 152c-2</td><td>br_x__N. Ύ f 8 τ 0 Oh</td><td>tR = 1.81 min (condition 2, -95%) LRMS: Anal. Calc. for Ci5Hi₉BrN4O2 386.05 found: 387.07 (M + H)⁺.</td>

<td>Example 152c-3</td><td>^Ν'^χίιΑ^οΧί Y O Ł 0</td><td>t_R = 1.84 min (condition 2, 94%) LRMS: Anal. Calc. for Ci5Hi₉BrN₂O5 386.05; found: 387.07 (M + H)⁺.</td>

<td>Example 152c-3a</td><td>AND^C'VA ⁰ V °</td><td>tR = 2.65 min; condition 1 LCMS: Anal. Calc. for Ci6H₂oClN₃05 369.11 found: 391.89 (M + Na)⁺.</td>

<td>Example 152c-4</td><td>AND Y; j V °</td><td>tR = 1.94 min, (condition 2) LCMS: Anal. Calc. for Ci6H₂iBrN₃O5 414.07 found: 414.11 (M + H)⁺.</td>

<td>Example 152c-5</td><td>A j V °^ΝΆνγ</td><td>tR = 2.22 min; condition 1 LCMS: Anal. Calc. for C14H18CIN3O5 343.09 found: not labeled.</td>

<td>Example 152c-6</td><td>Ά and V °</td><td>tR = 2.41 min, condition 1 LCMS: Anal. Calc. for these₄Hi8³⁷BrN₃O5 389.04 found: 412.03 (M + Na)⁺.</td>

Example 152d-1, step d.

This residue ((S) -1-2 (2- (2-chloropyrimidin-5-yl) -2-oxoethyl) pyrrolidin-1,2-dicarboxylate) tert-butyl was dissolved in xylenes (200 mL) and treated with NH4OAC (17.5 g , 0.23 mol). The mixture was heated at 140 ° C for 2 hours. in a thick-walled, flask with a twisted neck and cooled to ambient temperature and filtered under reduced pressure

253 pressure. The filtrate was then concentrated, partitioned between ethyl acetate and saturated NaHCO solution₃ and washed with brine, then dried (Na2SO4), filtered and concentrated. The original precipitate was partitioned between an aqueous NaHCO3 solution and ethyl acetate and sonicated for 2 min, then filtered under reduced pressure. The filtrate was washed with brine, dried over (Na2SO4), filtered and concentrated to dryness. Purification of the combined residue by Biotage ™ flash chromatography on silica gel (65M column, pre-equilibrating 2% B over 900 mL followed by elution with a gradient of 2% B to 2% B over 450 ml, then 2% B to 40% B over 3000 mL, where B = methanol and A = dichloromethane) gave the title compound (7.0 g, 44% yield, 2 steps, pure fraction) as an orange yellow foam. The mixed fractions were subjected to a second Biotage ™ silica gel chromatography (40M column, pre-equilibrating 1% B over 600mL followed by elution with a gradient of 1% B to 1% B over 150ml, followed by 1% B to 10% B over 1500mL, with B = MeOH and A = CH2Cl2) gave an additional title compound (2.8 g, 18%) as a brown-orange foam. 'H NMR (500 MHz, DMSO-dć) δ 12.24-12.16 (m, IH), 9.05 (s, 2H), 7.847.73 (m, IH), 4.90-4.73 (m, IH), 3.59-3, 46 (m, IH), 3.41-3.31 (m, IH), 2.32-2.12 (m, IH), 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 in 3 minutes, 1 minute stop 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. Calc. for you₆H₂iC1N₅O2 350.14; found: 350.23 (M + H)⁺.

HRMS: Anal. Calc. for you₆H2iClN₅ABOUT₂350.1384; found: 350.1398 (M + H)⁺.

The same method was used to prepare Examples 152d-2 to 152d-6.

LC conditions: Condition 1: Phenomenex LUNA C-18 4.6 x 50 mm, 0 to 100% B in 3 minutes, 1 minute stop 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 in 2 minutes, 1 minute stop time, A = 90% water, 10% methanol, 0.1% TFA, B = 10% water, 90% methanol, 0.1% TFA, 220nm, 5 pL injection volume.

t_R= 1.92 min (86.5%);

Example 152d-2

<img file="PL2049522T3_D0238.tif" />

condition 1

LRMS: Anal. Calc. for C.₁₆H₂iC1N₅O2 350.14; found: 350.23 (M + H)⁺.

HRMS: Anal. Calc. for C.₁₆H2iClN₅ABOUT₂350.1384; found: 350.1393 (M + H)

254

<td>Example 152d-3</td><td>"Ai z152C-4</td><td>t_R = 1.90min (&gt; 95%); condition 1 LRMS: Anal. Obi. for C.₁₆H₂iBrN₅ABOUT₂394.09; found: 393.82 (M + H)⁺. HRMS: Anal. Obi. for C._l6H₂₁BrN₅ABOUT₂394.0879; found: 394.0884 (M + H)⁺.</td>

<td>Example 152d-4</td><td>Ά ty0</td><td>t_R = 1.45 min (condition 2, 100%) LRMS: Anal. Obi. for C,₅H, 9BrN₄02 366.07 found: 367.07 (M + H)⁺.</td>

<td></td><td>from 152c-3</td><td></td>

<td>Example 152d-5</td><td>* Y; . Y "Αχ</td><td>t_R = 1.88 min (&gt; 95%); condition 1 LRMS: Anal. Obi. for C |₄hi₈BrN5O₂367.06; found: 368.10 (M + H)⁺.</td>

<td></td><td>from 152c-6</td><td></td>

<td></td><td rowspan="2">γ "τ, v ιχ</td><td>t_R= 1.66 min (85%); condition 1</td>

<td>Example 152d-6</td><td>LRMS: Anal. Obi. for you₄hi₈C1N₅ABOUT₂323.11; found: 324.15 (M + H)⁺.</td>

<td></td><td>from 152c-5</td><td></td>

Example 152e-1, step e.

Example 152e-1: (S) -2- (5- (2-chloropyrimidin-5-yl) -1 - ((2- (trimethylsilyl) ethoxy) methyl) 1H-imidazol-2-yl) pyrrolidine Tert-butyl carboxylate

<img file="PL2049522T3_D0239.tif" />

Sodium hydride (60% dispersion in mineral oil, 0.23 g, 5.72 mmol) was added in one portion to the mixed solution of (S) -2- (5- (2-chloropyrimidin-5-yl) -1H-imidazol-2-yl) pyrrolidine- tert-butyl l-carboxylate (152d-1, 2.0 g, 5.72 mmol) in dry DMF (45 mL) at ambient temperature under N₂. The mixture was stirred for 5 min, then SEM chloride (1.01 mL, 5.72 mmol) was added in steps of approximately 0.1 mL. The mixture was stirred for 3h then quenched with saturated NH4Cl solution and diluted with ethyl acetate. The organic phase was washed with saturated NaHCO solution₃ and brine, dried (Na₂SO₄), filtered, and

255 concentrated. The original aqueous phase was extracted twice as much and the combined residue was purified by Biotage ™ flash chromatography (40M column, 50 mL / min, pre-equilibrating 5% B over 750 mL, followed by a gradient elution step of 5% B to 5% B over 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 eluate gave the title compound as a pale yellow foam (2.35 g, 85%).

