TW201038558A - Hepatitis C virus inhibitors - Google Patents

Abstract

This disclosure concerns novel compounds of Formula (I) as defined in the specification and compositions comprising such novel compounds. These compounds are useful antiviral agents, especially in inhibiting the function of the NS5A protein encoded by Hepatitis C virus (HCV). Thus, the disclosure also concerns a method of treating HCV related diseases or conditions by use of these novel compounds or a composition comprising such novel compounds.

Description

201038558 VI. INSTRUCTIONS OF THE INVENTION: TECHNICAL FIELD OF THE INVENTION The present invention relates generally to antiviral compounds, and more particularly to compounds which inhibit the function of the NS5A protein encoded by hepatitis C virus (HCV), including Compositions of such compounds and methods of inhibiting the function of NS 5 A proteins. This application claims the benefit of U.S. Provisional Application No. 61/164,531, filed on March 30, 2009. [Prior Art] HCV is a major human pathogen that is estimated to affect 170 million people worldwide - about five times the number of human immunodeficiency virus type 1 infections. Most of these HCV-infected individuals develop severe progressive liver disease, including cirrhosis and hepatocellular carcinoma. Current HCV care standards using a combination of pegylated interferon and ribavirin have a poor success rate in achieving sustained viral responses and cause numerous side effects. Therefore, there is a clear and long-term need to develop effective therapies to address this unmet medical need. HCV is a positive-stranded RNA virus. HCV has been classified as an independent genus of the Flaviviridae family based on a comparison of inferred amino acid sequences and extensive similarity in the 5' untranslated region. All members of the Flaviviridae family have enveloped virions containing a positive strand of RNA encoding all known virus-specific proteins by translating a single, uninterrupted open reading frame. Due to the lack of corrective-reading ability of RNA, 146976.doc 201038558 RNA polymerase has a higher error rate, so significant heterogeneity is found in the nucleotides and encoded amino acid sequences of the entire HCV genome. Sex. At least six major genotypes have been characterized, and more than 50 subtypes have been described to be distributed worldwide. The clinical significance of HCV genetic heterogeneity has shown a tendency to mutate during monotherapy treatment, thus requiring other treatment options for use. The possible regulatory role of genotypes in pathogenic mechanisms and therapies remains elusive. The single-stranded HCV RNA genome is approximately 9500 nucleotides in length and has a single open ® reading frame (ORF) encoding a single large polymeric protein of approximately 3000 amino acids. In infected cells, this polymeric protein is cleaved by cellular proteases and viral proteases at multiple sites to produce structural proteins and non-structural (NS) proteins. In the case of HCV, the production of mature non-structural proteins (NS2, NS3, NS4A, NS4B, NS5A and NS5B) is achieved by two viral proteases. The first is believed to be a metalloproteinase and cleaves at the NS2-NS3 junction; the second is a serine protease (also referred to herein as NS3 protease) contained within the N-terminal region of NS3 and mediates NS3 All subsequent lysis in the downstream: cis cleavage at the NS3-NS4A cleavage site and trans cleavage at the remaining 〇NS4A-NS4B, NS4B-NS5A, NS5A-NS5B sites. The NS4A protein appears to perform multiple functions by acting as a cofactor for the NS3 protease and aiding NS3 and other viral replicase components for membrane localization. Formation of the NS3-NS4A complex is necessary to increase the proper protease activity of the proteolytic efficiency of the cleavage event. The NS3 protein also exhibits nucleoside triphosphatase and RNA helicase activities. NS5B (also referred to herein as HCV polymerase) is an RNA-dependent RNA polymerase involved in the replication of HCV by other HCV proteins (including NS5A) in the replicase complex. 146976.doc 201038558 Requires a compound suitable for the treatment of HCV-infected patients that selectively inhibits HCV viral replication. In particular, compounds that effectively inhibit the function of the NS5A protein are required. The HCV NS5 A protein is described, for example, in the following references: SL Tan et al, Wro/o Magic;, 284: 1-12 (2001); K. -J. Park et al., 5 ί·ο/· CTzem., 30711 -30718 (2003); TL

Tellinghuisen et al, iVaiwre, 435, 374 (2005); R. A. Love et al, J. Virol, 83, 4395 (2009); N. Appel et al, J. Biol. Chem., 281, 9833 (2006) L. Huang, J. Biol. Chem., 280, 36417 (2005); C. Rice et al., WO2006093867 ° [Summary of the Invention] The present invention provides a compound which selectively inhibits HCV virus replication, which is characterized by I):

Or a pharmaceutically acceptable salt thereof, wherein: L is selected from the group consisting of -〇-, -CH2CH2-, -CH=CH-, -C=C-, -OCH2-,

X is hydrogen (H) or halogen and Z is hydrogen; or 146976.doc -6 - 201038558 X and Z together with the carbon atom to which they are attached form, as the case may be, 1 or 2 of which are selected from nitrogen, oxygen and sulfur. A 5 to 8 membered aromatic or non-aromatic mooring of an atom, wherein the 5 to 8 member is optionally substituted by hydrazine, 2 or 3 substituents independently selected from the group consisting of: alkoxy, alkoxyalkyl group Oxygen group, alkyl, alkyl aryl, aryl & arylalkyl, fluorenyl, thiol, aryl, dentate, aldentyloxy, dentate, hydroxy, Hydroxyalkyl, _Rb, (NRaRb), *(NRaRbm*, pendant oxy-) and spiro; X' is hydrogen (H) or halogen and Z is hydrogen; or X and Z are attached thereto The carbon atoms together form from 5 to 8 shells of aromatic or non-aromatic condensate, optionally containing from 1 or 2 heteroatoms selected from nitrogen, oxygen and sulfur, wherein the 5 to 8 members are cyclically enthalpy, 2 or 3 substituents independently selected from the group consisting of: an alkoxy group, an alkoxy group, an alkoxy group, an alkyl group, a aryl group, an aryl group, an arylalkyl group, an arylsulfonyl group, Carboxyl, methylidene-based, self-hospital oxygen , haloalkyl, thiol, phenyl-based, ❹-NRaRb, (NRaRb)alkyl, (NRaRb)carbonyl, pendant oxy and spiro; ¥ and ¥' are each independently -ch2-, -CH2CH2- or - Ch2〇_, wherein the -CH2〇_ is depicted by combining an oxygen atom with a carbon atom substituted by Rv and Rq or RvjRq;

Rp is hydrogen or an alkyl group;

Rq is hydrogen, alkyl or halo; or ... and Rq together with the carbon atom to which it is attached form a cycloalkyl ring;

Rv is selected from the group consisting of hydrogen, alkyl, halo and hydroxy; or

Rv& Rq forms a vinyl or cycloalkyl group with the carbon atom to which it is attached 146976.doc 201038558 Ring; RP is hydrogen or Ciic* alkyl;

Rq' is hydrogen, alkyl or halo; or

Rp and Rq' together with the carbon atom to which they are attached form a cycloalkyl ring;

Rv is independently selected from the group consisting of hydrogen, alkyl, halo and hydroxy; or R and R together with the carbon atom to which they are attached form an ethylene or cycloalkyl ring; R and Rw are independently selected from hydrogen and alkyl; R1 is hydrogen or -C(0)Rx; R2 is hydrogen or -C(0)Ry;

Rx and Ry are independently selected from cycloalkyl, heteroaryl, heterocyclyl, alkoxy and alkyl, the alkyl being substituted by one or more substituents independently selected from aryl, alkenyl a cycloalkyl group, a heterocyclic group, a heteroaryl group, _〇r3, _c(〇)〇r4, -NRaRb, and -C(〇)NRcRd, wherein any of the aryl and heteroaryl groups may be subjected to one or more Substituents independently selected from the group consisting of alkenyl, alkyl, decyl, arylalkyl, heterocyclyl, heterocyclylalkyl, cyclane, cyano, nitro, _c(〇)〇R4 , -OR, -NRR, (NRaRb)alkyl and (Me〇)(H〇)p(〇)〇 and any of the cycloalkyl and heterocyclic groups may be fused to the aromatic ring as appropriate, and may optionally be Substituted by one or more substituents independently selected from the group consisting of alkyl, thiol, i, aryl, ruthenium Rb, pendant oxyl (〇) 〇r4; R is fluorene, alkyl or aryl R4 is alkyl or arylalkyl; R is hydrazine, alkyl or arylalkyl; 146976.doc 201038558

Ra and Rb are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, arylalkyl, heteroaryl, -C(0)R6, _c(〇)〇R7, -C(0)NRCRd and (NRCRd) An alkyl group, or, Ra and Rb, together with the nitrogen atom to which they are attached, form a 5 or 6 membered ring or bridged bicyclic structure wherein the 5 or 6 membered ring or bridged bicyclic structure optionally contains 1 or 2 independently selected from Other heteroatoms of nitrogen, oxygen and sulfur, and may contain 1, 2 or 3 substituents independently selected from the group consisting of: ^ to ^ alkyl, ^ to C4 haloalkyl, aryl, hydroxy, (^ to ^ Alkoxy, hydrazine alkoxy and halogen; R is a hospital group; R7 is alkyl, arylalkyl, cycloalkyl or haloalkyl;

Re and ... are independently selected from the group consisting of hydrogen, alkyl, arylalkyl and cycloalkyl. In a first embodiment of the first aspect, the present invention provides a compound of formula (1) further characterized by the formula (1 illusion: °

Or a pharmaceutically acceptable salt or tautomer thereof, wherein X is hydrogen or gas (ci) and z is hydrogen; or the aromatic or non-aromatic thick X and Z together with the carbon atom to which they are attached form 6 members Ring; X1 is hydrogen or gas (ci) and z, is hydrogen; or non-aromatic χι and Z' with the carbon atom to which they are attached form a 6-membered aromatic or 146976.doc 201038558 fused ring; Y is -CH2- , -CH2CH2- or -CH2〇-, wherein the _ch2〇- is depicted by combining an oxygen atom with a carbon atom substituted by R and Rq;

Rp is hydrogen or (^ to (: 4 alkyl);

Rq is hydrogen, alkyl or halo; or

Rp and Rq together with the carbon atom to which they are attached form a cycloalkyl ring; and RV is selected from the group consisting of hydrogen 'alkyl, dentate and hydroxy; or R and Rq together with the carbon atom to which they are attached form a vinyl or cycloalkyl ring . In a second embodiment of the first aspect, the invention provides a compound of formula (1) further characterized by formula (Ib):

Or a pharmaceutically acceptable salt or tautomer thereof. In the first aspect: r f gentleman H, the present invention provides a compound of the formula (1) further characterized by the formula (Ic):

Or a pharmaceutically acceptable salt or tautomer thereof 146976.doc 201038558 The present invention provides a compound of formula (1) in a fourth embodiment of the first aspect, further characterized by formula (Id)

(Id), -N \\

Or a pharmaceutically acceptable salt or i-isomer thereof.

In a fifth embodiment of the first aspect, the present invention provides a compound of the formula (Ia) or a pharmaceutically acceptable salt thereof, wherein R1 is -C(0)Rx; R2 is -C(0) Ry; π and independently substituted by at least one _NRaRb, characterized by formula (A):

(A), wherein: m is 0 or 1; R8 is hydrogen or an alkyl group; and R9 is selected from the group consisting of hydrogen, a cycloalkyl group, an aryl group, a (tetra) group, a heterocyclic group, and an alkyl group, and the alkyl group is optionally obtained from the following Substituted silk: aryl, dilute, cycloalkyl, heterocyclyl, heteroaryl, heterobicyclo, _〇r3, _c(〇)〇r4, -NRaRbA-C(0)NRcRd,

146976.doc • 1U 201038558 Any of the aryl and heteroaryl groups may be optionally substituted with one or more substituents independently selected from the group consisting of alkyl, dentyl, arylalkyl, heterocyclyl, heterocycle Alkyl group, i element, cyano group, nitro group, _C(0)0R4, _〇r5, _NRaRb, (NRaRb) alkyl group and (Me〇)(H〇)p(〇)〇_, and any of them The cycloalkyl and heterocyclic groups may be fused to the aromatic ring as appropriate, and may be optionally substituted with one or more substituents independently selected from the group consisting of alkyl, hydroxyl, hydroxyl, aryl, -NRaRb, side oxygen. And _c(〇)〇R4; and R, R4, R5, Ra, Rb, m Rd are as defined in the formula (1). In a sixth embodiment of the first aspect, the invention provides a compound of formula (Ia) or a pharmaceutically acceptable salt thereof, wherein: m is hydrazine; r8 is hydrogen or (^ to (: 4 alkyl; R9 is selected from the group consisting of hydrogen, and optionally substituted Cil C6 alkyl: 0R, C3 to c6 cycloalkyl, allyl, _CH2C(0)NRcRd,

Wherein j is 0 or 1; 146976.doc •12-201038558 k is 1 '2 or 3; η is 0 or an integer selected from 1 to 4; each R10 is independently hydrogen, Q to C4 alkyl, Ci to C4 Haloalkyl, halogen, nitro, -OBn or (MeO)(OH)P(0)0-; R" is hydrogen, (^ to (:4 alkyl or phenylhydrazine; R12 is hydrogen, (^ to (: 4 alkyl or benzyl;

Ra is hydrogen or (: 彳 to ^ alkyl; ... is ^ to decyl, a to C6 cycloalkyl, benzyl, 3-pyridyl 'pyrimidin-5-yl, ethyl thiol, _c (〇) 〇R7 4_c(〇)NRCRd ; R is (^ to 匸4 alkyl or (^ to 匸4 halogen);

Re is hydrogen or (: 〖to <: 4 alkyl; and

Rd is hydrogen, (^ to (: 4 alkyl or c3 to (: 6 cycloalkyl). In a seventh embodiment of the first aspect, the invention provides a compound of formula (Ia) or a pharmaceutically acceptable thereof a salt thereof, wherein: m is 0; R8 is hydrogen; R is a stupid group, optionally substituted with 5 substituents independently selected from the group consisting of: 6 to 6 alkyl, CjC4 haloalkyl, halo And a decyloxy group, a hydroxy group, a cyano group, and a nitro group; and the NRaRb is a heterofluorenyl group or a heterobicyclo group (.sup.-)-(N)/?(R13)n? . -Ν N-R14 146976.doc •13- 201038558

Wherein η is 〇, 1 or 2; each R13 is independently selected from (^ to (6 alkyl, phenyl, trifluoromethyl, halogen, thio, methoxy and pendant); and R is C ^C: 6 alkyl, phenyl, benzoinyl or _c(〇)〇Ri5 group, wherein R15 is <: 丨 to (: 4 alkyl, phenyl or benzyl. In the first aspect In the eighth embodiment, the invention provides a compound of the formula (Ia) or a pharmaceutically acceptable salt thereof, wherein: m is 1; R8 is hydrogen; R9 is a C1 to C6 alkyl group, an arylalkyl group or a hetero Arylalkyl; Ra is hydrogen;

Rl^_C(0)0R7, where ... is ^ to decyl. In the ninth embodiment of the first aspect, the present invention provides a compound or a pharmaceutically acceptable salt thereof, wherein: R1 is -C(0)Rx; and R2 is -c( o) Ry;

Rm is independently selected from the group consisting of the following (tetra) or heterocyclic groups

(R13)n

146976.doc •14· 201038558

Wherein η is 〇 or an integer selected from 1 to 4; each R13 is independently selected from the group consisting of hydrogen, (^ to decyl, (^ to ^ haloalkyl, stupid, stupid methyl, (^ to (: 6) Alkoxy, <^ to (: 4 halogen-oxyl, heterocyclic, i-, NReRd, hydroxy, cyano and pendant oxy, wherein Rc and Rd are independently hydrogen or (^ to (:4) And R14 is hydrogen (H), (^ to decyl, methyl or -C(0)0R4, wherein R4 Ο is (^ to (6 alkyl). In the tenth embodiment of the first aspect In one embodiment, the present invention provides a compound of the formula (Ia) or a pharmaceutically acceptable salt thereof, wherein: R1 is -c(o)rx; R2 is -c(o)Ry; and R and Ry are independently selected from The following cycloalkyl groups:

146976.doc 15- 201038558 wherein j is 0, 1, 2 or 3; k is Ο, 1 or 2; η is 0 or an integer selected from 1 to 4; each R13 is independently selected from hydrogen, toxin. Alkyl, (^ to haloalkyl, (^ to (: 6 alkoxy, halogen, hydroxy, cyano and nitro;

Ra&Rb is each independently hydrogen, C丨 to C6 alkyl or -C(0)0R7, wherein R7 is C1 to C6 alkyl. In a third embodiment of the first aspect, the invention provides a compound of formula (ia) or a pharmaceutically acceptable salt thereof, wherein: R1 is -C(0)Rx; R2 is -C(0)Ry 1^ and 1^ independently, the arylalkyl group may be optionally substituted with (NRaRb)alkyl;

Ra&Rb is independently hydrogen, ClSC0 alkyl or benzyl, or

Rb, together with the nitrogen atom to which it is attached, forms a 5 or 6 membered ring selected from the group consisting of fN〇+N"yR15 +Ν〇0: C6 alkyl or phenylhydrazine. In a twelfth embodiment of the first aspect, The present invention provides a compound or a pharmaceutically acceptable salt thereof, wherein: R is the same as R2 and is selected from the group consisting of: wherein R is 5 is hydrogen, Ci is of the formula (: 146976.doc 201038558)

The waveform key (1) in the structure indicates that the stereo symmetric center to which the key is connected can adopt the (R) or (S) configuration as long as the chemical bonding principle is not violated. In a thirteenth embodiment of the first aspect, the invention provides a compound of the formula (1) or a pharmaceutically acceptable salt thereof, wherein: R1 is -c(o)rx; R2 is -c(o)Ry And «^ and! ^ are all third butoxy groups. In a fourteenth embodiment of the first aspect, the present invention provides a compound of the formula (1) or a pharmaceutically acceptable salt thereof, wherein: 146976.doc • 17· 201038558 Both R1 and R2 are hydrogen. In a second aspect, the invention provides a compound of formula (π):

Rq,

(II), or a pharmaceutically acceptable salt thereof, wherein: L is selected from the group consisting of -〇_, _CH2CH2_-C=C--och2-'-CH=CH--ch2o- > -CH2OCH2-

X and Χ· are independently hydrogen (H) or halogen; R is hydrogen or (^ to (: 4 alkyl, and γ is hydrogen, or RP and R (J together with the carbon atom to which they are attached form a cyclopropyl group) Ring; R is hydrogen or (:! to (: 4 yards, and γ is hydrogen, or, RP, and Rql together with the carbon atom to which they are attached form a cyclopropyl ring; R1 is hydrogen or -C(0)Rx R2 is hydrogen or -C(0)Ry; αν is independently selected from cycloalkyl, heteroaryl, heterocyclyl, alkoxy and alkane = 'the alkyl group is independently selected from one or more of the following Substituents: aryl, alkenyl, cycloalkyl, heterocyclyl, heteroaryl, -(10), -C(0)0R4, wherein any of the following aryl and heteroaryl groups may be replaced by Substituent: alkyl, south alkyl, or a plurality of independently selected arylalkyl, heterocyclic 146976.doc -18· 201038558, heterocyclylalkyl, i, cyano, nitro, _C (0 0R4, -OR5, -NRaRb, (NRaRb)alkyl and (MeO)(HO)P(〇)〇-, and any of the cyclo and heterocyclic groups may be fused to the aromatic ring as appropriate, and The situation is substituted by one or more substituents independently selected from the group consisting of alkyl and hydroxy , halogen, aryl, -NRaRb, pendant oxy and _C(0)0R4; R3 is hydrogen, alkyl or arylalkyl; R4 is alkyl or arylalkyl; R5 is hydrogen, alkyl or aryl Base base

Ra and Rb are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, arylalkyl, heteroaryl, -C(0)R6, -C(〇)〇R7, alkyl, or Ra and Rb The attached nitrogen atoms together form a 5 or 6 membered ring or bridged bicyclic structure wherein the 5 or 6 membered ring or bridged bicyclic structure optionally contains 1 or 2 other heteroatoms independently selected from nitrogen, oxygen and sulfur. And may contain 1, 2 or 3 substituents independently selected from the following: ^ to ^ alkyl, ^ to Q-alkyl, aryl, hydroxy, C^C6 alkoxy, c^C4i| Oxyl and halogen; R is alkyl; R7 is alkyl, arylalkyl or haloalkyl; and ... are independently selected from the group consisting of hydrogen, alkyl, arylalkyl and cycloalkyl. In a first sample, the invention provides a composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, wherein '(I) is according to the above Any of the embodiments described in the first aspect of the invention are defined. In a first embodiment of the third aspect, the composition further comprises at least one of 146976.doc -19-201038558 other compounds having anti-HCV activity. In a second embodiment of the third aspect, at least one other compound is an interferon or a virus 3 sitting. In a third embodiment of the third aspect, the interferon is selected from the group consisting of interferon alpha 2, pegylated interferon alpha, consensus interferon, interferon alpha 2, and lymphoblastiod interferon tau. In a fourth embodiment of the third aspect, the present invention provides a pharmaceutically acceptable carrier comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, and at least one other compound having anti-HCV activity The composition, wherein at least one other compound is selected from the group consisting of interleukin 2, interleukin 6, interleukin 2, a compound which enhances the type 1 helper cell reaction, interferes with RN A, antisense RNA, miso Imiqimod, viral spit, myoblast 5'-monoacid dehydrogenase inhibitor, amantadine and rimantadine. In a fifth embodiment of the third aspect, the invention provides a compound comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable carrier, and at least one other compound having anti-HCV activity A composition wherein at least one other compound is effective to inhibit a function selected from the group consisting of HCV metalloproteinase, HCV serine protease, HCV polymerase, HCV helicase, HCV NS4B protein, HCV entry, HCV assembly, HCV outlet, HCV NS5A protein and IMPDH. In a fourth aspect, the invention provides a method of treating a 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, wherein formula (I) It is defined in accordance with any of the embodiments described above in the first aspect of the invention 146976.doc -20-201038558. In a first embodiment of the fourth aspect, the method further comprises administering at least one other compound having anti-HCV activity before, after or simultaneously with administration of the compound of formula (1) or a pharmaceutically acceptable salt thereof. In a second embodiment of the fourth aspect, at least one other compound is an interferon or a viral sigma. In a third embodiment of the fourth aspect, the interferon is selected from the group consisting of interferon alpha 2 Β, pegylated interferon alpha, consensus interferon, interferon alpha 2 guanidine, and steroid-like lymphoblast interferon tau. In a fourth embodiment of the fourth aspect, the invention provides a method of treating a 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, And administering at least one other compound having anti-HCV activity before, after or simultaneously with the compound of formula (1) or a pharmaceutically acceptable salt thereof, wherein at least one other compound is selected from the group consisting of interleukin 2 and interleukin 6, interleukin 12, enhanced sputum-type helper τ cells ◎ reaction-induced compounds, interfering RNA, antisense RNA, imiquimod, disease carbazole, inosine 5'-monophosphate dehydrogenase inhibitor, tricyclic Indoleamine and rimantadine. In a fifth embodiment of the fourth aspect, the invention provides a method of treating a HCV infection in a patient comprising administering to the patient a therapeutically effective amount of a compound of formula (1) or a pharmaceutically acceptable salt thereof, and Administration of at least one other compound having anti-HCV activity before, after or simultaneously with a compound of formula (1) or a drug thereof, and at least one other compound in & effective inhibition of a county for treating HCV infection Function, the standard is selected from 146976.doc -21- 201038558 HCV metalloproteinase, HCV serine protease, HCV polymerase, HCV helicase, HCV NS4B protein, HCV inlet, HCV assembly, HCV outlet, HCV NS5A Protein and IMPDH. The compounds of the invention are effective in inhibiting the function of the HCV NS5A protein. In particular, the compounds of the invention are effective in inhibiting the HCV lb genotype or multiple HCV genotypes. Accordingly, the present invention also encompasses: (1) a composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier; and (2) a method of treating HCV infection in a patient, It comprises administering to the patient a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. Other aspects of the invention may include suitable combinations of the embodiments disclosed herein. Other aspects and examples can be found in the description provided herein. The description of the invention herein is to be understood as being consistent with the laws and principles of chemical bonding. In some cases, it may be necessary to remove any hydrogen atom at a given location to accommodate the substituent. Some of the features of the structure of formula (I) are further explained below:

146976.doc -22- 201038558 In the above formula (i), for example, (1) the tautomeric form of the imidazole ring, (2) the absolute configuration of the stereosymmetric center on the oxaridinyl ring, and (3). The ratio of the "Bilobital-imidazole" moiety on the left side of the "bonding group" to the substituent on the right side of the bonding group is more than the substituent on the nitrogen of each of the 11. The pyridyl-imidazole moiety is irrelevant, i.e., R and R are independent of each other' although in some cases, they are preferably the same. It should be understood that the description of the pyrrolidine moiety on the "left" side or the "right" side is for illustrative purposes only and does not limit the scope of the invention in any way. In the linkage of formula (I), the linkage between "L" and the two benzene rings covers all of the following combinations:

Wherein the "p-pair", "p-inter" and "inter-inter" linkages are preferred), which can be similarly in the formula (I), when L is a phenyl group (〇 〇 the following two Adjacent benzene ring linkage.

146976.doc -23· 201038558 Among them, "right" and "inter" are better arranged, and "right" is better arranged. In the formula (1), when L is a vinyl group CH=CH_), it may adopt a trans or cis configuration as follows:

1~ (cis), h

(trans) In the formula (I), when L is a stretching propyl group (which may be trans or cis to each other, the following four configurations are formed)

(R-) (S-)), when two phenyl substituents "the propyl ring is fused to the haha bite group, that is, when (RP, Rq) - is H: ... relative to the group The scale bite ring can be in the α_4β_mesh cyclopropyl hydrazine as described below: 146976.doc -24- 201038558

(β-), κ-

Thus, the invention is intended to cover all possible stereoisomers, even when a single stereoisomer is described in the structure or stereochemistry is not described. The linkage between the benzene ring of the 'bonding group' and the imidazole ring of the D-pyridyl-imidazole moiety in the formula (I) may be at the C_4 or c-5 position of the imidazole ring (see below). As the general practitioner should understand, due to the tautomerism of the imidazole ring, the bond between the benzene ring and the 〇 c_4 position can be equivalent to the bond between the benzene ring and the C-5 position, as shown in the following formula.

This representative principle also applies to the substituent X or X. Accordingly, the present invention is intended to cover all possible tautomers, even when the structure describes only one of them. In the present invention, a structural floating bond (e.g., H-) or a floating substituent (e.g., -R13) means that the bond or substituent can be attached to the available location of the structure by removing hydrogen from any available location. It will be appreciated that in a bicyclic or polycyclic structure, the position of the H floating bond or floating substituent will not be limited to a particular ring unless otherwise explicitly stated. Therefore, the following two substituents should be considered equivalent:

146976.doc -25- 201038558 It is to be understood that the compounds encompassed by the present invention are compounds which are suitable for stable use as pharmaceutical agents. It is contemplated that the definition of any substituent or code at a particular position in a molecule is independent of its definition elsewhere in the molecule. For example, for the substituent (R1G)n', when η is 2, each of the two Ri〇 groups may be the same or different. All patents, patent applications and references cited in this specification are hereby incorporated by reference in their entirety. In case of inconsistency, the present specification (including definitions) will prevail. Definitions The above has been long: the definition of each group that is derogatory. In addition, the following definitions will be used. As used herein, the singular forms """ Unless otherwise specified, all aryl, cycloalkyl, heteroaryl and heterocyclic groups of the invention may be substituted as described for each of their respective definitions. For example, the aryl moiety of the 'arylalkyl group can be substituted as defined in the definition of the term "aryl". The term "ethinyl" as used herein refers to _C(〇)CH3. The term "alkenyl" as used herein refers to a monovalent, straight or branched hydrocarbon chain having one or more, preferably i to two, double bonds. The double bond of the alkenyl group may be unconjugated or co-linked with the other unsaturated group. Suitable alkenyl groups include, but are not limited to. 2 to. . Alkenyl group, such as vinyl, allyl, butenyl, pentenyl, hexenyl, butadienyl, pentadienyl, hexadienyl, 2 ethylhexene 146976.doc -26 - 201038558 olefin Base, 2-propyl-2-butenyl, 4-(2-indolyl-3-butenyl)-pentenyl. The alkenyl group may be unsubstituted or substituted with 1 or 2 suitable substituents. The term "alkoxy" as used herein refers to an alkyl group attached to the parent molecular moiety through an oxygen atom. Representative examples of alkoxy include, but are not limited to, methoxy (CH3 〇-), ethoxy (CH3CH2 〇-), and third butoxy ((CH3)3C〇_). The term "alkylalkylalkyl" as used herein refers to an alkyl group substituted with i, 2 or 3 alkoxy groups.

The term "alkoxycarbonyl" as used herein means that an alkoxy group is attached to the parent molecular moiety via a carbonyl group. As used herein, reference is made to a group derived from a linear or branched chain saturated hydrocarbon by the removal of hydrogen from a saturated carbon. The alkyl group preferably has from 1 to 10 carbon atoms. Representative examples of alkyl include, but are not limited to, mercapto, ethyl, isopropyl, and tert-butyl. The term "alkylene" as used herein, refers to a moiety attached to a parent molecular moiety through a plurality of groups. Representative examples of alkylcarbonyl include, but are not limited to, 'ethylcyano (-c(o)ch3), propyl (-c(〇)CH, broad rt2LH3), n-butyl fluorenyl (-C(0)CH2CH2CH3 And 2,2-dimethyl- &#β-mercaptopropyl or tert-amyl (-c(o)c(ch3)3). The term "alkylsulfonyl, private A*I" as used herein, refers to an alkyl group attached to the parent molecular moiety via a sulfonyl group. The term "dilute propyl" as used herein refers to an even CH=CH2 group. The term "aryl" as used herein refers to a group derived from an aromatic carbocyclic ring by the removal of a hydrogen atom from the aromatic ring. Aryl can be & „J horse early, bicyclic or polycyclic aryl, wherein in bicyclic or polycyclic aryl, the aromatic rabbit can be slightly combined to another 4 146976.doc -27- 201038558 to 6 Representative aromatic or non-aromatic carbocyclic rings. Representative examples of aryl groups include, but are not limited to, the present group, indanyl, indole I, naphthyl, and 1,2,3,4-tetrahydronaphthalen-5-yl The term "aryl aryl" as used herein means that the aryl group is substituted with 1, 2 or 3 aryl groups, wherein the aryl moiety of the arylalkyl group may optionally be substituted to 5 independently selected from T. Base substitution: alkyl, C丨 to C4_alkyl, Cl to C6 alkoxy, _, cyano and nitro. Representative examples of arylalkyl groups include, but are not limited to, benzyl, 2-phenylethylethyl (10)-), (naphthalen-1-yl)fluorenyl, and (naphthalene-2-yl)methyl . The term "arylarylsulfonyl" as used herein, refers to an aryl group attached to the parent molecular moiety through a sulfonyl group. The term "phenylhydrazine" as used herein means that one hydrogen atom on the methyl group is replaced by a phenyl group, wherein the phenyl group may be optionally substituted with from 1 to 5 substituents independently selected from the group consisting of methyl, trifluoro Mercapto (_CF3), methoxy (_〇CH3), i- and nitro (-N〇2). Representative examples of phenylhydrazine include, but are not limited to, 卩11(:112-, 4-1^0-(:6114(:112- and 2,4,6-trimethyl-(:汨4(:) 112-. The term "bridged double-ring" as used herein refers to a ring structure comprising a bridgehead between two ring members' wherein the ring and the bridge head may independently comprise one or more, preferably one to two, independently A hetero atom selected from the group consisting of nitrogen, oxygen, and sulfur. Illustrative examples of bridged bicyclic structures include, but are not limited to,

I νΛΛΛ/ Ν

146976.doc -28· 201038558 The term "cap/cap" as used in the formula (I) refers to a group which is placed on the nitrogen atom of pyridinium and hydrazine in the compound of the formula (I). It should be understood that "cap" may also refer to a precursor that is the precursor of the final "cap" of the compound and is flanked on the pyrrole - the reagent used as the starting material in the reaction to produce the final product. That is, it contains a compound which will be functionalized in the compound of the formula (1). Alkidine The term "carbonyl" as used herein means -C(O)-. The term "carboxy" as used herein refers to _c〇2h. The term "cyano" as used herein refers to -CN. The term "cycloalkyl" as used herein refers to a group derived from a saturated carbocyclic ring preferably having from 3 to 8 carbon atoms by removal of a hydrogen atom from a saturated carbocyclic ring, wherein the saturated carbocyclic ring may be as thick as possible. Combined with one or two other aromatic ^ non-aromatic carbocyclic rings. Representative examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclopentyl, cyclohexyl and 1,2,3,4-tetrahydronaphthyl. The term "methyl thiol" as used herein refers to _CH 〇. The terms "dentate base" and "pinger" as used herein mean F, cl, Br or I. The term "decyloxy" as used herein refers to a link of a neokyl group to a parent molecular moiety. Atom The term "dentate radical" as used herein refers to a radical substituted with at least one dentate atom. The self-burning group may be a group in which all hydrogen atoms are substituted by (iv). Representative examples of dentate alkyl include, but are not limited to, trifluoromethyl (Ch-), hydrazine-chloroethyl (C1CH2CH2-), and 2,2,2-trifluoroethyl (cf3ch2_). As used herein, the term "heteroaryl" is used to remove hydrogen from aryl ring 146976.doc -29- 201038558 by a single ring, double ring or multiple ring containing at least one aromatic ring. The group obtained by the compound 'The at least one aromatic ring contains one or more, preferably i to 3, heteroatoms independently selected from nitrogen, oxygen and sulfur. As is well known to those skilled in the art, the heteroaryl ring has fewer aromatic characteristics than its all carbon counterpart. Thus, for the purposes of the present invention, a heteroaryl group only needs to have a certain degree of aromatic character. Illustrative examples of heteroaryl groups include, but are not limited to, pyridinyl, pyridazinyl, pyrimidyl, pyrazyl, triazinyl, pyrrolylpurinyl, imidazolyl, (1,2) , 3)-triazolyl and (1,2,4)-triazolyl, pyrazinyl, pyrimidinyl, tetrazolyl, furyl, bisphenyl, isoxazolyl, thiazole The group, the isoxazolyl group, the oxazolyl group, the fluorenyl group, the quinolyl group, the isoquinolyl group, the benzisoxazole group, the benzothiazolyl group, the benzothiophene group, and the β ratio β are each combined. Than the base. The term "heteroarylalkyl" as used herein refers to an alkyl group substituted with deuterium, 2 or 3 heteroaryl groups. The term "heterobicyclo" as used herein refers to a ring structure comprising two fused rings or bridges, the rings comprising carbon and one or more, preferably from 3 to 3 independently selected from nitrogen, oxygen and A hetero atom of sulfur. The heterobicyclic structure is a subgroup of heterocycles and can be saturated or unsaturated. Examples of heterobicyclic structures include, but are not limited to, tr〇pane, acridine and 7-azabicyclo[22]heptane. The term "heterocyclyl" as used herein, refers to a radical derived from a monocyclic, bicyclic or polycyclic compound comprising at least one non-aromatic ring by removal of a hydrogen atom from a non-aromatic ring, the at least one non-aromatic ring Containing one or more, preferably up to, heteroatoms independently selected from the group consisting of nitrogen, oxygen and sulfur. Heterocyclyl groups encompass heterobicyclic groups. The heterocyclic group of the present invention may be bonded to the parent moiety 146976.doc -30- 201038558 via a carbon atom or a nitrogen atom of the group. Examples of heterocyclic groups include, but are not limited to, phosphatyl, hydrazine, hydrazine, ketone, _-, tetrahydro (tetra), thio- cylinyl, and propyl. The term "heterocyclylalkyl" as used herein refers to alkyl radicals! , 2 or 3 heterocyclic groups are substituted. The term "hydroxy" as used herein refers to -OH. The term "hydroxyalkyl" as used herein means that the alkyl group is substituted with 1, 2 or 3 hydroxyl groups. The term "nitro" as used herein refers to _N〇2. * The term "-NRaRb" as used herein means that two groups Ra&Rb are attached to the parent molecular moiety via a nitrogen atom or that the gas atom to which they are attached together form, as appropriate, 丨, 2 or 3 independently selected A 5 or 6 membered ring or fused or bridged bicyclic structure from other heteroatoms of nitrogen, oxygen and sulfur. The term "-NRcRd" is defined similarly. The term "(NRaRb)alkyl" as used herein refers to an alkyl group substituted with 1> 2 or 3 -NR R groups. The term "(NRCRd)alkyl" is defined similarly. The term "lateral oxy" as used herein refers to 〇. The term "determining thiol" as used herein means _s 〇 2 _ as used herein, the term "trialkylsulfanyl" refers to -siR3, wherein each R is (: 丨 to 匚 4 alkyl or phenyl. The three R groups may be the same or different. Representative examples of "trialkylsulfanyl" include, but are not limited to, trimethyldecylalkyl (TMS), tert-butyldiphenyldecyl (TBDps), Tributyl dimethyl fluorenyl (TBS or TBDMS) and triisopropyl decyl (TIps). Asymmetric centers exist in the compounds of the invention. Substituents for 146976.doc • 31 - 201038558 around the palmar carbon atom. Depending on the configuration, these centers are designated by the symbols "R" or "S." It is to be understood that the invention encompasses all stereochemically isomeric forms having the ability to inhibit (iv) eight or mixtures thereof. Individual stereoisomers of the compounds Prepared synthetically from a commercially available starting material containing a palmitic center or by preparing a mixture of enantiomeric products, followed by separation, such as conversion to a mixture of diastereomers, followed by separation or Recrystallization, chromatography, or in the palm chromatography The enantiomers are isolated by direct separation on a column. Starting compounds having specific stereochemistry are commercially available or can be prepared and resolved by techniques known in the art. Certain compounds of the invention may also be separated into different stable structures. Formal forms exist. Torsional asymmetry due to limitations in the rotation of asymmetric single bonds (eg, due to steric hindrance or ring stress) may allow for the separation of different conformers. The present invention encompasses the various conformational isoforms of such compounds. And mixtures thereof. The term "compounds of the invention" and equivalent expressions are intended to encompass the compounds of formula (1) and their pharmaceutically acceptable enantiomers, diastereomers and salts. Similarly, 'where context permits 'The intermediate is intended to cover its salt. The invention is intended to include all isotopes of the atoms present in the compounds of the invention. Isotopes include the same number of atoms but different numbers of atoms. As a general example and not limiting, hydrogen Isotopes include helium and gas. Carbon isotope = C and " C. Isotopically labeled compounds of the invention are generally known to those skilled in the art.习知姑你: 4, 丄Λ < ^ know the technology or by a method similar to the one described here to make (d) the isotope-labeled test sword instead of the other unlabeled reagents used. These compounds can have a variety of Potential uses, for example as standards and reagents in the determination of biological activity. In the case of stable isotopes 146976.doc -32 - 201038558 'These compounds may have the potential to advantageously improve biological, pharmacological or pharmacokinetic properties. The compound of the present invention may exist in the form of a pharmaceutically acceptable salt. The term "pharmaceutically acceptable salt" as used herein means a salt or zwitterion of a compound of the present invention which is soluble or dispersible in water or oil. Form, which is suitable for use with the patient group in a reasonable medical rhyme, without hypertoxicity, i.e., irritation, allergic reaction or other problems or complications, matching the reasonable benefit/risk ratio and Effective for its intended use. The salt can be prepared during the final isolation and purification of the compound or independently by reacting a suitable nitrogen atom with a suitable acid. Representative acid addition salts include acetates, adipates, alginates, citrates, aspartates, benzoates, besylate, hydrogen sulfate, butyrate, campholes , camphor sulfonate, digluconate, glycerol phosphate, hemisulfate, heptanoate, hexanoate, formate, fumarate, hydrochloride, hydrobromide, hydrogen iodine Acid salt, 2-hydroxyethane sulfonate, lactate, maleate, mesitylene sulfonate, decane sulfonate, naphthalene sulfonate, nicotinic acid salt, 2-naphthalene sulfonic acid Salt, oxalate, pamoate, pectate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, Dilactate, bis-acetate, sulphate, sulphate, bicarbonate, p-sulfonate and undecanoate. Examples of acids which can be used to form pharmaceutically acceptable addition salts include inorganic acids such as hydrochloric acid, chloroform acid, sulfuric acid and phosphoric acid; and organic acids such as oxalic acid 'succinic acid, succinic acid and citric acid . The base addition salt can be used to make the treason and 146976.doc -33· 201038558 suitable for testing (such as metal cation hydroxide, carbonate or bicarbonate) or with ammonia or organic first stage during the final separation and purification of the compound. It is prepared by reacting an amine, a secondary amine or a tertiary amine. The cations of the pharmaceutically acceptable salts include lithium, sodium, potassium, calcium, magnesium and aluminum; and non-toxic quaternary amine cations such as ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, Triethylamine, diethylamine, ethylamine, tributylamine, ° ratio, N,N-didecylaniline, N-mercaptopiperidine, N-methylmorpholine, dicyclohexylamine procaine (procaine), benzhydrylamine, N,N-benzhydrylaniline and N,N-phenylphenylethylenediamine. Other representative organic amines suitable for use in the formation of test addition salts include ethylenediamine, ethanolamine, diethanolamine, piperidine and beta-azine. For use in therapy, when a therapeutically effective amount of a compound of formula (1) and a pharmaceutically acceptable salt thereof may be administered as a chemical source, it is possible to render the active ingredient in the form of a pharmaceutical composition. Accordingly, the present invention further provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (1) or a pharmaceutically acceptable salt thereof and one or more, preferably up to three pharmaceutically acceptable carriers, diluted Agent or excipient. The term "therapeutically effective amount" as used herein refers to the total amount of each active ingredient sufficient to exhibit a meaningful patient benefit (e.g., a sustained reduction in viral load). When applied to an individual active ingredient, that is, when the active ingredient is administered separately, the term refers to the individual ingredients. When used in combination, the term refers to the combined amount of active ingredients which produce a therapeutic effect' whether administered in combination, continuously or simultaneously. The compound of the formula (1) and a pharmaceutically acceptable salt thereof are as described above. The carrier, diluent or excipient must be acceptable in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient. According to another aspect of the present invention, there is also provided a method of preparing a pharmaceutical formulation of 146976.doc-34-201038558, which comprises reacting a compound of the formula (1) or a pharmaceutically acceptable salt thereof with one or more, preferably Mix with 3 pharmaceutically acceptable carriers, diluents or excipients. The term "pharmaceutically acceptable" as used herein refers to a method suitable for use in contact with a patient's tissue in a reasonable medical judgment, without excessive toxicity, punctuality, allergic reaction or other problems or concurrency. Symptoms, their compounds, substances, compositions and/or dosage forms that match the reasonable benefit/risk ratio and are effective for their intended use. The pharmaceutical formulation may be in the form of a single unitary dose containing a predetermined amount of active ingredient per unit dose. In monotherapy for the prevention and treatment of HCV-mediated diseases, it is preferred that the agent f is usually between about 1 mg per mg of body weight per day and about 25 mg (mg/kg of) of the compound of the invention. Between 0.05 mg and about 1 mg of the compound of the invention per kg body weight per day. Typically, the pharmaceutical compositions of the present invention will be administered from about one to about five times per day, or administered as a continuous infusion. The administration can be used as a chronic therapy or an acute therapy. The amount of active ingredient which can be combined with the carrier materials to produce a single dosage form will vary depending upon the condition being treated, the severity of the condition, the time of administration, the route of administration of the compound employed, the duration of treatment, and the age, sex, and Change in weight and condition. Preferred unit dosage formulations are those containing the active ingredient per amphibious or sub-dose or an appropriate portion thereof as described above. Generally, treatment is initiated in small doses that are substantially less than the optimal dose of the compound. Thereafter, the dose is increased in small increments until the best results in these situations are achieved. In general, the compounds are most desirably administered at a concentration level which will generally result in an effective antiviral effect without causing any harmful or adverse side effects. 146976.doc -35- 201038558 When a composition of the invention comprises a combination of a compound of the invention and one or more additional therapeutic or prophylactic agents, the dose of the compound and the other agent is typically the dose normally administered in a monotherapy regimen. It is about 10% to 15% and more preferably about 10% to 80%. The pharmaceutical formulation may be adapted for administration by any suitable route, such as orally (including buccal or sublingual), rectal, nasal, topical (including buccal, sublingual or transdermal), vaginal or parenteral ( Including subcutaneous, intradermal, intramuscular, intra-articular, intrasynovial, intrasternal, intralesional, intralesional, intravenous or intradermal injection or infusion). Such formulations may be prepared by any method known in the art of pharmacy', e.g., by combining the active ingredient with carriers or excipients. Oral administration or injection administration is preferred. Pharmaceutical formulations suitable for oral administration may be in discrete units such as capsules or lozenges, powders or granules;; solutions or suspensions in aqueous or non-aqueous liquids; edible foams or foams Or an oil-in-water liquid emulsion or a water-in-oil emulsion. For example, for oral administration in the form of a troche or capsule, the active drug mash can be combined with a pharmaceutically acceptable oral non-toxic inert carrier such as ethanol, glycerol, water, and the like. A powder is prepared by comminuting the compound to a suitable fine size and mixing with a similarly comminuted pharmaceutical carrier such as an edible ground water compound such as starch or mannitol. Flavoring agents, preservatives, dispersions, and coloring may also be present. Capsules are prepared by preparing a powder mixture as described above and filling the shaped gelatin shell. Sliding agents and lubricants such as colloidal cerium oxide, talc, stearic acid, stearic acid I46976.doc-36 - 201038558 calcium or solid polyethylene glycol can be added to the powder mixture prior to the filling operation. A disintegrant or solubilizing agent such as agar-agar, calcium carbonate or sodium carbonate may also be added to improve drug availability when the capsule is ingested. In addition, suitable binders, lubricants, decontaminants and coloring agents may also be incorporated into the mixture, if necessary or desired. Suitable binders include starch, gelatin, natural sugars (such as glucose or P_lactose), corn sweeteners, natural and synthetic gums (such as acacia, tragacanth) or sodium alginate, carboxymethyl fibers. , polyethylene glycol and their analogues. The agents used in these dosage forms include sodium oleate, gasified sodium and the like. Disintegrators include, but are not limited to, starch, methylcellulose, agar, bentonite, xanthan gum, and the like. The tablet is formulated by, for example, preparing a powder mixture, granulating or slugging, adding a lubricant and a disintegrant, and compressing into a tablet. A powder mixture is prepared by mixing a suitably comminuted compound with a diluent or a base as described above; and optionally a binder such as carboxymethyl cellulose, alginate, gelling agent or polyvinylpyrrole a ketone; q solution retardant, such as paraffin; a resorption enhancer such as a quaternary salt; and/or an absorbent such as bentonite, kaolin or dicalcium phosphate. The powder mixture can be granulated by wetting with a binder such as a syrup, starch paste, acadia mucilage or a solution of cellulosic material or polymeric material and forcing through a sieve. As an alternative to granulation, the powder mixture can be passed through a tablet press, and as a result, the incompletely formed slug is broken into granules. The granules can be lubricated by the addition of stearic acid, stearate, talc or mineral oil to prevent sticking to the tablet forming mold. The lubricated mixture is then compressed into a tablet. The compound of the present invention can also be combined with a free-flowing inert carrier and directly compressed into a tablet without granulation or dry pressing. 146976.doc -37- 201038558. A clear or opaque protective coating consisting of a shellac seal coat, a sugar or polymeric coating, and a enamel finish coat may be provided. Dyes can be added to these coatings to distinguish between different unit doses. Oral solutions such as solutions, sugars and granules can be prepared in unit dosage form such that the compound containing the amount of hydrazine is quantified. A syrup can be prepared by dissolving the compound in a suitably flavored aqueous solution, and using a non-toxic vehicle to prepare an ugly agent. Solubilizers and emulsifiers such as ethoxylated iso-hard erythritol and polyoxyethylene sorbitan preservatives; flavor additives such as thin oil or natural sweeteners, or saccharin or other artificial sweeteners may also be added. Agents; and analogs thereof. , k-field% can be used for oral administration of the dosage unit formulation for microcapsules can also be prepared by prolonging or maintaining the formulation, for example, by coating or embedding the particulate material in a polymer, wax or the like. freed. He = (1) the compound and its pharmaceutically acceptable salt can also be used as a liposome delivery system such as a single layer of micro-microbes, an early layer of liposome and a multi-layered liposome. The body can be formed from a variety of phospholipids such as cholesterol, stearylamine or phospholipid choline. = (1) The Q compound and its pharmaceutically acceptable salt can also be delivered by using a monoclonal antibody to which the compound is coupled as an individual carrier. The compound is also coupled to a soluble polymer as a dry drug carrier. Such polymerizations include a polyvinylpyrrolidone substituted with a fluorenyl residue, a piper copolyphenol hydroxy methacrylate phenol, polyhydroxyethyl aspartame or 146976. Doc -38- 201038558 Polyoxyethylene polyisallic acid. In addition, the compounds can be coupled with biodegradable polymers suitable for drug controlled release, such as polylactic acid, poly(ε-caprolactone) (p〇iepsil〇n capr〇lact〇ne), polyhydroxybutyrate , polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates, and crosslinked or amphoteric block copolymers of hydrogels. Pharmaceutical formulations suitable for transdermal administration may be discrete patches intended to remain in intimate contact with the epidermis of the recipient for a prolonged period of time. For example, the active ingredient can be delivered from the patch by iontophoresis (i〇nt〇pWsis) as described in the heart, 3(6):318 (1986). Pharmaceutical formulations suitable for topical administration may be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols or oils. For the treatment of the eye or other external tissues (such as the mouth and skin), the formulation is administered in the form of a sputum ointment or cream. When formulated as an ointment, the active ingredient can be employed with a paraffinic base or a water miscible ointment base. Alternatively, the wound is formulated into a cream with an oil-in-water cream base or a water-in-oil base. The pharmaceutical formulations of the eye and the eye include an eye drop which dissolves or suspends the active ingredient in a suitable carrier, especially an aqueous solvent. Pharmaceutical formulations suitable for topical administration to the mouth include buccal tablets, tablets and elixirs. Pharmaceutical formulations suitable for rectal administration may be in the form of a suppository or enemas. A pharmaceutical formulation suitable for nasal administration wherein the carrier is solid comprises a course powder having a particle size within the range of a gentleman's meter, the schedule of 146976.doc • 39-201038558 = in the form of a nasal discharge Investing, that is, the powder w (four) hole that is close to the nose is quickly sucking. The formulation in which the carrier is a liquid suitable for administration as a nasal spray or nasal formulation comprises an aqueous or oily solution of the active ingredient. Pharmaceutical formulations suitable for administration by inhalation include finely divided powders or mists which can be produced by means of various types of metered doses of pressurized aerosols, nebulizers or insufflators. Pharmaceutical formulations suitable for vaginal administration may be in the form of a pessary, tampons, cream, gel, paste, foam or spray formulation. Pharmaceutical formulations for parenteral administration include aqueous and non-aqueous sterile injectable solutions which may contain antioxidants, buffers, inhibitors, and solutes which promote the formulation and the expected liquid of the recipient; Aqueous and non-aqueous sterile heart floats, which may include suspending agents and suturing agents. Formulations may be present in unit dose or multi-dose containers (eg, sealed ampoules and vials) and may be stored under lyophilized (lyophilized) conditions, requiring only the addition of a sterile liquid carrier prior to use (eg, Zhuang Shoot water). The ready-to-use injection solutions and suspensions can be prepared from sterile powders, granules and granules. It will be appreciated that 'in addition to the ingredients specifically mentioned above, il and the type of formulation' may also include other agents conventional in the art, for example, formulations suitable for oral administration may include flavoring agents. . The term "patient" includes humans and other mammals. D° /α therapy J refers to '(1) prevention of a disease, disorder or condition in a person who is predisposed to the disease and/or condition of the disease but has not yet been diagnosed as suffering from the disease or illness of the brother; (1)) Inhibition of a disease, disorder or condition, and also amelioration of the disease, condition or condition, even if the disease, condition and/or condition is diminished 146976.doc -40· 201038558. The compounds of the invention may also be administered with cyclosporin (e.g., cyclosporin A). In clinical trials, cyclosporin A has been shown to be active against HCV (/fepaio/o, 38:1282 (2003); 5/op/z less.

Commun., 313:42 (2004); J. Gastroenterol., 38:567 (2003)) 0 Table 1 below lists some illustrative examples of compounds that can be administered with the compounds of the invention. The compounds of the invention may be administered co-administered with other anti-HCV active compounds in combination therapy, or by combining the compounds into a composition. Table 1 Trade Name Physiological Type Inhibitor or Target Type Source Company NIM811 Debio-025 cyclophilin inhibitor Novartis Debiopharm Zadaxin Immunomodulator SciClone Suvus Yarnin Blue Bioenvision Actilon (CPG10OlOl) TLR9 agonist Coley Batabulin (T67) Anticancer Agent β-Tubulin Inhibitor Tularik Inc., South San Francisco, CA ISIS 14803 Antiviral Antisense ISIS Pharmaceuticals Inc, Carlsbad, CA/Elan Pharmaceuticals Inc” New York, NY Summetrel Antiviral Agent Antiviral Agent Endo Pharmaceuticals Holdings Inc., Chadds Ford, PA GS-9132 (ACH-806) Antiviral Agent HCV Inhibitor Achillion/Gilead ° Compared to Sputum and Squeezing Compounds and Salts from WO 2005/47288 April 26, 2005 Antiviral Agent HCV Inhibitor Arrow Therapeutics Ltd. 146976.doc -41 - 201038558 , ! _ Trademark Name Physiological Type Inhibitor or Target Type Source Company Levovirin Antiviral Agent IMPDH Inhibitor Ribapharm Inc_5 Costa Mesa, CA Merimepodib ( VX-497) Antiviral Agent IMPDH Inhibitor Vertex Pharmaceuticals Inc., Cambridge, MA XTL Biopharmaceuticals Ltd" Rehovot, Israel XTL-6865 (XTL-002) Antiviral Agent Monobody Telaprevir (VX-950, LY-570310) Antiviral Agent NS3 Serine Protease Inhibitor Vertex Pharmaceuticals Inc" Cambridge, MA/ Eli Lilly and Co., Inc., Indianapolis, IN HCV-796 Antiviral Agent NS5B Replicase Inhibitor Wyeth/Viropharma NM-283 Antiviral Agent NS5B Replicase Inhibitor Idenix/Novartis GL-59728 Antiviral Agent NS5B Replicase Inhibition Gene Labs/Novartis GL-60667 Antiviral Agent NS5B Replicase Inhibitor Gene Labs/Novartis 2'C MeA Antiviral Agent NS5B Replicase Inhibitor Gilead PSI6130 Antiviral Agent NS5B Replicase Inhibitor Roche R1626 Antiviral Agent NS5B Replicase Inhibitor Roche 2'C decyl adenosine antiviral NS5B replicase inhibitor Merck JTK-003 Antiviral RdRp inhibitor Japan Tobacco Inc., Tokyo, Japan Levovirin Antiviral virus Sputum ICN Pharmaceuticals, Costa Mesa, CA Ribavirin Antiviral Agent Virus "Sitting Schering-Plough Corporation, Kenilworth, NJ Viramidine Antiviral Agent Viral Oxide Prodrug Riba Pharm Inc., Costa Mesa, CA Heptazyme Antiviral ribonuclease Ribozyme Pharmaceuticals Inc., Boulder, CO Boehringer Ingelheim Pharma KG, Ingelheim, Germany BILN-2061 Antiviral agent serine protease inhibitor SCH 503034 Antiviral agent Sour egg (2) m inhibition department 丨 Schering-Plough 146976.doc -42· 201038558

Trade Name Physiological Type Inhibitor or Target Type Source Company Zadazim Immunomodulator Immunomodulator SciClone Pharmaceuticals Inc., San Mateo, CA Ceplene Immunomodulator Immunomodulator Maxim Pharmaceuticals Inc” San Diego, CA CELLCEPT® Immunosuppressant HC V IgG immunosuppressant F. Hoffinann-La Roche LTD, Basel, Switzerland Civacir immunosuppressant HCV IgG immunosuppressant Nabi Biopharmaceuticals Inc., Boca Raton, FL Albuferon-a interferon albumin IFN-a2b Human Genome Sciences Inc" Rockville, MD Infergen A Interferon-1 (IFN alfacon-1) InterMune Pharmaceuticals Inc" Brisbane, CA Omega IFN Interferon IFN-ω Intarcia Therapeutics IFN-β and EMZ701 Interferon IFN-β and EMZ701 Transition Therapeutics Inc” Ontario, Canada REBIF® Interferon IFN-β la Serono, Geneva, Switzerland Roferon A Interferon IFN-a2a F· Hoffinann-La Roche LTD, Basel, Switzerland Intron A Interferon IFN-a2b Schering-Plough Corporation, Kenilworth, NJ Intron A and Zadaxin interferon IFN-ot2 b/a 1 - Thymosin RegeneRx Biopharma. Inc., Bethesda, MD/SciClone. Pharmaceuticals Inc, San Mateo, CA Rebetron Interferon IFN-a2b/Virus 唆Schering-Plough Corporation, Kenilworth, NJ Actimmune Interferon INF-γ InterMune Inc" Brisbane, CA Interferon-β Interferon-β-la Serono Multiferon Interferon Long-acting IFN Viragen/Valentis Wellferon Interferon-type Lymphocyte IFN-anl GlaxoSmithKline plc5 Uxbridge,UK -43- U6976.doc 201038558 Trade name Physiological Inhibitors or Target Type Sources | Omniferon Interferon Natural IFN-a Viragen Inc., Plantation, FL Pegasys Interferon Pegylated IFN-a2a F· Hoffmann-La Roche LTD, Basel, Switzerland Pegasys and Ceplene Interferon PEGylated IFN-a2a/immunomodulator Maxim Pharmaceuticals Inc., San Diego, CA Pegasys and Ribavirin Interferon PEGylated IFN-a2a/ribavirin F. Hoffmann-La Roche LTD, Basel, Switzerland PEG- Intron Interferon Pegylated IFN-a2b Schering-Plough Corporation, Kenilworth, NJ PEG-Intron/Ri Bavirin interferon PEGylated IFN-a2b/virus saliva Schering-Plough Corporation, Kenilworth, NJ IP-501 Liver protectant anti-fibrotic agent Indevus Pharmaceuticals Inc., Lexington, MA IDN-6556 Liver protectant --- Kas Caspase inhibitor Idun Pharmaceuticals Inc., San Diego, CA ITMN-191 (R-7227) Antiviral agent serine protease inhibitor InterMune Pharmaceuticals Inc., Brisbane, CA GL-59728 Antiviral agent NS5B replicase Inhibitor Genelabs ANA-971 4/U Viral TLR-7 Agonist Anadys Boceprevir Antiviral Serine Protease Inhibitor Schering-Plough TMS-435 Antiviral Agent Serine Protease Inhibitor Tibotec BVBA, Mechelen, Belgium BI -201335 Antiviral agent serine protease inhibitor Boehringer Ingelheim Pharma KG, Ingelheim, Germany MK-7009 Antiviral agent serine protease inhibitor 杳, 丨 Merck PF-00868554 Antiviral replication enzyme inhibition Γ '' 'Pfizer Anadys Pharmaceuticals, Inc., San Diego, CA, USA Idenix Pharmaceuticals, Cambridge, MA, USA ANA598 Antiviral Agent M«nssb^ IDX375 antiviral agent non-nucleotide replicase inhibition] ---~1146976.doc -44· 201038558 Trade name -- Physiological inhibitor or source company Boehringer Ingelheim Canada Ltd R&D, Laval, QC , Canada Pharmasset, Princeton, NJ, USA BILB 1941 Antiviral Agent NS5B Polymerization Inhibitor PSI-7851 Antiviral Agent Nucleoside Polymerization VCH-759 Antiviral Agent__ Polymerization Per Suppression Sword ViroChem Pharma ViroChem Pharma VCH-916 Antiviral Agent NS5BI synthase inhibits sword GS-9190 antiviral agent NS5B polymerase inhibitor Gilead Peg-interferon lamda antiviral agent interferon '''--- ZymoGenetics/Bristol-Myers Squibb The compounds of the invention may also be used as laboratory reagents. Compounds can help provide knowledge of strategies for designing viral replication assays, validating animal assay systems, and structural biology studies to further enhance HCV disease mechanisms. Further, the compounds of the invention are useful for establishing or determining binding sites for other antiviral compounds, such as by competitive inhibition. The compounds of the invention may also be used to treat or prevent viral contamination of materials, and thus reduce exposure to such materials as blood, tissue, surgical instruments and garments, laboratory equipment and garments, and blood collection or transfusion devices and materials. Risk of viral infection in the room or medical staff or patient. The present invention is intended to cover compounds of formula (1) prepared by synthetic methods or by metabolic processes, including metabolic processes carried out in humans or animals (in vivo) or in vitro. [Embodiment] Those skilled in the art are familiar with the abbreviations used in the present application, including in particular the illustrative examples below. Some of the abbreviations used are as follows: TFA refers to trifluoroacetic acid; min or min· or mins refers to minutes; MeCN or ACN refers to acetonitrile; 146976.doc -45- 201038558 LDA refers to lithium diisopropylamide; DMSO refers to Dimethyl sulfoxide; h or hr or hrs means hour; Boc or BOC means third butoxycarbonyl; HATU means 0-(7-azabenzotriazol-1-yl)-N hexafluorophosphate N,N',N'-tetramethylguanidine; RT or Rt or rt means residence time or room temperature (context will be indicated), · Me means methyl; DMF means N,N-dimethylhydrazine Amine; Pd(Ph3P)4 means yttrium triphenylphosphine palladium; MeOH means decyl alcohol; MeOD means CD4OD; TEA means triethylamine; Ph means phenyl; TBDPS means tributyldiphenyl decane EtsN or TEA means triethylamine; DMAP means hydrazine, hydrazine-dimercaptoaminopyridine; EtOAc means ethyl acetate; TBAF means tetrabutylammonium fluoride; THF means tetrahydroanthracene; DIEA or DIPEA or ipr2NEt refers to diisopropylethylamine; NCS refers to N-pyrene diimide imine; NBS refers to N-bromosuccinimide; DCM refers to dioxane; SEM system Refers to 2-(trimethylsulfonylalkyl)ethoxycarbonyl; DCE refers to 1,2-diethylene bromide EDCI refers to 1-ethyl-3-(3-didecylaminopropyl)carbodiimide; DBU refers to 1,8-diazabicyclo[5.4.0]non-7-ene; pd( t-Bu3P)2 refers to bis(tributylphosphine); HMDS refers to hexamethyldioxane aminide; TMSCHN2 refers to trimethylsulfonyl-based diazonium; HD-Ser-OBzl refers to D- Benzyl methacrylate; i-PrOH means isopropyl alcohol; LiHMDS means bis(trimethyldecane)amine lithium; DIBAL· or DIBALH means diisobutyllithium hydride; TBDMS means tributyl Dimercaptoalkylene; CBz refers to alkoxycarbonyl; Bn refers to benzyl; DEAD refers to diethyl azodicarboxylate; mcpBA refers to m-chloroperoxybenzoic acid; TMSCN refers to trimethyl cyanide Base decane; dpppe means 1,5-bis (one linyl) pentyl, TMEDA means tetramethylethylenediamine; 〇ac means acetate; DMA means N,N-dimercaptoacetate Amine; and d means day. 146976.doc -46 - 201038558 The present invention will now be described in connection with certain embodiments, which are not intended to limit the scope of the invention. Rather, the invention encompasses all alternatives, modifications, and equivalents that may be included in the scope of the patent application. Therefore, the following examples of the present invention are intended to be illustrative of the embodiments of the present invention, and are to be construed as The most applicable and easiest to understand descriptor of a conceptual aspect. Starting materials can be obtained from commercial sources or prepared by accepted methods known to those skilled in the art. Examples Purity evaluations were performed on a Shimadzu LC system and retention time (Rt) measurements and low resolution mass analysis were performed on a Shimadzu LC system coupled to a Waters MICROMASS® ZQ MS system, unless otherwise indicated. It should be noted that the residence time between machines may vary slightly. Condition 1 Column = PHENOMENEX®, C18, 3.0x50 mm, 10 μπι ❹ Starting Β%=0 Final Β%=100 Gradient time=2 min Stop time=3 min Flow rate=4 mL/min Wavelength=220 nm Solvent A = 10% methanol/90% water solvent with 0.1% TFA B = 90°/sterol/10% water with 0·1°/〇TFA 146976.doc -47- 201038558 Condition 2 Column = XTERRA® , C18, 3.0x50 mm, S7 Starting B%=0 Final B%=100 Gradient time=2 min Stop time=3 min Flow rate=5 mL/min Wavelength=220 nm Solvent A=0.2% H3P〇4 10% methanol/90% water solvent B = 90% methanol/10% water condition with 0.2% H3P04 3 column = PHENOMENEX®, C18, 3.0x50 mm, 10 μιη Starting Β%=0 Final Β%=100 Gradient Time = 3 min Stop time = 4 min Flow rate = 4 mL / min Wavelength = 220 nm Solvent A = 10% sterol / 90% aqueous solvent containing 0.1 % TFA B = 90% methanol / 10% containing 0.1 % TFA Water condition 4 Column = XTERRA®, C18, 3.0x50 mm, S7 Starting B% = 0 Final B% = 100 146976.doc • 48- 201038558 Gradient time = 1 〇 min Stop time = 11 min Flow rate = 5 mL /min Wavelength = 220 nm Solvent A = 10% methanol/90% water solvent containing 0.2% H3P〇4 B = 0.2% 90°/ of H3P〇4. Sterol/10% water condition 5

