TW201502120A - Hepatitis c virus inhibitors - Google Patents

Abstract

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

Description

Hepatitis C virus inhibitor

The present invention relates generally to antiviral compounds, and more particularly to combinations of compounds that inhibit the function of the NS5A protein encoded by hepatitis C virus (HCV), compositions comprising such combinations, and methods of inhibiting NS5A protein function .

HCV is a major human pathogen, affecting approximately 170 million people worldwide, approximately 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.

In the past decade, the standard of care for chronic HCV treatment has been the combination of pegylated interferon and ribavirin. This treatment has a non-optimal success rate in achieving sustained viral response (SVR) against the six major HCV genotypes, with a particularly low success rate for genotype 1 and numerous side effects. Recently approved drug (PI) (Victrelis ® and Incivek ® ) targeting HCV NS3/4A protease is administered with pegylated interferon and ribavirin and the percentage of patients experiencing SVR and the duration of treatment required to achieve SVR Major improvements are provided in terms of time. However, there is a clear and urgent need to develop additional therapies to combat protease inhibitor resistance, improve efficacy in all HCV genotypes, and advance antiviral therapy to the ultimate goal of no interferon cure.

HCV is a single open reading frame (ORF) of a positive-stranded RNA virus of approximately 9500 nucleotides in length and having a single large polypeptide encoding approximately 3000 amino acids. In infected cells, this polymeric protein is cleaved by cellular proteases and viral proteases at multiple sites, resulting in 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 caused by two diseases. Toxic protease is achieved. The first is believed to be a metalloproteinase and cleaves at the junction of NS2-NS3; 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 NS4A-NS4B, NS4B-NS5A, NS5A-NS5B sites. The NS4A protein is a cofactor for the NS3 protease. The formation of the NS3-NS4A complex is required for proper protease activity. The NS3 protein also exhibits nucleoside triphosphatase and RNA helicase activities. NS5A is a multifunctional protein required for viral RNA replication and virion assembly. NS5B (also referred to herein as HCV polymerase) is an RNA-dependent RNA polymerase responsible for viral RNA synthesis.

Due to the high error rate of the RNA-dependent RNA polymerase encoded by the proof-reading capability, a considerable amount of nucleotides and encoded amino acid sequences are found throughout the HCV genome. Heterogeneity. The clinical significance of HCV genetic heterogeneity lies in the propensity to mutate during monotherapy treatment, thereby requiring the use of combination therapies with HCV inhibitors that have pan-genotype coverage and function via independent mechanisms.

Compounds that selectively inhibit HCV viral replication and are useful in the treatment of patients with HCV infection. In particular, compounds that effectively inhibit the function of the NS5A protein are required. The function and basic role of the NS5A protein for HCV replication is described, for example, in the following references: SLTan et al, Virology , 284: 1-12 (2001); K.-J. Park et al, J. Biol. Chem. , 30711 -30718 (2003); TLTellinghuisen et al, Nature , 435, 374 (2005); RALove 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); M. Gao et al, Nature (2010); C. Rice et al, WO2006093867.

A method for identifying compounds that exhibit synergistic inhibition of HCV replicon activity when combined with an HCV NS5A inhibitor such as BMS-790052 has been described (PCT/US2011/043785, filed on Jul. 13, 2011). Briefly, each compound is essentially inactive or minimally active when tested individually for some NS5A resistant variants, and Synergistic inhibitory activity was only tested when tested in combination with the NS5A targeting compound. Titration of the test compound is used in the presence of a fixed concentration of an HCV NS5A inhibitor (such as BMS-790052) to identify the synergistic compound.

In a first aspect, the invention provides a combination comprising an NS5A targeting compound and an NS5A potentiator which, when administered, provides synergistic resistance against variants containing mutations that confer resistance to a single NS5A targeting compound HCV activity. In a first embodiment of the first aspect, the combination comprises two or more pharmaceutically acceptable carriers. In a second embodiment, the NS5A targeting compound and the NS5A synergist are grouped and in the same pharmaceutically acceptable carrier.

In a third embodiment, the invention provides a combination comprising an NS5A targeting compound and an NS5A potentiator which, when administered, provides synergistic resistance against variants containing mutations that confer resistance to the NS5A targeting compound alone HCV activity wherein the NS5A synergist is a compound of formula (I): Or a pharmaceutically acceptable salt thereof, wherein L is absent or selected from C ₂ alkyl, C ₂ alkenyl, C ₂ alkynyl, C ₄ alkynyl and C ₃ cycloalkyl; A is absent or selected from iso Quinolinyl, naphthyl, phenyl, pyrazinyl, pyridyl, pyrimidinyl and quinolyl; B is selected from the group consisting of fluorenyl, benzofuranyl, bicycloalkyl, indanyl, decyl, naphthalene Base, phenyl, pyridyl, pyrimidinyl, pyrazinyl, tetrahydronaphthyl, thienyl and Each X system is independently selected from the group consisting of O and NR ^{q '} wherein R ^{q '} is selected from the group consisting of hydrogen, alkyl, hydroxy and -NH ₂ ; each R ¹ is independently selected from alkoxyalkyl, alkyl, aryl , arylalkyl, cycloalkyl, haloalkyl, heterocyclyl and hydroxyalkyl; each R ^1a is independently selected from hydrogen and alkyl; or R ¹ and R ^1a are taken together with the carbon atom to which they are attached to form a saturated Or an unsaturated 3 to 6 membered spiro ring, wherein the spiro ring is optionally fused to the phenyl ring when between 4 and 6 members, and wherein each ring system is independently selected from one or two independently Substituting alkyl and halo groups; each R ^f is independently selected from the group consisting of hydrogen, methyl, hydroxy, and -NH ₂ (R ^z ), wherein R ^z is alkyl; each R ^p is independently selected from hydrogen, An alkyl group, a cyano group, a halogen group, a haloalkoxy group, and a haloalkyl group; each R ^q is independently selected from the group consisting of hydrogen, an alkyl group, a halogen group, and -P(O)-(OR) ₂ , wherein each R is the same Or different alkyl groups; and each R ² is independently selected from the group consisting of hydrogen, alkenylcarbonyl, alkoxyalkylcarbonyl, alkoxyalkylcarbonylcarbonyl, alkoxycarbonyl, alkoxycarbonylalkylcarbonyl, alkoxy Carbocarbonylcarbonyl, alkyl, alkylcarbonyl, alkylcarbonylalkylcarbonyl , alkylcarbonylcarbonyl, alkylsulfinyl, alkylsulfonyl, alkynyl, alkynyloxycarbonyl, alkynylcarbonyl, arylcarbonyl, arylcarbonylcarbonyl, arylalkenylcarbonyl, arylalkoxy Carbocarbonyl, arylalkylcarbonyl, aryloxyalkylcarbonyl, arylthioalkylcarbonyl, arylsulfinyl, arylsulfonyl, bicycloalkylcarbonyl, carboxyalkylcarbonyl, carboxycarbonyl, Cyanoalkylcarbonyl, (cycloalkenyl)alkylcarbonyl, (cycloalkyl)alkyl, (cycloalkyl)alkylcarbonyl, cycloalkylcarbonyl, cycloalkylcarbonylcarbonyl, cycloalkoxycarbonyl, halogen Alkenylcarbonyl, haloalkoxyalkylcarbonyl, haloalkylcarbonyl, haloalkylcarbonylcarbonyl, heterocyclyl, (heterocyclyl)alkylcarbonyl, heterocyclylcarbonyl, heterocyclylcarbonylalkylcarbonyl, hetero Cyclocarbonylcarbonyl, hydroxyalkenylcarbonyl, hydroxyalkylcarbonyl, (NR ^c R ^d )alkylcarbonyl, (NR ^c R ^d )carbonyl, (NR ^c R ^d )carbonylalkylcarbonyl, (NR ^c R ^d ) Carbonyl carbonyl, and Wherein R and R' are each an alkyl group, or together with the carbon atom to which they are attached, form a five or six membered ring containing an oxygen or nitrogen atom; or R ² and R ^f together with the nitrogen atom to which they are attached, as appropriate a five or six membered ring substituted with one or two groups independently selected from the group consisting of an alkoxycarbonylamino group and an oxo group; or R ² and R ^f are formed together with the nitrogen atom to which they are attached

In a fourth embodiment, the invention provides a combination comprising an NS5A targeting compound and an NS5A potentiator which, when administered, provides synergistic resistance against variants containing mutations that confer resistance to the NS5A targeting compound alone HCV activity, wherein the NS5A synergist is a compound of formula (II) Or a pharmaceutically acceptable salt thereof, wherein: Y is selected from the group consisting of O, O(CR ^z ) ₂ and (C(R ^z ) ₂ ) _n , wherein n is 1 or 2, and each R ^z is independently selected From hydrogen, alkyl and halo; each R ¹ is independently selected from alkoxyalkyl, alkyl, aryl, arylalkyl, cycloalkyl, haloalkyl, heterocyclyl and hydroxyalkyl; Each R ^1a is independently selected from the group consisting of hydrogen and alkyl; or R ¹ and R ^1a together with the carbon atom to which they are attached form a saturated or unsaturated 3 to 6 membered spiro ring, wherein the spiro ring is between 4 and 6 members. Optionally, fused to the phenyl ring, and wherein each ring system is optionally substituted with one or two groups independently selected from the group consisting of alkyl and halo; each R ^f is independently selected from hydrogen, methyl And a hydroxyl group and -NH ₂ (R ^z ), wherein R ^z is an alkyl group; each R ^p is independently selected from the group consisting of hydrogen, alkyl, cyano, halo, haloalkoxy and haloalkyl; each R ^q is Independently selected from the group consisting of hydrogen, alkyl, halo and -P(O)-(OR) ₂ wherein each R is the same or different alkyl; and each R ² is independently selected from alkenylcarbonyl, alkoxyalkyl Carbocarbonyl, alkoxyalkylcarbonylcarbonyl, alkoxycarbonyl, alkoxycarbonylalkylcarbonyl, alkane Carbocarbonylcarbonyl, alkyl, alkylcarbonyl, alkylcarbonylalkylcarbonyl, alkylcarbonylcarbonyl, alkylsulfinyl, alkylsulfonyl, alkynyl, alkynyloxy, alkynylcarbonyl, aryl Carbonyl, arylcarbonylcarbonyl, arylalkenylcarbonyl, arylalkoxycarbonyl, arylalkylcarbonyl, aryloxyalkylcarbonyl, arylthioalkylcarbonyl, arylsulfinyl, aryl Sulfonyl, bicycloalkylcarbonyl, carboxyalkylcarbonyl, carboxycarbonyl, cyanoalkylcarbonyl, (cycloalkenyl)alkylcarbonyl, (cycloalkyl)alkyl, (cycloalkyl)alkylcarbonyl, ring Alkylcarbonyl, cycloalkylcarbonylcarbonyl, cycloalkoxycarbonyl, haloalkenylcarbonyl, haloalkoxyalkylcarbonyl, haloalkylcarbonyl, haloalkylcarbonylcarbonyl, heterocyclyl, (heterocyclyl)alkane Alkylcarbonyl, heterocyclylcarbonyl, heterocyclylcarbonylalkylcarbonyl, heterocyclylcarbonylcarbonyl, hydroxyalkenylcarbonyl, hydroxyalkylcarbonyl, (NR ^c R ^d )alkylcarbonyl, (NR ^c R ^d )carbonyl, (NR ^c R ^d )carbonylalkylcarbonyl, (NR ^c R ^d )carbonylcarbonyl, and Wherein R and R' are each an alkyl group, or together with the carbon atom to which they are attached, form a five or six membered ring containing an oxygen or nitrogen atom, or R ² and R ^f together with the nitrogen atom to which they are attached;

In a fifth embodiment, the invention provides a combination comprising an NS5A targeting compound and an NS5A synergist which, when administered, provides synergistic resistance against variants containing mutations that confer resistance to a single NS5A targeting compound HCV activity, wherein the NS5A synergist is a compound of formula (III) Or a pharmaceutically acceptable salt thereof, wherein: A and B are independently selected from the group consisting of isoquinolyl, naphthyl, phenyl, pyrazinyl, pyridyl, pyrimidinyl and quinolyl; each R ^p is independently Is selected from the group consisting of hydrogen, alkyl, cyano, halo, haloalkoxy and haloalkyl; each R ^q is independently selected from the group consisting of hydrogen, alkyl, halo and -P(O)-(OR) ₂ , Wherein each R is the same or different alkyl; each R ¹ is independently selected from: Wherein m is 0, 1, 2 or 3; and n is 0, 1, 2 or 3; the constraint is that at least one R ^{1 is} not Each R ² is independently selected from alkenyl, alkoxy, alkoxyalkyl, alkoxyalkylcarbonyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonyl, alkylcarbonyl Alkyl, alkynyl, alkynyloxy, aryl, arylalkenyl, arylalkoxy, arylalkyl, arylcarbonyl, aryloxy, aryloxyalkyl, arylthioalkyl, Carboxyl, carboxyalkyl, cyanoalkyl, (cycloalkenyl)alkyl, cycloalkyl, (cycloalkyl)alkyl, cycloalkylcarbonyl, cycloalkoxy, haloalkenyl, haloalkoxyalkyl , haloalkyl, heterocyclic, (heterocyclyl)alkyl, heterocyclylcarbonylalkyl, heterocyclylcarbonyl, hydroxyalkenyl, hydroxyalkyl, -NR ^c R ^d , (NR ^c R ^d ) Alkyl, (NR ^c R ^d )carbonylalkyl, and Wherein R and R' are each an alkyl group, or together with the carbon atom to which they are attached, form a five or six membered ring containing, optionally, an oxygen or nitrogen atom; each R ³ is independently selected from the group consisting of an alkyl group, a halogen group, and a hydroxyl group; Wherein the alkyl group optionally forms a fused three to six membered ring with an adjacent carbon, forms a bridged four or five membered ring with another carbon atom on the ring, or forms a helical ring of three to six members with the carbon atom to which it is attached a ring; wherein each ring is optionally substituted with one or two groups independently selected from the group consisting of alkoxy, alkyl, halo and haloalkyl; each R ⁶ is -N(R')-N(R") ( R'''); wherein each R' and R" are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl and haloalkyl; each R''' is independently selected from alkoxycarbonyl, alkyl and aromatic Or R" and R''' together with the nitrogen atom to which they are attached form a ring selected from the group consisting of oxazole, morpholine, N-methylpiperazine, piperidine and pyrrolidine; each R ⁷ is independently selected from the group consisting of alkane Oxyalkyl, alkyl, aryl, arylalkyl, cycloalkyl, haloalkyl, heterocyclyl and hydroxyalkyl; each R ^7a is independently selected from hydrogen and alkyl; or R ⁷ and R ^7a form a saturated or unsaturated 3 to 6 together with the carbon atom they are attached a spiro ring, wherein the spiro ring is optionally fused to the phenyl ring when interposed between 4 and 6 members, and wherein each ring system is independently selected from the group consisting of an alkyl group and a halogen group by one or two Substituted; each R ^f is independently selected from the group consisting of hydrogen, methyl, hydroxy, and -NH ₂ (R ^z ), wherein R ^z is alkyl; and each R ⁸ is independently selected from alkenylcarbonyl, alkoxyalkane Carbonyl group, alkoxyalkylcarbonylcarbonyl group, alkoxycarbonyl group, alkoxycarbonylalkylcarbonyl group, alkoxycarbonylcarbonyl group, alkyl group, alkylcarbonyl group, alkylcarbonylalkylcarbonyl group, alkylcarbonylcarbonyl group, alkane Isosulfonyl, alkylsulfonyl, alkynyl, alkynyloxycarbonyl, alkynylcarbonyl, arylcarbonyl, arylcarbonylcarbonyl, arylalkenylcarbonyl, arylalkoxycarbonyl, arylalkyl Carbonyl, aryloxyalkylcarbonyl, arylthioalkylcarbonyl, arylsulfinyl, arylsulfonyl, bicycloalkylcarbonyl, carboxyalkylcarbonyl, carboxycarbonyl, cyanoalkylcarbonyl, Cycloalkenyl)alkylcarbonyl, (cycloalkyl)alkyl, (cycloalkyl)alkylcarbonyl, cycloalkylcarbonyl, cycloalkylcarbonylcarbonyl, cycloalkoxycarbonyl, haloalkenyl Carbonyl group, haloalkoxyalkylcarbonyl group, haloalkylcarbonyl group, haloalkylcarbonylcarbonyl group, heterocyclic group, (heterocyclic)alkylcarbonyl group, heterocyclic carbonyl group, heterocyclic carbonylalkylcarbonyl group, heterocyclic group Carbonylcarbonyl, hydroxyalkenylcarbonyl, hydroxyalkylcarbonyl, (NR ^c R ^d )alkylcarbonyl, (NR ^c R ^d )carbonyl, (NR ^c R ^d )carbonylalkylcarbonyl, (NR ^c R ^d )carbonylcarbonyl ,and Wherein R and R' are each an alkyl group, or together with the carbon atom to which they are attached, form a five or six membered ring containing an oxygen or nitrogen atom; or R ⁸ and R ^f together with the nitrogen atom to which they are attached, as appropriate a five or six membered ring substituted with one or two groups independently selected from the group consisting of an alkoxycarbonylamino group and a pendant oxy group; or R ² and R ^f together with the nitrogen atom to which they are attached