1 H NMR (500 MHz, DMSO-d₆) δ 9.04 (s, 2H), 7.98-7.95 (m, 1H), 5.70-5.31 (3m, 2H), 5.024.91 (m, 1H), 3.59-3.49 (m, 3H), 3.45-3 , 35 (m, 1H), 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 in 2 minutes, 2 minutes stop 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. Calc. for CALsCINjOsS, 480.22; found: 480.23 (M + H)⁺.

HRMS: Anal. Calc. for 022Η₃₅αΝ₅0₃8ί 480.2198; found: 480.2194 (M + H)⁺.

The same method was used to prepare 152e-2 to 152e-4

LC conditions: Condition 1: Phenomenex LUNA C-18 4.6 x 50 mm, 0 to 100% B in 3 minutes, 1 minute stop 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 in 2 minutes, 1 minute stop time, A = 90% water, 10% methanol, 0.1% TFA, B = 10% water, 90% methanol, 0.1% TFA, 220nm, 5 pL injection volume.

<td>Example 152e-2</td><td>S from 152d-2</td><td>tR = 2.34 min (85.7%); condition 1 LCMS: Anal. Calc. for C.₂2H35ClN₅ABOUT₃Si 480.22; found: 480.22 (M + H)⁺. HRMS: Anal. Calc. for C.₂2H₃₅CLN₅ABOUT₃Si 480.2198 found: 480.2198 (M + H)⁺.</td>

<td>Example 152e-3</td><td> &gt;^fromAo-o from 152d-3</td><td>tR = 3.18 min (&gt; 95%); condition 1 LCMS: Anal. Calc. for C.₂₂H₃5⁷⁵BrN₅ABOUT₃Si 526.17; found: 525.99 (M + H)⁺. HRMS: Anal. Calc. for C.₂2H₃5⁷⁵BrN₅ABOUT₃Si 526.1692; found: 526.1674 (M + H)⁺.</td>

<td>Example 152e-4</td><td>And you/-</td><td>tR = 2.14 min (condition 2, 96%) LRMS: Anal. Calc. for C.₂H₃₃BrN₄ABOUT₃si 496.15 found: 497.13 (M + H)⁺.</td>

256

152d-4

Examples I52f-1 to 152 / -2 Example 15 2f-1 (S) -1- (2- (5- (2-chloropyrimidin-5-yl) -1H-imidazol-2-yl) pyrrolidin-1-yl) -2- (pyridin-3-yl) ethanone

<img file="PL2049522T3_D0240.tif" />

Cold (0 ° C) 4 N HCl in dioxanes (5 mL) was added by syringe to (S) -2- (5- (2-chloropyrimidin-5-yl) -1H-imidazol-2-yl) pyrrolidine-1-carboxylate tert -butyl (152d-1, 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 to dryness and placed under high vacuum for 1h. Intermediate (S) -2-chloro-5- (2- (pyrrolidin-2-yl) -1H-imidazol-5-yl) pyrimidine trihydrochloride as a pale yellow solid (with an orange shade), which was used without further purification .

HATU (0.60 g, 1.57 mmol) was added in one portion to a mixed solution of the (S) -2-chloro-5- (2- (pyrrolidin-2-yl) -1H-imidazol-5-yl) pyrimidine trichlorohydrochloride solution (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 after which DMF was removed in vacuo. The residue was dissolved in CH2Cl2 and subjected to Biotage ™ flash chromatography on silica gel (40M column, initial equilibration 0% B over 600 mL followed by a gradient elution step 0% B to 0% B over 150 mL followed by 0% B to 15 % B for 1500 mL followed by 15% B to 25% B for 999 mL, where B = MeOH and A = CH2Cl2). The title compound (0.131 g, 25%, 2 steps) was isolated as a yellow solid.

* H NMR (500 MHz, DMSO-d₆) δ 9.10-9.08 (2s, 2H), 8.72-8.55 (m series, 2H), 8.21-8.20 and 8.11-8.10 (2m, IH), 8.00 and 7.93 (2s, IH), 7.84-7.77 (m series, 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 in 3 minutes, 1 minute stop 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. Calc. for C._i8hi₈C1N₆At 369.12; found: 369.11 (M + H)⁺.

HRMS: Anal. Calc. for you₈hi₈C1N6O 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 in 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.

257

<td>Example 152f-2</td><td>0 obtained with Ib by the same procedure described for the preparation of 152f-lz 152d-l</td><td>t_R = 1.56min (&gt; 95%) LRMS: Anal. Calc. for C.₂oH₂oBrN₄0 413.08; found: 412.99 (M + H)⁺.</td>

Examples 152g-1 to 152g-16

Example 152g-1z lc and 152e-l. (S) -2- [5- (2- {4- [2 - ((S) -1-tert-Butoxycarbonyl-pyrrolidin-2-yl) -3E [-imidazol-4-yl] -phenyl acid tert-butyl ester } -pyrimidin-5-yl) -l- (2trimetylsilanylo-ethoxymethyl) -lH-imidazol-2-yl] -pyrrolidine-l-carboxylic acid ethyl ester

<img file="PL2049522T3_D0241.tif" />

Pd (Ph₃)₄ (0.12 g, 0.103 mmol) was added in one portion to the mixed suspension of (S) -2 (5- (4- (4,4,5,5-tetramethyl-1,3-dioxaborolan-2-yl) phenyl) -1H tert-butyl pyrimidol-2-yl) pyrrolidine-1-carboxylate (Ic, 1.00 g, 2.27 mmol), (S) -2- (5- (2-chloropyrimidin-5-yl) -1 - ((2 (trimethylsilyl) ethoxy) methyl) -1H-imidazol-2-yl) pyrrolidine-1-carboxylate tert-butyl (152c-1, 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 in a pre-heated (80 ° C) water 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. sol. NaHCO₃ and brine, then dried over anhydrous sodium sulfate and concentrated solvent. Purification of the residue by Biotage ™ flash chromatography on silica gel using a 40M column (pre-equilibrated 40% B, followed by a gradient elution step of 40% B to 40% B over 150 mL, 40% B to 100% B over 1500 mL, 100% B to 100% B for 1000 mL, where B = ethyl acetate and A = hexanes) gave the title compound as a yellow foam (1.533 g, 98%). A small amount of yellow foam was further purified for characterization by pHPLC (Phenomenex GEMINI, 30 x 100 mm, S10, 10 to 100% B in 13 minutes, 3 minutes hold time, 40 mL / min, A = 95% water, 5 % acetonitrile, 10 mM NH₄OAc, B = 10% water, 90% acetonitrile, 10 mM NH4OAC) to give 95% pure title compound as a white solid.

'HNMR (500 MHz, DMSO-d₆) δ 12.30-11.88 (3m, IH), 9.17-9.16 (m, 2H), 8.43- 8.31 (m, 2H), 7.99-7.35 (m series, 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), 1.46-1.08 (2m, 18H), 0.95-0.84 (m, 2H), -0.01 ( s, 9H).