Column = PHENOMENEX®, C18, 3.0x50 mm, 10 μηι Start Β% = 0 Final Β%=100 Gradient time = 4 min Stop time = 5 min Flow rate = 4 mL/min Wavelength = 220 nm Solvent A = Contain 0.1% TFA 10% methanol / 90% water solvent B = 90 ° / 〇 methanol / 10% water condition with 0.1% TFA 6 column = Phenomenex-Luna, C18, 4.6x50 mm, S10 Starting B% = 0 Final B%=100 Gradient time=3 min Stop time=4 min Flow rate=4 mL/min Wavelength=220 nm 146976.doc 49- 201038558 Solvent A=10% sterol/90% aqueous solvent B containing 0.1% TFA = 90% sterol/10% water condition with 0.1% TFA 7 column = Phenomenex-Luna, C18, 3. 〇 x 50 mm, S10 Starting B° / 〇 = 0 Final B% = 100 Gradient time = 2 min Stop time = 3 min Flow rate = 4 mL / min Wavelength = 220 nm Solvent A = 1% sterol/90% water solvent with 0.1% TFA B = 90% sterol/10% water condition with 0.1% TFA 9 Columns^Waters Sunfire, C18, 4.6x150 mm, 3.5 μιη Starting Β%=10 Final Β%=50 Gradient time=20 min Stop time=25 min Flow rate=1 mL/min Wavelength=220 and 254 nm Solvent A = 5% with 0.1% TFA CH3CN/95% H20 Solvent B = 95% with 0.1% TFA CH3CN/5% H20 Condition 9a Except for stop time = 3 5 min, same as condition 9 146976.doc -50- 201038558 Condition 9a.l Column = Waters Sunfire, C18, 4.6x150 mm, 3.5 μηι Start B%= 30 Final B%=100 Gradient time=20 min Stop time=25 min Flow rate=1 mL/min Wavelength=220 and 254 nm 〇Solvent A=5% of 0.1% TFA CH3CN/95% H20 Solvent B=0.1 % TFA 95% CH3CN/5% H20 Condition 10 Column = Waters Xbridge phenyl, C18, 4.6x150 mm, 3 μιη Start B% = 10 Final B% = 5 0 Gradient time = 20 min Stop time = 25 min Ο Flow rate = 1 mL/min Wavelength = 220 and 254 nm Solvent A = 5% with 0.1% TFA CH3CN/95% H20 Solvent B = 95% CH3CN/5°/〇H20 with 0.1% TFA Condition 10a Except for stop time =3 5 min, the same conditions as Condition 10 10a.1 Column = Waters Xbridge phenyl, C18, 4.6x150 mm, 3 μιη 146976.doc -51 - 201038558 Initial B%=40 Final B%=100 Gradient time= 20 min Stop time = 25 min Flow rate = 1 mL/min Wavelength = 220 and 254 nm Solvent A = 5% CH3CN/95°/ with 0.1% TFA. H20 Solvent B = 95% CH3CN/5% H20 with 0. 1% TFA Condition 1 Ob String = Sunfire, C18, 3.0x150 mm, 3.5 μιη Start B% = 10 Final B% = 40 Gradient time = 1 5 Min stop time = 1 8 mi η flow rate = 1 mL / min wavelength 1 = 220 nm wavelength 2 = 254 nm solvent A = 5 ° / with 0.1% TFA. MeCN/95°/hydrophobic solvent B = 95% with 0.1% TFA MeCN/5°/hydrophobic conditions l〇c Column = Xbridge Phenyl, C18, 3.0x150 mm, 3.5 μπι Start Β%=10 Final Β % = 40 Gradient time = 15 min 146976.doc -52- 201038558 Stop time = 1 8 min Flow rate = 1 mL/min Wavelength 1 = 220 nm Wavelength 2 = 254 nm Solvent A = 5% MeCN with 0.1% TFA /95°/hydrophobic solvent B = 95% with 0_1% TFA MeCN/5% water condition 10d Column = PHENOMENEX®-Luna, C18, 2.0x50 mm, 3 μιη Ο Starting Β°/〇=0 Final Β %=100 Gradient time=4 min Stop time=5 min Flow rate=0.8 mL/min Wavelength=220 nm Solvent A=10% sterol/90% water solvent containing 0.1% TFA B=0.1°/〇TFA 90% methanol/10% water oven temperature = 40 ° C Condition 10e (Agilent 1200 Series LC system) Column = Xbridge phenyl, C18, 4.6x150 mm, 3.5 μηη Solvent Α = Buffer: CH3CN (95:5) Solvent B = Buffer: CH3CN (5:95) Buffer = Η20 with 0.05% TFA (ρΗ 2.5, adjusted with dilute ammonia) Start B% = 10 Final B% = 100 146976.doc -53 - 201038558 Gradient time = 12 min equal intensity time = 3 min stop time = 23 min Dynamic rate = 1 mL / min Wavelength = 220 and 254 nm Condition 10f (Agilent LC-1200 series coupled with 6140 single quad mass spectrometer, ESI + ve mode) Column = Zorbax SB, C18 , 4.6x50 mm, 5 μπι Solvent A = MeOH (10%) + H2O (90%) with 0.1% TFA Solvent B = MeOH (90%) + H2O (10o/0) with 0.1% TFA Starting B% = 0 Final B°/〇=100 Gradient time=3 min Equal intensity time=1 min Stop time=5 min Flow rate=5 mL/min Wavelength=220 nm Condition lOg (Agilent LC connected to 6140 single quadrupole mass spectrometer) -1200 Series, ESI+ve mode) Column = Ascentis Express, C-8, 2.1x5 mm, 2.7 μη Solvent A=CH3CN (2%) + Η20 (980/〇) with 10 mM NH4COOH Solvent B=CH3CN ( 98%) + HAP% with 10 mM NH4COOH) Start B% = 0 Final B% = 100 146976.doc · 54· 201038558 Gradient time = 1.5 mi η Equal intensity time = 1.7 min Stop time = 4 min Flow rate = 1 mL/min Wavelength = 220 nm Condition 10h Tube column = PHENOMENEX®-Luna, C18, 4.6x30 mm, S10 Start B° / 〇 = 0 最终 Final B% = 100 Gradient time = 3 min Stop time = 4 min Flow Rate = 4 mL / min Wavelength = 220 nm Solvent A = 10% methanol/90% water with 0.1% TFA Solvent B = 90% sterol/10% water with 0.1% TFA Condition 11

Q column = PHENOMENEX®-Luna, C18, 50x2 mm, 3 μιη Starting Β%=0 Final Β%=100 Gradient time=4 min Stop time=5 min Flow rate=0.8 mL/min Wavelength=220 nm Solvent A = 5% methanol / 95% water: 10 mM ammonium acetate 146976.doc -55- 201038558

Solvent B = 95% methanol / 5% water: 10 mM ammonium acetate oven temperature = 40 ° C Condition 12 (Waters Acquity HPLC with Waters PDA UV-Vis detector and Waters SQ MS-ESCI probe) Columns Waters Acquity BEH, C18, 15〇χ2·1 mm ID, 1.7 μηη (at 35 ° C) Mobile phase A = water mobile phase containing 0.05% TFA B = acetonitrile solvent system containing 0. 05% TFA: 10% retention B : 0-1 min ; 10-98% B : 1-32 min ; 98% B : 32-35 min ; 98-10% B : 35-35.3 min ; 10% B : 35.3-40 min Flow rate =0.35 ml/min 11¥Detection=3 3 5 11111 Example OL-1

Example OL-1, step a

146976.doc -56- 201038558 To a chloroform (3.05 mL, 41.92 mmol) in tetrahydrogen. 4,4,-oxybis(benzoic acid) dimethyl ester (1 5 g, 5 24 mm 〇1) was added to the solution in the methane (50 mL), and the resulting solution was cooled to -78 °C. LDA (29 mL, 52 mmol) in i 8 M solution in tetrahydrofuran was added dropwise, and the resulting smudge suspension was stirred for 15 minutes at _78 &lt;&gt;&gt;c. A solution of glacial acetic acid in tetrahydrofuran (10 mL in 50 mL) was then slowly added, and the brown mixture was stirred for 10 minutes under _78, then allowed to reach room temperature. The mixture was dissolved in ethyl acetate and brine (1:1, 50 mL) and then the organic layer was separated, washed with brine and brine, dried (MgSO.sub.4), filtered and concentrated in vacuo. The residue was subjected to flash chromatography (EtOAc: EtOAc: EtOAc) NMR (5 〇〇 MHz, DMSO-d6) δ ppm 5.17 (s, 4H), 7.22 (d, 1 = 8.85 Hz, 4H), 8.06 (d, J = 8.85 Hz, 4H). LC (Condition 2): RT = 1.53 min, </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; Example OL-1 'step b

A mixture of OL-la (0.6 g'1_85 mmol) and sodium dimercaptosodium hydride (42 g, 4.45 mmol) in EtOAc (20 mL) was warmed to reflux for 4 h. The solvent was removed under reduced pressure and the remaining residue was redissolved in 5% EtOAc (30 mL) and warmed to reflux and maintained at 2146976.doc - 57 - 201038558. The mixture was cooled in an ice-water bath and the resulting precipitate was filtered, washed with ethyl alcohol and ethyl ether and dried in vacuo. The recovered light brown solid was used (0.66 g) without further purification. 4 NMR (500 MHz, DMSO-d6) δ ppm 4.54 (s, 4H), 7.25 (d, J = 8.85 Hz, 4H), 8.11 (d, J = 8.55 Hz, 4H), 8.52 (br s, 6H) . LC (Condition 1): rt = 1.24 min; LRMS: (M+H) + C16H17N203 Analysis: 285. Example OL-1, step c

I jade 15 knife in the 'NB 〇 cL - amino acid (0.8 g, 3.73 mmol), HATU (1.48 g, 3_88 mmol), OL-lb (0.66 g, 1.85 mmol) and dimethylformamide ( n,N-Diisopropylethylamine (1.13 mL, 6.47 mmol) was added dropwise to a heterogeneous mixture of 15 mL) and was stirred for 4 hours under ambient conditions. Most of the volatile components were removed in vacuo, and the residue obtained was partitioned between ethyl acetate (30 mL) and water (20 mL). The organic layer was dried <RTI ID=0.0>(M </RTI> <RTI ID=0.0> The residue was prepared from the residue and subjected to flash chromatography (gelatin; 65-85% ethyl acetate /

己 ))) gave 〇L_lc (〇 7 g) as a light brown solid. iH NMR (500 MHz, DMS 〇-d6) δ ppm 1.39/1.34 (spin isomer, s, 18H), 1-70-1.91 (m, 6H)? 2.00-2.25 (m, J=8.55 Hz, 2H ), 3.22-3.33 (m, 2H), 3.32-3.47 (m, J=10.68, 10.68 Hz, 2H), 4.08-4.26 146976.doc -58- 201038558 (m,2H),4.56 (ddd, J=36.93 , 18.16, 5.34 Hz, 4H), 7.19 (d, J = 8.85 Hz, 4H), 8.06 (d, j = 7 93 Hz, 4H), 8.11-8.24 (m, J = 5.49 Hz, 2H). LC (Cond. i): RT = 2.55 min; LRMS: (M+H) + C36H47N409 Analysis calculated: 679.33,,,,,,,,,,,,,,,,,,,,,

In a sealed tube, a mixture of 〇L_lc (〇7 g, 1. 25 mmol) and ammonium acetate (〇·79 g, 10 min〇l) in xylene (5 mL) under microwave irradiation at 140° Heat at C for 1.2 hours. The volatile component was removed in vacuo, and the residue was carefully partitioned between ethyl acetate and water, then a sufficient saturated solution of sodium bicarbonate was added to allow the pH of the aqueous phase to be slightly tested after shaking the two-phase system. Sex. The layers were separated&apos; and the aqueous layer was extracted with additional ethyl acetate. The combined organic phases were dried <RTI ID=0.0>(M </RTI> </RTI> <RTIgt; The obtained material was subjected to flash chromatography (silica gel; 15-25% acetone/dichloromethane) to afford OL-ld (0.13 g). NMR (500 MHz, DMSO-d6) δ ppm 1.17/1.48 (spinomer, s, 18H), 176_193 (m, 4H), 193·2.06 (m, J=l〇.〇7 Hz, 2H), 2.10-2.30 (m, 2H), 3.32-3.39 (m, 2H), 3.45-3.62 (m, 2H), 4.69-4.80 (m, 1H), 4.83 (d, J=7.02 Hz, 1H), 6.97 ( d, J=7.93 Hz, 4H), 7.00-7.22 (m, 1H)S 7.40/7.62 (rotomer, m, 2H), 7.73 (d, J = 8.55 Hz, 3H), 146976.doc 59- 201038558 11.74/11.81/12.07 (The 搂 辘 搂 Λ Λ τ τ 、 、 、 、 、 、 、 丈 。 。 。 。 。 。 。 。 。 。 。 。 。 。 Lc (condition 2): RT=1·53 theory, homogeneity index 93. /. LCMS: (m+h) calcd. Example OL-1, step e

To a solution of OL-ld (0.13 g, 0.2 bribe 1) in 3 mL of dichloromethane was added HCl mL 4 M solution of HCl in dioxane. The reaction was stirred at room temperature for 2 hr and concentrated. The residue obtained was redissolved in a minimum amount of decyl alcohol, and the desired product was triturated with diethyl ether, filtered and dried in vacuo. The light brown solid (〇. 11 g) was recovered and used without further purification. NMR (500 MHz, DMSO-d6) Sppm 1.92-2.07 (m, 2H), 2.12· 2.25 (m, 2H), 2.37-2.47 (m, 4H), 3.30-3.47 (m, 4H), 4.9〇- 5.02 (m, 2H), 7.15 (d, J=8.55 Hz, 4H), 7.91 (d, J=8.24 Hz 4H), 7·97 (s, 2H), 9·74 (br· s, 2H), 10.25 (br. s, 2H). Note that the 15 m salin NH is too wide to determine the chemical shift e lc (condition 1): RT = 1.68 min ′ LRMS : (M+H) + C26H29N60 analytical value: 441.24, experimental value: 441.30. Example OL-1 to OL-le (3 5 mg, 0.06 mmol), diisopropylethylamine (58 pL, 0.33 mmol) and cap-1 (22 mg, 0.12 mmol) in dimethyl decylamine (3) HATU (52 mg, 0.137 mmol) was added to the mixture in mL), and the mixture was stirred at ambient temperature 146976.doc -60 - 201038558 for 3 hours. The volatile component was removed in vacuo, and the residue was purified from EtOAc (EtOAc/EtOAc) 4 NMR (500 MHz, DMSO-D6) δ ppm 1.82-1.93 (m, 2H), 1.94-2.08 (m, 4H), 2.14-2.24 (m, 2H), 2.29-2.40 (m, 4H), 2.83 ( s, 4H), 2.97-3.07 (m, 4H), 3.97 (t, J=8.24 Hz, 2H), 4.89-5.20 (m, 2H), 5.34-5.73 (m, 2H), 7.00-7.22 (m, 6H), 7.49-7.64 (m, 9H), 7.70-7.89 (m, 5H), 10.20 (br.s, 2H). LC (Condition 1): 〇RT=2.48 min; LRMS: (M+H)+ C46H51N803 calc.: 763.41, calc. 763.56; HRMS: (M+H)+ C46H51N803 calc.: 763.4084, Experimental value: 763.4109. Examples OL-2 and OL-3

例 Examples OL-2 and OL-3 in the form of trifluoroacetate were prepared by substituting Cap-1 for each acid using the same procedure as described for Example OL-1. Example Λ RT (LC-condition);] v^ data. Acid OL-2 Ηδ lamp: 2.^2 min. LC (Condition 2); LCMS: (M+H) + C42H4 丨N6 〇5 calc. calc.: 709.31, experimental value·· 709.41; HRMS ·· (M+H)+ C42H4lN6〇s analytical value: 709.3138 , Experimental value: 709.3147 Almond acid 146976.doc -61 _ 201038558 Example Jy RT (LC-condition); MS data acid OL-3 ph^ RT = 3.65 min. </RTI> <RTI ID Example OL-4 ~N〆

In a sealed tube, 3-bromobenzoic acid decyl ester (5 g, 23.2 mmol), 4-hydroxybenzoic acid decyl ester (5_3 g, 34.87 mmol), carbonic acid were combined in dioxane (100 ml). (15.12 g, 46.4 mmol), copper (1) (0.44 g, 2.3 2 mmol) and N,N-dimethyl hydrochloride (0.97 g, 6.96 mmol), and the mixture was heated to 90° C, maintain 1 5 hours. The solvent was removed under reduced pressure and the residue was crystalljjjjjjjjj The organic layer was washed with a saturated aqueous solution of sodium carbonate, water and brine, dried (MgSO.sub.4), 146976.doc -62 - 201038558 and concentrated in vacuo. The obtained material was purified by flash chromatography (yield: EtOAc, 5% ethyl acetate / hexane) to afford OL-4a (5.8 g) as a transparent oil. iH NMR (500 MHz, DMSO-d6) δ ppm 3.83 (s, 6H), 7.10 (d, J=8.55 Hz, 2H), 7.43 (dd, J=8.09, 2.59 Hz, !H), 7.56 (S, 1H), 7.61 (t, J=7.93 Hz, 1H), 7.81 (d, 1 = 7.63 Hz, 1H), 7.98 (d, J = 8.55 Hz, 2H). LC (Condition 2): RT = 1.53 min; LCMS: (M+l) + C16H1505 calc. Example OL-4, step b

〇L_4b was prepared from 〇L_4a according to the same procedure used to prepare OL-la. NMR (500 MHz, DMSO-d6) δ ppm 5.14 (s, 2H), 5.20 (s, 2H), 7.13 (d, J = 8.85 Hz, 2H), 7.43-7.49 (m, 1H), 7.64 (t, QJ=8.09 Hz, 1H), 7.66-7.68 (m, 1H), 7.85 (d, J=7.93 Hz, 1H), 8.02 (d, J=8.85 Hz, 2H). LC (Condition RT : RT = 51 min; LRMS: (M+H) + C16H13Cl2 〇3: 323 〇2, experimental value: 323.07 ° Example OL-4, step

146976.doc •63- 201038558 OL-4c was prepared from Example -4L-4b according to the same procedure as used in Preparation Example OL-lb. 4 NMR (500 MHz, DMSO-d6) δ ppm 4.52 (s, 2H), 4.56 (s, 2H), 7.16 (d, J = 8.85 Hz, 2H), 7.51 (dd, J = 8.24, 2.44 Hz, 1H ), 7.68 (t, J=7.93 Hz, 1H), 7.71-7.75 (m, 1H), 7.91 (d, J=7.63 Hz, 1H), 8.07 (d, J=8.85 Hz, 2H), 8.60 (s , 6H) ° LC (Condition 2): (M+H) + C16H17N203 Analysis calculated: 285.12 ' Experimental value: 285.15. Example OL-4d

Instance OL-4d was prepared from Example _L_4c according to the same procedure used for the preparation of Example OL-1 c. H NMR (500 MHz, DMSO-d6) δ ppm 1.38/1.33 (spin isomer, s, ΐ8Η), 1.69^91 (m,6Η), 195_ 2.19 (m, 2Η), 3.20-3.31 (m5 2H) , 3.32-3.47 (m, 2H), 4.08-4.23 (m, 2H), 4.43-4.68 (m, 4H), 7.10 (d, J=8.55 Hz, 2H), 7.42 (dd, J=8.09, 1.98 Hz , 1H), 7.57-7.70 (m, 2H), 7.86 (d, J=7.02 Hz, 1H), 8.03 (d, J=7.93 Hz, 2H), 8.08-8.24 (m, 2H). </ RTI> <RTI ID=0.0></RTI> </ RTI> </ RTI> </ RTI> <RTIgt; 146976.doc • 64 - 201038558 Example OL-4e

An example 〇L-4e was prepared from the example 〇L_4d according to the same procedure as used in the preparation example OL-ld. 4 NMR (500 MHz, DMSO-d6) δ ppm Ο 1.14/1.17/1.38/1.40 (spin isomer, s, i8H), 171_2. 〇6^6H), 2.09-2.28 (m, J=25.79, 13.89 Hz, 2H), 3.31-3.40 2H), 3.51 (s, 2H), 4.65-4.89 (m, 2H), 6.80 (t, J=8.39 jjz 1H), 6.91-7.10 (m, 2H), 7.28-7.55 (m, 5H), 7.58-7.80 (m 2H), 11.66-12.21 (m, 2H). </ RTI> <RTI ID=0.0></RTI> </ RTI> <RTI ID=0.0></RTI> </RTI> <RTIgt; Example OL-4f

According to the same procedure as used in the preparation example OL-1e, the example OL-4f was obtained from the example 〇L_4e. 4 NMR (500 MHZ, DMs〇_d6) δ ppm 1 % 2.06 (m, 2H), 2.09-2.23 (m, 2H), 2.28-2.38 (m, 1H), 2 37 • 65- 146976.doc 201038558 2.47 (m, 3H), 3.27-3.50 (m, 4H), 4.90 (br. s, 1H), 4.99 (br. s, 1H), 7.00 (d, J = 7.93 Hz, 1H), 7.13 (d, J =8.55 Hz,2H), 7.49 (t, J=7.93 Hz, 1H), 7.62 (s, 1H), 7.69 (d, J=7.63 Hz, 1H), 7.92 (d, J=8.55 Hz, 2H), 7.99 (s, 2H), 9.58 (br. s, 1H), 9.84 (br. s, 1H), 10.25 (br·d, J = 22.28 Hz, 2H). Note: The signal of the oxazole NH is too wide to break the chemical shift. LC (Condition 1): RT = 1.72 min; LRMS: (M+H) + C26H29N60: 441.24, 441.29 °. Example OL-4 The same procedure used in the preparation example OL-1, from example 〇L Example 4 was prepared as -4f. NMR (500 MHz, DMSO-d6) δ ppm 1.83-1.92 (m, 4H), 1.95-2.09 (m, 8H), 2.11-2.23 (m, 4H), 2.75-2.88 (m, 2H), 2.92 (s , 1H), 2.96-3.12 (m, 2H), 3.97 (t, J=8.39 Hz, 2H), 5.14 (dd, J=17.70, 7.02 Hz, 2H), 5.41 (s, 2H), 6.91-7.11 ( m, J=49.75 Hz, 2H), 7.14 (d, J=7.93 Hz, 2H), 7.44-7.68 (m, 12H), 7.79 (d, J=8.54 Hz, 2H), 7.84-8.02 (m, J =9.16 Hz, 2H), 10.21 (s, 1H). Note: The signal for imidazole NH is too wide to determine the chemical shift. LC (Condition 1): RT = 1.78 min; LRMS: (M+H) + C46H51N803: Calculated: 763. HRMS : (M+H)+ C46H51N803 analytical value·· 763.4084, experimental value: 763.4067 ° 146976.doc •66· 201038558 Examples OL-5 and OL-6

Examples OL-5 to OL-6 in the form of trifluoroacetate were prepared by substituting cap-1 for each of the same method as described for Example OL-4. Examples Λ Acid RT (LC-condition); MS data OL-5 ph^ HO Mandelic acid RT = 1.78 min. LC (Cond. 2); LCMS: (M+H) + C42H41N calc. calc. 709.31, calc.: 709.42; HRMS: (M+H)+ calc.: 709.3138, calc.: 709.3130 OL-6 Ηγ- Cap-4 RT = 1.96 min. LC (Cond. 2); LCMS: (M+H) + C46H47N807: calc.: 823.36, calc.: 82.51; HRMS: (M+H)+ C46H47N807 Analysis calculated: 823.3568, Experimental value: 823.3588

Example OL-7

146976.doc -67- 201038558 Example OL-7a

Add 4-hydroxybenzoic acid (6.9 g) to a solution of 4-(methylmethyl)benzoic acid (8.53 g, 50 mmol) and sodium hydroxide (1 〇g '0.25 mol) in water (40 mL) , 50 mmol) and a solution of sodium hydroxide (6 g, 〇_15 mol) in water (50 mL). The resulting mixture was heated to reflux temperature for 15 hours, and after cooling to room temperature, it was filtered and acidified with a solution of sulfuric acid in water (1:1 '200 mL). The resulting precipitate was filtered, washed with water and dried in vacuo. An off-white solid (9.3 g) was used without further purification. NMR (500 MHz, DMSO-d6) δ ppm 5.27 (s, 1H), 7.10 (d, J = 8.85 Hz, 2H), 7.56 (d, J = 8.24 Hz, 2H), 7.89 (d, J = 8.85 Hz , 2H), 7.96 (d, J-8.24 Hz, 2H), 12.36 (br s, 2H). LC (Condition 2). Note that the molecules are not sufficiently ionized in the LC/MS system and therefore no accurate mass is obtained. Example OL-7b

But bath&apos; and the mixture was stirred overnight at ambient temperature. When the addition is complete, remove the cold night. The solvent was removed under reduced pressure, EtOAc EtOAc EtOAc (EtOAc). The obtained material was purified by EtOAc EtOAc (EtOAc) 4 NMR (500 MHz, DMSO-d6) δ ppm 3.80 (s, 3H), 3.85 (s, 3H), 5.29 (s, 2H), 7.13 (d, J=8.85 Hz, 2H), 7.59 (d, J =8.24 Hz, 2H), 7.91 (d, J=9.16 Hz, 2H), 7_98 (d, J=8.24 Hz, 2H). LC (Condition 1): RT = 2.56 min; LRMS: (M+H) + C17H1605. Calculated value: 30i.il, experimental Ο value: 301.22. Example OL-7c

CI

Example OL-7c was prepared from Example _L_7b according to the same procedure as used in Preparation Example OL-la. 4 NMR (500 MHz, DMSO-d6) δ ppm 5.09 (s, 2H), 5.18 (s, 2H), 5.34 (s, 2H), 7.15 (d, J = 8.85 Hz, 2H), 7.62 (d, J =8.55 Hz, 2H), 7.95 (d, J=9.16 Hz, 2H), 8.00 (d, J=8.55 Hz, 2H). LC (Condition 1): RT = 2 36 min; LRMS: (M+H) + Ci7H15Cl2 〇3 calc.: 337 〇4, Experimental value: 337.09 ° 146976.doc -69- 201038558 Example OL-7d

An example 〇L-7d was prepared from the example -7L-7c according to the same procedure used in the preparation example 〇L-lb. 4 NMR (500 MHz, DMS 〇-d6) δ ppm 4.49 (s, 2H), 4.57 (s5 2H), 5.38 (s, 2H), 7.19 (d, J=8.85 Hz, 2H), 7.66 (d, J = 8.24 Hz, 2H), 8.00 (d, J = 8.85 Hz, 2H), 8.05 (d, J = 8.24 Hz, 2H), 8.45 (s, 6H). LC (Condition 1): RT = 1.26 min; LRMS: (M+H) + C17H19N203 Analysis calculated: 299.14, Experimental value: 299.19 ° Example OL-7e

Example OL-7e was prepared from Example -7L-7d according to the same procedure as used in the preparation example OL-lc. 1HNMR (500 MHz, DMSO-ίi6) δ ppml.30-1.47 (m, 18H), 1.65-1.89 (m, 6H), 2.01-2.20 (m, 2H), 3.24-3.34 (m, 2H), 3.34-3.43 (m, 2H), 4.09-4.25 (m, 2H), 4.44-4.68 (m, 4H), 5.33 (s, 2H), 7.13 (d, J = 8.85 Hz, 2H), 7.60 (d, J = 8.24 Hz, 2H), 7.99 (dd, J=20.29, 8.09 Hz, 4H), 8.04- 146976.doc -70- 201038558 8.22 (m, J=31.74 Hz, 2H). LC (Condition 2): RT = 1.53 min, </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; Example OL-7f

, Ν^νΝ, Βο〇/ ΗΝ^ 0 According to the same procedure used in the preparation example 〇L-ld, the example OL-7f was prepared from the example -7L-7e.咕NMR (500 MHz, DMSO-d6) δ ppm 1.06_ 1.52 (m, 18H), 1.69-2.08 (m, 6H), 2.08-2.30 (m, 2H), 3.33, 3.43 (m, 2H), 3.52 ( s, 2H), 4.75 (s, 1H), 4.83 (s, 1H), 5.〇6 (s5 2H), 6.92-7.10 (m, J=7.63 Hz, 2H), 7.20-7.33 (m, 13⁄4) 7.40 (d, J=7.63 Hz, 2H), 7.46 (d, J=8.55 Hz, 1H), 7.64 (d J=7.63 Hz, 2H), 7.75 (d, J=7.93 Hz, 2H), 11.47-12.18 (m 2H). </RTI> <RTI ID=0.0></RTI> </RTI> <RTI ID=0.0></RTI> Example OL-7g

Instance OL-7g was prepared from the example 〇L_7f according to the same procedure used for the preparation of Example OL-. 1h NMR (500 MHz, DMSO-d6) δ ppm 1.93_ 2.07 (m, 2H), 2.13 - 2.26 (m, 2H), 2.40-2.48 (m, 3H), 3.3l 146976.doc -71 · 201038558 3.52 ( m, 5H), 4.91-5.09 (m, 2H), 5.21 (s, 2H), 7.17 (d, J=8.85 Hz, 2H), 7.57 (d, J=8.24 Hz, 2H), 7.87 (d, J =8.85

Hz, 2H), 7.93 (d, J = 8.24 Hz, 2H), 8.03 (d, J = 16.79 Hz, 2H), 9.78 (s, 1H), 9.95 (s, 1H), 10.31 (s, 2H). Note: The signal of taste t^NH is too wide to determine the chemical shift. </RTI> <RTI ID=0.0></RTI> </RTI> <RTI ID=0.0></RTI> Example OL-7 Instance OL-7 was prepared from Example _L_7g according to the same procedure used for the preparation of Example OL-1. NMR (500 MHz, DMSO-d6) δ ppm 1.90 (d, 1 = 2.44 Hz, 2H), 2.04 (d, J = 3.66 Hz, 4H), 2.21 (s, 2H), 2.36 (d, J = 1.83 Hz , 2H), 2.42-2.46 (m, 4H), 2.83 (br. s, 4H), 2.99-3.11 (m, 2H), 3.98 (d, J = 7.02 Hz, 2H), 5.18 (s, 4H), 5.42 (d, J=8.55 Hz, 2H), 7.08-7.28 (m, 3H), 7.50-7.67 (m, 11H), 7.73 (d, J = 7.32 Hz, 2H), 7.80 (d, J=7.93 Hz , 2H), 7.85-7.98 (m, J = 10.3 8 Hz, 1H). Note: The signal for imidazole NH is too wide to determine the chemical shift. LC (Condition 3): RT = 2.94 min; LRMS: (M+H) + C47H52N803 Analysis calculated: 777.42, Experimental value: 777.51; HRMS: (M+H)+ C47H53N803 analytical value·· 777.4241, experiment Value: 777.4265. Example OL-8

146976.doc -72· 201038558 Example OL-8 in the form of a trifluoroacetate salt was prepared by substituting cap-1 for each acid in the same manner as described for Example OL-7. Example ---------| Jy acid J «=- RT (LC-condition); MS data OL-8 &quot;Λ HNV 〇 T N cap-4 — --- 丨丨 RT=3.70 min. </RTI> <RTI ID OL-9

Add palladium/carbon (10%, 300 mg) to a solution of 4,4·-(ethin-1,2diyl)dibenzoic acid diacetic acid (2 g, 6.76 mmol) in methanol (100 mL) . The suspension was purged with N2, placed under 1 atm h2 (balloon) and stirred overnight at ambient temperature. The mixture was then filtered through a pad of Celite (CELITE®) and the solvent was concentrated under reduced pressure. A white solid (1.42 g) was obtained and used without further purification. 4 NMR (500 MHz, CDC13) δ ppm 2.98 (s, 4H), 3.90 146976.doc -73- 201038558 (s, 6H), 7.18 (d, J=7.32 Hz, 4H), 7_93 (d, J=7.32 Hz, 4H). LC (Condition 1): RT = 2.65 min; LRMS: (M+H) + C18H1904: Calculated: 299.21. Example OL-9b

Instance OL-9b was prepared from Example -9L-9a according to the same procedure used for the preparation of </RTI> OL. 4 NMR (500 MHz, CDC13) δ ppm 3.02 (s, 4 Η), 4.67 (s, 4H), 7.25 (d, J = 8.24 Hz, 4H), 7.86 (d, J = 8.24 Hz, 4H). </RTI> <RTI ID=0.0></RTI> </RTI> <RTI ID=0.0></RTI> Example 〇L-9c

Example OL-9c was prepared from the example 〇L_9b according to the same procedure as used in the preparation example OL-lb. NMR (500 MHz, DMSO-d6) δ ppm 3.03 (s, 4H), 4.51 (s, 4H), 7.43 (d, J = 8.55 Hz, 4H), 7.92 (d, J = 8.24 Hz, 4H), 8.50 (s, 6H). LC (Condition 3): RT = 1.90 min; LRMS: (M+H)+ </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; 146976.doc -74· 201038558 Example 〇L-9d

〇 Example -9L-9d was prepared from the example 〇L_9c according to the same procedure as used in the preparation example OL-lc. lH NMR (500 MHz, CDC13) δ ppm m.56 (m, 18H), 1.83-2.00 (m, 4H), 2.08-2.38 (m, 4H), 3.01 (s, 4H), 3.32-3.65 (m, 4H), 4.28 (br. s, 1H), 4.39 (br. s, 1H), 4.63-4.71 (m, 2H), 4.72-4.84 (m, J=4.58 Hz, 2H), 7.01 (s, 1H) , 7.18-7.33 (m, 4H), 7.47 (s, 1H), 7.87 (d, J = 7.93 Hz, 4H). LC (Conditions 〇 : RT = 2 56 min ; LRMS : (M+H). Calculated for C38H5iN408: 691.3 7. Found: 691.48. Example OL-9e

An example 〇L-9e was prepared from the example 〇L-9d according to the same procedure as used in the preparation example 〇L-ld. 4 NMR (500 MHz, DMSO-d6) δ ppm 1.15/1.39 (spin isomer, s, 18H), 1.75-1.92 (m, 3H), 1_96 (s, 3H), 2.09-2.27 (m, J= 32.04 Hz, 2H), 2.81-2.90 (m, 4H), 3.31-3.40 (m5 2H), 3.52 (s, 2H), 4.66-4.88 (m, J=35.40 Hz, 146976.doc -75- 201038558 2H) , 7.14 (d, J=7.02 Hz, 4H), 7.21 (s, 1H), 7.31-7.41 (m, 1H)&gt; 7.51 (d? j=6.41 Hz, 1H), 7.61 (d5 J=7.93 Hz, 3H), 11.62-12.08 (m, 2H). LC (Condition 1): rt = 2.20 min; LRMS: (M+H)+ C38H49N604 calc.: 653.38, calc.: 653.47 ° Example 0L-9f

Prepare 2.05 (m, 2H), 2.11-2.25 (m, 2H), 2.40-2.47 (m, 4H), 2.89-3.03 (m, 4H) from the example 〇L_9e according to the same procedure used in the preparation example OL-1e. , 3.32-3.39 (m, 2H)} 3.40-3.49 (m, 2H), 5.02 (t, J-7.78 Hz, 2H), 7.32 (d, J=8.24 Hz, 4H), 7.80 (d, J=8.24 Hz' 4H), 9.91 (s, 2H), 10·32 (s, 2H). Note: The imidazole signal is too wide to determine the chemical shift. Lc (Condition 5): RT = 2 52 min; LRMS: (M+H) + C28H33N6 calc. Example OL-9 Example OL-9 was prepared from the example 〇L_9f according to the same procedure as in the preparation example OL-b. H NMR (just MHz, DMs 〇 d6) δ ppm 丨82 ι % (m, 2H), 1.97-2.10 (m, 4H), 2.15-2.27 (m, J=4.58 Hz, 2H) U2.45 (m , 4H), 2·72_2. δ8 (m, 4H), 2.94 (s, 5H), m 146976.doc -76- 201038558 3.07 (m, 2H), 3.97 (t, J=9.77 Hz, 2H), 5.17 (d, J=6.10 Hz, 2H), 5.41 (s, 2H), 7.12 (s, 1H), 7.38 (d, J=7.32 Hz, 4H), 7.51-7.62 (m, 9H), 7.69 (d, J = 7.93 Hz, 4H), 7.93 (s, 2H). Note: The signal for imidazole NH is too wide to determine the chemical shift. LC (Condition 5): RT = 2.87 min; LRMS: (M+H) + C48H55N802 calc.: 775.44, Found: 775.51; HRMS: (M+H)+ C48H55N802 Analysis calculated: 775.4448, experimental value : 775.4454. Example OL-10 to OL-13

Example OL-10 to OL-13 in the form of a trifluoroacetate salt were prepared by substituting cap-1 for each acid in the same manner as described for Example OL-9. Example Λ Acid RT (LC-condition); MS data OL-10 杏仁 Almondic acid RT = 2.64 min. </ RTI> <RTI 11 HV, ο cap _4 RT = 2.88 min. </RTI> <RTI ID=0.0></RTI> <RTI ID=0.0></RTI> </RTI> <RTI ID=0.0></RTI> </ RTI> </ RTI> </ RTI> <RTIgt; • 77- 201038558 Example human RT (LC-condition); MS data acid OL-12 〇 Ph 丫ΗΙ ^ Ι Ο Ο ΝΗ RT = 4.20 min. </RTI> <RTI ID I Cap -46 OL-13 〇Ηή 丫. ΝΗ ΝΗ Cap - 48 RT = 5.11 min. </ RTI> <RTI 14

Triethyl decane (5.84 mL) was added dropwise to a solution of 4-mercaptobenzoic acid vinegar (5 g, 30.46 mmol) and tribromide (0.273 g, 0.61 mmol) in acetonitrile (75 mL). , 3 6.55 mmol), and stir the opaque solution for 15 minutes at ambient temperature. The volatiles were removed under reduced pressure and the residue was dissolved in EtOAc EtOAc EtOAc. The organic layer was washed with water and brine, dried (MgSO. The recovered solid was then subjected to flash chromatography (silica gel; 10-20% ethyl acetate /hexane) to afford OL-14a (3.05 g). 4 NMR (500 MHz, CDC13) δ ppm 3.84 (s, 6H), 4.65 (s, 4 Η), 7.51 (d, J = 8.24 Hz, 4 Η), 7.95 (d, J = 8.24 Ηζ, 4 Η). </RTI> <RTI ID=0.0></RTI> </RTI> <RTI ID=0.0></RTI> Example OL-14b

实施 Example -14L-14b was prepared from Example OL-14a according to the same procedure as used in Preparation Example OL-1a. 4 NMR (500 MHz, DMSO-d6) δ ppm 4.67 (s, 4H), 5.19 (s, 4H), 7.55 (d, J = 8.24 Hz, 4H), 7.98 (d, J = 8.24 Hz, 4H). LC (Condition 5): RT = 3.85 min; LRMS: 〇 (M+H) + C18H17C1203 calc.: 351.05, calc.: 351.06 ° Example OL-14c Ο

Example -14L-14c was prepared from Example 1 according to the same procedure as used in Preparation Example OL-1b. NMR (500 MHz, DMSO-d6) δ ppm 4.55 146976.doc -79- 201038558 (s, 4H), 4.69 (s, 4H), 7.57 (d, J=8.24 Hz, 4H), 8.02 (d, J= 8.55 Hz, 4H), 8.53 (s, 6H). LC (Condition 1): RT = 1.29 min; LRMS. (M+H) + C18H21N2O3: 313. Example OL-14d

Example OL-14d was prepared from Example -14L-14c according to the same procedure as used in the preparation example OL-lc. 4 NMR (500 MHz, DMSO-d6) δ ppm 1.34/1.40 (spin isomer, 3, 1811), 1.70-1.92 (111, 611), 1.99-2.20 (m, 2H), 3.24-3.33 (m, 2H), 3.35-3.44 (m, 2H), 4.11-4.25 (m, 2H), 4.50-4.65 (m, 4H), 4.66 (s, 4H), 7.53 (d, J=8.24 Hz, 4H), 7.99 (d5 J=7.93 Hz, 4H), 8.09-8.23 (m, 2H). LC (Condition 1): RT = 2.49 min; LRMS: (M+H) + C38H5iN4 〇9 Analysis: 707.36, experimental value · 707.50. Example OL-14e

Instance OL-14e was prepared from Example -14L-14d according to the same procedure as used in Preparation Example OL-1d. 4 NMR (500 MHz, DMSO-d6) δ ppm 1.14/1.39 (spin isomer, s, 18H), 1.76-2.06 (m, 6H), 2.08- 146976.doc • 80 - 201038558 2.30 (m, 2H) , 3.31-3.41 (m, 2H), 3.52 (s, 2H), 4.49 (s, 4H), 4.70-4.78 (m,1H), 4.79-4.90 (m,1H), 7.29/7.35 (rotomers) , d, J = 7.93 Hz, 4H), 7.40-7.54 (m, 2H), 7.71/7.61 (spin isomer, d, J = 7.93 Hz, 4H), 11.72-12.19 (m, 2H). LC (Condition 1): RT = 2.14 min; LRMS: (M+H) + C38H49N. Example OL-14f

Example OL-14f was prepared from Example -14L-14e according to the same procedure used for the preparation example OL-le. 1H NMR (500 MHz, DMSO-d6) δ ppml·94-2.06 (m, 2H), 2.11-2.25 (m, 2H), 2.38-2.48 (m, 4H), 3.32-3.50 (m, 4H), 4.60 (s , 4H), 4.92-5.06 (m, 2H), 7.48 (d, J=7.93 Hz, 4H), 7.89 (d, J=7.93 Hz, 4H), 8.04 (s, 2H), 9.78 q (s, 2H ), 10·28 (s, 2H). Note: The signal for imidazole NH is too wide to determine the chemical shift. LC (Cond. i): RT = 1 69 min; LRMS: (M+H) + CmHmNsO: 469.27, calc.: 469.34 ° Example OL-14 The same procedure used in the preparation example OL-1, from the example 〇L_14f preparation example 0!^-14.1^1 should be 11 (5〇〇 bribe 2, 〇^^0-(16)3卩卩1111.82-2.11 (m, 6H), 2.18 (d, J=6.10 Hz , 2H), 2.31-2.47 (m, 4H), 2.98-3.10 (m, 2H), 3.92-4.07 (m, 2H), 4.59 (s5 4H), 5.10- 146976.doc -81 - 201038558 5.22 (m, 2H), 5.42 (s, 2H), 7.07-7.13 (m, 2H), 7.40-7.51 (m, 4H), 7.54-7.67 (m, 10H), 7.75 (d, J = 7.32 Hz, 4H). The signal of imidazole NH is too wide to determine the chemical shift. The signal of the Me group of the cap is below the solvent peak. LC (Condition 4): RT = L83 min ; LRMS : (M+H) + C48H55N803 Analysis calculated value: 791.44, Experimental value: 791.60. HRMS: (M+H) + C48H55N803. Calcd.: 791.4397, found: 791.4406 ° Example OL-15 to OL-19

Examples OL-15 to OL-19 in the form of the trifluoroacetate salt were prepared by substituting cap-1 with the respective acid in the same manner as described for Example OL-14. Example 酸 Acid ' ΙίΒΙ*ίΒ8=^TM 1 |„ RT (LC-condition); MS data 1 OL-15 HO Mandelic acid RT=2.86 min. LC (Condition 4); LCMS: C44H45N6〇5 Analysis calculated: 737.34, Experimental value: 737.38; HRMS: (M+H)+ C44H45N605 calc.: 737.3451, found: 737.3452 OL-16 HFV0, 0 cap-4 RT=3.45 min LC (condition 4) ; LCMS : ( Analysis of calculated values for M+H)+ C48H5iNs〇7: 851.39, Experimental value: 851.40; HRMS: (M+H)+ C48H51N807 Analysis calculated value: 851.388 Experimental value: 851.3910 146976.doc • 82- 201038558

Example Λ Acid RT (LC-condition); MS data OL-17 0 Ph 丫~, —丫. ^NH cap -45a RT = 1.16 min. LC (Cond. 2); LCMS: (m.sup..sup.sssssssssssssssssssssssssssssssssssssssssssssss 18 〇Ηί^ΙγΟ ^ΝΗ Cap·46 RT=1.24 min. LC (Condition 2); LCMS: C5〇H56Ni〇〇5 analytical value·· 877·45, experimental value·· 877.70 ; HRMS : (M+H)+ C5〇H57Ni〇〇5 analysis ten calculation : 877.4513, Experimental value: 877.4506 · OL-19 0 Phv^ ΗΝγΟ αΝΗ Cap-48 RT=1.43 min. LC (Condition 2); LCMS: (m+H)+ C56H65Ni 〇〇5 calc.: 957.51, calc. 957.84; HRMS: (M+H)+ C56H65N10O5 analytical value · 957.5139, experimental value: 957.5142 Example OL-20

ο 146976.doc • 83- 201038558

Sodium hydride (0.76 g, 18.95 mmo, 6 g wt%) was slowly added to a solution of methyl 4-(hydroxymethyl)benzoate (3 mL of amine (25 mL). The obtained dark blue solution was stirred at ambient temperature. The resulting yellow solution was stirred for one hour with a portion of methyl 3-(bromomethyl)benzoate (3 76 §, &quot; Μ mmol), and then the volatiles were removed under reduced pressure. The residue was taken up in EtOAc EtOAc (EtOAc)EtOAc. Example OL-20a (2.49 g) as a clear oil. A NMR (300 MHz, CDC13) δ ppm 3.91 (d, J-1.83 Hz, 6H), 4.61 (d, J = 2.56 Hz, 4H), 7.39- 7.49 (m, 3H), 7.54-7.61 (m, 1H), 7.93-8.00 (m, 1H), 7.99-8.07 (m, 3H). LC (Condition 1) · RT = 2.56 min ; LRMS : (M+ H) + C18H1905 analytical calculated value: 3 i 5 · 12, experimental value: 3 i 5.22. Example OL-20b

Example OL-20b was prepared from Example -20L-20a according to the same procedure used for the preparation example OL-la. 4 NMR (500 MHz, CDC13) δ ppm 4.65 (d, J=4.58 Hz, 4H), 4.69 (d5 J=3.36 Hz, 4H), 7.47-7.54 (m, J=7.63, 7.63 Hz, 3H), 7.62 (d, J = 7.63 Hz, 1H), 7.89 (d, J = 7.93 Hz, 1H), 7.93-8.00 (m, 3H). LC (Condition 1): RT = 2.34 min; LRMS: (M+H)+ CUH 丨7C1203 calc.: 146976.doc ·84· 201038558 351.05, experimental value: 351·12 °

Example 〇L-2〇C

Nh2 Instance OL-20c was prepared from the example 〇l_2〇b according to the same procedure as used in the preparation example OL-lb. 4 NMR (300 MHz, DMSO-d6) δ ppm 4.57 (d, J = 2.93 Hz, 4H), 4.68 (d, J = 5.85 Hz, 4H), 7.52-7.67 (m, J=B.60, 8.60 Hz , 3H), 7.73 (d, J=7.68 Hz, 1H), 7.90-8.10 (m, 4H), 8.53 (s, 6H). LC (Condition i): rt = 1.32 min; LRMS: (M+H)+ C18H21N203 Analysis calculated: 3i3 i5, experimental value: 313.24 ° Example OL-20d

实施 Example OL-20d is prepared from the example 〇l_20c according to the same procedure as used in the preparation example OL-lc. NMR (500 MHz, DMSO-d6) δ ppm 1.39/1.34 (spin isomer, 3, 18 deduction, 1.69-1.95 (111, 611), 2.00-2.18 (m, J = 23.80 Hz, 2H), 3.23- 3.33 (m, 2H), 3.34-3.43 (m, 2H), 4.11-4.23 (m, 2H), 4.50-4.63 (m, 4H), '4.65 (d, J=6.71 Hz, 4H), 7.48-7.56 (m, 3H)} 7.66 (d, J=7.63 Hz, 1H), 7.89- 146976.doc -85- 201038558 8.02 (m, 4H), 8.06-8.25 (m, 2H). LC (conditions!): RT =2 53 min ; LRMS : (M+H) + C38H51N409 analytical value · 7〇7 36, Experimental value: 707.44. Example OL-20e ?oc Η

Example OL-20e was prepared from the example 〇L-20d according to the same procedure as used in the preparation example OL-ld. NMR (500 MHz, DMSO-d6) δ ppm 1.14/1.39 (spinomer, 3, 1811), 1.76-2.07 (111, 611), 2.08-2.29 (m, 2H), 3.31-3.40 (m, 2H), 3.52 (br s, 2H), 4.44-4.59 (m, J=8.55 Hz, 4H), 4.75 (br. s, 1H), 4.83 (br. s, 1H), 7.08-7.23 (m, 2H), 7.30 (d, J = 7.63 Hz, 2H), 7.34-7.50 (m, 2H), 7.53-7.67 (m, 1H), 7.68-7.79 (m, 3H), 11.70-12.22 (m, 2H). </RTI> <RTI ID=0.0></RTI> </RTI> <RTI ID=0.0></RTI> Example OL-20f

146976.doc •86- 201038558 According to the same procedure used in the preparation example Shen Qi, the example 〇L-2〇f is prepared from the example 〇L_2〇e. 1H NMR (500 MHz, DMS〇_D6) s ppm i 94_ 2.08 (m, 2H), 2.12-2.24 (m, 2H), 2.39-2.48 (m, J=5.19 Hz, 4H), 3.27-3.49 (m , 4H), 4.6i (d, J=4 88 Hz, 4H), 4 94 5 〇9 (m, J=7.93 Hz, 2H), 7.38 (d, J=7.32 HZj 1H), 7.45-7.53 (m ,

3H), 7.83 (d, 】=7·63 Hz, 1H), 7.90 (d, J=7.02 Hz, 3H), 8.07 (s, 2H), 9.86 (br. s, 2H), 10.33 (br. s , 2H). Note: The signal for imidazole NH 〇 is too wide to determine the chemical shift. </RTI> <RTI ID=0.0></RTI> </RTI> <RTI ID=0.0></RTI> Example OL-20 Instance OL-20 was prepared from Example 〇L 2 〇f according to the same procedure used for the preparation of Example OL-1. lHNMR (500 MHz, DMSO-d6) δ ppml.84-1.95 (m, J - 5.19 Hz, 2H), 1.95-2.09 (m, J = 8.24 Hz, 4H) 2.15-2.28 (m, 2H), 3.02 (q , J=7.73 fjz, 2H), 3.93-4.05 (m, Ο 2H), 4.61 (br. s, 4H), 5.12-5.22 (m, 2H), 5.42 (br.s, 2H), 7.12 (br. s, 1H), 7.39 (s, 1H), 7.45-7.51 (m, J = 7.32 Hz, 3H) 7.53-7.64 (m, 9H), 7.66-7.82 (m, 4H), 7.96 (s, 2H). Note: The signal for imidazole NH is too wide to determine the chemical shift. The signal for the Me group of the cap is below the solvent peak. </RTI> <RTI ID=0.0></RTI> </RTI> <RTI ID=0.0> HRMS: (M+H)+ calcd. 146976.doc • 87 · 201038558 Examples OL-21 to OL-25

Examples 0L·21 to 〇L·25 in the form of trifluoroacetate were prepared by substituting cap-1 with each acid in the same manner as described for Example OL-20. Examples Hydric acid RT (LC-condition); MS data OL-21 Ηδ mandelic acid RT = 2.97 min. LC (Cond. 4); LCMS: (M+H) + C4^5N calc. calc.: 737.34, calc.: 737.46; HRMS: (M+H)+ C44H45N605 calc.: 737.3451, calc.: 737.3459 OL -22 ΗΝγ°χ 0 Cap-4 RT=3_59 min. </ RTI> <RTI 23 0 phVV, —丫0 /NH cap-45a RT=1.15 min. LC (Condition 2); LCMS: (M+H) + C48H52N10O5. Calculated value: 849·42 'Experimental value: 84946; HRMS: calculus: 849.42 〇〇, experimental value: ----- - 146976.doc -88- 201038558 Example. Acid RT (LC-condition); MS data OL-34 〇ph 丫V 岫丫. Factory ‘cap-46 RIM.24 min. LC (Cond. 2); mp. : 877.4510 OL-25 0 Ph 丫Ηή 丫0 〇rNH Cap -48 RT=4.89 min. LC (Condition 4); LCMS: (M+H) + C56H64N10O5: 1 Calculated value: 957.51, found: 957.82; HRMS: (M+H)+ C56H65N1G〇5 Analysis calculated value: 957 5139, Experimental value: 957.5150 Example Dl

Example D-1, step a

146976.doc -89- 201038558 To 15 minutes, to W-Boc-L-proline (7.14 g, 33.17 mmol), HATU (13.32 g '35.04 mmol), 2-amino-1-(4- benzene Add A^TV-isopropylethylamine (is mL, 103.3 mmol) to the heterogeneous mixture of ethyl ketone hydrochloride (8.13 g '32.44 mmol) and DMF (105 mL) and under ambient conditions The mixture was stirred for 55 minutes. Most of the volatiles were removed in vacuo, and the residue was partitioned between ethyl acetate (3 mL) and water (2 mL). The organic layer was washed with EtOAc (EtOAc)EtOAc. A silica gel sieve was prepared from the residue, and subjected to flash chromatography (yield: 50-60% ethyl acetate / hexane) to afford D-la (12.8 g) as a white solid. NMR (500 MHz, DMSO-d6) δ ppm 1.40/1.34 (two apparent broad single peaks, 9H), 1.90-1.70 (m, 3H), 2.18-2.20 (m, 1H), 3.30-3.23 (m, 1H), 3.43-3.35 (m, 1H), 4.22-4.12 (m, 1H), 4.53 (dd, /=18.1, 5.6, 1H), 4.61 (dd, /=18.3, 5.7, 1H), 7.75 (br d, J = 8.6, 2H), 7.92 (br d, J = 8.0, 2H), 8.25-8.14 (m, 1H). LC (Condition 7): RT = 1.70 min; LRMS: (M+Na)+

Analytical calculated value of CuHuBrNsNaO4: 433 〇7, experimental value: 433.09 ° Example D-1, step b

A mixture of D-la (12.8 g, 31.12 mmol) and NH4OAc (12.0 g, 155.7 mmol) in xylene (155 mL) was heated at 140 ° C for 2 hours. The volatile component was removed in vacuo, and the residue 146976.doc -90-201038558 was carefully partitioned between ethyl acetate and water, after which sufficient NaHC03 saturated solution was added so that after shaking the two-phase system, the aqueous phase The pH is slightly alkaline. The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organics were washed with EtOAc (EtOAc m. The resulting material was recrystallized from ethyl acetate / hexanes to yield two portions of the imidazole D-lb as a pale yellow solid, which weighed 5.85 g. The mother liquor was concentrated in vacuo and subjected to flash chromatography (EtOAc: 30% ethyl acetate /hexane) to afford 2.23 g. 4 NMR (500 MHz, DMSO-d6) δ ppm Ο 1.40/1.15 (apparent broad single peak, 9H), 2.30.75 (m, 4H), 3.36 (m, 1H), 3.52 (apparent broad single peak, 111), 4.86-4.70 (111, 111), 7.72-7.46/7.28 (m, 5H), 12.17/11.92/11.86 (m, 1H). </RTI> <RTI ID ·· 392.0959. The optical purity of two samples of Example D-lb was evaluated according to the palm HPLC conditions described below (combined batch ee &gt;99%; EG = 96.7% of the sample obtained by flash chromatography): tube Column: ChiralpakAD, 10 μιη, 4.6x50 mm Solvent: 2% ethanol/heptane (equal strength) Flow rate: 1 mL/min Wavelength: 220 or 254 nm Relative residence time: 2.83 min (i?), 5.34 min (51 ). 146976.doc -91- 201038558 Example D-l, step c

Pd(Ph3P)4 (469 mg '0.41 mmol) was added to D-lb (4.01 g, 10.22 mmol), bis(pinadol) diboron (5.42 g, 21.35 mmol), potassium acetate (2.57 g, 26.21 mmol) and a mixture of 1,4-dioxane (8 〇mL) in a pressure tube. The pressure tube was purged with nitrogen, capped and heated at 80 ° C for 16.5 hours in an oil bath. The reaction mixture was filtered and concentrated in vacuo. The crude residue was carefully partitioned between CH2C! 2 (150 mL) and aqueous medium (50 mL water and 10 mL NaHC03 sat.). #CH2C12 The aqueous layer was extracted and dried (MgSO.sub.4). The obtained material was purified by flash chromatography (yield of the sample together with the solvent of the solvent; 20-3 5% ethyl acetate / CH.sub.2 C.sub.2) to give an example D-1 c as an off-white solid, which was contaminated with pinacol. The relative molar ratio of Example D-1C to pinacol was about 10: l^H NMR). After about 25 days under high vacuum, the sample weighed 3.925 g. 4 NMR (500 MHz, DMSO-d6) δ ppm 1.45-1.10 (m, 21 Η), 2.27-1.77 (m, 4 Η), 3.36 (m, 1 Η), 3.52 (apparent broad unimodal, 1H), 4.86- 4.70 (m, 1H), 7.79-7.50/7·34· 7.27 (m, 5H), 12.22/11.94/11.87 (m, 1H). LC (Condition 7): RT = 1.64 min; LRMS: [M+H]+ C24H35BN3 〇4 calc.: 440.27, 440.23. 146976.doc -92· 201038558 Example D-l, step d Ο

To D-lc (320 mg, 〇·85 mmol), 1,4-diiodobenzene (loo mg, 0 3 mmol) and sodium hydrogencarbonate (180 mg, 2.18 mmol) in dimethoxyethane (2.4) A stirred suspension of mL) and water (7 mL) was added (17.5 mg, 0.015 mmol) in one portion with hydrazine triphenylphosphine and heated to 9 ° C for 2 h. The reaction was diluted with ethyl acetate and washed with saturated sodium hydrogen sulfate. The organic layer was dried over sodium sulfate &lt The filtrate was dissolved in decyl alcohol, filtered through a nylon syringe filter, and purified by preparative HPLC to afford D-ld (101.1 mg, 20% yield) as a white solid. 4 NMR (500 MHz, DMSO-A) δ ppm 1.17 (br s, 9H), 1.41 (br s, 9H), 1.80-2.06 (m, 4H), 2.13-2.32 (m, 4H), 3.35-3.43 ( m, 2H), 3.56 (br s, 2H), 4.80 (br s, 2H), 7.54 (d, J-10.07 Hz, 2H), 7.73 (d, /=7.63 Hz, 4H), 7.79 (s, 4H ), 7.83 (d, «7=8.24 Hz, 4H). LC (Condition 6): RT = 2.5 (m); 146976.doc -93- 201038558 Example D-l, step e

In addition to the use of sterol (1 mL) instead of chloroform, 1 e was prepared from D-1 d according to the same private sequence used to prepare 七7. This gave D-le (101.5 mg, 96% yield) as a brown solid. H NMR (500 MHz, DMSO-d6) δ ppm 1.93-2.30 (m, 9H), 2.32-2.44 (m, 3H), 4.69-4.86 (m, 2H), 7.68-7.87 (m, 12H), 7.90 (d, J = 8.24 Hz, 2H), 9.48-9.75 (m, 2H). LC (Condition 6): RT = 1.99 min; HRMS: (M+H) + C32H33N6 calc. Example D-1 According to the same procedure used in the preparation example OL-1, since! )_16 Preparation Example d-1 (difluoroacetate). This gave an example D_丨 (3 7 8 mg, 54% yield) as a brown solid. 4 NMR (500 MHz, DMSO-A) δ ppm 2.05 (d, 7=8.55 Hz, 8H), 3.49-3.57 (m, l〇H), 3.94 (br s, 2H) 5.52 (d, *7=7.63 Hz, 2H), 7.31-7.47 (m, 10H), 7.72 (d «7=7.02 Hz, 2H), 7.87-8.01 (m, 12H). LC (Condition 6): RT = 2 41 min; HRMS: (M+H) + C52H51N8 〇6 analytical value · 883.3932 ′ Experimental value: 883.3947. 146976.doc • 94· 201038558 Example 0-2

Example D-2 (difluoroacetate). This gave Example D-2 (15.4 mg, 38% yield) as pale yellow solid. 4 NMR (500 MHz, DMSO-i/6) δ ppm 2.50-1.70 (m, 14H), 2.98-2.62 (m, 6H), 4.05-2.98 (m5 4H), 5.79-5.12 (m, 4H), 8.20 -7.10 (m, 24H), 10.25 (br s, 2H). Note: The signal for imidazole NH is too wide to determine the chemical shift. LC (Condition 6): RT = 2.08 min; HRMS: (M+H) + C52H55N8 〇2 〇 calc. Example D-3 〇γ°

146976.doc -95· 201038558 Example D-3, step a

To 6-bromo-3,4-dihydronaphthalene-l(2i/)-one (available from J &amp; W pharmLab, LLC) (3.00 g, 13.33 mmol) and 48% hydrogen bromide (2 〇μί, 1333) Ment) A solution of bromine (683 μί, 13.33 mmol) in acetic acid (7 mL) was added dropwise to a cold (1 (rc) solution in acetic acid (120 mL). After the addition was completed, the mixture was allowed to warm to room temperature. The mixture was stirred at room temperature for 1 hour, then diluted with a two-gas simmer and washed with water (3 X), a saturated solution of sodium hydrogencarbonate, dried over anhydrous sodium sulfate and concentrated. 4.19 g, 97% yield) - solidified to a white solid upon standing under high vacuum. This material was used without further purification. 1H NMR (500 MHz, DMSO-c/6) δ ppm 7.85 (1 Η, d , /=8.5 Hz), 7.71 (1H, s), 7.62 (1H, dd, */=8.5, 1.8 Hz), 5.06 (1H, dd, J=6.l, 3.7 Hz), 2.93-3.15 (2H , m), 2.55-2.64 (1H, m), 2.32-2.42 (1H, m). RT = 2.67 min (condition 6); LC/MS: [M+H]+ Cl〇H979Br2 分析304.90, experimental value: 304.91. Examples D-3bl and D-3b2 (step b) According to the same procedure used in the preparation example M3 step g, from D_3a and appropriate Preparation of D-3bl and D-3b2 by Boc-protected proline. 146976.doc -96· 201038558 D-3bl BW〇Mc RT=3.00 and 3.19 min (condition 3) ; LC/MS : [M+Na]+ For C20H2579BrNO5: 460.08 'Experimental value: 460.10 D-3b2 b, w〇\5h Η RT=2.99 and 3.17 min (condition 3); LCMS: [M+Naf C21H2579BrN05 calc.: 472.07, 472. Examples D-3cl and D-3c2 (step c)

D-3cl and D_3c2 were prepared from D-3bl and D-3b2, respectively, according to the same procedure as used in the preparation of Example M3. D-3cl Brm HN-^ )....' Β〇(ΤΝ) Prepared from D-3bl ^ NMR (500 MHz, A/eOD, lack of taste sputum-Η) δ ppm 7.32-7.43 (3H, m), 4.86 -4.97 (1H, m), 3.63-3.74 (1H, m), 3.47-3.57 (1H, m), 2.98-3.07 (2H, m), 2.83 (2H, d, J=8.2 Hz), 2.25-2.45 (1H, m), 2.00-2.11 (2H, m), 1.93-1.99 (1H, m), 1.25-1.48 (9H, 2s). RT = 2.24 min (condition 3) ; LC/MS : [M+H Analysis of C+QH2579BrN3〇2: 418.13, found: 418.10. HRMS: [M+H]+ C21H2579BrN302 Analysis calculated: 430.1125, Experimental value: 430.1124. D-3c2 ΗΝ 乂 Boc - Ν士η Η Preparation of D-3b2 RT=2.28 min (Condition 3); LC/MS: [M+H]+ QnH^BrN3. 2 Analysis calculated value: 430.11, Experimental value: 430·16. HRMS: [M+H]+ For C21H2579BrN302: calcd.: 430.1. Analysis of the value of +H)+〇2ιΗ2381ΒιΝ3〇2: 430 10, experimental value: 429.98. 146976.doc 97- 201038558 Example D-3dl (step d)

D-lb (1.5 g, 3,82 mmol), triphenylphosphine (0.20 g, 0.77 mmol), diethylamine (4.25 mL, 40.70 mmol), copper telluride in a microwave vessel at room temperature 1) (40 mg, 0.21 mmol) and -diqi (bistriphenylphosphine)! Bar (11) (149 mg, 0-21 mmol) in hexane (1.4 mL) was added ethynyl trimethyl sulfide Burn (0·59 mL, 4.25 mmol). The container was capped and irradiated at 120 ° C for 25 minutes. Two identical 1.5 g reactants were used in succession. The reaction mixture was diluted with diethyl ether and ethyl acetate, combined and shaken with &lt;RTI ID=0.0&gt; After standing for 20 minutes, the suspension was suction filtered, and the pad was washed with diethyl ether and ethyl acetate. The organic phase was then separated, washed with brine, dried over sodium sulfate and concentrated. The crude product (4.2 g) in the form of a slightly smear-red foam was isolated, dissolved in dioxane, and directly added to a column of Thompson 110 acid. Take 2〇〇/0 B

The degree of dissolution, obtained after evaporation of the eluent, is in g, 40% yield), which is used directly. LC/MS: [Μ+ΗΓ C23H32N3 〇 2Si calc.: 41 〇 23, found: 410.12. 146976.doc •98- 201038558 D-3d2 to D-3d4 were prepared according to the procedure described for D-3dl. D-3d2 HN~^ )'&quot;i\ Boc - Prepared from M3 step h RT=2.34 min (Condition 3); LC/MS: [M+H]+ C24H32N302Si Analysis calculated value: 422.22, experimental value: 421.85 . D-3d3 RT=2.43 min (Condition 3); LC/MS: [M+H]+ C26H34N302Si Analysis calculated value: 448.24, experimental ΗΝ 乂).·丨丨\ B0C^N^h Η |D_3c2 Preparation value: 448.82. D-3d4 RT=2.51 min (Condition 3); LC/MS: (M+H)+ C26H32N302Si Analysis calculated: 446.23, experiment HN^if V, H Prepared from D-3c3 446.05.