In a sixth embodiment, the invention provides a combination comprising an NS5A targeting compound and an NS5A potentiator which, when administered, provides synergistic resistance against variants containing mutations that confer resistance to a single NS5A targeting compound HCV activity, wherein the NS5A synergist is a compound of formula (IV) Or a pharmaceutically acceptable salt thereof, wherein: A is absent or selected from the group consisting of isoquinolyl, naphthyl, phenyl, pyrazinyl, pyridyl, pyrimidinyl and quinolyl; each R ¹ is independently selected From alkoxyalkyl, alkyl, aryl, arylalkyl, cycloalkyl, haloalkyl, heterocyclyl and hydroxyalkyl; each R ^1a is independently selected from hydrogen and alkyl; or R ¹ And R ^1a together with the carbon atom to which it is attached form a saturated or unsaturated 3 to 6 membered spiro ring, wherein the spiro ring is optionally fused to the phenyl ring when between 4 and 6 members, and wherein each ring The system is optionally substituted with one or two groups independently selected from the group consisting of alkyl and halo; each R ^f is independently selected from the group consisting of hydrogen, methyl, hydroxy and -NH ₂ (R ^z ), wherein R ^z is an alkane Each R ^p is independently selected from the group consisting of hydrogen, alkyl, cyano, halo, haloalkoxy, and haloalkyl; each R ^q is independently selected from the group consisting of hydrogen, alkyl, halo, and -P(O). —(OR) ₂ , wherein each R is the same or different alkyl; each R ² is independently selected from alkenylcarbonyl, alkoxyalkylcarbonyl, alkoxyalkylcarbonylcarbonyl, alkoxycarbonyl, alkane Oxycarbonylcarbonylcarbonyl, alkoxycarbonylcarbonyl Alkyl, alkylcarbonyl, alkylcarbonylalkylcarbonyl, alkylcarbonylcarbonyl, alkylsulfinyl, alkylsulfonyl, alkynyl, alkynyloxycarbonyl, alkynylcarbonyl, arylcarbonyl, aryl Carbonylcarbonyl, arylalkenylcarbonyl, arylalkoxycarbonyl, arylalkylcarbonyl, aryloxyalkylcarbonyl, arylthioalkylcarbonyl, arylsulfinyl, arylsulfonyl, Bicycloalkylcarbonyl, carboxyalkylcarbonyl, carboxycarbonyl, cyanoalkylcarbonyl, (cycloalkenyl)alkylcarbonyl, (cycloalkyl)alkyl, (cycloalkyl)alkylcarbonyl, cycloalkylcarbonyl, Cycloalkylcarbonylcarbonyl, cycloalkoxycarbonyl, haloalkenylcarbonyl, haloalkoxyalkylcarbonyl, haloalkylcarbonyl, haloalkylcarbonylcarbonyl, heterocyclyl, (heterocyclyl)alkylcarbonyl, hetero Cyclocarbonyl, heterocyclylcarbonylalkylcarbonyl, heterocyclylcarbonylcarbonyl, hydroxyalkenylcarbonyl, hydroxyalkylcarbonyl, (NR ^c R ^d )alkylcarbonyl, (NR ^c R ^d )carbonyl, (NR ^c R ^d ) a carbonylalkylcarbonyl group, (NR ^c R ^d )carbonylcarbonyl, and Wherein R and R' are each an alkyl group, or together with the carbon atom to which they are attached, form a five or six membered ring containing an oxygen or nitrogen atom; or R ² and R ^f together with the nitrogen atom to which they are attached, as appropriate a five or six membered ring substituted with one or two groups independently selected from the group consisting of an alkoxycarbonylamino group and a pendant oxy group; or R ² and R ^f together with the nitrogen atom to which they are attached

In a seventh embodiment, the invention provides a combination comprising an NS5A targeting compound and an NS5A potentiating agent which, when administered, provides synergistic resistance against variants containing mutations that confer resistance to a single NS5A targeting compound HCV activity, wherein the NS5A synergist is a compound of formula (V) Or a pharmaceutically acceptable salt thereof, wherein: L is absent or selected from the group consisting of C ₂ alkenyl, C ₂ alkynyl, C ₄ alkynyl and phenyl; and A and B are independently selected from azabenzimidazole, Aza-naphthoimidazole, Each R ¹ is independently selected from the group consisting of an alkoxyalkyl group, an alkyl group, an aryl group, an arylalkyl group, a cycloalkyl group, a haloalkyl group, a heterocyclic group, and a hydroxyalkyl group; each R ^1a is independently selected from the group consisting of hydrogen And an alkyl group; or R ¹ and R ^1a together with the carbon atom to which they are attached form a saturated or unsaturated 3 to 6 membered spiro ring, wherein the spiro ring may optionally be fused to benzene when between 4 and 6 members a base ring, wherein each ring system is optionally substituted with one or two groups independently selected from the group consisting of alkyl and halo; each R ^f is independently selected from the group consisting of hydrogen, methyl, hydroxy and -NH ₂ (R ^z Wherein R ^z is an alkyl group; each R ^p is independently selected from the group consisting of hydrogen, alkyl, cyano, halo, haloalkoxy, and haloalkyl; each R ^q is independently selected from hydrogen, alkyl, a halo group and -P(O)-(OR) ₂ , wherein each R is the same or different alkyl group; and each R ² group is independently selected from an alkenylcarbonyl group, an alkoxyalkylcarbonyl group, an alkoxyalkylcarbonyl group Carbonyl group, alkoxycarbonyl group, alkoxycarbonylalkylcarbonyl group, alkoxycarbonylcarbonyl group, alkyl group, alkylcarbonyl group, alkylcarbonylalkylcarbonyl group, alkylcarbonylcarbonyl group, alkylsulfinyl group, alkylsulfonate Mercapto, alkynyl, alkynyloxycarbonyl, Carbocarbonyl, arylcarbonyl, arylcarbonylcarbonyl, arylalkenylcarbonyl, arylalkoxycarbonyl, arylalkylcarbonyl, aryloxyalkylcarbonyl, arylthioalkylcarbonyl, arylsulfin Mercapto, arylsulfonyl, bicycloalkylcarbonyl, carboxyalkylcarbonyl, carboxycarbonyl, cyanoalkylcarbonyl, (cycloalkenyl)alkylcarbonyl, (cycloalkyl)alkyl, (cycloalkyl) Alkylcarbonyl, cycloalkylcarbonyl, cycloalkylcarbonylcarbonyl, cycloalkoxycarbonyl, haloalkenylcarbonyl, haloalkoxyalkylcarbonyl, haloalkylcarbonyl, haloalkylcarbonylcarbonyl, heterocyclyl, Heterocyclyl)alkylcarbonyl, heterocyclylcarbonyl, heterocyclylcarbonylalkylcarbonyl, heterocyclylcarbonylcarbonyl, hydroxyalkenylcarbonyl, hydroxyalkylcarbonyl, (NR ^c R ^d )alkylcarbonyl, (NR ^c R ^d )carbonyl, (NR ^c R ^d )carbonylalkylcarbonyl, (NR ^c R ^d )carbonylcarbonyl, and Wherein R and R' are each an alkyl group, or together with the carbon atom to which they are attached, form a five or six membered ring containing an oxygen or nitrogen atom; or R ² and R ^f together with the nitrogen atom to which they are attached, as appropriate a five or six membered ring substituted with one or two groups independently selected from the group consisting of an alkoxycarbonylamino group and a pendant oxy group; or R ² and R ^f together with the nitrogen atom to which they are attached

In an eighth embodiment, the invention provides a combination comprising an NS5A targeting compound and an NS5A potentiator, which when administered, provides synergistic resistance against variants containing mutations that confer resistance to a single NS5A targeting compound HCV activity, wherein the NS5A synergist is a compound of formula (VI) Or a pharmaceutically acceptable salt thereof, wherein: A is selected from the group consisting of isoquinolyl, naphthyl, phenyl, pyrazinyl, pyridyl, pyrimidinyl, quinolyl, and Each R ¹ is independently selected from the group consisting of an alkoxyalkyl group, an alkyl group, an aryl group, an arylalkyl group, a cycloalkyl group, a haloalkyl group, a heterocyclic group, and a hydroxyalkyl group; each R ^1a is independently selected from the group consisting of hydrogen And an alkyl group; or R ¹ and R ^1a together with the carbon atom to which they are attached form a saturated or unsaturated 3 to 6 membered spiro ring, wherein the spiro ring may optionally be fused to benzene when between 4 and 6 members a base ring, wherein each ring system is optionally substituted with one or two groups independently selected from the group consisting of alkyl and halo; each R ^f is independently selected from the group consisting of hydrogen, methyl, hydroxy and -NH ₂ (R ^z Wherein R ^z is an alkyl group; each R ^q is independently selected from the group consisting of hydrogen, alkyl, halo and -P(O)-(OR) ₂ , wherein each R is the same or different alkyl; each R ^p is Independently selected from the group consisting of hydrogen, alkyl, cyano, halo, haloalkoxy, and haloalkyl; and each R ² is independently selected from alkenylcarbonyl, alkoxyalkylcarbonyl, alkoxyalkylcarbonyl Carbonyl group, alkoxycarbonyl group, alkoxycarbonylalkylcarbonyl group, alkoxycarbonylcarbonyl group, alkyl group, alkylcarbonyl group, alkylcarbonylalkylcarbonyl group, alkylcarbonylcarbonyl group, alkylsulfinyl group, alkylsulfonate Mercapto, alkynyl, alkynyloxycarbonyl, Carbocarbonyl, arylcarbonyl, arylcarbonylcarbonyl, arylalkenylcarbonyl, arylalkoxycarbonyl, arylalkylcarbonyl, aryloxyalkylcarbonyl, arylthioalkylcarbonyl, arylsulfin Mercapto, arylsulfonyl, bicycloalkylcarbonyl, carboxyalkylcarbonyl, carboxycarbonyl, cyanoalkylcarbonyl, (cycloalkenyl)alkylcarbonyl, (cycloalkyl)alkyl, (cycloalkyl) Alkylcarbonyl, cycloalkylcarbonyl, cycloalkylcarbonylcarbonyl, cycloalkoxycarbonyl, haloalkenylcarbonyl, haloalkoxyalkylcarbonyl, haloalkylcarbonyl, haloalkylcarbonylcarbonyl, heterocyclyl, Heterocyclyl)alkylcarbonyl, heterocyclylcarbonyl, heterocyclylcarbonylalkylcarbonyl, heterocyclylcarbonylcarbonyl, hydroxyalkenylcarbonyl, hydroxyalkylcarbonyl, (NR ^c R ^d )alkylcarbonyl, (NR ^c R ^d )carbonyl, (NR ^c R ^d )carbonylalkylcarbonyl, (NR ^c R ^d )carbonylcarbonyl, and Wherein R and R' are each an alkyl group, or together with the carbon atom to which they are attached, form a five or six membered ring containing an oxygen or nitrogen atom; or R ² and R ^f together with the nitrogen atom to which they are attached, as appropriate a five or six membered ring substituted with one or two groups independently selected from the group consisting of an alkoxycarbonylamino group and a pendant oxy group; or R ² and R ^f together with the nitrogen atom to which they are attached

In a ninth embodiment, the invention provides a combination comprising an NS5A targeting compound and an NS5A synergist which, when administered, provides synergistic resistance against variants containing mutations that confer resistance to a single NS5A targeting compound HCV activity wherein the NS5A targeting compound is a compound of formula (VII): Or a pharmaceutically acceptable salt thereof, wherein: L is absent or selected from the group consisting of -O-, -CH ₂ -O-CH ₂ -, -OCH ₂ -, C ₂ alkyl, C ₂ alkynyl, cyclopropyl , ethynylbenzyl, phenyl, pyrazinyl and pyridyl; A is selected from the group consisting of aryl, cycloalkenyl and heteroaryl; B is selected from aryl, bicycloalkyl, cycloalkenyl and heteroaryl Each R ¹ line is independently selected from Each m is independently 0, 1 or 2; each X is independently selected from CH ₂ , NH and NR ^a ; wherein R ^a is alkyl; each R ² is independently selected from alkyl, halo and hydroxy; The alkyl group may optionally form a fused three to six membered ring with an adjacent carbon, a bridged four or five membered ring with another carbon atom on the ring, or a three to six membered ring of a spiral ring attached thereto. Wherein each ring is optionally substituted with one or two groups independently selected from the group consisting of alkyl, halo and haloalkyl; or R ² together with the carbon atom to which it is attached form a C ₂ olefin; each R ³ is independently selected From alkoxy, alkyl, arylalkoxy, arylalkyl, cycloalkyl, (cycloalkyl)alkyl, cycloalkoxy, heterocyclyl, heterocyclylalkyl, (NR ^c R ^d ) alkenyl and (NR ^c R ^d )alkyl; each R ⁴ is independently selected from the group consisting of hydrogen, alkyl, cycloalkyl and haloalkyl; each R ⁵ is independently selected from hydrogen and alkyl; ^{The p} is independently selected from the group consisting of hydrogen, alkyl, cyano, halo, haloalkoxy, and haloalkyl; and each R ^q is independently selected from the group consisting of hydrogen, alkyl, halo, and -P(O)-( OR) ₂ wherein each R is the same or a different alkyl group.

In a tenth embodiment, the invention provides a combination comprising an NS5A targeting compound and an NS5A synergist which, when administered, provides synergistic resistance against variants containing mutations that confer resistance to a single NS5A targeting compound HCV activity wherein the NS5A targeting compound is a compound of formula (VIII): Or a pharmaceutically acceptable salt thereof, wherein: m and n are independently 0, 1 or 2; L is absent or selected from C ₂ alkynyl, naphthyl, phenyl, pyridyl, pyrazinyl, pyrimidinyl ,and X and Y lines are each independently selected from among them Represents the connection point with L and Represents the point of attachment to the pyrrolidine ring; each R ^q is independently selected from the group consisting of hydrogen, alkyl, halo and -P(O)-(OR) ₂ wherein each R is the same or different alkyl; R ¹ and R ² is each independently selected from the group consisting of an alkoxy group, an alkyl group, a halogen group, a haloalkyl group, and a hydroxyl group; wherein the alkyl group may form a fused three to six membered ring with an adjacent carbon, and another carbon atom on the ring. Forming a bridged four or five membered ring, or a carbon atom to which it is attached, forming a three to six membered ring of a spiro ring; wherein each ring is optionally selected from one or two groups independently selected from the group consisting of an alkyl group, a halogen group, and a haloalkyl group. Substituting; or R ² together with the carbon atom to which it is attached to form a C ₂ olefin; and R ³ and R ⁴ are each independently selected from alkoxy, alkyl, arylalkoxy, arylalkyl, cycloalkyl (cycloalkyl)alkyl, cycloalkoxy, heterocyclyl, heterocyclylalkyl, (NR ^c R ^d )alkenyl and (NR ^c R ^d )alkyl.

In an eleventh embodiment, the invention provides a combination comprising an NS5A targeting compound and an NS5A potentiator, which when administered, provides synergy against variants containing mutations that confer resistance to a single NS5A targeting compound Anti-HCV activity wherein the NS5A targeting compound is a compound of formula (IX): Or a pharmaceutically acceptable salt thereof, wherein: L is absent or selected from C ₂ alkyl, -C(O)-, isoquinolyl, naphthyl, phenyl, pyrimidinyl, pyrazinyl, pyridyl Quinoline, Wherein Q is selected from the group consisting of O, O(CR ^z ) ₂ and (C(R ^z ) ₂ ) _n , wherein n is 1 or 2, and each R ^z is independently selected from the group consisting of hydrogen, alkyl and halo; X and Y lines are each independently selected from among them Represents the connection point with L and Representing a point of attachment to a pyrrolidine ring; each R ^q is independently selected from the group consisting of hydrogen, alkyl, halo, and -P(O)-(OR) ₂ , wherein each R is the same or different alkyl; When L is or When one of X and Y is not m and n are each 0, 1 or 2; R ¹ and R ² are each independently selected from the group consisting of alkyl, halo and hydroxy; wherein the alkyl may optionally form a fused three to six membered ring with the adjacent carbon, Another carbon atom on the ring forms a bridged four or five membered ring, or a carbon atom to which it is attached, forming a three to six membered ring of a spiro ring; wherein each ring is independently selected from an alkyl group, a halo group by one or two Substituting a group of a haloalkyl group; or R ² together with a carbon atom to which it is bonded to form a C ₂ olefin; and R ³ and R ⁴ are each independently selected from the group consisting of an alkoxy group, an alkyl group, an aryl alkoxy group, and an aromatic group. Alkyl, cycloalkyl, (cycloalkyl)alkyl, cycloalkoxy, heterocyclyl, heterocyclylalkyl, (NR ^c R ^d )alkenyl and (NR ^c R ^d )alkyl.