258

HPLC Phenomenex LUNA C-18 4.6 x 50 mm, 0 to 100% B in 3 minutes, 1 minute stop 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. Calc. for C40H57N8O5S1 757.42; found: 757.42 (M + H)⁺.

HRMS: Anal. Calc. for C40H57N8O5S1 757.4221; found: 757.4191 (M + H)⁺.

The same procedure was used to prepare Examples 152g-2 to 152g-17:

LC conditions: Condition 1: Phenomenex LUNA C-18 4.6 x 50 mm, 0 to 100% B in 3 minutes, 1 minute stop 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 in 2 minutes, 1 minute stop 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>* Χ + ό Obtained from Ic and 152e-2</td><td>tR = 2.81 min (79%); Condition 1 LRMS: Anal. Calc. for C4oH57N₈0₅Si 757.42; found: 758.05 (M + H)⁺. HRMS: Anal. Calc. for C4oH₅₇N80₅Si 757.4221; found: 757.4196 (M + H)⁺.</td>

<td>Example 152g-3</td><td>Wi γ Oh_γο + - Μν-ϋ Obtained from Ic and 152e-3</td><td>tR = 2.89 min (&gt; 95%); Condition 1 LRMS: Anal. Calc. for C40H57N8O5S1 757.42; found: 757.35 (M + H)⁺. HRMS: Anal. Calc. for C40H57N8O5S1 757.4221; found: 757.4191 (M + H)⁺.</td>

<td>Example 152g-4</td><td>Λ A. MY&gt; Y Obtained from l-6c and 152e-2</td><td>tR = 2.87 min (97%); Condition 1 LRMS: Anal. Calc. for CssHssNsOsSi 731.41; found: 731.26 (M + H)⁺. HRMS: Anal. Calc. for C.₃8H₅₅N8O₅Si 731.4065; found: 731.4070 (M + H)⁺.</td>

259

<td>Example 152g-5</td><td>&lt;Νη "from ***** · * »8 yA 5 Ά Λ ° °&gt; °_Y° and Obtained from l-6c and 152e-l</td><td>tR = 2.94 min (&gt; 95%); Condition 1 LRMS: Anal. Calc. for C38H55N8O5S1 731.41; found: 731.26 (M + H)⁺. HRMS: Anal. Calc. for C.₃₈H₅₅N₈ABOUT₅Si 731.4065; found: 731.4046 (M + H)⁺.</td>

<td>Example 152g-6</td><td>χΑχ Obtained from l-6c and 152e-4</td><td>tR = 1.99 min (condition 2, 96%) LRMS: Anal. Calc. for C.₃7H5₃N₇O2Si 703.39; found: 704.34 (M + H)⁺.</td>

<td>Example 152g-7</td><td>-Tr °. 'Χ_;. Αχ Obtained from Ic and 152e-4</td><td>t_R= 1.99 min (condition 2, 96%) LRMS: Anal. Calc. for C.₃₉H₅₅N₇ABOUT₅Si 729.40 found: 730.42 (M + H)⁺.</td>

<td>Example 152g-8</td><td>Stoiya a_about&gt; »O / Χγ V Sq Obtained from l-5c and 152d-1</td><td>tR = 2.15 min (&gt; 95%); Condition 1 LRMS: Anal. Calc. for C₃₇H4iN₈O4 661.33; found: 661.39 (M + H)⁺. HRMS: Anal. Calc. for C₃₇H₄iN₈ABOUT₄ 661.3251; found: 661.3268 (M + H)⁺.</td>

<td>Example 152g-9</td><td>+ - + ί Obtained from lc and 152f-l</td><td>t_R = 1.71 min (&gt; 95%); Condition 1 LRMS: Anal. Calc. for C₃6H₄he₉0₃ 646.76; found: 646.47 (M + H)⁺. HRMS: Anal. Calc. for C₃6H₄he₉0₃ not made found: not made (M + H)⁺.</td>

260

<td>Example 152g-10</td><td>2¾ 9 Obtained from 152d-l and l-10c</td><td>tR = 1.71 min (&gt; 95%); Condition 1 LRMS: Anal. Obi. for C36H40N9O3 646.33; found: 646.37 (M + H)⁺. HRMS: Anal. Obi. for C36H40N9O3 646.3254; found: 646.3240 (M + H)⁺.</td>

<td>Example 152g-11</td><td>W3_ ,, a- Ax Obtained from l-6c and 152e-4</td><td>tR = 2.12 min (&gt; 93.9%); Condition 1 LRMS: Anal. Obi. for C33H42N7O4 600.33; found: 600.11 (M + H)⁺. HRMS: Anal. Obi. for C33H42N7O4 600.3298; found: 600.3312 (M + H)⁺.</td>

<td>Example 152g-12</td><td>wi _MObtained from lei 152d-5</td><td>tR = 2.13 min (97.3%); Condition 1 LRMS: Anal. Obi. for C32H41N8O4 601.33; found: 601.36 (M + H)⁺. HRMS: Anal. Obi. for C32H41N8O4 601.3251; found: 601.3253 (M + H)⁺.</td>

<td>Example 152g-13</td><td>ON^Ht «'rsv V - V Obtained from Ic and 152d-6</td><td>t_R = 2.11 min (98.5%); Condition 1 LRMS: Anal. Obi. for C32H41N8O4 601.33; found: 601.36 (M + H)⁺. HRMS: Anal. Obi. for C32H41N8O4 601.3251; found: 601.3253 (M + H)⁺.</td>

<td>Example 152g-14</td><td>AND ν Bpi *^0&gt;0 V and Αχ Obtained from l-8c and 152d-1</td><td>tR = 2.18 min (&gt; 95%); Condition 1 LRMS: Anal. Obi. for C33H43N8O4 615.34; found: 615.38 (M + H)⁺. HRMS: Anal. Obi. for C32H41N8O4 615.3407; found</td>

261

<td></td><td></td><td>: 615.3433 (M + H)⁺.</td>

<td>Example 152g-15</td><td>l^hv S &lt;0 ° y because "Aj-Ci Obtained from lei 152d-1</td><td>tR = 2.20 min (97.7%); Condition 1 LRMS: Anal. Calc. for C35H39N8O4 635.31; found: 635.36 (M + H)⁺. HRMS: Anal. Calc. for C35H39N8O4 635.3094; found: 635.3119 (M + H)⁺.</td>

<td>Example 152g-16</td><td>and. A 8 A ° νγ γ because Obtained from l-9c and 152d-1</td><td>tR = 2.26 min (&gt; 95%); Condition 1 LRMS: Anal. Calc. for C₃₆H₄iN₈ABOUT₄ 649.33; found: 649.39 (M + H)⁺. HRMS: Anal. Calc. for C₃6H₄| N8O₄ 649.3251; found: 649.3276 (M + H)⁺.</td>

<td>Example 152g-17</td><td>• "ASoi t τ Obtained from l-6c and 152e-3</td><td>tR = 2.98 min (98.5%); Condition 1 LRMS: Anal. Calc. for C.₃₈H₅₄N₈ABOUT₅Si 730.39; found: 731.40 (M + H)⁺. HRMS: Anal. Calc. for C.₃₈H₅₄N₈ABOUT₅Si 731.4065; found: 731.4045 (M + H)⁺.</td>