Example D-3el (step e)

Potassium carbonate (91 mg, 0.66 mmol) was added in one portion to a solution of D-3dl (2.7 g, 6.6 mmol) in MeOH (60 mL). The mixture was stirred for 1 hour and then concentrated in vacuo to reduce the volume. The residue was dissolved in methylene chloride and directly added to a 130 g Thompson. The residual 146976.doc-99-201038558 was subjected to gradient elution with 15% ethyl acetate in hexane to 100% ethyl acetate. After evaporation of the solvent, D-3el (2.04 g, 87% yield). A small amount (about 20 mg) of the product was then subjected to preparative HPLC to afford a crude D-3el sample as a white solid. NMR (500 MHz, MeOD, lack of imidazolium-oxime) δ ppm 7.68 (2H, d, J = 7.9 Hz), 7.46 (2H, d, /=8.2 Hz), 7.34-7.40 (1H, m), 4.89 ( 1H, m), 3.64-3.73 (1H, m), 3.49 (1H, m), 3.49 (1H, s), 3.31-3.34 (1H, m), 2.25-2.44 (1H, m), 1.99-2.11 ( 3H, m), 1.25 and 1.47 (9H, 2s). RT = 1.63 min (Cond. 3); LC/MS: (M+H) + C2 〇H24N302 calc.: 338. D-3e2 to D-3e5 were prepared according to the procedure described for the alkyne D-3el. </ RTI> <RTIgt; </RTI> </RTI> <RTI ID=0.0></RTI> </RTI> <RTIgt; b〇c-nQ々h H Prepared from D-3d3 D-3e4 RT=1.88 min (Condition 3); LC/MS: (M+H)+ C23H24N302 Analysis: HN-^ y ni, 374.19, experiment Value: 374.04. B〇c_NN&lt;i'vH H Prepared from D-3d4 146976.doc •100- 201038558 Example D-3fl (step f)

Boc &quot; D-3e5 / = 〇 N RT = 1.75 min (Cond. 3); LC/MS: [M+H] + C25H27N403 calc.: 431.21. Ο Η \ Using the procedure outlined for D-3hl and Example OL-1, prepared from D-3e4 and Cap-51 in a thick-walled screw cap vial, at room temperature, to Example D-3cl (300 mg, 0.717) Methyl), D-3el (315 mg, 0.932 mmol), triethylamine (0.40 mL, 2.87 mmol) and copper moth (1) (13.7 mg, 0.072 mmol) in anhydrous DMF (6 mL) To the mixture degassed by argon, hydrazine (triphenylphosphine) (83 mg, 0.072 mmol) was added in one portion. The mixture was stirred at room temperature for 16 hours and stirred at 40 ° C for 16 hours, followed by the addition of Cul (10 mg), TEA (0.4 mL) and Pd (PPh3) 4 catalyst (40 mg). Since the reaction was not completed by LCMS after 32 hours. The mixture was further stirred at 60 ° C for 10 hours, then cooled to room temperature, diluted with ethyl acetate, THF and water and suction filtered. The organic phase of the filtrate was separated, washed with saturated aqueous sodium bicarbonate and brine, then dried over anhydrous sodium sulfate and evaporated. The residue was dissolved in methylene chloride and added directly to a Thompson 80 g cartridge. At 30°/. The residue was subjected to gradient elution with ethyl acetate in hexanes to 100% ethyl acetate, then ethyl acetate in 0% methanol to 20% methanol in ethyl acetate. .doc -101 - 201038558 D-3fl (366.7 mg, 68% yield). A small amount (about 20 mg) of the product was then subjected to preparative HPlc to give a purer sample D-3fl sample as a brown solid. iH NMR (500 MHz, MeOD, lack of misoazole &gt; 1-Η) δ ppm 7.73 (2H, d, J = 8.2 Hz), 7.47-7.57 (4H, m), 7.41 (2H, br s), 4.96- 5.09 (1H, m), 4.89-4.96 (1H, m), 3.69 (2H, br s), 3.54 (2H, br s), 3.04-3.13 (2H, m), 2.83-2.94 (2H, m), 2.30-2.50 (2H, m), 1.94-2.17 (6H, m), 1.27-1.49 (18H, 2s). RT = 2. 〇 6 min (Cond. 3); LC/MS: (M+H) + C4 〇H47N604 calc.: 675.37. D-3f2 to D-3f4 were prepared according to the procedure described for D-3fl. D-3f2

</ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; D-3f3

RT = 2.14 min (Cond. 3); LC/MS: [M+H] + C44H49N6O4 calc.: 725. D-3f4

LCMS: </RTI> </RTI> <RTI ID=0.0></RTI> </RTI> </RTI> </RTI> </RTI> 146976.doc • 102· 201038558 Example D-3gl (step g)

Boc to D-3f1 (260 mg, 〇·39 mm〇1) in anhydrous methylene chloride (5 liters of activated manganese dioxide (2 〇g, 23 Μ (4)) The liquid was 6 small _, followed by the addition of active manganese dioxide (1. 〇g). The suspension was stirred at room temperature for another 14 hours, followed by suction filtration with MeOH-dried celite pad, and then with Me 〇H Washing the simmering several times. Then concentrating in a vacuum and filtering the liquid to give a D_3 as a yellow solid called 225" mg 82 / (&gt; yield). Then a small amount (about 20 mg) of the product was prepared for the preparation of muscle C. , a purer D-3gl sample in the form of a pale brown solid. iH NMR (500 MHz, MeOZ), lack of taste Ν Η Η δ δ ppm 8 43 (ih, this $

Hz), 8.19 (1H, br s), 7.68-7.78 (5H, m), 7.62 (2H, d, J=8.2 Hz), 7.54 (1H, s), 4.90-5.27 (2H, m), 3.76- 3.85 (1H, m)5 〇3.66 3.74 (1H, m), 3.51-3.66 (2H, m), 2.35-2.60 (2H, m), 1.94-2.21 (6H, m)j 1.49 (6H, br s) , 1.27 (6H, br s), 1.14 (6H, br s). Rt=2.12 min (Condition 3); LC/MS: (M+H)+ C4Gh45n6o4 Analysis: 673. D_3g2 was prepared according to the procedure described for D-3gl.

LCMS from D-3fi: 2.27 min (Cond. 3); LC/MS: (m+H) + C44H45N604 calc.: 721.35, calc.: 721.25 - 146976.doc 201038558 Example D-3hl (step h)

Except that methanol (1 mL) was used instead of dichloromethane, it was prepared from D-3fl, D-3gl 'D-3f2, D-3g2 and D-3f4 according to the same procedure used to prepare 〇L_上e. This is done after vacuum concentration of the solvent to give D-3hl to D-3h6 as the hydrochloride salt (or in the form of difluoroacetate when further purified by preparative HPLC). D-3hl ——. Wide NH H niiJ prepared from D-3fl~~—— RT=1.4+4 min (Condition 3) ; LC/MS : [M+H]+ CmH^N6 Analysis calculated value: 475.26, Experimental value: 475.16. D-3h2 broad NH H mJ Prepared from D-3gl 1H NMR (500 MHz, Λ/eao, lack of imidazole NH) δ ppm 8.46 (1H, d, /=8.5 Hz) 8.21 (1H, s), 7.84 (2H, d, J=8.2 Hz): 7.70-7.80 (4H, m), 7.64 (2H, d, J=8.5 Hz), 5.15 (1H, s), 4.97 (1H, s), 3.62-3.70 (1H, m ), 3.56 (3H, s), 2.65-2.75 (1H, m), 2.55-2.64 (1H, m), 2.17-2.53 (6H, a series of multiplets). Rt=i.61 min (Condition 3); LC/MS: (M+H) + C30H29N6: 473. D-3h3 — ---- NH HA was prepared from D-3G --- RT=1.62 min (Condition 3); LC/MS: (M+H)+ C32H29N6 Analysis: 497.25, Experimental value: 497.13 . Preparation of D-3h4 from D-3fi RT = 1.62 min (Cond. 3); LC/MS: [M+H]+ C34H33N6 calc. 525. 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。. D-3h6,. </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; Examples D-3 to D-11 (final step)

Examples D-3 to D-1 were prepared from D-3hl to D-3h6 and the appropriate acid according to the same procedure used for the preparation of Example OL-1. This gave examples D-3 to D-11 in the form of trifluoroacetate after purification by HPLC. D-3 RT = 1.80 min (Condition 3); LC/MS: [M+H] + Λ ΝΗ ΝΗ C44H53N806 Analysis calculated value: 789.4 实实 &lt; ΓΝ 九 值: 789.27. NMR (500 MHz, lack of imidazolium-oxime) δ ppm 7.86-7.91 (1H, m), 7.73-7.80 (2H, m), 7.64-7.71 (2H, m), 7.50-7.59 (3H, m), 5.59 -5.65 and 5.16-5.31 (2H, 2m), 4.21-4.29 (2H, m), 4.06-4.16 (2H, m), 3.81-3.93 (2H, m), prepared from D-3hl and cap 51 3.67 (6H , s), 3.15-3.24 (2H, m), 2.95-3.07 (2H, m), 2.51-2.65 (2H, m), 2.25-2.37 (2H, m), 2.14-2.23 (4H, m), 1.99 -2.11 (2H, m), 0.09-0.95 (12H, m), 0.97-1.05 (2 H, m). H6976.doc -105- 201038558

146976.doc -106- 201038558

146976.doc •107- 201038558 Example Ml

To the pressure tube (S)-2-(5-(4-phenylene)_ ΐΗ-σ米° sit-2-carbilol bite-1 _ tert-butyl formate (D-lb) (0.675 g Add Pd(Ph3P)4 (〇.〇78 g' 0.067 mmol) to a solution of 1.21 mmol) and 1,2-bis(trimethyltin) acetylene (0.3134 g '0.891 mmol) in DMF (5 mL) The mixture was boiled with nitrogen for 1 minute, and then heated at 90 ° C for 15 hours. The volatile component was removed in vacuo and the residue was directly purified by BIOTAGE® (110 g; EtOAc) to give a yellow-yellow foam. Alkyne Mla (430 mg) containing unidentified impurities and residual solvents. 4 NMR (DMSO, δ = 2.50 ppm, 400 MHz): 12.23/1 1.98/11.91 (three broad single peaks, 2H), 7.80- 7.3 5 (m, 10H), 4.84-4.76 (m, 2H), 3.54 (m, 2H), 3.39-3.33 (m, 2H), 2.28-1.78 (m, 8H), 1.40 (br s, 7.54H) , 1.16 (br s, 10.46H). LC/MS: [M+H]+ C38H45N604 calc. calc.: 649.35 </ br> </ br> </ br> </ br>

Add HC1/dioxane (4 N; 8 mL, 32.0 mmol), CH 2 C 12 (1 mL) to bis-amine phthalate Mla (0.427 g, 0.658 mmol)

MeOH (1.0 mL) and the heterogeneous mixture was stirred for 5 h. The volatiles were removed in vacuo and the residue was crystallisjjjjjjjjjj 1H NMR analysis indicated that the sample may contain residual dioxane (about 1 molar equivalent). lH NMR (DMSO, 5 = 2.50 ppm, 400 MHz): 10.29 (br s, 2H), 9.73 (br s, 2H), 8.11 (s, 2H), 7.96 (d, J=8.3, 4H), 7.67 (d, J=8.6, 4H), 4.97 (br m, 2H), 3.47-3.31 (m, 4H), 2.50-2.36 (『 m" overlaps with the solvent signal, 4 prints, 2.23-2.14 (111, 211), 2_07-1.95 (m, 2H). LC/MS: [M+H]+ C28H29N6 calc.: 449.25, 449.23 Example Ml to pyrrolidine Mlb/4HC1 (70.5 mg, 0.103 mmol), (S)-2-(methoxycarbonylamino)-3-mercaptobutyric acid (36.3 mg, 0.207 mmol) and DIEA (0.1 mL, HATU (0.069 g, 0.181 mmol) was added to a solution of 0.573 mmol) in DMF and was stirred at room temperature for 70 minutes. The volatile component was removed in vacuo and the residue was dissolved in MeOH and reversed. Purification by HPLC (MeOH/water/TFA) afforded m. m. m. </RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; /95% LC/MS (Condition 3): Rt = 1.78 min. 4 NMR (DMSO, δ = 2.50 ppm, 400 MHz): 8.10 (br s, 2H), 7.88-7.83 (m, 4H), 7.71 (d, J=8.3, 3.91H), 7.34 (d, J=8.5, 2H; NHC02), 6.92 (apparent broad singlet, 0.09H), 5.52 (br m , 0.17H), 5·12 (apparent triplet, 1.93Η), 4.11 (apparent triplet, 2Η), 3.89-3.77 (m, 4Η), 3_54 (s, 5.52H), 3.33 (s, 0.48) H), 2.41-2.33 (m, 2H), 2.21-1.93 (m, 8H), 0.89 (apparent triplet, 0.91H), 0.83/0.79 (two overlapping double peaks, J=6.8/6.8, 11.09H LC/MS : [M+H]+ C42H51N. Examples M2 to M2.1 Examples M2 to M2.1 in the form of trifluoroacetate were prepared from pyrrolidine M1b and the appropriate acid using the modified purification schemes described in the following table according to the procedure described for the Preparation Example M1.

Example R Analytical data M2 ViPh uses two different reverse phase HPLC conditions (column: Phenomenex Luna, 30x100 mm, S10; MeOH/water/TFA) and (Waters Sunfire, 30 O NHC〇2Me x100 mm, S5; CH3CN/water) 7TFA) Purified 〇LC (Conditions 9 and 10): Homogeneity Index &gt; 95%. LC/MS (Condition 3): Rt = 2.04 min. LC/MS: Anal. Calcd.: 437. M2.1.p was purified using two different reverse phase HPLC conditions (column: Xbridge, 19x100 mm, S5; MeOH/water/TFA) and (Waters Sunfire, 30x100 mm5 S5; CH3CN/water/TFA). LC (Conditions 9 and 10): Homogeneity means 95% of O' l4HC02Me. LC/MS (Condition 10d): R «= 2.82 min. </RTI> <RTI ID=0.0></RTI> </RTI> <RTI ID=0.0></RTI> 146976.doc •110- 201038558 Example M3

Example M3, step a

Ο π to (S)-5-(methyl group) ° ratio 17 each. Add a solution of dibutyl chlorodiphenyl decane (25.6 g, 93 mmol), Et3N (12.1 mL, 87 mmol) and DMAP in a solution of dimethyl-2-one (10 g, 87 mmol) in CH2C12 (50 mL) (1.06 g, 8.7 mmol). The mixture was stirred at room temperature until the starting pyrrolidone was completely consumed, and then diluted with CH2C12 (50 mL) and washed with water (50 mL). The organic layer was dried (Na2SO4), EtOAcjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj rate). W-NMR (400 MHz, DMSO-d6, δ=2·5 ppm) 7·69 (br s, 1H), 7.64-7.61 (m, 4H), 7.50-7.42 (m, 6H), 3.67-3.62 ( m, 1H), 3.58-3.51 (m, 2H), 2.24-2.04 (m, 3H), 1.87-1.81 (m, 1H), 1.00 (s, 9H). LC/MS (M+H)+=354.58 ° 146976.doc -Ill - 201038558 Example M3, step b

Adding solid dicarbonate in portions to a solution of decyl ether M3a (31.2 g, 88.3 mmol), Et3N (8.93 g, 88 mmol) and DMAP (1.08 g, 8.83 mmol) in CH2C12 (200 mL) Di-tert-butyl ester (3 8.5 g '177 mmol) and stirred at 24 ° C for 18 hours. Most of the volatiles were removed in vacuo and the crude material was dissolved in 2% Et EtOAc / hexanes and applied to a 2 L funnel containing &lt;RTI ID=0.0&gt; And 2 L 50〇/. The EtOAc was dissolved. After concentrating the desired fractions in a rotary evaporator, a white solid slurry was formed, which was filtered, washed with hexanes and dried in vacuo to give the amine succinic acid M3b (32.65 g, 82% yield) as a white solid. rate). 111^^]^11(400]^1 along, 〇]\48〇- d6, 5=2.5 ppm) 7.61-7.59 (m, 2H), 7.56-7.54 (m, 2H), 7.50-7.38 (m, 6H), 4.18 (m, 1H), 3.90 (dd, J=10.4, 3.6, 1H), 3.68 (dd, J=10.4, 2.1, 1H), 2.68-2.58 (m, 1H), 2.40-2.33 (m5 1H), 2.22-2.12 (m, 1H), 2.01-1.96 (m, 1H), 1.35 (s, 9H), 0.97 (s9 9H). LC/MS (M-Boc+H)+ = 354.58. Example M3, step c

146976.doc •112· 201038558 A three-necked flask equipped with a thermometer and a nitrogen inlet was fed with urethane M3b (10.05 g ' 22.16 mmol) and toluene (36 mL) and cooled to -55 ° C. In the bath. When the internal temperature of the mixture reaches -50. (:, triethylborohydride (23 mL 1.0 M/THF, 23.00 mmol) was added dropwise over 30 minutes, and the mixture was spoiled for 35 minutes while maintaining the internal temperature between -50 ° C and -45 ° Between C. Hunig's base (16.5 mL, 94 mmol) was added dropwise over 1 Torr. Then, DMAP (34 mg, 0.278 mmol) was added in one portion, followed by addition of trifluoromethane over 15 minutes. Acetic anhydride (3·6 mL, 25.5 mmol) while maintaining the internal temperature between _50 ° C and -45 ° C. After 1 min, the bath was removed and the reaction mixture was stirred for 14 hours while warming To ambient temperature, it was diluted with toluene (15 mL), cooled in ice-water bath, and slowly treated with water (55 mL) over 5 min. The phases were separated and washed with water (50 mL, 2 EtOAc) The crude material was purified by EtOAc EtOAc EtOAc (EtOAc) ): 111=2.41111111. 111 is ^01 (400 ^ 1112, 0 PCT 80-d6, 5 = 2.5 ppm) 7.62-7.58 (m, 4H), 7.49-7.40 (m, 6H), 6.47 (br s, 1H ), 5.07/5.01 (overlapping wide double peak) ,1H), 4.18 (br s,1H), 3.89 (br s, 0.49H), 3.69 (br s, 1.51H), 2.90-2.58 (br m, 2H), 1.40/1.26 (overlapping wide single peak, 9H ), 0.98 (s, 9H). LC/MS: [M+Na]+=460_19. 146976.doc •113- 201038558 Example M3, step d TBDPS^0\,, V(~&quot;^

I

Boc M3d-1: trans-isomerized M3d-2: cis-isoformed for 15 minutes, cooled to hydrazine (-30 °C) to dihydropyrrole M3c (3.94 g, 9 〇mm〇1) (27 mL) Diethylation (19 mL, about 1.1 Μ, 20.9 mmol in 曱 曱) was added dropwise to the solution. After 1 minute, the gas iodide was added dropwise (stabilized on copper; 3.0 mL, 41.2 mm 〇i) and maintained at _25. (: stirring at bath temperature for 1 hour) and at -25 ° C and -21. (: stirring for 18.5 hours. The reaction mixture was exposed to air, and a 5 % by weight NaHC 3 saturated solution was slowly added (40 (m) quenched 'and then removed from the cooling bath and stirred at ambient temperature for 20 minutes. Filtered through filter paper and washed with a white cake at 5 mL of toluene. The organic phase of the filtrate was separated and taken with water ( 40 mL, 2x) Wash, dry (MgS 〇 4) and concentrate in vacuo. Use a BI〇TAGE® system (35 〇 Shi Shijiao, load the sample with 7% EtOAc/hexane; 7-20 〇/〇 The crude material was purified by EtOAc / EtOAc (EtOAc) elute elute elute elute Trans isomer ratio.] lc/Ms (Condition 7): Rt = 2.39 min. W-NMR (400 MHz, DMSO-d6, 6 = 2.5 ppm) 7.62-7.60 (m, 4H), 7.49-7.40 ( m, 6H), 3.77/3.67 (overlapping wide single peak, 3H), 3.11-3.07 (m, 1H), 2_23 (apparent broad single peak, 1H), 2.05-2.00 (m, 1H), l 56_15〇 ( m, 1H), 133 (very wide single peak '9H), 1.00 (s, 9H) . Square 8〇 (m, 1H), square 3〇 (m, Gang 146976.doc -114- 201038558 LC / MS: [M + Na] + = 474.14 Example M3, step e ~ (7.

I

Boc M3e-1: trans isomer M3e_2: cis isomer was added dropwise to a solution of the carbamate ether M3d-1/M3d-2 (3.13 g, 6.93 mmol) in THF (30 mL) over 5 min. TBAF (7.27 mL, 1.0 Μ in THF, 7.27 mmol) was added and the mixture was stirred at ambient temperature for 4.75 hours. After a saturated solution of NH4C1 (5 mL) was added, most of the volatiles were removed in vacuo, and the residue was partitioned between CH2C12 (70 mL) and 50% NH4Cl1 (30 mL). The aqueous phase was extracted with CH.sub.2Cl.sub.2 (30 mL). The crude material was purified using EtOAc (EtOAc: EtOAc: EtOAc: EtOAc) Contaminated by low Rf points. [Note: The exact cis/trans isomer ratio was not determined at this stage. ^-NMR (400 MHz, DMSO-d6, δ = 2.5 ppm) 4.70 (t, J=5.7, 1H), 3.62-3.56 (m, 1H), 3.49-3.44 (m, 1H), 3.33-3.27 ( m, 1H), 3.08-3.04 (m, 1H), 2.07 (br m, 1H), 1.93-1.87 (m, 1H), 1.51-1.44 (m, 1H), 1.40 (s, 9H), 0.76-0.71 (m, 1H), 0.26 (m, 1H). LC/MS (M+Na)+ = 236.20. 146976.doc -115- 201038558 Example M3, step f Ύψ ° Boc M3f-1: trans isomer M3f-2: cis isomer to alcohol M3e-1/M3e-2 (2.15 g, 10.08 mmol) A solution of Nal® 4 (6.46 g, 30.2 mmol) in H20 (31 mL) was added to a solution of CH3CN (20 mL) and CC14 (20 mL). RuC13 (0.044 g, 0.212 mmol) was then added and the heterogeneous reaction mixture was stirred vigorously for 75 min. The reaction mixture was diluted with H.sub.2O (60 mL). The combined organic phases were treated with 1 mL MeOH, left to stand for ca. 5 min, and then filtered over celite pad (CELITE®). The CELITE® was washed with CH.sub.2Cl.sub.2 (50 mL). W-NMR analysis of this crude material indicated the trans acid M3f-1: cis acid M3f-2: assuming the by-product 3- s-oxy-2-azabicyclo[3.1.0]hexane-2-carboxylic acid The molar ratio of butyl ester is 1.00:0.04:0.18. The crude material was dissolved in EtOAc (ca. 10 mL) under heating and was then inoculated at ambient temperature. After entering the cooling phase for about 15 minutes, rapid formation of crystals was observed. After about 1 hour, hexane (about 6 mL) was added and the mixture was chilled overnight (seemingly no more material precipitated). The mixture was filtered and washed with EtOAc/EtOAc (EtOAc (EtOAc)EtOAc. The mother liquor was concentrated in vacuo, and the residue was dissolved in EtOAc (3 mL) EtOAc, and then stood at ambient temperature for 1 hour, and then 3 hexanes were added and stored in the refrigerator for about 15 hours. Recovered in a similar manner 146976.doc -116- 201038558 The second batch of acid M3f-1 (grey crystals, 0.133 g) in a combined yield of 59%. Acid M3f-1: Rt = 1.48 min under the following HPLC conditions: solvent gradient 100% over 3 min A: 0% B to 0% A: 100% B (A = 1:9 Me0H with 0.1% TFA) /H20 ; B = 9:1 Me0H/H20 with 0.1% TFA; detected at 220 nm; PHENOMENEX®-Luna 3.0x50 mm S10 column. The melting point (decomposition) of the first batch = 147.5-149.5 °C. W-NMR (400 MHz, DMSO-d6, δ = 2.5 ppm) 12.46 (s, 1H), 3.88 (applied broad single peak, 1H), 3.27 (apparent broad single peak, 1H; overlap with water signal), 2.28 (br m,1H), 2.07 (apparent broad singlet, 1H), 1.56 (apparent monomodal, 1H), 1.40/1.34 (two overlapping singlet, 9H), 0.71 (m, 1Η), 0 · 45 (m, 1H). 13C-NMR (100.6 MHz, DMSO-d6, δ=39.21 ppm) 172.96, 172.60, 154.45, 153.68, 78.74, 59.88, 59.58, 36.91, 31.97,31.17, 27·77,27.52,14.86,14.53,13.69 «LC/ MS [M+Na]+=250.22. Analytical calculated values for CuHuNCU: C, 58.13; H, 7.54; N, 6.16. Experimental values (first batch): C, 58.24; H, 7_84; N, 6.07. The optical rotations of the first batch and the second batch (10 mg/mL in CHC13) were: [a] D = -216 and -212, respectively. Example M3, step g

Half of CH3CN (30 mL) to acid M3f-1 (1.697 g, 7.47 mmol) and 2-bromo-1-(4-bromophenyl)ethanone (2.01 g, 7.23 mmol) over 2 min DIEA (1.3 mL, 7.44 mmol) was added dropwise to the heterogeneous mixture and stirred at 146976.doc-117-201038558 for a period of 8 hours. The volatile component was removed in vacuo and the residue was dissolved in CH 2 Cl 2 (1 mL), washed with water (30 mL), dried (MgS 〇 4) and Oily ketone | M3g (3.076 g). i-NMR (400 MHz, DMSO-d6, δ=2·5 PPm): 7.92 (d, J = 8.3, 2H), 7.78 (d, J = 8.5, 2H), 5.61-5.42 (m, 2H), 4.16 (m,1H), 3.34 (“m” partially overlaps with the water signal, 1H), 2.40 (m, 2H), 1.63 (m, 1H), 1.41/1.35 (two overlapping “single peaks”, 9H), 0.74 (m, 1H), 0.53 (m, 1H). LC/MS: [M+Na] + calcd.

Feed ketoester M3g (3.07 g, 7.24 mmol), ammonium acetate (5.48 g '71.1 mmol) and diphenylbenzene (7 〇mL) into a 3 50 ml pressure tube, cap and oil bath (14 0 C) Heat for 4.5 hours. The reaction mixture was allowed to cool to room temperature and the volatile component was removed in vacuo. To the residue were added CH 2 Cl 2 (1 mL) and a 50% NaHC 3 saturated solution (30 mL), and stirred vigorously until gas ceased to escape, and the phases were separated. The organic layer was dried (MgSO4), concentrated in vacuo and purified with EtOAc EtOAc EtOAc EtOAc米„ MShGjOgrH-NMRMOOMI^DMSOOS.Sppm): 12.21 (s, 0.11H), 1.93 (s, 0.89H), 7.69 (d, J-8.8, 1.8H), 146976.doc -118- 201038558 7.62-7.55 (m, 0.4H), 7.53 (br d, J=2, 0.87H), 7.49 (d, J=8.5, 1.8H), 7.29 (br d, J=1.6, 0.13H), 4.59 (m, 1H) ), 3.41 (m, 1H), 2.37-2.17 (br m, 2H), 1.62 (m, 1H), 1.21 (extremely wide "single peak", 9H), 0.75 (m, 1H), 0.54 (m, 1H) LC/MS: [M+H] + C19H2381 BrN3〇2 analytical value 406.10' experimental value · 406.14. Example M3, step i

Pyrrolidine M3i (4HCl) was prepared from bromide M3h according to the procedure described for the synthesis of pyrrolidine Ml b (4HCl) from bromide D-lb. W-NMR (400 MHz, DMSO-d6, δ = 2.5 ppm): 10.51 (applied broad single peak, 4H), 8.08 (s, 2H), 7.92 (d, J = 7.8, 4H), 7.66 (d, J=8.5, 4H), 4.78 (m, 2H), 3.42 (m, 2H), 2.65 (m, 2H), approx. 2_53 (“m” partially overlaps with the solvent Q signal, 2H), 1.94 (m, 2H) , 1.10 (m, 2H), 0.86 (m, 2H). LC/MS: Anal. Calcd.: 437. Example M3 (and Examples M4-M7) Example m3 in the form of the trifluoroacetate salt was prepared from the guanidinium M3i (4 HCl) and the following table was highlighted by the procedure described for the synthesis example Μ1 and the appropriate acid. Analog Examples M4-M7. In the case of Example M7, the coupling step employed (S)-2-(methoxycarbonylamino)_3_methylbutyric acid and (s)_2_(methyladolyl)-2-(tetrahydro-2-indole) -&lt;» bottom _4_yl) acetic acid, etc., 146976.doc-119-201038558, and the resulting statistical product mixture was isolated by HPLC technique as described for Example M1. Example M3: LC (Conditions 9 and 10): Homogeneity Index > 95%. LC/MS (Condition 3): Rt = 1.89 min. </ RTI> <RTI ID=0.0></RTI> </RTI> <RTI ID=0.0></RTI>

Example Rt° Rt (Condition 3); Homogeneity Index % (Conditions 9 and 10); LC/MS data M4. η work. 1.74 min ; &gt;95% ; LC/MS : [M+H]+ C42H47N806 Analysis calculated: 759.36, Experimental value: 759.35 M5 ίο 4 /0 Ηί〇3-f° &gt; 1.98 min ; &gt;95% ; LC/MS : [M+H] + C46H51N806 calc.: 811.39, calc.: 811.37 M6 ίο π /0 ίο ΗΝ 1.67 min ; &gt;95% ; LC/MS : [M+H]+ C48H55N808 Analytical calculated value: 871.41, experimental value: 8 Ή.20 φ cP M7 ΗΝ^0 1.78 min ; &gt;95% ; LC/MS : [M+H]+ C46H53N807 Analysis calculated value: 829.40, Experimental value: 829.53 U ^ \ V

146976.doc -120- 201038558 Example M8-M9

NCS (0.0195 g, 0.143 mmol) was added to a solution of the title compound M3 (m.p. It was stirred at room temperature for 16 hours and at 50 ° C for 25 hours. The majority of the solvent was removed in vacuo and the residue was taken in MeOH and purified by reverse phase hpLC (MeOH/water/TFA) to afford the titled M8 trifluoroacetate (5 mg) Salt (17.5 mg).

Example Rt (Condition 3); Homogeneity Index % (Conditions 9a and 10a); LC/MS number = ~η M8 2.42 min; &gt;95% ; LC/MS : [M+H]+ C44H5〇C1N8〇6^ ^J^·^^— Experimental value · 821.31 ' M9 , —_ 2.95 min , &gt; 95%, LC/MS : [M+H] y77--- Experimental value: 855.24 Knife calculation value: 855.32 ' -_J Example M9.1-M9.2

Add NCS (0.021) to a solution of 146976.doc •121·201038558 (1.5 mL) in the form of the free base as Example M6 (obtained from the title, from the trifluoroacetate; 0.1059 g, quasi-Mcx free alkalinized square mm〇i) g, 0.158 mmol), and stirred at 50 ° C for 24 hours. The reaction mixture was diluted with MeOH (2.5 mL) and subjected to reverse phase HPLC purification conditions (XTERRA, 30x100 mm, S5; MeOH/water/TFA). The obtained sample was re-purified by different reverse phase HPLC conditions (Waters-Simfire, 30 X 100 mm, S5; acetonitrile/water/TFA) to give the compound M9.1 (38.8 mg) as a trifluoroacetic acid salt. 2 (32.6 mg). Example Rt (Condition 3); Homogeneity Index % (Conditions 9a and 10a); LC/MS Data M9.1: LC/MS: [M+H1+ C48H54C1Ns0; ^TM^ M9.2 0 1SI τύίΪμ * ' Τ · Γλ /ΓιΤΤΊ+ ττ οι χτ II------- /•/δ mm,,LL/iVlb · LM+HJ l44il53Ll2M8〇s&gt; 八上-- Experimental value: 939.40 Analysis calculated value: 939.34, ^ ________ — Examples M9.3

Under nitrogen, to cool (0 ° C) CH2C12 (22, JT added - ethyl zinc (1 Μ '60.5 mL, 6 0.5 mmo 1 in hexane), beer μ ' is called after 1 5 minutes Trifluoroacetic acid f 0.1 mL, 66.2 mmol) was added in 10 mL of EtOAc. The reaction was stirred for 15 minutes, and then 146976.doc -122· 201038558 was added dropwise to 10 mL of CH2C12 in dimethyl iodide (5.4 mL, 66·9 mmol). Continue to pour at 〇C: mix the reaction for 1 hour' and then add to (1) 2,2-diphenylethylene (2 g 'll.io mmol) in 1 〇 mL CH; 2C:12. The mixture was removed from the cooling bath and stirred at about 25 ° C for 20 hours under nitrogen. The reaction was quenched with 1N EtOAc (50 mL). The combined organic phases were washed with aq. EtOAc (EtOAc)EtOAc. The residue was subjected to flash chromatography (hexane) to give biphenyl hydrazine (. MU g) as a colorless oil. 1h NMR (400 MHz, CDC13) δ ppm 7.34-7.31 (m, 4H), 7.24-7.17 (m, 6H), 2.22-2.18 (m, 2H), 1.51-1.47 (m, 2H). Example M9.3, step b

To a solution of hydrazine M9_3a (3'3 g, 16.99 mmol) in 1,2-dimethoxyethoxy (197 mL) and water (82 mL) was added nbS (12_09 g, 67.9 mmol). The reaction flask was covered with aluminum foil and stirred at room temperature for 5 hours. The reaction was partitioned between EtOAc (EtOAc m. The residue was subjected to flash chromatography (yield eluted with chloroform; eluted with hexanes) to give a mixture of the dibromolysed product (31 g) as a white solid. By the palm 146976.doc •123- 201038558 SFC (Chiral pak AD-H column, 30&gt;&lt;25〇111111, 5 4111; 80% (3〇2-20% EtOH; 35°C; 150 bar) (bar); 70 mL/min, 20 min; 220 nm) separation of the stereoisomeric mixture, separation of two enantiomers: M9.3M (white solid, 1.1 g); 4 NMR (400 MHz , CDC13) δ ppm 7.43 (d, J=8.6 Hz, 4H), 7.02 (d, J=8.6 Hz, 4H), 2.12-2.09 (m, 2H), 1.47-1.43 (m, 2H); or: + 3 6 1.7 9 '3 · 15 mg in 1 mL CH C13, λ = 5 8 9 nm, 50 mm cuvette. M9.3b2 (white solid, 1.2 g); 4 NMR (400 MHz, CDCI3) δ ppm 7.43 (d, J=8.6 Hz, 4H), 7.02 (d, J=8.6 Hz, 4H), 2.12-2.09 (m, 2H), 1.47-1.43 (m, 2H); or: -376.70, 3.03 mg, λ = 589 nm, 50 mm cuvette in 1 mL CHC13. Example M9.3, step c

To dibromide M9.3 bl (0.8806 g, 2.501 mmol) and tributyl (ethethoxyethyl sulfonyl) tin (2.71 g, 7.50 mmol) in 1,4-diox (17 mL) Digas bis(triphenylphosphine) je(n) (〇1〇5 g, 〇15〇mmo1) was added to the solution. The reaction was thoroughly blown with nitrogen, sealed and at 80. (: Heat for 16 hours. Remove the reaction from the heating, add 1 N HCl (aq) (17 mL) and stir the mixture for 4 hr. dilute the mixture with water (20 mL) and

Extract with EtOAc (3 x 50 mL). The combined organic layers were dried over MgS 4 and filtered and vacuumed. The residue was purified by flash chromatography (35% ethyl acetate / hexanes) and the residue was purified by flashing (3 x 5 〇mL) to give a white solid 146976.doc -124 - 201038558 Ketone M9.3c (412.5 mg). 4 NMR (400 MHz, CDC13) δ ppm 7.92 (d, J=8.5 Hz, 4H), 7.23 (d, J=8.6 Hz, 4H), 2.61 (s, 6H), 2.32-2.28 (m, 2H), 1.67-1.63 (m, 2H). LC/MS: calcd for </RTI> &lt;RTI ID=0.0&gt; Example M9.3, step d

To a solution of the ketone M9.3c (0.4072 g, 1.463 mmol) in THF (7 mL), phenyltrimethylammonium tribromide (1.10 g, 2.93 mmol), and the mixture was stirred at about 25 ° C 15 hours. Volatile components were removed in vacuo and the residue was partitioned between water (25 mL) and CH2C12 (100 mL). The organic layer was dried with EtOAc (EtOAc m. </RTI> <RTI ID=0.0></RTI> </RTI> Example M9.3, step e r\

To a solution of dibromide M9.3d (ca. 1.463 mmol) and acid M3fl (0.698 g, 3.07 mmol) in acetonitrile (10 mL), Ν, Ν-diisopropylethylamine (0.537 mL, 3.07 mmol) And, at about 25 ° C, the reactants were mixed 5 times 146976.doc -125- 201038558. The volatile component was removed in vacuo, and the residue was dissolved in chloroform (4 mL) and loaded onto a hydrazine column and dissolved in 8 〇 / 〇 ethyl acetate / monomethane in 296 mL of solvent. A diketone vinegar M9.3e (0.723 g) in the form of a pale yellow foam was obtained which contained an unknown impurity. iH (4〇〇mHz, DMSO-d6) δ ppm 7.90 (d, J=8.0 Hz, 4H), 7.37 (d, J=8.3 Hz, 4H), 5.59-5.40 (m, 3H), 4.24-4.09 ( m, 2H), 3.37-3.25 (m, 2H), 2.47-2.36 (m5 5H)9 1.87-1.80 (m, 2H), 1.72-1.68 (m, 2H), 1.57-1.49 (m, 2H), 1.41 (s, 7H), 1.35 (s, 11H), 0.80-0.67 (m, 2H), 〇.58_0·48 (m, 2H). </ RTI> </ RTI> <RTI ID=0.0></RTI> Example M9.3, step f

In a sealed reaction vessel, a mixture of diketone ester M9.3e (0.723 g, 0.992 mmol) and ammonium acetate (1.529 g, 19.84 mmol) in xylene (1 mL) was heated at 140 ° C. hour. After the reactants were allowed to cool to ambient conditions, the volatile components were removed in vacuo. Dissolve the residue in 2%

MeOH/CHCl3 (50 mL), and sat. sat. NaHC.sub.3 (aq. The aqueous layer was extracted with EtOAc / EtOAc (EtOAc)EtOAc. The residue was dissolved in CHC13 (4 mL), loaded onto a Shih-hsing column and dissolved in 45% ethyl acetate/dichloromethane in 1296 mL. 146976.doc -126- 201038558

The imidazole M9.3f (261.7 mg) was obtained as an orange solid. iH NMR (400 MHz, DMS 〇-d6) δ ppm 12.08 (s, 0.5H), 11.81 (s, 1.5H), 7.64 (d, J = 8.3 hz, 3H), 7.55 (d, J = 8.3 Hz, 1H), 7.41 (d, J=1.7 Hz, 1.7H), 7.19-1.17 (m, 1.3H), 7.11 (d, j=8.3 Hz, 3H), 4.59 (apparent broad single peak, 2H), 3 41 (apparent broad single peak, 2h), 2.37-2.14 (m, 6H), 1.68-1.57 (m, 2H), 1.48-1.40 (m, 2H), 1.40-0.95 (br s, 18H), 0.79- 0.69 (m, 2H), 0.59-0.48 (m, 2H). Calcd for mp </RTI> </RTI> <RTI ID=0.0> Example M9.3, step g

A solution of the carbamate M9.3f (0.2391 g, 0.347 ◎ mmol) in 25% TFA/CH2C12 (1.7 mL) was stirred at about 25 °C for one hour. The volatile component was removed in vacuo to give pyrrolidine M9 3 g trifluoroacetate (328 mg) as a brown foam. 4 NMR (400 MHz, DMSO-d6) δ ppm 10.01 (br s, 2H), 7.70-7.68 (m, 6H), 7.20 (d, J = 8.6 Hz, 4H), 4.63-4.58 (m, 2H), 3.37-3.33 (m, 2H), 2.51-2.42 (m, 6H), 2.24-2.20 (m, 2H), 1.93-1.86 (m, 2H), 1.51-1.47 (m, 2H), 1.16-1.09 (m , 2H), 0.084-0.78 (m, 2H) ° LC/MS: [M+H] + C31H33N6 calc.: 489.28, calc.: 489.26 ° 146976.doc -127· 201038558 Example Μ9·3 to pyrrolidine M9.3g/trifluoroacetate (〇·〇834 g '0.088 mmol), (S)-2-(methoxycarbonylaminomercaptobutyric acid (0.034 g, 0.194 mmol) and N,N-diisopropyl Add HATU (0.070 g, 0.185 mmol) to a solution of EtOAc (0.12 mL, EtOAc) (EtOAc) The reaction mixture was purified by reverse phase HPLC (XTERRA, 30.times.sup.sssssssssssssssssssssssssssssssssss DMSO-d6) δ ppm 14.90-14.20 (bs, 3H), 8.00 (br s, 2H), 7.68 (d, J=8.3 Hz, 4H), 7.34 (d, J-8.6 Hz, 4H), 7.25 (d , J=8.6 Hz, 2H), 5.ΟΟ-4 95 (m, 2H), 4.42-4. 39 (m, 2H), 3.79-3.69 (m, 2H), 3.54 (s, 6H), 2.38-2.31 (m, 5H), 2.16-2.07 (m, 2H), 1.95-1.88 (m, 2H), 1.61- 1.58 (m, 2H), 0.97-0.90 (m, 8H), 0_80 (d, J = 6 5 Hz, 8H).

Rt=1.96 min (condition 3); homogeneity index>95% (conditions 9 and (9); LC/MS: [M+H]+ C45H55N8〇6 analysis calculated value: 8〇3 42, experimental value: 803.43 ° Example M9.4

146976.doc -128, 201038558 Preparation of fluoroacetate and (S)-2-(methoxycarbonylamino)-2-(tetrahydro-2H-pyran-4-yl)acetic acid M9.4. 4 NMR ( 400 MHz, DMSO-d6) δ ppm 15-14 (bs, 6H), 7.98 (br s, 2H), 7.66 (d, J=8.3 Hz, 4H), 7.34-7.32 (m, 5H), 4.98-4.94 (m, 2H), 4.50-4.46 (m, 2H), 3.84-3.78 (m, 6H), 3.54 (s, 6H), 3.32-3.18 (m, 4H), 2.39. 2.29 (m, 4H), 2.11 -1.97 (m, 2H), 1.97-1.88 (m, 2H), 1.6〇. 1.57 (m, 2H), 1.51-1.26 (m, 8H), 0.99-0.87 (m, 2H), Ο.84. 0 · 72 (m, 2H). Rt=1.77 min (Condition 3); Homogeneity Index &gt; 95% (Articles 9 and 10); LC/MS: [M+H]+ C49H59N808 Analysis calculated: 887.45, Experimental value: 887.50 ° Example M9 .5 and M9.6

实例Examples of preparations in the form of trifluoroacetate based on the procedure described in the preparation of Examples M9.3 and M9.4 from the corresponding stereoisomers of dibromide M9.3bl, starting from dibromide M9.3b2 M9.5 and M9.6. Example R Rt (Condition 3); Homogeneity Index (Conditions 9 and 10); LC/MS data: M9.5 1.98 min; &gt;95%; LC/MS: [M+H]+ C45H55N806. 803.42, experimental value: 803.43 ^ M9.6 〇α% 1.77 min ; &gt;95% ; LC/MS : [M+H]+ C49H59N808t stalk calculated value: 887.45, experimental value: 887.60 ^ ----__________ 146976 .doc -129- 201038558 Examples

Example M9.7 (trifluoro 7 s, v v acetate) was prepared from the dibromide M9.3d and IM12, 2c according to the procedure for the preparation of the compound M9.3. 4 NMR (400 MHz, DMS〇-d6) δ ppm 14.90-14 4? ru w h.42 (br s,4H), 8.02 (br s, 2H), 7.70 (d, J = 8.5 Hz, 4H), 7.36 (d, J==8.6 Hz, 4H), 7.25 (d, J=8.3 Hz, 2H), 5.07 (dd, J=l0.7 Hz/7”Hz, 2H), 4 18_ 4.13 (apparent triple Peak, 2H), 4.12_4, 〇8 (apparent triplet, 2h), 3 is (s, 6H), 3.42-3.37 (apparent triplet, 2H), 2 is called 2 39 (m, 2H), 2.37 -2.31 (apparent triplet, 2H), 2.02-1.93 (m, 2H), 1.87-1.78 (apparent quartet, 2H), 1.62-1.59 (apparent triplet, 2H), 1.14 (d, J = 6.3 Hz, 6H), 0.82 (d, J = 6.5 Hz, 6H), 0.77 (d, J = 6.8 Hz, 6H). Rt = 3.12 min (conditional lOd); homogeneity index &gt; 95 〇 / 〇 (conditions 9 and 10); LC/MS: [M+H] + C45H59N806 Analysis calculated: 8〇7 46, Experimental value: 807.45 . Example M9.8

146976.doc -130- 201038558 According to the procedure described for Preparation Example M9.4, an example of the preparation of ruthenium bromide M9.3d and acid M12.2c Μ9·7 (trifluoroacetate Rt = 3 〇 1 min (condition 10 (1) 'Beibei index> 95% (conditions 9 and 1); [匚/1^8: []^+11] + C49H63N8〇8 Analysis calculated value: 891.48, experimental value: 891.52. M10

By using the procedure described in J. Med_Chem., 49: 3520-3535 (2006) for the ethyl ester analog of the human title compound, 5 oxime from the quinone The procedure produces a compound containing diastereomeric impurities. 1H NMR (CDCI3, 400 MHz): 4.3 5 (edge 〇% 4.25 (m, 0.5H), 4.05 (m, 0.5H), 3.90 (m, 0 5ΗΊ 〇h 3·73 Cs 3Η), 2.20 (m, 1H), 2.00 (m5 2H), 1.65 (m, 1H) i . 5 Α '5〇/1·4η (two overlapping broad single peaks, 9H), 1.31 (d, J=6.0, 3H). Example M10 , step b

H3C

146976.doc -131 - 201038558 To a solution of the ester M10a (1.8 g, 7. 4 mmol) in ethanol (1 mL) was added dropwise lithium hydroxide (0.23 g, 9.62 mmol) in water (5 mL) The solution was stirred at room temperature for 17 hours. Most of the solvent was evaporated, and the residue was diluted with water, and 1N HCl was added dropwise to reach pH 3. Extracted with ethyl acetate (20 mL, EtOAc) (EtOAc)EtOAc. The white solid was filtered and dried in vacuo ( 142 g). iH NMR (CDC13, 400 MHz, d=7.24 ppm): 4.35 (m, 1H), 3.95 (m, 1H), 2.35 (m, 1H), 2.05 (m, 2H), 1.70 (m, 1H), 1.50 (br s, 9H), 1.25 (d, J = 7.1, 3H). Example Μ1 0, step c

Slowly add diisopropyl B to a solution of the acid M10b (2.16 g' 9.42 mmol) and 2-bromo-1-(4-bromophenyl)ethanone (2_62 g, 9.42 mmol) in acetonitrile (50 mL) Amine (1.645 mL, 9.42 mmol) ' and the reaction mixture was stirred at room temperature for 5 h. The solvent was removed in vacuo and the residue was partitioned between ethyl acetate and water (1:1 &apos; 100 mL). The organic layer was washed with EtOAc EtOAc m. 1η NMR (400 MHz, DMSO-d6, 5 = 2.5 ppm): 7.92 (d, J = 8.3, 2H), 7.78 (d, J = 8.5, 2H), 5.6-5.4 (m, 2H), 4.35 (m , 1H), 146976.doc -132- 201038558 3.85 (m, 1H), 2.25 (m, 1H), 2.05 (m, 2H), 1.60 (m, 1H), 1.5/1.4 (two overlapping wide single peaks, 9H), 1.18 (d, J = 6.6, 3H). LC/MS: [M+Na]+ calcd. Example M10, step d

Ammonium acetate (7.05 g, 91 mmol) was added to a solution of M10c (3.9 g, 9.15 mmol) in dimethylbenzene (60 mL). The reaction vessel was sealed and heated at 140 ° C for 5 hours. The solvent was removed in vacuo and the residue was partitioned between CH.sub.2Cl.sub.2 (1 mL) and water (1 mL). The organic layer was washed (NaHC.sub.3), dried (Na.sub.2) and evaporated in vacuo. The crude material was purified by flash chromatography (30-100%EtOAc) elute 1H NMR (DMSO-d6, 6 = 2.5 ppm, 400 MHz): 11.77 (s, 1H), 7.70 (d, J = 8.5, 2H), 7.52 (br s5 1H), 7.50 (d, J = 8.5, 2H) , 4.80 (m, 1H), 3.85 (m, 1H), 2.10 (m, 3H), 2.70 (m, 1H), 1.5/1.3 (overlapping wide single peak, 9H), 1.20 (m, 3H). </RTI> <RTI ID=0.0></RTI> </RTI> <RTI ID=0.0> Example M10, step e

146976.doc -133- 201038558 Pyrrolidine M1〇e (hydrochloride) was prepared from bromide M10d according to the procedure described for the synthesis of pyrrolidine Mib (hydrochloride) from bromide Dlb. Example M10 An example M1 oxime (trifluoroacetate) was prepared from the bromide pyrrolidine MlOe (hydrochloride) according to the procedure described for the synthesis of the compound M1* from pyrrolidine M3i (hydrochloride). H NMr (DMSO-d6, δ=2_5 ppm, 400 MHz): 8.05 (s, 2H), 7.85 (d, J=8.1, 4H), 7.69 (d, J=7.6, 4H), 7.56 (d, J -8.0, 2H), 5.5 (m, 0.4H), 5.0 (m, 1.6H), 4.75 (1.6H), 4.l〇(m, 0.4H), 3.95 (m5 2H), 3.50 (s, 6H ) 5 2.50-2.30 (m, 4H), 2.10 (m, 2H), 1.85 (m, 4H), 1.46 (d, J=6.6, 5H), 1.20 (d, J=6.8, 1H), 0.9-0.9 (m, 7.2H), 0.74 (d, J = 6.8, 4.8H). LC (conditions 9 and 10): homogeneity index &gt; 95%. LC/MS (Condition 3): Rt = 2.03 min. </RTI> <RTI ID=0.0></RTI> <RTI ID=0.0></RTI> EXAMPLES Mil-Ml2 Example Μ11-Μ12 trifluoroacetate was prepared according to the procedure described for example M10 and by using the appropriate acid.

146976.doc •134- 201038558 Example M12.1

ο Example ------------------- Rt (Condition 3); Homogeneity Index. /. (Conditions 9 and 10); LC/MS data Mil Η; 〇 〇 1.89 min ; &gt;98%; LC/MS : [Μ+Η]+ 〇»This is the score of 06: 763.39, experimental value :763.40. M12 ίο HN 0 1.82 min ; &gt;98%; LC/MS : [M+H]+ C48H59N808 analytical wing value: 875.45, experimental value: 875.42. to. Bilo bite M10e/hydrochloride (119 mg, 0.191 mmol), (S)-2-(indolylamino)-2-(tetrahydro-2-indole-π-n-butyl-4-yl)acetic acid (49 · 0 mg, 0.226 mmol) and (S)-2-(oxabinocarbyl)-3-mercaptobutyric acid (40.9 mg, 0.233 mmol) in DMF (5 mL) DIEA (0.200 mL, 1.147 mmol) and HATU (148 mg, 0.390 mmol), and the mixture was stirred at room temperature for 1 hour. The solvent was removed in vacuo and the residue was dissolved in EtOAc and purified by reverse phase HPLC (MeOH/TFA/water) to isolate the product mixture, one of the product of the example M12.1 (tri-gas acetate; Yellow foam; 55 mg). 4 NMR (DMSO-d6, 5=2.5 ppm, 400 146976.doc -135 - 201038558 MHz): 8.09-7.82 (m, 6H), 7.68-7.-55 (m, 6H), 5.00 (m, 2H) , 4.64 (apparent triplet, 2H), 4.21-3.75 (m, 6H), 3.53 (m, 6H), 3.17 (m5 2H), 2.33-2.21 (m, 6H), 1.85 (m, 3H), 1.62 -1.17 (“d” overlaps with “m”, J=6.6 Hz, 9H), 0.88 (m, 3.6H), 0.74 (d, J=6.8 Hz, 2.4H). LC (Conditions 9 and 10): Homogeneity Index &gt; 95%. LC/MS (Condition l〇h): Rt = 1.92 min. </RTI> <RTI ID=0.0></RTI> </RTI> <RTI ID=0.0></RTI> Example Μ 12.2

Example Ml2.2, step a

M12.2a-1 M12.2a-2 M12.2a-3 According to the procedure described in Tetrahedon Letters, 2003, 3203-3205, from (S)-5. Sideoxypyrrolidine-1,2-didecanoic acid 1-Terbutyl ester 2-nonyl ester to prepare the above three esters.