In a twelfth embodiment, the invention provides a combination comprising an NS5A targeting compound and an NS5A potentiator, which when administered, provides synergy against variants containing mutations that confer resistance to a single NS5A targeting compound Anti-HCV activity wherein the NS5A targeting compound is a compound of formula (X): Or a pharmaceutically acceptable salt thereof, wherein: A is selected from the group consisting of indanyl, phenyl and pyridyl; and L is absent or selected from C ₂ alkenyl, C ₂ alkynyl, R ¹ is selected from among them Indicates the point of attachment to L; R ² is selected from and Each m is independently 0, 1 or 2; each R ³ is independently selected from alkyl, halo and hydroxy; or R ³ together with the carbon atom to which it is attached forms a C ₂ olefin; and each R ⁴ is independently selected From alkoxy, alkyl, arylalkoxy, arylalkyl, cycloalkyl, (cycloalkyl)alkyl, cycloalkoxy, heterocyclyl, heterocyclylalkyl, (NR ^c R ^d ) alkenyl and (NR ^c R ^d )alkyl; each R ⁵ and R ⁶ are independently selected from hydrogen and methyl; R ^x is selected from hydrogen and alkyl; and X is selected from CH ₂ , CH ₂ CH ₂ , CHR ³ , C(R ³ ) ₂ and O.

In a thirteenth embodiment, the invention provides a combination comprising an NS5A targeting compound and an NS5A potentiator, which when administered, provides synergy against variants containing mutations that confer resistance to a single NS5A targeting compound Anti-HCV activity, wherein the NS5A targeting compound is a compound of formula (XI): Or a pharmaceutically acceptable salt thereof, wherein: L is selected from the group consisting of C ₂ alkenyl groups and

In a fourteenth embodiment, the invention provides a combination comprising a NS5A targeting compound and an NS5A potentiator, which when administered, provides synergy against variants containing mutations that confer resistance to a single NS5A targeting compound Anti-HCV activity wherein the NS5A targeting compound is a compound of formula (XII): Or a pharmaceutically acceptable salt thereof, wherein: L is R ¹ is selected from and Each R ² is independently selected from alkoxy, alkyl, arylalkoxy, arylalkyl, cycloalkyl, (cycloalkyl)alkyl, cycloalkoxy, heterocyclyl, heterocyclyl An alkyl group, (NR ^c R ^d ) alkenyl group and (NR ^c R ^d ) alkyl group; n is 0, 1 or 2; each R ³ group is selected from the group consisting of hydrogen, hydroxyl group, -NR ^a R ^b and And each R ⁴ is independently selected from the group consisting of an alkyl group, a halogen group, and a hydroxyl group; wherein the alkyl group optionally forms a fused three to six membered ring with an adjacent carbon and forms a bridge with another carbon atom on the ring. a five-membered ring, or a carbon atom to which it is attached, forms a three- to six-membered ring of a spiro ring; wherein each ring is optionally substituted with one or two groups independently selected from the group consisting of an alkyl group, a halo group, and a haloalkyl group; or two The R ⁴ groups together form an extended ethyl group.

In a fifteenth embodiment, the invention provides a combination comprising a NS5A targeting compound and an NS5A potentiator, which when administered, provides synergy against variants containing mutations that confer resistance to a single NS5A targeting compound Anti-HCV activity wherein the NS5A targeting compound is a compound of formula (XIII): Or a pharmaceutically acceptable salt thereof, wherein: each R ¹ is independently selected from the group consisting of an alkoxy group, an alkyl group, an aryl alkoxy group, an arylalkyl group, a cycloalkyl group, a (cycloalkyl)alkyl group, Cycloalkoxy, heterocyclyl, heterocyclylalkyl, (NR ^c R ^d )alkenyl and (NR ^c R ^d )alkyl.

In a sixteenth embodiment, the invention provides a combination comprising a NS5A targeting compound and an NS5A potentiator, which when administered, provides synergy against variants containing mutations that confer resistance to a single NS5A targeting compound Anti-HCV activity wherein the NS5A targeting compound is a compound of formula (XIV): Or a pharmaceutically acceptable salt thereof, wherein: L is C ₂ alkyl; and each R ¹ is independently selected from alkoxy, alkyl, arylalkoxy, arylalkyl, cycloalkyl, (Cycloalkyl)alkyl, cycloalkoxy, heterocyclyl, heterocyclylalkyl, (NR ^c R ^d )alkenyl and (NR ^c R ^d )alkyl.

In a sixteenth embodiment, the NS5A targeting compound is selected from

In a second aspect, the invention provides a combination comprising an NS5A targeting compound and an NS5A synergist or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. In a first embodiment of the second aspect, the composition additionally comprises one or two additional compounds having anti-HCV activity. In a second embodiment of the second aspect, at least one of the additional compounds is an interferon or ribavirin. In a third embodiment of the second aspect, the interferon is selected from the group consisting of interferon alpha 2B, pegylated interferon alpha, consensus interferon, interferon alpha 2A, pegylated interferon lambda, and lymphoblastoid interference Prime τ.

In a fourth embodiment of the second aspect, the invention provides a combination comprising an NS5A targeting compound and an NS5A synergist or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable carrier, and at least An additional compound having anti-HCV activity, wherein at least one of the additional compounds is selected from the group consisting of interleukin 2, interleukin 6, interleukin 12, a compound which enhances type 1 helper T cell reaction, and interfering RNA , antisense RNA, Imiqimod, ribavirin, inosine 5'-monophosphate dehydrogenase inhibitor, amantadine and rimantadine.

In a fifth embodiment, the invention provides a combination comprising an NS5A targeting compound and an NS5A synergist or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable carrier, and at least one having anti-HCV activity An additional compound, wherein at least one of the additional compounds is effective to inhibit the function of a target selected from the group consisting of HCV protein alcohol, HCV polymerase, HCV helicase, HCV NS4B protein, HCV importer , HCV assembly, HCV exporter, HCV NS5A protein and IMPDH.

In a third aspect, the invention provides a method of treating a HCV infection in a patient comprising administering to the patient a therapeutically effective amount comprising a NS5A targeting compound and an NS5A synergist Or a combination of pharmaceutically acceptable salts thereof. In a first embodiment of the third aspect, the method additionally comprises administering one or two additional compounds having anti-HCV activity before, after or simultaneously with the combination. In a second embodiment of the third aspect, at least one of the additional compounds is an interferon or ribavirin. In a third embodiment of the third aspect, the interferon is selected from the group consisting of interferon alpha 2B, pegylated interferon alpha, consensus interferon, interferon alpha 2A, pegylated interferon lambda, and lymphoblastoid interference Prime τ.

In a fourth embodiment of the third 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 NS5A-targeting compound and an NS5A potentiator or a pharmaceutically acceptable agent thereof a combination of acceptable salts (when administered, which provides synergistic anti-HCV activity against variants containing mutations that confer resistance to a single NS5A targeting compound) and administration of at least one anti-antibody before, after or simultaneously with the combination An additional compound of HCV activity, wherein at least one of the additional compounds is selected from the group consisting of interleukin 2, interleukin 6, interleukin 12, a compound that enhances type 1 helper T cell responses, interfering RNA, antisense RNA, imiquimod, ribavirin, inosine 5'-monophosphate dehydrogenase inhibitor, amantadine and rimantadine.

In a fifth embodiment of the third 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 NS5A-targeting compound and an NS5A potentiator or a pharmaceutically acceptable agent thereof a combination of salts (when administered, which provides synergistic anti-HCV activity against variants containing mutations that confer resistance to a single NS5A targeting compound) and one or two prior to, after, or simultaneously with the combination An additional compound having anti-HCV activity, wherein at least one of the additional compounds is effective to inhibit the function of a target selected from the group consisting of HCV protease, HCV polymerase, HCV helicase, HCV NS4B protein, HCV inlet body, HCV assembly, HCV export body, HCV NS5A protein and IMPDH.

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.

In this context, the description of the invention should be construed in accordance with the laws and principles of chemical bonding. In some cases, it may be desirable to remove a hydrogen atom to accommodate a substituent at any given location.

In some cases, the number of carbon atoms in the group is shown prior to the description of any particular group. For example, the term "C _2-6 alkenyl" means an alkenyl group having two to six carbon atoms. When such designated names exist, they supersede all other definitions contained herein.

It is to be understood that the compounds encompassed by the present invention are compounds suitable for stable use as pharmaceutical agents.

The definition of any substituent or variable at a particular position in the molecule is independent of its definition at other positions in the molecule. For example, when n is 2, the two R ² 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 the event of inconsistency, the present invention, including definitions, will control.

The following terms as used in this specification have the meaning indicated: As used herein, the singular forms "

Unless otherwise specified, all aryl, cycloalkyl and heterocyclic groups of the invention may be substituted as described for each of their respective definitions. For example, the aryl moiety of an arylalkyl group can be substituted as described in the definition of the term "aryl".

As used herein, the term "NS5A potentiator" means the following molecules: a targeting compound which is weaker than NS5A activity against wild-type HCV demonstrated the individual, but increased the compounds targeting NS5A and EC in combination demonstrated the effectiveness of ₅₀ The efficacy of the NS5A targeting compound alone is more than three times.

As used herein the term "synergistic anti-HCV activity" means the potency EC ₅₀ alone increased targeting NS5A three times more potency of the compound.

The term "NS5A targeting compound" as used herein refers to an assay that inhibits HCV replication, at least one of which is localized to the NS5A protein and most typically, but not limited to, within the first 100 residues of NS5A.

The term "alkenyl" as used herein refers to a straight or branched chain group having from two to six carbon atoms and containing at least one carbon to carbon double bond.

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

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

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

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

The term "alkoxyalkoxy" as used herein refers to an alkoxyalkyl group attached to the parent molecular moiety through an oxygen atom.

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

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

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

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

The term "alkoxycarbonylalkyl" as used herein refers to an alkyl group substituted with one or two alkoxycarbonyl groups.

The term "alkoxycarbonylalkylcarbonyl," as used herein, refers to a carbonyl group attached to An alkoxycarbonylalkyl group of the parent molecular moiety.

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

The term "alkoxycarbonylamino" as used herein refers to R"O-C(O)-N(H)-, wherein R" is alkyl.

The term "alkyl" as used herein refers to a radical derived from a straight or branched chain saturated hydrocarbon containing from one to seven carbon atoms.

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

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

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

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

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

The term "alkylthio" as used herein refers to an alkyl group attached to the parent molecular moiety through a sulfur atom.

The term "alkylsulfinyl" as used herein refers to an alkyl group attached to the parent molecular moiety through a sulfinyl group.

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

The term "alkynyl" as used herein refers to a straight or branched chain hydrocarbon having from two to six carbon atoms and containing at least one carbon-carbon reference.

The term "alkynyloxy" as used herein refers to a moiety attached to the parent molecule through an oxygen atom. Alkynyl group.

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

The term "aryl" as used herein refers to phenyl, or a bicyclic or tricyclic fused ring system wherein at least one ring is phenyl. The bicyclic fused ring system consists of a phenyl fused to a four to six membered aromatic or non-aromatic carbocyclic ring. The tricyclic fused ring system consists of a bicyclic fused ring system fused to a four to six membered aromatic or non-aromatic carbocyclic ring. The aryl group of the present invention may be attached to the parent molecular moiety through any substitutable carbon atom in the group. Representative examples of aryl include, but are not limited to, indanyl, indenyl, naphthyl, phenyl, and tetrahydronaphthyl. The aryl group of the present invention is optionally substituted with one, two, three, four or five substituents independently selected from the group consisting of alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkane Base, alkylcarbonyl, second aryl, aryloxy, alkoxy, arylalkyl, arylcarbonyl, aryloxy, cyano, cycloalkyl, halo, haloalkoxy, haloalkyl , heterocyclyl, heterocyclylalkyl, heterocyclylcarbonyl, hydroxy, hydroxyalkyl, nitro, -NR ^x R ^y , (NR ^x R ^y )alkyl, pendant oxy and -P(O)OR ₂ wherein each R is independently selected from the group consisting of hydrogen and alkyl; and wherein the alkyl portion of the arylalkyl and heterocyclylalkyl groups is unsubstituted, and wherein the aryl portion of the second aryl or arylalkyl group The aryl moiety of the arylcarbonyl group, the aryl moiety of the aryloxy group, the cycloalkyl group, the heterocyclic group, and the heterocyclic group of the heterocyclylalkyl group and the heterocyclic carbonyl group are further optionally one, two or three. Substituents substituted independently from alkoxy, alkyl, cyano, halo, haloalkoxy, haloalkyl and nitro are substituted.

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

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

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

The term "arylalkoxycarbonyl," as used herein, refers to a carbonyl group attached to the parent. A subunit of an arylalkoxy group.

The term "arylalkyl" as used herein refers to an alkyl group substituted with one, two or three aryl groups. The alkyl portion of the arylalkyl group is further optionally substituted with one, two or three other groups independently selected from the group consisting of alkoxy, alkylcarbonyloxy, halo, haloalkoxy, haloalkyl a base group, a heterocyclic group, a hydroxyl group, and -NR ^c R ^d , wherein the heterocyclic group is further substituted with one or two substituents independently selected from the group consisting of an alkoxy group, an alkyl group, an unsubstituted aryl group. Unsubstituted arylalkoxy, unsubstituted arylalkoxycarbonyl, halo, haloalkoxy, haloalkyl, hydroxy, -NR ^x R ^y and pendant oxy.

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

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

The term "arylcarbonylcarbonyl" as used herein refers to an arylcarbonyl group attached to the parent molecular moiety through a carbonyl group.

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

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

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

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

The term "arylthio" as used herein refers to an aryl group attached to the parent molecular moiety through a sulfur atom.

The term "arylthioalkyl" as used herein refers to an alkyl group substituted with one, two or three arylthio groups. The alkyl portion of the arylthioalkyl group can be further processed as appropriate Or two halo groups.

The term "arylthioalkylcarbonyl" as used herein refers to an arylthioalkyl group attached to the parent molecular moiety through a carbonyl group.

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

The term "bicycloalkyl" as used herein refers to a saturated, fused, bridged or spirocyclic bicyclic hydrocarbon ring system having six to twelve carbon atoms and zero heteroatoms. The bicycloalkyl groups of the invention are optionally substituted with one, two or three groups independently selected from the group consisting of alkyl, halo and haloalkyl.

The term "bicycloalkylcarbonyl," as used herein, refers to a bicycloalkyl group attached to the parent molecular moiety through a carbonyl group.

The term "carbonyl" as used herein refers to -C(O)-.

The term "carboxy" as used herein refers to the -CO ₂ H.

The term "carboxyalkyl" as used herein refers to an alkyl group substituted with one, two or three carboxy groups.

The term "carboxyalkylcarbonyl," as used herein, refers to a carboxyalkyl group attached to the parent molecular moiety through a carbonyl group.

The term "carboxycarbonyl" as used herein refers to a carboxy group attached to the parent molecular moiety through a carbonyl group.

The term "cyano" as used herein refers to -CN.

The term "cyanoalkyl" as used herein refers to an alkyl group substituted with one, two or three cyano groups.

The term "cyanoalkylcarbonyl" as used herein refers to a cyanoalkyl group attached to the parent molecular moiety through a carbonyl group.

The term "cycloalkenyl" as used herein refers to a non-aromatic, partially unsaturated monocyclic, bicyclic or tricyclic ring system having three to fourteen carbon atoms and zero heteroatoms. Representative examples of cycloalkenyl include, but are not limited to, cyclohexenyl, octahydronaphthyl, and Alkenyl. The cycloalkenyl groups of the invention are optionally substituted by one, two or three alkyl groups.

The term "(cycloalkenyl)alkyl" as used herein refers to an alkyl group substituted with one, two or three cycloalkenyl groups. The alkyl portion of the (cycloalkenyl)alkyl group may be further substituted with an alkoxycarbonyl group as appropriate.

The term "cycloalkyl" as used herein refers to a saturated monocyclic, bicyclic or tricyclic hydrocarbon ring system having three to fourteen carbon atoms and zero heteroatoms. The bicyclic and tricyclic systems can be fused, bridged or spiro systems or any combination thereof. Representative examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclopentyl, bicyclo[3.1.1]heptyl, and adamantyl. The cycloalkyl group of the present invention is optionally substituted with one, two, three, four or five substituents independently selected from the group consisting of alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, An alkyl group, an alkylcarbonyl group, an alkylcarbonyloxy group, an aryl group, an arylalkyl group, a cyano group, a cycloalkenyl group, a second cycloalkyl group, an exocyclic double bond optionally substituted with one or two halo groups, Halo, haloalkoxy, haloalkyl, heterocyclyl, heterocyclylcarbonyl, heterocyclylcarbonyloxy, hydroxy, hydroxyalkyl, nitro, -NR ^x R ^y , (NR ^x R ^y ) alkane a (NR ^x R ^y )carbonyloxy group and a pendant oxy group; wherein the aryl group, the aryl moiety of the arylalkyl group, the cycloalkenyl group, the second cycloalkyl group and the heterocyclic group are further passed through one or two Or three substituents independently selected from the group consisting of alkoxy, alkyl, cyano, halo, haloalkoxy, haloalkyl and hydroxy.