Example 152h-l-152h-7

Example 152h-lz 152g-1,5 - ((S) -2-Pyrrolidin-2-yl-3H-imidazole-4-yl) -2- [4 - ((S) -2-pyrrolidin-2-yl-3H -imidazole-4-needle) -phenyla] -pyrimidine

<img file="PL2049522T3_D0242.tif" />

TFA (8 mL) was added in one portion to the mixed solution of (S) -2- [5- (2- {4- [2 - ((S) -1-tert-butoxycarbonylpyrrolidinyl ester / er] -butylic acid 2-yl) -3H-imidazol-4-yl] phenyl} -pyrimidin-5-yl) -1- (2-trimethylsilanyl-ethoxymethyl) -1H-imidazol-2-yl] pyrrolidine-1-carboxylic acid (1.50 g , 1.98 mmol) in dry CH2Cl2 (30 mL) at room temperature. The flask was closed and the mixture was stirred at room temperature for 16h before the solvent (s) were removed in vacuo. The residue was dissolved in methanol, filtered through a PVDF syringe filter (13mm x 0.45pm), distributed into 8 vials

262 pHPLC and chromatographed by HPLC (gradient elution from 10% B to 100% B over 13 min on a Phenomenex C18 column, 30 x 100mm, 10 pm, where A = 90% water, 10% methanol, 0.1% TFA, B = 10% water, 90% methanol, 0.1% TFA). After concentrating selected tubes by rapid vacuum evaporation, the product was dissolved in methanol and neutralized by passing the solution through an anion exchange cartridge UCT CHQAX 110M75. The title compound was isolated as a mustard yellow solid (306.7 mg, 36% yield) after concentration of the eluate.

1 H NMR (500 MHz, DMSO-d₆) p 12.50-11.80 (br m, 2H), 9.18 (s, 2H), 8.36 (d, 7 = 8.5 Hz, 2H), 7.89 (d, 7 = 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 in 3 minutes, 1 minute stop time, A = 90% water, 10% methanol, 0.1% TFA, B = 10% water, 90% methanol, 0.1% TFA, RT = 1.33 min,&gt; 95% homogeneity index.

LRMS: Anal. Calc. for C.₂₄H₂₇N₈ 427.24; found: 427.01 (M + H)⁺.

HRMS: Anal. Calc. for C.₂₄H₂₇N₈ 427.2359; found: 427.2363 (M + H)⁺.

The same conditions were used to prepare Examples 152h-2 to 152h-14.

LC conditions: Condition 1: Phenomenex LUNA C-18 4.6 x 50 mm, 0 to 100% B in 3 minutes, 1 minute stop 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 in 2 minutes, 1 minute stop time, A = 90% water, 10% methanol, 0.1% TFA, B = 10% water, 90% methanol, 0.1% TFA, 220nm, 5 pL injection volume.

<td>Example 152h-2</td><td>Obtained from 152g-3</td><td>tR = 1.36 min (98%); Condition 1 LRMS: Anal. Calc. for C.₂₄H₂₇N₈ 427.24; found: 427.48 (M + H)⁺. HRMS: Anal. Calc. for C.₂₄H₂₇N₈ 427.2359; found: 427.2339 (M + H)⁺.</td>

<td></td><td></td><td>tR = 1.17 min (&gt; 95%); Condition 1</td>

<td rowspan="2">Example 152h-3</td><td rowspan="2">gOLs b</td><td>LRMS: Anal. Calc. for</td>

<td>C₂₂H₂₅N₈ 401.22;</td>

<td></td><td>Obtained from 152g-4</td><td>found: 401.16 (M + H)⁺.</td>

263

<td></td><td></td><td>HRMS: Anal. Calc. for C.₂₂H₂₅N₈ 401.2202; found: 401.2193 (M + H)⁺.</td>

<td></td><td></td><td>t_R= 1.28 min (89.3%); Condition 1</td>

<td></td><td>IN? n * ^B ifjL _N</td><td>LRMS: Anal. Calc. for C.₂₂H₂₅N₈ 401.22;</td>

<td>Example 152h-4</td><td>and . ΑΧ)</td><td>found: 401.16 (M + H)⁺.</td>

<td></td><td>Obtained from 152g-5</td><td>HRMS: Anal. Calc. for C.₂₂H₂₅N₈ 401.2202; found: 401.2201 (M + H)⁺.</td>

<td></td><td>HM</td><td>t_R = 0.93 min; Condition 2</td>

<td></td><td>-M) ____ Xs? ^N [χ</td><td>LRMS: Anal. Calc. for</td>

<td></td><td></td><td>C23H25N7 399; found:</td>

<td>Example 152h-5</td><td></td><td rowspan="2">400 (M + H)⁺.</td>

<td></td><td>N- &amp; / Nh</td>

<td></td><td>Obtained from 152g-7</td><td></td>

<td></td><td>^Η\ Λ</td><td>t_R = 0.81 min; Condition 2</td>

<td></td><td> «5&gt;</td><td>LRMS: Anal. Calc. for</td>

<td rowspan="2">Example 152h-6</td><td>nL JL</td><td>C₂H₂3N₇ 373; found:</td>

<td>V, N^N Y. y-NH,</td><td>374 (M + H)⁺.</td>

<td></td><td>Obtained from 152g-6</td><td></td>

<td></td><td></td><td>t_R = 1.14 min (&gt; 95%); Condition 1</td>

<td></td><td>^{4 N} id</td><td>LRMS: Anal. Calc. for</td>

<td></td><td></td><td>C₂₃H₂₆N₇ 400.23;</td>

<td rowspan="3">Example 152h-7</td><td></td><td>found: 400.14</td>

<td></td><td></td>

<td></td><td>(M + H)⁺.</td>

<td></td><td>σ</td><td>HRMS: Anal. Calc. for</td>

<td></td><td>Obtained from 152g-11</td><td>C₂₃H26N₇ 400.2250; found: 400.2234 (M + H)⁺.</td>

264

<td>Example 152h-8</td><td>mm Obtained from 152g-12</td><td>tR = 1.29 min (&gt; 95%); Condition 1 LRMS: Anal. Calc. for C.₂₂H₂₅N₈ 401.22; found: 401.21 (M + H)⁺. HRMS: Anal. Calc. for C22H₂₅N₈ 401.2202; found: 401.2204 (M + H)⁺.</td>

<td></td><td></td><td>t_R= 1.29 min (97.6%); Condition 1</td>

<td>Example 152h-9</td><td>MK3</td><td>LRMS: Anal. Calc. for C.₂2H₂₅N₈ 401.22; found: 401.21 (M + H)⁺.</td>

<td></td><td>Obtained from 152g-13</td><td>HRMS: Anal. Calc. for C.₂2H₂₅N₈ 401.2202; found: 401.2220 (M + H)⁺.</td>