Example Ml2.2, step b /° -136· I46976.doc 201038558 Add borane-methyl sulfide complex to a solution of vinegar M12.2a-2 (1.4 g, 5_44 mmol) in THF (25 mL) 5.44 mL, 10.88 mmol) j J. The reaction mixture was heated at 40 ° C for 7 hours. The volatiles were removed in vacuo and the residue was partitioned betweenEtOAc and water (50 mL). The aqueous layer was extracted with EtOAc (30 mL). The resulting colorless oil was purified by flash chromatography eluting elut elut elut elut 4 NMR (CDC13, 5 = 7.24 ppm, 400 MHz): 4.29-4.18 (m, 1H), 3.78- 3.66 (m, 4H), 2·99 (apparent triplet, j=i〇.i, 1H) , 2.43 - 2.97 (m, 1H), 2.43-2.37 (m, 1H), 2.30-2.18 (m, 1H), 1.60-1.52 (m, 1H), 1.47/1.42 (two "single peaks", 9H) , 1.08-1.05 (m, 3H). Example M12.2, step c

HO To a solution of the ester M12.2b (1.69 g, 6-95 mmol) in ethanol (10 mL) was added a solution of LiOH (0.250 g ' 10.42 mmol) in water (5.00 mL) and allowed to react at room temperature The mixture was allowed to stand for 5 hours. The organic solvent was evaporated <RTI ID=0.0></RTI> and the residue was diluted with water (10 mL) It was cooled in an ice-water bath and acidified to a pH range of about 2 with 1 N HCl. It was then extracted with EtOAc (20 mL, EtOAc). The organic layer was dried <RTI ID=0.0>(M </RTI> </RTI> <RTI ID=0.0></RTI> </RTI> <RTIgt; ): 4.39-4.22 (m, 1H), 3.80-3.69 (m, 146976.doc -137· 201038558 0.91H), 3.59-3.35 (m, 0.18H), 3.03-2.89 (m, 0.91H), 2.51- 2.22 (m, 2H), 1.98-1.91 (m, 0.71H), 1.68-1.60 (0.29H), 1.50/1.44 (two "single peaks", 9H), 1〇9 (apparent multiplet, 3H) Example M12.2, step d

Add DIEA (1_051 mL, to a solution of M12.2c (1.38 g, 6.02 mmol) and 2-di-1-(4-diphenyl)ethanone (1.673 g, 6.02 mmol) in acetonitrile (35 mL) 6.02 mmol). It was disturbed for 5 hours at room temperature. The solvent was evaporated in vacuo and EtOAc EtOAc (EtOAc m. (2.71 g) which was used in the next step without further purification. 4 NMR (DMSO-d6, δ = 2.5 ppm, 400 MHz): 7.91 (m, 2H), 7.78 (d, J = 8.5 Hz, 2H), 5.60-4.90 (m, 2H), 4.29 (apparent triplet) ,1H), 3.61 (m, 1H), 2.85 (m, 1H), 2.35-1.80 (m, 2H), 1.65 (m, 1H), 1.40-1.32 (two single peaks, 9H), 1.02 (d, J = 6.5 Hz, 3H). LC/MS: [M+Na] </RTI> </RTI> <RTI ID=0.0></RTI> Example Ml2.2, step e

146976.doc • 138· 201038558 Ammonium acetate (4.65 g, 60.3 mmol) was added to a pressure tube containing a solution of ketone vinegar M12.2d (2.57 g, 6.03 mmol) in xylene (50 mL). The vessel was capped and heated at 14 °t for 5 hours. Volatile components were removed in vacuo and the residue was partitioned between DCM (50 mL) and water (40 mL). The organic layer was dried with Naj.sub.4 and concentrated in vacuo. The crude mixture was purified by flash chromatography eluting elut elut elut elut elut elut 4 NMR (DMSO-d6, δ=2.5 ppm, 400 MHz): 7.69 (d, J=8.5 Hz, 2H), 7.58-7.48 (m, 3H), 4.70 (m, 1H), 3.65 (m, 1H) , 3.02 (m5 1H), 2.37 (m, 1H), 2.22 (m, 1H), 1.74-1.54 (m, 1H), 1.37-1.08 (two single peaks, 9H), 1.03 (d, J = 6.3 Hz , 3H). </RTI> <RTI ID=0.0></RTI> </RTI> <RTI ID=0.0></RTI> Example M12.2, step f

Pyrrolidine Ml2.2f (hydrochloride) was prepared from bromide Ml2.2e according to the procedure described for the synthesis of pyridoxine 1 b (hydrochloride) from bromide D1 b. Example M12.2 to Bir-pyrrolidine M12.2f/hydrochloride (200 mg, 0.321 mm〇l) and (S)_2_(曱oxylkamino)-3-mercaptobutyric acid (124 mg, 0.707) Methyl acetate (0.337 mL, 1.928 mmol) and 146976.doc • 139-201038558 HATU (250 mg, 0.659 mmol) were added to a mixture of EtOAc. The volatile component was removed by vacuum, and the reverse phase was 1 〇&gt;1^(?1^11〇11^1^\-

Luna 30x100 mm, S10 Axia; MeOH/TFA/water) purified residue. The obtained sample was re-purified by a different reverse phase HPLC (Water-Sunfire 3 〇xl 〇〇 s ss; ACN/TFA/water) to give an example M12.2 trifluoroacetate (77.1 mg) as a pale yellow foam. 4 NMR (sterol-d4, δ = 3.29 ppm, 400 MHz): 7.90 (s, 2H), 7.74 (d, J = 8.6 Hz, 4H), 7_67 (d, J = 8.5 Hz, 4H), 5.18 ( m, 2H), 4·30 (apparent triplet, 2H), 4.18 (d, J = 7.3 Hz, 2H), 3.63 (s, 6H), 3.38 (m, 2H), 2.63 (m, 2H), 2.51 (m, 2H), 1.98 (m, 2H), 1.81 (m, 2H), 1.21 (d, J = 6.3 Hz, 6H), 0.83-0.90 (m, 12H). LC (Conditions 9 and 10): Homogeneity Index &gt; 95%. LC/MS (Condition l〇h): Rt = 2.01 min. LC/MS: [M+H]+. Found: s. Example M12.3

According to the procedure described in Preparation Example 2.2 12.2, from pyrrolidine M12.2f/HCl and (S)-2-(indolyloxycarbonylamino)-2-(tetrahydro-2-indole-pyran-4-yl) An example of the preparation of acetic acid Μ12·3 (trifluoroacetate). Rt : LC (Conditions 9 and 1): Homogeneity Index &gt; 95%. LC/MS (Condition l〇h): Rt = 1.89 min. 146976.doc -140- 201038558 LC/MS : [M+H]+ C48H59N808 analytical value: 875.45, experimental value: 875.42 ° Example M12.4-M12.5

Add NCS (17.56 mg, 0·13 1) to a solution of Μ12·2 (using MCX column and 2 N NH3/MeOH for free) (80 mg, 0.101 mmol) in DMF (5 mL) (mmol) and heated at 50 ° C for 3 hours. Additional NCS (5 mg, 0.037 mmol) was added to the mixture and heating was continued for a further 5 hours. The volatile component was removed in vacuo and the residue was taken in MeOH EtOAc (EtOAc/EtOAc/EtOAc) 24 mg) and Example M12.5/trifluoroacetate (light yellow foam, 28 mg). Example Ml2.4 / bismuth trifluoroacetate: if! NMR (DMSO-d6, δ = 2·5 ppm, 400 MHz): 8.17 (s, 1H), 7.83-7.73 (m, 6H), 7.66 (d, J=8.6 Hz, 2H), 7.30 (d, J=8.3 Hz, 1H), 7.22 (d, J=8.3 Hz, 1H), 5.05 (m, 1H), 4.85 (m, 1H), 4.16-4.02 ( m, 4H), 3.52 (s, 6H), 3.37 (m, 1H), 3.23 (m, 1H), 2.54-2.24 (m, 4H), 1.87-1.63 (m, 4H), 1.13-1.08 (m, 6H), 0.85-0.74 (m, 12H). LC (Conditions 9a.1 and lOa.l): Homogeneity Index &gt; 95%. LC/MS (Condition 11): Rt = 4.26 min. LC/MS: [M+H]+ calcd.: </ br </ br> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> Example M12.5 / trifluoroacetate: (DMSO-d6, δ = 2_5 ppm, 400 MHz): 7.79 (d, J = 8.4 Hz, 4 Η), 7.66 (d, J = 8.4 Ηζ, 4H), 7.22 ( d, J = 8.3 Hz, 2H), 4.85 (m, 2H), 4.13 (apparent triplet, 2H), 4_04 (apparent triplet, 2H), 3.53 (s, 6H), 3.24 (apparent triplet) , 2H), 2.39 (m, 2H), 2.26 (m, 2H), 1.90 (m, 2H), 1.66 (m, 2H), 1.09 (d, J = 6.5 Hz, 6H), 0.85 (d, J= 6.8 Hz, 6H), 0.80 (d, J = 6.5 Hz, 6H). LC (Conditions 9a and lOa.l): Homogeneity Index &gt; 95%. LC/MS (Condition 11): Rt = 4.44 min. </RTI> <RTI ID=0.0></RTI> </RTI> <RTI ID=0.0></RTI> Example M12.6-M12.7

Example 12.6-12.7 was prepared as the trifluoroacetate salt from Example M12.3 according to the procedure described for the preparation of Example 12.4-1. Example RT (Condition 12); Homogeneity Index % (Condition 12); MS data M12.6 13.68 min; &gt;95%; LC/MS: [M+H]+ C48H58C1N808 Analysis calculated: 909.41, Experimental value: 909.8 M12.7 17.12 min ; &gt;95% ; LC/MS : [M+H]+ C48H57C12N808 calc.: 943.37, calc.: 943.7 146976.doc -142- 201038558 Example M12.8

To pyrrolidine Μ12·2ί7 hydrochloride (120 mg, 0.193 mmol) and (S)-2-(methoxycarbonylamino)-3-mercaptobutyric acid (35.1 mg, 0.200 mmol) in DMF (2 mL) DIEA (0.168 mL, 0.964 mmol) was added to the mixture, and then HATU (70.4 mg, 0·1 85 mmol) was added, and the mixture was stirred at room temperature for 1 hour. The volatile component was removed in vacuo, and the residue was taken from EtOAc EtOAc EtOAc (EtOAc) Acetate (36 mg). The sample was free-basified (MCX column; MeOH wash; 2N NH3 /MeOH eluted) to afford a yellow solid (22.3 mg). LC/MS: [M+H]+ calcd. -(Methoxy 146976.doc -143- 201038558 arylamino)-2-(tetrahydro-2H-pyran-4-yl)acetic acid (丨 2.99 mg, 0.060 mmol) in DMF (2 mL) DieA (0.018 mL, 0.106 mmol) and HATU (13.65 mg, 0.036 mmol) were added and the mixture was stirred at room temperature for 2 hr. The volatile component was removed in vacuo and the residue was dissolved in MeOH&apos; and subjected to reverse phase HPLC conditions (column:

Phenomenex-Luna 30x100 mm, S10 Axia; MeOH/TFA/water). The obtained sample was re-purified by a reverse phase HPLC (column: Water-SunHre 3 0 X 100 mm S5; ACN/TFA/water) to give an example of a pale yellow foam. Mg). 4 NMR (sterol-d4, δ-3.29 ppm, 400 MHz): 7.92 (d, J = 5.0 Hz, 2H), 7.77 (d, J = 8.5 Hz, 4H), 7.72-7.69 (m, 4H), 5.21 (m, 2H), 4.39-4.22 (m, 4H), 3.92 (m, 2H), 3.67 (s, 6H), 3.47-3.28 (m, 4H), 2.68 (m, 2H), 2.54 (m, 2H), 2.06-1.85 (m, 4H), 1.25 (d, J = 6.5 Hz, 6H), 0.93 (d, J = 6.7 Hz, 3H), 0.91 (d, J = 7.3 Hz, 6H). LC (Conditions 9 and 10): Homogeneity Index &gt; 95 Å/〇. Lc/MS (Condition 10d): Rt = 3.10 min. LC/MS: [M+H]+ C46H57N807 Analysis: 833.44 &gt; Experimental value: 833.47 ° Example M12.9

146976.doc · 144- 201038558 Example M12.9, step a

Superhydride (19.20) was added dropwise to a mixture solution of [V>12.2a-1 and ^12.2&amp;-2 (4.75 g' 18.46 mmol) in a dry ice/acetone bath at -50 °C. mL, 19.20 mmol) for 1 min. Add Shig's base (13.5 8 mL '78 mmol), and stir for 10 minutes, and add solid DMAP (0.122 g, 0.997 mmol), stir for 15 minutes, and add trifluoroacetic anhydride (2.98 mL) dropwise over 15 minutes. , 21.08 mmol). The dry ice/acetone bath was then removed and the reaction mixture was stirred for 4 hours while thawing to room temperature. The reaction mixture was washed with water (50 mL) EtOAc. Purification by flash chromatography (8-60%EtOAcEtOAcEtOAc) NMR (CDC13, 400 MHz): 6.36 (s, 0.5H), 6_25 (s, 0.5H), 4.70-4.57 (m, 1H), 3.78 (s, 3H), 2.96 (m, 1H), 2.54 (m , 1H), 1.70 (s, 3H), 1.50 (s, 4.5H), 1.44 (s, 4.5H). Example M12.9, step b

M12.9b-1 M12_9b-2 was added dropwise to a solution of ester Ml2.9a (5.23 g '21.68 mmol) in 146976.doc -145-201038558 (-23 ° C) toluene (60 mL) over 20 min. Diethyl (M Μ in toluene, 59.1 mL, 65.0 mmol) ' and stirred for 1 min. Chloroiodomethane (9.44 mL, 130 mmo] [) was added dropwise over a period of (7) minutes, and the reaction mixture was stirred at _2 rc for 16 hours. Saturated NaHC〇3 (6 〇 mL) was added to the reaction mixture, the cooling bath was removed, and the mixture was stirred for 1 hr. It was then filtered and the filter cake was washed with toluene (50 mL). The filtrate was partitioned and the org. The crude material was purified by flash chromatography (2 EtOAc / EtOAc / EtOAc). Two dissolvates; colorless oil; 1_〇1 g). The relevant stereochemistry was determined based on NOE studies. Ester M12.9b-1 : &gt;H NMR (CDC13, 400 MHz): 4.65-4.52 (m, 1H), 3-72 (s, 3H), 3.28-3.17 (m, 1H), 2.44-2.32 (m , 1H), 2.16-2.10 (m, 1H), 1.51-1.42 (two single peaks '9H), 1.24 (s, 3H), 1.07 (m, 1H), 0.69-0.60 (m, 1H). Example Ml 2.9, step c

A solution of LiOH (0.324 g, 13.54 mmol) in water (10.00 mL) was added to a solution of M12.9b-1 (2.88 g, 11.28 mmol) in ethanol (20 mL) and the mixture was stirred at room temperature 6 hour. Most of the volatile component was removed in vacuo and the residue was partitioned between water (20 mL) and diethyl ether (20 mL). The aqueous layer was cooled with EtOAc (30 mL, 4x). The organic phase was dried over Na2SO4 EtOAc EtOAc EtOAc EtOAc. 4 NMR (CDC13, 400 MHz): 4.64 (m, 1H), 3.25 (apparent monomodal, 1H), 2.70-2.40 (m, 1H), 2.14 (m, 1H), 1.54-1.44 (m, 9H) , 1.27 (s, 3H), 1.10-0.80 (m, 1H), 0.67 (m, 1H). Example M12.9, step d

Add 2-bromo-1-(4-diphenyl)ethanone (2.361 g, 8.50 mmol) to a solution of EtOAc (EtOAc) (EtOAc) 1.484 mL, 8.50 mmol) 'and the reaction mixture was stirred at room temperature for 16 hours. Most of the volatiles were removed in vacuo and residue was partitioned between EtOAc (50 <RTIgt; The organic layer was washed with EtOAc EtOAc (EtOAc)EtOAc. 〇 LC/MS : [M+Na]+ calcd. Example M12.9, step e

Add ammonium acetate (6.16 g, 80 mmol) to a mixture of ketoester M12.9e (3.5 g, 7.99 mmol) and diphenylbenzene (80 mL) in a pressure tube, and seal the mixture 146976.doc •147· 201038558 The lid was heated at 140 ° C for 4.5 hours. The volatiles were removed in vacuo and residue was partitioned between DCM (EtOAc) The organic layer was washed with EtOAc (EtOAc)EtOAc. The crude material was purified by EtOAc (EtOAc:EtOAc) 4 NMR (DMSO-d6, δ=2.5 ppm, 400 MHz): 7.68 (m, 2H), 7.57-7.49 (m, 3H), 5.08 (m5 1H), 3.20 (m, 1H), 2.45-2.09 (Μ , 2H), 1.69-1.52 (m, 1H), 1.42-1.16 (m, 12H), 0.62 (m, 1H). </RTI> <RTI ID=0.0></RTI> </RTI> <RTI ID=0.0> Example M12.9, step f

Add to a pressure tube containing a solution of bromide M12.9e (0-354 g' 1.007 mmol) and 1,2-bis(trimethyltin) acetylene (0.354 g, 1.007 mmol) in DMF (15 mL) Pd(Ph3P)4 (0.070 g, 0.060 mmol) and the reaction mixture was degassed for 1 min and the reaction vessel was capped and heated at 90 °C for 14 h. Most of the volatile components were removed in vacuo and the residue was partitioned between DCM (60 mL) and water (40 mL). The organic layer was dried with Na2SO4 and evaporated in vacuo. The crude material was purified by flash chromatography eluting elut elut elut elut elut </ RTI> <RTI ID=0.0></RTI> </RTI> <RTI ID=0.0></RTI> Example M12.9, step g

A solution of 4 N HCl in dioxane (3.90 mL, 128 mmol) was added to the carbamic acid ester M12.9f (0.3 g, 0.428 mmol), and the mixture was stirred at room temperature for 5 hours. The volatiles were removed in vacuo and the residue was dried EtOAcjjjjjjjj LC/MS: [M+H]+ calcd.: </RTI> &lt;RTI ID=0.0&gt;&gt; DIEA (0.097 mL, 0.557 mmol) and HATU (72.7 mg, 0.191 mmol) were added to a mixture of methoxycarbonylamino)-3-mercaptobutyric acid (35.8 mg, 0.204 mmol) in DMF (2 mL) The reaction mixture was stirred at room temperature for 2 hours. Volatile components were removed in vacuo and the residue was taken in MeOH and purified by reverse phase HPLC (Phenomenex-Luna 30 X 100 mm, S10 Axia; MeOH/TFA/water). The obtained sample was re-purified by a second reverse phase HPLC (Water-SunHre 30x150 mm OBD; ACN/TFA/water) to give an example M12.9 trifluoroacetate (37 mg) as a pale yellow foam. LC/MS (Condition l〇d): Rt = 3.08 min. LC (Conditions 9 and 10): Homogeneity Index &gt; 95%. </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; Example Μ13

(The SEM chemistry was not determined) To a solution of the bromide M3h (1.0 g, 2.47 mmol) in DMF (25 mL) was added sodium hydride (60%; 0.109 g, 2 - 72 mmol) and the mixture was stirred at room temperature 20 minutes. Then (2-(chloromethoxy)ethyl)tridecyldecane (0.482 mL, 2.72 mmol) was added dropwise and the mixture was stirred for 21 hr. The volatile component was removed in vacuo and the residue was partitioned between ethyl acetate (25 mL) and water (25 mL). The aqueous layer was extracted with EtOAc (EtOAc (EtOAc)EtOAc. The residue was dissolved in CHC13 (2 mL), and the ruthenium was loaded on a Thomson second cartridge which was dissolved in 25% ethyl acetate/hexane to obtain a blutonide-like bromide having unknown chemical composition. M13a (1.171 g).咕NMR (DMS〇_d6, δ=2 5 ppm, 4〇〇MHz): 7.71 (s, 1H), 7.69 (d, J=8.6, 2H), 7.52 (d, J=8.6, 2H), 5.62 -5.31 (br s, 1H), 5.26 (d, J=l〇.8, 1H), 4.84-4.66 146976.doc •150- 201038558 (apparent broad single peak, 1H), 3.57-3.36 (apparent width) Single peak, 1H), 3.50 (t, J=8.1, 2H), 2.44-2.20 (apparent broad single peak, 2H), 177_16〇 (apparent broad single peak, 1H), 1.52-1.23 (br s, 4H ), 1.23-0.96 (br s, 5H), 0.92-0.79 (m, 2H), 0.78-0.69 (m, 1H), 0.64-0.55 (apparent broad single peak ' 1H), 〇.〇〇(s, 9H). </RTI> <RTI ID=0.0></RTI> </RTI> <RTI ID=0.0></RTI> Example M13, step b

(The SEM site chemistry was not determined) To the sealed reaction vessel, bromide M13a (0.5542 g, 1.037 mmol) and triethylamine (0.434 mL, 3.11 mmol) in 2-propanol (2.000 mL) and water (1 mL) Potassium vinyl trifluoroborate (〇1 g, 1.348 mmol) was added to the solution, followed by addition of ι, ι'·bis(diphenylphosphino)ferrocene-dichlorinated (π) diterpene chloroformate complex (0.085 g, 0.104 mmol). The reaction mixture was purged with nitrogen and capped at 100. (The next heating was carried out for 17 hours. The volatile component was removed in vacuo and residue was partitioned between ethyl acetate (25 mL) and water (25 mL) and the aqueous phase was extracted with ethyl acetate (2×25 mL). The combined organic phases were dried <RTI ID=0.0></RTI> to <RTI ID=0.0></RTI> to <RTI ID=0.0> Light yellow oily olefin M13b (345.4 mg). 4 NMR (DMSO-d6, δ=2.5 ppm, 400 MHz): 146976.doc -151 - 201038558 7.71 (d, J=8.3, 2H) 7 67 / , 7·67 (s,1H), 7.45 (d,J=8.3, 2H) 6 72 (dd,J=17.6, lia ζ. β 翻官里庵m (dd, Bu G 8,17.6,1H), 5.60 -5·29 5.26 (d? J=i〇8j m)j 5 22 (d? j=n 8 1H), 4.83-4.67 (apparent broad single peak, m), 3.51 (t 卜 8 ^ peak 1H) , 3.59_3.35 (appearance width single (,8·1,2H), 2.41-2.23 (apparent broad single peak, 2H) (apparently broad single peak, called '丨^力^观宽单峰, ^ )' (m,1H)' 0.65-0.56 (Table _ Palace „ 1U, ΛΛίΛ, 衣眺I早峰' 1Η), 0·0〇(s,9Η). LC/MS : [Μ+ΗΓ Γ. Μ χτ ^ 欣"L27 Analytical calculated value of H4QN3〇3Si: 482.28, experimental value: 482.24. Example Μ1 3, step c

Grubbs second generation catalyst (0.132 g, 0.155 mm 〇1) was added to a solution of olefin M13b (0.748 g, 1.552 mmol) in CH2C12 (2 mL) and stirred at room temperature under nitrogen for 18 hr. The reaction product was loaded onto a Thomson-tank cartridge of 30 〇 / 〇 acetic acid / hexane to give a brown foamy M13c (0.50 g). NMR (DMSO-d6, δ = 2.5 ppm, 400 MHz): 7.74 (d, J = g.4, 4H), 7.68 (s, 2H), 7.58 (d, J = 8.3, 4H), 7.22 (s, (H), 5. · 201038558 2.45-2.20 (apparent broad single peak, 4H), 1.88-1.57 (apparent broad single peak, 2H), 1.57-1.26 (br s, 8H), 1.26-0.98 (br s, l〇H), 0.93-0.80 (m, 4H), 0.80-0.69 (m, 2H), 0.69-0.51 (apparent broad singlet, 2H), 0.00 (s, 18H). Example M13, step d

To a flask containing M13c (0.4799 g, 〇·513 mmol) cooled in an ice/water bath was carefully added 4 N HC 1 / dioxane (1 3 mL). A mixture of water (4 mL) and 12 N HCl (2 mL) was added to the mixture, and the cooling bath was removed, and the mixture was continuously stirred for 24 hours. Add to the reactants

MeOH (2 mL) and stirring was continued for 17 h. All solvents were removed in vacuo to afford pyrrolidine M13d (4 HCl) (317 mg) as a yellow brown solid. 4 NMR (DMS〇-d6, δ=2.5 ppm, 400 MHz): 10.78-9.87 (very wide single peak, approx. 3H), 8.01 (s, 2H), 7.87 (d, J=8.4, 4H), 7.71 ( d,

OJ=8.6, 4H), 7.35 (s, 2H), 4.76 (apparent triplet, J=8.8, 2H), 3.43 (apparent triplet, J=5.1, 2H), 2.64 (m, 2H), 2.55 -2.52 (m, 2H), 1.95 (m, 2H), 1.16-1.05 (m, 2H), 0.86 (m, 2H). LC/MS: [M+H] + calcd.: </RTI> &lt;RTI ID=0.0&gt;&gt; Example of the preparation of methoxycarbonylamino)_3_methylbutyric acid 146976.doc -153- 201038558 M13 trifluoroacetate. iH NMR (DMS0_d6, δ = 2 5 ppm, 4 〇〇 MHz): 8.14-7.95 (br s, 2H), 7.80-7.74 (m, 8H), 7.40 (s, 2H), 7.25 (d, J = 8.3 , 2H), 5_0 (apparent triplet, j=7.3, 2H), 4_41 (apparent triplet, J=7.6, 2H), 3.81_3 67 (m, 2H), 3 54 (s, 6H), 2.57 -2.46 (overlap with DMS0-d6) (m, 2H), 2 44_2 31 (m, 2H), 2.19-2.05 (m, 2H), 1.98-1.87 (m, 2H), 1.02-0.89 (m, 7' 5H), 0.89-0.70 (m, 8.5H). </RTI> <RTI ID=0.0></RTI> </RTI> <RTI ID=0.0></RTI> EXAMPLES M14-M15 Example MI4 (trifluoroacetate) was prepared from pyrrole^Ml3d and the appropriate acid by using the procedure described for the synthesis example M1. In the case of Example M15, the coupling step employed (S)-2-(methoxycarbonylamino)_3_mercaptobutyric acid with 2-(indolylcarbonylamino)-2-(tetrahydro-2H-pyran) A molar mixture of -4-yl)acetic acid and the resulting statistical product mixture was isolated by HPLC techniques as described for example M1.

146976.doc -154 201038558 Examples Ri r2 Rt (Condition 3); Homogeneity Index % (Conditions 9 and 10); LC/MS data M14: II. 〇ΗΝ 1.72 min ; &gt;98% ; LC/MS : [M+H]+ C48H57N808 calc.: 873.43, calc.: 873.48 o ^ M15 ί〇c· /〇1.82 min ; &gt;98% ; LC/MS : [M+H] + C 46 H 55 N calc. calc.: 831.42.

Instance N1

实例 Example N1, step a

Add sodium bicarbonate (4.02 g, 47.9 mmol) to a suspension of 2-amino-1-(4-bromophenyl)ethanone hydrochloride (4.0 g, 15.97 mmol) in DCM (50.0 mL ). Next, a third butoxycarbonyl anhydride (3.89 mL, 16.77 mmol) was added to the solution, and the reaction mixture was warmed to room temperature and stirred for 18 hr. Then DIEA (3 mL, 17.18 mmol) was added and the mixture was stirred at room temperature 146976. doc - 155 - 2010 38558 mixture for 2 hr. The reaction mixture was diluted with EtOAc EtOAc EtOAc (EtOAc m. Purification was used in the next step. 1 NMR (400 MHz, MeOD) ppm 7.89 (2H, m), 7.68 (2H, m, •7=8.53 Hz), 4.52 (2H, s), 1.38-1.51 (9H, m). LC/MS (Condition lOd): Rt = 3.56 min. </ RTI> <RTI ID=0.0></RTI> </RTI> <RTI ID=0.0></RTI> Example N1, Step b &gt; BocHN-^^-NHBoc Addition of 1,2-bis(trimethylstannyl) to a solution of amino citrate Nla (2.0 g, 6.37 mmol) in DMF (5 mL) Acetylene (1.119 g, 3.18 mmol). The reaction mixture was degassed, hydrazine (triphenylphosphine) was added (0) (0·1 84 g, 0-1 59 mmol), and the mixture was heated at 90 ° C for 4 hours. The crude reaction mixture was fed into a 90 g silicone cartridge which was dissolved in a 20-minute gradient of 0-60% EtOAc in hexanes. The alkyne Nlb (0.83 g) was collected as a yellow solid. LC/MS (Condition 10d): Rt = 4.1 min. </RTI> <RTI ID=0.0></RTI> </RTI> <RTI ID=0.0> Example N1, step c

146976.doc - 156- 201038558 Add 4 M HCl in dioxane to a solution of the bulk hydrocarbon Nlb (1.13 g, 2.294 mmol) in 1,4-dioxo (5 mL) (4 mL, 16.00 mmol ). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated to dryness to give a yellow solid. The solid was washed with hexanes and EtOAc then dried to give the amine s. 4 NMR (400 MHz, MeOD) ppm 8.10 (4H, d, J = 8.53 Hz), 7.78 (4H, d, «7=8.53 Hz), 4.64 (4H, s). LC/MS (Condition lOd): Rt = 1.94 min. LC/MS: calcd for </RTI> &lt;RTI ID=0.0&gt; Example Ν 1, step d

To (S)-l-(t-butoxycarbonyl)-4,4-difluoro&quot;bibrididine-2-furic acid (0.25 g, 0.995 mmol), amine ketone Nlc dihydrochloride (0.182 g, DIEA (0.521 mL, 2.99 mmol) was added to a mixture of EtOAc (EtOAc). The reaction mixture was stirred at room temperature for 3 hours. The crude mixture was fed into a 80 g tantalum cartridge which was dissolved in a 20-minute gradient of 0-1 00% EtOAc in hexanes. The ketoxime Nld (0.12 g) was collected as a yellow solid. LC/MS (Condition 10d): Rt = 4.08 min. </ RTI> <RTI ID=0.0></RTI> </RTI> <RTIgt; 146976.doc -157- 201038558 Example N1, step e

A mixture of ketoxime Nld (0-12 g, 〇158 mm〇1) and ammonium acetate (0.122 g, 1.582 mmol) in xylene (2 mL) was heated at 140 C for 4 hours. The reaction mixture was partitioned between Et EtOAc and EtOAc. The residue was dissolved in a small amount of dichlorohydrazine and was applied to a 40 g silica gel cartridge eluted with a 20 min gradient of EtOAc EtOAc. The imidazole Nle (0.054 g) was collected as a yellow solid. LC/MS (Condition l〇d): Rt = 3.3 min. LC/MS: [M+H] + calcd. Example N1, step f

To the solution of milidine Nle (0.054 g '0.075 mmol) in 1,4-dioxin was added 4 M HCl. A miscible solution (〇_5 mL, 2.0 mmol) and a few drops of MeOH. The reaction mixture was stirred at room temperature for 4 hr and concentrated to give a crystallite. LC/MS (Condition 10d): Rt = 2.94 min. LC/MS: [M+H]+ calcd. 146976.doc •158· 201038558 Example N1 to (S)_2_(methoxycarbonylamino)_3_methylbutyric acid (0.014 g, 0.079 mmol), ° ratio 11 唆Nlf tetrahydrochloride (0.025 g, 0.038 Addition of DIE(R) (0·03 9 mL, 0.225 mmol) to a mixture of EtOAc, EtOAc (EtOAc). The reaction mixture was stirred at rt EtOAc (EtOAc)EtOAc. LC (Conditions 10b and 10c): Homogeneity Index &gt; 95%. LC/MS (Condition 10d): Rt = 3.11 〇 min. LC/MS: calcd. Calcd.: 437. Example N2

Pyrrolidine Nlf was coupled with 2-(methoxycarbonylamino)-2-(tetrahydro-2H-pyran-4-yl)acetic acid by the procedure described for Synthesis Example N1. The resulting three diastereomers (trifluoroacetate) were isolated by the following conditions: column = Waters-Sunfire 30 x 100 mm S5; starting B% = 0; final B% = 32; gradient time = 25 min Stop time = 25 min; flow rate = 40 mL/min; wavelength = 220 nm; solvent A = 10% MeCN/90% water with 0.1% TFA; solvent B = 90% Me 0.1/10 TFA % water. H6976.doc -159- 201038558 Example - Analytical conditions N2 LC (conditions l〇b and 10c): homogeneity index &gt; 95%. LC/MS (Condition 10d): Rt = 2.90 min. LC/MS: [M+H]+ </RTI> </RTI> <RTI ID=0.0></RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; LC/MS (Condition l?d): Rt = 2.96 min. LC/MS: [M+H]+ C46H5iF4N8 〇8 analytical value·· 9丨937, experimental value. 919.4 卜 · N4 LC (conditions 10b and 10c): homogeneity index &gt; 95%. LC/MS (Condition 〇〇 min. LC/MS: [M+H] + C46H5iF4N 808 calc. calc.: s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s Example N5 N7 (trifluoroacetate) was prepared from Nlc and the appropriate starting material obtained from commercial source.

Example R Analysis conditions N5 0 Η ο^^Νγ0, : Homogeneity index &gt; 95%. Piece i〇d): Rt=3.05—. Lc/ms : [M+H] calcd. calcd. N6, calving '°^γΝγ0^ Tm, and 1〇C): tannin index &gt; 95%. </ RTI> <RTI ID=0.0></RTI> </ RTI> <RTI ID=0.0></RTI> </ RTI> </ RTI> <RTIgt; · N7 ΟΗ Ο^Ο ΗΝ-^ 0~ ϋϋ1? and 10c): The homogeneity index is 93%. LC/I^S+ (Conditions: Rt=3. 〇6 min. LC/MS: [M+H] calc. calc.: 795 38, calc.: 795.4. '--^-- 146976.doc -160- 201038558 N7.1 'Prepared HN-^0 0-, LC (Conditions 10b and 10c): Homogeneity index 97% LC/MS (Condition lOd): Rt=3.056 min. LC/MS : [M+ Anal. Calcd.: 787.39, found: 787.4. LC/MS: calcd. Calcd.: 495. Example N8

❹ According to the procedure described for the preparation of pyrrolidine Nlf, the amine ketone Nlc and (13,3 3,5 8)-2-(t-butoxycarbonyl)-2-azabicyclo[3.1.0]hexane- 3-carboxylic acid (for its preparation, see WO2004/052850) is the starting material for the preparation of pyrrolidine N8a (hydrochloride). 4 NMR (MeOD, δ=3.33 ppm, 400 MHz): 7.98 (s, 2H), 7.87 (d, J=8.4, 4H), 7.69 (d, J=8.4, 4H), 5.59 (dd, J=10.2) , 5.4, 2H), 3.61-3.56 (m, 2H), 3.05-2.98 (m, 2H), 2.67 (dd, J=14.2, 5.4, 2H), 2.20-2.14 (m, 2H), 146976.doc - 161 - 201038558 1.28-1.22 (m, 2H), 1.19-1.13 (m, 2H). </RTI> <RTI ID=0.0></RTI></RTI> Example N8 Example N8 was prepared from pyrrolidine N8a according to the procedure described for Preparation Example N1, except for purification under modified reverse phase HPLC conditions (ACN / water / NH4OAc). Example N8 was recovered as a pale yellow solid. LC (Condition 10e): Homogeneity Index &gt; 99%. LC/MS (Condition 10f): Rt = 2.21. min. 4 NMR (DMSO, δ = 2.50 ppm, 400 MHz): 12.33 (s, 0.28H), 11.86 (s, 1.72H), 7.74 (d, J = 8.4, 3.42H), 7.65 (d, J = 8.4, 0.58H), 7.55 (d, J=8.4, 0.58H), 7.51 (s, 2H), 7.49 (d, J=8.4, 3.42H), 7.31 (d, J=8.8, 2H), 5.39 (apparent) Double peak, 〇·15Η), 3.34 (dd, J=l〇.8, 2.4, 3.85Η), 4.29 (apparent triplet, 2Η), 3.90 (br m, 2H), 3.55 (s, 6H) , 2.64-2.56 (m, 2H), 2.17 (apparent double peak ' 2H), 2.08-1.98 (m, 2H), 1.79-1.74 (m, 4H), 0.92-0.83 (m, 14H). </ RTI> <RTI ID=0.0></RTI> <RTI ID=0.0></RTI> Example N9

Except for the ACN/water/TFA solvent system used in the purification, according to the procedure described for Preparation Example N1, from pyrrolidine N8a and (^)_2_(曱oxycarbonyl i46976.doc •162- 201038558 Amino)-2 -(Tetrahydro-2H-piperazin-4-yl)acetic acid to give compound N9 (trifluoroacetate). LC (Condition 10e): Homogeneity Index &gt; 97%. LC/MS (Condition 10g): Rt = 1.82 min. LC/MS: calcd.: 437.21. Example J1, step a

Examples J1 to J1.1

Add DIPEA (2.8) to the slurry of acid M3f (2.00 g, 8.80 mmol) and 2-bromo-1-(3-bromophenyl)ethylidene (2.22 g, 8.00 mmol) in acetonitrile (25 mL). mL, 16 mmol), and the reaction mixture was stirred at room temperature. The reaction mixture was concentrated <RTI ID=0.0></RTI> to <RTI ID=0.0></RTI> to <RTI ID=0.0></RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> LC-MS retention time 1.853 min; m/z 423 and 425.98 (1:1) 146976.doc -163· 201038558 (MH+). LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters Xterra MS 7 μ C18 3.0 x 50 mm column and using a SPD-1 〇AV UV-Vis detector with a detector wavelength of 220 ηΜ. The dissolution conditions were 4 mL/min flow rate, 1% solvent a/〇〇/. Solvent b to 〇〇/〇 solvent A/100% solvent B gradient, 2 min gradient time, 1 min retention time and 3 min analysis time 'where solvent a is 5% MeOH/95% H20/1 mM ammonium acetate' And solvent b is 5% H20/95% MeOH / 10 mM acetic acid. MS data was measured using a Micromass Platform using an electrode mist mode LC. NMR (400 MHz, CDC13) δ ppm 8.04 (t, /=1.8 Hz, 1H)? 7.83 (d, J=7.8 Hz, 1H), 7.75 (d, J=8.0 Hz, 1H), 7.38 (t, 7=7.9 Hz, 1H), 5.33-5.59 (m, 1H), 5.13-5, 32 (m, 1H), 4.22 (br s, 1H), 3.40-3.63 (m, 1H), 2.52-2.63 (m , 1H), 2.46 (dd, J=13A, 9.3 Hz, 1H), 1.63-1.73 (m, 1H), 1.47 (br s, 9H), 0.86 (br s, 1H), 0_51 (br s, 1H) . Example J1, step b

Add vinegar to the acetic acid recorded in the pressure bar (5 _ 94 g, 77 mmol)

A solution of Jla (3.33 g, 7.85 mmol) in diphenylbenzene (75 mL). The reaction vessel was sealed and then placed in an oil bath that had been preheated to i4〇t: and the reaction was held at the temperature for 6 hours. The reaction was allowed to cool to room temperature and stirred overnight and at 140. (The next addition was 146976.doc 201038558 heat for 5 hours. Additional ammonium acetate (3.0 g) was added and the reaction was stirred at 145 °C for The oil was partitioned between DCM (ca. 200 mL) and EtOAc EtOAc (EtOAc: EtOAc) The crude orange solidified foam was purified by hexane, 160 g of Si 2 (2) to give the imidazole Jlb (2.03 g) as a yellow solidified foam. LC-MS retention time 2.450 min; m/z 404 and 406.06 ( 1:1) Ό (MH+). Shimadzu LC-10AS liquid phase layer equipped with a Phenomenex-Luna 10 μ C18 3.0x50 mm column and using a SPD-10AV UV-Vis detector with a detector wavelength of 220 nM The LC data was recorded on the analyzer. The dissolution conditions were 4 mL/min flow rate, 100% solvent A/0°/〇 solvent B to 0% solvent A/100% solvent B gradient, 3 min gradient time, 1 min retention time. And 4 min analysis time, where solvent A is 5% MeOH/95% H2O/10 mM ammonium acetate and solvent B is 5% H20/95% MeOH/10 mM acetic acid. Micromass using LC in electrospray mode Platform to determine MS data. 4 NMR (400 MHz, MeOD) δ ppm 7.89 (br s, 1H), 7.65 (d, /=6.5 Hz, 1H), 7.32-7.44 (m, 2H), 7.26 (t, 7 =7.8 Hz, 1H), 4.66 (br s, 1H), 3.52-3.63 (m, 1H), 2.51 (dd, J=13.1, 8.8 Hz, 1H), 2.25-2.37 (m, 1H), 1.66-1.75 (m, 1H), 1.29 (br s, 9H), 0.84 (ddd, J=8.2, 6.0, 5.8 Hz, 1H), 0.56-0.63 (m, 1H). 146976.doc -165- 201038558 Example J1, Step c

Nitrogen was bubbled through a stirred solution of bromide Jlb (854 mg, 2.18 mmol) and 1,2-bis(trimethylstannyl)acetylene (403 mg, 1.15 mmol) in DMF (10 mL). 10 minutes. Pd(PPh3)4 (79 mg, 0.069 mmol) was then added, nitrogen was bubbled through the reaction for 1 min and then the reaction was heated at <RTI ID=0.0># </ RTI> The reaction mixture was allowed to cool to room temperature ') to agglomerate to a slightly oily oil and was purified on Biotage Horizon (40 g Si02, 70-100% EtOAc/hexanes, loaded with DCM) Alkyne Jlc (500 mg). 1^-]^8 retention time 2.876 11^11; 111/7 649.51 (1411+). LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna 10 μC18 3.0 x 50 mm column and using a SPD-10AV UV-Vis detector with a detection wavelength of 220 nM. The dissolution conditions were 4 mL/min flow rate, 100% solvent A/0% solvent B to 0% solvent A/100 〇/〇 solvent B gradient, 3 min gradient time, 1 min retention time and 4 min analysis time. Solvent A was 5% MeOH / 95 ° /. H2O/10 mM ammonium acetate, and solvent B was 5% H2 〇 / 950 / 〇 MeOH / 10 mM acetic acid. Using electrospray

The LC of the mode was measured by the Micromass Platform. NMR (400 MHz, MeOD) δ ppm 7.89 (s, 2H), 7.67-7.74 (m, 2H), 7.35-7.44 (m, 6H), 4.85-5.04 (m, 2H), 3.64-3.74 (m, 2H ), 146976.doc -166- 201038558 3.47-3.56 (m, 2H), 2.29-2.45 (m, 2H), 1.90-2.13 (m, 6H), 1.48 (br s,6H), 1.26 (br s,12H ). Example J1, step d

Add TFA (3 mL, 38·9 mmol) to the amide solution of the urethane Jlc (238 mg, 0-367 mmol) in DCE (7 mL) and stir the reaction for 1 hour at room temperature . The reaction mixture was concentrated in vacuo to give the crystals of the crystals of yyyyy. LC-MS retention time 2.505 min; m/z 449.22 (MH+). LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna 10 μC18 3.0 x 50 mm column and using a SPD-10AV UV-Vis detector with a spectrometer wavelength of 220 nM. The dissolution conditions were 4 mL/min flow rate, 100% solvent A/0% solvent B to 0% solvent A/100% 〇 solvent B gradient, 3 min gradient time, 1 min retention time and 4 min analysis time, where solvent A is 5% MeOH/95% H2O/10 mM ammonium acetate, and solvent B is 5% H20/95% MeOH/10 mM ammonium acetate. MS data was measured using a Micromass Platform using an electrospray mode LC.丨11 NMR (400 MHz, MeOD) δ ppm 7.96-8.00 (m, 2H), 7.79 (dt, J=6.6, 2.1 Hz, 2H), 7.65 (s, 2H), 7.41-7.48 (m, 4H), 4.91 (t, /=7.8 Hz, 2H), 3.44-3.61 (m, 4H), 2.51-2.62 (m, 2H), 2.27-2.45 (m, 4H), 2.16-2.24 (m, 2H). 146976.doc -167- 201038558 Examples J1 to Jl.l to pyrrolidine Jld trifluoroacetate (110 mg, 0.12 mmol) and (S)-2-(methoxylkamino)-3-mercapto HATU (61.8 mg, 0.162 mmol) was added to a stirred solution of butyric acid (28.5 mg, 0.162 mmol) in DMF (0.7 mL) and EtOAc (EtOAc) The reaction mixture was stirred at room temperature for 3 hours' and then concentrated under a stream of nitrogen. The reaction was purified by preparative HPLC (Me〇H/water/10 mM ammonium acetate) in two portions to give an example η (3 h 5 mg) as a pale yellow solid and as a pale yellow solid. .1 (41.1 mg). Example J1: LC-MS retention time 2.605 min; m/z 763.36 (MH+). LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a phenomenex_Luna 1 〇 μ ci8 3.0 x 50 mm column and using a SPD-1 OAV UV-Vis detector with a detector wavelength of 220 nM. The dissolution conditions were 4 mL/min flow rate, 1 〇〇% solvent A/Ο% solvent B to 0% / gluten A/100% solvent b gradient, 3 min gradient time, 1 min retention time and 4 min analysis time Where solvent a is 5% MeOH/95% H20/1 mM acetonitrile money' and solvent b is 5% H20/950/. MeOH/lO mM acetic acid bond. The MS data was measured using a Micromass Plat form using an LC of the electric fog mode. NMR presents a 4:1 mixture of rotamers. The main rotamers are: NMR (400 MHz, MeOD) δ ppm 7.86 (s, 2H), 7.64-7.70 (m, 2H), 7.36-7.43 (m, 4H), 7.34 (s, 2H), 5.17 ( Dd, J=7.8, 5.3 Hz, 2H), 4.24 (d, J=7.3 Hz, 2H), 3.95-4.04 (m, 2H), 3.84-3.92 (m, 2H), 3.66 (s, 6H), 2.17 -2.42 (m, 6H), 2.00-2.13 (m, 4H), 0.96 (d, J=6.8 Ηζ?&gt; 6H), 0.91 (d, 146976.doc -168- 201038558 *7=6.8 Hz, 6H) . Example Jl.l: LC-MS retention time 2.620 min; m/z 606.23 (MH+). LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna 10 μC18 3.0 x 50 mm column and using a SPD-10AV UV-Vis detector with a detector wavelength of 220 Μ. The dissolution conditions were 4 mL/min flow rate, 100% solvent A/0% solvent B to 0% solvent A/1 00% solvent B gradient, 3 min gradient time, 1 min retention time and 4 min analysis time, where solvent A is 5% MeOH/95% H2O/10 mM ammonium acetate and solvent B is 5% H20/95% MeOH / 10 mM ammonium acetate. The MS data was measured using a Micromass Platform using an LC in electrospray mode. 4 NMR presents a 3:1 mixture of rotamers. 1H NMR (400 MHz, MeOD) δ ppm 7.94 (s, 1H), 7.87 (s, 1H), 7.74 (ddd, J = 5.6, 3.4, 1.8 Hz, 1H), 7.65-7.70 (m, 1H), 7.51 (s, 1H), 7.36-7.44 (m, 6H), 7.35 (s, 1H), 5.18 (dd, J=7.7, 5.4 Hz, 1H), 4.68 (t} J=7.8 Hz, 1H), 4.24 ( d, /=7.5 Hz, 1H), 3.95-4.06 (m, 1H), 3.85-3.92 (m, 1H), 3.66 (s, 3H), 3.35-3.52 (m5 2H), 2.01-2.50 (m, 9H ), 0.96 (d, 7=6.8 Hz, 3H), 0.91 (d, /=6.8 Hz, 3H). Example J2

To n piroxime jid three i acetate (93.4 mg, 0.103 mmol) and (S)-2- 146976.doc -169- 201038558 (hydroxylamino)-2-(tetrazo-2H-0 Addition of HATU (118 mg, 0.3 10 mmol) to a stirred solution of D. Amido-4-yl)acetic acid (67_3 mg '0.310 mmol) in DIPEA (0.18 mL, 1.0 mmol) and DMF (1 mL) The reaction was stirred at room temperature for 2 hours. The reaction was concentrated under EtOAc (EtOAc)EtOAc. LC-MS retention time 2.428 min; m/z 847.39 (MH+). LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna 10 μC18 3.0 x 50 mm column and using a SPD-10AV UV-Vis extractor with a detector wavelength of 220 nM. The dissolution conditions were 4 mL/min flow rate, 100% solvent A/0% solvent B to 0% solvent A/100% solvent B gradient, 3 min gradient time, 1 min retention time and 4 min analysis time. It was 5% MeOH/95% H2O/10 mM ammonium acetate, and solvent B was 5% H20/95% MeOH/10 mM ammonium acetate. MS data was measured using a Micromass Platform using an electrospray mode LC. 4 NMR showed a 4:1 mixture of rotamers. The main rotamer is ·· 4 NMR (400 MHz, MeOD) δ ppm 7.83 (s, 2H), 7.62-7.67 (m, 2H), 7.33-7.42 (m, 6H), 5.15 (dd, J=7.5 , 5.5 Hz, 2H), 4.32 (d, /=8.3 Hz, 2H), 3.89-4.08 (m, 6H), 3.66 (s, 6H), 3.33-3.50 (m, 6H), 2.23-2.40 (m, 4H), 2.13-2.22 (m, 2H), 1.92-2.10 (m, 4H), 1.61-1.71 (m, 4H), 1.32-1.56 (m, 4H). 146976.doc -170- 201038558

Example J3

Example J3, step a

The evolution J3a was prepared from the acid M3f according to the procedure described for bromide j1b.

Example J3, step b

The gas was bubbled through the bromide J3a (825 mg, 2.041 mmol) and 1,2-bis(trimethylstannyl)acetylene (378 mg ' 1.074 mmol) in DMF (10 mL). , lasts 1 minute. Next, Pd(PPh3)4 (74.5 mg '0.064 mmol) was added to the reaction mixture, nitrogen was bubbled through the reaction for 1 minute, and then the reaction was heated at 90 ° C under nitrogen for 17 hours. The reaction mixture was cooled to rt EtOAc EtOAc EtOAc EtOAc EtOAc (EtOAc) Alkyd J3b (312 mg) in the form of a yellow solid. LC-MS retention time 2.800 min; m/z 671.53 (MH-). LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna 10 μC18 3.0 x 50 mm column and using a SPD-10AV UV-Vis detector with a wavelength of 220 nM. The dissolution conditions were carried out at a flow rate of 4 mL/min, 100 °/. Solvent A / 0% solvent B to 0% solvent A / 1000 /. Solvent B gradient, 3 min gradient time, 1 min retention time, and 4 min analysis time, where solvent A was 5% MeOH/95°/〇H2O/10 mM ammonium acetate, and solvent B was 5% H20/95% MeOH /10 mM ammonium acetate. MS data was measured using a Micromass Platform using an electrospray mode LC. 4 NMR (400 MHz, MeOD) δ ppm 7.89 (s, 2H), 7.70 (ddd, J=5.6, 3.3, 1.9 Hz, 2H), 7.38-7.43 (m, 6H), 4.69 (br s, 2H), 3.59 (br s, 2H), 2.53 (dd, 7=13.2, 8.9 Hz, 2H), 2.28-2.39 (m, 2H), 1.68-1.77 (m, 2H), 1.29-1.31 (m, 18H), 0.85 (dt, J = 8.5, 5.8 Hz, 2H), 0.58-0.64 (m, 2H). Example J3, step c

Add TFA (3 mL, 3 8.9 mmol) to a stirred solution of the amine phthalate J3b (316 mg '0.470 mmol) in DCE (7 mL) 146976.doc • 172 201038558 and stir at room temperature 1 hour. The reaction mixture was concentrated in vacuo to give purified crystals eluted eluted elute LC-MS retention time 2.711 min; m/z 473.24 (MH+). LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna 10 μC18 3.0 x 50 mm column and using a SPD-10AV UV-Vis detector with a detector wavelength of 220 nM. The dissolution conditions were 4 mL/min flow rate, 100% solvent A/0% solvent B to 0% solvent A/100% solvent B gradient, 3 min gradient time, 1 min retention time and 4 min analysis time. 5% MeOH/95% H20/1 mM ammonium acetate, and solvent B was 5% H20/95% MeOH/10 mM ammonium acetate. MS data was measured using a Micromass Platform using an electrospray mode LC. Example J3 To a dose of J3c trifluoroacetate (56.7 mg, 0.061 mmol) and (S)-2-(methoxycarbonylamino)-3-methylbutyric acid (32.1 mg, 0.183 mmol) in DMF ( HATU (69.6 mg, 0. 183 mmol) was added to a stirred solution of 0.7 mL) and EtOAc (0.11 mL, 0.61 mmol), and the mixture was stirred at room temperature for 3 hours. The reaction was concentrated under a mp. EtOAc (EtOAc) (EtOAc). ). LC-MS retention time 2.605 min; m/z 787.36 (MH+). Shimadzu 146976.doc -173- 201038558 LC-10AS liquid chromatograph equipped with a Phenomenex-Luna 10 μ C18 3.0x50 mm column and using a SPD-10AV UV-Vis detector with a detector wavelength of 220 nM The LC data is recorded on it. The dissolution conditions were carried out at a flow rate of 4 mL/min, 100. /❶solvent a/ο% solvent b to 〇% solvent a/ 100% solvent B gradient, 3 min gradient time, 1 min retention time and 4 min analysis time 'where solvent A is 5% MeOH/95% H2O/10 mM ammonium acetate, and solvent B is 5% H20/95% MeOH/10 mM ammonium acetate. Using electrospray

The LC of the mode was measured by the Micromass Platform. NMR (400 MHz, MeOD) δ ppm 7.87 (s, 2H), 7.65-7.71 (m, 2H), 7.37-7.43 (m, 4H), 7.36 (s, 2H), 5.16 (dd, J=8.8, 4.8 Hz, 2H), 4.59 (d, J=6.5 Hz, 2H), 3.67 (s, 6H), 3.63-3.68 (m, 2H), 2.49-2.58 (m, 2H), 2.37-2.45 (m, 2H) , 2.10-2.21 (m, 2H), 1.98-2.07 (m, 2H), 1.12 (ddd, 7=8.7, 5.6, 5.5 Hz, 2H), 1.01 (d, 7=6.8 Hz, 6H), 0.93 (d , J = 6.8 Hz, 6H), 0.78 (br s, 2H). Example J4

Pyrrolidine J3c trifluoroacetate (98 mg, 0.106 mmol) and (S)-2-(indolyloxycarbonylamino)-2-(tetrahydro-2H-pyran-4-yl)acetic acid (68.8 mg, To a stirred solution of DIPEA (0.18 mL, 1.1 mmol) and DMF (1 mL), HATU (120 mg, 0.317 mmol). The reaction was concentrated under a stream of nitrogen, dissolved in MeOH and purified by preparative HPLC (MeOH / water / EtOAc / /0.1% TFA) was repurified to afford the title compound <RTIgt; LC-MS retention time 2.463 min; m/z 869.40 (MH-). LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna 10 μC18 3.0 x 50 mm column and using a SPD-10AV UV-Vis detector with a detector wavelength of 220 nM. The dissolution conditions were carried out at a flow rate of 4 mL/min, 100% solvent A/0% solvent B to 0°/. Solvent A/100°/〇^ Solvent B gradient, 3 min gradient time, 1 min retention time and 4 min analysis time, where solvent eight is 5% MeOH/95°/〇H2O/10 mM ammonium acetate, and solvent B 5% H20/95% MeOH/10 mM ammonium acetate. MS data was measured using a Micromass Platform using an electrospray mode LC. 4 NMR (400 MHz, MeOD) δ ppm 7.89-7.92 (m, 2H), 7.87 (s, 2H), 7.74 (dt, J = 7.8, 1.5 Hz, 2H), 7.61-7.66 (m, 2H), 7.54 -7.60 (m, 2H), 5.11 (dd, 7=9.0, 7.0 Hz, 2H), 4.59 (d, J=7.5 Hz, 2H), 3.91-3.99 (m, 4H), 3.83 (t, J=4.8 Hz, 2H), 3.67 (s, Ο 6H), 3.33-3.45 (m, 4H), 2.67 (dd, /=13.7, 9.4 Hz, 2H), 2.43-2.52 (m, 2H), 2.02-2.14 (m , 4H), 1.39-1.63 (m, 8H), 1.03-1.11 (m, 2H), 0.83-0.90 (m, 2H). Example J5

146976.doc 175· 201038558 Example J5, step a O', bubbling nitrogen through (S)-2-(4-(4-bromophenyl)-1Η-imidazol-2-yl)pyrrole 1-carboxylic acid Triterpenoids (Diluted D-lb) (400 mg, 1.02 mmol), 4-ethynylphenyl-acid (149 mg, 1.02 mmol) and sodium bicarbonate (2 14 mg, 2_5 5 mmol) in DME (8) The stirred solution in mL) and water (2 mL) was continued for 15 minutes. Pd(PPh3)4 (58.9 mg, 0.051 mmol) was then added and nitrogen was continued to bubble for 5 minutes, then the reaction vessel was sealed and heated at 90 °C overnight. The reaction was cooled, diluted with THF, washed with brine and concentrated to dry. The residue was purified with EtOAc EtOAc (EtOAc) LC-MS retention time 2.911 min; m/z 723.64 (MH-). LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna 10 μC18 3.0 x 50 mm column and using a SPD-10AV UV-Vis detector with a debt detector wavelength of 220 nM. The dissolution conditions were 4 mL/min flow rate, 100% solvent A/0% solvent B to 0% solvent A/100% solvent B gradient, 3 min gradient time, 1 min retention time and 4 min analysis time, where solvent A 5% MeOH / 95% H2O / 10 mM ammonium acetate, and solvent B was 5% H20 / 95 / MeOH / 10 mM ammonium acetate. MS data was measured using a Micromass Platform using an electrospray mode LC. 4 NMR (400 MHz, MeOD) δ ppm 7.78 (d, J=8.0 Hz, 2H), 7.72 (d, 146976.doc -176- 201038558 «7=8.0 Hz, 2H), 7.64-7.69 (m, 4H) , 7.58 (d, "7=8.3 Hz, 2H), 7.52 (d, /=8.3 Hz, 2H), 7.31-7.41 (m, 2H), 4.86-5.03 (m, 2H), 3.68 (br s, 2H ), 3.46-3.57 (m, 2H), 2.37 (br s, 2H), 1.89-2.13 (m, 6H), 1.47 (br s, 6H), 1.25 (br s, 12H). Example J5, step b

TFA (250 pL ' 3.24 mmol) was added to a solution of the carbazide J5a in DCM (1 mL), and the The reaction was concentrated under a stream of nitrogen to give pyrrolidine J5b trifluoroacetate (45 mg). LC-MS retention time 2.928 min; m/z 525.32 (MH+). LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna 10 μC18 3.0 x 50 mm column and using a SPD-10AV UV-Vis detector with a detector wavelength of 220 nM. The dissolution conditions were 4 mL/min flow rate, 100% solvent A/0% solvent B to 〇% solvent A/100% solvent B gradient, 4 min gradient time, 1 min retention time and 5 min analysis time, where solvent A It was 5% MeOH/95% H20/1 mM ammonium acetate, and solvent 3 was 5% H20/95% MeOH/10 mM ammonium acetate. MS data was measured using a Micromass Platform using an electrospray mode LC. Example J5 to J5b trifluoroacetate (45 mg, 0.046 mmol) and (S)-2-(methoxymethoxyamino)-3-mercaptobutyric acid (24.2 11^, 0.138 111111〇1) Add HATU (53 146976.doc -177-201038558 mg, 0.14 mmol) to a solution of 0.71 </ RTI> and TEA (0.038 mL, 0.28 mmol) and stir the reaction for 30 min. Purification by preparative HPLC (MeOH EtOAc/EtOAc) elute elute elut elut elut elut elut LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna 10 μC18 3.0 x 50 mm column and SPD-10AV UV-Vis detector with a detector wavelength of 220 nM. Flow rate of 4 mL/min, 100% solvent A/0% solvent B to 0% solvent A/100% solvent B gradient, 4 min gradient time, 1 min retention time and 5 min analysis time, wherein solvent A is 5% MeOH/95% H2O/10 mM ammonium acetate, and solvent B was 5% H2 〇/95% MeOH/10 mM ammonium acetate. MS data was determined using an electrospray mode LC using a Micromass Platform. NMR (400 MHz, MeOD δ ppm 7.73-7.78 (m, 2H), 7.65-7.71 (m, 6H), 7.57-7.62 (m, 2H), 7.52 (d, J=8.5 Hz, 2H), 7.33-7.36 (m, 2H) , 5.18 (dt, /=7.6, 5.2 Hz, 2H), 4.21-4.27 (m, 2H), 3.96-4.05 (m, 2H), 3.84-3.92 (m, 2H), 3.66 (s, 6H), 2.17 -2.42 (m, 6H), 2.00-2.13 (m, 4H), 0.95 (dd, /=6.8, 1·3 Hz, 6H), 0.91 (dd, /=6.8, 1.0 Hz, 6H). Synthesis • / 6 combined treatment sequence: Purity evaluation and low-resolution mass analysis were performed on a Shimadzu LC system coupled to the Waters Micromass ZQ MS system. It should be noted that the residence time between machines may vary slightly. Other LC conditions may apply to this section unless otherwise indicated. 146976.doc •178· 201038558 Condition MS-Wl Column = XTERRA 3·〇χ50 mm S7 Starting B°/〇=0 Final B%=100 Gradient time=2 min Stop time=3 min Flow rate=5 mL/ Min Wavelength = 220 nm 〇 Solvent Α = 0% 1% TFA 10% decyl alcohol / 90% Η 20 Solvent Β = 90% methanol/10% with 0.1% TFA Η20 Condition MS-W2 Column = XTERRA 3.0x50 mm S7 Start B% = 0 Final B% = 100 Gradient time = 3 min Stop time = 4 min 〇 Flow rate = 4 mL / min Wavelength = 220 nm Solvent A = 10% sterol / 90% H20 with 0.1% TFA Solvent B = 90% methanol/10% H20 with 0.1% TFA. Condition MS-W5 Column = XTERRA 3.0x50 mm S7 Starting B% = 0 Final B% = 3 0 146976.doc -179- 201038558 Gradient time min Stop Time = 3 min Flow rate = 5 mL/min Wavelength = 220 nm Solvent A = 10% decyl alcohol with 0.1% TFA / 90% H20 Solvent B = 90% sterol/10% H20 with 0.1% TFA Condition D1 tube Column = XTERRA C18 3.0x50 mm S7 Starting B% = 0 Final B% = 100 Gradient time = 3 min Stop time = 4 min Flow rate = 4 mL / min Wavelength = 220 nm Solvent A = 1 0 with 0.1 % TFA % methanol / 90% H20 Solvent B = 90% sterol/10% H20 with 0.1% TFA Condition m Column = Phenomen ex-Luna 4.6x50 mm S10 Start B% = 0 Final B°/〇 = 100 Gradient time = 3 min Stop time = 4 min Flow rate = 4 mL/min Wavelength = 220 nm 146976.doc -180- 201038558 Solvent A = 10% decyl alcohol with 0.1% TFA / 90% H20 Solvent B = 90% methanol/10% H20 with 0% 1% TFA Condition MD1

Column = XTERRA 4.6x50 mm S5 Starting B%=0 Final B%=100 Gradient time = 3 min Stop time = 4 min Flow rate = 4 mL/min Wavelength = 220 nm Solvent A = 10% with 0.1% TFA Methanol / 90% H20 Solvent B = 90% sterol/10% H20 with 0.1% TFA Condition M3 Column = XTERRA C18 3.0x50 mm S7 Starting B% = 0 Final B% = 40 Gradient time = 2 min Stop time =3 min Flow rate = 5 mL/min Wavelength = 220 nm

Solvent A = 10% methanol with 0.1% TFA / 90% H20 Solvent B = 90% methanol/10% H20 with 0.1% TFA Condition 01A Column = Phenomenex-Luna 3.0x50 mm S10 146976.doc -181- 201038558 Start B%=0 Final B%=100 Gradient time=4 min Stop time=5 min Flow rate=4 mL/min Wavelength=220 nm Solvent A=10% sterol with 0.1% TFA/90% H20 Solvent B= 90% methanol/10% H20 with 0.1% TFA Condition OL2 Column = Phenomenex-Luna 5〇x2 mm 3 μ Start Β%=0 Final Β%=100 Gradient time=4 min Stop time=5 min Flow rate= 0.8 mL/min oven temperature = 40 ° C wavelength = 220 nm

Solvent A = 10% acetonitrile / 90% H2 oxime containing 0.1% TFA Solvent B = 90 ° / containing 0.1% TFA. Acetonitrile/10% H20 Condition I Column = Phenomenex-Luna 3·0χ50 mm S10 Starting B% = 0 Final B% = 100 Gradient time = 2 min 146976.doc -182- 201038558 Stop time = 3 min Flow rate = 4 mL/min wavelength = 220 nm

Solvent A = 10% methanol containing 0. 1% TFA / 90% H20 Solvent B = 90% sterol/10% H20 containing 0, 1% TFA Condition II

Column = Phenomenex-Luna 4.6 &gt; 50 mm S10 Starting B% = 0 Final B% = 100 Gradient time = 2 min Stop time = 3 min Flow rate = 5 mL / min Wavelength = 220 nm

Solvent A = 10% methanol with 90% TFA / 90% H20 Solvent B = 90% methanol/10% H20 with 0.1% TFA Condition III Column = XTERRA C18 3.0x50 mm S7 Starting B% = 0 Final B% =100 Gradient time = 3 min Stop time = 4 min Flow rate = 4 mL / min Wavelength = 220 nm Solvent A = 10% methanol with 90% TFA / 90% H20 146976.doc -183- 201038558 Solvent contains 0.1% TFA 9〇〇/0 sterol/10〇/o H2〇

To a mixture of (R)-2-phenylglycine (1 〇g, 66 2 mmol), formaldehyde (33 mL, 37% by weight in water), in HC1 (30 mL) and decyl alcohol (30 mL) A suspension of 100/〇Pd/C (2.0 g) in decyl alcohol (10 mL) was added and placed under H2 (60 psi) for 3 h. The reaction mixture was filtered through Celite® and the filtrate was concentrated in vacuo. The obtained crude material was recrystallized from isopropyl alcohol to give a white needle-like cap-1 hydrochloride (4· g). Optical rotation: -117.1. [c = 9.95 mg/mL in H20; λ = 589 nm]. 4 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 I): RT = 0.25; LC/MS: [M+H]+ calcd., calcd., calcd., calcd.

NaBH3CN (6·22 g ') was added portionwise to a cooled (ice/water) mixture of (R)-2-phenylglycine (6.02 g, 39.8 mmol) and decyl alcohol (100 mL) over a few minutes. 94 mmol) and stirred for 5 minutes. Ethylene 146976.doc -184- 201038558 aldehyde (10 mL) was added dropwise over 1 min, and stirring was continued at the same cooling temperature for 45 minutes and at ambient temperature for about 6.5 hours. The reaction mixture was quenched with ice-water bath, taken with water (3 mL) and then EtOAc EtOAc EtOAc. The cooling bath was removed and the concentrated hydrochloric acid was added to maintain the pH of the mixture at about 15 _2. The reaction mixture was stirred overnight and filtered to remove a white solid. The crude material was recrystallized from ethanol to give two portions of cap-2 hydrochloride as a bright white solid (1, 4.16 g; 2nd: 2 19 g). H NMR (DMSO-d6, &lt;5=2.5 ppm, 400 MHz): 10.44 (1.00, br s, 1H), 7.66 (m, 2H), 7.51 (m, 3H), 5.30 (s, 1H), 3.15 (br m, 2H), 2.98 (br m, 2H), 1.20 (apparent broad single peak, 6H). Batch 1: [α] 25 - 102.21. (c=0.357, H20); Batch 2: [α]25 _99 7. (c=0.357, Η2〇). LC (Cond. I): RT = 0.43 min; LC/MS: [M+H] + C12H18N02 calc.: 208.

M-s

Add B to the cooled (about 15 ° C) mixture of (R)-2-phenylglycine (3.096 g, 20.48 mmol), 1 n HCl (30 mL), and decyl alcohol (40 mL) A suspension of aldehyde (5.0 mL, 89.1 mmol) and 10% Pd/C (720 mg) in methanol / H.sub.2 (4 mL / 1 mL). The cooling bath was removed and the reaction mixture was stirred under a H2 balloon for 17 h. Additional acetaldehyde (10 mL, 178.2 146976.doc • 185·201038558 mmol) was added and the mixing was continued for 24 hours in a Η2 atmosphere [Note: Η2 supply was added as needed throughout the reaction]. The reaction mixture was filtered through Celite® and the filtrate was concentrated in vacuo. The obtained crude material was recrystallized from isopropyl alcohol to give (R)-2-(ethylamino)-2-phenylacetic acid hydrochloride (2.846 g) as a white solid. 4 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 (apparent triplet, /= 7.2, 3H). LC (Condition I): RT = 0.39 min; Homogeneity &gt;95%; LC/MS: [M+H]+ C 丨〇H 丨 4N02 Analysis calculated: 180.10, experimental value: 180.18. To (R)-2-(ethylamino)-2-phenylacetic acid/HC1 (1.492 g, 6-918 mmol), formaldehyde (20 mL, 37 wt. 0/〇 in water), 1 N HCl (20 mL) A mixture of 10% Pd/C (536 mg) in methanol / H20 (3 mL / 1 mL) was added to a mixture of decyl alcohol (23 mL). The reaction mixture was stirred under a H2 balloon for about 72 hours, and the supply was replenished as needed. The reaction mixture was filtered through celite (EtOAc) and evaporated. The crude material was recrystallized from EtOAc (EtOAc:EtOAc) NMR (DMSO-d6, δ=2·5 ppm, 400 MHz): δ 10.48 (br s,1H), 7.59-7.51 (m,5H), 5.26 (s,1H),3_08 (apparent broad single peak, 2H), 2.65 (br s, 3H), 1.24 (br m, 3H). LC (Condition I): RT = 0.39 min; Homogeneity Index &gt;95%; LC/MS: [M+H] + CuHwNCh analytical value·· 194,12, experimental value: 194.18; HRMS: [M+ Analysis calculated for H]+ CuH丨6N02: 194.1180, found: 194.1181. 146976.doc -186- 201038558 cap-4

To a solution of (R)-2-amino-2-phenylacetic acid tert-butyl ester/HC1 (9.877 g, 40.52 mmol) and diisopropylethylamine (14-2 mL, 81.52 mmol) over 6 min. ClC02Me 0 (3.2 mL, 41.4 mmol) was added dropwise to a cooled (ice/water) THF (410 mL) half solution and stirred at a similar temperature for 5.5 hours. The volatile component was removed in vacuo and the residue was partitioned between water (100 mL) and ethyl acetate (200 mL). The organic layer was washed with EtOAc (EtOAc)EtOAc. The obtained colorless oil was obtained by trituration with hexanes, and then washed with (100 mL) to give (R)-2-(indoleoxycarbonylamino)_2-phenylacetic acid as a white solid. Tributyl ester (7·7 g). 4 NMR (DMSO-d6, δ=2_5 ppm, 400 MHz): 7.98 (d, /=8.0, 1H), 7.37-7.29 (m, 5H), 5.09 (d, OJ:8' 1H), 3.56 (s , 3H), 1.33 (s, 9H). LC (Condition I): RT = 1.53 min; </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; TFA (16 mL) was added dropwise to a cooled (ice/water) CH.sub.2Cl.sub.2 (16 mL) solution. Since the protecting group was not completely removed, TFA (1.0 mL) was added and stirring was continued for another 2 hours. The volatile component was removed in vacuo and the obtained oily residue was purified eluted eluted elute The precipitate was filtered and washed with diethyl ether / hexane (EtOAc: EtOAc: EtOAc) Optical rotation: -176.9 ° [c = 3.7 mg/mL in H20; λ = 589 nm]. 4 NMR (DMSO-d6, 6=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 I): RT = 1.01; Homogeneity Index > 95%; LC/MS: [M+H] + C. For C12N04, calcd.: 210.08, found: 210.17; HRMS: [M+H]+ C1 () H12N04 calc.: 210.0766, found: 210.0756.