The term "(cycloalkyl)alkyl" as used herein refers to an alkyl group substituted with one, two or three cycloalkyl groups. The alkyl portion of the (cycloalkyl)alkyl group may be further substituted with one or two groups independently selected from the group consisting of an alkoxy group, an alkoxycarbonyl group, a halogen group, and a hydroxyl group.

The term "(cycloalkyl)alkylcarbonyl, as used herein, refers to a (cycloalkyl)alkyl group attached to the parent molecular moiety through a carbonyl group.

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

The term "cycloalkylcarbonylcarbonyl" as used herein refers to a carbonyl group attached to the parent group. a sub-part of the cycloalkylcarbonyl group.

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

The term "cycloalkoxycarbonyl," as used herein, refers to a cycloalkoxy group attached to the parent molecular moiety through a carbonyl group.

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

The term "methyl thiol" as used herein refers to -CHO.

The term "halo" as used herein refers to Cl, Br, F or I.

The term "haloalkenyl" as used herein refers to an alkenyl group substituted with one, two, three or four halogen atoms.

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

The term "haloalkoxyalkyl" as used herein refers to an alkyl group substituted with one, two or three haloalkoxy groups.

The term "haloalkoxyalkylcarbonyl," as used herein, refers to a haloalkoxyalkyl group attached to the parent molecular moiety through a carbonyl group.

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

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

The term "haloalkylcarbonyl," as used herein, refers to a haloalkyl group attached to the parent molecular moiety through a carbonyl group.

The term "haloalkylcarbonylcarbonyl" as used herein refers to a haloalkylcarbonyl group attached to the parent molecular moiety through a carbonyl group.

The term "heteroaryl" as used herein refers to an aromatic five or six membered ring wherein at least one atom is selected from the group consisting of N, O and S and the remaining atoms are carbon. The term "heteroaryl" also includes bicyclic systems wherein the heteroaryl ring is fused to a four to six membered aromatic or non-aromatic ring containing zero, one or two other heteroatoms selected from N, O and S. A heteroaryl group is attached to the parent molecular moiety through any substitutable carbon or nitrogen atom in the group. Representative examples of heteroaryl include, but are not limited to, benzooxadiazolyl, benzoxazolyl, benzofuranyl, benzothienyl, furyl, imidazolyl, oxazolyl, fluorenyl, Isoxazolyl, isoquinolyl, isothiazolyl, Pyridyl, oxadiazolyl, oxazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyrrolyl, quinolyl, thiazolyl, thienopyridyl, thienyl, triazole Base, thiadiazolyl and triazinyl.

The term "heterocyclyl" as used herein, refers to a single-ring, five-, six-, or seven-membered ring containing one, two, three, or four heteroatoms independently selected from nitrogen, oxygen, and sulfur. . The four-member ring has zero double bonds, the five-member ring has zero to two double bonds, and the six- and seven-member rings have zero to three double bonds. The term "heterocyclyl" also includes bicyclic and tricyclic systems wherein at least one ring is heterocyclic. The bicyclic and tricyclic systems can be fused, spiro, bridging systems or combinations thereof. The heterocyclic group of the present invention may be attached to the parent molecular moiety through any carbon or nitrogen atom in the group. Examples of heterocyclic groups include, but are not limited to, benzothienyl, furyl, imidazolyl, porphyrinyl, fluorenyl, isoquinolyl, isothiazolyl, isoxazolyl, morpholinyl, oxalic Azyl, oxetane, piperazinyl, piperidinyl, pyrazolyl, pyridyl, pyrrolidinyl, pyrrolopyridyl, pyrrolyl, quinolyl, tetrahydrofuranyl, tetrahydropyranyl, Thiazolyl, thienyl and thiomorpholinyl. The heterocyclic group of the present invention is optionally substituted by one, two, three, four or five substituents independently selected from the group consisting of alkenyl, alkoxy, alkoxyalkoxycarbonyl, alkoxy. Alkyl, alkoxyalkylcarbonyl, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylsulfonyl, aryl, arylalkoxycarbonyl, arylalkyl, arylcarbonyl, cyano, a cycloalkylcarbonyl group, a cycloalkoxycarbonyl group, an exocyclic double bond optionally substituted by one or two halo groups, a halo group, a haloalkoxy group, a haloalkoxycarbonyl group, a haloalkyl group, a second heterocyclic group , heterocyclylalkyl, heterocyclylcarbonyl, hydroxy, hydroxyalkyl, nitro, -NR ^x R ^y , (NR ^x R ^y )alkyl and pendant oxy, wherein arylalkyl and heterocycloalkyl The alkyl moiety is unsubstituted, and wherein the aryl group, the aryl moiety of the arylalkyl group, the aryl moiety of the arylcarbonyl group, the cycloalkyl group, the second heterocyclic group, and the heterocyclylalkyl group and the heterocyclic group The heterocyclyl moiety of the carbonyl group is further optionally substituted by one, two or three independently selected from the group consisting of alkoxy, alkyl, cyano, halo, haloalkoxy, haloalkyl, hydroxy and nitro Substituted.

The term "heterocyclylalkoxy" as used herein refers to a heterocyclic group attached to the parent molecular moiety through an alkoxy group.

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

The term "heterocyclylalkyl" as used herein refers to an alkyl group substituted with one, two or three heterocyclic groups. The alkyl portion of the heterocyclylalkyl group is further optionally substituted with one, two or three other groups independently selected from the group consisting of alkoxy, alkylcarbonyloxy, aryl, halo, haloalkoxy a group, a haloalkyl group, a hydroxyl group, and -NR ^c R ^d , wherein the aryl group is further substituted with one or two substituents independently selected from the group consisting of an alkoxy group, an alkyl group, an unsubstituted aryl group, Unsubstituted arylalkoxy, unsubstituted arylalkoxycarbonyl, halo, haloalkoxy, haloalkyl, hydroxy and -NR ^x R ^y .

The term "heterocyclylalkylcarbonyl," as used herein, refers to a heterocyclylalkyl group attached to the parent molecular moiety through a carbonyl group.

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

The term "heterocyclylcarbonylalkyl" as used herein refers to an alkyl group substituted with one, two or three heterocyclylcarbonyl groups.

The term "heterocyclylcarbonylalkylcarbonyl," as used herein, refers to a heterocyclylcarbonylalkyl group attached to the parent molecular moiety through a carbonyl group.

The term "heterocyclylcarbonylcarbonyl," as used herein, refers to a heterocyclylcarbonyl group attached to the parent molecular moiety through a carbonyl group.

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

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

The term "hydroxy" as used herein refers to -OH.

The term "hydroxyalkenyl" as used herein refers to an alkenyl group substituted with one, two or three hydroxy groups.

The term "hydroxyalkyl" as used herein refers to an alkyl group substituted with one, two or three hydroxy groups. The alkyl portion of the hydroxyalkyl group is further substituted with one, two or three halo groups, as appropriate.

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

The term "nitro" as used herein refers to -NO ₂ .

The term "-NR ^c R ^d " as used herein refers to two groups R ^c and R ^d attached to the parent molecular moiety through a nitrogen atom. R ^c and R ^d are independently selected from the group consisting of hydrogen, alkenyloxycarbonyl, alkoxyalkyl, alkoxyalkylcarbonyl, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylsulfonyl, alkynyl , alkynyloxycarbonyl, aryl, arylalkoxycarbonyl, arylalkyl, arylalkylcarbonyl, arylcarbonyl, aryloxycarbonyl, arylsulfonyl, cyanoalkyl, cycloalkyl , cycloalkoxy, cycloalkoxycarbonyl, cycloalkylsulfonyl, decyl, haloalkoxycarbonyl, haloalkyl, heterocyclyl, heterocyclylalkoxycarbonyl, heterocyclylalkyl ,heterocyclylalkylcarbonyl,heterocyclylcarbonyl,heterocyclyloxycarbonyl,hydroxyalkylcarbonyl,(NR ^e R ^f )alkyl,(NR ^e R ^f )alkylcarbonyl,(NR ^e R ^f ) a carbonyl group, (NR ^e R ^f )sulfonyl group, -C(NCN)OR', and -C(NGN)NR ^x R ^y , wherein R' is selected from an alkyl group and an unsubstituted phenyl group, and an aryl group thereof The alkyl moiety of the alkyl, arylalkylcarbonyl, heterocyclylalkyl and heterocyclylalkylcarbonyl is further optionally substituted with a -NR ^e R ^f group; and wherein aryl, arylalkoxycarbonyl , arylalkyl, arylalkylcarbonyl, arylcarbonyl, aryloxycarbonyl And an aryl moiety of an arylsulfonyl group, a heterocyclic group, and a heterocyclylalkoxycarbonyl group, a heterocyclylalkyl group, a heterocyclylalkylcarbonyl group, a heterocyclic carbonyl group, and a heterocyclic oxycarbonyl group. The cycloalkyl moiety is further optionally substituted with one, two or three substituents independently selected from the group consisting of alkoxy, alkyl, cyano, halo, haloalkoxy, haloalkyl and nitro.

The term "(NR ^c R ^d )alkenyl" as used herein refers to

Wherein R ^c and R ^{d are} as defined herein and each R ^{q is} independently hydrogen or C _1-3 alkyl.

The term "(NR ^c R ^d )alkyl" as used herein refers to an alkyl group substituted with one, two or three -NR ^c R ^d groups. The alkyl moiety of (NR ^c R ^d )alkyl is further optionally substituted with one or two other groups selected from the group consisting of alkoxy, alkoxyalkylcarbonyl, alkoxycarbonyl, alkylthio, Arylalkoxycarbonyl, carboxy, cycloalkyl, heterocyclyl, heterocyclylcarbonyl, hydroxy and (NR ^e R ^f )carbonyl; wherein the heterocyclic group is further passed through one, two, three, four Substituted with one or five substituents independently selected from the group consisting of alkoxy, alkyl, cyano, halo, haloalkoxy, haloalkyl and nitro.

As used herein the term "(NR ^c R ^d) alkylcarbonyl" means a carbonyl group attached to via (NR ^c R ^d) alkyl of parent molecular moiety. The alkyl portion of the (NR ^c R ^d )alkylcarbonyl group may be optionally substituted with one or two groups independently selected from the group consisting of an aryl group and a cycloalkyl group.

As used herein, the term "(NR ^c R ^d) carbonyl group" means a carbonyl group attached via -NR ^c R ^d to a group of the parent molecular moiety.

The term "(NR ^c R ^d )carbonylalkyl" as used herein refers to an alkyl group substituted with one, two or three (NR ^c R ^d )carbonyl groups.

As used herein the term "(NR ^c R ^d) carbonyl alkylcarbonyl group" refers to a carbonyl group via (NR ^c R ^d) carbonyl group of the parent molecular moiety.

As used herein the term "(NR ^c R ^d) carbonyl group a carbonyl group" refers to a carbonyl group via (NR ^c R ^d) carbonyl group of the parent molecular moiety.

The term "-NR ^e R ^f " as used herein refers to two groups R ^e and R ^f attached to the parent molecular moiety through a nitrogen atom. R ^e and R ^f are independently selected from hydrogen, alkyl, unsubstituted aryl, unsubstituted arylalkyl, unsubstituted cycloalkyl, unsubstituted (cycloalkyl)alkyl Unsubstituted heterocyclic group, unsubstituted heterocyclylalkyl group, (NR ^x R ^y )alkyl group and (NR ^x R ^y )carbonyl group.

The term "(NR ^e R ^f )alkyl" as used herein refers to an alkyl group substituted with one, two or three -NR ^e R ^f groups.

As used herein the term "(NR ^e R ^f) alkylcarbonyl" means a carbonyl group attached to via (NR ^e R ^f) alkyl group of the parent molecular moiety.

As used herein, the term "(NR ^e R ^f) carbonyl group" refers to a carbonyl group by -NR ^e R ^f group of the parent molecular moiety.

As used herein the term "(NR ^e R ^f) acyl sulfo" means a sulfo by acyl attached to -NR ^e R ^f group of the parent molecular moiety.

The term "-NR ^x R ^y " as used herein refers to two groups R ^x and R ^y attached to the parent molecular moiety through a nitrogen atom. R ^x and R ^y are independently selected from the group consisting of hydrogen, alkoxycarbonyl, alkyl, alkylcarbonyl, unsubstituted aryl, unsubstituted arylalkoxycarbonyl, unsubstituted arylalkyl , unsubstituted cycloalkyl, haloalkoxycarbonyl, haloalkyl, unsubstituted heterocyclic, unsubstituted heterocyclylcarbonyloxy and (NR ^x' R ^{y '} )carbonyl, wherein R ^X' and R ^{y '} are independently selected from the group consisting of hydrogen and alkyl.

The term "NR ^x' R ^{y '} as used herein refers to two groups R ^{x '} and R ^{y '} attached to the parent molecular moiety through a nitrogen atom. R ^{x '} and R ^{y '} are independently selected from the group consisting of hydrogen and alkyl.

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

As used herein, the term "(NR ^x R ^y) carbonyl group" means a carbonyl group via the parent molecular moiety attached to the -NR ^x R ^y groups.

As used herein, the term "(NR ^{x 'R y')} carbonyl" refers to a carbonyl group via the parent molecular moiety -NR of ^{x 'R y'} group.

The term "sideoxy" as used herein refers to =0.

The term "sulfinyl" as used herein refers to -S(O)-.

The term "sulfonic acyl" herein used refers to the -SO ₂ -.

Asymmetric centers are present in the compounds of the invention. Depending on the configuration of the substituents around the palm carbon atom, these centers are named by the symbol "R" or "S". It will be appreciated that the invention encompasses all stereochemically isomeric forms or mixtures thereof that have the ability to inhibit NS5A. Individual stereoisomers of a compound may be prepared synthetically from a commercially available starting material containing a palmitic center; or by preparation of a mixture of enantiomeric products, followed by separation, such as conversion to diastereomers The mixture is prepared by separation or recrystallization, chromatographic techniques, or direct separation of the enantiomers on a palm chromatography column. Starting compounds having a particular stereochemistry are either commercially available or can be prepared and resolved by techniques known in the art.

Certain compounds of the invention may also exist in different stable conformational forms which are separable. Torsional asymmetry due to limitations on the rotation of asymmetric single bonds (e.g., due to steric hindrance or ring stress) may allow separation of different conformers. The present invention includes each of the configurational isomers of such compounds and mixtures thereof.

The compounds of the invention also exist in tautomeric forms; therefore, the invention also encompasses all tautomeric forms.

The term "compounds of the invention" and equivalent expressions are intended to encompass the compounds which form the combinations of the invention, as well as the pharmaceutically acceptable enantiomers, diastereomers and salts thereof. Similarly, if the context permits, the intermediate is referred to as its salt.

The invention is intended to include all isotopes of the atoms present in the compounds of the invention. Isotopes include those atoms that have the same number of atoms but different mass numbers. As a general example and not a limitation, hydrogen isotopes include ruthenium and osmium. Carbon isotopes include ¹³ C and ¹⁴ C. Isotopically labeled compounds of the invention can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described herein, using an appropriate isotopically labeled reagent in place of an otherwise employed unlabeled reagent. Such compounds can have a variety of potential uses, such as standards and reagents when determining biological activity. In the case of stable isotopes, such compounds may have the potential to advantageously improve biological, pharmacological or pharmacokinetic properties.

The compounds of the invention may exist in the form of a pharmaceutically acceptable salt. The term "pharmaceutically acceptable salt" as used herein denotes a salt or zwitterionic form of a compound of the invention which is soluble or dispersible in water or oil and which is suitable for patient tissue in the context of sound medical judgment. Exposure to use without excessive toxicity, irritation, allergic reactions or other problems or complications, matching the reasonable benefit/risk ratio and being effective for its intended use. Salts can be prepared during the final isolation and purification of the compound, or separately 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, camphorate , camphor sulfonate, digluconate, glycerol phosphate, hemisulfate, heptanoate, hexanoate, formate, fumarate, hydrochloride, hydrobromide, hydrogen iodine Acid salt, 2-hydroxyethane sulfonate, lactate, maleate, mesitylene sulfonate, methane sulfonate, naphthalene sulfonate, nicotinic acid salt, 2-naphthalene sulfonate , oxalate, pamoate, pectate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, tri Chloroacetate, trifluoroacetate, phosphate, glutamate, bicarbonate, p-toluenesulfonate and undecanoate. Examples of acids which can be used to form pharmaceutically acceptable addition salts include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid; and organic acids such as oxalic acid, maleic acid, succinic acid and citric acid. .