<td></td><td></td><td>t_R= 1.26 min (86.4%); Condition 1</td>

<td></td><td>cwjmem Η H Jl</td><td>LRMS: Anal. Calc. for C.₂₄H₂₇N₈ 427.24;</td>

<td>Example 152h-10</td><td>jS 3 η M mm</td><td>found: 427.48 (M + H)⁺.</td>

<td></td><td>Obtained from 152g-2</td><td>HRMS: Anal. Calc. for C24H₂₇N₈ 427.2359; found: 427.2339 (M + H)⁺.</td>

<td></td><td></td><td>tR = 1.26 min (&gt; 95%); Condition 1</td>

<td></td><td>CHM O</td><td>LRMS: Anal. Calc. for</td>

<td>Example 152h-11</td><td>mm</td><td>C31H32N9O 546.27; found: 546.28 (M + H)⁺.</td>

<td></td><td>Obtained from 152g-9</td><td>HRMS: Anal. Calc. for C31H32N9O 546.2730</td>

265

<td></td><td></td><td>found: 546.2739 (M + H)⁺.</td>

<td>Example 152h-12</td><td>P Y 'v Obtained from 152g-10</td><td>t_R= 1.39 min (95%); Condition 1 LRMS: Anal. Calc. for C31H32N9O 546.27; found: 546.32 (M + H)⁺. HRMS: Anal. Calc. for C.₃, H3₂N₉At 546.2730; found: 546.2719 (M + H)⁺.</td>

<td>Example 152h-13</td><td>s κκΊ J and HW akd Obtained from 152g-14</td><td>t_R = 1.42 min; Condition 1 LRMS: Anal. Calc. for C.₂₃H₂₆N₈ 414.24; found: 415.27 (M + H)⁺. HRMS: Anal. Calc. for C.₂₃H₂₆N₈ 415.2359; found: 415.2371 (M + H)⁺.</td>

<td>Example 152h-14</td><td>Obtained from 152g-17</td><td>t_R= 1.30 min; Condition 1 LRMS: Anal. Calc. for C.₂₂H₂₄N₈ 400.21; found: 401.24 (M + H)⁺. HRMS: Anal. Calc. for C.₂₂H₂₄N₈ 401.2202; found: 401.2198 (M + H)⁺.</td>

Example 152i-1 to 152i-3

Example 152i-lz 152g-8. (S) -2- (5- {2- [4 - ((S) -2-Pyrrolidin-2-yl) 3H-imidazol-4-yl) -phenyl] -pyrimidin-5-yl} - tert-butyl ester lei-imidazol-2-yl) -pyrrolidine-carboxylic acid

From

<img file="PL2049522T3_D0243.tif" />

and, N

266

Solution of (S) -2- [5- (2- {4- [2 - ((S) -1-Benzyloxycarbonylpyrrolidin-2-yl) -3H-imidazol-4-yl] -phenyl} acid tert-butyl ester -pyrimidin-5-yl) -1H-imidazol-2-yl] pyrrolidine-1-carboxylic acid (317.1 mg, 0.48 mmol) in MeOH (1 mL) was added to a mixed 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 filled and pumped under vacuum three times with H2 and stirred for 3h at atmospheric pressure. Additional catalyst (20 mg) was then added and the reaction mixture was stirred further for 3h before it was filtered off under reduced pressure through diatomaceous earth (Celite®) and concentrated. The residue was diluted with MeOH, filtered through a PVDF syringe filter (13mm x 0.45pm), poured into 4 pHPLC vials and subjected to chromatography (gradient elution from 20% B to 100% B over 10 min on a Phenomenex-Gemini C 18 column (30 x 100mm , 10pm), where A = 95% water, 5% acetonitrile, 10 mM NH4OAC, B = 10% water, 90% acetonitrile, 10 mM NH4OAC). After concentration of selected tubes by rapid evaporation under reduced pressure, the title compound was isolated as a yellow solid (142.5 mg, 56% yield).

1 H NMR (400 MHz, DMSO-d₆) δ 12.35-12.09 (br m, IH), 9.17 (s, 2H), 8.35 (d, 7 = 8.3Hz,

2H), 7.87 (d, 7 = 8.3Hz, 2H), 7.80-7.72 (m, IH), 7.56 (s, IH), 4.92-4.77 (m, IH), 4.21-4.13 (m, IH), 3.61 -3.05 (2m, 4H), 3.02-2.80 (2m, 2H), 2.37-1.67 (m series, 6H), 1.41 and 1.17 (2s, 9H). LCMS Phenomenex LUNA C-18 4.6 x 50 mm, 0 to 100% B in 3 minutes, 1 minute stop time, A = 90% water, 10% methanol, 0.1% TFA, B = 10% water, 90% methanol,

0.1% TFA, RT = 1.77 min,&gt; 95% homogeneity index.

LRMS: Anal. Calc. for 0₂₉Η₃₅Ν8θ₂ 527.29; found: 527.34 (M + H)⁺.

HRMS: Anal. Calc. for C29H35N8O2 527.2883; found: 527.2874 (M + H)⁺.

The same procedure was used to prepare Examples 152Ϊ-2 to 152i-3. LC conditions: Condition 1: Phenomenex LUNA C-18 4.6 x 50 mm, 0 to 100% B in 3 minutes, 1 minute stop 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 in 2 minutes, 1 minute stop time, A = 90% water, 10% methanol, 0.1% TFA, B = 10% water, 90% methanol, 0.1% TFA, 220nm, 5 pL injection volume.

<td></td><td></td><td>t_R = 1.70 min (95.7%); Condition 1</td>

<td></td><td rowspan="2"></td><td>LRMS: Anal. Calc. for</td>

<td></td><td>C27H33N8O2 501.27;</td>

<td>Example 152i-2</td><td>* 1 Η Y • Ayo</td><td>found: 501.35 (M + H)⁺. HRMS: Anal. Calc. for</td>

<td></td><td>Obtained from 152g-15</td><td>C27H33N8O2 501.2726 found: 501.2709 (M + H)⁺.</td>

267

Example 152Ϊ-3

<img file="PL2049522T3_D0244.tif" />

tR = 1.77 min (&gt; 95%); Condition 1

LRMS: Anal. Calc. for C.₂₈H₃₅N₈ABOUT₂ 515.29;

found: 515.37 (M + H)⁺.

HRMS: Anal. Calc. for C.₂₈H₃₅N₈ABOUT₂ 515.2883 found: 515.2869 (M + H)⁺.

Examples 152j-1 to 152J-28

Examples 152j was isolated as the TFA or AcOH salt obtained using the conversion procedure of Example 148e to 148.