(R)-2-Phenylglycine (1.0 g, 6.62 mmol), 1,4 - dimethylidene (1·57 g ' 7.27 mmol) and Na2C03 (2.10 g, 19.8 mmol) in ethanol (40 The mixture in mL) was heated for 21 hours at TC (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 to pH 3-4 with 1 N HCl. The volatile component was removed in vacuo. The obtained crude material was purified by reverse phase HPLC (water/methanol/TFA) to afford to afford a semi-viscous white foam-like cap--5-trifluoroacetate (1.0 g). DMSO-d6, δ=2.5, 500 MHz) δ 10.68 (br s, 1H), 7.51 (m, 5Η), 5.23 (s, 1Η), 3.34 (apparent broad single peak, 2Η), 3.05 (apparent width) Single peak, 2H), 1_95 (apparent broad single peak, 4H); RT = 0.30 min (condition 146976.doc -188- 201038558 I); homogeneity index &gt;98%; LC/MS : [M+H] + C12H16N02 analytical calculated value: 206.12, experimental value: 206.25. Cap-6

Cap-6 trifluoroacetate was synthesized from (R)-2-phenylglycine and 1-bromo-2-(2-indolyl bromoethoxy)ethane using the procedure for the preparation of cap-5. 4 NMR (DMSO-d6, 6=2.5, 500 MHz) δ 12.20 (br s, 1H), 7.50 (m, 5H), 4.92 (s, 1H), 3.78 (apparent broad single peak, 4H), 3.08 ( Apparently broad single peak, 2H), 2.81 (apparent broad single peak, 2H); RT=0.32 min (condition I); &gt;98% ; LC/MS : [M+H]+ C12H16N03 222.11, calcd.: 222.20; HRMS: [M+H] + C12H16N03. Cap-7

Cap-7a·.Enantiomer-1 Cap-7b: Enantiomer-2 to (S)-2-hydroxy-2-phenylacetic acid benzyl ester (10.0 g, 41.3 mmol), triethyl Addition of p-toluenesulfonate to amine (5.75 mL, 41.3 mmol) and 4-dimethylamino D in π (0.504 g, 4.13 mmol) cooled (-5 ° C) CH2C12 (200 mL) Gas (8.65 g, 45.4 mmol) of CH2C12 (200 mL) 146976.doc -189- 201038558 solution while maintaining the temperature between _5t and 〇t:. The reaction was stirred at 〇t&gt;c for 9 hours and then stored in a freezer (-25 Torr for 14 hours. Thawed to ambient temperature with water (2 〇〇 mL), 1 n HCl (100 mL) Washing with brine (100 mL), drying (MgS 〇 4), filtered and concentrated in vacuo to give phenyl phenyl phthalate as a viscous oil. It solidifies when it is standing. The palmity integrity of the product was not checked and the product was used in the next step without further purification. 1{1]^^111(0]^8〇- d6, δ=2.5, 500 MHz) δ 7.78 (d, 7=8.6, 2H), 7.43-7.29 (m, l〇H), 7.20 (m, 2H), 6.12 (s, 1H), 5.16 (d, J=12.5, 1H), 5.10 (d, J-12.5, 1H), 2.3 9 (s, 3H). RT = 3. 〇〇 (conditional ni); homogeneity index &gt;90%; LC/MS : [M+H] + 匕 This coffee is analytically calculated: 419·09, experimental value: 419 〇 4. Phenyl phenyl 2-phenyl-2-(toluenesulfonyloxy)acetate (6 〇g, 151 mmol), 1-methyl 0 (3 3 6 mL, 3 0.3 mmol) and N,N- A solution of diisopropylethylamine (13.2 mL, 75.8 mmol) in THF (75 mL) was evaporated. The reaction was allowed to cool to ambient temperature and the volatile components were removed in vacuo. The residue was partitioned between EtOAc (EtOAc m. The crude material was purified by flash chromatography (EtOAc EtOAc EtOAc) (456 g). A palmitic HPLC analysis (Chiralcel 0D_H) indicated that the sample was a mixture of enantiomers at a ratio of 38.2 to 58.7. Enantiomeric separation was achieved as follows: The product was dissolved in 120 mL ethanol/heptane (1:1) and injected (5 mL per injection) to 85:15 heptane/ethanol at 75 mL/min Dissolution and 146976.doc -190- 201038558 Monitoring of the palmitic hplC column at 220 nm (Chiracel OJ, 5 cm ID x 50 cm L, 20 μηι; ^. Recovery of the enantiomer in the form of a viscous oil) (1.474 g) and enantiomer 2 (2 2149 g) e iH nMR (CDC13, 5 = 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, /=12.5, IH), 4.02 (s,ih), 2.65-2.38 (apparent broad single peak, 8H), 2.25 (s, 3H). RT = 2.1 〇 (condition in); homogeneity index &gt;98%; lc/MS: [M+H] + C2GH25N202 analytical value: 325.19, experimental value: 〇^ 325.20. Addition of any of the enantiomers of 2-(4-methylnidonium-1-yl)-2-phenylacetate benzyl ester to a suspension of % Pd/C (120 mg) in fermentation (5.0 mL) A solution of the construct (1.0 g '3.1 mmol) in methanol (10 mL) was placed under a hydrogen balloon under careful monitoring for &lt;50 min. After the reaction was completed, immediately The catalyst was filtered off through Celite®, and the filtrate was concentrated in vacuo to give a brown foam-like cap -7 (867.6 mg; mass above theoretical yield) which was contaminated with phenylacetic acid. Further purification was used in the next step. 咕NMR (DMSO-d6, δ=2·5,500 ΜΗζ) δ 7.44-7.37 (m, 2 Η), 7.37-7,24 (in, 3 Η), 3.92 (s, 1Η), 2.63-2.48 (apparent broad single peak, 2H), 2.48-2.32 (m, 6H), 2.19 (s, 3H); RT=0.31 (condition II); homogeneity index &gt;90%; LC/ MS: [M+H]+ calcd for C13H19N2 〇2: 235.14 </ br>

Analysis of Ci3Hi9N&quot;2〇2 §10 nose value.235.1447, experimental value. 235.1440 〇According to the synthesis of cap-7' by SN2 replacement step using the appropriate amine (also 146976.doc -191 - 201038558 -hydroxypiperidine and The cap is used for the cap-8 using 4 s -9 using the (s)_3-fluoropyrrole stereoisomeric intermediate pyridine) and using the following as described for separating the individual modification conditions for the towel _8 and cap _ Synthesis of 9.

Enantiomeric separation of the intermediate 2-(4-hydroxypiperidine-indolyl)-2-phenylphenyl phthalate by the following conditions: The compound (5 〇〇mg) was dissolved in ethanol/heptane (5 mL / 45 mL). The resulting solution was injected (5 mL per injection) to a palmitic HPLC column (Chiracei 〇j, 2 cm IDx25(10), which was lysed at 80:20 heptane/ethanol at 1 〇mL/min and monitored at 220 nm. On L, 10 μηι), 186.3 mg of enantiomer-1 and 209-1 mg of enantiomer-2 were obtained as a pale yellow viscous oil. Hydrogenolysis of these stupid methyl esters according to the preparation of cap-7 gave cap-8: 4 NMR (DMSO-d6, δ=2.5, 5 〇〇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 (Conditional Π); Homogeneity Index &gt;98%; LC/MS: [M+H]+ C13H18N03 Analysis calculated: 236.13, found: 236.07; HRMS: [M+H]+ C13H18N03 Value: 236.1287, experimental value: 236.1283. 146976.doc •192· 201038558 Cap-9

9a: diastereomer-1 9b: diastereomer-2 The intermediate 2-((S)-3-fluoropyridin-1-yl)-2- was achieved by the following conditions Diastereomeric separation of phenyl phenylacetate: dissolution in 95% C02/5% methanol with 0.1% TFA at a pressure of 10 bar, a flow rate of 70 mL/min and a temperature of 35 °C The vinegar (220 mg) was separated on a palm HPLC column (Chiracel OJ-H, 0·46 cm ID x 25 cm L, 5 μηι). The HPLC isolates of each of the stereoisomers were concentrated, and the residue was dissolved in CH.sub.2 C.sub.2 (20 mL) and washed with an aqueous medium (10 mL water + 1 mL NaHC03 saturated solution). The organic phase was dried <RTI ID=0.0>(M </RTI> <RTI ID=0.0></RTI> </RTI> <RTIgt; These phthalic esters were subjected to hydrogenolysis according to the preparation of Cap-7 to obtain caps 9a and 9b. Cap-9a (diastereomer-1; purified on reverse phase HPLC using H20/nonanol/TFA solvent to give a sample in the form of trifluoroacetate): 4 NMR (DMSO-d6, δ=2.5, 400 MHz) 7.55-7.48 (m, 5H), 5.38 (multiple sets of double peaks, /=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 I); Homogeneity Index &gt;95%; LC/MS: [M+H] + C12H15FN02 calc.: 224.11, Found: 224.14; 2) : 4 NMR (DMSO-d6, δ=2.5,400 MHz) 7.43-7.21 (m, 5Η), 5·19 (multiple sets of double peaks, *7=55.9,1Η), 3.97 (s,1H), 2.95-2.43 (m, 4H), 2.19-1.78 (m, 2H). 146976.doc -193 - 201038558 RT=0.44 (Conditions; LC/MS: [M + H] + Ci2H丨 5FN〇2 Analysis calculated: 224.11, experimental value: 224.14. Cap-10

Add 1% pd/c (5〇) to a solution of D-proline (2.0 g, 17 mmol) and furfural (2. 〇mL, 37% by weight in h2) in methanol (15 mL). 〇mg) a suspension in decyl alcohol (5 mL). The mixture was stirred under a hydrogen balloon for 23 hours. The reaction mixture was filtered with EtOAc EtOAc (EtOAc) iHNMRCDMSO-dh 6=2.5, 500 MHz) 3.42 (m, 1H), 3.37 (dd, J-9.4, 6.1, 1H), 2.85-2.78 (m, 1H), 2.66 (s, 3H), 2.21-2.13 ( m, 1H), 1.93-1.84 (m, 2H), 1.75-1.66 (m, 1H) ° RT = 0_28 (condition II); homogeneity index &gt;98%; LC/MS : [M+H]+ C6Hi2N分析2 analytical calculation: 130·09 ' Experimental value: 129.96. Cap-11

(2S,4R)-4-fluoropyrrolidine-2-carboxylic acid (0.50 g, 3.8 mmol), hydrazine (〇 5 mL, 37% by weight in H20), 12 N HCl (0.25 mL) under hydrogen balloon And a mixture of 1% Pd/c (5 〇 mg) in decyl alcohol (20 mL) was stirred for 19 hours. The reaction mixture was filtered through celite (EtOAc) and filtered and evaporated. The residue was recrystallized from isopropyl alcohol to afford EtOAc (yield: &lt 111 face 11 (〇^/18〇_(16,3=2.5,500 MHz) 5.39 (dm, /=53.7, 1H), 4.30 (m, 1H), 3.90 (ddd, ^=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 II) 'Homogeneous Sex index &gt;98./.; LC/MS: [M+H]+ Analysis of CeHnFNC^ §10. 148.08' Experimental value: nog. Ο Cap -12 (same as cap 52)

L Dissolve L-alanine (2·〇g, 22 5 mm〇1) in 1% aqueous sodium carbonate solution (5〇mL), and add dimethyl formate (4.0 mL) to THF (50 mL) ) solution. The reaction mixture was stirred at ambient temperature for 4 h and concentrated in vacuo. The obtained white solid was dissolved in water, and the resulting solution was extracted with ethyl acetate (3 χ(10) red) by acidification to pH value 2 3 HCl, and dried (Na 2 S 4 ). The mixture was concentrated in vacuo to give a colourless oil (2.5 g). Purification of $(9) mg of this material by reverse phase Ηριχ(Η2〇/sterol) gave 15% of a cap of colorless oil _12. 屯nmr (DMSO-d65 5=2.5, 500 MHz) 7.44 (d, ^7.3 , 0.8H), 7.10 (br S' 〇.2H), 3.97 (m, 1H), 3.53 (s, 3H), 1.25 (d, &gt; 7.3, 3H). Cap-13

IO 146976.doc •195· 201038558 'L-alanine (2.5 g, 28 mmol), furfural (8.4 g, 37 wt. 0/〇), 1 N HC1 (30 mL) under hydrogen atmosphere (50 psi) A mixture of 10% Pd/C (500 mg) in methanol (30 mL) was stirred for 5 hours. The reaction mixture was filtered through EtOAc (EtOAc) elutingEtOAc. The product was used without further purification. Ijj NMR (DMSO-d6j 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) 0 cap-14

#锧i : Stir in the sterol at 0 ° C (r) _ (a) _D_ phenylglycine tert-butyl ester (3.00 g, 12.3 mmol), NaBH3CN (0.773 g, 12.3 mmol), ΚΟΗ (0· 690 g, 12.3 mmol) and acetic acid (0.352 mL, 6.15

a mixture of mmol). To this mixture, glutaraldehyde (2.23 mL, 12.3 mmol) was added dropwise over 5 minutes. The reaction mixture was stirred while warming the reaction mixture to ambient temperature and stirring was continued at ambient temperature for 16 hours. The solvent was then removed' and the residue was partitioned between 丨〇% aqueous NaOH and ethyl acetate. The organic phase was separated and dried (MgSO4), filtered and concentrated to dryness This material was obtained by reverse phase preparative HPLC (Primesphere C-18, 30x100 mm; CH3CN-H2O-0.1% TFA) pure 146976.doc -196- 201038558 to give the intermediate ester as a clear oil (2.70 g, 56 %bιΉ NMR (400 MHz, CDC13) δ 7.53-7.44 (m,3H),7,40-7.37 (m, 2H), 3.87 (d, /-10.9 Hz, 1H), 3.59 (d, /=10.9) Hz, 1H), 2.99 (t, J-ll.2 Hz, 1H), 2.59 (t, /=11.4 Hz, 1H), 2.07-2.02 (m, 2H), 1.82 (d, "7=1.82 Hz, 3H), 1.40 (s, 9H). LC/MS: (M+H) + C17H25N02 Analysis calculated: 275, found: 276. Step 2: Intermediate ester (1.12 g, 2.88 surface 〇1) TFA (3 mL) was added to a stirred solution of EtOAc (EtOAc). HPLC (Primesphere c_18, 3〇χ1()() mm; CH3CN-H2〇-〇.i%. The oil was purified. The appropriate fractions were combined and concentrated in vacuo to dryness. In methanol, and applied to the MCXLP extraction cartridge (2x6g). Rinse the cartridges with methanol (4〇mL) and connect The solution of the desired sigma was dissolved by using a solution of 2 hydrazine in methanol (50 mL). The fractions containing the product were combined and concentrated, and the residual Q was 'combined in water. The solution was lyophilized' to give a light Title titled yellow solid. (0.492 g, 78%). &gt;iMR (DMSO-d6) δ 7.50 (s, 5 Η), 5.13 (S, 1 Η), 3.09 (br s, 2 Η), 2.92-2.89 (m, 2Η), 1.74 (called 占), [.48 (br s, 2Η). LC/MS: (Μ+Η)+ C13H17N02 Analysis calculated value: 219, experimental value: 220.

ΌΗ Br A

Cap -15 - 丄 Χ Me Me Me Me Me Me Me Me Me Me To α_ desert benzoic acid (10.75 g, 0.050 m〇l), (8)·(a) small phenylethanol (7% §, 〇〇65 mol) and DMAP (0.61 g, 5.0 mm〇l) in anhydrous two gas (1) Solid EDCI (12 46 g, 〇〇65) was added in one time to the mixture in the squeaking. The resulting solution was stirred at room temperature for 18 hours under Ar, and then diluted with ethyl acetate, washed (Η2〇χ2 </ RTI> </ RTI> <RTI ID=0.0></RTI> </RTI> <RTI ID=0.0></RTI> The title compound (11.64 g '73%) as a solid. 4 NMR (400 MHz, CDC13) δ 7.53-7.17 (m, 10 Η), 5.95 (q, J = 6.6 Hz, 0.5 Η), 5·94 (q, &gt;6.6 Ηζ, 〇.5H), 5.41 (s, 0.5H), 5.39 (s, 0.5H), 1.58 (d, y=6.6 Hz, 1.5H), 1.51 (d, J=6.6 Hz, 1.5H #耀耀 2: (R)-2-(4-Hydroxy-4-mercaptopiperidine-1-yl)_2-phenylacetic acid (S)-1-phenethyl ester: 2-bromo-2- Phenylacetic acid (s)-l-phenylethyl ester (0 464 g, 丨45 mmol) was added triethylamine (〇61, 4 35 mmol) in a solution of THF (8 mL), followed by the addition of 215 g of deuterated tetrabutyl bond, 〇58 mmol). The reaction mixture was stirred for 5 min, and then a solution of 4-methyl-4-methylpyramine (0.251 g, 2.18 mmol) in THF (2 mL) was added. The mixture was stirred at room temperature for 1 hour and then Heating at 55_60 ° C (oil bath temperature) for 4 hours. The cooled reaction mixture 'wash strips (Η2〇χ2, brine) was diluted with ethyl acetate (3 mL), dried (MgS〇4), filtered and filtered. The residue was purified by EtOAc (EtOAc-EtOAc) And then the corresponding (S,S)-isomer (012 〇g, 146976.doc 201038558 23%) was also obtained as a white solid. (S,R)-isomer: 4 NMR (CD3OD) δ 7.51 -7.45 (m, 2H), 7.41-7.25 (m, 8H), 5.85 (q, 6 Hz, 1H), 4.05 (s, 1H), 2.56-2.45 (m, 2H), 2.41-2.29 (m, 2H) ), 1.71-1.49 (m, 4H), 1.38 (d, 7 = 6.6 Hz, 3H), 1.18 (s, 3H). </RTI> <RTI ID=0.0></RTI> (S,S)-isomer: 4 NMR (CD3OD) δ 7.41-7.30 (m, 5H), 7.20-7.14 (m, 3H), 7.06-7.00 (m, 2H), 5.85 (q, J=6.6 Hz, 1H), 4.06 (s, 1H), 2.70-2.60 (m, 1H), 2.51 (dt, J=6.6, 3.3 Hz, 1H), 2.44-〇2.31 (m, 2H), 1.75-1.65 (m , 1H), 1.65-1.54 (m, 3H), 1.50 (d, /=6.8 Hz, 3H), 1.20 (s, 3H). </RTI> <RTI ID=0.0></RTI> #摩3 : (R)-2-(4-Hydroxy-4-indolylpiperidinyl)_2_phenylacetic acid: To (R)-2-(4-hydroxy-4-methylpiperidine_ι_ Add a solution of dihydric acid (1 mL) to a solution of diphenylacetic acid (1) diphenylacetate (0.185 g, 0.52 mmol) in dichloromethane (3 mL). hour. The volatiles were then removed in vacuo and the title compound was purified mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj In the form of trifluoroacetate) (〇128 g, 98%). LCMS: (M+H) + calcd. Cap-16

Listening &gt; Cap-16 146976.doc -199 201038558 #杂7 : 2-(2-Fluorophenyl)acetic acid (S)-l-Phenylethyl ester: 2-fluorophenylacetamidine (5.45 g ' 35.4 mmol The mixture of (s)-l-phenylethanol (5.62 g, 46.0 mmol), EDCI (8.82 g, 46.0 nmol) and DMAP (0.561 g, 4.60 mmol) in CHjClJlOOmL) was stirred at room temperature for 12 hours. The solvent was then concentrated and the residue was partitioned between H20 and ethyl acetate. The phases were separated and the aqueous layer was back extracted with ethyl acetate (2 EtOAc). The organic phase was combined (He, brine) dried (Na2EtOAc) filtered. The title compound (8 38 g, 92%) was obtained. Η NMR (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). #杂2 : (R)-2-(2-fluorophenyl)-2-(piperidinyl-i-yl)acetic acid phenylethyl ester): 2-(2-fluorophenyl) at 〇 °C Add acetic acid (s)-!-Phenylethyl ester (5 〇 () g, 19.4 mmol) in THF (1200 mL), add DBU (6 19 g, 40.7 mmol), and warm the solution to room Warm, maintain for 3 minutes. The solution was then cooled to -78 ° C, and a solution of CBr 4 (13.5 g, 40.7 mmol) in THF (100 mL) was added, and the mixture was warmed to -10 C and stirred at this temperature for 2 hours. The &amp; NH4C1 saturated aqueous solution was quenched and the layers were separated. The aqueous layer was back-extracted with ethyl acetate (2 EtOAc) and the combined organic phases were washed (salt, brine) and dried (Na.sub.2.sub.4). A brigade bit (5.73, 58 j 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 purified EtOAc EtOAc EtOAc EtOAc EtOAc The mixture (ratio 2:1 by 1 H NMR) (2.07 g, 31 °/.), and the unreacted starting material (2.53 g '51%). The title compound (0.737 g, 11%) was obtained as a colorless oil. NMR (400 MHz, CD3〇D) 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, /=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, Ο 1H), 1.38 (d, "7=6.6 Hz, 3H). LCMS: (M+H) + calcd. #杂3 : (R)-2_(2- Iphenyl)-2-(Pinge-1-yl)acetic acid: '(R)_2_(2) at room temperature and under heavy load (H2 balloon) -murine phenyl)-2-(bunk l-yl)acetic acid ((S)-l-phenylethylhydrazine) (0.737 g, 2.16 mmol) and 20% Pd(〇H)2/C (0.070) g) The mixture in ethanol (30 mL) was hydrogenated for 2 h. It was then filtered through Celite® with Ar purification solution and concentrated in vacuo. The title compound (0.503 g, 98%) was obtained as a colourless solid. 4 NMR 〇 (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), 3.07-3.13 (m, 4H), 1.84 (br s, 4H), 1.62 (br s, 2H). </RTI> <RTI ID=0.0></RTI> Cap -17

Q-Cap-17 I46976.doc . 201 - 201038558 黄杂7 . (R)_2-(4_Hydroxy~4_phenylpiperidin-1-yl)-2-phenylacetic acid (s)_ 1-benzene Ethyl ester: Triethylamine (1 31 rainbow) was added to a solution of (S)-1-phenylethyl 2-bromo-2-phenylacetate (1.5 〇g, 47 〇 mmol) in THF (25 mL) '9·42 mmol) 'Subtetraethylammonium iodide (〇347 g, ο.% mmol) was subsequently added. The reaction mixture was stirred at room temperature for 5 min and then a solution of phenylphenyl-4-hydroxypiperidine (m. The mixture was stirred for 16 hours and then diluted with ethyl acetate (1 mL), washed (EtOAc, EtOAc) The residue was purified on a silica gel column (0-60% ethyl acetate-hexanes) to afford a mixture of diastereomers of about 2: i as judged by H NMR. Separation of the isomers by supercritical fluid chromatography (Chiralcel OJ-H, 30 X 250 mm; 20% ethanol in c〇2 at 35 ° C) afforded the title compound (R) )-isomer (0.534 g, 27%) and then the corresponding (S)-isomer (0.271 g, 14%) which was also obtained as a yellow oil. (S,R)-isomer: 1H NMR (400 MHz, CD3OD) δ7·55-7.47 (m, 4H), 7.44-7.25 (m, 10H), 7.25-7.17 (m, 1H), 5.88 (q, J=6.6 Hz, 1H), 4-12 (s, 1H), 2.82-2.72 (m, 1H), 2.64 (dt, 11.1, 2.5 Hz, 1H), 2.58-2.52 (m, 1H), 2.40 (dt , J=Ul, 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, J = 6.5 Hz, 3H). LCMS: (M+H) + calcd.: </RTI> </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; , 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, J-6.6 Hz, 1H), 4.12 (s, 146976.doc •202· 201038558 1Η), 2.95-2.85 (m, 1H), 2.68 (dt, J= 11.1, 2.5 Hz, 1H), 2.57-2.52 (m, 1H), 2.42 (dt, J = 11.1, 2.5 Hz, 1H), 2.25 (dt, J = 12.1, 4.6 Hz, 1H), 2.12 (dt, J-12.1, 4.6 Hz, 1H), 1.73 (dd, J=13.6, 3.0 Hz, 1H) , 1.64 (dd, /=13.6, 3.0 Hz, 1H), 1.40 (d, /=6.6 Hz, 3H). LCMS: (M+H) + calc. The following esters were prepared in a similar manner:

Intermediate -17a ΟγΟ^Ο 0 03⁄4 Diastereomer 1 : b NMR (500 MHz, DMSO-de) δ ppm 1.36 (d, /=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, J=6J\ Hz, 1H) 7.15-7.52 (m, 15H). Calcd.: </RTI> </RTI> <RTI ID=0.0></RTI> Diastereomer 2 : 4 NMR (500 MHz, DMSO-d6) δ ppm 1.45 (d, J = 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, J = 6.71 Hz, 1H) 7.12 (dd, /=6.41, 3.05 Hz, 2H) 7.19-7.27 (m, 3H) 7.27-7.44 (m,1 OH). Calcd.: </RTI> </RTI> <RTI ID=0.0></RTI> Intermediate: -m cV ° 03⁄4 diastereomer 1 : RT = 11.76 min (Cond. II); LCMS: (M+H) + C2 〇H22N203 calc. Diastereomer 2: RT = 10.05 min (Cond. II); LCMS: (M+H) + C2QH22N2 〇3 calc.: 338. Intermediate -17c ό 03⁄4 diastereomer 1 : TR = 4.55 min (Cond. I); LCMS: (M+H) + C21H26N202 Analysis Calculated: 338.20. Diastereomer 2: TR = 6.00 min (Cond. I); LCMS: (M+H) + C21H26N202: Calculated: 338. 146976.doc -203- 201038558 Intermediate -ΓΜ - --------- Diastereomer 1 : RT = 7.19 min (Condition I); LCMS: &lt;M+H&gt;+ C27H29N〇2 Analytical calculated value: 399.22, experimental value: 400.48. Diastereomer 2: RT = 9.76 min (Cond. I); V LCMS: (M+H) + C27H29N02. Calculated Calculated: 03.

Determination of residence time versus palmar SFC conditions Condition I

Column: Chiralpak AD-H column, 4.62x50 mm, 5 μιη Solvent: 90% CO2-10% decyl alcohol and 0.1% DEA Temperature: 35 °C Pressure: 150 bar Flow rate: 2.0 mL/min At 220 nm UV monitoring injection: 1.0 mg / 3 mL sterol conditions II column: Chiralcel OD-H column ' 4.62x50 mm, 5 μιη Solvent: 90% C〇2-1 〇% sterol and 〇. 1 % DEA Temperature: 35 ° C Pressure: 15 0 bar Flow rate: 2.0 mL / min UV monitoring at 220 nm Injection: 1.0 mg / mL methanol cap 17, step 2: (R)-2-(4-hydroxy-4-phenyl Piperidin-1-yl)-2-phenyl 146976.doc -204 · 201038558 Acetic acid: to (R)-2-(4-hydroxy-4-phenylpyridin-1-yl)-2-phenylacetic acid To a solution of (S)-1-phenylethylacetic acid (0.350 g, 0. 84 mmol) in dichloromethane (5 mL) was added trifluoroacetic acid (1 mL), and the mixture was stirred at room temperature for 2 hr. The volatiles were then removed in vacuo and the title compound was purified eluted elut elut ) (0.230 g, 88%). LCMS: (M+H) </RTI> <RTI ID=0.0></RTI> </RTI> <RTIgt;

Cap -17a RT=2.21 (Condition II);]H NMR (500 MHz, DMSO-d6) δ ppm 2.20-2.35 (m, 2H) 2.34- T 2.47 (m, 2H) 3.37 (s, 4H) 3.71 (s , 1H) 5.06 (s, 2H) 7.06-7.53 (m, 10H). </ RTI> <RTI ID=0.0></RTI> </RTI> <RTI ID=0.0></RTI> <RTIgt; </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; X. ^OH U 〇cap -17c 1 RT=0.48 (Condition II); LCMS: (M+H)+ C13H18N202 Analysis calculated: 234.14, Experimental value: 235.3 rrVH u 〇 Cap-Vld RT=2.21 (Conditions I.; LCMS: (M+H) + C19H21. V 〇VH 146976.doc -205- 201038558

LCMS conditions for determining residence time Condition I Column: Phenomenex-Luna 4.6x50 mm S10 Starting B%=0 Final B% = 100 Gradient time = 4 min Flow rate = 4 mL/min Wavelength = 220

Solvent A=10% Methanol-90% Η2〇-0·1% TFA Solvent Β=90% Methanol-10% Η2Ο-0·1% TFA Condition II Column: Waters-Sunfire 4.6x50 mm S5 Starting 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 Β=90% Methanol-1 0% Η2Ο-0.1 % TFA Conditions in Column: Phenomenex 10 μ 3.0x50 mm Starting Β%=0 Final Β%=100 Gradient time=2 min -206 146976.doc 201038558 Flow rate*~4 mL/iuin Wavelength=220

Solvent Α=10ο/〇 Methanol _9〇〇/0 H2O-0.1% TFA Solvent B=90% Methanol]〇% h2〇-〇.1% TFA

Cap-18

N〆

Steps i. (R,S)-2-(4-e ratio bite base)-2-acetic acid ethyl acetate·· under argon under argon to a 4-° ratio. Add DBU (0.99 mL, 6.66 mmol) to a solution of EtOAc (EtOAc) (EtOAc) To -78 ° C. To this mixture was added CBr4 (2.21 g, 6.66 mmol), and stirring was continued at -78 °C for 2 hours. The reaction mixture was then quenched with a saturated aqueous solution of NH4Cl, and the phases were separated. The organic phase was washed with brine (Na2SO4), filtered and concentrated in vacuo. The title compound (1.40 g, 95%) was obtained. 4 NMR (400 MHz, CDC13) δ 8.62 (dd, J=4.6, 1.8 Hz, 2H), 7.45 (dd, /=4.6, 1.8 Hz, 2H), 5.24 (s, 1H), 4.21-4.29 (m, 2H), 1.28 (t, "7=7.1 Hz, 3H). </RTI> <RTI ID=0.0></RTI> </RTI> <RTI ID=0.0></RTI> 146976.doc -207- 201038558 : (R,S)-2-(4-Acridine)-2-(N,N-didecylamino)acetate: at room temperature, to (R, Add dimethylamine (2 于 in THF, 8.5 mL ' 17.0 mmol) to a solution of ethyl bromoacetate (1.40 g, 8.48 mmol) in DMF (10 mL) . After completion of the reaction (as judged by thin layer chromatography), the volatiles were removed in vacuo and purified by flash chromatography (Bi </ RTI> </RTI> </ RTI> 40 <RTIgt; The title compound was obtained (jjjjj: iH nmr (400 MHz, CDC13) δ 8.58 (d, "7=6.0 Hz, 2H), 7.36 (d, "/=6 〇Hz, 2H), 4.17 (m, 2H), 3.92 (s, 1H), 2.27 (s,6H), 1.22 (t &gt;7.0 Hz). </RTI> <RTI ID=0.0></RTI> Step 3: (R,S)-2-(4-pyridyl)·2-(anthracene, fluorenyl-dimethylamino)acetic acid: at room temperature, to (R,S)-2-(4 -Pyridyl)_2_(Ν,Ν_didecylamino)acetate (0.200 g, 0.960 mm 〇1) was added to a solution of THF decyl _ η 2 〇 mixture (1.1.1 '6 mL) Shape][^〇11(〇12〇g, 4 99 mm〇1). Stir the solution for 3 hours and then use! It is acidified to pH 6 by n hci. The title compound dihydrochloride (containing [s)) was obtained as a yellow solid. The product was as η NMR (400 MHz, DMSO-d6) δ 8.49 (d, / = 5.7 Hz, 2H), 7 34 /jr , ' . (d&gt; J~Sl Hz, 2H), 3.56 (s, 1H) , 2.21 (s, 6H). The following example was prepared in a similar manner using the above method; 146976.doc 201038558 Cap-19 NMe2 ry^c〇2H N LCMS : (M+H)+ C9H12N2〇2 Analysis calculated value: 180, experimental value :181. Cap-20 NMe2 〇^c〇2H LCMS: Not ionized. 1H NMR (400 MHz, CD3OD) δ 8.55 (d, J = 4.3 Hz, 1H), 7.84 (apparent triplet, / = 5.3 Hz, 1H), 7.61 (d, J = 7.8 Hz, 1H), 7.37 (apparent triplet, J = 5.3 Hz, 1H), 4.35 (s, 1H), 2.60 (s, 6H).帽-21 NMe2 [f^Y^C02H LCMS: (M+H)+ C9HuC1N202 calc.: 214, 216. Cap-22 NMea. 2 furnaces. Anal. Calcd.: </RTI> &lt;RTI ID=0.0&gt; Measured value: 229, calcd.: 230.帽-24 NMe2 F3C^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ CAP - 25 NMe2 cCr LCMS : (M+H) + CuHi2F3N02: 247.帽 -26 NMe2 C^c 〇 2H LCMS : (M+H) + C1QHi2FN02 calc. Anal. Calcd.: 247, calcd.帽 N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N N 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。. m 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。.帽-31 NMe2 g/::Y^C〇2H 丫 W LCMS : (M+H)+ C8H12N2 〇2S Analysis calculated: 200, Experimental value: 201. Anal. Calcd.: 185. Found: 186.帽-33 NMe2 g/^J^C02H LCMS: (M+H)+ C8HnN02S calc.帽-34 V^y^co2h '〇 N N LCMS : (M+H)+ CnH12N203 calc. 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。. 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 ^-37

Cap-37

Β -210- Μβ2Ν^Ύ〇Β Ο

A 146976.doc 201038558 #锧7 : (R,S)-2-(quinolin-3-yl)-2-(N,N-didecylamino)-ethyl acetate: bubbling with Ar gas Ethyl hydrazide, ethyl hydrazide-diaminoacetate (0.462 g '3.54 mmol), K3P04 (1.90 g, 8..95 mmol), Pd(t-Bu3P)2 (0.090 g, 0.176 mmol) and toluene ( The 10 mL) mixture was degassed for 15 minutes. The reaction mixture was then heated at 100 ° C for 12 hours, then allowed to cool to room temperature and poured into H20. The mixture was extracted with EtOAc (2×). Purification of the residue by reverse phase preparative HPLC (Primesphere C-18, 30 X 100 mm; CH3CN-H20-5 mM NH4OAc) followed by flash chromatography (SiOV hexane ethyl acetate, 1:1) The title compound (0.128 g, 17%). 4 NMR (400 MHz, CDCls) 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, 7=8.3, 6.8, 1.5 Hz, 1H), 4.35 (s, 1H), 4.13 (m, 2H), 2.22 (s, 6H), 1.15 (t, « /=7.0 Hz, 3H). </RTI> <RTI ID=0.0></RTI> <RTI ID=0.0></RTI> #杂2 : (R,S)_2-(quinolin-3-yl)-2-(N,N-dimethylamino)acetic acid: (R,S)-2-(quinoline-3- A mixture of ethyl 2-(N,N-dimethylamino)acetate (0.122 g, 0.472 mmol) and 6 M EtOAc (3 mL) was obtained. (The next heating was carried out for 12 hours. The solvent was removed in vacuo to give the title compound di hydrochloride as a pale yellow foam (0.169 g, &gt; 1% ρ unpurified material was used in the next step without further purification. LCMS : (M+H) + C13H 丨 4N2 〇 2 Analysis calculated: 230, calc.: 231. 146976.doc -211· 201038558

OH F NR1R2 A cap-38

Huangza 7 : (R)_2-(dimethylamino)-2-(2-fluorophenyl)acetic acid ((S)_U stupid ethyl ester) and (S)-2-(dimethylamino) _2_(2-fluorophenyl)acetic acid ((s)"-p-ethyl ester): to (RS)-2-(dimethylamino)_2_(2.fluorophenyl)acetic acid (2 6 〇笆, 13.19 EDCI (3.29 g, I7" 5 mmol) was added to a mixture of mmol), DMAP (0.209 g, 171 mm 〇1) and (8) phenylethanol (2.09 g, 17·15 mmol) in CH2C12 (40 mL). The mixture was stirred at room temperature for several hours. The solvent was then removed in vacuo and the residue was partitioned betweenEtOAc andEtOAc. The layers were separated, the aqueous layer was extracted with EtOAc (EtOAc) (EtOAc) (EtOAc) The residue was purified by reverse phase preparative HPLC (Primesphere C-18, 30 X 100 mm; CH3CN-H2O-0.1% TFA). R)-2-(didecylamino)-2-(2-fluorophenyl)acetic acid (Μ-ΐ-phenylethyl ester (0.501 g, 13%) followed by (S)-2-(dimethyl Amino) 2_(2-IL-based)-acetic acid (S)-l-phenylethylacetate (0.727 g, 18%), both in the form of trifluoroacetate. (S,R)-isomer : NMR (400 MHz, -212- 146976.doc 201038558 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: (M+H)+ C18H2 〇FN02 calc.: 301, calc.: 302; (S,S)- isomer: 4 NMR (400 MHz, CD3OD) δ 7.58-7.63 (m, 1H ), 7.18-7.31 (m ,6H), 7.00 (dd, /=8.5, 1.5 Hz, 2H), 6.02 (q, /=6.5 Hz, 1H), 5.60 (s, 1H), 2.88 (s,6H), 1.54 (d, "7 = 6.5 Hz, 3H). LCMS: (M+H) + C18H2 () FN02 Analysis calculated: 301, found: 302. # (2) (R)-2-(didecylamino)-2 -(2-fluorophenyl)acetic acid: (r)_2_(dimethylamino)-2-(2-fluorophenyl)acetic acid ((S)-l at room temperature and atmospheric pressure (H2 balloon) -Phenylethyl ester)trifluoroacetate (125 g, 3.01 mmol) and a mixture of 20% Pd(OH)2/C (0.125 g) in ethanol (3 Torr) were hydrogenated for 4 hours. Filtration over celite (EtOAc) EtOAc (EtOAc) 1h NMR (400 MHz, CD3OD) δ 7.53-7.63 (m, 2 Η), 7.33-7.38 (m, 2 Η), 5.36 (s, 1 Η), 2.86 (s, 6 Η). For LCMS: (Μ+Η)+ C10H 丨2FN02: 197. The 8-isomer can be obtained in a similar manner from (S)-2-(dimethylamino)_2_(2-fluorophenyl)acetic acid ((S)-l-phenylethyl)trifluoroacetate. Cap-39 146976.doc

CI

OH cap &gt;39 213- 201038558 (R)-(2-chlorophenyl)glycine (0.300 g, 1.62 mmol), furfural (35% aqueous solution, 〇 at room temperature and atmospheric pressure (Η2 balloon) A mixture of .8 〇 mL, 3.23 mmol) and 20% Pd(OH) 2 /C (0.050 g) was hydrogenated for 4 hours. It was then filtered with Celite Purification Solution (Celite®) and concentrated in vacuo. The title compound (R)-2-(didecylamine) was obtained as a colorless oil (m. 2-(2-Chlorophenyl)acetic acid trifluoroacetate (0-290 g, 55%). NMR (400 MHz, CD3OD) δ 7.59-7.65 (m, 2 Η), 7.45-7.53 (m, 2 Η), 5.40 (s, 1 Η), 2.87 (s, 6 Η). LCMS: (M+H)+ calcd.

Cap-4Q 〇

Cap 40 was added dropwise to an ice-cold solution of (R)_(2-indolyl)glycine (1·〇〇g, 5.38 mmol) and NaOH (0_862 g '21.6 mmol) in H20 (5_5 mL) Anthraquinone oleate (1.00 mL, 13.5 mmol). The mixture was stirred at 0 ° C for 1 hour and then acidified by the addition of concentrated hydrochloric acid (2.5 mL). The mixture was extracted with EtOAc (EtOAc) (EtOAc) (EtOAcjjjjjjj -(曱Oxocarbonylamino)-2-(2-phenylphenyl)acetic acid (1.31 g, 960/〇). NMR (400 MHz, CD3OD) δ 146976.doc • 214· 201038558 7.39-7.43 (m, 2H), 7.29-7.31 (m, 2H), 5.69 (s, 1H), 3.65 (s, 3H) LCMS : (M Analysis calculated for +H)+ C1()H1() C1N04: 243, Found: 244.

Cap-41

Cap-41 To a suspension of 2-(2-(methylmethyl)phenyl)acetic acid (2 〇〇g, 1 〇 8 mm 〇l) in THF (20 mL) was added morpholine (1.89 g, 21.7 (mmol), and the solution was mixed for 3 hours at room temperature. The reaction mixture was then quenched with ethyl acetate and extracted with H.sub.2 (2x). The title compound 2-(2-((N-morpholinyl)methyl) was obtained as a colorless solid. Phenyl)acetic acid (2.22 g, 87%). H NMR (400 MHz, CD3 〇D) 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 · (M+H) + Ci3H"N 〇 3 analytical value: 235, experimental value · · 236. The following examples were prepared similarly using the method described for Cap-41:

146976.doc -215- 201038558 Cap-4 5 a

帽-45a cap-43 0^0Η LCMS: (M+H)+ C13H17N02 calc. Analysis calculated by Cap-44 Mes /N, Me LCMS: (M+H) + CuH15N02: 193, Found: 194. Anal. Calcd.: 248. Found: 249. Add HMDS (1.85 mL, 8.77 mmol) to a suspension of (R)-2-amino-2-phenylacetic acid p-toluenesulfonate (2.83 g, 8.77 mmol) in CH2C12 (10 mL) The mixture was stirred at room temperature for 30 minutes. Add a portion of decyl isocyanate (0.5 g, 8.77 mmol) in a portion and continue stirring for 30 minutes. The reaction was quenched by the addition of H20 (5 mL) and filtered and evaporated. (R)-2-(3-Methylureido)-2-phenylacetic acid (1.5 g, 82%) was obtained as a white solid, which was used without further purification. 1H NMR (500 MHz, DMSO-d6) δ ppm 2.54 (d, /=4.88 Hz, 3H) 5.17 (d, /=7.93 Hz, 1H) 5.95 (q, 146976.doc -216· 201038558 /=4.48 Hz, 1H) 6.66 (d, 7=7.93 Hz, 1H) 7.26-7.38 (m, 5H) 12.67 (s, 1H). LCMS: (M+H)+ calcd.: calc. % methanol, 0.1% TFA, B = 10% water, 90% methanol, 0.1% TFA, RT = 1.3 8 min, homogenization index 90%. Cap-46

Nh2 • p-toluenesulfonate

Cap-46 The desired product was prepared according to the procedure described for cap-45a. 1H NMR (500 MHz, DMSO-d6) Sppm 0.96 (t, J = 7.17 Hz, 3H) 2_94-3.05 (m, 2H) 5.17 (d, J = 7.93 Hz, 1H) 6.05 (t, J = 5.19 Hz , 1H) 6.60 (d, /=7.63 Hz, 1H) 7.26-7.38 (m, 5H) 12.68 (s, 1H). LCMS: (M+H)+ CnH^lSbOs: 222.10,

Experimental value: 223.15. HPLC XTERRA C-18 3.0 x 506 mm, 0 to 100% B over 2 minutes, 1 minute hold time, A = 90% water, 10% methanol, 0.2% H3P〇4, B = 10% water, 90% methanol, 0.2% H3P〇4, RT=0.87 min, homogenization index 90%.

Cap-47

B

146976.doc •217- 201038558 · (R)_2_(3,3-Dimethylureido)_2-phenylacetic acid tert-butyl ester: .2 〇 知 , , , , , , , , , , , , , , ·Diethyl phenylacetate (1〇g, 41〇mmol) and Hughes 〇79, 1〇25 mm〇i) DM was added dropwise in a stirred solution in DmF (40 mL) Chloramine methyl hydrazine (〇 38 mL, 418 mmol). After stirring at room temperature for 3 hours, the reaction was concentrated under reduced vacuo. The organic layer was washed with aq. EtOAc, EtOAc (EtOAc). Obtained (R)-2-(3,3-dimethylureido)_2-phenylacetic acid tert-butyl ester as a white solid

(0.86 g '75%) ' and used without further purification. Ipj NMR (500 MHz, DMSO-d6) δ ppm 1.33 (s, 9H) 2.82 (s, 6H) 5.17 (d5 J=7.63 Hz, 1H) 6.55 (d, /=7.32 Hz, 1H) 7.24-7.41 (m , 5H). LCMS : (M+H)+ calcd. Minute hold time, a=90% water, 10〇/sterol, 〇·1〇/0 TFA ' Β = 10ο/〇水, 90〇/〇 methanol, 〇.1〇/0 TFA, RT=2.26 min The homogeneity index is 97%. : (R)-2-(3,3-Dimercaptoureido)_2_phenylacetic acid: to ((R)_2_(3,3-methylmethyl)-2-phenylacetic acid tert-butyl TFA (15 mL) was added dropwise to a stirred solution of CH2C12 (250 mL), and the resulting solution was stirred at room temperature for 3 hours. Then the desired compound was self-contained with EtOAC: In a solution of the mixture (5:20), the mixture was filtered off and dried under reduced pressure to give (R)- 2 - (3,3-didecylureido)-2-phenylacetic acid as a white solid. 0.59 g, 86%) and used without further purification. 1H NMR (500 MHz, DMSO-d6) δ ppm 2.82 146976.doc •218· 201038558 (s, 6H) 5.22 (d, J=7.32 Hz, 1H 6.58 (d, 7=7.32 Hz, 1H) 7.28 (t, J=7.17 Hz, 1H) 7.33 (t, J=7.32 Hz, 2H) 7.38-7.43 (m, 2H) 12.65 (s, 1H). LCMS Analysis calculated for (M+H)+ CnH14N203: 222.24, found: 223.21. HPLC XTERRA C-18 3.0x50 mm, 0 to 100% B over 2 minutes B, 1 minute retention time, A=90% water, 10 % methanol, 0.2% H3P〇4, B = 10% water, 90% methanol, 0.2% H3P〇4, RT=0.75 min, homogeneity index 93%. Cap-48

#摩七 : (R)-2-(3-Cyclopentylureido)_2_phenylacetic acid tert-butyl ester: to (R)-2-amino-2-phenylacetate after 1 minute Cyclohexane isocyanate (〇46) was added dropwise to the admixture of the acid salt (1. g, 4 1 mmol) and Hugh's base (10 mL, 6.15 mmol) in DMF (15 mL). After the mixture was stirred for 3 hours, the reaction was concentrated under reduced pressure and the residue was dissolved in ethyl acetate. The organic layer was washed with EtOAc (br.) (EtOAc m. (i 32 g, 100%), and used without further purification. lH nmr (5 〇〇 MHz, CD3CI-D) δ ppm 1.50-1.57 (m, 2H) 1.58-1.66 (m, 2H) 1.87- 146976.doc •219- 201038558 1.97 (m, 2H) 3.89-3.98 (m, 1H) 5.37 (s, 1H) 7.26-7.38 (m, 5H). LCMS · (M+H) Analysis of C18H26N203: 318.19 , Experimental value: 319.21; HPLC XTERRA C_18 3·〇χ5〇mm, 0 to 100% over 4 minutes B, 1 minute retention time, a=9〇〇/0 water' 1 〇% sterol, 0.1〇/〇TFA 'B = 10% water, 90 〇/〇methanol, 〇i〇/〇TFA, RT=2.82 min, homogeneity index 96°/〇. : (R)-2-(3-cyclopentylureido)_2 _Phenylacetic acid: a solution of (8)_2_(3_cyclopentylureido)-2-phenylacetic acid tert-butyl ester (1 Η g, 41〇mm〇1) in CH2C12 (25 mL) TFA (4 mL) and triethyl decane (1·64 mL ' 10.3 mmol) were added dropwise, and the resulting solution was stirred at room temperature for a few hours. The (R)_2-(3-cyclopentylureido)-2-phenylacetic acid (0·69 g') was obtained as a white solid. 64%). 1H 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, ^=7.93 Hz, 1H) 6.12 (d, J=7.32 Hz, 1H) 6.48 (d, /=7.93 Hz, 1H) 7.24-7.40 (m,5H) 12.73 (s , 1H). LCMS: (M+H) + C14H18N2 〇3 calc.: 262.31, calc.: 263.15. HPLC XTERRA C-18 3.0x50 mm, 0 to 100% B over 2 minutes B, 1 minute retention time, A = 90% water, 10% methanol, 0.2% H3P〇4, B = 10% water, 90% methanol, 〇·2〇/0 H3P〇4, RT=1.24 min, homogenization index 100%. 146976.doc -220- 201038558 Cap-49

Cap-49 To a stirred solution of 2-(benzylamino)acetic acid (2.0 g, 12.1 mmol) in EtOAc (EtOAc) (EtOAc) After maintaining at 70 ° C for 5 hours, the reaction mixture was concentrated under reduced pressure to 20 mL, and a white solid precipitated. After filtration, the mother liquor was collected and further concentrated under reduced pressure to give a crude material. By reverse phase preparative HPLC (Xterra 30x100 mm, detection at 220 nm, flow rate 35 mL/min, 0 to 35% B over 8 minutes; A = 90% water, 10% sterol, 0.1% TFA, Purification of B = 10% water, 90% decyl alcohol, 0.1% TFA) afforded the title compound 2-(phenylphenyl(methyl)-amino)acetic acid trifluoroacetate (723 mg, 33%) ). !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: (M+H) + calcd. Cap-50

Cap-50 Add K2C03 (2.63 g, 19.1 mmol) and benzene to a stirred solution of 3-methyl-2-(decylamino)butyric acid (0.50 g, 3.81 mmol) in water (30 mL) Chlorine (1.32 g, 11.4 mmol). Stir the reaction mixture at ambient temperature 146976.doc -221 - 201038558 1 hour. The reaction mixture was extracted with ethyl acetate (2×30 mL), and the aqueous layer was evaporated,jjjjjjjjjjjjjjjjj Purified by 20% to 80% B in 6 minutes, A=90% water, 10% methanol, 0.1% TFA, B = 10% water, 90% sterol, 0.1% TFA) to give a colorless wax 2-(phenylhydrazino(methyl)amino)-3-methylbutanoic acid trifluoroacetate (126 mg, 19%). '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 : (M+H) + C13H19N02: Calculated: 221.

Add Na2C〇3 (1.83 g, 17.2 mmol) to a solution of L-glycine (3.9 g, 33.29 mmol) in NaOH (33 mL, 1 M/H.sub.2,. Solution. The hydrazine decanoate (2.8 mL, 36.1 mmol) was added dropwise over 15 minutes, the cooling bath was removed, and the reaction mixture was stirred at ambient temperature for 3.25 hours. The reaction mixture was washed with diethyl ether (50 mL, 3×), and then evaporated and evaporated. The organic phase was dried <RTI ID=0.0>(M </RTI> <RTI ID=0.0> Primary 146976.doc -222 - 201038558 1H NMR to beomers (DMSO-d6, δ = 2.5 ppm, 500 MHz): 12.54 (s, 1H), 7.33 (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 : [M+H]+ C^HmNCU analytical value: 176.0923, Experimental value: 176.0922. Cap 51 (alternative route)

Add DIEA (137.5 mL, 0.766) to a suspension of (5> 2-amino-3-methylbutyric acid tert-butyl ester hydrochloride (75 〇g, 357.357 mol) in THF (900 mL) Mol), and the mixture was cooled to 〇°c (ice/water bath). The decyl phthalate (29.0 mL '0.375 mmol) was added dropwise over 45 minutes, the cooling bath was removed, and the temperature was dropped at zh. The organic mixture was washed with EtOAc (EtOAc) (EtOAc) (EtOAc). Filtration and concentrating under reduced pressure. The crude material was obtained (yield: EtOAc) (hexanes (1), hexanes (4 L) and 15:85 EtOAc/hexanes (4 L). -(Methoxycarbonylamino)-3-methylbutyric acid tert-butyl ester (82.0 g, 99% yield) h-NMR (500 MHz, DMSO-^6, δ=2.5 ppm) 7.34 (d, 7=8.6, 1H), 3.77 (dd, J=8.6, 6.1, 1H), 3.53 (s, 3H), 1.94-2.05 (m, 1H), 1.39 (s, 9H), 0.83-0.92 (m, 6H) 13C-NMR (126 MHz, DMSO-' 6 = 39.2 ppm) 170.92, 156.84, 80.38, 60.00, 51.34, 29.76, 146976.doc -223- 201038558 27.62, 18.92, 17.95 LC/MS: [M+Na]+ 254.17. (3) (3)-(2-(oxycarbonylcarbonylamino)-3-mercaptobutyric acid butyl ester (82.0 g, 0.355 mol) in CH2C12 (675 mL) Trifluoroacetic acid (343 mL, 4.62 mol) and Et3SiH (142 mL, 0.887 mol) were added sequentially to the solution, and the mixture was disturbed for 4 hours at the temperature of the sibling. The volatile components were removed under reduced pressure, and The resulting oil was triturated with EtOAc (EtOAc) (EtOAc)EtOAc. Form of crystal form _ 57 (54.8 g' 88% yield). Melting point = 108.5-109.5 ° C. 4 NMR (5 00 MHz, OMSO-de, 5 = 2.5 ppm) 12.52 (s, 1H), 7.31 ( d, J-8.6, 1H), 3.83 (dd, J=8.6, 6.1, 1H), 3.53 (s, 3H), 1.94-2.07 (m, 1H), 0.86 (dd, /=8.9, 7.0, 6H) . 13C NMR (126 MHz, DMSO-^6, 5 = 39.2 ppm) 173.30, 156.94, 59.48, 51.37, 29.52, 19.15, 17.98. LC/MS: [M+H]+ = 176.11. Analysis for C7H13N04: C, 47.99; H, 7.48; N, 7.99. Found: C, 48.17; H, 7.55; N, 7.99. Optical rotation: [a] D = _4.i6 (12.02 mg / mL; MeOH). Optical purity: &gt;99·5. /. Ee. Note: This optical purity evaluation was performed on the zhi 5i oxime ester derivative prepared under the standard TMSCHN 2 (benzene/MeOH) esterification scheme. HPLC analysis conditions: column, chiralPak AD-H (4.6 x 250 mm, 5 μιη); solvent, 95% heptane / 5% IPA (equal strength); flow rate, 1 mL/min; temperature, 35 ° C; UV monitoring was performed at 205 nm. [Note: Cap 51 is also available from Flamm. ] 146976.doc -224· 201038558 Cap-52 (same as Cap-12)

Cap-52 was synthesized from L-alanine according to the procedure described for Synthetic Cap-5-1. For the purpose of characterization, a portion of the crude material was purified by reverse phase HPLC (H.sub.2/MeOH/TFA) to afford a cap-52 as a colorless oil. iH NMR (DMSO-d6, δ=2·5 ppm, 500 MHz): 12.49 (br s, 1H), 7.43 (d, ·7=7_3, 0.88H), 7_09 (apparent broad single peak, 0.12H) , 3.97 (m, 1H), 3.53 (s, 3H), 1.25 (d, /=7.3, 3H). Prepare 艨-53 to 嫘- from the appropriate starting material according to the procedure described for the synthesis 艨-5 1 (if any).

Cap structure data φ§~53α : (R) mib : (S) /〇γΝ^ΑΟΗ *Η NMR (DMSO-d6, δ=2.5 ppm, 500 MHz) : δ 12.51 (br s,1Η), 7.4 (d , J=7.9, 0.9Η), 7.06 (apparent single peak, 0.1 printed, 3.86-3.82 (111, 111), 3.53 (3, 31'1), 1.75-1.67 (m, 1H), 1.62-1.54 ( m, 1H), 0.88 (d, J = 7.3, 3H). RT = 0.77 min (Cond. 2); LC/MS: [M+Na]+ C6HuNNa04 Analysis calculated: 184.06, Experimental value: 184.07. HRMS: [M+Na]+ Calculated for C6HuNNa04: 184.0586, Experimental value: 184.0592. m-54a: (R) m-54b: (S) Η ί /〇γΝγ^〇Η *H NMR (DMSO-de, 5= 2.5 ppm, 500 MHz): δ 12.48 (s, 1H), 7.58 (d, ·7=7.6, 0.9H), 7_25 (apparent list 0.1H), 3.52 (s, 3H), 3.36-3.33 (m, 1H), 1.ΙΟΙ.01 (m, 1H), 0.54-0.49 (m, 1H), 0.46-0.40 (m, 1H), 0.39-0.35 (m, 1H), 0.31-0.21 (m, 1H). HRMS: Calculated for [M+H]+ C7H12N04: 174.0766, Experimental: 174.0771 146976.doc -225- 201038558 Cap-55 Η y* /〇丫ν-Λ)Η 0, !Η NMR (DMSO-de, δ=2.5 ppm, 500 MHz) : δ 12.62 (s,1Η), 7.42 (d, J=8.2, 0_9Η), 7.07 (apparent monomodal, 0.1Η) , 5.80-5.72 (m, 1Η), 5.10 (d, "7=17.1, 1H), 5.04 (d, J = 10.4, 1H), 4.01-3.96 (m, 1H), 3.53 (s, 3H), 2.47 -2.42 (m,1H), 2.35-2.29 (m, 1H). Cap-5 6 /0 丫 0 :,? *H NMR (DMSO-d6, 5 = 2.5 ppm, 500 MHz): δ 12.75 (s, 1H), 7.38 (d, /=8.3, 0.9H), 6.96 (apparent monomodal, 0.1H), 4.20- 4.16 (m, 1H), 3.60-3.55 (m, 2H), 3.54 (s, 3H), 3.24 (s, 3H). Cap-57 Η η* /0 丫n-Adh 0 Ξ, !H NMR (DMSO-de, 5=2.5 ppm, 500 MHz) : δ 12.50 (s, 1H), 8.02 (d, J=7.7, 0.08H ), 7.40 (d, J=7.9, 0.76H), 7.19 (d, J=8.2, 0.07H), 7.07 (d, J=6J, 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). </RTI> <RTI ID=0.0></RTI> </RTI> <RTI ID=0.0></RTI> </RTI> <RTIgt; Cap-58 Η π* /〇ΥΝ,,ι 0Η 0 ,νη2 0 lH NMR (DMSO-de, 5=2.5 ppm, 500 MHz) : δ 12.63 (br s, 1H), 7.35 (s, 1H), 7.31 (d, J=8.2, 1H), 6.92 (s, 1H), 4.33-4.29 (m, 1H), 3.54 (s, 3H), 2.54 (dd, J = 15.5, 5.4, 1H), 2.43 (dd, J=15.6, 8.0, 1H). RT = 0.16 min (Cond. 2); LC/MS: [M+H]+ calc.: 191. Household: (R) fi-59b : (S) ,. ΚΚ^Χ〇Η *H NMR (DMSO-de, 5=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, J=7.2, 3H). HRMS: [M+H]+ calcd. The crude material was purified by reverse phase HPLC (H.sub.2/MeOH/TFA) to afford a colourless viscous oil which crystallised as a white solid. 1H NMR (DMSO-d6, 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 single peaks, 3H), 1.30 (m, 2H), 0.98 (m, 2H). HRMS: [M+H]+ C6H10NO4. Found: 160.0610, Found: 160.0604. Cap-61 'Η NMR (DMSO-de, 5=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: Analysis calculated for [M+H]+ C6Hi2N04: 162.0766, Found: 162.0765. 146976.doc -226- 201038558 Cap-62 〆〇丫n^A〇h 12 74^ (〇ΐΗ^〇406ί 5=2'5 PPm, 400 ΜΗζΤΪΤΊ 12.74 (br s,1Η), 4.21 (d, Ηο. 3. 6Η) \ δ ^10.0, 0.4Η), 3.62/3.60 3Η) 3 〇f: 3Η), 2.14-2.05 (m, 1Η), 〇.95 (d J:6 3 3Η) 〇g; (d , J=6.6, 3H) 〇LC/MS: [MH]' C8H; 4N〇:^v Analysis calculated value·· 188.G9 'Experimental value: ^ . Must be 4 knife cap -63 &quot;°T^0H [Note: The reaction time is longer than the time stated in the general procedure. NMR (DMSO-d6, 6=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). </ RTI> </ RTI> <RTI ID=0.0></RTI> ' Cap-64 Η π* &quot;°χΝ^〇Η [Note: The reaction time is longer than the time β described in the general procedure] 1h NMR (DMSO-d6, 5=2.5 ppm, 400 MHz): 12.35 (br s,1H) , 7.77 (s, 0.82H), 7.56/7.52 (overlapping wide single peak 0.18H), 3.50 (s, 3H), 2.47-2.40 (m, 2H), 2 14-2 07 (m, 2H), 1.93- 1.82 (m, 2H). Cap-65

After 5 minutes, to Na2CO3 (0.449 g, 4.23 mmol), Na〇H (8.2 G mL, 1 M/H20, 8.2 mmol) and (5)-2-amino-3-carbyl-3-indolyl To a cooled (ice-water) mixture of the acid (1.04 g, 7. <RTI ID=0.0>1 </RTI> </RTI> <RTIgt; </RTI> <RTIgt; </ RTI> </ RTI> was added dropwise (0.65 mL, 8.39 mmol). The reaction mixture was stirred for 45 minutes and then the cooling bath was removed and stirring was continued for a further 3.75 hours. The reaction mixture was washed with CH.sub.2Cl.sub.2, and the aqueous phase was cooled with ice-water bath and acidified to a pH range of 1-2 with concentrated hydrochloric acid. The volatile component was removed in vacuo, and the residue was dissolved in a 2:1 mixture (15 mL) of &lt;RTI ID=0.0&gt; .doc • 227- 201038558 MHz): δ 6.94 (d, /=8.5, 0.9H), 6.53 (br s, 0.1H), 3.89 (d, •/=8.8, 1H), 2.94 (s, 3H), 1.15 (s, 3H), 1.13 (s, 3H).艨-66 and 艨-67 were prepared from the appropriate commercially available starting materials by employing the procedure described for Synthetic-65. Fg-66

!H NMR (DMSO-d6, δ = 2.5 ppm, 400 MHz): δ 12.58 (br s, 1H), 7.07 (d, /-8.3, 0.13H), 6.81 (d, 7 = 8.8, 0.67H), 4.10-4.02 (m, 1.15H), 3.91 (dd, /=9.1, 3·5, 0.85H), 3.56 (s, 3H), 1.09 (d, ·7=6·2,3H). [Note: Only the main signal of NH is indicated] 0 Cap-67

!H NMR (DMSO-d6, δ=2.5 ppm, 400 MHz): 12.51 (br s, 1H), 7.25 (d, J=8.4, 0.75H), 7.12 (br d, J=0.4, 0.05H), 6.86 (br s, 0.08H), 3.95-3.85 (m, 2H), 3.54 (s, 3H), 1.08 (d, •7=6.3, 3H). [Note: Only the main signal of NH is indicated]. Cap-68

146976.doc •228- 201038558 To 1 N NaOH (aqueous solution) (9.0 ml, 9.0 mmol), 1 M NaHC〇3 (aqueous solution) (9.0 ml '9.0 mol), L-aspartic acid 0-benzaldehyde ( Methyl chloroformate (0.38 m b 4_9 mmol) was added dropwise to a mixture of 1.0 g '4.5 mmol) and dioxane (9 ml). The reaction mixture was stirred at ambient temperature for 3 h and then washed with ethyl acetate (50 ml, 3×). The aqueous layer was acidified to pH ~ 2 with 12 N HCl and extracted with ethyl acetate (3×5 EtOAc). The organic layer was combined with EtOAc (EtOAc m.jjjjjjjjjjjjjjjjj NMR (DMSO-d6, 5=2.5 ppm, 500 MHz): δ 12.88 (br s, 1H), 7.55 (d, 7=8.5, 1H), 7.40-7.32 (m, 5H), 5.13 (d, /=12.8, 1H), 5.10 (d, 7=12.9, 1H), 4.42-4.38 (m, 1H), 3.55 (s, 3H), 2.87 (dd, J = 16.2, 5.5, 1H), 2.71 (dd , J = 16.2, 8.3, 1H). LC (Case 2): RT = 1.90 min; LC/MS: [M+H] + C13H16N06i. Calculated value: 282.10, experimental value: 282.12. Cap-69a and cap-69b

Cap-69a: ff?)-Enantiomer Cap-69 &amp;.7S)-Enantiomer to alanine (1.338 g, 15.0 mmol) cooled (about 15 ° C) water (17 mL) NaCNBH3 (2.416 g, 3 6.5 mmol) was added portionwise in MeOH (10 mL). After a few minutes, acetic acid (4.0 mL, 71.3 mmol) was added dropwise over 4 min, the cooling bath was removed, and the reaction mixture was stirred under ambient conditions for 6 hours. Additional acetaldehyde (4.0 mL) was added and the reaction was stirred for 2 h. Concentrated hydrochloric acid was slowly added to the reaction mixture at 146976.doc -229-201038558 until the pH reached about 1.5, and the resulting mixture was heated at 40 ° C for 1 hour. Most of the volatile components were removed by vacuum and purified by Dowex® 50WX8-100 ion exchange resin (washing the column with water and dissolving the compound by dilute ΟΗ4ΟΗ prepared by mixing 18 ml of NH4OH with 282 ml of water) The residue gave 艨-69 (2.0 g). 4 NMR (DMSO-d6, δ=2·5 ppm, 400 MHz): δ 3.44 (q, J=7.1, 1H), 2.99-2.90 (m, 2H), 2.89-2.80 (m, 2H), 1.23 ( d, J=7A, 3H), 1.13 (t, J=7.3, 6H). The 艨-70 to 艨-7 was prepared by using the appropriate starting materials according to the procedure described for the synthetic oxime-69. Fg-70a · (R) 0-7Ob : (S) JH NMR (DMSO-d6, 5=2.5 ppm, 400 MHz): δ 3.42 (q, 7=7.1, 1H), 2.68-2.60 (m, 4H) , 1.53-1.44 (m, 4H), 1.19 (d, J=7.3, 3H), 0.85 (t, •7=7.5, 6H). LC/MS : [M+H]+ C9H2 〇N02 calc.: 174.15 s. M-71a : (R) m-7ib : (s) 〇ν^οη !H NMR (DMSO-d6, 6=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, &gt;7.2, 6H), 0.91 (t, /=7.3, 3H) e LC/MS : [M Analysis calculated for +H]+ C8H18N02: 16〇13, Experimental value: 160.06. Cap-72 〇ν^Χοη !H NMR (DMSO-d6, 6=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, 0:9 (d, J=6.5, +3H), 0.85 (d, j=6.55 3H) 〇LC/MS : [M+H] Analytical value of C9H2〇N02: m 15, experiment Value: 174.15. · Cap-7 3, 〇1 忿. ((4), 2·99·2;: -------- 146976.doc • 230· 201038558

OH cap-75, step a

Bn cap-Ί4 Η NMR (DMSO-d6, 6=2.5 ppm, 500 MHz): δ 7.54 (s, 1H), 6.89 (s, 1H), 3.81 (t, J=6.6, k, 1H), 2.82- 2.71 (m, 4H), 2.63 (dd, J=15.6, 7.0, 1H), 2.36 (dd, /=15.4, 6.3, 1H), 1.09 (t, /=7.2, Τη2 6H). </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt;帽-74x ^j^OH LC/MS : [M+H]+ C1GH22N02 calc.: 188.17, calcd: 188.2 〇 HD cooled to HD-Ser-OBzl HC1 (2.0 g, 8. 6 mmol) (Bly/water bath) NaBH3CN (1.6 g, 25.5 mmol) was added to a solution of water (25 ml) / methanol (15 ml). Ethyl ether (1.5 mL, 12.5 mmol) was added dropwise over 5 minutes, the cooling bath was removed, and the mixture was stirred for 2 hrs under ambient conditions. The reaction was carefully quenched with 12 N EtOAc and concentrated in vacuo. The residue was dissolved in water and purified by reverse phase HPLC (MeOH/H20/TFA) to afford </RTI> Fluoroacetate (1.9 g) ° *H NMR (DMSO-d6, 6 = 2.5 ppm, 500 MHz): δ 9.73 (br 146976.doc • 231 - 201038558 s, 1H), 7.52-7.36 (m, 5H), 5.32 (d, /=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=7.2, 6H). </ RTI> </ RTI> <RTI ID=0.0></RTI> </ RTI> </ RTI> <RTIgt; Cap-75 To the cooled (ice water) THF (3.0) of (R)-2-(diethylamino)-3-hydroxypropanoic acid dimethyl ester diacetate (0.3019 g '0.8264 mmol) prepared above NaH (0.0727 g, 1.82 mmol '60%) was added to the solution, and the mixture was stirred for 15 min. Iodomethane (56 咕, 〇 9 〇 mmol) was added and stirring was continued for 18 hours while the bath was thawed to ambient conditions. The reaction was quenched with water and loaded onto MexH pre-conditioned MCX (6 cartridges, washed with methanol, followed by dissolution of the compound with 2 N NHV methanol. Vacuum removal of volatile components gave Yellow semi-solid _ 75 (100 mg), which was contaminated with (R)_2_(diethylamino)-3 hydroxypropionic acid. The product was used as it was without further purification.