The base addition salt can be used to ultimately separate and purify the compound by reacting a carboxyl group with a suitable base such as a hydroxide, carbonate or bicarbonate of a metal cation or with ammonia or an organic primary, secondary or tertiary amine. The reaction is prepared. The cation of a pharmaceutically acceptable salt includes Lithium, sodium, potassium, calcium, magnesium and aluminum; and non-toxic amine cations such as ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, diethylamine, ethylamine , tributylamine, pyridine, N,N-dimethylaniline, N-methylpiperidine, N-methylmorpholine, dicyclohexylamine, procaine, diphenylmethylamine, N, N-Diphenylmethylphenethylamine and N,N'-benzhydrylethylenediamine. Other representative organic amines suitable for use in forming base addition salts include ethylenediamine, ethanolamine, diethanolamine, piperidine, and piperazine.

For use in therapy, it is possible to present the active ingredient in the form of a pharmaceutical composition when the compound in a therapeutically effective amount of the compound and the pharmaceutically acceptable salt thereof may be administered as a chemical ingredient. Accordingly, the present invention further provides a pharmaceutical composition comprising a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients. The term "therapeutically effective amount" as used herein refers to the total amount of each active ingredient sufficient to exhibit a meaningful patient benefit (eg, a sustained reduction in viral load). When applied to individual active ingredients administered separately, the term refers to the individual ingredients. When applied to a combination, the term refers to the combined amount of active ingredient that produces a therapeutic effect, whether administered in combination, serially or simultaneously. The combined compounds and their pharmaceutically acceptable salts 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 process for the preparation of a pharmaceutical formulation comprising combining a compound or a pharmaceutically acceptable salt thereof with one or more pharmaceutically acceptable carriers, diluents or The excipients are mixed. The term "pharmaceutically acceptable" as used herein means suitable for use in contact with patient tissue in the context of sound medical judgment without excessive toxicity, irritation, allergic reaction or other problems or complications, and reasonable benefits/ The compounds, substances, compositions and/or dosage forms that match the risks and are effective for their intended use.

The pharmaceutical formulation can be in unit dosage form containing a predetermined amount of active ingredient per unit dosage. In monotherapy for the prevention and treatment of HCV-mediated diseases, a dosage of between about 0.01 mg per kilogram of body weight per day and about 250 mg ("mg/kg") is usually employed, preferably A compound of the invention between about 0.05 mg and about 100 mg per kilogram of body weight per day. Typically, the pharmaceutical compositions of this invention will be administered from about 1 to about 5 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 the active ingredient which can be combined with the carrier materials in a single dosage form will depend on the condition being treated, the severity of the condition, the time of administration, the route of administration, the rate of excretion of the compound employed, the duration of treatment, and the age, sex, Change in weight and condition. Preferred unit dosage formulations are those containing a daily or sub-dose as described above or an appropriate fraction thereof. In general, the treatment is initiated with a small dose that is substantially less than the optimal dose of the compound. Thereafter, the dose is increased in small increments until the best effect in these circumstances is 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 deleterious or adverse side effects.

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 dosage of the compound with the other agent is typically from about 10% to 150% of the dose normally administered in a monotherapy regimen and More preferably from 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, intrathecal, intralesional, intravenous or intradermal injection or infusion) routes. Such formulations may be prepared by any method known in the art of pharmacy, for example 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 individual units such as capsules or lozenges; powders or granules; solutions or suspensions in aqueous or nonaqueous liquids; edible foams or foaming agents; or Oil-in-water liquid emulsion or water-in-oil emulsion.

For example, for oral administration in the form of a lozenge or capsule, the active drug component can be combined with a pharmaceutically acceptable oral non-toxic inert carrier such as ethanol, glycerol, water, and the like. By pulverizing the compound to a suitable fine size and in a similar manner A powdered pharmaceutical carrier such as an edible carbohydrate such as starch or mannitol is mixed to prepare a powder. Flavoring agents, preservatives, dispersing agents, and coloring agents may also be present.

Capsules are prepared by preparing a powder mixture as described above and filling the shaped gelatin shell. A slip agent and a lubricant such as colloidal cerium oxide, talc, magnesium stearate, calcium stearate or solid polyethylene glycol may be added to the powder mixture prior to the filling operation. A disintegrant or solubilizing agent such as agar, calcium carbonate or sodium carbonate may also be added to improve drug availability when the capsule is ingested.

In addition, suitable binders, lubricants, disintegrants, and color formers may be incorporated into the mixture as needed or desired. Suitable binders include starch, gelatin, natural sugars (such as glucose or beta-lactose), corn sweeteners, natural and synthetic gums (such as acacia, tragacanth) or sodium alginate, carboxymethylcellulose, poly Ethylene glycol and its analogues. Lubricants used in such dosage forms include sodium oleate, sodium chloride, 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 base as described above; and optionally a binder such as carboxymethylcellulose, alginate, gelling agent or poly A vinyl pyrrolidone; a solution retardant such as a 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 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 unformed dry slug is broken into granules. The particles may 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 invention may also be combined with a free-flowing inert carrier and compressed directly into a tablet without granulation or dry pressing. Can mention A clear or opaque protective coating consisting of a seal coat of shellac, a coating of sugar or polymeric material, and a polishing coating of wax. Dyes can be added to these coatings to distinguish between different unit doses.

Oral solutions such as solutions, syrups, and elixirs can be prepared in unit dosage form such that the compound can contain a predetermined amount. A syrup can be prepared by dissolving the compound in a suitably flavored aqueous solution, while preparing an elixirs via the use of a non-toxic vehicle. Solubilizers and emulsifiers such as ethoxylated isostearyl alcohol and polyoxyethylene sorbitol ether; preservatives; flavoring additives such as peppermint oil or natural sweeteners, or saccharin or other artificial sweeteners may also be added. ; and its analogues.

The dosage unit formulation for oral administration can be microencapsulated as appropriate. Formulations may also be prepared for prolonged or sustained release, for example, by coating or embedding particulate material on/in a polymer, wax or the like.

The compound of formula (I) and its pharmaceutically acceptable salts can also be administered in the form of liposome delivery systems such as monolayer small vesicles, monolayer large vesicles and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids such as cholesterol, stearylamine or phospholipid choline.

The combined compounds and their pharmaceutically acceptable salts can also be delivered by using monoclonal antibodies that are coupled to the molecules of the compound as individual carriers. The compound can also be coupled to a soluble polymer that is a targetable drug carrier. The polymers may include polyvinylpyrrolidone, piperene copolymer, polyhydroxypropylmethacrylamide, polyhydroxyethylaspartame or polyethylene oxide substituted with a hexadecanolyl residue. Polyaminic acid. In addition, the compounds can be coupled to a class of biodegradable polymers suitable for drug controlled release, such as polylactic acid, poly(ε-caprolactone), polyhydroxybutyrate, polyorthoesters, polyacetals. , polydihydropyran, polycyanoacrylate, and hydrogel crosslinked or amphiphilic block copolymer.

Pharmaceutical formulations suitable for transdermal administration may be in the form of individual patches intended to be 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 as generally described in Pharmaceutical Research 1986, 3 (6), 318.

The pharmaceutical formulation suitable for topical administration can be formulated into ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols or oils.

For treatment of the eye or other external tissues, such as the mouth and skin, the formulation is preferably administered as a topical 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 active ingredient can be formulated into a cream with an oil-in-water cream base or a water-in-oil base.

Pharmaceutical formulations suitable for topical administration to the eye include eye drops which are dissolved or suspended in a suitable carrier, especially an aqueous solvent.

Pharmaceutical formulations suitable for topical administration to the mouth include buccal tablets, tablets and mouthwashes.

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 coarsely divided agent having a particle size, for example, in the range of from 20 to 500 micrometers, which is administered by nasal inhalation, that is, a powder which is kept close to the nose. The container is quickly inhaled through the nostrils. Formulations suitable for administration as a nasal spray or nasal drops, which are liquid, include aqueous or oily solutions 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 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 suitable for parenteral administration include aqueous and non-aqueous sterile injectable solutions, which contain antioxidants, buffers, bacteriostatic agents, and solutes which cause the formulation to be isotonic with the intended recipient's blood; Non-aqueous sterile suspensions which may include suspending agents and thickening agents. Formulations may be present in unit dose containers or multi-dose containers (eg, sealed ampoules and vials) and may be stored under lyophilization (lyophilization) conditions, requiring only the addition of a sterile liquid carrier (eg, water for injection) prior to use. . Prepared from sterile powders, granules and lozenges Injection solutions and suspensions.

It will be appreciated that in addition to the ingredients specifically mentioned above, depending on the type of formulation, the 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.

The term "treatment" means: (i) preventing a disease, condition or condition from occurring in a patient who may be susceptible to the disease, condition and/or condition but has not yet been diagnosed with the disease, condition and/or condition. (ii) inhibiting the disease, condition or condition, ie, halting its development; and (iii) reducing the disease, condition or condition, even if the disease, condition and/or condition is diminished.

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 ( Hepatology 2003, 38 , 1282; Biochem. Biophys. Res. Commun. 2004, 313 , 42; J. Gastroenterol. 2003, 38 , 567).

Table A 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 separately or separately with other anti-HCV active compounds in combination therapy, or by combining the compounds into a composition.

The compounds of the invention may also be used as laboratory reagents. Compounds can help provide insights into designing viral replication assays, validating animal assay systems, and structural biology research to further enhance the mechanisms of HCV disease. Furthermore, the compounds of the invention are useful for establishing or determining binding sites for other antiviral compounds, for example by competitive inhibition.

The compounds of the invention may also be used to treat or prevent viral contamination of materials and thereby reduce contact with such materials as blood, tissues, surgical instruments and garments, laboratory equipment and garments, and blood collection or transfusion devices and materials. Risk of viral infection in a laboratory or medical staff or patient.

The present invention is intended to cover compounds of formula (I) prepared by synthetic processes or by metabolic processes, including those carried out in humans or animals (in vivo) or in vitro.

Those skilled in the art are familiar with the abbreviations used in this application, including in particular the illustrative processes and examples below. Some of the abbreviations used are as follows: min or mins means minutes; TFA means trifluoroacetic acid; ACN or MeCN means acetonitrile; MeOH means methanol; OAc means acetate; Bn means benzyl; DCM means dichloromethane; DIEA or DiPEA or DIPEA Represents diisopropylethylamine; HATU represents O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyl hexafluorophosphate EtOAc means ethyl acetate; RT or rt means room temperature or residence time (indicated by context); h or hr or hrs means hour; DMSO means dimethyl hydrazine; DME means dimethoxyethane; DMF means N, N-dimethylformamide; Boc or BOC represents a third butoxycarbonyl group; Hex represents hexane; Et represents an ethyl group; AcOH represents acetic acid; THF represents tetrahydrofuran; n-BuLi represents n-butyllithium; NBS represents N - bromobutanediamine; Ph represents phenyl; TBTU represents O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyltetrafluoroborate ; TEA or Et ₃ N for triethylamine; DMAP for 4-N,N-dimethylaminopyridine; Cbz for benzyloxycarbonyl; HBTU for hexafluorophosphate O-benzotriazole-N,N,N ',N'-tetramethyl EtOH stands for ethanol; Ph stands for phenyl; Me stands for methyl; TMSCN stands for trimethyldecane cyanide; PCC stands for pyridinium chlorochromate; DCC stands for dicyclohexylcarbodiimide; DMA stands for N,N-dimethyl Ethyl decylamine; DEA means diethylamine; Et ₂ O means diethyl ether; BuOH means butanol; EtO means ethoxide; Bu ₂ O means dibutyl ether; AcCl means acetamidine; TPP means meso-tetraphenyl Basil porphyrin; TBAF means tetrabutylammonium fluoride; dppf means diphenylphosphinoferrocene; DDQ means 2,3-dichloro-5,6-dicyano-1,4-benzoquinone; LDA means Lithium diisopropylamide; PCC means pyridinium chlorochromate; OMe means methoxide; CDI means 1,1-carbonyldiimidazole; DCE means 1,2-dichloroethane; and HMPA means hexamethylphosphonium Triamine.

The invention will now be described in connection with certain embodiments that are not intended to limit the scope of the invention. On the contrary, the invention is to cover all alternatives, modifications and equivalents Therefore, the following examples, including the specific examples, are intended to illustrate one embodiment of the invention, and are to be understood The most applicable and easiest to understand descriptor of a conceptual aspect.

Starting materials are available from commercial sources or by accepted literature methods known to those of ordinary skill in the art.

LC-MS method

Condition N-1:

Column = Phenomenex, 2.0 × 50mm, 3μm

Start B%=0; final B%=100

Gradient time = 4 min; stop time = 5 min

Flow rate = 0.8 mL / min; wavelength = 220 nm

Solvent A = 10% methanol / 90% water with 0.1% TFA

Solvent B = 90% methanol/10% water with 0.1% TFA

Oven temperature = 40 ° C

Condition N-2:

Column = Sunfire, C18, 3.0 × 150mm, 3.5μm

Start B%=0; final B%=100

Gradient time = 15 min; stop time = 18 min

Flow rate: 1mL/min

Wavelength 1 = 220 nm; wavelength 2 = 254 nm

Solvent A = 5% MeCN/95% water with 0.1% TFA

Solvent B = 95% MeCN/5% water with 0.1% TFA

LC-MS method YT-1

Start B%=0; final B%=100

Gradient time = 3 min; stop time = 4 min

Flow rate = 0.8 mL / min; wavelength = 220 nm

Solvent Pair = MeOH: H ₂ O: TFA

Solvent A = 10% MeOH - 90% H ₂ O - 0.1% TFA

Solvent B = 90% MeOH - 10% H ₂ O - 0.1% TFA

Column: Phenomenex 2.0×30mm 3μm

LC-MS method YT-2

Start B%=0; final B%=100

Gradient time = 4 min; stop time = 5 min

Flow rate = 1 mL / min; wavelength = 220 nm

Solvent Pair = MeOH: H ₂ O: TFA

Solvent A = 10% MeOH - 90% H ₂ O - 0.1% TFA

Solvent B = 90% MeOH - 10% H ₂ O - 0.1% TFA

Column: Phenomenex 2.0×30mm 3μm

LC-MS method YT-3

Start B%=0; final B%=100

Gradient time = 2 min; stop time = 3 min

Flow rate = 0.8 mL / min; wavelength = 220 nm

Solvent Pair = MeOH: H ₂ O: TFA

Solvent A = 10% MeOH - 90% H ₂ O - 0.1% TFA

Solvent B = 90% MeOH - 10% H ₂ O - 0.1% TFA

Column: Phenomenex 2.0×30mm 3μm

LC-MS method P-1

Start B%=0; final B%=100

Gradient time = 3 min; stop time = 4 min

Flow rate = 0.8 mL / min; wavelength = 220 nm

Solvent A = 10% MeOH - 90% H ₂ O - 0.1% TFA

Solvent B = 90% MeOH - 10% H ₂ O - 0.1% TFA

Column: Phenomenex 2.0×50mm 3μm

LC-MS method P-2

Start B%=0; final B%=100

Gradient time = 2 min; stop time = 3 min

Flow rate = 1 mL / min; wavelength = 220 nm

Solvent A = 10% MeOH - 90% H ₂ O - 0.1% TFA

Solvent B = 90% MeOH - 10% H ₂ O - 0.1% TFA

Column: Phenomenex 2.0×30mm 3μm

LC-MS method P-3

Start B%=0; final B%=100

Gradient time = 4 min; stop time = 5 min

Flow rate = 0.8 mL / min; wavelength = 220 nm

Solvent A = 10% MeOH - 90% H ₂ O - 0.1% TFA

Solvent B = 90% MeOH - 10% H ₂ O - 0.1% TFA

Column: Phenomenex 2.0×50mm

LC-MS method PS-1

Wavelength = 220nm

Mobile phase: A=5:95 ACN: water; B=95:5 ACN: water

Modifier = 10mM NH ₄ OAc

Gradient: 0%-100% B over 8 minutes, then 1 minute at 100% B

Flow rate = 2.0mL/min

Column: Supelco Ascentis Express 4.5×50mm 3μm C18

LC-MS method PS-2

Mobile phase A: 5:95 acetonitrile: water and 10 mM ammonium acetate

Mobile phase B: 95:5 acetonitrile: water with 10 mM ammonium acetate

Gradient: 0.5 min at 0% B, 0-100% B over 4 minutes, then 0.5 min at 100% B; flow rate = 1 mL/min. Column: Waters BEH C18, 2.0 × 50mm, 1.7μm particles

LC-MS method PS-3

Mobile phase A: 5:95 methanol: water and 10 mM ammonium acetate

Mobile phase B: 95:5 methanol: water with 10 mM ammonium acetate

Gradient: 0.5 minutes at 0% B, 0-100% B over 4 minutes, then at 100% Hold for 0.5 minutes at B; flow rate = 0.5 mL/min; column: Waters BEH C18

Condition L-1:

Column = Phenomenex, 2.0 × 50mm, 3μm

Start B%=0; final B%=100

Gradient time = 4 min; stop time = 5 min

Flow rate = 0.8 mL / min; wavelength = 220 nm

Solvent A = 10% MeCN/90% water with 0.1% TFA

Solvent B = 90% MeCN/10% water with 0.1% TFA

Oven temperature = 40 ° C

Condition L-2:

Column = Phenomenex, 3.0 × 2mm, 3μm

Start B%=0; final B%=100

Gradient time = 2 min; stop time = 3 min

Flow rate = 1 mL / min; wavelength = 220 nm

Solvent A = 10% MeCN/90% water with 0.1% TFA

Solvent B = 90% MeCN/10% water with 0.1% TFA

Oven temperature = 40 ° C

Condition W-1:

Column = Phenomenex, 2.0 × 30mm, 3μm

Start B%=0; final B%=100

Gradient time = 2 min; stop time = 3 min

Flow rate = 1 mL / min; wavelength = 220 nm

Solvent A = 10% MeOH/90% water with 0.1% TFA

Solvent B = 90% MeOH/10% water with 0.1% TFA

Oven temperature = 40 ° C

Condition W-2:

Column = Phenomenex Luna C18, 2.0 × 30mm, 3μm

Start B%=0; final B%=100

Gradient time = 2 min; stop time = 3 min

Flow rate = 1 mL / min; wavelength = 220 nm

Solvent A = 10% CH ₃ CN/90% water with 0.1% TFA

Solvent B = 0.1% TFA of 90% CH ₃ CN / 10% water

Oven temperature = 40 ° C

Condition W-3:

Column = Phenomenex Luna C18, 2.0 × 30mm, 3μm

Start B%=30; final B%=100

Gradient time = 4 min; stop time = 5 min

Flow rate = 1 mL / min; wavelength = 220 nm

Solvent A = 5% CH ₃ OH / 95% water with 10 mM NH ₄ OAc

Solvent B = 95% CH ₃ OH / 5% water with 10 mM NH ₄ OAc

Oven temperature = 40 ° C

Condition B-1:

Column = Xbridge phenyl, 4.6 × 150mm, 3.5μm

Solvent A = buffer: CH ₃ CN (95: 5)

Solvent B = buffer: CH ₃ CN (5:95)

Buffer = H ₂ O with 0.05% TFA (pH 2.5, adjusted with dilute ammonia)

Start B%=10; final B%=100

Gradient time = 12 min; stop time = 23 min

Equal concentration extraction time = 3min

Flow rate = 1 mL / min; wavelength = 220 and 254 nm

Condition B-2:

Column = Sunfire C18, 4.6 × 150mm, 3.5μm

Solvent A = buffer: CH ₃ CN (95: 5)

Solvent B = buffer: CH ₃ CN (5:95)

Buffer = H ₂ O with 0.05% TFA (pH 2.5, adjusted with dilute ammonia)

Start B%=10; final B%=100

Gradient time = 12 min; stop time = 23 min

Equal concentration extraction time = 3min

Flow rate = 1 mL / min; wavelength = 220 and 254 nm

Condition B-3:

Column = YMC triart, 4.6 × 150mm, 5μm

Solvent A = buffer: CH ₃ CN (95: 5)

Solvent B = buffer: CH ₃ CN (5:95)

Buffer = H ₂ O with 0.05% TFA (pH 2.5, adjusted with dilute ammonia)

Start B%=10; final B%=100

Gradient time = 12 min; stop time = 23 min

Equal concentration extraction time = 3min

Flow rate = 1 mL / min; wavelength = 220 and 254 nm

Condition B-4:

Column = Sunfire C18, 4.6 × 150mm, 3.5μm

Solvent A = buffer: CH ₃ CN (95: 5)

Solvent B = buffer: CH ₃ CN (5:95)

Buffer = H ₂ O with 0.05% TFA (pH 2.5, adjusted with dilute ammonia)

Start B%=0; final B%=50

Gradient time -1=15min

Final B%=100

Gradient time -2=3min

Equal concentration extraction time = 5min

Stop time = 28min

Flow rate = 1 mL / min; wavelength = 220 and 254 nm

Condition B-5:

Column = Sunfire C18, 4.6 × 150mm, 3.5μm

Solvent A = buffer: CH ₃ CN (95: 5)

Solvent B = buffer: CH ₃ CN (5:95)

Buffer = H ₂ O with 0.05% TFA (pH 2.5, adjusted with dilute ammonia)

Start B%=10; final B%=100

Gradient time = 25 min; stop time = 36 min

Equal concentration extraction time = 5min

Flow rate = 1 mL / min; wavelength = 220 and 254 nm

Condition B-6:

Column = Xbridge phenyl, 4.6 × 150mm, 3.5μm

Solvent A = buffer: CH ₃ CN (95: 5)

Solvent B = buffer: CH ₃ CN (5:95)

Buffer = H ₂ O with 0.05% TFA (pH 2.5, adjusted with dilute ammonia)

Start B%=10; final B%=100

Gradient time = 25 min; stop time = 36 min

Equal concentration extraction time = 5min

Flow rate = 1 mL / min; wavelength = 220 and 254 nm

Condition B-7:

Column = Eclipse XDB C18, 4.6 × 150mm, 3.5μm

Solvent A = H ₂ O with 20 mM NH ₄ OAc

Solvent B=CH ₃ CN

Start B%=10; final B%=100

Gradient time = 25 min; stop time = 36 min

Equal concentration extraction time = 5min

Flow rate = 1 mL / min; wavelength = 220 and 254 nm

Condition B-8:

Column = Eclipse XDB C18, 4.6 × 150mm, 3.5μm

Solvent A = H ₂ O with 20 mM NH ₄ OAc

Solvent B=CH ₃ CN

Start B%=10; final B%=100

Gradient time = 12 min; stop time = 26 min

Equal concentration extraction time = 8min

Flow rate = 1 mL / min; wavelength = 220 and 254 nm

Condition B-9:

Column = Zorbax SB C18, 4.6 x 50mm, 5μm

Solvent A = MeOH (10%) + H ₂ O (90%) with 0.1% TFA

Solvent B = MeOH (90%) + H ₂ O (10%) with 0.1% TFA

Start B%=0; final B%=100

Gradient time = 2 min; stop time = 3 min

Flow rate = 5mL / min; wavelength = 220nm

Condition B-10:

Column = Purospher@star RP-18, 4.0 × 55mm, 3μm

Solvent A = ACN (10%) + H ₂ O (90%) with 20 mM NH ₄ OAc

Solvent B = ACN (90%) + H ₂ O (10%) with 20 mM NH ₄ OAc

Start B%=0; final B%=100

Gradient time = 2 min; stop time = 3 min

Equal concentration extraction time = 0.5min

Flow rate = 2.5 mL / min; wavelength = 220 nm

Condition B-11:

Column = Purospher@star RP-18, 4.0 × 55mm, 3μm

Solvent A = ACN (10%) + H ₂ O (90%) with 20 mM NH ₄ OAc

Solvent B = ACN (90%) + H ₂ O (10%) with 20 mM NH ₄ OAc

Start B%=0; final B%=100

Gradient time = 1.8 min; stop time = 4 min

Equal concentration extraction time = 1.5min

Flow rate = 2.5 mL / min; wavelength = 220 nm

Condition B-12:

Column = Ascentis Express C18, 2.1 × 50mm, 2.7μm

Solvent A = CH ₃ CN (2%) + H ₂ O (98%) with 10 mM NH ₄ COOH

Solvent B = CH ₃ CN (98%) + H ₂ O (2%) with 10 mM NH ₄ COOH

Start B%=0; final B%=100

Gradient time = 1.4 min; stop time = 4 min

Stop time = 4min

Flow rate = 1 mL / min; wavelength = 220 nm

Condition B-13:

Column = Ascentis Express C8, 2.1 × 50mm, 2.7μm

Solvent A = CH ₃ CN (2%) + H ₂ O (98%) with 10 mM NH ₄ COOH

Solvent B = CH ₃ CN (98%) + H ₂ O (2%) with 10 mM NH ₄ COOH

Start B%=0; final B%=100

Gradient time = 1.5 min; stop time = 4 min

Equal concentration extraction time = 1.7min

Flow rate = 1 mL / min; wavelength = 220 nm

Condition B-14:

Column = Ascentis Express C8, 2.1 × 50mm, 2.7μm

Solvent A = CH ₃ CN (10%) + H ₂ O (90%) with 10 mM NH ₄ COOH

Solvent B = CH ₃ CN (90%) + H ₂ O (10%) with 10 mM NH ₄ COOH

Start B%=0; final B%=100

Gradient time = 1.6 min; stop time = 4 min

Equal concentration extraction time = 1.6min

Flow rate = 1 mL / min; wavelength = 220 nm

Condition B-15:

Column = Ascentis Express C18 2.1 × 50mm, 2.7μm

Solvent A = CH ₃ CN (2%) + H ₂ O (98%) with 10 mM NH ₄ COOH

Solvent B = CH ₃ CN (98%) + H ₂ O (2%) with 10 mM NH ₄ COOH

Start B%=0; final B%=100

Gradient time = 1.5 min; stop time = 4 min

Equal concentration extraction time = 1.7min

Flow rate = 1 mL / min; wavelength = 220 nm

Condition B-16:

Column = Acquity BEH C18, 2.1 × 50mm, 3μm

Solvent A = ACN (5%) + H ₂ O (95%) containing 5 mM NH ₄ OAc

Solvent B = ACN (95%) + H ₂ O (5%) with 5 mM NH ₄ OAc

Start B%=5; final B%=95

Gradient time = 1.1 min; stop time = 2.4 min

Equal concentration extraction time = 0.6min

Flow rate = 0.8 mL / min; wavelength = 220 nm

Condition B-17:

Column = ACE Excel 2 C18, 3.0 × 50mm, 2.0μm

Solvent A = CH ₃ CN (2%) + H ₂ O (98%) with 10 mM NH ₄ COOH

Solvent B = CH ₃ CN (98%) + H ₂ O (2%) with 10 mM NH ₄ COOH

Start B%=5; final B%=100

Gradient time = 1.8 min; stop time = 4 min

Equal concentration extraction time = 0.8min

Flow rate = 1.2 mL / min; wavelength = 220 nm

Condition B-18:

Column = BEH C18, 3.0 × 50mm, 5.0μm

Solvent A = CH ₃ CN (5%) + H ₂ O (95%) with 10 mM NH ₄ OAc

Solvent B = CH ₃ CN (95%) + H ₂ O (5%) with 10 mM NH ₄ OAc

Start B%=5; final B%=100

Gradient time = 1.8 min; stop time = 4 min

Equal concentration extraction time = 1.4min

Flow rate = 1.2 mL / min; wavelength = 220 nm

Condition B-19:

Column = Xbridge C18, 2.1 × 50mm, 2.5μm

Solvent A = CH ₃ CN (5%) + H ₂ O (95%) containing 10 mM NH ₄ HCO ₃

Solvent B = CH ₃ CN (95%) + H ₂ O (5%) with 10 mM NH ₄ HCO ₃

Start B%=0; final B%=100

Gradient time = 1.7 min; stop time = 4 min

Equal concentration extraction time = 1.5min

Flow rate = 1.0 mL / min; wavelength = 220 nm

Condition B-20:

Column = Zorbax SB-Aq, 4.6 x 50mm, 3.5μm

Solvent A = CH ₃ CN (5%) + H ₂ O (95%) with 10 mM NH ₄ COOH

Solvent B = CH ₃ CN (95%) + H ₂ O (5%) with 10 mM NH ₄ COOH

Start B%=5; final B%=95

Gradient time = 1.7 min; stop time = 4 min

Equal concentration extraction time = 1.5min

Flow rate = 1.0 mL / min; wavelength = 220 nm

Condition B-21:

Column = Ascentis Express C18, 2.1 × 50mm, 2.7μm

Solvent A = CH ₃ CN (2%) + H ₂ O (98%) with 10 mM NH ₄ COOH

Solvent B = CH ₃ CN (98%) + H ₂ O (2%) with 10 mM NH ₄ COOH

Start B%=0; final B%=100

Gradient time = 1.6 min; stop time = 4 min

Equal concentration extraction time = 1.6min

Flow rate = 1 mL / min; wavelength = 220 nm

Condition B-22:

Column = Ascentis Express C8, 2.1 × 50mm, 2.7μm

Solvent A = CH ₃ CN (2%) + H ₂ O (98%) with 10 mM NH ₄ COOH

Solvent B = CH ₃ CN (98%) + H ₂ O (2%) with 10 mM NH ₄ COOH

Start B%=0; final B%=100

Gradient time = 1.5 min; stop time = 4 min

Equal concentration extraction time = 1.7min

Flow rate = 1 mL / min; wavelength = 220 nm

Condition B-23:

Column = Zorbax SB C18, 4.6 x 50mm, 3.5μm

Solvent A = ACN (10%) + H ₂ O (90%) with 20 mM NH ₄ OAc

Solvent B = ACN (90%) + H ₂ O (10%) with 20 mM NH ₄ OAc

Start B%=0; final B%=100

Gradient time = 2.5 min; stop time = 3 min

Flow rate = 2.5 mL / min; wavelength = 220 nm

Condition B-24:

Column = Zorbax SB C18, 2.1 × 30mm, 3.5μm

Solvent A = CH ₃ CN (2%) + H ₂ O (98%) with 10 mM NH ₄ COOH

Solvent B = CH ₃ CN (98%) + H ₂ O (2%) with 10 mM NH ₄ COOH

Start B%=6; final B%=100

Gradient time = 1.5 min; stop time = 3 min

Equal concentration extraction time = 1.7min

Flow rate = 2.5 mL / min; wavelength = 220 nm

Condition B-25:

Column = Zorbax SB-Aq, 4.6 x 50mm, 3.5μm

Solvent A = ACN (10%) + H ₂ O (90%) containing 0.1% HCOOH

Solvent B = ACN (90%) + H ₂ O (10%) with 0.1% HCOOH

Start B%=0; final B%=20

Gradient time -1=1.5min

Final B%=95

Gradient time -2 = 2.5 min; stop time = 4 min

Flow rate = 1 mL / min; wavelength = 220 nm

Condition B-26:

Column = Xbridge BEH C18, 2.1 × 50mm, 2.5μm

Solvent A = H ₂ O with 0.1% HCOOH

Solvent B = ACN with 0.07% HCOOH

Start B%=10; final B%=100

Gradient time = 2.0 min; stop time = 4.0 min

Equal concentration extraction time = 1min

Flow rate = 1.2 mL / min; wavelength = 220 nm

Condition B-27:

Column = Zorbax SB C18, 2.1 × 30mm, 3.5μm

Solvent A = CH ₃ CN (2%) + H ₂ O (98%) with 10 mM NH ₄ COOH

Solvent B = CH ₃ CN (98%) + H ₂ O (2%) with 10 mM NH ₄ COOH

Start B%=6; final B%=100

Gradient time = 1.5 min; stop time = 3 min

Equal concentration extraction time = 0.7min

Flow rate = 1.5 mL / min; wavelength = 220 nm

Condition B-28:

Column = Ascentis Express C18, 4.6 x 50mm, 2.7μm

Solvent A = CH ₃ CN (5%) + H ₂ O (95%) with 10 mM NH ₄ COOH

Solvent B = CH ₃ CN (95%) + H ₂ O (5%) with 10 mM NH ₄ COOH

Start B%=0; final B%=100

Gradient time = 4 min; stop time = 5 min

Flow rate = 4.0 mL / min; wavelength = 220 nm

Condition B-29:

Column = Xbridge C18, 2.1 × 50mm, 2.5μm

Solvent A = 10 mM NH ₄ HCO ₃

Solvent B=CH ₃ CN

Start A%=100; final B%=100

Gradient time = 1.7 min; stop time = 4 min

Equal concentration extraction time = 1.5min

Flow rate = 1.0 mL / min; wavelength = 220 nm

Condition B-30:

Column = Sunfire C18, 4.6 × 150mm, 3.5μm

Solvent A = buffer: CH ₃ CN (95: 5)

Solvent B = buffer: CH ₃ CN (5:95)

Buffer = H ₂ O with 0.05% TFA (pH 2.5, adjusted with dilute ammonia)

Start B%=10; final B%=100

Gradient time = 12 min; stop time = 18 min

Equal concentration extraction time = 3min

Flow rate = 1 mL / min; wavelength = 220 and 254 nm

Condition B-31:

Column = XBridge, 4.6 × 150mm, 3.5μm

Solvent A = buffer: CH ₃ CN (95: 5)

Solvent B = buffer: CH ₃ CN (5:95)

Buffer = H ₂ O with 0.05% TFA (pH 2.5, adjusted with dilute ammonia)

Start B%=10; final B%=100

Gradient time = 12 min; stop time = 18 min

Equal concentration extraction time = 3min

Flow rate = 1 mL / min; wavelength = 220 and 254 nm

Condition B-32:

Column = Sunfire C18, 4.6 × 150mm, 3.5μm

Solvent A = buffer: CH ₃ CN (95: 5)