LC conditions: Condition 1: Phenomenex LUNA C-18 4.6 x 50 mm, 0 to 100% B in 3 minutes, 1 minute stop 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 in 2 minutes, 1 minute stop 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>Union Name</td><td>Structure</td><td>Data</td>

<td>Example 152j-l</td><td>(1 R) -2 - ((2S) -2- (5- (2- (4 (2 - ((2S) -1 - ((2R) -2 (dimethylamino) -2-phenylacetyl) -2-pyrrolidinyl) -1Himidazol- 5-yl) phenyl) 5-pyrimidinyl) -1Himidazol-2-yl) -1-pyrrolidinyl) -N, N-dimethyl-2-oxo-1 phenylethanamine</td><td>χχ 5 AND Obtained from 152h-1 and CapA.</td><td>tR = 1.61 min; (&gt; 95%); Condition 1 LRMS: Anal. Calc. for C44H49N10O2 749.40 found: 749.32 (M + H)⁺HRMS: Anal. Calc. for C.₄₄H₄9NiqO₂749.4040 found: 749.4042 (M + H)⁺</td>

<td>Example 152j-2</td><td>((R) -2 - ((2S) -2- (5- (2- (4- (2 - ((2S) -l - ((2R) -2- ((methoxycarbonyl) amino no) -2-phenylacetyl) -2-pyrrolidinyl) -1Himidazol-5-yl) phenyl) 5-pyrimidinyl) -1Himidazol-2-yl) -1-</td><td>Obtained from 152h CapA</td><td>tR = 1.99 min (&gt; 95%); Condition 1 LRMS: Anal. Calc. for C.₄₄H₄₅Nio0₆809.35 found: 809.17 (M + H)⁺HRMS: Anal. Calc.</td>

268

<td></td><td>pyrrolidinyl) -2-oxo-1 phenylethyl) carbamate methyl</td><td></td><td>for C44H45N10O6 809.3524 found: 809.3505 (M + H)⁺</td>

<td>Example 152J-3</td><td>((1R) -2-oxo-1-phenyl2 - ((2S) -2- (5- (4- (5- (2 ((2S) -1- (3-pyridinylacetyl) -2-pyrrolidinyl) -1Himidazol-5- yl) -2-pyrimidinyl) phenyl) 1H-imidazol-2-yl) -1-pyrrolidinyl) ethyl) carbam methyl minate</td><td>2%. 9 Obtained from 152h-11 and Cap-4</td><td>tR = 1.65 min (92.3%); Condition 1 LRMS: Anal. Obi. for C41H41N10O2 737.33 found: 737.49 (M + H)⁺HRMS: Anal. Obi. for C41H41N10O4 737.3312 found: 737.3342 (M + H)⁺</td>

<td>Example 152J-4</td><td>((1R) -2-oxo-1-phenyl2 - ((2S) -2- (5- (2- (4- (2 ((2S) -1- (3-pyridinylacetyl) -2-pyrrolidinyl) -1Himidazol-5- yl) phenyl) 5-pyrimidine (lo) -1-Himidazol-2-yl) -1-pyrrolidinyl) ethyl) carbam methyl minate</td><td>° at XX Obtained from 152h-l 2 and Cap-4</td><td>tR = 1.64 min (&gt; 95%); Condition 1 LRMS: Anal. Obi. for C41H41N10O4 737.33 found: 737.75 (M + H)⁺HRMS: Anal. Obi. for C41H41N10O4 737.3312 found: 737.3284 (M + H)⁺</td>

<td>Example 152J-5</td><td>5- (2 - ((2S) -1 - ((2R) -2-phenyl-2- (1-piperidinyl) acetyl) 2-pyrrolidinyl) -1Himidazol-5-yl) -2- (4 (2 - ((2S) - l - ((2R) -2fenylo-2- (lpiperydynylo) acetyl) -2-pyrrolidinyl) -1H-imidazol-4-yl) phenyl) pyrimidine</td><td>Obtained from 152h-l and Cap-14</td><td>tR = 1.70 min (&gt; 95%); Condition 1 LRMS: Anal. Obi. for C50H57N10O2 829.47 found: 829.39 (M + H)⁺HRMS: Anal. Obi. for C50H57N10O2 829.4666 found: 829.4658 (M + H)⁺</td>

269

<td>Example 152) -6</td><td>(2R) -N-methyl-2-phenyl-N - ((1S) -1- (4- (4 (5- (2 - ((2S) -1 - ((2R) -2-phenyl-2- (1-piperidinyl) acetyl ) -2-pyrrolidinyl) -1H-imidazol-5-yl) -2-pyrimidinyl) phenyl) -lH-imidazol-2-yl) ethyl) -2- (lpiperydynylo) -acetamide</td><td>A-¾ ABOUT AA Obtained from 152h-13 and Cap-14</td><td>tR = 1.66 min (&gt; 95%); Condition 1 LRMS: Anal. Calc. for C49H57N10O2 817.47 found: 817.44 (M + H)⁺HRMS: Anal. Calc. for C49H57N10O2 817.4666 found: 817.4673 (M + H)⁺</td>

<td>Example 152) -7-</td><td>(R) -2 - ((2S) -2- (5- (5- (4- (2 - ((2S) -l - ((2R) -2- (dimethylamino) -2fenyloacetylo) -2pirolidynylo) -1H-imidazol-5 -yl) phenyl) 2-pyrazinyl) -1Himidazol-2-yl) -1-pyrrolidinyl) -N, N-dimethyl-2-oxo-1 phenylethanamine</td><td> 0 ^Y;'/' Obtained from 152h-2 and Cap-i</td><td>tR = 1.60 min (&gt; 95%); Condition 1 LRMS: Anal. Calc. for C41H49N10O2 749.40 found: 749.31 (M + H)⁺HRMS: Anal. Calc. for C41H49N10O2 749.4040 found: 749.4031 (M + H)⁺</td>

<td>Example 152) -8</td><td>((R) -2 - ((2S) -2- (5- (5- (4- (2 - ((2S) -l - ((2R) -2- ((methoxycarbonyl) amino no) -2-phenylacetyl) -2-pyrrolidinyl) -1Himidazol-5-yl) phenyl) 2-pyrazinyl) -1Himidazol-2-yl) -1-pyrrolidinyl) -2-oxo-1 phenylethyl) carbamate methyl</td><td>χΑΑ Obtained from 152h-2 and Cap-4</td><td>tR = 2.01 min (&gt; 95%); Condition 1 LRMS: Anal. Calc. for C44H45N10O6 809.35 found: 809.24 (M + H)⁺HRMS: Anal. Calc. for C44H45N10O6 809.3523 found: 809.3493 (M + H)⁺</td>

<td>Example 152) -9</td><td>(R) -2 - ((2S) -2- (5- (6- (4- (2 - ((2S) -l - ((2R) -2- (dimethylamino) -2fenyloacetylo) -2pirolidynylo) -lH</td><td>Obtained from</td><td>tR = 1.76 min (&gt; 95%); Condition 1 LRMS: Anal. Calc. for C44H49N10O2</td>

270

<td></td><td>imidazol-5-yl) phenyl) 3-pyridazinyl) -1H-imidazol-2-yl) -1-pyrrolidinyl) -N, N-dimethyl-2-oxo-1 phenylethanamine</td><td>5 about Ajo 152h-10 and CapA</td><td>749.40 found: do not follow (M + H)⁺HRMS Anal. Calc. for C44H49N10O2 749.4040 found: 749.4056 (M + H)⁺</td>