To a solution of 〇S&gt;4-amino-2-(t-butoxycarbonylamino)butyric acid (2 17 g, 9 mmol), was added (about 12 mL) to NaCNBH3 (1 - 60 g) , 24.2 mmol). After a few minutes, ethyl acetate (2.7 mL, 4·1 mmol) was added dropwise over 2 min 遂 146976.doc - 232 - 201038558, the cooling bath was removed, and the reaction mixture was stirred under ambient conditions for 3.5 hours. Additional acetaldehyde (2.7 mL, 48.1 mmol) was added and the reaction was stirred for 20.5 hrs. &lt;RTI ID=0.0&0&0&0&0&0&0&0&0&0&0&0&0&0&0&0&0&0&0&0&0&0&0&0&0&0& Heat for 2 hours. The volatiles were removed in vacuo and the residue was taken &lt;RTI ID=0.0&gt;&gt; ® 5〇WX8-100 ion exchange resin (washing the column with water and dissolving the compound with dilute NH4OH prepared from 18 ml of 4NH4OH and 282 ml of water) to purify the residue to give an intermediate as an off-white solid (S) 2-amino-4-(diethylamino)butanoic acid (1_73 g). After 11 minutes, to Na2CO3 (0.243 g, 2.29 mm) Add chloroformic acid (0.36 mL, 4.65 mmol) dropwise to a cooled (ice-water) mixture of ol), NaOH (4.6 mL, 1 M/H2O, 4.6 mmol) and the above product (802·4 mg) The reaction mixture was stirred for 55 minutes, and then the cooling bath was removed, and stirring was continued for a further 5.25 hours. The reaction mixture was diluted with an equal volume of water and washed with ◎ CH 2 C 12 (30 mL, 2 χ) and cooled with ice-water bath The phases were acidified to the pH region of 2 with concentrated hydrochloric acid. The volatile component was then removed in vacuo and washed with &lt;RTI ID=0.0&gt;&gt; The crude material was basified to give mp s-76 (704 mg) as pale white solid. 4 NMR (MeOH-d4, δ = 3.29 ppm, 400 MHz): δ 3.99 (dd, /= 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, «7=7.3,6H).LC Analysis: </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> Cap-77 a and cap-71}) α/οΗ According to the procedure described for Zhi_7, the intermediate 2_ is realized by using the 7-azabicyclo[22 heptane for the SN2 substitution step and by using the following conditions: Enantiomeric separation of 7-azabicyclo[2·2·1;|hept-7-yl)-2-phenylacetate benzyl ester to synthesize 艨-77: intermediate (303.7 mg) in ethanol And the resulting solution is injected into the palmar tendon (10) b (four) adh column, 30x250 mm, 5 μιη), which is dissolved at 9 mL% CO" 10% EtOH at 70 mL/min and 35 r. Obtained 124 5 mg of enantiomer] and 133.8 mg of enantiomer 2. According to the preparation of _7, the benzyl ester was subjected to nitrogen solution to obtain therapeutic-77: NMR (DMSO-d6, δ= 2.5 ppm, 400 MHz) · δ 7.55 (m5 2H), 7.38-7.30 (m, 3H), 4.16 (s, 1H), 3.54 (apparent broad single peak, 2H), 2 〇8_188 (m, 4H), 1 57 1 46 4H). LC (Condition: RT = 〇 67 _ ; LC/MS: [M+H] + C14H 丨 8N02 Analysis calculated: 232 13. Experimental value: 232 18. HRMS · [M+H Analysis of CmH18N〇2: 232.1338, experimental value: 232.1340. 146976.doc

OH N -234· 201038558 to (Λ)-2-(ethylamino)-2-phenylacetic acid hydrochloride (intermediate synthesis of hydrazone-3; 0.9923 mg, 4.60 mmol) and (1-ethoxyl) NaCNBH3 (0.5828 g, 9.27 mmol) was added to a mixture of cyclopropoxy)trimethyl sulphate (1.640 g, 9.40 mmol) in MeOH (10 mL), and the semi-hetero mixture was heated in an oil bath at 50 °C. 20 hours. (1-Ethoxycyclopropoxy)triterpene (150 mg, 0.86 mmol) and NaCNBH3 (52 mg, 0.827 mmol) were then added and the reaction mixture was warmed for 3.5 hours. It was then cooled to ambient temperature and acidified to a pH of about 2 with concentrated hydrochloric acid and the mixture was filtered and the filtrate was then evaporated. The obtained crude material was dissolved in ζ·-PrOH (6 mL) and heated to effect dissolution, and the undissolved portion was filtered off and the filtrate was concentrated in vacuo. Approximately 1/3 of the crude material was purified by reverse phase HPLC (H20/MeOH/TFA) to afford s. H NMR (DMSO-d6, δ = 2.5 ppm, 400 MHz; after D20 exchange): δ 7.56-7.49 (m, 5H), 5.35 (S, 1H), 3.35 (m, 1H), 3.06 (apparent) Broad single peak, 1H), 2_66 (m, 1H), 1.26 (t, ·7 = 7.3, 3H), 〇·92 (m, 1H), 0.83-0.44 (m, 3H). </RTI> <RTI ID=0.0></RTI> </RTI> <RTI ID=0.0></RTI> HRMS: [M+H]+ calcd. Cap-79

146976.doc -235- 201038558 Ozone was bubbled through a solution of Chi-5 5 (3 6 9 mg, 2 · 1 3 mm ο 1) in a cooled (-78 ° C) CH2C12 (5.0 mL) for approximately 50 minutes. Until the color of the reaction mixture is blue. Me2S (10 drops of pipette) was added and the reaction mixture was stirred for 35 minutes. The -78 °C bath was replaced with a -10 °C bath and stirring was continued for a further 30 minutes, and then the volatile component was removed in vacuo to give a colorless viscous oil. To a solution of the above crude material and EtOAc (EtOAc) (EtOAc, EtOAc. It was allowed to cool to ice-water temperature and treated with concentrated hydrochloric acid to bring the pH to about 2.0, and then stirred for 2.5 hours. The volatile component was removed in vacuo, and the residue was purified with a mixture of MCX resin (MeOH wash; 2.0 N NH3 / MeOH) and reverse phase HPLC (H20 / MeOH / TFA) to give a temporary 7 9. For the consumption of morpholine contaminants, the above materials were dissolved in CH2C12 (1.5 mL) and treated with Et3N (0.27 mL, 1.94 mmol), then treated with acetic anhydride (0.10 mL, 1_06 mmol) and stirred under ambient conditions 18 hours. THF (1.0 mL) and H2O (0.5 mL) were added and stirring was continued for 1.5 hours. The volatiles were removed in vacuo and the residue was purified eluting with EtOAc EtOAc EtOAc EtOAc step. Cap-80a and cap-80b

Cap-80a: S/S-diastereomeric cap-8 〇b.·S/R-diastereomer 146976.doc -236· 201038558 to (S)-3-amine over 15 minutes Base 4-(benzyloxy)-4-oxobutanoic acid (10.04 g, 44.98 mmol) and MeOH (300 mL) cooled (ice-water) SOC 12 (6.60 mL) , 90.5 mmol), the cooling bath was removed and the reaction mixture was stirred under ambient conditions for 29 hours. Most of the volatile components were removed in vacuo and the residue was carefully partitioned between Et.sub.1 (l.sup.5 mL) and sat. The aqueous phase was extracted with EtOAc (150 mL, EtOAc) (m.). 4-methyl ester 4-methyl ester (9.706 g) °H NMR (DMSO-d6, 5 = 2.5 ppm, 400 MHz): 3 7.40-7.32 (m, 5H), 5.11 (s, 2H), 3.72 (apparent triple Peak, /=6.6, 1H), 3-55 (s, 3H), 2.68 (dd, /=15.9, 6.3, 1H), 2.58 (dd, 7=15.9, 6-8,1H), 1.96 (s, 2H). </RTI> <RTI ID=0.0></RTI> </RTI> <RTI ID=0.0></RTI> </RTI> <RTIgt; To (S)-2-aminosuccinic acid 1-benzoic acid 4-methyl ester (4.5 g, 19.0 mmol), 9-bromo-9-phenyl-9//-pyrene (6.44) over 1 min. g, 20.0 mmol) and Et3N (3.0 mL, 21.5 mmol) in CH2C12 (80 mL)

Pb(N〇3)2(6.〇6 g, 18.3 mmol)' and the heterogeneous mixture was stirred under ambient conditions for 48 hours. The mixture was filtered&apos; and the filtrate was treated with MgSCU and filtered again, and the final filtrate was concentrated. The obtained crude material was subjected to Bi〇tage purification (350 g of phthalocyanine, CH/h dissolving) to obtain (s) 2-(9-phenyl-9H--9-ylamino) in a very viscous colorless oil. Succinic acid ι_ alum acid ester 4_ brewing (7 % g). NMR (DMSO-d6, δ=2·5 ppm, 400 MHz): δ 7.82 (m 2H), 7.39-7.13 (m, 16H), 4.71 (d, "7=12.4, 1H), 4·51 (d , 146976.doc -237 - 201038558 J=12.6, 1H), 3.78 (d, J=9.1, NH), 3.50 (s, 3H), 2.99 (m, 1H), 2·50-2.41 (m, 2H, Partial overlap with solvent). </RTI> <RTI ID=0.0></RTI> </RTI> <RTI ID=0.0></RTI> </RTI> <RTIgt; To (S)-2-(9-phenyl-9H-fluoren-9-ylamino)succinic acid 1-phenyl decyl 4-nonyl ester (3.907 g, 8.18 mmol) was cooled over 10 min ( LiHMDS (9.2 mL, 1.0 M/THF, 9.2 mmol) was added dropwise to a solution of THF (50 mL) and stirred for about 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 while the cooling bath was thawed to room temperature. After quenching with a saturated solution of NH4C1 (5 mL), most of the organic fractions were removed from vacuo, and the residue was partitioned between CH2C12 (1 〇〇mL) and water (4 〇mL). The organic layer was dried <RTI ID=0.0>(M </RTI> <RTI ID=0.0></RTI> 2S/3S and 2S/3R diastereomeric mixture of 9H-fluoren-9-ylamino) 1-phenylmethyl succinate 4-methyl ester in a ratio of about 1.0:0.65 (4 NMR). At this time, the stereochemistry of the main isomer was not determined, and the mixture was subjected to the next step without separation. Partial NMR data (DMSO-d6, δ = 2.5 ppm, 400 MHz): major diastereomer δ 4.39 (d, / = 12.3, 1H, CH2), 3.33 (s, 3H, overlap with H2 〇 signal) , 3.50 (d, "7 = 10.9, NH), 1.13 (d, J = 7_l, 3H); minor diastereomer δ 4.27 (d, J = 12.3, 1H, CH2), 3.76 (d, J=l〇.9, NH), 3.64 (s, 3H), 0.77 (d, ·7=7·0, 3H). </RTI> <RTI ID=0.0></RTI> </RTI> <RTI ID=0.0></RTI> 146976.doc -238 - 201038558 (2S)-3-Methyl-2-(9-phenyl-9H-indol-9-ylamino)succinic 1-benzoate prepared above for 10 minutes To a solution of the ester 4- oxime ester (3.37 g, 6.86 mmol) in THF (120 mL) EtOAc (EtOAc (EtOAc) Stir at -78 °C for 20 hours. The reaction mixture was removed from the cooling bath and quickly poured into about 1 M H3P〇4/H2O (250 mL) with a mixture and the mixture was extracted with a riddle (1 〇〇 mL, 2 χ). The combined organic phases were washed with brine, dried (MgSO.sub.4). The crude material was prepared by chromatography and chromatographed (25% EtOAc / hexanes; hexanes) to give (2S,3S)-4-hydroxy-g which was contaminated with benzyl alcohol and was a colorless viscous oil. Phenyl phthalate of 3-methyl-2-(9-phenyl-9//-fluoren-9-ylamino)butyrate and (2S,3R)-4 containing the (2S,3R) stereoisomer -Hydroxy-3-methyl-2-(9-phenyl-9//-fluoren-9-ylamino)butyric acid benzyl ester. The latter sample was subjected to the same column chromatography purification condition to obtain 750 mg of a purified material in the form of a white foam. [Note: Under the above conditions, the (2S, 3S) isomer is dissolved before the (2S, 3R) isomer]. (2S,3S) isomer: 4 NMR (DMSO-d6, δ=2.5 ppm, 400 MHz): 7.81 (m, 2H), 7.39-7.08 (m, 16H), 4.67 (d, /=12.3, 1H ), 4.43 (d, ·7=12.4,1H), 4.21 (apparent triplet, /=5.2, OH), 3·22 (d, "7=10.1, NH), 3.17 (m, 1H), 3.08 (m, 1H), about 2.5 (m, 1H, overlapping with the solvent signal), ι·58 (m, 1H), 0.88 (d, *7 = 6.8, 3H). </RTI> <RTI ID=0.0></RTI> </RTI> <RTI ID=0.0></RTI> (2S,3R) isomer: NMR (DMSO-d6, δ=2·5 ppm, 400 MHz): 7.81 (d, /=7.5, 2H), 7.39-7.10 (m, 16H), 4.63 (d, 146976.doc •239- 201038558 •/=12.1,1H), 4.50 (apparent triplet, j=4_9,1H), 4.32 (d, J=\2.\, 1H), 3.59-3.53 (m, 2H) ), 3.23 (m, 1H), 2.44 (dd, «/=9.0, 8.3, 1H), 1.70 (m, 1H), 0.57 (d, J = 6.8, 3H). LC (Case 1): RT = 1.92 min; LC/MS: [M+H] + C31H3 〇N03 Analysis: 464.45. The relevant stereochemistry of the DIBAL reduction products was determined based on NOE studies performed on the lactone derivatives prepared from the respective isomers by the following scheme: to (2S,3S)-4-hydroxy-3-indole Addition of LiHMDS to a cooled (ice-water) THF (2_0 mL) solution of benzyl-2-(9-phenyl-9β-indol-9-ylamino)butyric acid benzoquinone g (62.7 mg, 0.135 mmol) (50 μί, 1.0 M/THF, 0.05 mmol), and the reaction mixture was stirred at a similar temperature for about 2 hours. Volatile components were removed in vacuo and the residue was partitioned between CH2C12 (30 mL), water (20 mL) and EtOAc (1 mL). The organic layer was dried (MgSO4), EtOAc (EtOAc m. Methyl-3-(9-phenyl-9-indole-9-ylamino)dihydrofuran-2(3 ugly)-one (28.1 mg). Treatment of (2S,3R)-4-hydroxy-3-indolyl-2-(9-phenyl-9-p--9-ylamino)butyric acid benzyl ester in a similar manner to give (3S, 4R) 4-mercapto-3-(9-phenyl-9//-fluoren-9-ylamino)dihydrofuran-2(3 ugly)-one. (3S,4S)-Lactone isomer: 1H NMR (DMSO-d6, δ=2·5 ppm, 400 MHz), 7.83 (d, «7=7.5, 2H), 7.46-7.17 (m, 11H), 4·14 (apparent triplet, J=8.3, 1H), 3.60 (d,·7=5_8, NH), 3.45 (apparent triplet, ·7=9.2, 1H), about 2.47 (m, 1H, Partially overlapping with the solvent signal), 2.16 (m, 1H), 0.27 (d, &gt; 6.6, 3H). 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。. (3S,4R)-Lactone isomer: 4 NMR (DMSO-d6, δ=2.5 ppm, 400 MHz), 7.89 (d, /=7.6, 1H), 7.85 (d, /=7.3, 1H), 7.46-7.20 (m, 11H), 3.95 (dd, /=9.1, 4.8, 1H), 3.76 (d, J=8.8, 1H), 2.96 (d, 7=3.0, NH), 2.92 (dd, /= 6.8, 3, NCH), 1.55 (m, 1H), 0.97 (d, ·7=7·0,3H). </RTI> <RTI ID=0.0></RTI> </RTI> <RTI ID=0.0></RTI> <RTI ID=0.0> To (2S,3S)-4-benzyl-3-methyl-2-(9-phenyl-9H-indol-9-ylamino)butyric acid benzyl ester (119.5 mg, 0.258 mmol) of CH2C12 ( 3 ml) butyl 801^18-01 (48 111 §, 0.312 111111 〇 1) was added to the solution, followed by the addition of savory (28.8 mg, 0.423 mmol), and the mixture was stirred under ambient conditions for 14.25 hours. The reaction mixture was diluted with EtOAc EtOAc (EtOAc) The crude material was purified using EtOAc (EtOAc: EtOAc (EtOAc) Benzo-2-(9-phenyl-9H-fluoren-9-ylamino)butyric acid benzyl ester (124.4 mg), which was contaminated with impurities based on TBDMS. Treatment of (2S,3R)-4-hydroxy-3-methyl-2-(9-phenyl-9H-indol-9-ylamino)butyric acid phenyl phthalate in a similar manner to give (2S,3R)- 4-(t-butyldidecyldecyloxy)-3-methyl-2-(9-phenyl-9H--9-ylamino)butyric acid phenyl phthalate. (2S,3S)-decyl ether isomer: 4 NMR (DMSO-d6, δ=2·5 ppm, 400 MHz), 7.82 (d, /=4.1, 1H), 7.80 (d, J=4.0, 1H), 7.38-7.07 (m5 16H), 4.70 (d, J=12A, 1H), 4.42 (d, J=12.3, 1H), 3.28-3.19 (m, 146976.doc -241 · 201038558

3H), 2.56 (dd, ΑΐίΜ, 5 5, 1H),! 61 (m, 1H), 〇9〇 (d, 7=6.8, 3H), 0.70 (s, 9H), -0.13 (s, 3H), -0.16 (s, 3H) 〇LC (condition 1 ' which works The time was extended to 4 minutes): RT = 3 26 min; LC/MS. [M+H] + C37H44N03Si. (2S,3R)-decyl ether isomer: 4 NMR (DMSO-d6, 6 = 2.5 ppm, 400 MHz), 7.82 (d, J = 3.0, 1H), 7.80 (d, J-3A, 1H) , 7.39-7.10 (m, 16H), 4.66 (d, J=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, 1H), 3.41 (dd, J=l〇, 6.2, 1H), 2.55 (dd, J=9.5, 7.3, 1H), 1.74 (m, 1H), 0.77 (s, 9H), 0.61 (d , J=1A, 3H), -0.06 (s, 3H), -0.08 (s, 3H). Hydrogen balloon with (2S,3S)-4-(t-butyldidecyldecyloxy)-3-methyl-2-(9-phenyl-9-dan-9-ylamino) A mixture of benzyl benzyl ester (836 mg, 1.447 mmol) and 10% Pd/C (213 mg) in EtOAc (16 mL) was then stirred and the mixture was stirred at room temperature for about 21 hours, refilled to the balloon if necessary Into H2. The reaction mixture was diluted with EtOAc (EtOAc) (EtOAc) (EtOAc) The pad. The combined organic phases were concentrated, and the EtOAc was obtained from EtOAc EtOAc (EtOAc (EtOAc) 2S,3S)-2-Amino-4-(t-butyldimethylsulfonyloxy)-3-methylbutyric acid (325 mg). Treatment of (2S,3R)-4-(t-butyldimethylammoniooxy)-3-indolyl-2-(9-phenyl-9Η--9-ylamino)butyric acid in a similar manner Phenyl phthalate gives (2S,3R)-2-amino-4-(t-butyl dimethyl fluorene 146976.doc -242·201038558 oxy)-3-mercaptobutyric acid. (2S,3S)-Amino acid isomer: 4 NMR (sterol-d4, δ=3.29 ppm, 400 MHz), 3.76 (dd, */=10.5, 5.2, 1H), 3.73 (d, J= 3.0,1H),3.67 (dd,/=10,5,7 〇,1H),2 37 (m, 1H),0.97 (d,/=7.0,3H),0.92 (s, 9H),〇1〇 (s, 6H). LC/MS: [M+H]+ </RTI> &lt;RTI ID=0.0&gt; (2S,3R)-Amino acid isomer: ijj nMR (sterol·&lt;14 6=3.29 ppm, 400 MHz), 3.76-3.75 (m&gt; 2H), 3.60 (d, J=4.is 1H ), 2.16 (m, 1H), 1.06 (d, /=7.3, 3H), 0.91 (s, 9H), 〇.〇9 (s, 6H). [M+H]+ CiiH^NC^Si Analysis calculated: 248.17, found: 248.44 ° (2S,3S)-2-amino-4-(t-butyldidecyldecyloxy)_3 Add water (1 mL) and Na〇H (〇18 mL, 1 〇Μ/Η2〇, 0.18 mmol) to a mixture of _methylbutyric acid (41.9 mg, 0.169 mmol) and Na2C03 (li.9 mg, 0.112 mmol) ), and the sonication was carried out for about 1 minute to allow the reactants to dissolve. The mixture was then cooled in an ice-water bath to add methyl chloroformate (0.02 mL, 0.259 mmol) over 3 sec. and continued vigorously stirred at similar temperatures for 40 minutes&apos; and then stirred vigorously at ambient temperature for 27 hours. The reaction mixture was diluted with water (5 mL), cooled in ice-water bath, and was applied dropwise with &lt;1&gt; The mixture was further diluted with water (1 mL) and extracted with CH2C12 (15 mL, 2 EtOAc). Dry (MgS04) EtOAc EtOAc (EtOAc) Treatment of (2S,3R)-2-amino-4-(t-butyldimethyl oxanthoxy)3-methylbutyric acid in a similar manner gave hydrazine-80b.艨-80a : 4 NMR (DMSO-d6, 6=2.5 ppm, 4〇0 MHz), 12.57 (br s, 1H), 7.64 (d, 146976.doc •243- 201038558 J=8.3, 0.3H), 7.19 (d, 7=8.8, 0.7H), 4.44 (dd, J=8.1, 4.6, 0.3H), 4.23 (dd, J=8.7, 4.4, 0.7H), 3.56/3.53 (two single peaks, 3H) , 3.48-3.40 (m, 2H), 2.22-2.10 (m, 1H), 0.85 (s, 9H), about 0.84 (d, 0.9H, overlap with the t-Bu signal), 〇·79 (d, "7 =7, 2.1H), 0.02/0.01/0.00 (three overlapping single peaks, 6H). </RTI> <RTI ID=0.0></RTI> </RTI> /f-80b : *H NMR (CDC13, δ=7.24 ppm, 400 MHz), 6.00 (br d, J=6.8, 1H), 4.36 (dd, J=7.1, 3.1, 1H), 3.87 (dd, 7 =10.5, 3.0, 1H), 3.67 (s, 3H), 3.58 (dd, 7=10.6, 4.8, 1H), 2.35 (m, 1H), 1.03 (d, /=7.1, 3H), 0.90 (s, 9H), 0_08 (s, 6H). [M+Na] calcd. for calcd. The crude product was used without further purification. Cap-81 ΟΗ According to the Falb expert, the price is as described in 1993 23 2839. Cap-82 to Cap-85 艨-4, 艨-1^, _51 and Dart _52) Similar line profiles are synthesized from appropriate starting materials according to the procedure described for Zhi-51 or 艨-13. -82 to 艨_85. The sample exhibits its enantiomer (ie,

Cap-84 &quot;/ο cap-82 cap-83 cap-85 146976.doc -244- 201038558 cap-86

Me02CHN .0

OMe〇H Add ClC02Me dropwise to a mixture of 0-mercapto-L-threonine (3.0 g, 22.55 mmol), NaOH (0.902 g, 22.55 mmol) in H20 (15 mL) at 0 °C (1.74 mL, 22.55 mmol). The mixture was stirred for 12 hours and acidified to pH 1 using 1N HCl. The aqueous phase was extracted with EtOAc (EtOAc (EtOAc)EtOAc. Use the next steps. 1H NMR (400 MHz, CDC13) δ 4.19 (s, 1 Η), 3.92-3.97 (m, 1H), 3.66 (s, 3H), 1.17 (d, J = 7.7 Hz, 3H). LCMS: (M-H) </RTI> calcd.

Cap-87 Me〇2CHN 〇HO OH Add dropwise to a mixture of L-homoserine (2.0 g, 9.79 mmol), Na2CO3 (2.08 g, 19.59 mmol) in H20 (15 mL) at 0 °C ClCO2Me (0.76 mL, 9-79 mmol). The mixture was stirred for 48 hours and acidified to pH 1 using 1 N HCl. The aqueous phase was extracted with EtOAc (EtOAc (EtOAc)EtOAc.巾146976.doc -245- 201038558 NMR (400 MHz, CDC13) δ 4·23 (dd, "7=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: (M+H)+ calcd. Cap-88

L-Lynamine (1.0 g, 8.54 mmol), 3-°° ratio (1.8 mL, 18.7 mmol), K2C03 (2.45 g, 17.7 mmol) and Cul (169 mg, 0.887)

A mixture of mmol) in DMSO (10 mL) was heated at 100×: for 12 h. The reaction mixture was cooled to rt EtOAc (EtOAc)EtOAc. The organic layer was extracted with a small amount of H20 and the combined aqueous phases were acidified to pH about 2 with 6 N HCl. The volume was reduced to about 1/3 and 20 g of cation exchange resin (Strata) was added. The pellet was allowed to stand for 20 minutes and loaded onto a cation exchange resin liner (Strata) (about 25 g). The pad was washed with h20 (200 mL), MeOH (200 mL) and then NH3 (3 EtOAc in MeOH, 2 X 200 mL). The appropriate fractions were concentrated in vacuo and the residue (ca. 1.1 g) was dissolved in H.sub.2&apos; The title compound (1.02 g ' 62%) was obtained as a foam. H NMR (400 MHz, DMSO-d6) δ 8.00 (s, br, 1H), 7.68-7.71 (m, 1H), 7.01 (s, br, 1H), 6.88 (d, 7 = 7.5 Hz, 1H) , 5.75 (s, br, 1H), 3.54 (s, 1H), 2.04-2.06 (m, 1H), 0.95 (d, /=6.0 Hz, 3H), 0.91 (d, ·7=6.6 Hz, 3H) . Analytical calculations for LCMS · (M+H): 194, experiment 146976.doc • 246- 201038558 Value: 195. Cap-89

L-Proline (1.0 g, 8.54 mmol), 5-bromopyrimidine (4.03 g, 17.0 mmol), K2C〇3 (2.40 g, 17.4 mmol) and Cul (179 mg, 0.94 mmol) in DMSO (10) The mixture in mL) was heated at 100 ° C for 12 hours. The reaction mixture was cooled to rt EtOAc (EtOAc)EtOAc. The organic layer was extracted with a small amount of H20 and the combined aqueous phases were acidified to pH about 2 with 6 N HCl. The volume was reduced to about 1/3, and 20 g of a cation exchange resin (Strata) was added. The slurry was allowed to stand for 20 minutes and loaded onto a cation exchange resin liner (Strata) (about 25 g). The pad was washed with H20 (200 mL), MeOH (200 mL) and then NH.sub.3 (3 EtOAc in MeOH, 2 X 200 mL). The appropriate fractions were concentrated in vacuo and the residue (~ 1.1 g) was dissolved in H20, lyophilized and lyophilized. The title compound (1.02 g, 62%) was obtained. 4 NMR (400 MHz, CD3OD) showed the mixture to contain valine and the purity could not be estimated. This material was used as it is in the subsequent reaction. LCMS: (M+H)+ calcd. Cap-90 NMe2 146976.doc • 247 · 201038558 艨-90 was prepared according to the method described for Preparation 1. The crude material is used as such in the subsequent steps. LCMS: (M-Η)· CnHuNC^ analytical value: 193, experimental value: 192. The following caps were prepared according to the procedure used for the preparation of caps 5 1 : s. s.. s. s. s. s. CAP-92 NHC02Me LCMS: (M-H)···················· Anal. Calcd.: </RTI> <RTI ID=0.0></RTI>帽-94 0 fNY^T^0H V HN 0, H I LCMS ·· (M+H)+ C8HnN304 Analysis Calculated: 213, Cap-95^ X O^NH 0 Q^Aoh LCMS: (M-H)· C13H17N04 Analysis Calculated: 251. Analysis of the caps - 96 〇 NH 〇 LCMS: (M-Η)· C12H15N04 Calculated: 237, Found: 236. 146976.doc -248- 201038558 Cap-97, X, 0 eight NH 0 & Η LCMS : (Μ-Η)_ Analysis of C9H15N04 Calculated: 201, Experimental value: 200. Cap-98 〇,. Analysis calcd.: calcd. Cap-99,. Human ΝΗ A co2h *H NMR (400 MHz, CD3OD) δ 3.88-3.94 (m, 1 Η), 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). Cap-99a \〇^^NH *H NMR (400 MHz, CD3OD) δ 3.88-3.94 (m, 1H), 3.60, 3.61 (s, 3H), 2.80 (m, 1H), 2.20 (m 1H), ό t〇2H 1.82-1.94 (m, 3H), 1.45-1.71 (m, 2H). The value of the calculated value: 255, experimental value: 256. calcd. calcd. m. Cap-101 〇,. Human ΝΗ r^C02H ό LCMS : (Μ-Η)· (: ηί^3Ν04 Analysis calculated: 223, experimental value: 222. Cap-102,. ρ |^C02H ό LCMS : (MH)- CuH13N04 Analysis calculated: 223, found: 222. 146976.doc • 249 - 201038558 cap-103 ^&quot;co2h 6 LCMS : (Μ+Η)+ Ch) Analysis of the value of Hi2N204: 224, experimental value: 225. Cap-104 ΗΝ—^〇〇2Η 〇/° 'H NMR (400 MHz, CD3〇D) 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). Cap-105 ΗΝ&quot;&lt; V*C02H /° ]H NMR (400 MHz, CD3OD) δ 3.60 (s, 3H), 3.33-3.35 (m, 1H, partially masked by solvent), 2.37-2.41 and 2.16-2.23 (m, 1H), 1.94-2.01 (m, 4H), 1.43-1.53 (m, 2H), 1.17-1.29 (m, 2H). Cap-106 ]Ν{)^〇2Η was prepared from cis-4-aminocyclohexane decanoic acid and acetaldehyde by a similar procedure as described for Synthetic Cap-2. The crude hydrochloride salt was taken through EtOAc (EtOAc (EtOAc)EtOAc 'H NMR (400 MHz, CD3〇D) δ 3.16 (q, J=7.3 Hz, 4H), 2.38-2.41 (m, 1H), 2.28-2.31 (m, 2H), 1.79-1.89 (m, 2H) , 1.74 (apparent, ddd, J=3_5, 12.5, 15.9 Hz, 2H), 1.46 (apparent doublet, J=4.0, 12.9 Hz, 2H), 1.26 (t, J = 7.3 Hz, 6H).帽-107 &lt;/ν1〇Γ^0Η V1 ην 丫0, 0 LCMS : (M+H)+ C8H1() N204S Analysis calculated: 230, found: 231.帽-108 &lt;/νιΟγ^οη V ΗΝ 0, Ph^ 〇 LCMS ·· (M+H)+ C15H17N304 Analysis calculated: 303, experimental value: 304. Cap-109,. Anal. calcd. calcd. calcd. 146976.doc -250- 201038558

Cap-m,. 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。. Cap-111,. Ι^Η ^^co2h φ MeO, \〇Η LCMS : (M+H)+ C12H16N08P Analysis calculated: 333, experimental value: 334. Cap-112,. 。 Η Η Η Η Η ^ ^ ^ 02 02 02 02 02 02 02 02 262 262 262 262 262 262 262 262 262 262 262 262. Cap-113, 〇人... j^C02H Φ OBn LCMS : (M+H)+ C18H19N05 Analysis Calculated value: 329, Experimental value: 330. Cap-114 /C〇2Me El lU NMR (400 MHz, CDC13) δ 4.82-4.84 (m, 1H), 4.00-4.05 (m, 2H), ^co2h 3.77 (s, 3H), 2.56 (s,br, 2H). Cap-115 x:o2h NHC02Me ]H NMR (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, J=9.1 Hz, 3H). Cap-116 !H NMR (400 MHz, CDC13) δ 5.10 (d, J=S.6 Hz, 1H), 3.74-3.83 (m, NHCQ2Me 1H), 3.69 (s, 3H), 2.54-2.61 (m, 2H), 1.88 (seven peaks, J=7.0 Hz, 1H), 0.95 (d, J=7.0 Hz, 6H). 146976.doc -251 - 201038558 Cap-117 to Cap-123 To prepare 艨-117 to 艨-123, a Boc amino acid was obtained from a commercial source and the protecting group was removed by treatment with a solution of 25% TFA in CH2C12. After the completion of the reaction was judged by LCMS, the solvent was removed in vacuo, and the corresponding trifluoroacetic acid amine of the amino acid was methylated by chloro decanoate according to the procedure described for 艨-51. Cap structure LCMS cap-117, NH 0 ΗLCMS : (Μ+Η)+ Ci2H15N04 Analysis calculated: 237, experimental value: 238.帽-118 V , ΝΗ 0 Α^οη LCMS : (M+H)+ Ci〇Hi3N04S Analysis calculated: 243, experimental value: 244. Analysis calculated by Cap-119 V ΝΗ 0 ΛΑ〇 LC LCMS : (M+H)+ C10H13NO4S: 243, Experimental value: 244. CAP, ΝΗ ΛΛ η η η η η η η η η η η η LC LC LC LC LC LC LC LC LC 243 243 243 243 243 243 243 243 243 243 243 243 243 243 243. ( S cap -121 0 ^ΝΗ ^y^co2H !H NMR (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). 146976.doc -252- 201038558

OH cap -122 0,. The human NH^y, 'C02H 4 NMR profile is similar to the outline of its enantiomer cap-121. Analysis calculated for Cap-123 0 / VnH 0 LCMS: (M+H) + C27H26N206: 474. Cap-Υ2Λ According to the procedure for 艨-5 1 , L-threonine tert-butyl ester hydrochloride was methylated. The crude reaction mixture was acidified to pH 1 with 1N EtOAc (EtOAc) The combined organic phases were concentrated in vacuo to give a colourless oil which solidified. The aqueous layer was concentrated with EtOAc EtOAc (EtOAc)EtOAc. The two batches were combined to give 0.52 g of solid. 1H NMR (400 MHz, CD3OD) δ 4.60 (m, 1H), 4.04 (d, 7 = 5.0 Hz, 1H), 1.49 (d, *7 = 6.3 Hz, 3H). </RTI> <RTI ID=0.0></RTI>艨-125

BocHN 146976.doc •253 - 201038558 Add to a suspension of Pd(OH)2 (20%, 100 mg), aqueous formaldehyde (37% by weight, 4 ml), acetic acid (0.5 mL) in methanol (15 mL) (S)-4-Amino-2-(t-butoxycarbonylamino)butyric acid (1 g, 4.48 mmol). The reaction was purged with hydrogen several times and stirred overnight at room temperature under a hydrogen balloon. The reaction mixture was filtered through a pad of Celite® and the volatile component was removed in vacuo. The crude material obtained was used in the next step as it was. LC/MS: (M+H)?艨-126

CIC02Me, NaHC03 THF / H2〇 / 〇°C /^NMe

Co2h MeO, CHN cap-i26 This program is a modification of the procedure for preparing 嫘-5 1. Add NaHCO3 (0.88 g, 10.5 mmol) to a suspension of 3-mercapto-L-histamine (0.80 g, 4.70 mmol) in THF (10 mL) and H2O (10 mL). . The resulting mixture was treated with ClC 〇 2Me (0.40 mL, 5·20 mmol), and the mixture was stirred at 0 °C. After stirring for about 2 hours, LCMS showed no starting material remaining. The reaction was acidified to pH 2 with 6 N HCl. The solvent was removed in vacuo and the residue was suspended in 20 mL 20% MeOH EtOAc. The mixture was filtered and concentrated to give a pale yellow foam (1.21 g). LCMS and 1H NMR showed the material to be a 9:1 mixture of the dec. This material was dissolved in THF (10 mL) and H.sub.2 (10 mL), cooled to EtOAc. After stirring for about 1 hour, LCMS showed no remaining ester. Therefore, the mouth was treated with 6 N HCl 1 146976.doc -254- 201038558 and the solvent was removed in vacuo. LCMS&amp; confirmed that the ester did not exist. The title compound (19i g, &gt; ι〇〇%) in the form of the hydrochloride salt was obtained, which was contaminated with an inorganic salt. This compound was used as it is in the subsequent step without purification. H NMR (400 MHz, CD3OD) δ 8.84 (s, 1H), 7.35 (s' 1Η)' 4.52 (dd,&gt;5·0, 9·1 Ηζ,1Η), 3.89 (s, 3Η), 3.62 ( s, 3H), 3.35 (dd, "7=4.5, 15_6 Hz, 1H, partially obscured by solvent", 3.12 (dd, J-9.0, 15.6 Hz, 1H). LCMS : (M+H)+ C9H13N304

Analytical juice calculation value: 227.09, experimental value: 228.09 » 艨-127 Μ, νΊ\ N^j CIC02Me, NaHCO; H2N^, co2h thf/h2o/o°c cj-26

According to the above method, amino group _3_(1_mercapto-1H-imidazol-4-yl)propionic acid (iu g, 6 56 譲〇1), Nafjco^ 21 〇g, 14·4 mmo1) #J-127 was prepared by using C1C〇2Me (0.56 mL, 7.28 mmol) as a starting material. The title compound (179 L, &gt; 100%) was obtained as the hydrochloride salt, which was contaminated with inorganic salts. LCMS and 1H NMR showed the presence of ca. The crude mixture was used as it was without further purification. NMR (400 MHz, CD3OD) δ 8.90 (s, 1H), 7.35 (s, 1H), 4.48 (dd, J=5.0, 8.6 Hz, 1H), 3.89 (s, 3H), 3.62 (s, 3H), 3.35 (m, 1H), 3.08 (m, 1H); LCMS: (M+H) + C9H13N304 calc. 146976.doc •255- 201038558 Preparation cap

C02H ° C BocHN

Cbz-CI / DMAP CH2CI2/iPr2NEt

C〇2Bn cj-27a cj-27b sodium ascorbate _3 / DMF / H2〇 65°C/12h

BnBr / CuS04-5H2〇

BocHN C02Bn cj-28

Ph-^ 1) TFA/CH2CI2 2) CIC02Me / NaHCOs THF-H20

C02Bn cj-29

H2 / Pd-C MeOH

Cap-728 ##厂制备(S)-2-(Tertiary butoxycarbonylamino)pent-4-ynyl benzyl ester (cj-27b)

C02Bn cj-27b 〇/-·27α (1·01 g, 4.74 mmol), DMAP (58 mg, 0.475 mmol) and iPr2NEt (1.7 mL, 9.8 mmol) in CH2Cl2 (1 mL) at 〇 °C Cbz-Cl (0.68 mL, 4.83 mmol) was added to the solution. The solution was mixed for 4 hours at 0 ° C, washed with EtOAc (1 N KHSO4, brine). The residue was purified by EtOAcjjjjjjjjj NMR (400 MHz, CDC13) δ 7.35 (s, 5Η), 5.35 (d, br, J=8.1 Hz, 1H), 5.23 (d, J=\2.2 Hz, 1H), 5.17 (d, J=\2.2 Hz, 1H), 4.48-4.53 (m, 1H), 2.68- 146976.doc - 256- 201038558 2.81 (m, 2H), 2.00 (t, 7=2.5 Hz, 1H), 1.44 (s, 9H). </RTI> <RTI ID=0.0></RTI> #銶2·Preparation of (S)-3-(l-benzyl-1H-1,2,3-triazol-4-yl)-2-(t-butoxycarbonylamino)propionic acid benzyl ester (cj-28)

ΟΟρΒπ cj-28 to (S)-2-(t-butoxycarbonylamino)pent-4-ynoic acid phenyl decyl ester (0.50 g, 1.65 mmol), sodium ascorbate (0.036 g, 0.18 mmol) at room temperature Add BnBr (0.24 mL, 2.02 mmol) to a mixture of CuS 〇 4-5H2 〇 (0.022 g, 0.09 mmol) and NaN3 (0.13 g, 2.1 mmol) in DMF-H2 (5 mL, 4:1) And the mixture was allowed to warm to 65 °C. After 5 hours, LCMS indicated a lower conversion rate. An additional portion of NaN3 (100 mg) was added and heating was continued for 12 hours. The reaction was poured into EtOAc and H20 and was shaken. The layers were separated, EtOAc (EtOAc m. The residue was purified by EtOAc EtOAc EtOAc (EtOAc) That is, solidification. NMR was consistent with the desired product but indicated the presence of DMF. This material was used as it was without further purification. 1H NMR (400 MHz, DMSO-d6) δ 7.84 (s, 1 Η), 7.27-7.32 (m, 10H), 5.54 (s, 2H), 5.07 (s, 2H), 146976.doc • 257- 201038558 4.25 ( m, 1H), 3.16 (dd, /=1-0, 5.3 Hz, 1H), 3.06 (dd, J=5.3, 14.7 Hz), 2.96 (dd, J=9.1,14.7 Hz,1H), 1.31 (s , 9H). LCMS: (M+H)+ calcd. 4-yl)-2-(indolylcarbonylamino)propionate (cj-29)

Ph-^

Cj-29 C〇2Bn to (S)-3-(l-stupyl-1H-1,2,3-triazol-4-yl)-2-(t-butoxycarbonylamino)propionic acid benzene Methyl ester (〇·52 g, 1.15 mmol) was added to a solution of CH.sub.2. The mixture was stirred at room temperature for 2 hours. The mixture was concentrated in vacuo to give a colorless oil which solidified upon standing. This material was dissolved in THF-H20 and cooled to 0 °C. Solid NaHCO3 (0.25 g, 3.00 mmol) was added followed by ClCO2Me (0.25 mL, 3.25 mmol). Grant

After 1.5 hours of mixing, the mixture was acidified to pH about 2 with 6 N HCl and then poured into HW-EtOAc. The layers were separated and the aqueous phase was extracted twice with Et EtOAc. The combined organic layers were washed with EtOAc (EtOAc m.) (HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH It solidifies when it is resting on the system. This material was used as received without further purification. lH NMR (4〇() MHz, DMSO-d6) δ 7.87 (s, 1Η), 7.70 (d, Hz? m)? 7&gt;27„7.32 (m, 10H), 5.54 (s, 2H), 5.10 ( d, Hz; m))5.〇6 (d? 146976.doc -258 - 201038558 7=12.7 Hz, 1H), 4.32-4.37 (m, 1H), 3.49 (s, 3H), 3.09 (dd, / = 5.6, 14.7 Hz, 1H), 2.98 (dd, "7=9.6, 14.7 Hz, 1H) LCMS: (M+H)+ CuHu^O4 Analysis calculated: 394, experimental value: 395. #锵1 Preparation of (S)-2-(oximeoxycarbonylaminotriazol-4-yl)propionic acid (cap-128)

(s)-3_(1_Benzyl-1H-1,2,3-triazol-4-yl)-2-(methoxycarbonylamine) in the presence of Pd-C (82 mg) at atmospheric pressure The benzyl propyl propionate (5 〇 2 mg, 1.11 mmol) was hydrogenated in MeOH (5 mL) for 12 h. The mixture was filtered through celite (EtOAc) and concentrated in vacuo. Obtaining (s)-2-(methoxyheptylamino)_3-(lH-l,2,3-tris-methyl-4-yl)propionic acid (266 mg, 111%) as a colorless gum. It is contaminated by about 10% decyl ester. This material was used as it was without further purification. NMR (400 MHz, DMSO-d6) δ 12.78 (s, br, 1 Η), 7.59 (s, 1H), 7.50 (d, /=8.0 Hz, 1H), 4.19-4.24 (m, 1H), 3.49 (s , 3H), 3.12 (dd, J=4.8 Hz, 14.9 Hz, 1H), 2.96 (dd, "7=9.9, 15.0 Hz, 1H). For LCMS: (M+H) + calcd. Preparation cap-129

CH3CN / 50°C cj-30

hD r N^=\

1) H2 Pd-C/MeOH

CbzHN 八 C02H q-31 2) CIC02Me

N^=\ Γ MeQ2CHN C02H

NaHC03/THF-H20 cap-i29 146976.doc -259- 201038558 Preparation of (S)-2-(p-methoxycarbonylamino)_3_(1H_pyrazole-indole-yl)propionic acid (cj-31)

CbzHN

NIN N. c iX %

r^02H Benzyl (S)-2-oxooxetane-3-ylaminobenzoate (〇67 g '3.03 mmol) and pyrazole (0 22 g ' 3.29 mmol) in CH3CN ( The suspension in 12 mL) was heated at 50 ° C for 24 hours. The mixture was allowed to cool to room temperature overnight and the solid was filtered to afford (S) </RTI> &lt;RTI ID=0.0&gt;&gt;&gt; The filtrate was concentrated in vacuo, and then wet-milled with a small portion (: 1130 </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> Melting point (lit mp): 168.5-169.5 [Vederas et al., 乂J/w. CAem. SW· 1985, 707, 7105]. 4 NMR (400 MHz, CD3OD) δ 7.51 (d, «7=2.0, 1H) , 7.48 (s, J=1.5 Hz, 1H), 7.24-7.34 (m, 5H), 6.23 (m, 1H), 5.05 (d, 12.7H, 1H), 5.03 (d, J-12.7 Hz, 1H) S 4.59-4.66 (m, 2H), 4.42-4.49 (m, 1H). LCMS: (M+H) + C14H15N3 〇4 Analysis calculated: 289, calc.: 290. #耀入制备(S)- 2-(oximeoxycarbonylamino)-3-(1Η-.bizozol-1-yl)propionic acid (0-129)

M

N CH

NIN

02h zcc X n-129 146976.doc - 260 - 201038558 (s)_2_(Benzyloxycarbonylamino)-3-(1Η-&quot;Biazole in the presence of Pd-C (45 mg) at atmospheric pressure -1-yl)propionic acid (〇·2〇g, 〇.70 mm 〇1) was hydrogenated in MeOH (5 mL) for 2 hr. The product appeared to be insoluble in MeOH, so the reaction mixture was diluted with 5 mL H.sub.2 and a few drops of 6 N HCl. The homogenous solution was filtered through Celite® and Me〇H was removed in vacuo. The remaining solution was cold-bundled and dried to give a yellow foam (188.9 mg). This material was suspended in THF-H20 (1:1 '10 mL) and then cooled to hydr. Hey. NaHCO3 (146.0 mg ' 1.74 mmol) (escaped from C02) was carefully added to the cold mixture. After the gas ceased to escape (about 15 minutes), ciC02Me (0.06 mL, 0.78 mmol) was added dropwise. The mixture was stirred for 2 hours&apos; and it was acidified to pH 2 with 6 N EtOAc and poured into EtOAc. The layers were separated and the aqueous extracted with EtOAc (EtOAc). The combined organic layers were washed with EtOAc EtOAc m. NMR (400 MHz, DMSO-d6) δ 13.04 (s, 1 Η), 7.63 (d, /=2.6 Hz, 1H), 7.48 (d, /=8.1 Hz, 1H), 7.44 (d, /=1.5 Hz, 1H), 6.19 (apparent triplet, /=2.0 Hz, 1H), 4.47 (dd, J=3.0, 12.9 Hz, 1H), 4.29-4.41 (m, 2H), 3.48 (s, 3H). </RTI> <RTI ID=0.0></RTI> <RTI ID=0.0></RTI>艨-130

AcHN C02H is similar to Calmes, M_; Daunis, J.; Jacquier, R·; Verducci, J. 146976.doc • 261 · 201038558 rwM Heart State, 1987, α(10), 2285艨_130 was prepared from commercially available (R)-phenylglycine. Cap-131

: (S)-2-Amino-3-mercaptobutyric acid agaric acid ester hydrochloride (2 44 g, 10 mmol) and Hugh's base (3.67 mL, 21 mmol) in THF (50 mL) Dimethylamine formazan (0.92, 1 () mmQl) was slowly added to the solution. The resulting white suspension was searched overnight (1 6 hours) under OBL and concentrated under reduced pressure. The residue was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried (MgSO4), filtered and evaporated. The resulting yellow oil was purified by flash chromatography eluting with ethyl acetate:hexane (1:1). The fractions collected by vacuum were reduced to give 2.35 g (85%) of a clear oil. 4 NMR (300 MHz, DMSO-d6) δ ppm 0.84 (d, J = 6.95 Hz, 3H), 0-89 (d, J = 6.59 Hz, 3H), 1.98-2.15 (m, 1H), 2.80 (s , 6H), 5.01-5.09 (m, 7=12.44 Hz, 1H), 5.13 (d, J-12.44 Hz, 1H), 6.22 (d, J=8.05 Hz, 1H), 7.26-7.42 (m, 5H) . LC (Condition 1): RT = 1.76 min; MS: [M+H] + C16H22N203 Analysis: 279.17, experimental value 279.03. Step 'Record ^: Add Pd/C (100/〇, 200 mg) to a solution of the above prepared intermediate (2.35 g, 8.45 mmol) in MeOH (50 mL). Liquid and placed at 1 atm H2. The mixture was stirred overnight at room temperature and filtered through a microfiber filter to remove catalysis. 146976.doc -262- 201038558

Agent. The resulting clarified residue was combined with EtOAc (yield: EtOAc): lH NMR (500 MHz, DMSO-d6) δ ppm 〇.87 (d, J=4.27 Hz, 3H), 0.88 (d, /=3.97 Hz, 3H), 1.93-2.11 (m, 1H), 2.80 (s , 6H), 3.90 (dd, J=8.39, 6.87 Hz, 1H), 5.93 (d, 7=8.54 Hz, 1H), 12.36 (s, 1H). LC (Cond. l): RT = 0.33 min; MS: [M+H] + C8h17n2o3 calc. Cap-132

According to the method described by Zhi, the preparation of benzene from (s)_2_aminopropionate hydrochloride was carried out. NMR (500 MHz, DMSO-d6) δ ppm 1.27 (d, J = 7.32 Hz, 3H), 2.80 (s, 6H), 4.06 (qt, 1H), 6.36 (d, *7 = 7.32 Hz, 1H), 12.27 (s, 1H). </RTI> <RTI ID=0.0></RTI> </RTI> <RTI ID=0.0></RTI> Cap-133

HCI

艨-733. 4 NMR (500) prepared from (S)-2-amino-3-mercaptobutyric acid tert-butylacetate hydrochloride and 2-fluoroethyl chloroformate according to the method described in the procedure -47 MH DMSO DMSO δ δ δ δ δ (m, 1H), 4.20-4.25 (m, 1H), 4.50-4.54 (m, 1H), 4.59-4.65 (m, 1H), 7.51 (d, /=8.54 Hz, 1H), 12.54 (s, 1H) ). Cap-134

Prepared from (S)-diethylalanine and methyl formate according to the method described in JI-57. 734. 4 NMR (500 MHz, DMSO-d6) δ ppm 0.72-0.89 (m, 6H) , 1.15-1.38 (m, 4H), 1.54-1.66 (m, 1H), 3.46-3.63 (m, 3H), 4.09 (dd, J=8.85, 5.19 Hz, 1H), 7.24 (d, J=8_85 Hz , 1H), 12.55 (s, 1H). </RTI> <RTI ID=0.0></RTI> </RTI> <RTI ID=0.0></RTI> Cap-135

D-Amino-(4-fluorophenyl)acetic acid (338 mg, 2.00 mmol), 1 iV HCl in scaly solution (2.0 mL) at 10 ° palladium on carbon (60 mg) at 25 °C , 2_0 mmol) and a solution of formalin (37%, 1 mL) in methanol (5 mL) for balloon hydrogenation for 16 h. The mixture was then filtered through celite to give 146976.doc: 264-201038558 </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; 1H NMR (300 MHz, MeOH-d4) δ 7.59 (dd, 7 = 8.80, 5.10 Hz, 2H), 7.29 (t, 7 = 8.6 Hz, 2H), 5.17 (s, 1H), 3.05 (v br s, 3H ), 2.63 (v br s5 3H); Rt=〇.19 min (condition MS-W5); homogeneity index 95%; LRMS: [M+H]+C1()H13FN02 analytical value: 198.09, experimental value :198.10. Cap-136

To a solution of 1-phenylhydrazin-1 ugly-β-million (1.58 g, 10.0 mmol) in anhydrous diethyl ether (50 mL), cooled (-50. (:)) n-Butyllithium (2.5 于 in hexane, 4.0 mL, 10.0 mmol). After stirring at -5 0 (3 hrs), dry carbon dioxide (by Drierite) was bubbled into the reaction mixture for 10 minutes, then The temperature was raised to 25. (: Filtering a large amount of precipitate formed when carbon dioxide was added to the reaction mixture to obtain a hygroscopic white solid, which was dissolved in water (7 mL), acidified to pH = 3, cooled and borrowed. Crystallization was induced by scraping. The precipitate was filtered to give a white solid, which was crystalljjjjjjjjjjjjjjjjjjj , 艨-736 hydrochloride (817 mg, 40%) was obtained as a white solid. 4 NMR (300 MHz, DMSO-d6) δ 7.94 (d, J = 1.5 Hz, 1H), 7.71 (d, *7=1.5 Hz, 1H), 7.50-7.31 (m, 5H), 5.77 (s, 2H); Rt=0.51 min (condition MS-W5); homogeneity index 95%; LRMS: [M+H]+ Analytical calculated value of CnH12N202: U6976.doc - 265- 201038558 203.08, experimental value: 203.11. Cap-137 οςτ co2h cap-U7, step a under nitrogen, 1_chloro-3-cyanoiso(tetra) (188 mg' i 〇〇_〇1; according to WO 2003 Prepared by the procedure in 099274) (10) post, i〇〇_吟fluorinated planer (303.8 mg, please mmQl), two gasified double (triple_t-butyl) palladium (10 mg, 0.02 mmol) and 2- (three A suspension of butylstannyl)furan (378, 1.20 mmol) in dry dioxane (1 mL) was heated at 8 ° C &lt;c&gt;c for 16 h then cooled to 25t with vigorous stirring Treated with a saturated aqueous solution of potassium fluoride for 1 hour. The mixture was partitioned between ethyl acetate and water, and the organic phase was separated and washed with brine, dried over NaeCU, filtered and concentrated on a silica gel (0% to 30°/ The residue was purified by ethyl acetate / hexane (EtOAc: EtOAc): Homogeneity index 90%; LRMS : [M+H]+ C}4H8N20 Analysis calculated: 221.07, experimental value: 221.12. 146976.doc -266 - 201038558 Cap-137 Cap 137 Step a{\ Add hydrated trichlorination to a suspension of sodium perchlorate (1,3 mL) in acetonitrile (1 mL), acetonitrile (1 mL) and water (1.5 mL).钌 (2 mg, 0.011 mmol). The mixture was stirred at 25 ° C for 2 hours and then partitioned between methylene chloride and water. The aqueous layer was separated and extracted twice with dichloromethane. EtOAc m. The residue was triturated with hexane to give EtOAc (EtOAc: EtOAc) Rt=1.10 min (conditions MS-W2); homogeneity index 90%; LCMS: [M+H]+ CnH8N202 analytical value··200.08, experimental value: 200.08. Cap 1381 158

Synthesis Strategy: Method A

BMCL 2001, 11,1885-1888.

mCPBA DCWT

Ο cap-138

Co2h cap-13 8, step a

146976.doc •267- 201038558 to 5-hydroxyisoquinoline (prepared according to the procedure in WO 2003/099274) (2.0 g, 13_8 mmol) and two scales (4_3 g ' 16.5 mmol) in anhydrous tetrahydrofuran (20 mL) Anhydrous methanol (0.8 mL) and azo·monoformic acid monoethyl acetate (3.0 mL, 16·5 mmol) were added portionwise to the stirred suspension. The mixture was stirred at room temperature for 20 hours, then diluted with ethyl acetate and washed with brine &lt The residue was pre-adsorbed onto a matte gel, and chromatographed (dissolved in 40% ethyl acetate / hexanes) to give a pale a solid (a. g, 45%). 4 NMR (CDC13, 500 MHz) δ 9.19 (s, 1Η), 8.51 (d, J=6.0 Hz, 1H), 7.99 (d, J=6.0 Hz, 1H), 7.52-7.50 (m, 2H), 7.00 -6.99 (m, 1H), 4·01 (s,3H) ; Rt=0.66 min (condition D2); homogeneity index 953⁄4 ; LCMS : [M+H]+ C丨〇H丨〇NO analytical value : 160.08, experimental value · · 160.1. Cap-138, step b

Add to the micro-a (2.34 g, 14.7 mmol) in anhydrous dichlorohydrazine (50 mL) under a dish to a dish; remove the solution with one part of m-chloroperbenzoic acid (77% ' 3.42 g) '19·8 mmol). After stirring for 20 hours, 'powdered potassium carbonate (2.0 g)' was added and the mixture was stirred at room temperature for 1 hour, followed by filtration and concentration in vacuo to give a treatment as a light yellow solid _/3 §, recorded ^(2· 1 5 g '83%), pure enough to be used directly. iH NMR (CDC13, 400 MHz) δ 8.73 (d, J=l.5 Hz, 1H), 8.11 (dd, J=7.3, 1.7 146976.doc -268- 201038558

Hz, 1H), 8.04 (d, J=7.1 Hz, 1H), 7.52 (t, J=8.1 Hz, 1H), 7.28 (d, J=8.3 Hz, 1H), 6.91 (d, J=7.8 Hz, 1H), 4.00 (s, 3H); Rt=〇.92 min (condition Dl); homogeneity index 90%; LCMS: [M+H] Ci〇Hi〇N〇2 analytical value: 176.07, experimental value : 176.0 .