Solvent B = buffer: CH ₃ CN (5:95)

Buffer = H ₂ O with 0.05% TFA (pH 2.5, adjusted with dilute ammonia)

Start B%=10; final B%=100

Gradient time = 12 min; stop time = 20 min

Equal concentration extraction time = 3min

Flow rate = 1 mL / min; wavelength = 220 and 254 nm

Condition B-33:

Column = Zorbax-SB-CN, 4.6×150mm, 5.0μm

Solvent A = CH ₃ CN (10%) + H ₂ O (90%) with 10 mM NH ₄ COOH

Solvent B = CH ₃ CN (90%) + H ₂ O (10%) with 10 mM NH ₄ COOH

Start B%=10; final B%=100

Gradient time = 20 min; stop time = 27 min

Equal concentration extraction time = 5min

Flow rate = 1 mL / min; wavelength = 220 and 254 nm

Condition B-34:

Column = Kinetex C-18, 2.1 × 50mm, 2.6μm

Solvent A = ACN (2%) + H ₂ O (98%) with 0.1% NH ₄ COOH

Solvent B = ACN (98%) + H ₂ O (2%) with 0.1% NH ₄ COOH

Start B%=0; final B%=100

Gradient time = 1.7 min; stop time = 4 min

Equal concentration extraction time = 1.5min

Flow rate = 1 mL / min; wavelength = 220 nm

Condition B-35:

Column = Xbridge phenyl, 4.6 × 150mm, 3.5μm

Solvent A = buffer: CH ₃ CN (95: 5)

Solvent B = buffer: CH ₃ CN (5:95)

Buffer = H ₂ O with 0.05% TFA (pH 2.5, adjusted with dilute ammonia)

Start B%=10; final B%=100

Gradient time = 12 min; stop time = 18 min

Equal concentration extraction time = 3min

Flow rate = 1 mL / min; wavelength = 220 and 254 nm

Condition B-36:

Column = Eclipse XDB C18, 4.6 × 150mm, 3.5μm

Solvent A = H ₂ O with 10 mM NH ₄ OAc

Solvent B=CH ₃ CN

Start B%=10; final B%=100

Gradient time = 12 min; stop time = 17 min

Equal concentration extraction time = 3min

Flow rate = 1 mL / min; wavelength = 220 and 254 nm

Condition B-37:

Column = Zorbax SB C18, 4.6 x 50mm, 3.5μm

Solvent A = ACN (10%) + H ₂ O (90%) with 20 mM NH ₄ OAc

Solvent B = ACN (90%) + H ₂ O (10%) with 20 mM NH ₄ OAc

Start B%=10; final B%=100

Gradient time = 2.0 min; stop time = 3 min

Flow rate = 2.5 mL / min; wavelength = 220 nm

Example N-1

Example N-1, step a

Add (S)-2-(benzyloxycarbonylamino)- to a suspension of 2-amino-1-(4-bromophenyl)ethanone hydrochloride (1 g, 3.99 mmol) in DCM 3-methylbutyric acid (1.003 g, 3.99 mmol), DIPEA (1.534 mL, 8.78 mmol) and HATU (1.518 g, 3.99 mmol). The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with EtOAc, washed with saturated NaHCO _3, water and saturated NaCl, dried over anhydrous Na ₂ SO _4, filtered and concentrated to give the product as a pale yellow solid of (S) -1- (2- (4- bromo- Phenyl)-2-oxoethylaminoamino)-3-methyl-1-oxobutan-2-ylcarbamic acid benzyl ester. This product was used without further purification. LC / MS (Condition N-1): [M + H] + 447.12, R t = 3.766min.

Example N-1, step b

To (S)-1-(2-(4-bromophenyl)-2-oxoethylethylamino)-3-methyl-1-oxobutan-2-ylamine at room temperature yl carboxylic acid benzyl ester (1.9g, 4.25mmol) in pyridine (6mL) was added in the POCl ₃ (3mL, 32.2mmol). The reaction mixture was heated at 75 ° C for 3 hours. The reaction mixture was diluted with EtOAc and slowly poured into a cold saturated NaHCO ₃ solution at 0 °C. Washed with water, the organic phase was washed with saturated NaCl, dried over anhydrous Na ₂ SO _4, filtered and concentrated to give an oil. The residue was fed into a 80 g silica gel cartridge which was eluted with a gradient of 0-100% EtOAc in hexanes over 20 min. The product (S)-1-(5-(4-bromophenyl)oxazol-2-yl)-2-methylpropylaminocarbamate (0.71 g) was obtained as a yellow oil. LC / MS (Condition N-1): [M + H] + 429.17, R t = 4.193min. ¹ H NMR (400 MHz, DMSO- d ₆ ) ppm 8.06 (1 H, d, J = 8.78 Hz), 7.59-7.75 (5 H, m), 7.16-7.41 (5 H, m), 5.07 (2H, s), 4.58 (1 H, t, J = 8.16 Hz), 2.20 (1 H, dq, J = 13.90, 6.91 Hz), 0.97 (3 H, d, J = 6.78 Hz), 0.86 (3 H, d , J = 6.78Hz).

Example N-1, step c

To 4,4,4',4',5,5,5',5'-octamethyl-2,2'-linked (1,3,2-dioxaboron) (0.461 g, 1.871 mmol) and (S)-1-(5-(4-bromophenyl)oxazol-2-yl)-2-methylpropylaminocarbamate (0.39 g, 0.908) Potassium acetate (0.223 g, 2.271 mmol) was added to a solution of EtOAc (3 mL). The reaction mixture was degassed for 5 min then hydrazine (triphenylphosphine) palladium (0) (0.052 g, 0.045 mmol). The reaction mixture was heated at 85 ° C for 6 hours. The reaction mixture was diluted with EtOAc, washed with saturated NaCl saturated NaHCO _3, water, dried over anhydrous Na ₂ SO _4, filtered and concentrated to give an oil. The crude product was fed into a 40 g silica gel cartridge eluting with a gradient of 0-100% EtOAc in hexanes over 20 min. The product (S)-2-methyl-1-(5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaboron) was collected as a yellow oil. Phenylmethyl-2-yl)phenyl)oxazol-2-yl)propylcarbamate (0.35 g). LC / MS (Condition N-1): [M + H] + 477.31, R t = 4.353min.

Example N-1, step d

To (S)-2-methyl-1-(5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaboron) Benzyl-2-phenyl)phenyl)oxazol-2-yl)propylcarbamate (0.35 g, 0.735 mmol) and (S)-1-(5-(4-bromophenyl)oxazole- To a solution of benzyl 2-methyl)-2-methylpropylaminocarbamate (0.35 g, 0.815 mmol) in EtOAc (1 mL) . The reaction mixture was degassed for 5 min then bis(triphenylphosphine)palladium(0) (0.042 g, 0.037 mmol). The reaction mixture was heated at 80 ° C for 6 hours. The reaction mixture was diluted with EtOAc, washed with saturated NaCl saturated NaHCO _3, water, dried over anhydrous Na ₂ SO _4, filtered and concentrated to give a solid. The crude product was fed into a 80 g silica gel cartridge which was eluted with a gradient of 0-100% EtOAc in hexanes over 20 min. The product (1S,1'S)-1,1'-(5,5'-(biphenyl-4,4'-diyl)bis(oxazol-5,2-diyl)) double was collected as a yellow solid. Benzyl (2-methylpropiono-1,1-diyl)diaminecarboxylate (0.32 g). LC / MS (Condition N-1): [M + H] + 699.37, R t = 4.53min.

Example N-1, step e

Under N ₂ , to (1S,1'S)-1,1'-(5,5'-(biphenyl-4,4'-diyl)bis(oxazol-5,2-diyl)) bis ( Add Pd/C (0.015 g, 0.014 mmol) to a mixture of benzyl 2-methylpropion-1,1-diyl)diaminecarboxylate (0.1 g, 0.143 mmol) in EtOAc (2 mL). 6N HCl / dioxane (0.1 mL). The reaction mixture was stirred at room temperature under H ₂ for 4 days. The reaction mixture was filtered and the solid was washed with EtOAc. The filtrate was concentrated to give (1S,1'S)-1,1'-(5,5'-(biphenyl-4,4'-diyl)bis(oxazol-5,2-diyl) as a pale yellow solid. )) bis(2-methylpropan-1-amine) (0.06 g). LC / MS (Condition N-1): [M + Na] + 453.25, R t = 3.05min.

Example N-1

To (1S,1'S)-1,1'-(5,5'-(biphenyl-4,4'-diyl)bis(oxazol-5,2-diyl))bis(2-methylpropane) 1-amine) (0.03 g), (R)-2-(methoxycarbonylamino)-3-methylbutyric acid (0.024 g, 0.139 mmol) and HATU (0.058 g, 0.153 mmol) in DMF ( DIEA (0.049 mL, 0.279 mmol) was added to the mixture in 1 mL). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was purified by EtOAc (EtOAc): LC / MS (Condition N-1): [M + H] + 745.49, R t = 4.183min. ¹ H NMR (400 MHz, MeOD) ppm 7.74-7.87 (8 H, m), 7.50 (2 H, s), 4.92-5.01 (4H, m), 3.63 (6 H, s), 2.30-2.44 (2 H, m), 2.10 (2 H, d, J = 6.78 Hz), 1.04-1.12 (6 H, m), 0.99 (16 H, dd, J = 9.41, 6.90 Hz), 0.96 (2 H, s) .

Example N-2

To (1S,1'S)-1,1'-(5,5'-(biphenyl-4,4'-diyl)bis(oxazol-5,2-diyl))bis(2-methylpropane) DIEA (0.049 mL, 0.279 mmol) was added to a mixture of <RTI ID=0.0>>&&&&&&&&&&&&&& The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was purified by EtOAc (EtOAc): LC / MS (Condition N-1): [M + H] + 599.45, R t = 4.408min. ¹ H NMR (400 MHz, MeOD) ppm 7.74-7.82 (8 H, m), 7.50 (2 H, s), 4.97-4.99 (1 H, m), 4.96 (1 H, s), 2.29-2.47 (2 H, m), 1.21-1.30 (18 H, m), 1.04-1.10 (6 H, m), 0.95 (6H, d, J = 6.53 Hz).

Example N-3

Example N-3, step a

To a suspension of 2-amino-1-(4-bromophenyl)ethanone hydrochloride (4.0 g, 15.97 mmol) elute Then Boc-anhydride (3.89 mL, 16.77 mmol) and DIEA (3 mL, 17.18 mmol) were added to the solution and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with EtOAc and water, washed with 5% citric acid, water and the organic phase was washed with saturated NaCl, dried over anhydrous Na ₂ SO _4, filtered and concentrated to give a yellow solid of 2- (4-bromophenyl) - Tri-butyl 2-ethyloxyethylcarbamate (5.0 g) was used in the next step without further purification. ¹ H NMR (400 MHz, MeOD) ppm 7.89 (2H, m), 7.68 (2H, m, J = 8. Hz), 4.52 (2H, s), 1.38-1.51 (9H, m). LC/MS (Cond. N-1): R _t = 3.56 min. LC / MS: [M + Na ] + C 13 H 16 BrNaNO 3 Calculated: 336.03; Found: 335.97.

Example N-3, step b

Add 1,2-bis (trimethyl) to a solution of 2-(4-bromophenyl)-2-oxoethylaminocarbamic acid tert-butyl ester (2.0 g, 6.37 mmol) in DMF (5 mL) Alkylalkyl)acetylene (1.119 g, 3.18 mmol). The reaction mixture was degassed, hydrazine (triphenylphosphine)palladium(0) (0.184 g, 0.159 mmol) was added, and the mixture was heated at 90 ° C for 4 hours. The crude reaction mixture was fed into a 90 g silica gel cartridge eluting with a gradient of 0-60% EtOAc in hexanes. 2,2'-(4,4'-(acetylene-1,2-diyl)bis(4,1-phenylene))bis(2- oxoethyl-2,1) was collected as a yellow solid -Diyl) tert-butyl diamine (0.83 g). LC/MS (Cond. N-1): R _t = 4.1 min. LC / MS: [M + Na ] + C 28 H 32 NaN 2 O 6 Calculated: 515.23; Found: 515.10.

Example N-3, step c

To 2,2'-(4,4'-(acetylene-1,2-diyl)bis(4,1-extended phenyl))bis(2-trioxyethane-2,1-diyl) To a solution of butyl carbamic acid (1. 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 1,1'-(4,4'-(acetylene-1,2-diyl)bis(4,1-phenylphenyl))bis(2-amine Ethyl ethyl ketone) dihydrochloride (0.508 g). ¹ H NMR (400 MHz, MeOH) mp. 8.10 (4H, d, J = 8.35 Hz), 7.78 (4H, d, J = 8.35 Hz), 4.64 (4H, s). LC/MS (Condition N-1): R _t = 1.94 min. LC / MS: [M + H ] + C 18 H 17 N 2 O 2 Calculated: 293.12; Found: 293.07.

Example N-3, step d

To (S)-2-(t-butoxycarbonylamino)-3,3-dimethylbutyric acid (0.190 g, 0.821 mmol), 1,1'-(4,4'-(acetylene-1 ,2-diyl)bis(4,1-phenylene))bis(2-aminoethyl ketone) dihydrochloride (0.15 g, 0.411 mmol), HATU (0.312 g, 0.821 mmol) in DCM (2 mL) DIEA (0.359 mL, 2.053 mmol) was added to the mixture. The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was fed into a 40 g silica gel cartridge which was dissolved in a gradient of 0-100% EtOAc in hexanes over 20 min. (2S,2'S)-1,1'-(2,2'-(4,4'-(acetylene-1,2-diyl)bis(4,1-phenylene)) was collected as a yellow solid. Bis(2-oxoethoxy-2,1-diyl))bis(azirodiyl)bis(3,3-dimethyl-1-oxobutan-2,1-diyl)diamine T-butyl formate (0.3 g). LC / MS (Condition N-1): [M + Na] + 741.70, R t = 4.39min.

Example N-3, step e

In the sealed tube, (2S, 2'S)-1,1'-(2,2'-(4,4'-(acetylene-1,2-diyl)bis(4,1-phenylene)) Bis(2-oxoethoxy-2,1-diyl))bis(azirodiyl)bis(3,3-dimethyl-1-oxobutan-2,1-diyl)diamine A mixture of tert-butyl formate (0.3 g, 0.417 mmol) and ammonium acetate (0.322 g, 4.17 mmol) in EtOAc (5 mL) The reaction mixture was diluted with EtOAc and water, the organic layer with saturated NaHCO ₃ and saturated NaCl, dried over anhydrous Na ₂ SO _4, filtered and concentrated. The residue was taken up in a 40 g silica gel cartridge eluting with a gradient of 0-100% EtOAc/hexanes over 15 min. The product (1S,1'S)-1,1'-(5,5'-(4,4'-(acetylene-1,2-diyl)bis(4,1-phenylene) was collected as a yellow solid. Bis(butyl) (1H-imidazole-5,2-diyl))bis(2,2-dimethylpropane-1,1-diyl)dicarbamic acid (0.12 g). LC / MS (Condition N-1): [M + H] + 681.52, R t = 3.418min.

Example N-3, step f

To (1S,1'S)-1,1'-(5,5'-(4,4'-(acetylene-1,2-diyl)bis(4,1-phenylene))bis(1H-imidazole Reaction of -5,2-diyl)) bis(2,2-dimethylpropane-1,1-diyl)dicarbamic acid tert-butyl ester (0.12 g, 0.176 mmol) in DCM (3 mL) 4M hydrogen chloride in dioxane (2 ml, 8.00 mmol) and a little MeOH were added to the mixture. The reaction was stirred at rt for 4 h then concentrated to dryness afforded (1S,1's)-1,1'-(5,5'-(4,4'-(acetylene-1,2) -diyl)bis(4,1-phenylene))bis(1H-imidazol-5,2-diyl))bis(2,2-dimethylpropan-1-amine) tetrahydrochloride (0.1 g). LC / MS (Condition N-1): [M + H] + 481.32, R t = 3.228min.

Example N-3

To 3-methylbutyric acid (0.018 g, 0.176 mmol), (1S, 1'S)-1,1'-(5,5'-(4,4'-(acetylene-1,2-diyl) bis ( 4,1-Extended phenyl))bis(1H-imidazole-5,2-diyl))bis(2,2-dimethylpropan-1-amine)tetrahydrochloride (0.05 g, 0.080 mmol) and DIEA (0.084 mL, 0.479 mmol) was added to a mixture of EtOAc (EtOAc). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was purified by EtOAc EtOAc (EtOAc) LC / MS (Condition N-1): [M + H] + 649.54, R t = 3.456min. ¹ H NMR (400 MHz, MeOD) ppm 7.92 (2 H, s), 7.77-7.82 (4H, m), 7.68-7.73 (4H, m), 4.95 (2H, s), 2.17-2.35 (4) H, m), 1.98-2.14 (2 H, m), 1.09-1.17 (18 H, m), 0.91-1.00 (12 H, m).