<td>Example 152J-10</td><td>((R) -2 - ((2S) -2- (5- (6- (4- (2 - ((2S) -l - ((2R) -2- ((methoxycarbonyl) amino no) -2-phenylacetyl) -2-pyrrolidinyl) -1Himidazol-5-yl) phenyl) 3-pyridazinyl) -1Himidazol-2-yl) -1-pyrrolidinyl) -2-oxo-1-phenylethyl) carbamate methyl</td><td>EI about Obtained from 152h-10 and Cap-4</td><td>t_R = 2.17 min (&gt; 95%); Condition 1 LRMS: Anal. Calc. for C44H45N10O6 809.35 found: 809.59 (M + H)⁺HRMS: Anal. Calc. for C44H45N10O6 809.3524 found: 809.3499 (M + H)⁺</td>

<td>Example 152J-11</td><td>(2R) -2- (dimethylamino) -N ((1S) -1- (5- (4- (5- (2- ((2S) -l - ((2R) -2- (dimethylamino) -2fenyloacetylo) -2pirolidynylo) -1Himidazol-5-yl) -2-pyridinyl) phenyl) -1Himidazol-2-yl) ethyl) -2-phenylacetamide</td><td>Μχ 9 Oh hh Obtained from 152h-7 and Cap-1</td><td>t_R= 1.56 min (&gt; 95%); Condition 1 LRMS: Anal. Calc. for C43H4₈N9O₂722.39 found: 722.89 (M + H)⁺HRMS: Anal. Calc. for C43H48N9O2 722.3931 found: 722.3930 (M + H)⁺</td>

<td>Example 152j-12</td><td>((1R) -2 - ((2S) -2- (5- (6 (4- (2 - ((1S) -1 - (((2R) -2 ((methoxycarbonyl) ami no) -2-phenylacetyl) amino) ethyl) -1H-imidazol-5-yl) phenyl) -3-pyridinyl) -1Himidazol-2-yl) -1-pyrrolidinyl) -2-oxo-1 -</td><td>Obtained from 152h-7 and Cap-4</td><td>t_R = 1.95 min (&gt; 95%); Condition 1 LRMS: Anal. Calc. for C43H44N9O6 782.34 found: 782.93 (M + H)⁺HRMS: Anal. Calc. for C43H44N9O6 782.3415</td>

271

<td></td><td>phenylethyl) carbamate methyl</td><td></td><td>found: 782.3398 (M + H)⁺</td>

<td>Example 152j-13</td><td>(2R) -2- (dimethylamino) -N ((1S) -1- (5- (4- (6- (2- ((2S) -l - ((2R) -2- (dimethylamino) -2fenyloacetylo) -2pirolidynylo) -lH-5-yl) -3pirydazynylo) phenyl) -lH-imidazol-2-yl) ethyl) -2fenyloacetamid</td><td>ABOUT \ .κ and ", NH ' About «IM Obtained from 152h-3 and Cap-}</td><td>tR = 1.55 min (&gt; 95%); Condition 1 LRMS: Anal. Calc. for C42H47N10O2 723.39 found: 723.88 (M + H)⁺HRMS: Anal. Calc. for C42H47N10O2 723.3883 found: 723.3903 (M + H)⁺</td>

<td>Example 152J-14</td><td>((1R) -2 - ((2S) -2- (5- (6 (4- (2 - ((1S) -1 - (((2R) -2 ((methoxycarbonyl) amino) -2-phenylacetyl) amino) ethyl) -1H-imidazol-5-yl) phenyl) -3-pyridazinyl) -1Himidazol-2-yl) -1-pyrrolidinyl) -2-oxo-1 phenylethyl) methylcarbamate</td><td>"OA? Obtained from 152h-3 and Cap-4</td><td>tR = 1.95 min (&gt; 95%); Condition 1 LRMS: Anal. Calc. for C42H43N10O6 783.34 found: 783.95 (M + H)⁺HRMS: Anal. Calc. for C₄₂H43N_l0O6783.33 67 found: 783.3337 (M + H)⁺</td>

<td>Example 152J-15</td><td>((1R) -2 - ((2S) -2- (5- (2 (4- (2 - ((1S) -1 - (((2R) -2 ((methoxycarbonyl) ami no) -2-phenylacetyl) amino) ethyl) -1H-imidazol-5-yl) phenyl) -5-pyrimidinyl) -1Himidazol-2-yl) -1-pyrrolidinyl) -2-oxo-1-phenylethyl) carbamate</td><td>Obtained from 152h-4 and Cap-4</td><td>tR = 1.97 min (&gt; 95%); Condition 1 LRMS: Anal. Calc. for C42H43N10O6 783.34 found: 783.97 (M + H)⁺HRMS: Anal. Calc. for C42H43N10O6 783.3367 found: 783.3357 (M + H)⁺</td>

272

<td>Example 152j-16</td><td>(2R) -2- (dimethylamino) -N ((1S) -1- (5- (2- (4- (2- ((2S) -l - ((2R) -2- (dimethylamino) -2fenyloacetylo) -2pirolidynylo) -lH-5-yl) phenyl) -5-pyrimidinyl) -1H-imidazol-2-yl) ethyl) -2fenyloacetamid</td><td>ABOUT IM Obtained from 152h-9 and Cap- \</td><td>t_R = 1.61 min (&gt; 95%); Condition 1 LRMS: Anal. Calc. for C42H47N10O2 723.39 found: 723.52 (M + H)⁺HRMS: A nal. Calc. for C42H47N10O2 723.3883 found: 723.3893 (M + H)⁺</td>

<td>Example 152J-17</td><td>((1R) -2 - ((2S) -2- (5- (4 (5- (2 - ((1S) -1 - (((2R) -2 ((methoxycarbonyl) amino) -2-phenylacetyl) amino ) ethyl) -1H-imidazol-5-yl) 2-pyrimidinyl) phenyl) 1H-imidazol-2-yl) -1-pyrrolidinyl) -2-oxo-1 phenylethyl) methylcarbamate</td><td>ΑΑΑ Obtained from 152h-9 and Cap-4</td><td>t_R= 1.99 min (95.6%); Condition 1 LRMS: Anal. Calc. for C42H43N10O6 783.34 found: 783.44 (M + H)⁺HRMS: Anal. Calc. for C42H43N10O6 783.3367 found: 783.3328 (M + H)⁺</td>

<td>Example 152j-18</td><td>(2R) -2- (dimethylamino) -N ((1S) -1- (5- (5- (4- (2 ((2S) -l - ((2R) -2- (dimethylamino) -2fenyloacetylo) -2pirolidynylo) -lH-5-yl) phenyl) 2-pyrazinyl) -lH-2-yl) ethyl) -2fenyloacetamid</td><td>LY 5 Obtained from 152h-8 and Cap-1</td><td>t_R= 1.60 min (&gt; 95%); Condition 1 LRMS: Anal. Calc. for C42H47N10O2 723.39 found: 723.47 (M + H)⁺HRMS: Anal. Calc. for C42H47N10O2 723.3883 found: 723.3861 (M + H)⁺</td>

<td>Example 152J-19</td><td>((R) -2 - ((2S) -2- (5- (4- (5- (2 - ((S) -l - (((2R) -2- ((methoxycarbonyl) amino no) -2-</td><td>BJA ^and AND/ • ABOUT " Obtained from 152h-8 and Cap-4</td><td>t_R = 1.97 min (94.7%); Condition 1 LRMS: Anal. Calc.</td>