Cap-138, step C

CN 添加 Add to the mixed solution of saponin 6 (0.70 g, 4.00 mmol) and triethylamine (1·1 mL ' 8.00 mmol) in anhydrous acetonitrile (20 mL) at room temperature under nitrogen. Trimethyl cyanide cyanide (1.60 mL, 12.00 mmol). The mixture was heated at 75 ° C for 20 hours, then cooled to room temperature, diluted with ethyl acetate and washed with a saturated aqueous solution of sodium hydrogen carbonate and brine, and then dried over Na? The residue was subjected to flash chromatography on a Shi Xiyue (a gradient elution of 5 % acetic acid to a 25% ethyl acetate in hexane) to give a white crystalline solid. 7 step c (498.7 mg, 68%) and another 223 mg (30%) doped c recovered from the filtrate. *H NMR (CDC13, 500 MHz) δ 8.63 (d, J=5.5 Hz, 1H), 8.26 (d, /=5.5 Hz, 1H), 7.88 (d, /=8.5 Hz, 1H), 7.69 (t, J=8.0 Hz, 1H), 7.08 (d, J=7.5 Hz, 1H), 4.04 (s, 3H); Rt=1.75 min (condition Dl); homogeneity index 9〇%; LCMS: [M+H] Analysis calculated for CuHpI^O: 185.07, found: 185.10. 146976.doc -269- 201038558 Cap-138 The 艨-/3S# misc (0.45 g, 2.44 mmol) was treated with 5 μM sodium hydroxide solution (10 mL), and the resulting suspension was heated at 85 ° C for 4 hours. Cool to 25 ° C, dilute with dichloromethane and acidify with 1 # hydrochloric acid. The organic phase was separated, washed with EtOAc EtOAc EtOAcjjjjjjj 1H NMR (DMSO-d6, 400 MHz) δ 13.6 (br s, 1H), 8.56 (d, /=6.0 Hz, 1H), 8.16 (d, /-6.0 Hz, 1H), 8.06 (d, J-8.8 Hz , 1H), 7.71-7.67 (m, 1H), 7.30 (d, J=8.0 Hz, 1H), 4.02 (s, 3H); Rt=0.70 min (condition Dl); homogeneity index 95%; LCMS: [ M+H] +

Analytical calculated value of CnH1() N03: 204.07, experimental value: 204·〇5. Synthetic strategy: method Β (from 2001, 42, 6707)

Cap-139

Cap-13 9, step a

146976.doc •270- 201038558 to 1-Chloro-6-methoxyisoquine (1.2 g, 6.2 mmol; prepared according to the procedure in WO 2003/099274), potassium cyanide (0·40 g, 6.2 mmol) , 1,5_bis(diphenylphosphino)pentane (0.27 g' 0.62 mmol) and acetic acid (ι ) (7 〇 mg, 〇·31 mmol) in anhydrous toluene (6 mL) in argon Tetramethylethylenediamine (0.29 mL, 2.48 mmol) was added to the thick-walled screw cap vial of the degassed suspension. The vial was sealed, heated at 150 °C for 22 hours, and then allowed to cool to 25 °C. The reaction mixture was diluted with EtOAc (EtOAc)EtOAc. The residue was purified with EtOAc EtOAc EtOAc (EtOAc:EtOAc咕NMR (CDC13,500 MHz) δ 8.54 (d, "7=6.0 Hz, 1H), 8.22 (d, J=9.0 Hz, 1H), 7.76 (d5 /=5.5 Hz, 1H), 7.41-7.39 (m , 1H), 7.13 (d, /=2.0 Hz, 1H), 3.98 (s, 3H); Rt=1.66 min (condition Dl); homogeneity index 9〇%; LCMS: [M+H] + CuH9N2 Analytical calculation value · 185.07, experimental value: 185.2. Cap-139 was prepared according to the procedure described for the temporary /35, by alkaline hydrolysis of 艨-/39# heteroa with 5# NaOH to prepare -739. 1H NMR (400 MHz, DMSO-de) δ 13.63 (v br S5 1H), 8.60 (d, /=9.3 Hz, 1H), 8.45 (d, -^=5.6 Hz, 1H), 7.95 (d, /=5.9 Hz, 1H), 7.49 (d, /=2.2 Hz, 1H), 7.44 (dd, J=93, 2.5 Hz, 1H), 3.95 (s, 3H); Rt=0.64 min (condition Dl); homogeneity index 9〇%; [CMS : [M+H]+ CnHwNCh Analytical calculated value: 204.07, experimental value: 204.05. 146976.doc -271 - 201038558 cap-140

Co2h cap-14 0, step a

CN 1,3-dichloro-5-ethoxyisoquinoline (482 mg, 2.00 mmol; prepared according to the procedure in WO 2005/051410), acetic acid Ib (11) (9) under nitrogen at 25t Mg, 0.04 mmol), sodium carbonate (223 mg, 2.10 mmol) and 1,5-bis(diphenylphosphino)pentane (35 mg, 0.08 mmol) in anhydrous dimercaptoacetamide (2 mL) To the vigorously mixed mixture was added hydrazine, hydrazine, hydrazine, Ν'-tetradecylethylenediamine (60 mL, 0.40 mmol). After 10 minutes, the mixture was heated to 150 ° C, and then a stock solution of acetone cyanohydrin (manufactured from 457 μί of acetone cyanohydrin in 4.34 mL of DMA) was added using a syringe pump for 18 hours. The mixture was partitioned between EtOAc and EtOAc (EtOAc)EtOAc. The residue was purified on EtOAc (EtOAc EtOAc EtOAc EtOAc ). Rt=2.46 min (conditions MS-W2); homogeneity index: 90%; LCMS: [M+H]+ C12H9C1N20 Analysis calculated: 233.05, Experimental value: 233.08 ° 146976.doc -272 - 201038558 Cap-140 The hydrazine was prepared by acidic hydrolysis of 艨-740#锧α with 12 μV HC1 as described in the procedure for preparing hydrazine (described below). Rt = 2.24 min (conditions MS-W2); Homogeneity index: 90%; LCMS: [M+H] + C12HnClN03 Analysis calculated: 252.04, experimental value: 252.02. Cap-141

Cap-141, step a

As described in the procedure for the preparation of 艨-7扣#锧β (see above), from 1-bromo-3-fluoroisophthalocyanine (using J. Met/· C/zew· 1970, /3,613) The procedure was prepared from 3-amino-1-bromoisoquinoline to prepare 艨铐α.咕〇NMR (500 MHz, CDC13) δ 8.35 (d, J=8.5 Ηζ, 1Η), 7.93 (d, J=8.5 Hz, 1H), 7.83 (t, /=7.63 Hz, 1H), 7.77-7.73 ( m, 1H), 7.55 (s, 1H); Rt=1.60 min (condition Dl); homogeneity index 90%; LCMS: [M+H]+ C1C) Analysis of H6FN2: 173.05, experimental value: 172_99 ° Cap-141 Treatment of Chi-747 ‧ &lt; 3 (83 mg, 0.48 mmol) with 12 TV HC1 (3 mL), and heating the resulting slurry at 80 ° C for 16 hours, then cooling to room 146976.doc -273 - 201038558 Dilute with water (3 mL). The mixture was stirred for 1 min, and then was taken to give the snail-747 (44.1 mg &apos; 48%) as a white solid. The filtrate was diluted with dioxane and washed with brine, dried over Na 2 EtOAc and concentrated to afford &lt;RTIgt;&lt;/RTI&gt; </ RTI> </ RTI> 7 (29.3 0 mg, 32%). 4 NMR (DMSO-d6, 500 ΜΗζ) δ 14.0 (br s, 1H), 8.59-8.57 (m, 1H), 8.10 (d, J=8.5 Hz, 1H), 7.88-7.85 (m, 2H), 7.74 - 7.71 (m, 1H); Rt = 1.33 min (Cond. Dl); homogeneity index: 90%; LCMS: [M+H]+ C10H7FNO2: 192. Cap-142

Cap-142, step a

For example, for the preparation of the two-step procedure of Zhihuang Miscellaneous, the self-contained 4-bromoisophthalocyanine N-oxide is used as a temporary miscellaneous. .μ min (condition MS-W1); homogeneity index 90%; [CMS: [m+H]+ C10H6BrN2 analysis Measured value: 232.97, experimental value: 233.00. 146976.doc -274- 201038558 Cap-142, step b

CN to cap-142 Step a{\\6 mg, 0.50 mmol), tripotassate (170 mg, 0.80 mmol), acetic acid le (11) (3.4 mg, 0.015 mmol) and 2-(dicyclohexylphosphino) Addition of phenanthrene (11 mg, 0.03 mmol) to an argon gas degassed suspension of Q in anhydrous toluene (1 mL) (61 pL, 0.70 mmol). The mixture was heated at l ° ° C for 16 hours, cooled to 25 ° C, filtered over Celite® and concentrated. The residue was purified on EtOAc (EtOAc: EtOAc (EtOAc) . Rt=l.26 min (conditions MS-W1); Homogeneity index: 90%; LCMS: [M+H] + C14H14N30 Analysis calculated: 240.11, Experimental value: 240.13. Cap-142 〇 As described in the procedure for 艨73S, 涝-to 2 was prepared with 2# 麟^ and 5 sodium hydroxide. Rt = 0.72 min (conditions MS-W1); homogeneity index: 90%; LCMS: [M+H]+ C14H15N203 Analysis calculated: 259.11, found: 259.08 ° cap-14 3 οςτ° co2h 146976.doc -275 - 201038558 Cap-143, step a

Add sodium hydride (6 〇%, unwashed, 90) to a stirred solution of the female odorant (444 mg' 2.00 mmol) in anhydrous dimercaptoamine (10 mL) in March. Mg, 2.4 mmol). The mixture was stirred at 25 ° C for 5 minutes. Then 2 - bromoethyl ether (9 〇 %, 25 〇, 2 〇〇 mmol) was added and the mixture was further mixed at 25 C for 5 hours at 75 ° C. It was stirred for 72 hours' then it was allowed to cool to 25 s., quenched with saturated aqueous ammonium chloride and diluted with ethyl acetate. The organic layer was separated, washed with water and brine, dried over Na. The residue was purified on silica gel eluting with EtOAc EtOAc (EtOAc: EtOAc) Rt = 75 min (condition Ms_W1); homogeneity index: 9〇%; LCMS: [M+H]+ C13H14BrN2 〇 calc.: 293. Cap-143 Add a solution of n-butyllithium in hexane to a solution of 艨-743 step 锧α ( 154 mg, 0.527 mmol) in cold (_60 ° C) in anhydrous tetrahydrofuran (5 mL) (2'5 Μ '0_25 mL, 0.633 mmol). After 10 minutes, dry carbon dioxide was bubbled into the reaction mixture for 1 Torr, then quenched with 1 # HCb and allowed to warm to 25 °C. The mixture was then extracted with dioxane (3 x 30 mL) and the combined organic extracts were concentrated in vacuo. The residue was purified by reverse phase HPLC (MeOH / water / TFFA) to afford the m. m (16 mg, 146976.doc. 276 - 201038558 12%). Rt=l.i〇 min (conditions MS-Wl); homogeneity index 90%; LCMS: [M+H]+ Ci4H15N203 Analysis calculated: 259.11, experimental value: 259.08. Cap-144

Cap-144, step a

To the cold (0 mL) of fuming nitric acid (10 mL) and concentrated sulfuric acid (10 mL), add 1,3-dichloroisoquine (2.75 g, 13.89 mmol) in small portions of the solution. Mix the mixture at 0 °C. After 0.5 hours, it was gradually warmed to 25. 〇, and the mixture was stirred at the temperature for 16 hours. Then the mixture was poured into a beaker containing crushed ice and water and the resulting suspension was stirred at 〇 ° C for 1 hour. This was followed by filtration to give yt-7 as a yellow solid, which was used in the genus ra (2.73 g, 81%), which was used directly. Rt = 2.01 min (condition D1); homogeneity index 95%; LCMS: [M Analysis of calculated value of +H]+ C9H5C12N202: 242.97, experimental value: 242.92. Cap-144, step b

146976.doc • 277- 201038558 艨In step 缵α (0·30 g, L23 mmol) dissolved in methanol (6 〇 mL) and treated with platinum oxide (3 〇 mg) and at 7 psi H2 The suspension was subjected to Parr hydration for 1.5 hours, followed by the addition of formalin (5 mL) and another portion of platinum oxide (30 mg). The suspension was further subjected to Parr hydrogenation at 45 psi H2 for 13 hours followed by aspiration by Celite® and the condensation was reduced to % volume. The obtained precipitate was suction-filtered to give the title compound as a yellow solid, which was subjected to silica gel chromatography (gradient elution with 5% ethyl acetate in hexane to 25% ethyl acetate in hexane). , obtained as a pale yellow solid (231 mg, 78%).

Rt = 2.36 min (condition D1); homogeneity index 95%; 4 NMR (400 MHz, CDC13) δ 8.02 (s, 1H), 7.95 (d, J = 8.6 Hz, 1H), 7.57-7.53 (m, 1H) ), 7.30 (d, /=7.3 Hz, 1H), 2.88 (s, 6H); LCMS: [M+H]+ (:ηΗ&quot;(:12Ν2 analysis calculated value: 241〇3, experimental value: 241.02. HRMS: [M+H]+ CuHnChA: calcd.

CN According to the procedure described in Preparation-739#锧, self-treatment preparation is performed to ##c. Rt=2.19 min (Condition D1); Homogeneity Index 95%: LCMS: [M+H]+ CuHnClN: calc. HRMS: [M+H] </RTI> </RTI> <RTIgt; 146976.doc 278· 201038558 Cap-144 Prepare 艨-7« according to the procedure described for 艨-747. Rt = 2.36 min (condition D1); 90%; LCMS: [M+H] + C12H12C1N202 Analysis calculated: 238.01, experimental value: 238.09 ° cap - 145 to cap - 162 unless otherwise indicated (as outlined below), otherwise Cap-145 to Cap-162 were prepared from the appropriate 1-chloroisoquinoline for the procedure described for the preparation of Cap-138 (Method A) or Cap-139 (Method B). G _____ cap number cap method hydrolysis Rt (LC-condition); homogeneity index %; MS data cap -145 οςτει co2h Preparation of B 12iVHCl 1.14 min from commercial 1,3-dichloroisoquinoline (conditions!^-Wl) ; 90%; LCMS: [M+H]+ </RTI> <RTI ID=0.0></RTI> </RTI> <RTIgt; Cap-146 οςτ co2h Preparation of A 5N NaOH from commercially available 3-hydroxyisoquinoline 1.40 min (Condition Dl); 95%; LCMS: [M+H]+ C ???H1QN03 Analysis calculated: 204.07, Experimental value: 204.06 Cap-147 οφ co2h Preparation of B 5N NaOH from commercially available 1-ox-4-hydroxyisoquinoline 0.87 min (condition D1); 95% ; LCMS: [M+H]+ CuHwNOs Analysis: 204.07, experiment Value: 204.05. Cap-148 co2h Preparation of A-5N NaOH from commercially available 7-hydroxyisoquinoline 0.70 min (Condition D1); 95%; LCMS: [M+H]+ C s H1QN03 Analysis calculated: 204.07, experiment Value: 204.05. 146976.doc -279- 201038558 Cap-149 C〇2H Preparation of A 5N NaOH from commercially available 5-hydroxyisoquinoline 0.70 min (condition Dl); 95% ; LCMS: [M+H]+ CiiHiqN〇3 Value: 2〇4.07, experimental value: 204.05. Cap-150 TFA /0 co2h Preparation of A- 12JVHC1 0.26 min (condition D1); 95% ; LCMS: [M+H] ]+ CiiH1QN〇3 Analysis calculated: 204.07, experimental value: 204.04. Cap-151 δςτ C〇2H Self-conductible 5-methoxy-1,3_-qi 啥 啥 制备 Preparation B 12WHC1 1.78 min (condition D1); 90% ; LCMS : [M Analysis calculated for +H]+ C11H9CINO3: 238.03, found: 238.09. Cap-152 &quot;Χςτ co2h Prepared from commercially available 6-mercapto-1,3-dioxaquinoline B 12 7VHC1 1.65 min (condition D1); 95% ; LCMS : [M+H]+ C„H9C1N03 Analytical calculated value: 238.00, experimental value: 238.09. Cap-153 〇φΝ co2h Preparation of A 6iVHCl W1) from 4-bromoisoquinoline synthesized according to the procedure in WO 2003/062241; 95% ; LCMS : [M+ Analytical calculated value of H]+ C10H7BrNO2: 251.97, Experimental value: 251.95. Cap-154 Xp co2h Self-contained according to the procedure in WO 2003/099274 7. Preparation of fluorine small gas isoquinoline B 5N NaOH 0.28 min (condition)^ 3-W1) ; 90% ; LCMS : [M+H]+ C10H7FNO2 Analysis calculated: 192.05, Experimental value: 192.03. 146976.doc • 280- 201038558 Cap-155 co2h Follow the procedure in WO 2003/099274 Preparation of 1,7-di-iso-isoquinoline for the preparation of B5N NaOH 0.59 min_, MS-Wl); 90%; LCMS: [M+H]+ C10H7ClNO2 Analysis calculated: 208.02, found: 208.00. Cap-156 c, OpN COjH can be prepared according to the procedure in WO 2003/099274. Preparation of B6N NaOH 0.60 min Wl); 90% ; LCMS : [M Analytical calculated value of +H]+ C10H7ClNO2: 208.02, Experimental value: 208.03. Cap-157 〇φ co2h Preparation of B 12iVHCl 1.49 min from 1,4-diisoisoquinoline synthesized according to the procedure of WO 2003/062241 Condition D1); 95% ; LCMS: [M+H]+ C10H17C1NO Analysis calculated: 208.02, experimental value: 208.00. Cap-158 όφ co2h Self-consistent 1,5-two according to the procedure in WO 2003/099274 Preparation of B 5N NaOH by gas isoquinoline 0.69 min (conditions)\48-W1); 90%; LCMS: [M+H]+ Ci 〇H7C1N02 Analysis calculated value: 208.02, Experimental value: 208·(η. Cap- 159 όφ co2h Preparation of B 5N NaOH 0.41 min from the 5-fluoro-1-isoisoquinoline synthesized according to the procedure in WO 2003/099274 (condition "8-W1"; 90% ; LCMS : [M+H]+ Analytics calculated for C10H7FNO2: 192.05, found: 192.03. 146976.doc -281 - 201038558 Cap-160 FOyl co2h Preparation of B-5N NaOH 0.30 min (condition 1^8-W1); 90-fluoro-1 -isoquinoline synthesized according to the procedure in WO 2003/099274 </ RTI> <RTI ID=0.0></RTI> </RTI> <RTI ID=0.0></RTI> Cap-161 was prepared from 4-bromoquinoline-2-carboxylic acid and diamine (in DMSO at 10 ° C) for 0.70 min (condition D1); 95%; LCMS: [M+H]+ C12H13N2O2 Analytical calculated value: 217.10, experimental value: 217.06. Cap-162 N'iik 'C02H 'In violation of the procedure described in J. Hetero. Ozem. 1993, 17 and Heterocycles, 2003, YANG, 953, 0.65 min from m-aminoanisole (condition M3); 95 </ RTI> <RTI ID=0.0></RTI> </RTI> <RTI ID=0.0></RTI> Cap-163

OH To a solution of 2-S-butyric acid (1.0 g, 9.8 mmol) in diethyl ether (25 ml), phenylmagnium bromide (22 ml, 1 EtOAc in THF). The reaction was stirred at about 25 ° C for 17.5 hours under nitrogen. The reaction was acidified with 1N EtOAc (EtOAc m. The combined organic layers were washed with water and then brine and dried over EtOAc. After concentration in vacuo, a white solid was obtained. The solid hexane/ethyl acetate was recrystallized to give a white color 146976.doc - 282 - 201038558. 4 NMR (DMSO-d6, δ=2.5 ppm, 500 MHz): 12.71 (br s, 1H), 7.54-7.52 (m, 2H), 7.34-7.31 (m, 2H), 7.26-7.23 (m, 1H) , 5.52-5.39 (br s, 1H), 2.11 (m, 1H), 1.88 (m, 1H), 0.79 (apparent triplet, j = 7.4 Hz, 3H). Cap-164

2-Amino-2-phenylbutyric acid (1.5 g, 8.4 mmol), acetonide (14 mL, 37% in water), 1 N HCl (10 mL) and 10% Pd/C (0.5 mg) The mixture in MeOH (40 mL) was placed in a parr bottle at 50 psi H2 for 42 hours. The reaction was filtered with EtOAc (EtOAc)EtOAc. 1.7 Ο g). NMR (DMSO-d6, δ = 2.5 ppm, 500 MHz) 7.54-7.47 (m, 5H), 2.63 (m, 1H), 2.55 (s, 6H), 2.31 (m, 1H), 0.95 (apparent triplet) , J = 7.3 Hz, 3H). Cap-165

Add formaldehyde (0.6 ml) to a mixture of 2-amino-2-indancarboxylic acid (258.6 mg, 1.46 mmol) and formic acid (0.6 ml ' 15.9 mmol) in l,2-dichloroethane (7 ml) '37% in water). The mixture was stirred at about 25 ° C for 15 minutes, 146976.doc 283 · 201038558 followed by heating at 70 ° C for 8 hours. The volatile component was removed in vacuo and the residue was taken in EtOAc EtOAc (EtOAc) ). 4 NMR (DMSO-d6, δ = 2.5 ppm, 500 MHz): 7.29-7.21 (m, 4H), 3.61 (d, J = 17.4 Hz, 2H), 3.50 (d, J = 17.4 Hz, 2H), 2.75 (s, 6H). Analysis for LC/MS: [M+H] + C12H16N02 Calculated: 206.12. Cap-166a and cap-166b

Qll 0H cap-ieea: diastereomer-1 N cap · shed 6: diastereomer-2 / except using 85:1 5 heptane/ethanol mixture at 1 〇mL/min dissolution rate Separation of the benzyl ester intermediate by preparative chrialcel OJ column (20x250 mm, 10 μπι) in a 25-minute preparation, according to the method described for the synthesis of 艨7β and 艨- from (lS, 4S)-(+) -2-mercapto-2,5-diazabicyclo[2.2.1] heptane (2HBr) preparation "56α and 艨-76 (56. 艨-Μ: 4 NMR (DMSO-d6, δ=2.5 Ppm, 500 MHz): 7.45 (d, J=7.3 Hz, 2H), 7.27-7.19 (m, 3H), 4.09 (s, 1H), 3.34 (apparent broad single peak, 1H), 3'16 (table Viewing single peak, 1H), 2.83 (d, J=1〇"Hz, 1H), 2.71 (m, 2H), 2.46 (m, 1H), 2.27 (s, 3H), 1.77 (d, J=9.8 Hz, 1H), 1.63 (d, J = 9.8 Hz, 1H). LC/MS: [M+H]+ C14H19N202 calc.: 247.14, calc.: 247.11. 146976.doc •284- 201038558 cap-167

A solution of racemic Boc-1,3-dihydro-2H-isodecanoic acid (1·〇 g, 3.8 mmol) in 20% TFA/CH 2 C 12 was stirred at about 25 ° C for 4 hours. Vacuum removes all volatile components. The resulting crude material, a mixture of formaldehyde (15 mL, 37% in water), 1 N HCl (10 mL) and 10% Pd/C (10 mg) in MeOH was placed in a jar of H2 (40 PSI) Next 23 hours. The reaction mixture was passed through a mixture of celite and concentrated in vacuo to give a yellow foam (yield: i67 (873.5 mg). 4 NMR (DMSO-d6, δ = 2.5 ppm, 500 MHz) 7.59-7.38 (m, 4H), 5.59 (s, 1H), 4.84 (d, J=14 Hz, 1H), 4.50 (d, J=14.1) Hz, 1H), 3.07 (s, 3H). LC/MS: Anal. Calcd. Cap-168

Cap-169 prepared as described for the preparation of 艨-M7; ί - &amp;

146976.doc -285· 201038558 2-Amino-2-phenylpropionic acid hydrochloride (5.0 g, 2.5 mmol), hydrazine (15 ml, 37% in water), 1 N HCl (15 ml) A mixture of 10% Pd/C (1.32 g) in MeOH (60 mL) was placed in a pad and shaken under hydrogen (55 PSI) for 4 days. The reaction mixture was filtered through EtOAc (EtOAc)EtOAc. The residue was dissolved in MeOH and purified by reverse phase preparative HPLC (MeOH/water/TFA) to afford </RTI> as a viscous semi-solid. 4 NMR (CDC13, δ = 7.26 ppm, 500 MHz): 7.58-7.52 (m, 2H), 7.39-7.33 (m, 3H), 2.86 (br s, 3H), 2.47 (br s, 3H), 1.93 ( s, 3H). </ RTI> <RTI ID=0.0></RTI> <RTI ID=0.0></RTI> Cap-170

Add sodium carbonate to a solution of ("S>2-amino-2-(tetrahydro-2/--piperidin-4-yl))acetic acid (505 mg, 3.18 mmol; obtained from Astatech) in water (15 mL) (673 mg, 6.3 5 mmol), and the mixture was cooled to dryness, and then methyl phthalic acid methyl ester (····················· The mixture was thawed to ambient temperature. The reaction mixture was partitioned between 1 N EtOAc and ethyl acetate. The organic layer was removed and the aqueous layer was further extracted with two portions of ethyl acetate. Magnesium is dried, filtered and concentrated in vacuo to give a mp EtOAc (EtOAc: EtOAc: 1H, d, /=8.24 Hz), 3.77-3.95 (3H, m), 3.54 (3H, s), 3.11-3.26 (2H, m)5 1.82- 1.95 (1H, m), 1_41-1_55 (2H, m), 1.21-1.39 (2H, m); LC/MS: [M+H] + C9Hi6N 〇5 analysis s 舁 舁 value: 218.1, experimental value: 218.1. Cap-171

甲酯 2-(Benzaooxycarbonylamino)_2_(oxacyclobutane-3-phenyl)acetate methyl ester (200 mg, 721721_〇1; ^) by bubbling nitrogen through for 10 minutes.

Farmaco (2001), 56, 609-613) was degassed in ethyl acetate (7 ml) and cH2ci2 (4.00 ml). Next, dimethyl carbonate (0.116 m Bu 1.082 mmol) and Pd/C (20 mg '0.019 mm〇l) were added, and the reaction mixture was equipped with a hydrogen balloon, and stirred at ambient temperature overnight, at which time TLC (95: 5 CH2Cl2/MeOH: Observed by 1 g of Ce(NH4)2S04, 6 g of ammonium bismuth molybdate, 6 ml of sulfuric acid and 100 ml of water) indicates complete conversion. The reaction was filtered through celite and concentrated. Via Biotage® (loading the two gas to the 25 inlet (25 samplet); on the 25S column with digas methane (3CV) followed by 0 to 5% MeOH / dichlorodecane (250 ml) The dissolution was carried out' followed by 5% MeOH/dichloromethane (250 ml); The fractions containing the desired material were collected, and concentrated to 120 mg (yield: 81%) of methyl 2-(methoxycarbonylamino)-2-(oxetan-3-yl)acetate as a colorless oil. 1H NMR (500 MHz, chloroform-D) δ ppm 146976.doc -287· 201038558 3.29-3.40 (m, J=6.7\ Hz, 1H) 3.70 (s, 3H) 3.74 (s, 3H) 4 55 (t, J=6A\ Hz, 1H) 4.58-4.68 (m, 2H) 4.67-4.78 (m 2H) 5.31 (br s,1H). LC/MS: [M+H]+ calcd. Addition to methyl 2-(methoxycarbonylamino)_2_(oxetan-3-yl)acetate (50 mg '0.246 mm〇1)* in THF (2 mL) and water (0.5 mL) Hydrochloric acid monohydrate (10_33 mg, 0·246 mmo丨). Dissipate the passed solution overnight at ambient temperature. TLC (1:1 EA/hexane; Hanessian stain [1 g Ce(NH4)2S04, 6 g ammonium molybdate, 6 ml sulfuric acid and 100 ml water]) indicates multiplication by more than 4 约10°/. Starting material. An additional 3 mg of LiOH was added and stirred overnight, at which time TLC showed no starting material remaining. Concentrated in vacuo and placed under high vacuum overnight to give &lt;RTI ID=0.0&gt;&gt;&&&&&&&&&&&&&&&& 5ppm3.39- 3-47 (m, 1H) 3.67 (s, 3H) 4.28 (d, J=7.93 Hz, 1H) 4.64 (t, J=6.26 Hz, 1H) 4.68 (t, /=7.02 Hz, 1H ) 4.73 (d, /=7.63 Hz, 2H). Cap-172

146976.doc 201038558 The following heavy IL steps are from Barton, A.; Breukelman, S. P.;

Kaye, PT; Meakins, GD; Morgan, DJJCS Perkin / 1982, 159-164 modified: 2-amino-5-ethyl-1,3-thiazepine-4-pyruic acid methyl vinegar (186 mg , 1.0 mmol), CuS〇4*5H2〇 (330 mg, 1.32 mmol), NaCl (260 mg, 4.45 mmol) and H2S〇4 (5.5 mL) in water (7.5 mL) with stirring cold (0 ° C ) slowly added in the solution

A solution of NaN 2 (166 mg, 2.4 mmol) in water (0.6 mL). The mixture was stirred at 0 ° C for 45 minutes, and allowed to warm to room temperature, and stirred at room temperature for further 1 hour, followed by addition of CuCl (118 mg). The mixture was stirred for a further 16 hours at room temperature, then diluted with brine and extracted twice with diethyl ether. The combined organic layers were dried with EtOAc EtOAc EtOAc (EtOAc) (purity 80%) which was used directly in the next reaction. Rt=l.99 min (conditions MD1); LC/MS: [M+H]+ C7H9C1N02S Analysis calculated: 206·(Η, Experimental value: 206.05 ° Ο Cap-172 to 2-chloro-5-ethyl Add HCl (305 mg, 12.76 mmol) to a solution of thiazole-4-decanoate (175 mg) in THF / H2O / MeOH (20 mL / 3 mL / 12 mL). It was then concentrated to reduce the volume and was neutralized with aq. EtOAc (EtOAc) (EtOAc) i 72 (60 mg, 74%), which was used without further purification. 1H NMR (300 MHz, DMSO-d6) δ 146976.doc 289 - 201038558 ppm 13.03-13.42 (1H, m), 3.16 (2H, q, 7=7.4 Hz), 1.23 (3H, t, /=7.5 Hz). Rt=1.78 min(conditions]^[1)1) ; lC/MS ·· [M+H] + C6H7C1N02S analytical calculation : 191.99, experimental value: 191.99. Cap-173, step a

The following diazotization steps were modified from Barton, A.; Breukelman, SP; Kaye, PT; Meakins, GD; Morgan, DJJCS Perkin/1982, 159-164: 2-amino-5-ethyl-13 _ Thiazole-4-carboxylic acid decyl ester (186 mg '1.0 mmol) in 50% H3P02 (3.2 mL) was added NaNO2 (150 mg, 2.17 mmol) in water (1.0 ml) in a stirred cold (〇 ° C) solution. Solution in mL). Here. The mixture was stirred under stirring for an hour and allowed to warm to room temperature and stirred at room temperature for a further 2 hours. After cooling to 〇 ° C, the mixture was slowly treated with a solution of NaOH (85 mg) in water (10 mL). The mixture was then diluted with a saturated solution of NaHC(R)3 and extracted twice with diethyl ether. The organic layers were combined, dried and concentrated to give ethyl 5-ethyl-sodium succinate (yield &lt;RTI ID=0.0&gt; ), which is used directly in the next reaction. Rt = 1.5 8 min (condition 146976.doc -290- 201038558 MDl); LC/MS: [M+H]+ C7H1()N02S Analysis calculated: 172.05, Experimental value: 172.05 ° Cap-173 to 5-B Methyl thiazole-4-carboxylate (134 mg) was added to a solution of THF/H20/Me0H (18 mL/2_7 mL / 11 mL), EtOAc (281 mg, 11.74 mmol). The mixture was stirred overnight at room temperature and then concentrated to a reduced volume and neutralized with 1 &lt;RTIgt; The residue was extracted with EtOAc (EtOAc)EtOAc. iH NMR (300 MHz, DMSO-d6) δ ppm 12.74-13.04 (1Η, m), 3.20 (2Η, q, ·7=7·3 Hz), 1.25 (3Η, t,·7=7·5 Hz) . Rt = 1.27 min (Cond. MDl); LC/MS: [M+H]+ C6H8N02S Analysis: 158. Cap-174

Trifluoromethanesulfonic anhydride (5.0) was added dropwise to a cold (0 ° C) solution of methyl 3-hydroxypicolinate (2.5 g, 16.3 mmol) and TEA (2.5 mL, 18.0 mmol) in CH2C12 (80 mL) g, 18.0 mmol). The mixture was stirred at 0 ° C for 146976.doc -291 - 201038558 for 1 hour, then allowed to warm to room temperature and stirred at the temperature for an additional hour. The mixture was then quenched with aq. NaHCCb (40 mL), EtOAc (EtOAc)EtOAc. Methyl ester (i.e., Chi _ 7 74 step heteroa) (3.38 g '73°/.) (purity &gt; 95%) 'It was used without further purification. NMR (300 MHz, CDC13) δ ppm 8.72-8.79 (1 Η, m), 7.71 (1 Η, d, *7 = 1.5 Ηζ), 7.58-7.65 (1 Η, m), 4.04 (3H, s). </RTI> <RTI ID=0.0></RTI> </ RTI> <RTI ID=0.0></RTI> </ RTI> <RTIgt; CAP-174 To a solution of methyl 3-(trifluoromethylsulfonyloxy) pyridinecarboxylate (57 mg, 2.0 mmol) in DMF (20 mL), LiCl (254 mg, 6.0 mmol) Base (vinyl) tin (761 mg, 2.4 mmol) &amp; bis(triphenylphosphine)palladium dichloride (42 mg '0.06 mmol). The mixture was heated at 1 Torr: overnight. Then a KF saturated solution (2 〇 mL) was added to the reaction mixture at room temperature. The mixture was stirred for 4 hours, then passed through Celite® and washed with ethyl acetate. The aqueous phase of the filtrate was then separated and vacuumed to reduce the volume. The residue was treated with a solution of 4 tV HCl (2 mL), and the mixture was extracted with methanol &lt;&quot;&&&&&&&&&&&&&&&&&&&&&&&&& It was used without further purification. 1H NMR (300 MHz, DMSO-d6) δ ppm 8.21 (1 Η, d, *7 = 3.7 Hz), 7.81-7.90 (1Η, m), 7·09 (1Η, dd, /=7.7, 4.8 Hz), 6.98 (1H, dd, J=\1.9, 11.3 Hz), 5.74 (1H, dd 146976.doc -292- 201038558 /=17.9, 1·5 Hz), 5.20 (1H,d,·7=11.〇Hz ). Rt = 〇.39 min (conditions MD1); LC/MS: [M+H]+ C8H8N02 Analysis calculated value: 150.06 ′ Experimental value: 15 〇 〇7. Cap-175

Cap-175, step a

To the intermediate of 艨-/74, 3-(trifluoromethylsulfonyloxy)picolinate (i.e., 艨/73# 锣α) (57 mg, 2.0 mmol) in DMF (20 mL) LiCl (254 mg, 6.0 mmol), tributyl(ethenyl)stannane (761 mg '2.4 mmol) and bis(triphenylphosphine)palladium dichloride (42) were added to the solution.

Mg, 0.06 mmol). The mixture was heated at 1 °C for 4 hours, then the solvent was removed in vacuo. The residue was dissolved in acetonitrile (50 mL) and hexane (50 mL). The acetonitrile layer was then separated, filtered through celite and evaporated. The residue was purified by flash chromatography on EtOAc (EtOAc EtOAc EtOAc EtOAc Methyl picolinate (i.e., 'Chi-/75 yellow misa) (i3 mg, 40%). 4 NMR 146976.doc -293- 201038558 (300 MHz, CDC13) δ ppm 8.60 (1H, dd, J=4.6, 1.7 Hz), 7.94 (1H, d, J=ll Hz), 7.33-7.51 (2H, m ), 5.72 (1H, d, J=17.2

Hz), 5.47 (1H, d, ·7=11·0 Hz), 3.99 (3H, s). Rt=1.29 min (conditions MD1); LC/MS: [M+H]+ C9H1QN〇2 Analysis calculated: 164.07, Experimental value: 164.06 ° Cap-175, step b

To a solution of decyl 3-vinylpicolinate (120 mg, 0.74 mmol) in ethanol (10 mL) was added i. The suspension was stirred at room temperature under a hydrogen atmosphere for 1 hour, then filtered through Celite, and washed with Celite®. The filtrate was concentrated to reduce the volume to dryness to give 3-ethylpyridinium decanoate (i.e., 艨-775#, which was used directly in the next reaction. Rt = 1.15 min (conditions MD1); LC/MS: [M Analytical calculated value of +H]+ C9H12N02: 166.09, found: 166.09 ° Cap-175 to 3-ethyl acridinium decanoate in THF / H2 / MeOH (5 mL / 0.75 mL / 3 mL) To the solution was added Li〇H (35 mg, i 47 〇1). The mixture was stirred at room temperature for 2 days' followed by the addition of Li〇H (8 〇mg). After 24 hours at room temperature, the mixture was filtered. The solvent was removed in vacuo. The residue was taken in aq. EtOAc EtOAc EtOAc. Doc -294· 201038558 Used with further purification. 1H NMR (300 MHz, DMSO-d6) δ ppm 8.47 (1H, dd, j 5 Hz^ 7.82-7.89 (1H, m), 7.53 (1H, dd, 4.8 Hz ), 2.82 (2H, q, J=7.3 Hz), 1.17 (3H, t, *7=7.5 Hz). Rt==〇36 min (condition MD1) ; LC/MS : [M+H] +

Analytical calculated value of CsHmNO2: 152 〇7, experimental value: 1521 〇. Cap-176

Cap-176 \step a

To methyl 2-(phenylhydrazineoxycarbonylamino)_2_(dimethoxyphosphonyl)acetate (21.21 g '64.0 mm〇i) in 込^弘四曱基胍〇〇45 mL, 83 mmol) A solution of ι,4-dioxaspiro[4.5]decan-8-one (15 g, 96 mmol) in EtOAc (150 mL). The resulting solution was stirred at ambient temperature for 72 hours&apos; and then diluted with EtOAc (25 mL). The organic layer was washed with 1 N HCl (75 mL), H.sub.2 (100 mL) and brine (1 mL) and dried (MgSO.sub.4), filtered and concentrated. The residue was purified via EtOAc (5[Lambda] / EtOAc /EtOAc. The resulting fractions containing the product are then concentrated in vacuo and the residue is self-fired / recrystallized from Et.sub.sub.sub.sub. Snail 146976.doc -295- 201038558 [4.5] 癸-8-ylidene) White crystal of methyl acetate (6.2 g). 4 NMR (400 MHz, CDC13-c?) δ ppm 7.30-7.44 (5Η, m), 6.02 (1H, br s), 5.15 (2H, s), 3.97 (4H, s), 3.76 (3H, br s ), 2.84-2.92 (2H, m), 2.47 (2H, t, /=6.40 Hz), 1.74-1.83 (4H, m). LC (condition OL1): Rt = 2.89 min. LC/MS: calcd. calcd. Cap 176, step b

Preparation of ester cap yellow from olefin Zhiyun according to the method of Burk, Μ·J·; Gross, M_F. and Martinez JP (J. Am. Chem. Soc., 1995, 117, 9375-9376 and references) Condensation &amp;: Under the n2 layer, feed the deuterated] vieOH (200 mL) into a 500 mL still pressure bottle, followed by 7 7 (5 # poured ^ (3.5 g, 9.68 mmol). The solution was fed with tetrafluoroboric acid (_)_ 1,2_bis((2S,5S)-2,5-dimethylscale)ethane (cyclooctadiene) oxime (1) (0.108 g, 0.194 mmol), and the resulting mixture was boiled with N2 (3x) and fed to Η2 (3 χ). The solution was shaken vigorously at ambient temperature for 7 hours at 7 psi psi h2. The solvent was removed under reduced pressure and the remaining residue was dissolved. After filtration of the slightly brown solution, the solution was eluted with Et.sub.Ac. The solvent was concentrated in vacuo to give the crude oil (3 4 g) corresponding to the ester s. (500 MHz, CDCl3-d) δ ppm 7.28-7.43 (5H, m), 5.32 (1H,d,J=9.16 Hz), 5.06-5.16 (2H, m), 4.37 (1H,dd, 146976.doc - 296. 201038558 J=9.00, 5.04 Hz), 3.92 (4H, t, /=3.05 Hz), 3.75 (3H, s), 1.64-1.92 (4H, m), 1.37-1. 60 (5H, m). LC (Cond. OL1): Rt = 1.95 min. LC/MS: [M+H]+ C19H26NO6 Analysis: 364.18, Experimental value: 364.27. Cap 17 6, Step c

The ester latent 6 (4.78 g, 13.15 mmol) was dissolved in THF (15 mL), followed by water (10 mL), glacial acetic acid (26.4 mL, 460 mmol) and dichloroacetic acid (5·44 mL). 65.8 mmol). The resulting mixture was stirred at ambient temperature for 72 hours&apos; and the reaction was quenched by the slow addition of solid NasCO3 with vigorous stirring until no more gas was visible. The crude product was extracted into 10% ethyl acetate-di-methane, and organic layers were combined, dried (M.sup.4) and filtered. The resulting residue was purified via EtOAc (EtOAc EtOAc EtOAc) 4 NMR (400 MHz, CDCl3-i/) δ ppm 7.28-7.41 (5H, m), 5.55 (1H, d, J = 8.28 Hz), 5.09 (2H s), 4.46 (1H, dd, /=8.16, 5.14 Hz), 3.74 (3H, s), 2.18-2.46 (5H, m), 1.96-2.06 (1H, m), 1.90 (1H, ddd, J=12.99, 5.96 2 89 Hz), 1.44-1.68 (2H , m, /=12.36, 12.36, 12.36, 12.36, 4.77

Hz). LC (Condition OL1). Rt = i. 66 min. </ RTI> <RTI ID=0.0></RTI> </RTI> <RTI ID=0.0></RTI> 146976.doc •297· 201038558 Cap 1 7 6, step d

Add Deoxo-Fluor® (3.13 mL, 16.97 mmol) to a solution of ketone/7 (5# scale c (2.71 g, 8.49 mmol) in CH2C12 (50 mL), followed by a catalytic amount of EtOH (0.149 mL) </ RTI> </ RTI> </ RTI> <RTIgt; </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> The organic layer was filtered and dried to give a pale yellow oil.</RTI></RTI></RTI> <RTI ID=0.0></RTI> <RTIgt;艨7 7(5## white solid (1·5 g). 4 NMR (400 MHz, CDCl3-d) δ ppm 7.29-7.46 (5Η, m), 5.34 (1H, d, J=8.28 Hz ), 5.12 (2H, s), 4.41 (1H, dd, 7=8.66, 4.89 Hz), 3.77 (3H, s), 2.06-2.20 (2H, m), 1.83-1.98 (1H, m), 1.60- 1.81 (4H, m), 1.38-1.55 (2H, m). 19F NMR (376 MHz, CDCl3-〇δ ppm -92.15 (IF, d, •7=237.55 Hz), -102.44 (1F,d,/= </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; 176, step e

146976.doc • 298- 201038558 A fluorinated treatment 77 (5 steps of ί/(4 g, 11.72 mmol) was dissolved in MeOH (12 mL) and fed to Pd/C (1.247 g, 1.172 mmol). The suspension was boiled with N2 (3x) and the reaction mixture was placed under 1 atm h2 (balloon). The mixture was stirred at ambient temperature for 48 hours, then the sputum suspension was passed through diatomaceous earth and concentrated in vacuo to give Anhydrous amide/76# yeel oil (2.04 g), which was used without further purification. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.62 (3 Η, s), 3.20 (1H, d, /=5.77 Hz), 1.91-2.09 (2H, m), 1.50-1.88 (7H, m), 1.20-

1.45 (2H, m). 19F NMR (376 MHz, Ζ) Μ 5Ό-ί/6) δ ppm -89.39 (1F, d, 7 = 232.35 Hz), -100.07 (1F, d, &gt; 232.35 Hz). 13C NMR (101 MHz, DMSO-de) δ ppm 175.51 (1C, s), 124.10 (1C, t, J-241.21, 238.90 Hz), 57.74 (1C, s), 51.39 (1C, s), 39.23 (1C , br s), 32.02-33.83 (2C, m), 25.36 (1C, d, J=10.02 Hz), 23.74 (1C, d, /= 9.25 Hz). LC (Condition 〇L2): Rt = 0.95 min. </ RTI> <RTI ID=0.0></RTI> </RTI> <RTI ID=0.0></RTI> Cap 176, step f

Methyl formate (1.495 mL·' 19.30 mmol) was added to a solution of the amino acid (2 g, 9.65 mmol) and DIEA (6.74 mL '3 8.6 mmol) in CH2C12 (100 mL). The resulting solution was mixed at room temperature for 3 hours 146976.doc -299- 201038558, and the volatiles were removed. The residue was purified via Bi〇tage (〇% to 2 〇% EtOAc / hexanes). It was recovered as a clear oil (2 22 g) which solidified upon standing under vacuum and corresponded to urethane 艨-7% step. JH NMR (500 MHz, CDC13-^) δ ppm 5.27 (1Η, d, /=8.55 Hz), 4.39 (1H, dd, J-8.85, 4.88 Hz), 3.77 (3H, s), 3.70 (3H, s ), 2.07-2.20 (2H, m), 1.84-1.96 (1H, m), 1.64-1.82 (4H, m), 1.39-1.51 (2H, m) 〇19f NMR (471 MHz, CDC13-^) δ ppm -92.55 (IF, d, 7=237.13 Hz), -102.93 (IF, d, J=237.12

Hz). 13C NMR (126 MHz, CDC1W) δ ppm 171.97 (1C, s), 156.69 (1C, s), 119.77-125.59 (1C, m), 57.24 (1C, br s), 52.48 (1C, br s), 52.43 (1C, s), 39.15 (1C, s), 32.50-33.48 (2C, m)5 25.30 (1C, d, J=9.60 Hz), 24.03 (1C, d, J=9.60

Hz). LC (condition 〇Ll): Rt = i_49 min. </RTI> <RTI ID=0.0></RTI> </RTI> <RTI ID=0.0></RTI> Cap -17 6 Add [ί〇Η(0·379 g ' 15.83 mmol) to a solution of the amino phthalate 艨-776##/(2·1 g, 7.92 mmol) in THF (75 mL) The solution in water (25 mL) was stirred at ambient temperature for 4 h. The THF was removed in vacuo and the residual aqueous phase was acidified with EtOAc (2 <RTIgt; The dried (MgS04) combined organic layer was filtered and concentrated to give a white foam (1.92 g). 4 NMR (400 MHz, δ ppm 12.73 (1H, s), 7.50 (1Η, d, J=8.78 Hz), 3.97 (1H, dd, J-8.53, 6.02 Hz), 3.54 (3H, s), 1.92- 2.08 (2H, m), 1.57-1.90 (5H, m), 1.34- 146976.doc •300- 201038558

1.48 (1H, m), 1.27 (1H, qd, /=12.72, 3.26 Hz). 19F NMR (376 MHz, DMSO-d6) δ ppm -89.62 (IF, d, 7 = 232.35 Hz), -99.93 (IF, d, 7 = 232.35 Hz). LC (Condition OL2): Rt = 0.76 min. LC/MS: [MH]+ C1() H14F2N04 calc.: 250.09,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, Prepared, performed, and verified as described in O'Boyle et al., April 2005; 49(4): 1346-53. There is also a luciferin. The assay method for the enzyme reporter is also used as described (Apath.com). The currently described family of compounds was tested using HCV-neo replicon cells and replicon cells containing mutations in the NS5A region. The inhibitory activity of the compound against the mutant cell was measured to be 10 times or more smaller than that of the wild type cell. Thus, the compounds of the present invention are effective in inhibiting the function of the HCV NS5A protein quinone, and it is understood that the combination is as effective as previously described in the application PCT/US2006/022197 and commonly owned WO/O40 14852. Furthermore, the compounds of the invention are effective against the HCV lb genotype. It will also be appreciated that the compounds of the invention inhibit multiple HCV genotypes. Table 2 shows the EC5 enthalpy (50% effective inhibitory concentration) of representative compounds of the invention against the HCV lb genotype. In one embodiment, the compounds of the invention are inhibitory to the la, lb, 2a, 2b, 3a, 4a and 5a genotypes. The EC5 enthalpy against HCV lb is as follows: A (10-350 nM); Β (1-9·9 nM); C (0.1-0.99 146976.doc -301 - 201038558 nM); D(0.002-0.099 nM) ° π~ Compound number OL-1 lb EC50 (nM) Range name B (lR)-2-((2S)-2-(4-(4-(4-(2-((2S)))) -2-(dimethylamino)-2-phenylethenyl)-2-(pyridyl)-1Η-imidazol-5-yl)phenoxy)phenyl)-1Η-imidazole-2 -yl)-1-pyrrolidinyl)-N,N-dimethyl-2-oxo-1-phenylethylamine OL-2 9.1 B (lR)-2-((2S)-2-(4 -(4-(4-(2-((2S))-l-((2R)-2-hydroxy-2-phenylethyl)-2-)pyrrolidinyl)-1Η-imidazol-5-yl Phenoxy)phenyl)-1 Η-imidazole 2 -yl)-1-pyrrolidinyl)-2-yloxy-1·phenylethanol OL-3 B (oxybis(4,1-benzene) -1H-imidazole-4,2-diyl(2S)-2,l-indolepyridyldiyl ((lR)-2-yloxy-1-phenyl-2,1-ethanediyl) )) Tridecyl bis-aminoformate OL-4 0.07 D (lR)-2-((2S)-2-(4-(3-(4-(2-((2S)))) -2-(didecylamino)-2-phenylethenyl)-2-»pyrrolidyl)-1Η-imidazol-4-yl)phenoxy)phenyl)-1Η-imidazole-2- ))-1-pyrrolidinyl)-indole, fluorenyl-dimercapto-2-oxo-1-phenylethylamine OL-5 80 A (lR)-2-((2S)-2-(4- (3-(4-( 2-((2S)-l-((2R)-2-yl-2-phenethyl)-2-oxaridinyl)-1Η-imidazol-4-yl)phenoxy)phenyl) -1Η-imidazol-2-yl)-1--1-pyrrolidinyl-2-oxo-1-phenylethanol OL-6 D ((lR)-2-((2S)-2-(4- (3-(4-(2-((2S))-l-((2R)-2-((oxacarbonyl)amino)-2-phenylethyl)-2-pyrrolidinyl)-1Η- Imidazol-4-yl)phenoxy)phenyl)-1Η-imidazol-2-yl)-1-°pyrrolidyl)-2-oxo-l-phenylethyl)carbazinate OL -7 D (lR)-2-((2S)-2-(4-(4-((4-(2-(())))) -2- phenethyl)-2-pyrrolidyl)-1H-imidazol-4-yl) phenylmethyl)oxy)phenyl)-1 Η-imidazol-2-yl)-1-» Iridyl)-N,N-dimercapto-2-oxo-l-phenylethylamine OL-8 D ((lR)-2-((2S)-2-(4-(4-((4) -(2-((2S)-l-((2R)-2-((methoxycarbonyl)amino)-2-phenylethyl)-2-pyrrolidinyl)-1Η-imidazol-4-yl Phenylmethyl)oxy)phenyl)-1Η-imidazol-2-yl)-1-oxaridinyl)-2-oxo-l-phenylethyl)carbamic acid methyl ester

146976.doc -302- 201038558 Compound number lb EC5〇(nM) Range..... 1 Name OL-9 D (lR)-2-((2S)-2-(4-(4-(2-( 4-(2-((2S)-l-((2R)-2-(T^°-ylamino))-2-ylethyl)-2-°Bilyl)-1 H-flavor 11 Sodium-5-phenyl)ethyl)phenyl)-1H-imidazol-2-yl)-1 -pyrrolidinyl)2 dimethyl-2-oxo-1-phenylethylamine OL-10 D (lIU, R)-2,2,-(l,2-ethylenediylbis(4,1-extended phenyl-indole-;^? 4,2-diyl(28)-2,1-indole ratio Rhodium diyl))bis(2-o-oxy-1-phenylethanol) OL-11 D (1,2-ethylenediylbis(4,1-phenylphenyl-1 phthalimidazole-4,2-di) ;£^7 2,1-Pyrrolidinyldiyl ((lR)-2-Sideoxy-1-phenyl-2,1-ethanediyl))) Diaminodecyl decanoate OL-12 D N', N&quot;'-(1,2-Ethylenediyl(4,1-phenylene-1H-imidazol-4^7-yl (2S)-2,ln-pyrrolidinyl ((ir)- 2-sided oxy-1-phenyl_2 u ethanediyl))) bis(1-ethylglycan) ' OL-13 D 1-cyclopentyl-3-((lR)-2-((2S -2-(4-(4-(2-(4-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(((((((((((( ))-2-pyrrolidyl)-1Η-imidazole·5-yl)phenyl)ethyl)phenyl)-1Η-imidium-2-yl)-1 -pyrrolidinyl)-2-side Oxy-1 -Phenylethyl)urea OL-14 C (lR)-2-((2S)-2-(4-(4-(((())))) -(Amino)-2-phenylethenyl)-2-pyrrolidinyl)-1Η-imidazol-5-yl)benzyloxy)methyl)phenyl)-1Η-imidazole-2- ))-1-pyrrole)-Ν,Ν-dimercapto-2-oxo-1-phenylethylamine OL-15 1.1 B (lR)-2-((2S)-2-(4- (4-((4-(2-((2S))-l-((2R)-2-hydroxy_2-phenethyl)-2-n is a bite base)-1Η-Mijun-5- Benzyl)oxy)methyl)benzyl)-lH-c^e;^2-yl)-1-° piroxime-2-yloxy-1-phenylethanol OL-16 D (oxy bis(indenyl-4,1-phenylene-1H-imidazole-4,2-diyl(2S)-2,1-pyrrolidinyl ((lR)-2-yloxy) -1-phenyl-2,1-ethanediyl))) dimethyl dimethyl carboxylate OL-17 D 1-mercapto-3-((lR)-2-((2S)-2-(4) -(4-(((4-(2-(2-((2)))-((2R)-2-((methylaminomethyl)amino)-2-phenylethyl)-2-indole Birloidyl)-1Η-imidazole_5-yl)phenylhydrazinyloxy)indolyl)phenyl)-iH-imidazol-2-yl)-1 -pyrrolidinyl)-2-yloxy- 1-Phenylethyl)urea OL-18 D 1-ethyl-3-((lR)-2-((2S)-2-(4-(4-(((4-(2-((( -l-(C2R)-2-((ethylamine oxime)amino)-2-phenylethenyl)-2-pyrrolidinyl)-1Η-imi -5-yl)phenylhydrazinyloxy)methyl)phenyl)-lH-imidazol-2-yl)-1-pyrrolidinyl)-2-oxo-1-phenylethyl)urea 146976. Doc •303 - 201038558 —== — Compound No. OL-19 lb EC50 (nM) Range UK __M-„1 ,1 丨------···———— Name Β 1-Cyclopentyl-3- ((lR)-2-((2S)-2-(4-(4-(((4-(2-(()))) Amino) 2,2-phenidinyl) 2 -pyrrolidinyl)-1 -imidazol-5-yl)benzyloxy)methyl)phenyl)-1H-imidazole_2-yl)- 1 -indolepyridyl)_2_sideoxy_ 1 _phenethyl)urea OL-20 C (lR)-2-((2S)-2-(4_(3-((4-(2) -((2S)-l-((2R)-2-(dimethylamino)-2- oxaethyl)-2-indolylpyridinyl)-1H-imidazole-4.yl) Ethyl)oxy)indolyl)phenyl)-1Η-imidazol-2-yl)-1-pyrrolidinyl)-N,N-dimethyl-2-oxooxyphentamine OL-21 C ( lR)-2-((2S)-2-(4-(3-((2))))-(4-(2-(2-)) 2-°pyrrolidyl)-1Η-imidazol-4-yl)benzoyl)oxy)methyl)phenyl)-1 H-imidazol-2-yl)-1 -pyrrolidinyl)-2- Oxidyl-1-deuteroethanol OL-22 D ((lR)-2-((2S)-2-(4-(3-(((()))) )-2-((fluorenyloxy)amino group -2- phenylethyl hydrazino)-2-pyrrolidinyl)-1 Η-imidazol-4-yl)phenylhydrazinyloxy)indolyl)phenyl)-1 oxime-imidazyl)-buprolidine Methyl)-2-phenyloxy-1-phenethyl)amino decanoate OL-23 C 1-mercapto-3-((lR)-2-((2S)-2-(4-(3) -(((4-(2S)-l-((2R)-2-((methylaminoindenyl)amino)-2-phenylethyl)-2-pyrrolidinyl HH -imidazol-4-yl)phenylhydrazinyloxy)methyl)phenyl)-1 oxime-imidazol-2-yl)-1 -pyrrolidinyl)_2_sideoxy-1 -ethylidene) -24 D 1 -ethyl-3-((1 R)-2-((2S)-2-(4-(3 -((((())))) -2-((ethylaminoindenyl)amino)-2-phenylethenyl)-2-pyrrolidinyl)-1Η-imidazolyl)phenylphenyl)oxy)indolyl)phenyl) -1H_imidazole-2·yl)pyrrolidinyl-2-oxooxy-1 -ethylidene)urea OL-25 D 1-cyclopentyl-3-((lR)-2-((2S) -2-(4-(3-(((S)))-((2R)-2-((cyclopentylaminomethyl)amino)&gt; Benzyl-2-pyrrolidyl HH-imidazol-4-yl)benzyl)oxy)methyl)phenyl)-1H-imidazolidyl)pyrrolidinyl-2-oneoxy-1- Stupid ethyl)urea D-1 D (1,1 ·:4',1 triphenyl-4,4&quot;_diyl bis(1H-imidazole-4,2-diyl(2S)-2,1- »Biropyridine diyl (i r)-2-Sideoxy-1-phenyl-2,1-ethanediyl))) Didecyl dimethyl carbamate D-2 C (lR)-2-((2S)-2-(4 -(4"-(2-((2S)-l-((2R)-2-(dimethylamino)-2-phenylethenyl)-2-oxaridinyl)-1H-imidazole- 5-yl)-1,Γ:4',Γ-bitriphenyl-4-yl)-1Η-imidazol-2-yl)-1-indolylpyridinyl)-indole, fluorenyl-dimercapto-2 -Sideoxy-1 -phenylethylamine 146976.doc -304- 201038558 Compound number lb EC5〇(nM) Range name D-3 0.006 D ((lS)-l-(((2S)-2-(4- (4-((2-((2S))-l-((2S)-2-((methoxycarbonyl)amino)-3-indolyl))-2-pyryl. Stationary)-4,5-dioxime 1H-naphtho[l,2-d]imidazol-7-yl)ethynyl)phenyl)-1Η-imidazol-2-yl)-1-σ ratio 13 bites Methyl)-2-methylpropyl)amino decanoate D-4 D ((lR)-2-((2S)-2-(4-(4-((2-((2S) )-l-((2R)-2-((methoxycarbonyl)amino)-2-phenylethyl)-2-pyrrolidinyl)-4,5-dihydro-1H-naphtho[1, 2-d]imidazol-7-yl)ethynyl)phenyl)-1Η-imidazol-2-yl)-1-°pyrrolidine)-2_salyl-1-1-phenethyl)aminopurine Methyl ester D-5 D ((lR)-2-((2S)-2-(7-((4-(2-((2))))) Amino group &gt; 2-phenethyl fluorenyl-2-pyrrolidyl)-1 Η-imidazol-4-yl)phenyl)ethynyl)-1 Η-naphtho[l,2-d]imidazole- 2-yl)pyrrolidyl)-2-oxo-l-phenylethyl)carbamic acid methyl ketone D-6 D ((lS)-l-(((2S)-2-(4-( 4-((2-((2S)-l-((2S)-2-((methoxycarbonyl)amino)-3-indolyl)-yl)-pyridinyl)-1Η-naphthyl] 1,2-d]imidazol-7-yl)ethynyl)phenyl)-1Η-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-mercaptopropyl)carbazate D -7 D ((1S)-1 -(((1 R,3 S,5R)-3-(4-(4-((2-((l R,3 S,5R)-2-((2S) )-2-((methoxycarbonyl)amino)-3-methylbutanyl)-2-nitrogen Bicyclo[3·1.0]hex-3-yl)-1H-naphtho[1,2-d]imidazol-7-yl)ethynyl)phenyl)-1Η-imidazol-2-yl)-2-aza Dicyclo[3.1.0]hexan-2-yl)carbonyl)-2-mercaptopropyl)carbazate D-8 0.005 D ((1 R)-2-(( 1R,3 S,5R)- 3-(7-((4-(2-((1R,3S,5R)-2-((2R)-2-((oxacarbonyl)amino)-2-phenylethyl)-) 2-Azabicyclo[3.1.0]hex-3-yl)-1Η-imidazol-4-yl)phenyl)ethynyl)-1Η-naphtho[l,2-d]imidazol-2-yl)- Methyl 2-azabicyclo[3.1.0]hex-2-yl)-2-oxo-1-phenylethyl)carbamate D-9 D ((1S)-1 -(((1 R ,3 S,5R)-3-(7-((2-((1 R,3S,5R)-2-((2S)-2-((曱-oxycarbonyl)amino)-3-indolyl) )-2-azabicyclo[3 ·1·0]hex-3-yl)-4,5-dihydro-1H-naphtho[1,2-d]imidazol-7-yl)ethynyl)-4 ,5-Dihydro-1H-naphtho[1,2-d]imidazol-2-yl)-2-azabicyclo[3.1.0]hex-2-yl)carbonyl)-2-methylpropyl) Methyl amino decanoate D-10 D ((lS)-l-(((lR,3S,5R)-3-(7-((2-((3S)))) ((曱Oxycarbonyl)amino)-3-indolylbutenyl)-2-azabicyclo[3.1.0]hex-3-yl)-1Η-naphtho[1,2-d]imidazol-7-yl Ethynyl)-1Η-naphtho[1,2-d]imidazol-2-yl)-2-azapine [3.1.0] Methyl hex-2-yl)carbonyl)-2-mercaptopropyl)carbamate 146976.doc •305 201038558 Compound number lb EC5〇(nM) Range - -^ Name| - ... D- 11 D ((lS)-2-((lR,3S,5R)-3-(7-((2-((lR,3S,5R)-2-((2S)-2-((2S)-2-((曱ocarbonylcarbonyl) Amino)-3-indolylbutenyl)-2-azabicyclo[3.1.0]hex-3-yl)-1Η-naphtho[l,2d]imidazol-7-yl)ethynyl)-1H- Naphtho[l,2-d]imidazolium-2-yl)_2_azabicyclo[3.1.0]hex_2-yl)-2-oxo-l-(tetrahydro-2H-pyran-4- Methyl Ethyl ruthenic acid M Ml D ((lS)-l-(((2S)-2-(4-(4-(4-()))) 2S)-2-((methoxycarbonyl)amino)-3-indolylbutylidene)-2-pyrrolidinyl)-1Η-imidazol-4-yl)phenyl)ethynyl)phenyl)-iH-imidazole -2-yl)-1-. Methyl carbonyl 2-(methylpropyl) carbamic acid methyl ester M2 0.24 C (1,2-acetylenediyl bis(4,1·phenylphenyl-1H-imidazole-4,2-diyl) (2S)-2,l-&gt;&gt;pyrrolidinyl ((lR)-2-oxo-1-phenyl-2,1-ethanediyl))) bisamino phthalic acid dioxime Ester M2.1 D (1,2-acetylenediylbis(4,1-phenylene-111-imidazol-4,2-diyl(2S)-2,1-pyrrolidinyl) ((1 S) -2-Sideoxy-1 -(tetrahydro-2-indolyl-pyran-4-yl)-2,1-ethanediyl))) Didecyl dimethyl carbamate M3 D ((lS)-l-( ((lR,3S,5R)-3-(4-(4-((4-(2-(())))) -3-methylbutylidene)-2-azabicyclo[3.1.〇]hex-3-yl)-1Η-imidazolidinyl)phenyl)ethynyl)phenyl)-1Η-imidazol-2-yl) Methyl 2--2-azabicyclo[3.1.0]hex-2-yl)carbonyl)-2-methylpropyl)carbamate M4 D (1,2-acetylenediylbis(4,1-benzene) Base-1 -imidazole-4,2-diyl(111,38,511)-2-azabicyclo[3.1.0]hex-3,2-diyl((23)-1-sideoxy-1,2 -butadiyl))) dimethyl dimethyl carbamide M5 C (1,2-acetylenediyl bis(4,1-phenylene-1H-imidazole-4,2-diyl (1 Min 33,5) ))-2-azabicyclo[3.1_0]hex-3,2-diyl ((13) )-1-cyclobutyl-2-oxo-2,1-ethanediyl))) bisamino phthalic acid diacetate M6 0.0033 D (1,2-acetylene diyl bis (4,1-extension) Phenyl-1H-imidazole-4,2-diyl(1艮33,511)-2-azabicyclo[3.1.0]hex-3,2-diyl((18)-2-sideoxy_ 1 - (tetrazol-2H.pyr.beta-4-yl)-2,1-ethanediyl))) Diaminodecyl phthalate M7 D ((lS)-l-(((lR,3S,5R) )-3-(4-(4_((4-(2-(()))((2S)-2(((oxycarbonyl))amino)-2((tetrahydro-2H-) Piperidin-4-yl)ethylidene)-2-azabicyclo[3.1.0]hex-3-yl)-1Η-imidazol-4-yl) phenyl)ethynyl)phenyl)-1Η-imidazole -2-yl&gt;2-azabicyclo[3.1.0]hexan-2-yl)yl)-2-methylpropyl)carbamic acid oxime 146976.doc -306- 201038558