273

<td></td><td>phenylacetyl) amino) ethyl) -1H-imidazol-5-yl) 2-pyrazinyl) phenyl) 1H-imidazol-2-yl) -1-pyrrolidinyl) -2-oxo-1-phenylethyl) methyl carbamate</td><td></td><td>for C42H43N10O6 783.34 found: 783.69 (M + H)⁺HRMS: Anal. Calc. for C42H43N10O6 783.3367 found: 783.3345 (M + H)⁺</td>

<td>Example 152J-20</td><td>(2R) -2- (dimethylamino) -N ((S) -l- (5- (4- (5- (2- ((2S) -l - ((2R) -2- (dimethylamino) -2fenyloacetylo) -2pirolidynylo) -lH-5-yl) -2-pyrimidinyl) phenyl) -lH-imidazol-2-yl) ethyl) -N-methyl-2fenyloacetamid</td><td>, Μν. ABOUT Obtained from 152h-13 and Cap-1</td><td>tR = 1.54 min (&gt; 95%); Condition 1 LRMS: Anal. Calc. for C43H49N10O2 737.40 found: 737.54 (M + H)⁺HRMS: Anal. Calc. for C43H49N10O2 737.4040 found: 7374066 (M + H)⁺</td>

<td>Example 152J-21</td><td>((1R) -2 - ((2S) -2- (5- (2 (4- (2 - ((1S) -1 - (((2R) -2 ((methoxycarbonyl) amino) -2-phenylacetyl) (methyl) amin) ethyl) -1Himidazol-5-yl) phenyl) 5-pyrimidinyl) -1Himidazol-2-yl) -1-pyrrolidinyl) -2-oxo-1 phenylethyl) methyl carbamate</td><td>Obtained from 152h-13 and Cap-4</td><td>tR = 2.00 min (&gt; 95%); Condition 1 LRMS: Anal. Calc. for C43H45N10O6 797.35 found: 797.38 (M + H)⁺HRMS: Anal. Calc. for C43H45N10O6 797.3524 found: 797.3528 (M + H)⁺</td>

<td>Example 152J-22</td><td>((1R) -2 - ((2S) -2- (5- (4 (5- (2 - ((1S) -1 - (((2R) -2 ((methoxycarbonyl) amino) -2-phenylacetyl) amino ) ethyl) -1 H-imidazol-5-yl) 2-pyridinyl) phenyl) 1 H-imidazol-2-yl) -1 pyrrolidinyl) -2-oxo-1 -</td><td>&lt;Χ · "&lt;Q from</td><td>t_R = 1.46 min (condition 2, 98%) LRMS: Anal. Calc. for C43H43N9O6 781.33; found: 782.34 (M + H)⁺. HRMS: Anal. Calc. for C43H43N9O6</td>

274

<td></td><td>phenylethyl) carbamate methyl</td><td>Obtained from 152h-5 and Cap-4</td><td>782.3415 found: 782.3417 (M + H)⁺</td>

<td>Example 152j-23</td><td>((1R) -2 - (((1S) -1- (5- (6 (4- (2 - ((1S) -1 - (((2R) -2 ((methoxycarbonyl) amino) -2-phenylacetyl) amino) ethyl yl) -lH-imidazol-5-yl) phenyl) -3-pyridinyl) -lH-2-yl) ethyl) amino) -2-okso1fenyloetylo) carbamate methyl</td><td>AND, Obtained from 152h-6 and CapA</td><td>tR = 1.44 min condition 2, 90%) LRMS: Anal. Calc. for C41H41N9O6 755.32; found: 756.35 (M + H)⁺. HRMS: Anal. Calc. for C41H41N9O6 756.3258 found: 756.3239 (M + H)⁺.</td>

<td>Example 152j-24</td><td>(2R) -2- (dimethylamino) -N ((1S) -1- (5- (6- (4- (2 ((S) -l - (((2R) -2- (dimethylamino) -2fenyloacetylo) amino) ety lo) -1H-imidazol-5-yl) phenyl) -3-pyridinyl) -1Himidazol-2-yl) ethyl) -2-phenylacetamide</td><td>"Ά AND Obtained from 152h-6 and Cap 1</td><td>tR = 1.18 min (condition 2, 91%) LRMS: Anal. Calc. for C41H45N9O2 695.37; found: 696.37 (M + H)⁺. HRMS: Anal. Calc. for C41H45N9O2 696.3774 found: 696.3806 (M + H)⁺.</td>

<td>Example 152j-25</td><td></td><td>Obtained from 152i-3 and CapA</td><td>tR = 2.08 min (95.8%); Condition 1 LRMS: Anal. Calc. for C38H44N9O5 706.35; found: 706.53 (M + H)⁺. HRMS: Anal. Calc. for C38H44N9O5 706.3465; found: 706.3492 (M + H)⁺.</td>

275

<td>Example</td><td></td><td>AND</td><td>Άχ _s ° r AX</td><td>tR = 2.04 min (96.4%); Condition 1 LRMS: Anal. Obi. for C37H42N9O5 692.33; found</td>

<td>152J-26</td><td></td><td>Obtained from</td><td>1521-2 and CapA</td><td>: 692.49 (M + H)⁺. HRMS: Anal. Obi. for C37H42N9O5 692.3309; found: 692.3322 (M + H)⁺.</td>

<td></td><td></td><td></td><td></td><td>tR = 2.04 min (&gt; 95</td>

<td></td><td></td><td>CK *</td><td rowspan="2">Άχ- J Ax</td><td>%); Condition 1</td>

<td></td><td></td><td>⁰ ii</td><td>LRMS: Anal. Obi. for C39H44N9O5</td>

<td>Example 152J-27</td><td></td><td>Received</td><td>from 152i CapA</td><td>718.35; found: 718.49 (M + H)⁺. HRMS: Anal. Obi. for C39H44N9O5 718.3465; found: 718.3483 (M + H)⁺.</td>

<td></td><td>((R) -2 - ((2S) -2- (5- (5-</td><td rowspan="2">CWL _MHA AX</td><td></td><td>tR = 2.00 min</td>

<td></td><td>(4- (2 - ((1S) -1 - (((2R) -2 ((methoxycarbonyl) ami no) -2-</td><td>A. «JJ Ak. "</td><td>(&gt; 95%); Condition 1 LRMS: Anal. Obi.</td>

<td>Example</td><td>phenylacetyl) amino) ethyl) -1H-imidazol-5-</td><td>Obtained from</td><td>152h-14 and CapA</td><td>for C42H43N10O6 783.34 found:</td>

<td rowspan="2">152J-28</td><td>yl) phenyl) -2-</td><td></td><td></td><td>783.96 (M + H)⁺</td>

<td>pyrazinyl) -1H-</td><td></td><td></td><td>HRMS: Anal. Obi.</td>

<td></td><td>imidazol-2-yl) -l-</td><td></td><td></td><td>for C42H43N10O6</td>

<td></td><td>pyrrolidinyl) -2-oxo-1 -</td><td></td><td></td><td> 783.3367</td>

<td></td><td>phenylethyl) carbamate</td><td></td><td></td><td>found:</td>

<td></td><td>methyl</td><td></td><td></td><td>783.3375 (M + H)⁺</td>