Compound No. lb ECs〇(nM) Range Name M8 D ((13)-1-(((111,38,511)-3-(4-气-5-(4-((4-(2-(( 38, 5R)-2-((2S)-2-((methoxycarbonyl)amino)-3-indolyl decyl)-2-azabicyclo[3.1.0]hex-3-yl)-1Η- Imidazolyl-4-yl)phenyl)ethynyl)phenyl)-1Η-imidazol-2-yl)-2-azabicyclop.1.0]hex-2-yl)carbonyl)-2-mercaptopropyl) Methyl amino decanoate M9 D ((lS)-l-(((lR,3S,5R)-3-(4- gas-5-(4-((4-(4-)-2-(( lR, 3S,5R)-2-((2S)-2-((indolylcarbonyl)amino)-3-indolylbutenyl)-2-azabicyclo[3.1.0]hex-3-yl)- 1Η-imidazol-5-yl)phenyl)ethynyl)phenyl)-1Η-imidazol-2-yl)-2-azabicyclo[3.1.0]hex-2-yl)carbonyl)-2-indenyl Propyl)methyl carbamate M9.1 D ((lS)-2-((lR,3S,5R)-3-(4-(4-((4-(4-)) ,3S, 5R)-2-((2S)-2-((indolylcarbonyl)amino)-2-(tetrahydro-2H-pyran-4-yl)ethenyl)-2-azabicyclo [3.1.0]hex-3-yl)-ex-imidazole-5-yl)phenyl)ethynyl)phenyl)-1Η-imidazol-2-yl)-2-azabi-salt [3.1.0] Hex-2-yl)-2. oxo-1 -(tetrazo-2H-lafuran-4-yl)ethyl)amino decanoate M9.2 D (1,2-acetylene diyl) (4,1-Extenophenyl (4-a-111-imidazole-5,2-diyl)(lR,3S,5R)-2-azabicyclop.1.0]hex-3,2-diyl ( (1S)-2-Sideoxy-1-(tetrahydro-2H-piperazin-4-yl)-2,1-ethanediyl))) dimethyl dimethyl phthalate M9.3 D (( lS)-l-(((lR,3S,5R)-3-(4-(4-((lS,2S)-2-(4-(2-((lR, 3S,5R)) (2S)-2-((曱Oxocarbonyl)amino)-3-indolyl decyl)-2-azabicyclo[3.1.0]hex-3-yl)-1Η-imidazol-4-yl)phenyl Methyl cyclopropyl)phenyl)-1Η-imidazol-2-yl)-2-azabicyclo[3.1.0]hexan-2-yl)carbonyl)-2-mercaptopropyl)carbamate M9 .4 D ((18,23)-1,2-cyclopropyldiylbis(4,1-phenylene-111-imidazole-4,2-diyl(lR,3S,5R)-2-aza Bicyclo[3.1.0]hex-3,2-diyl ((lS)-2-sialyl-1-(tetrazo-2H-monopyran-4-yl)-2,1-ethanediyl)) Dihydroxy dimethyl carbazate M9.5 D ((lS)-l-(((lR,3S,5R)-3-(4-(4-((lR,2R)))) 2-((lR, 3S,5R)-2-((2S)-2-((indolylcarbonyl)amino)-3-methylbutanyl)-2-azabicyclop.1.0]hex-3- -1Η-imidazol-4-yl)phenyl)cyclopropyl)phenyl)-1Η-imidazol-2-yl)-2-azabicyclo[3.1.0]hex-2-yl)carbonyl)- Methyl 2-mercaptopropyl)amino decanoate 146976.doc -307 - 201 038558 Compound No. M9.6 lbEC5〇(nM) Range name D ((1 R,2R)-1,2-cyclopropyldiylbis(4,1-phenylene-1H-imidazole-4,2-diyl) (lR,3S,5R)-2-azabicyclo[3.1.0]hex-3,2-diyl((1 S)-2- oxo-1 -(tetrahydro-2H-pyran-4) -yl)-2,1-ethanediyl))) dimethyl bis-amino decanoate M9.7 D ((lS)-l-(((2S,4S)-2-(4-(4-( (lS,2S)-2-(4-(2-((2S)4S)-l-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanyl)-4-indole Benzyl-2-pyrrolidyl)-1Η-imidazol-4-yl)phenyl)cyclopropyl)phenyl)-yl)-4-mercapto-1-indenyl 11 - mercaptopropyl) decyl carbamate M9.8 D ((18,23)-1,2-cyclopropanediylbis(4,1-phenylene-111-imidazole-4,2-diyl) ((2S,4S)-4-mercapto-2,1-pyrrolidinyl) ((lS)-2- oxo-1 -(tetrahydro-2H-pyran-4-yl)-2, 1 - ethanediyl))) dimethyl dimethyl carbamate M10 D ((lS)-l-(((2S,5S)-2-(4-(4-(4-(2-(2-(( , 5S)-l-((2S)-2-((methoxycarbonyl)amino)-3-mercaptobutyl)-5-methyl-2-pyrrolidinyl)-1Η-imidazol-4-yl) Phenyl)ethynyl)phenyl)-1Η-imidazol-2-yl)-5-fluorenyl-1-pyrrolidinyl)carbonyl)-2-mercaptopropyl)amino decanoic acid methyl D (1,2-acetylenediyl bis(4, phenylphenyl-1H-imidazole-4,2-diyl((2S,5S)-5-methyl-2,1-n-pyridyldiyl) ((2S)-1-sideoxy·1,2-butanediyl))) dimethyl dimethyl phthalate M12 D (1,2-acetylenediyl bis(4,1-extended base) 1H-imidazole-4,2-diyl((2S,5S)-5-methyl-2,1-»pyrrolidinyl)((1 S)-2- oxo-1-(tetrahydro) -2 gal pyl-4-yl)-2,1-ethanediyl))) Diamino phthalic acid didecyl ester M12.1 D ((lS)-l-(((2S,5S)-2- (4-(4-(2-S(2S,5S)-l-((2S)-2-((indolyloxy)amino)-2-(tetrahydro-2H-pyran)- 4-yl)ethinyl)-5:methyl-2-pyrrolidinyl)-1Η-imidazol-4-yl)phenyl)ethynyl)phenylHH-imidazole_2-yl)-5-methyl Methyl 1-(pyrrolidinyl)carbonyl)-2-methylpropyl)carbamate M12.2 D ((lS)-l-(((2S,4S)-2-(4-(4-( (4-(2-((2S,4S)-l-((2S)-2-((methoxycarbonyl)amino)-3-mercaptobutyl)-4-mercapto-2-pyrrolidinyl) -1Η-imidazole-4(yl)(phenyl)ethynyl)phenyl)_ih-imidazol-2-yl)-4(indolyl-1-pyrrolidinyl)-yl)-2-mercaptopropyl)amino Ethyl citrate 146976.doc •308 - 201038558 Ο 化合物 Compound number lb ECso (nM) Range name Μ 12.3 0.014 D (1,2- Acetylene diyl bis(4,1-phenylphenyl-1H-imidazole-4,2-diyl((2S,4S)-4-mercapto-2,1-pyrrolidinyl) ((lS)-2 -Sideoxy-1-(tetrahydro-2H-piperazin-4-yl)-2,1-ethanediyl))) dimethyl dimethyl carbazide Μ 12.4 D ((lS)-l-( ((2S,4S)-2-(4-(4-((4-S,4S)-l-((2S)-2-((methoxycarbonyl))) -3-methylbutyridyl)-4-mercapto-2-oxaridinyl)-1Η-imidazol-5-yl)phenyl)ethynyl)phenyl)-1H-imidazol-2-yl)-4 - mercapto-1-pyrrolidyl)carbonyl)-2-methylpropyl)carbazinate Μ12.5 D ((1 S)-l-((2S,4S)-2-(4- Gas-5-(4-((4-S4-)-((2S,4S)-l-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanyl) 4-methyl-2-indolyl)-1Η-imidazol-5-yl)phenyl)ethynyl)phenyl)-1H-imidazol-2-yl)-4-methyl-1-pyrrole Methyl pyridine)carbonyl)-2-methylpropyl)amino decanoate Μ 12.6 D ((lS)-2-((2S,4S)-2-(4-(4-((4-) 4-a-2-((2S,4S)-l-((2S)-2-((methoxycarbonyl)amino)-2-(tetrahydro-2H-pyran-4-yl)ethenyl )-4-mercapto-2-°pyrrolidyl)-1Η-imidazol-5-yl)phenyl)ethynyl)phenyl)-1 H-imidazol-2-yl)-4-methyl-1 - oxaridinyl)-2-yloxy-1-(tetrahydro-2 Η-π 喃 -4- Ethyl)ethyl) carbamic acid oxime Μ 12.7 0.061 D (1,2-acetylenediyl bis(4,1-phenylene (4-a-1 Η-imidazole-5,2-diyl) (( 2S,4S)-4-methyl-2,1-»pyrrolidinyl)((lS)-2- oxo-l-(tetrahydro-2H-hamo-4-yl)-2, 1-Ethylenediyl))) Didecyl biscarbamate Μ 12.8 D ((lS)-2-((2S,4S)-2-(4-(4-((4-(2-(( 2S,4S)-l-((2S)-2-((methoxycarbonyl)amino)-3-methylbutylindolyl)-4-methyl-2-pyrrolidinyl)-1Η-imidazole_4·yl Phenyl)ethynyl)phenyl)-1Η-imidazol-2-yl)-4-mercapto-1-pyrrolidinyl)-2-yloxy-1-(tetrahydro-2H-pyran-4 -ethyl)ethyl)amino decanoate Μ 12.9 D ((1S)-1-(((1S,3S,5S)-3-(4-(4-((4-(2-(( 1S,3Ss5S)-2-((2S)-2-((indolylcarbonyl)amino)-3-indolylbutenyl)-5-indolyl-2-azabicyclo[3.1.0]hex-3- -1Η-imidazol-4-yl)phenyl)ethynyl)phenyl)-1Η-imidazol-2-yl)-5-indolyl-2-azabicyclo[3.1 ·0]hex_2-yl Methyl carbonyl)-2-methylpropyl)amino decanoate 146976.doc -309 - 201038558 Compound number lb EC50 (nM) Range name M13 D l丨丨一丨· ((1 S)-1 -( ((1 R,3 S,5R)-3 -(4-(4-((E)-2-(4-(2-(())))) -(( Oxymethyl)amine methylbutenyl)·2_azabicyclo[3·1·0]hex-3-yl)-lHH4-yl)phenyl)ethenyl)phenylHH-flavor-2-yl) -2-Azabicyclo[3丄〇]hex-2-yl)indenyl)-2-methylpropyl)carbamic acid formic acid M14 0.017 D ((E)-l,2-ethylenediylbis(4 , 1-phenylene-1Η-amidole, 4,2-diyl (lR,3S,5R)-2-azabicyclo[3.1.0]hex-3,2-diyl ((lS)-2 - pendant oxy-1-(tetrahydro-2H-piperazin-4-yl)_2,1-ethanediyl))) bis-amino decanoic acid M15 D ((lS)-2-((lR ,3S,5R)-3-(4-(4-((E))(4-(2-((lR,3S, 5R))-2-((2S)-2-((methoxycarbonyl) Amino)-3-mercaptobutyryl)_2_azabicyclo[3.1.0]hex-3-yl)-1Η-imidazolium)phenyl)vinyl)phenyl)-1H-imidazole_2-yl ) 2_2 azabicyclo[3.1.〇]hex_2_yl)-2-oxo-l-(tetrahydro-2H-piperazin-4-yl)ethyl)carbazate N1 D (( lS)-l-(((2S)-2-(4-(4-(4-())))) Oxycarbonyl)amino)-3-methylbutyryl)-2-pyrrolidyl)-1H-imidazol-4-yl)phenyl)ethynyl)phenyl)-1Η-imidazol-2-yl)-4 , 4-diqi-1-° piroxime) alkyl)-2-mercaptopropyl)amino decanoate N2 D ( Alkyn-1,2 diyl bis(4,1-extended base-1 zamidazole-5,2-diyl((2S)-4,4-difluoropyrrolidine-2,1-diyl) (( 1 S)-2-Alkyloxy-1 -(tetrazo-2H-0 bottom 0 -4-yl)ethyl-2,1-diyl))) dimethyl dimethyl phthalate N3 0.25 A ( (lR)-2-((2S)-2-(5-(4-(4-((2S))))) Oxycarbonyl)amino)-2-(tetrahydro-2H-piperidin-4-yl)ethenyl)pyrhodin-2-yl)-1Η-imidazol-5-yl)phenyl)ethynyl) Phenyl)-1Η-imidazole-2·yl)-4,4-difluoropyrrolidin-1-yl)-2-oxo-l-(tetrahydro-2H-nivine-4-yl)ethyl Amino decanoic acid N4 0.18 A (acetylene-1,2 diyl bis(4,1-phenylphenyl-1H-imidazole-5,2-diyl((2S)-4,4-difluoro) Pyrrolidine-2,1-diyl)((lR)-2-o-oxy-1-(tetrahydro-2Η-π&gt;^^-4-yl)ethyl-2,1-diyl))) Aminoguanidine phthalate-310- 146976.doc 201038558 Compound number lb EC50 (nM) Range name N5 D ((lS)-l-(((3S)-3-(4-(4-((4- (2-((3S)-4-((2S)-2-((曱Oxycarbonyl))amino)-3-indolyl)indolyl)-3-morpholinyl)-1Η-imidazol-4-yl)benzene Ethyl ethynyl)phenyl)-1 Η-imidazol-2-yl)-4-morpholinyl)carbonyl)-2-mercaptopropyl)carbamic acid methyl ester N6 A ((l S)-l-(((2S)-2-(4-(4-(4-(())))) 3-mercaptobutyl)-2-piperidinyl)-1Η-imidazol-4-yl)phenyl)ethynyl)phenyl)-1Η-imidazol-2-yl)-1-piperidinyl)carbonyl)- Methyl 2-methylpropyl)amino decanoate N7 D ((lS)-l-(((2S,4S)-4-hydroxymethoxycarbonyl)amino)-3-methylbutanyl)-2- . Biryridyl)-1Η-imidazol-4-yl)phenyl)ethynyl)phenyl)-1H-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-methylpropyl)amine Methyl decanoate N7.1 ((lS)-l-(((2S)-2-(4-(4-(()))) ((Methylhydrazinecarbonyl)amino)-3-methylbutyryl)-4-methylene-2-pyrrolidinyl)-1H-imidazol-4-yl)phenyl)ethynyl)phenyl)-1Η- Methyl imidazol-2-yl)-4-ylidene-1-pyrrolidinyl)carbonyl)-2-mercaptopropyl)carbamate N7.2 ((lS)-l-(((2S,4R) )-4-hydroxy-2-(4-(4-((4-(()))))) -3-methylbutanyl)-2-»pyrrolidyl)-1Η-imidazol-4-yl)phenyl)ethynyl)phenyl)-1H-imidazol-2-yl)-1-pyrrolidine Methyl)carbonyl)-2-mercaptopropyl)carbamic acid methyl ester N8 A ((lS,3S,5S)-3-(4-(4-((4-(2)) -((lS,3S,5S)-2-((2S)-2·((曱Oxycarbonyl)amino)-3-methylbutanyl)-2-azabicyclo[3.1.0]hex-3- -1Η-imidazol-4-yl)phenyl)ethynyl)phenyl)-1Η-imidazol-2-yl)-2-azabicyclo[3.1.0]hex-2-yl)carbonyl)-2 -methylpropyl)amino decanoate N9 D (1,2-acetylenediyl bis(4,1-phenylene-1H-imidazole-4,2-diyl (lS,3) S,5S)-2-azabicyclo[3.1.0]hex-3,2-diyl ((lS)-2- oxirane-1-(tetrazo-2Η-α^σ南-4-yl) )-2,1-Ethylenediyl))) Didecyl biscarbamate J1 D ((lS)-l-(((2S)-2-(4-(3-((3-(2-(2- (2S)-l-((2S)-2-((methoxycarbonyl)amino)-3-methylbutylindolyl)-2-pyrrolidinyl)-1Η-imidazol-4-yl)phenyl)ethynyl )phenyl)-1Η-imidazol-2-yl)-lDpyrrolidyl)carbonyl)_2-mercaptopropyl)carbazyl methacrylate 146976.doc •311 · 201038558 Compound number lb EC50 (nM) Range name J1.1 338.8 A ((lS)-2-mercapto-l_(((2S)-2-(4-(3-()))) 1Η-imidazol-4-yl)phenyl)ethynyl)phenyl)-1Η-imidazol-2-yl)-1-oxaridinyl)carbonyl)propyl)amino decyl decanoate J2 0.12 C (1 ,2-ethynyldiylbis(3,1-phenylene-1H-imidazole-4,2-diyl(2S)-2,l-°pyrrolidinyl ((lS)-2-yloxy 1-(tetrahydro-2H-piperazin-4-yl)-2,1-ethanediyl))) dimethyl dimethyl phthalate J3 D ((lS)-l-(((lR,3S) ,5R)-3-(4-(3-((3-(2-(()))))曱 醯 醯 )))-2-heterobicyclo[3.1.0]hex-3-yl)-1 Η-imidazol-4-yl)phenyl)ethynyl)benzene Base)-1Η-imidazol-2-yl)-2-azabicyclo[3.1.0]hex-2-yl)carbonyl)-2-mercaptopropyl)amino decanoate J4 D (1,2 - acetylene diyl bis(3,1-phenylene-1H-imidazole-4,2-diyl(1 R,3 S,5R)-2-azabicycloindole 1 ·0]hex-3,2- Dikis((1 S)-2-o-oxy-1-(tetrahydro-2H-piperidin-4-yl)-2,1-ethanediyl)))diaminocarbamate J5 D ( (lS)-l-(((2S)-2-(4-(4S)-l-((2S)-2-((2O))) Base) _3-mercapto-butyryl)-1Η-σ米n-4-yl)phenyl)ethynyl)-4-biphenyl)-1H-imidazol-2-yl)-1pyrrolidine Ethyl carbonyl)-2-methylpropyl)amino decanoate The compounds of the invention may inhibit HCV via a mechanism other than or in addition to inhibition of NS5A. In one embodiment, a compound of the invention inhibits an HCV replicon; and in another embodiment, a compound of the invention inhibits NS5A. It is obvious to those skilled in the art that the present invention is not limited to the foregoing illustrative examples, and the present invention may be embodied in other specific forms without departing from the basic attributes thereof. It is intended that the present invention be construed as being limited to the scope of the claims Inside. 146976.doc -312-

Claims (1)

201038558 VII. Patent application scope: 1. A compound of formula (1) (1), 0 or a pharmaceutically acceptable salt thereof, wherein: L is selected from the group consisting of -〇_, _CH2cH2_, _CH = CH_, _c = c X is hydrogen (H) or halogen and Z is hydrogen; or X and Z together with the carbon atom to which they are attached form 5 to 8 member aromatics containing, as the case may be, or 2 heteroatoms independently selected from nitrogen, oxygen and sulfur. a quaternary or non-cylinder fused ring; wherein the 5 to 8 member is optionally substituted with hydrazine, 2 or 3 substituents independently selected from the group consisting of an alkoxy group, an alkoxyalkyl group, a pyrocarbonyl group, an alkyl group, Alkylsulfonyl, aryl, arylalkyl, aryl rutyl, sulfo, aryl, aryl, dentate, dentate, thiol, ruthenium, _NRaRb, NRaRb), (NRaRb), oxo and spiro; X' is hydrogen (H) or halogen and B is hydrogen; or X, and z' Included as a case μ 146976.doc 201038558 {5 to 8 membered aromatic or non-aromatic fused rings independently from nitrogen, oxygen and sulfur heteroatoms; wherein the 5 to 8 members are treated as 丨, 2 or 3 Li = substituted by the following substituents: alkoxy, alkoxyalkyl, calcined, alkyl, alkyl aryl, aryl, arylalkyl, aryl sulfhydryl, carboxyl, formazan Base, halo, haloalkoxy , haloalkylhydroxy, hydroxyalkyl, -NRaRb, (NRaRb)alkyl, (NR Rb)carbonyl, pendant oxy and spiro; Y and Y, each independently _CIV, _CH2CH2i1CH2 〇, of which 5 hai - CH2〇_ is depicted by way of an oxygen atom bonded to a carbon atom substituted by Rv and Rq or Rv· and Rq; RP is hydrogen or (^ to decyl; Rq is hydrogen, alkyl or halo; R and R together with the carbon atom to which they are attached form a cycloalkyl ring, the core is selected from the group consisting of hydrogen, alkyl, halo and thiol; or R and Rq together with the carbon atom to which they are attached form a vinyl or cycloalkyl group Ring; Rp is hydrogen or (^ to (4) alkyl; Rq is hydrogen, alkyl or halo; or R and Rq together with the carbon atom to which they are attached form a cycloalkyl ring; R: is independently selected from hydrogen , alkyl, halo and hydroxy; or R and R together with the carbon atom to which they are attached form a vinyl or cycloalkyl ring; R and Rw are independently selected from hydrogen and alkyl; R1 is hydrogen or -C(〇 Rx; 146976.doc 201038558 R2 is hydrogen or -C(〇)Ry; γ Rx and Ry are independently selected from the group consisting of a cycloalkyl group, a heteroaryl group, a heterocyclic group, a methoxy group, and an alkyl group. One or more independent a substituent selected from the group consisting of an aryl group, an alkenyl group, a cycloalkyl group, a heterocyclic group, a heteroaryl group, -OR3, -C(〇)〇R4, _NRaRb, and c(〇)NRCRd, any of which The base and heteroaryl group may be optionally substituted with one or more substituents independently selected from the group consisting of alkenyl, alkyl, alkyl, aromatic Alkyl, heterocyclyl, heterocyclylalkyl, halogen, cyano, nitro, -C(9)OR4, _〇R5, Rb, (10) anthracenyl and (10)(7)(Η0)Ρ(0)0-, and Any of the cycloalkyl and heterocyclic groups may be fused to the aromatic ring as appropriate, and may be optionally substituted with one or more substituents independently selected from the group consisting of alkyl, hydroxy, halo, aryl, _NRaRb, side. Mercapto and -C(0)OR4 ; ^ R3 is hydrogen, alkyl or arylalkyl; R4 is an alkyl or aryl sulfonyl group; R is n, affinity or arylalkyl; Ra and Rb are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, arylalkyl, heteroaryl, _C ( 0) R6, -C(0)0R7, -C(0)NRCRd&amp;(NReRd)alkyl' or, Ra&Rb, together with the nitrogen atom to which it is attached, form a 5 or 6 membered ring or bridged bicyclic structure, wherein The $ or 6 membered ring or bridged bicyclic structure may optionally contain deuterium or two other heteroatoms independently selected from nitrogen, oxygen and sulfur, and may contain i, 2 or 3 substituents independently selected from: ( ^ to decyl, (^ to (: 4-haloalkyl, aryl, via 146976.doc 201038558, &lt;^ to (:6 alkoxy, (^ to (:4 haloalkoxy) and halogen; R6 is an alkyl group; R is an alkyl group, an arylalkyl group, a cycloalkyl group or a ?alkyl group; and Re and ... are independently selected from the group consisting of hydrogen, an alkyl group, an arylalkyl group and a cycloalkyl group. The compound of claim 1 is further characterized by the formula (Ia): 2 Z' (la), or a pharmaceutically acceptable salt or tautomer thereof, wherein: X is hydrogen or gas (ci) and z is hydrogen; or X and Z together with the carbon atom to which they are attached 6 An aromatic or non-aromatic fused ring; X is hydrazine or chlorine (C1) and Z' is hydrogen; or X and Z together with the carbon atom to which they are attached form a 6-membered aromatic or non-aromatic fused ring; , -CHsCH2· or -CH2〇-, wherein the _CH2 oxime is formed by combining an oxygen atom with a carbon atom substituted by IT and Rq / Rp is hydrogen or (^ to (: 4 alkyl; Rq is chlorine) Or an alkyl or haloalkyl group; or Rp and a carbon atom to which it is attached, form a cyclofilament; and R is selected from the group consisting of hydrogen, alkyl, yl and hydroxy; or 146976.doc 201038558 Rv and hydrazine are attached thereto The carbon atoms together form a vinyl or cycloalkyl ring. 3. The compound of claim 2, further characterized by the formula (丨匕): Y vi 或其 or a pharmaceutically acceptable salt or tautomer thereof. 4. The compound of claim 2, further characterized by formula (Ic) 5. The compound of claim 2, further characterized by the formula (id) or a pharmaceutically acceptable salt or tautomer thereof. Ο N^A X', •LO (Id), or a pharmaceutically acceptable salt or tautomer thereof. 6. The compound of claim 2, or a pharmaceutically acceptable salt or tautomer thereof, wherein: R1 is -C(0)Rx; R2 is -C(0)Ry; 146976.doc 201038558 one - NRaRb substituted alkyl, the specific Rx and R/ are independently characterized by at least formula (A): RVb (A), wherein: m is 0 or 1; R8 is hydrogen or alkyl; R is selected from the group consisting of hydrogen, cycloalkyl, aryl, heteroaryl, heterocyclyl and alkyl; the alkyl is selected as appropriate Substituted from the following substituents: aryl, alkenyl, cycloalkyl, heterocyclyl, heteroaryl, heterobicyclo...OR3, -C(0)〇R4, _NRaRb, and _c(〇)NRCRd any of which The aryl and heteroaryl groups may be optionally substituted with or a plurality of substituents independently selected from the group consisting of: a base group, an alkyl group, an aryl group, a heterocyclic group, a heterocyclic group, a dentate, a cyanogen , Schiffki, -c(9)(10), collar 5, _NRaRb, (take aRb) alkyl (HO)P(〇)〇_, and any of the ring and heterocyclic groups may be fused to the aromatic ring as appropriate, and visible In the case where - or a plurality of substituents independently selected from the group consisting of a substituent, a substituent, a halogen, an aryl group, a -NRaRb, a pendant oxy group, and -C(〇)〇R4; and R3, R4, R5, Ra, Rb, RlRdwf_m^. The compound of claim 6 or a pharmaceutically acceptable salt thereof or the interconversion 146976.doc 201038558 isomer, wherein: m is ο ; R 8 is hydrogen or (^ to ^ alkyl; R is selected from hydrogen, C i to C6 alkyl substituted by the following: Ο • OR, C3 to C6 cyclohexyl, dilute propyl, _cH2c: (〇)NRcRd, (R1V a (R1\ (NW) alkyl (R1〇) n S\^N Lv (R1〇)n No (R' (R10), (R1〇)n R11-N (R10), 〇ν~λί' (R1〇Vn, /, and, Ο where j is 0 or 1; k is 1, 2 or 3; n is 〇 or an integer selected from 1 to 4; each R10 independently Is hydrogen, (^ to (: 4 alkyl, (^ to (: 4 haloalkyl, halogen, nitro, -OBn or (Me0) (0H) P (0) 0-; Rl1 is hydrogen, C ^ C4 Alkyl or phenylhydrazine; R is hydrogen, (^ to decyl or benzyl; Ra is hydrogen or CdC4 alkyl; ^ is ^ to alkyl, C3 to C6 cycloalkyl, phenyl fluorenyl, 3 -. pyridine 146976.doc 201038558 amide 疋 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 或 或 或 或 或 或 或 或 或 或 或 或 或 或 或 或: 4 haloalkyl; RC is hydrogen or ci to C4 alkyl; and Rd is hydrogen, C1 to C4 alkyl or c3 to (:6 cycloalkyl. 8. The compound of claim 6, or its medicinal Acceptable scales or tautomers wherein: m is hydrazine; R8 is hydrogen; R9 is phenyl, optionally substituted with from 1 to 5 substituents independently selected from the group consisting of: (^6) , (^ to (: 4 haloalkyl, halogen, c 丨 to C6 calcining base, thiol, cyano and nitro; and NRaRb is a heterocyclic or heterobicyclic group selected from: (R13)n, / Λ! -N n-r14 +〇(R13)v Bu N3(Rl3)n Wherein η is ο, 1 or 2; each R13 is independently selected from (^ to (6 alkyl, phenyl 'trifluoromethyl, halogen, hydroxy, decyloxy and pendant oxy; and R1 is (^) a group of a 6 alkyl group, a phenyl group, a phenyl fluorenyl group or a _c(〇) 〇 Rl5 group, wherein R is a Ci to C4 alkyl group, a phenyl group or a benzyl group. 9. The compound of claim 6, or Pharmaceutically acceptable salts or tautomers 146976.doc 201038558 Isomers, which m· is m; [; R8 is hydrogen; R is G to C: 6 alkyl, arylalkyl or heteroarylalkane And a compound of claim 2, or a pharmaceutically acceptable salt or isomer thereof, wherein: R1 is - C(0)Rx; R2 is -c(o)Ry; ^ and Ry are heteroaryl or heterocyclic groups independently selected from the group consisting of: 146976.doc 201038558 wherein η is 0 or an integer selected from 1 to 4; each R13 is independently selected from the group consisting of hydrogen, ^ to decyl, ^ to haloalkyl, phenyl, benzyl, CjCe alkoxy , CjC4_decyloxy, heterocyclic, halogen, NR Rd, hydroxy, cyano and pendant oxy, wherein ... and Rd are independently hydrogen or (^ to (^4 alkyl; and R14 is hydrogen (H) , Ci to C6 alkyl, benzyl or _c(〇) 〇 R4, wherein "for the heart to ^ alkyl. 11. The compound of claim 2, or a pharmaceutically acceptable salt or tautomer thereof a construct, wherein: R1 is -c(o)rx; R2 is -c(o)Ry; R and Ry are cycloalkyl groups independently selected from the group consisting of: Wherein j is 0, 1, 2 or 3; k is 〇, 1 or 2; n is 〇 or an integer selected from 1 to 4; each R 3 is independently selected from hydrogen, (^ to decyl, ^ to匕 haloalkyl, Cl to h alkoxy, dentate, hydroxy, cyano and nitro; and / and ! are each independently hydrogen, (^ to decyl or _c (〇) 〇 R7, wherein R7 is a compound of &lt;^ to (6 alkyl). The compound of claim 2, or a pharmaceutically acceptable salt thereof or tautomer 146976.doc -10- 201038558 isomer, wherein: R1 is -C (0) Rx; R2 is -C(0)Ry; Rx&amp;Ry is independently arylalkyl, wherein the aryl portion of the arylalkyl group is optionally substituted with (NRaRb)alkyl; and Ra and Rb are independently hydrogen, (^ to decyl or phenyl) Or, Ra and Rb together with the nitrogen atom to which they are attached form a ring selected from the group consisting of K3,, -〇, (- 6th member N-R15 and R15 hydrogen thereof, &lt;^ to (6 alkyl or benzene) The compound of claim 2, or a pharmaceutically acceptable salt or isomer thereof, wherein: R1 is the same as R2 and is selected from the group consisting of: 201038558 The wave opening in the eight-in, Q-structure &gt; key (...) indicates that the stereo-symmetric center to which the key is connected can be in the (8) or (S) configuration as long as it does not violate the principle of chemical bonding, ie, &quot;5J* 〇14. 15 16. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein: R8 is -C(0)Rx; R2 is -c(o)Ry; and 1^舆1^ It is a third butoxy group. The compound of claim 1 or its pharmaceutically acceptable _R1 and R2 are both hydrogen. Now, 肀 a compound of formula (II), L is selected from the group consisting of -〇-, _CH2CH2-, -CH=CH-, _CsC, -BuY-OCH2-'-CH20-'-CH2OCH2-X and X' is independently hydrogen (Η) or halogen 146976.doc -12· 201038558 is hydrogen or q to C4 alkyl, and Rq is hydrogen, or Rl^Rq together with the carbon atom to which it is attached forms a cyclopropyl ring; Rp is hydrogen or (^ to (:4 alkyl) Rq, which is hydrogen, or, rp, and Rq, together with the carbon atom to which it is attached, forms a cyclopropyl ring; R1 is hydrogen or -C(〇)Rx; R2 is hydrogen or -C(o;)Ry; Rx and Ry is independently selected from the group consisting of a ring-based group, a heteroaryl group, a heterocyclic group, a deuterated group, and an alkyl group substituted with one or more substituents independently selected from the group consisting of an aryl group, an alkenyl group, and a ring. Alkyl, heterocyclic, heteroaryl, -OR3, -C(〇)〇R4, _NRaRb, and c(〇)NRCRd wherein any of the aryl and heteroaryl groups may be independently selected from one or more independently Substituted substituents: affinity, cardinyl, arylalkyl, heterocyclyl, heterocyclyl, dentate, aryl, nitro, -C(9)OR4, Vision 5, aRb, (10)aRb) &amp; And (MeO)(HO)P(〇)〇_, and any of the cycloalkyl groups and The ring group may optionally be fused to the aromatic ring and optionally substituted with one or more substituents independently selected from the group consisting of alkyl, perylene, _, aryl, _NRaRb, pendant oxy and -C ( 0) OR4; R3 is hydrogen, alkyl or arylalkyl; R is alkyl or arylalkyl; R5 is hydrogen, alkyl or arylalkyl; Ra and Rb are independently selected from hydrogen, alkyl , cycloalkyl, arylalkyl, heteroaryl, -C(0)R6, _C(0)〇r7, _c(〇)NRCRd&amp;146976.doc •13- 201038558 (NRR into the base 'or 'RlRb and its The nitrogen atom to which it is attached - which is a 5 or 6 membered or bridged bicyclic structure wherein the 5 or 6 membered ring or bridge 1 double ring structure optionally contains - other heteroatoms independently selected from nitrogen, oxygen and squash And may contain hydrazine, 2 or 3 substituents independently selected from the group consisting of C. to C6 alkyl, CjC4 haloalkyl, aryl, hydroxy, (^ to 匸6 alkoxy, (^ to. And alkoxy and halogen; a compound' or its medicinal The salt accepted is selected from the group consisting of: (lR)-2-((2S)-2-(4-(4-(4-(2-((2))))) 2-(Dimethylamino)-2-phenylethenyl)-2-° ratio "each bite group" -1 Η-imidol-5-yl)phenoxy)phenyl)-1 Η-mi. -2,N-dimercapto-2-oxo-i-phenylethylamine; (lR)-2-((2S)-2-(4- (4-(4-(2-((2S))-l-((2R)-2-yl-2-ylethylidene)-2-° ratio thiol)-1Η-imidazole-5-yl Phenoxy)phenyl)-ih-imidazol-2-yl)-1-pyrrolidinyl)-2-oxo-1-phenylethanol; (oxybis(4,1-phenylene-1H-) Imidazole-4,2-diyl(2S)-2,ln-pyridyldiyl((lR)-2-yloxy-1-phenyl-2,1-ethanediyl))) bis-aminocarboxylic acid Dimethyl ester; (lR)-2-((2S)-2-(4-(3-(4-(2-((2S))-l-((2R)-2-(didecylamino)) -2- phenethyl)-2-pyrrolidyl)-1Η-imidazol-4-yl)phenoxy)benzene 146976.doc -14· 201038558 base)-1Η-imidazol-2-yl)- L-'I-pyridyl)-N,N-dimethyl-2-oxooxy-1_phenethylamine; (lR)-2-((2S)-2-(4-(3-(4) -(2-((2S)-l-((2R)-2-yl-2-phenylethenyl)-2-.pyridyl)-1Η-imidazol-4-yl)phenoxy) Phenyl)-1Η-α-carbazol-2-yl)-1-11-pyridyl)-2-oxo-1-phenylethanol; ((lR)_2-((2S)-2-(4 -(3-(4-(2-((2S))-l-((2R)-2-((methoxy)amino)-2-phenylethyl))) ))-1Η-imidazol-4-yl)phenoxy)phenyl)-1Η-imidazol-2-yl)-1-°pyrrolidyl)-2-oxo-1·phenethyl)amine Methyl decanoate; (lR)_2-((2S)-2-(4-(4-((4-(2-(2)))) (2)-phenyl-phenylacetate)-2 - nfcb alkalyl)-1Η-°m ββ-4-yl)benzyloxy)phenyl)-1Η-imidazol-2-yl)-1 -&quot;pyrrolidyl)-oxime, fluorene-dimethyl-2-oxo-l-phenylethylamine; ((lR)-2-((2S)-2-(4-(4-( (4-(2-((2S)-l-((2R)-2-((methoxy))))))))) ^ °-4-yl)benzyloxy)phenyl)-1Η-imidazol-2-yl)-1-»pyrrolidyl)-2-oxophenethyl)amino decanoic acid Methyl ester; (lR)-2-((2S)-2-(4-(4-(2-(4-(4-(2-)))) Benzyl)-2-phenylethenyl)-2-«pyrrolidyl)-1Η-imidazol-5-yl)phenyl)ethyl)phenyl)-1Η-imidin-2-yl)-1- ° 比 σ 定 base) - N, N- dimethyl 2 - pendant oxy-1- phenylethylamine; (111, 1 '1 〇 -2, 2 '- (1, 2- ethanediyl bis ( 4,1-Extended Phenyl-1 Zami Sex Salivation _4,2· Diyl (2S)-2,l-«Byrrolidine II )) bis(2-o-oxy-1-phenylethanol); (1,2-ethylenediylbis(4,1-phenylphenyl-1H-imidazole-4,2-diyl 146976.doc -15-) 201038558 ° ratio n 唆diyl ((lR)-2-sided oxy-1-phenyl_2,1_ethanediyl))) didecyl dimethyl carbamate; Ni, N'''-( l,2-Ethylenediylbis(4,1-phenylene-1H-imidazole-4,2-diyl(2S)-2,1-pyrrolidinyl ((lR)-2-yloxy-1 Phenyl-2, 丨-ethanediyl))) bis(1-ethylurea); 1-cyclopentyl-3-((lR)-2-((2S)-2-(4-(4) -(2-(4-(2-((2S))-l-((2R)-2-((cyclopentylaminomethyl)amino)-2-phenylethenyl)_2_d) -1Η-imidapy-5-yl)phenyl)ethyl)phenyl)-iH-imidin-2-yl)-indole-πpirobityl)-2-ylideyl-1-phenethyl ) (lR)-2-((2S)-2-(4-(4-(((())))) -2 - phenylethyl ketone) - 2 ° ratio 11 π base) -1 Η - σ4 ^ sal-5-yl) phenyl hydrazino) oxy) methyl) phenyl) - 1 Η - σ 嗤-2-yl)-1 -.比, Ν-dimercapto-2 - oxo-1 -phenethylamine, (lR)-2-((2S)-2-(4-(4-(((4- (2-((2S)-l-((2R)-2-]-yl-2-phenylethenyl)-2-.pyrrolidyl)-1Η-imidazol-5-yl)phenyl)oxyl Methyl)phenyl)-1Η-imidazol-2-yl)-1-pyrrolidyl)-2-oxo-1-phenylethanol; (oxy bis(methylene-4,1-) Phenyl-1H, imidazole-4,2-diyl(23)-2,1-° ratio 11 (1^)-2-yloxy-1-phenyl-2, 1-Ethylenediyl))) dimethyl dimethyl carbamate; 1-mercapto-3-((lR)-2-((2S)-2-(4-(4-(((4-(2) -((2S)-l-((2R)-2-((methylaminomethyl)amino)-2- phenylethyl)-2-&quot;pyrrolidyl)-iH-imidazole- 5-yl)benzyl)oxy)methyl)phenyl)-1Η-imidazol-2-yl)-1-indolyl sigma) -2- 2-mercapto-1 -phenethyl) gland, 1 -ethyl-3-((lR)-2-((2S)-2-(4-(4-(((())))) - 201038558 -2-((ethylaminoindenyl)amino)-2-phenylethenyl)-2-pyrrolidinyl)_ih-imidazol-5-yl) phenylmethyl)oxy)indolyl) Phenyl)-1Η-imidazol-2-yl)-1-oxaridinyl)-2-side oxygen -1-phenethyl)urea; 1-cyclopentyl-3-((lR)-2-((2S)-2-(4-(4-(((((((((((((((( 1-((2R)-2-((cyclopentylaminomethyl)amino)-2-phenylethenyl)-2-.pyrrole.Deuterated)-1Η-imidazole-5-yl)phenylhydrazine (yl)oxy)methyl)phenyl)-1Η-imiva-2-yl)-1-°pyrrolidyl)-2-oxo-1-phenylethyl)urea; (lR)-2 -((2S)-2-(4-(3-(((4-(2-(2-))))) -2-°pyrrolidyl)-1Η-imidazol-4-yl)phenylhydrazino)oxy)indolyl)phenyl)-1Η-mimi"--2-yl)-1-° ratio D N-N-dimethyl-2-oxo-1-phenylethylamine; (lR)-2-((2S)-2-(4-(3-(((4-(2) -((2S)-l-((2R)-2-yl-2-phenylethyl)-2-pyrrolidinyl)-lH-imidazol-4-yl)phenylhydrazine)oxy)methyl Phenyl)-1 Η-imidazol-2-yl)-1-pyrrolidyl)-2-oxo-1-phenylethanol; ((lR)-2-((2S)-2-(4- (3-((4-(2-((2S))-l-((2R)-2-((methoxycarbonyl)amino)-2-phenylethenyl)-2-&quot;pyrrolidyl )-1Η-imidazol-4-yl)benzyl)oxy)indolyl)phenyl)-1Η-imidazol-2-yl)-1-°pyrrolidyl)-2-yloxy-1- Phenethyl ) guanidine hydroxyacetate; 1-mercapto-3-((lR)-2_((2S)-2-(4-(3-()))) 2R) -2-((decylamine-mercapto)amino)_2-phenethyl)-2-pyrrolidinyl)-1Η-imidazol-4-yl)benzoyl)oxy)indolyl) Phenyl)-1Η-imidazol-2-yl)-1-oxaridinyl)-2-oxo-1-phenylethyl)urea; 1-ethyl-3-((lR)-2-( (2S)-2-(4-(3-(((()))))) Mercapto)-2-oxaridinyl)·1 Η- 146976.doc -17· 201038558 imidazol-4-yl)benzyloxy)methyl)phenyl)-1 oxime-imidazol-2-yl )-1-. Bipyridyl)-2-oxo-1-phenylethyl)urea; 1-cyclopentyl-3-((lR)-2-((2S)-2-(4-(3-(( (4-(2-((2S)-l-((2R)-2-((cyclopentylaminomethyl)amino)-2-phenylethyl)-2-pyrrolidinyl)·1Η -imidazol-4-yl)phenylhydrazinyloxy)indolyl)phenyl)-1Η-imidazol-2-yl)-bu &quot;pyrrolidyl)-2-oxo-1-phenylethyl Urea; (1,1':4',1,'-bitriphenyl-4,4,,-diyl bis (1 ratio imidazole-4,2-diyl (28) • 2,1_&quot; Pyridinyl ((1R)-2-yloxy-1-phenyl-2,1-ethanediyl)))diguanidinium dicarboxylate; (lR)-2-((2S)-2- (4-(4i,-(2-((2S)-l-((2R)-2-(didecylamino)-2-phenylethyl)-2-indolyl)·1Η- Mimi" sit-5-yl)-1,1,:4,,1,--triphenyl-4-yl)-1Η-imidazol-2-yl)_1_pyrrolidinyl)-Ν,Ν-二Mercapto-2-yloxy-1-phenylethylamine; ((lS)-l-(((2S)-2-(4-(4-(4-((2S)))) )-2-((methoxycarbonyl)amino)-3-indolyl decyl)-2- τ piroxicam)-4,5-dihydro-1H-naphtho[l,2-d]imidazole- 7-yl)ethynyl)phenyl)-iH-imidazol-2-yl)-1-pyrrolidinyl)carbonyl)-2-indole Methyl propyl)methyl carbamate; ((lR)-2-((2S)-2-(4-(4-((2)))) Methoxycarbonyl)amino)-2-phenylethenyl)-2·-pyrrolidyl)_4,5-dihydro-1H-naphtho[l,2-d]imidazol-7-yl)ethynyl )phenyl)_1H_, oxazol-2-yl)_丨_吼 吼 啶 & & 2 2 2 2 2 2 2 ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( -2-(7-((4-(2-((2)))-((2R)-2-((f oxycarbonyl)amino)-2-phenylethyl))-2-pyrrolidazole _4_yl)phenyl)ethynyl)-111-naphtho[1,2-(1]imidazol-2-yl)-1-indole&gt;pyridinyl)_2-sideoxy-b 146976.doc -18- 201038558 methyl phenethyl)carbamate; ((lS)-l-(((2S)-2-(4-(4-(4-((2S)))) -2-((f oxycarbonyl)amino)-3-methylbutanyl)-2-pyrrolidyl)-1Η-naphtho[1,2-d]imidazol-7-yl)ethynyl)benzene Methyl)-1Η-imidazol-2-yl)-1-«pyrrolidyl)carbonyl)-2-methylpropyl)amino decanoate; ((lS)-l-(((lR,3S) ,5R)-3-(4-(4-((2-((lR,3S,5R)-2-((2S)-2-((methoxycarbonyl)amino)-3-methylbutyl) 2-Azabicyclo[3.1.0]hex-3-yl)-1Η-naphtho[l,2-d]imidazole-7 -yl)ethynyl)phenyl)-1Η-imidazol-2-yl)-2-azabicyclo[3.1.0]hexan-2-yl)carbonyl)-2-methylpropyl)carbazinate ;((lR)-2-((lR,3S,5R)-3-(7-((4-(2-((lR,3S)5R)-2-((2R) -2-((A) Oxycarbonyl)amino)2-2-phenethyl)-2-azabicyclo[3.1.0]hex-3-yl)-1Η-imidazol-4-yl)phenyl)ethynyl)-1Η-naphtho [l,2-d]imidazol-2-yl)-2-azabicyclo[3.1.0]hex-2-yl)-2-oxo-l-phenylethyl)amino decanoate; ((IS)-1-(((1R,3 S,5R)-3-(7-((2-((lR,3S,5R)-2-((2S)-2-((2S)-2-((oxycarbonyl) Amino)-3-methylbutyryl)-2-azabicyclo[3.1.0]hex-3-yl: M,5-dihydro-1H-naphtho[l,2-d]imidazole-7- Ethyl)-4-,5-dihydro-111-naphtho[1,2-(1]imidazol-2-yl)-2-azabicyclo[3.1.0]hex-2-yl)carbonyl) 2-methylpropyl)amino decanoate; ((lS)-l-(((lR,3S,5R)-3-(7-((2-((3S)))) 2S), 2-((methoxy)amino)-3-methylbutanyl)_2_azabicyclo[3·l·0]hex-3-yl)-lH-naphtho[l,2- Ci]imidazole·7-yl)ethynyl)_lH-naphtho[l,2-d]imidazolium-2-yl)-2-azabicyclo[3.1.0 ]]~_2-yl)carbonyl)-2methylpropyl)aminomethyl 146976.doc -19· 201038558 methyl ester; ((1 S)-2-(( lR,3S,5R)-3-( 7-((2-((lR,3S,5R)-2-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanyl)-2-azabicyclo[3.1.0 Hexyl-3-yl)-1Η-naphtho[l,2-d]imidazole-7-yl)ethynyl)-1Η-naphtho[1,2-d]imidazol-2-yl)-2-nitrogen Heterobicyclo[3.1.0]hex-2-yl)-2-oxo-l-(tetrahydro-2H.piperidin-4-yl)ethyl)amino decanoate; ((lS)- L-(((2S)_2-(4-(4-((4-(2-(())))) Butyryl) 2-1-oxazolidinyl)-1 Η-imidazol-4-yl)phenyl)ethynyl)phenyl)-1Η-imidazol-2-yl)-1-pyrrolidyl)carbonyl)-2 - mercaptopropyl) carbamic acid carbazate; (1,2-acetylenediyl bis(4,1-phenylphenyl-1 s-imidazole-4,2-diyl(28)-2,1-pyrrolidine Dibasic ((ir)_2_sideoxy_1_phenyl_2,1_ethanediyl))) dimethyl bis-carbamate; (1,2-acetylene diyl bis (4,1-extension) Phenyl-iH-imidazole-4,2-diyl(2S)-2,1-decalyldiyl ((18)-2-Sideoxy-1-(tetrahydro-211-pyran-4- Base)-2, Ethylene )) dimethyl dimethyl carbazate; ((ISR-1-S(5R)-3-(4-(4-(4-(2-(2-(()))) -2-((2S)-2-((methoxy)amino)_3_mercaptobutyl)-2_azabicyclo[3.1.0]hex-3-yl)-1Η-imidazol-4-yl Phenyl)ethynyl)phenyl)_1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexan-2-yl)carbonyl)-2-methylpropyl)carbamic acid methyl ester (1,2-acetylenediyl bis(4,1_extension base_1H_imidazole_4,2_diyl(lR,3S,5R)-2-azabicyclo[3_1.〇]hex-3 ,2-diyl((2S)-1-o-oxy-1,2-butanediyl)))didecyl dimethyl carbamate; 146976.doc -20- 201038558 (1,2-acetylene diyl double (4,1-Extended Phenyl-1H-imidazole_4,2-diyl(lR,3S,5R)-2-azabicyclo[3.1.0]hex-3,2-diyl ((is)" · Cyclobutyl-2-oxo-2,1-ethanediyl))) dimethyl dimethyl carbazate; (1,2-acetylenediyl bis(4,1-phenylphenyl-1H-imidazole) _4,2_diyl (lR,3S,5R)-2-azabicyclo[3.1.0]hex-3,2-diyl ((1S)_2_ oxo-l-(tetrahydro-2H- Dimethyl benzyl-4-yl)-2,1-ethanediyl))) bis carbamic acid; ((lS)-l-(((lR,3S,5R)-3-(4- (4-((4-(2-((lR,3S,5R)-2)((2S)-2-((oxakilyl)amino)-2-(tetrahydro-2H- brim-4 -yl)ethinyl)_2-aza bis[3.1.0]hex-3-yl)-1 Η-^ °-4-(yl)phenyl)-phenyl]phenyl)-1Η-imidazole- 2-(yl)-2-azabicyclo[3.1.0]hex_2-yl)yiyl)-2-methylpropyl)amino phthalic acid methyl vinegar; ((IS)· 1-((( 1R ,3S,5R)-3-(4-Chloro-5-(4-((4-(2-(())))) Base)_3_曱基丁醯基)_2_azabicyclo[3.1.0]hex-3-yl)-1Η-imidazol-4-yl)phenyl)ethynyl)phenyloxazol-2-yl)-2- Azabicyclo[no]hex_2-yl)carbonyl)_2-mercaptopropyl)carbamic acid decyl ester; ((ISR)-1-(((lR,3S,5R)-3-(4-chloro) 5-(4-(4-(4-chloro-2-((lR,3S, 5R)-2-((2S)-2-((methoxycarbonyl)amino))-3-methylbutenyl) _2_Azabicyclo[3.1.0]hex-3-yl)-lH-imidazol-5-yl)phenyl)ethynyl)phenyl)_1H_imidazol-2-yl)-2-azabicyclo[3.10] Methyl 2,2-yl)carbonyl)_2-methylpropyl)amino decanoate; ((lS)-2-((lR,3S,5R)-3-(4-(4-((4- (44-2-((lR,3S,5R)-2-((2S)-2-((曱-oxycarbonyl)) Base)_2_(tetrahydro-2H-pyranyl-4-yl)acetamidine 146976.doc •21· 201038558 base)-2 -nitrogen"hetero-double bad [3.1.0]hex-3-yl)-1Η -flavor . Sodium-5-yl)phenylene)ethynyl)phenyl)-1Η-imidazol-2-yl)-2-azabicyclo[no]hexyl-2-yl)_2_sideoxy-1-(tetrahydro) -2H-piperidin-4-yl)ethyl)amino decanoate; (1,2-6 alkynyl bis(4,1-phenylene) (4-chloro-1H-flavor _5, 2-diyl)(lR,3S,5R)-2-azabicyclo[3·ι·0]hexyl-3,2_diyl ((ls)_2_sideoxy-1-(tetraindole-2H- Dimethyl 2-pyranyl-4,1-ethanediyldicarboxylate; ((1 S )-1-((1R, 3 S,5R)-3-(4-(4- (( 1 S,2S)-2-(4-(2-((1 R,3S, 5R)-2_((2S)-2-((methoxy))))) _2_Azabicyclo[3.1.0]hex-3-ylimidazolium-4-yl)phenyl)cyclopropyl)pyridin-2-yl)-2-azabicyclo[3丨〇]hex_2 Ethyl)carbonyl)_2_mercaptopropyl) carbamic acid carbazate; ((lS,2S)-l,2j bis-diyl phenyl-ih-imidazole _4,2_diyl (lR,3S,5R -2-|U quasi-bicyclo[31 〇]hexyl _3,2_diyl ((is) 2_sideoxy-1-(tetrahydro 2H η succinyl-4-ylethylenediyl))) bisamine Di-decyl carbamate; ((1S)-1-(((1R53S,5R).3.(4-(4-((iRj2r).2.(4_(2-((1R53S, 5R)2(( 2) ((methyl carbonyl) amine)-3-基 醯 ) ) ) ) 3 3 3 3 3 3 3 3 3 3 坐 坐 坐 坐 坐 坐 坐 坐 坐 坐 坐 坐 坐 坐 坐 坐 坐 坐 坐 坐 坐 坐 坐 坐 坐 坐 坐 坐 坐 坐 坐 坐 坐Bicyclo[3.1〇]hex_2_yl)yl)_2-methylpropyl)methyl carbamate; ((1R,2R)-1'2-cyclopropanediylbis(4,1-phenylene) -1H-imidazole-4,2-diyl(1R,3S]5R)_2·azabicyclo[3] ̄·••diyl ((is)_2_sideoxy-1-(tetrahydro-2H) - (4S, 4) 2-(4-(4-((lS,2S)-2-(4-(2-((2S,4S)-l-((2S)-2_((oxycarbonyl))amino)-3- Mercaptobutyl)-4-methyl-2-pyrrole)-1Η-imidazol-4-yl)phenyl)cyclopropyl)phenyl)_1H-imidazol-2-yl)-4-methyl-l Methyl pyridinyl)carbonyl)_2-methylpropyl)carbamate; ((lS)-l-(((2S55S)-2-(4-(4-((4-(2-(2-(( 2S,5S)-l-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanyl)_5_methyl-2-°pyrrolidyl)-1H-imidazole_4- Phenyl)ethynyl)phenyl)_1H-imidazol-2-yl)-5-fluorenyl-1-pyrrolidyl)carbonyl)_2_曱(1,2-ethynyldiylbis(4,1-phenylene-1H-imidazole-4,2-diyl((2S,5S)-5-fluorenyl) -2,1-pyrrolidinodiyl)((2S)-1-o-oxy-1,2-butanediyl)))didecyl dimethyl carbamate; (1,2-acetylenediyl bis (4 , 1-phenylphenyl-1H-imidazole-4,2-diyl ((2S,5S)-5-methyl-2,1-. Bilobyldiyl)((ls)-2-Sideoxy-1-(tetramethylene-2H-piperidin-4-yl)-2,1-ethanediyl))) dimethyl dimethyl carbamate ;((lS)-l-(((2S,5S)-2-(4-(4-((4-(2-((2S)))) Oxycarbonyl)amino)-2-(tetrahydro-2H-piperidin-4-yl)ethenyl)-5-methyl-2-indolyl)-m-imidazol-4-yl)phenyl Ethyl ethyl)phenyl)-1 oxime-imidin-2-yl)-5-methyl-1-pyrrolidinyl)carbonyl)-2.methylpropyl)carbamic acid methyl ester; ((lS)- L-(((2S,4S)-2-(4-(4-S(4-(2-(2S,4S)-l-((2S)-2-((methoxy)yl)) -3 -methylbutyryl)-4-mercapto-2-%11 each α-based) _ 1Η-imidazol-4-yl)phenyl)ethynyl)phenyl)-1Η-imidazol-2-yl -4-methyl-1-pyrrolidyl)carbonyl)-2-mercaptopropyl)carbamic acid methyl vinegar; 146976.doc -23- 201038558 (1,2-acetylene diyl double (4,1- Phenyl-1H-imidazole-4,2-diyl((2S,4S)-4-mercapto-2,1-pyrrolidinyl) ((lS)-2- oxo-1-(four) Hydrogen-2H-pyran-4-yl)-2,1-ethanediyl))) Diamino phthalic acid dinonyl ester; ((lS)-l-(((2S,4S)-2-(4 -(4-((4-S4-chloro-2-((2S,4S)-l-((2S)-2-((methoxycarbonyl) Amino)-3-mercaptobutyl)-4-mercapto-2-pyrrolidinyl)-1Η-imidazole-5-yl)phenyl)ethynyl)phenyl)_ih-imidazol-2-yl)- Ethyl 4-mercapto-1-pyrrolidinyl)carbonyl)_2-methylpropyl)carbamate; ((lS)-l-(((2S,4S)-2-(4-Ga-5-) (4-((4-S4-(2-(2-(2-(2-(2-(((((((((((())))) Benzyl-2-pyrrole α-decyl)-1Η-imidazol-5-yl)phenyl)ethynyl)phenyl)-lH-imidazol-2-yl)-4-indolyl-1-pyrrolidinylcarbonyl)_2 - mercaptopropyl) guanidinium carbamate; ((lS)-2-((2S,4S)-2-(4-(4-((4-(4-) -l-((2S) -2-((indolylcarbonyl)amino)-2-(tetrahydro-2H-piperidin-4-yl)ethenyl)-4-methyl-2-. (rhoidyl)_1H-imidazol-5-yl)phenyl)ethynyl)phenyl)_ih-m-[sodium-2-yl)-4-methyl-1-pyrrolidinyl)_2-sideoxy-1 Methyl (tetrahydro-2H-piperazin-4-yl)ethyl)carbamate; (1,2-acetylenediylbis(4,1-phenylene)(4-chloro-1H-imidazole-5 , 2-diyl) ((2S, 4S)-4-mercapto-2, l-'J is more than o. Dimethyl)((lS)-2-yloxy-l-(tetrahydro-2H-piperidin-4-yl)-2,1-ethylenediyl))) dimethyl dimethyl phthalate; ((lS)-2-((2S,4S)-2_(4-(4-S(4-(2-(2S,4S)-l-((2S))) Amino)-3-methylbutyryl)_4_fluorenyl-2-.Bilobityl)-lH-flavored syl-4-yl)phenyl)ethyl)phenyl)_ 1H- Methyl cyano-2-yl)-4-mercapto·1 piroxime)-2-oxo-l-(tetrahydro-2-indole-pyran-4-yl)ethyl)amino decanoate ; 146976.doc -24- 201038558 ((IS ,3 S,5())(((is 3S, 5 S )-3-(4-(4-(())) -2- ((2S)-2-((indolyl)amino)_3_mercaptobutyl);)_5_methyl-2azabicyclo[3.1.0]hex-3-yl)-1Η- Imidazolyl-4-yl)phenyl)ethynyl)phenyl)-1H-mimino-2-yl)-5-methyl-2-azabicyclo[3.1.0]hex-2-yl)carbonyl) Methyl 2-methylpropyl)carbamate; ((lS)-l-(((lR,3S,5R)-3-(4-(4-((E)-2-(4-(2) -((lR,3S,5R)-2-((2S)-2-((indolyl)amino)_3_methylbutanyl)_2_azabicyclo[3.1.0]hex-3-yl )-1Η-imidazol-4-yl)phenyl)vinyl)phenyl)_ih-m. Methyl-2-azabicyclo[3.1.0]hex-2-yl)carbonyl)-2-methylpropyl)carbamate; ((E)-l,2-ethylenediylbis(4,1 _ phenyl-1H-imidazole-4,2-diyl (lR,3S,5R)-2-azabicyclo[3.1.0]hex-3,2-diyl ((lS)-2-side oxygen Dimethyl-1-(tetrahydro-2H-piperazin-4-yl)-2,1-ethanediyl))) bis-amino decanoate; ((lS)-2-((lR,3S, 5R)-3-(4-(4-((E)-2-(4-(2-(())))) -3-mercaptobutyl hydrazino)-2-azabicyclo[3.1.0]hex-3-yl)-1 Η-imidazol-4-yl)phenyl)vinyl) stupyl)-1Η-imirene_2 _ base)_2_azabicyclo[3.丨·〇]hex_2_yl)_2_sideoxy_丨_(tetrahydro-2H-pyran-4-yl)ethyl)amine ruthenate Ester; ((lS)-l-(((2S)-2-(4-(4-(4-(2-((2S))), 4-difluoro-l-((2S)-2) - ((曱Oxycarbonyl)amino)-3·mercaptobutyl)-2-pyrrolidinyl)-1Η-imidazol-4-yl)phenyl)ethynyl)phenyl)_1H-imidazole_2-yl) _4,4_Difluoro-丨_0 ratio hexyl)carbonyl)-2-mercaptopropyl)amino decanoate; (acetylene-1,2 diyl bis(4,1-phenylene) -1H-imidazole-5,2-diyl ((2S)-146976. Doc -25- 201038558 4,4-Difluoropyrrolidine-2,1-diyl)((18)-2-Sideoxy-1-(tetrahydro-211-pyran-4-yl)ethyl-2 ,1-diyl))) Didecyl biscarbamate; ((lR)-2-((2S)-2-(5-(4-(4-(2-(2-(2)))) 4-di-a-l-((2S)-2-((indolylcarbonyl)amino)-2-(tetrahydro-2H-pyran-4-yl)ethyl)pyrrolidin-2-yl) -1Η-imidazole-5-yl)phenyl)ethynyl)phenyl)-lH-imidazol-2-yl) _4,4-dihydropyrrolidine-1-yl)-2-oxo- 1-(tetrazole-21^-'1 pentan-4-yl)ethyl)amino decanoate; (acetylene-1,2-diylbis(4,1-phenylene-1H-imidazole) -5,2-diyl((2S)-4,4-difluoropyrrolidine-2,1-diyl)((111)-2- oxo-l-(tetrahydro-211-pipe ◎ ° (-4-()))) 4-(2-((3S)-4-((2S)-2-((曱Oxycarbonyl))amino)-3-methylbutanyl)-3-morpholinyl)-1Η-imidazol-4-yl Phenyl) ethynyl)phenyl)-1 Η-imidazol-2-yl)-4-morpholinylcarbonyl)-2-mercaptopropyl) carbazate; ((lS)-l-( ((2S)-2-(4-(4-((4-(2-((2S))-l-((2S)-2-((A) Oxycarboyl)amino)-3-methylbutyryl)-2-n-bottomyl)-1Η-_ °-4-yl)phenyl)ethynyl)phenyl)-1Η- -2-yl)-1-indenyl), benzylidene decanoate; ((lS)-l-(((2S,4S)-4-hydroxyl) -2-(4-(4-((4-((2S,4S)-4-)-yl-1-((28)-2-(())-yl) Butyl)-2-1»比略11定基)-1Η-imidazol-4-yl)phenyl)ethynyl)phenyl)_1H-imidazol-2-yl)pyrrolidinyl)carbonyl)-2- Mercaptopropyl)methyl carbamate; ((1S)-1-(((1S,3 S,5S)-3-(4-(4-((4-(2-(()) 5 S)-2-((2S)-2-((methoxy)amino)-3-methylbutyryl)_2_azabicyclo 146976.doc •26- 201038558 [3.1.0] -3-yl)-1Η-imidazol-4-yl)phenyl)ethynyl)phenyl)_1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hex_2-yl)carbonyl) _2 曱 曱 ) ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( - azabicyclo[3·1·〇]hexyl-3,2-diyl ((1S)_2_ oxo-l-(tetrahydro-2H-pyran-4-yl)-2,l- Dimethyl dimethyl carbamic acid dimethyl ester; ((lS)-l-(((2S)-2-(4-(3-()))) )-2-((methoxycarbonyl)amino)-3-methylbutanyl)-2-pyrrolidinyl)-ih-imidazol-4-yl)phenyl)ethynyl)benzyl)-1Η-_ η sits _2 基 ) ) ) ) ) ) ) ) ) ) ) ) ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( (3-((3-(2-((2S)))))))))))))))))))) Methyl) propyl) carbamic acid methyl vinegar; (1,2- acetylenediyl bis(3,1-phenylene-1-H-imidazole _4,2-diyl (2S)-2,1- . Bilobyldiyl ((13)_2_sideoxy_1_(tetrahydro-211-piperidin-4-yl)-2,1-ethanediyl)))diguanidinium dicarboxylate; (( lS)-l-(((lR,3S,5R)-3-(4-(3-((3-(2-(()))) Methoxymethyl)amino)-3-indolyl decyl)-2-azabicyclo[3.1.0]hex-3-yl)-out-oxazol-4-yl)phenyl)ethynyl)phenyl _111_ oxazol-2-yl)-2-azabicyclo[3.1.0]hexan-2-yl)carbonyl)-2-mercaptopropyl) carbamic acid decyl ester; (1,2-acetylene II Bis (3,1-extended base-1H-imidazole-4,2-diyl(lR,3S,5R)-2-azabicyclo[3_1.0]hex-3,2-diyl ((1S) _2-side oxygen 146976.doc -27· 201038558 -1-(tetrahydro-2H-piperazin-4-yl)-2,1-ethylenediyl))) bis-diamino decanoate; (18,28)-1,2-cyclopropyldiylbis(4,1-phenylene-111-imidazole-4,2-diyl((2S,4S)-4-mercapto-2,1- ° ratio d to each D base) ((lS)-2 - pendant oxy-1-(tetrahydro-2H-piperidin-4-yl)-2,1-ethanediyl))) bisaminopurine Dimethyl ester; ((lS)-l-(((2S)-2-(4-(4-(4-(2-((2S)))) Oxycarbonyl)amino)-3-indolylbutenyl)-4-indenyl-2-indole )-1Η-imidazol-4-yl)phenyl)ethynyl)phenyl)-1Η-imidazol-2-yl)-4-indolyl-1pyrrolidinyl)carbonyl)-2-methylpropyl Aminomethyl decanoate; ((lS)-l-(((2S,4R)-4-hydroxy-2-(4-(4-(4-(4-(()))) -hydroxy-l-((2S)-2-((methoxycarbonyl)amino)-3-mercaptobutyl)-2-anthracene)-1Η-oxazol-4-yl)phenyl)acetylene Methyl)phenyl)-1H-imidazol-2-yl)-1_D-pyridyl)carbonyl)-2-methylpropyl)carbamic acid methyl ester; ((18)-1-(((28) -2-(4-(4^-((4-(2-((28)-1-((28)-2-((曱o)carbonyl)amino)-3-indolyl)-pyrrole Pyridyl)_1H_imidazolyl)phenyl)ethynyl)-4-biphenyl)_1H-imidazol-2-yl)-1-pyrrolidinyl)methyl-2-methylpropyl)carbamic acid Methyl ester; and its corresponding stereoisomers and tautomers. 18. A composition comprising a compound of claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. 19. The use of a compound of claim 1 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of HCV infection in a patient. 146976.doc •28- 201038558 IV. Designation of Representative Representatives (1) The representative representative of the case is: (none) ' (2) A brief description of the symbol of the representative figure: 5. If there is a chemical formula in this case, please reveal the most A chemical formula that shows the characteristics of the invention: (I) 146976.doc