Example N-4 to N-6

Example N-4 to N-6 (bistrifluoroacetate) was prepared by starting with the procedure described for Synthesis Example N-3 starting with the amino ketone N-3c and the appropriate starting material from commercial sources. .

Examples N-7 to N-9 and P-1 to P-2

By using the procedure described for Synthesis Example N-3, 2-bromo-1-(4-(6-(2-bromoethyl)naphthalen-2-yl)phenyl)ethanone and obtained from commercial Examples N-7 to N-9 and P-1 to P-2 (bistrifluoroacetate) were prepared starting from the appropriate starting materials from the source.

Example N-10

Example N-10, step a

To 1,1'-(biphenyl-4,4'-diyl)bis(2-bromoethyl ketone) (0.25 g, 0.631 mmol) and Boc-1-amino-1-cyclobutanecarboxylic acid (0.285 g) DIEA (0.243 mL, 1.389 mmol) was added to a solution of EtOAc. The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was fed into a 40 g silica gel cartridge which was dissolved in a gradient of 0-100% EtOAc in hexanes for 15 min. The product bis(1-(t-butoxycarbonylamino)cyclobutanecarboxylic acid) 2,2'-(biphenyl-4,4'-diyl) bis(2-sideoxy) was collected as a white solid. Ethylene-2,1-diyl)ester (0.25 g). LC / MS (Condition N-1): [M + Na] + 687.47, R t = 4.37min.

Example N-10, step b

In a sealed tube, bis(1-(t-butoxycarbonylamino)cyclobutanecarboxylic acid) 2,2'-(biphenyl-4,4'-diyl) bis(2-sided oxyethyl) A mixture of -2,1-diyl)ester (0.25 g, 0.376 mmol) and ammonium acetate (0.290 g, 3.76 mmol) in xylene was heated at 130 °C for 4 hours. The reaction mixture was diluted with EtOAc and water, the organic layer was washed with saturated NaHCO ₃ and saturated NaCl, dried over anhydrous Na ₂ SO _4, filtered and concentrated. The residue was taken up in a 40 g silica gel cartridge eluting with a gradient of 0-100% EtOAc/hexanes over 15 min. The product 1,1'-(4,4'-(biphenyl-4,4'-diyl)bis(1H-imidazole-4,2-diyl))bis(cyclobutane-1) was collected as a yellow solid. , 1-diyl)dibutyl carbamic acid tert-butyl ester (0.1 g). LC / MS (Condition N-1): [M + H] + 625.23, R t = 3.201min.

Example N-10, step c

To 1,1'-(4,4'-(biphenyl-4,4'-diyl)bis(1H-imidazole-4,2-diyl))bis(cyclobutane-1,1-diyl) To a reaction mixture of dimethyldiaminedicarboxylate (0.1 g, 0.160 mmol), EtOAc (EtOAc) The reaction was stirred at room temperature for 4 hours. The reaction mixture was concentrated to dryness to give 1,1'-(4,4'-(biphenyl-4,4'-diyl)bis(1H-imidazole-4,2-diyl)) as a yellow solid. Cyclobutylamine tetrahydrochloride (0.08 g). LC / MS (Condition N-1): [M + H] + 425.22, R t = 2.502min.

Example N-10

To 1,1'-(4,4'-(biphenyl-4,4'-diyl)bis(1H-imidazole-4,2-diyl))bicyclobutylamine tetrahydrochloride (0.034 g, 0.08 mmol), (S)-2-(methoxycarbonylamino)-3-methylbutyric acid (0.014 g, 0.080 mmol), and a mixture of HATU (0.067 g, 0.176 mmol) in DMF (1 mL) DIEA (0.056 mL, 0.320 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was purified by EtOAc EtOAc (EtOAc) LC / MS (Condition N-1): [M + H] + 739.51, R t = 3.033min. ¹ H NMR (400 MHz, MeOD) ppm 7.80-7.96 (10 H, m), 3.89 (2H, d, J = 7.28 Hz), 3.64 (6 H, s), 2.90-3.00 (2 H, m), 2.77-2.89(2 H,m), 2.64(4 H,ddd, J =13.74,8.60,5.52Hz), 2.20-2.36(2 H,m), 2.00-2.19(4 H,m),1.02(12 H, t, J = 7.03 Hz).

Example N-11 to N-27

By using the procedure described for Synthesis Example N-10, from 1,1'-(biphenyl-4,4'-diyl)bis(2-bromoethyl ketone) and suitable starting materials from commercial sources Preparation Examples N-11 to N-27 (bistrifluoroacetate).

Example N-28

Example N-28, step a

To 1,1'-(biphenyl-4,4'-diyl)bis(2-bromoethylketone) (0.85 g, 2.146 mmol) and (S)-2-(t-butoxycarbonylamino) To a solution of -3,3-dimethylbutyric acid (1.042 g, 4.51 mmol) in EtOAc (EtOAc) The reaction mixture was stirred at room temperature for 16 hours. , The reaction was diluted with EtOAc and washed with sat NaHCO _3, water and saturated NaCl, dried over anhydrous Na ₂ SO _4, filtered and concentrated to give the product as a pale yellow solid of (2S, 2'S) - bis (2- (Third Butoxycarbonylamino)-3,3-dimethylbutyric acid) 2,2'-(biphenyl-4,4'-diyl)bis(2-trioxyethane-2,1-diyl) ) ester (1.5 g). LC / MS (Condition N-1): [M + H] + 697.41, R t = 4.488min.

Example N-28, step b

In the sealed tube, (2S, 2'S)-bis(2-(t-butoxycarbonylamino)-3,3-dimethylbutyric acid) 2,2'-(biphenyl-4,4' -diyl)bis(2-oxoethoxy-2,1-diyl)ester (1.5 g, 2.153 mmol) and a mixture of ammonium acetate (1.659 g, 21.53 mmol) in xylene at 130 ° C. hour. The reaction mixture was diluted with EtOAc and water, the organic layer was washed with saturated NaHCO ₃ and saturated NaCl, dried over anhydrous Na ₂ SO _4, filtered and concentrated. The residue was taken up in a 80 g silica gel cartridge eluting with a gradient of 0-100% EtOAc/hexanes over 15 min. The product (1S,1'S)-1,1'-(4,4'-(biphenyl-4,4'-diyl)bis(1H-imidazole-4,2-diyl)) was collected as a yellow solid. Tert-butyl (2,2-dimethylpropane-1,1-diyl)dicarbamic acid (0.86 g). LC / MS (Condition N-1): [M + H] + 657.55, R t = 3.295min.

Example N-28, step c

To (1S,1'S)-1,1'-(4,4'-(biphenyl-4,4'-diyl)bis(1H-imidazole-4,2-diyl))bis(2,2- Addition of 4M Hydrogen Chloride Dioxane (2 ml, 8.00 mmol) to a reaction mixture of dimethyl propyl-1,1-diyl)diamine carboxylic acid (3 butyl) (0.86 g, 1.309 mmol) in DCM (3 mL) ) and a little MeOH. The reaction was stirred at room temperature for 4 hours. The reaction mixture was concentrated to dryness to give (1S,1's)-1,1'-(4,4'-(biphenyl-4,4'-diyl) bis (1H-imidazole-4,2) as a yellow solid. -Diyl)) bis(2,2-dimethylpropan-1-amine) tetrahydrochloride (0.8 g). LC / MS (Condition N-1): [M + H] + 457.35, R t = 2.988min.

Example N-28

To (1S,1'S)-1,1'-(4,4'-(biphenyl-4,4'-diyl)bis(1H-imidazole-4,2-diyl))bis(2,2- Dimethylpropan-1-amine) tetrahydrochloride (0.07 g, 0.116 mmol), (R)-2-(methoxycarbonylamino)-3-methylbutyric acid (0.041 g, 0.232 mmol) DIEA (0.081 mL, 0.465 mmol) was added to a mixture of EtOAc (EtOAc). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was purified by EtOAc EtOAc (EtOAc) LC / MS (Condition N-1): [M + H] + 771.71, R t = 3.29min. ^{1 H NMR (400MHz, MeOD)} ppm 7.79-8.02 (10 H, m), 4.95 (2 H, s), 4.06 (2 H, d, J = 7.53Hz), 3.58-3.72 (6 H, m), 2.03 (2 H, dq, J = 13.87, 6.84 Hz), 1.10 - 1.25 (18 H, m), 0.89 - 1.08 (12 H, m).

Examples N-29 to N-44 and P-3 to P-10

By using the procedure described for Synthesis Example N-28, 1,1'-(biphenyl-4,4'-diyl)bis(2-bromoethyl ketone) and suitable starting materials from commercial sources were employed. Examples N-29 to N-44 and P-3 to P-10 (bistrifluoroacetate) were prepared initially.

Examples N-45a, N-45b, N-45c

By using the procedure described for Synthesis Example N-28, (1S,1'S)-1,1'-(4,4'-(biphenyl-4,4'-diyl)bis(1H-imidazole- 4,2-Diyl))bis(2,2-dimethylpropan-1-amine) tetrahydrochloride is coupled with 2,2-difluorocyclopropanecarboxylic acid. The resulting three diastereomers (trifluoroacetate) were isolated by the following conditions: column = Phenomenex AXIA 5μ 30 x 100 mm column, starting B% = 0; final B% = 65; gradient time = 20 min Stop time = 22 min; flow rate = 40 mL/min; wavelength = 220 nm; solvent A = 10% MeOH/90% water with 0.1% TFA; solvent B = 90% MeOH/10% water with 0.1% TFA. Example N-45a: LC/MS (Cond. N-1): [M+H] ⁺ 665.43, R _t = 3.051 min. ¹ H NMR (400 MHz, MeOD) ppm 7.82-7.93 (10 H, m), 4.92-4.96 (2H, m), 2.89 (2H, ddd, J = 13.05, 10.79, 7.78 Hz), 1.93-2.08 ( 2 H, m), 1.75-1.91 (2 H, m), 1.03-1.23 (18 H, m). Examples of N-45b: LC / MS (Condition N-1): [M + H] + 665.43, R t = 3.111min. ¹ H NMR (400 MHz, MeOD) ppm 7.92 (2H, d, J = 6.78 Hz), 7.83-7.90 (8 H, m), 4.94 - 4.96 (1 H, s), 4.93 (1 H, s), 2.78-2.98 (2H, m), 1.89-2.08 (2H, m), 1.73-1.89 (2H, m), 1.10-1.20 (18 H, m). Example N-45c: LC/MS (Cond. N-1): [M+H] ⁺ 665.43, R _t = 3.15 min. ¹ H NMR (400 MHz, MeOD) ppm 7.92 (2H, s), 7.84-7.92 (8H, m), 4.94 (2H, s), 2.83 (2H, ddd, J = 13.05, 10.79, 7.78 Hz ), 1.90-2.03 (2 H, m), 1.73-1.86 (2 H, m), 1.09-1.21 (18 H, m).

Examples N-46 to N-66, N-111 to N-117, P-11 to P-47, Y-1 to Y-10

By using the procedure described for Synthesis Example N-28, (1S, 1'S)-1,1'-(4,4'-(biphenyl-4,4'-diyl)bis(1H-imidazole- Preparation of Examples N-46 to N by 4,2-diyl))bis(2,2-dimethylpropan-1-amine)tetrahydrochloride and starting from a suitable starting acid obtained from commercial or in-house preparation -66, N-111 to N-117, P-11 to P-47, Y-1 to Y-10 (bistrifluoroacetate).

Example N-67

By using the procedure described for Synthesis Example N-28, 1,1'-(biphenyl-4,4'-diyl)bis(2-bromoethyl ketone) and suitable starting materials from commercial sources were employed. Starting to prepare Example N-67 (bistrifluoroacetate). LC / MS (Condition N-1): [M + H] + 625.44, R t = 3.37min. ¹ H NMR (400 MHz, MeOD) ppm 7.92 (2 H, s), 7.83-7.90 (8 H, m), 4.98 (2 H, s), 2.17-2.37 (4 H, m), 1.99-2.15 (2 H, m), 1.09-1.20 (18 H, m), 0.91-1.00 (12 H, m).

Example N-68

Example N-68, step a

To a solution of 1,1'-(9H-indole-2,7-diyl)diethyl ketone (0.5 g, 1.998 mmol) in AcOH was added dropwise Br ₂ (0.226 mL, 4.39 mmol) in AcOH (1 mL) Solution in ). The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with EtOAc, ₂ SO ₃ and washed with saturated Na, and saturated aqueous NaCl. The solid was filtered, washed with DCM and dried to give <1"""""""""

Example N-68, step b

To 1,1'-(9H-indole-2,7-diyl)bis(2-bromoethyl ketone) (0.57 g) and (S)-2-(t-butoxycarbonylamino)-3- To a solution of methyl butyric acid (0.637 g, 2.93 mmol) in EtOAc (EtOAc) The reaction mixture was stirred at room temperature for 6 hours. The reaction was diluted with EtOAc, washed with saturated NaHCO _3, water and saturated NaCl, dried over anhydrous Na ₂ SO _4, filtered and concentrated to give a pale yellow solid. The crude product was dissolved in a small amount of dichloromethane and was applied to a 40 g silica gel cartridge eluting with a gradient of 0-80% EtOAc in hexanes. (2S,2'S)-bis(2-(t-butoxycarbonylamino)-3-methylbutyric acid) 2,2'-(9H-茀-2,7-di was collected as a pale yellow solid Bis(2-o-ethoxyethyl-2,1-diyl) ester (0.75 g). LC / MS (Condition N-1): [M + Na] + 703.40, R t = 4.393min.

Example N-68, step c

In the sealed tube, (2S, 2'S)-bis(2-(t-butoxycarbonylamino)-3-methylbutyric acid) 2,2'-(9H-茀-2,7-diyl A mixture of bis(2-oxoethoxy-2,1-diyl)ester (0.75 g, 1.102 mmol) and ammonium acetate (0.849 g, 11.02 mmol) in xylene was heated at 130 ° C for 3 hours. The reaction mixture was diluted with EtOAc and water, the organic layer with saturated NaHCO ₃ and saturated NaCl, dried over anhydrous Na ₂ SO _4, filtered and concentrated. The residue was dissolved in dichloromethane and taken into a 40 g silica gel cartridge eluting with a gradient of 0-100% EtOAc/hexanes for 15 min and 100% EtOAc. (1S,1'S)-1,1'-(4,4'-(9H-茀-2,7-diyl)bis(1H-imidazole-4,2-diyl)) double was collected as a yellow solid (2-methylpropan-1,1-diyl)diaminocarbamic acid tert-butyl ester (0.28 g). LC / MS (Condition N-1): [M + H] + 641.2, R t = 3.38min.

Example N-68, step d

To (1S,1'S)-1,1'-(4,4'-(9H-茀-2,7-diyl)bis(1H-imidazole-4,2-diyl))bis(2-methyl To a reaction mixture of dimethyl-1,1-diyldiaminediaminecarboxylate (0.28 g, 0.437 mmol), EtOAc (EtOAc) The reaction was stirred at room temperature for 3 hours. The reaction mixture was concentrated to dryness. (1S,1'S)-1,1'-(4,4'-(9H-茀-2,7-diyl)bis(1H-imidazole-4,2-diyl)) double was collected as a yellow solid (2-Methylpropan-1-amine) tetrahydrochloride (0.26 g). LC / MS (Condition N-1): [M + H] + 441.13, R t = 2.756min.

Example N-68

To (1S,1'S)-1,1'-(4,4'-(9H-茀-2,7-diyl)bis(1H-imidazole-4,2-diyl))bis(2-methyl DIEA (0.075 mL) was added to a mixture of propanolamine (0.042 g), pivalic acid (0.015 g, 0.143 mmol) and HATU (0.060 g, 0.158 mmol) in DMF (volume: 1 mL) , 0.430 mmol). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was purified by reverse phase HPLC to afford trifluoroacetic acid salt (0.033 g). LC / MS (Condition N-1): [M + H] + 609.15, R t = 3.305min. ¹ H NMR (400 MHz, MeOD ) ppm 8.01 (1 H, s), 7.98 (3H, d, J = 5.0 Hz), 7.88 (2H, s), 7.78 (2H, dd, J = 8.0, 1.5 Hz), 4.89 (2 H, dt, J = 9.8, 3.5 Hz), 4.06 (2 H, s), 2.36-2.50 (2 H, m, J = 9.7, 6.6, 6.6, 6.6, 6.6 Hz), 1.21. - 1.27 (18 H, m), 1.16 (6 H, d, J = 6.5 Hz), 0.92 (6H, d, J = 6.8 Hz).

Example N-69 to N-73

Examples N-69 to N-73 (trifluoroacetate) were prepared by the procedure described for the synthesis of Example 68 starting from the diamine 68d and the appropriate acid.

Example N-74

Example N-74, step a

To a suspension of aluminum chloride (0.925 g, 6.94 mmol) and acetonitrile chloride (4.93 mL, 69.4 mmol) cooled to 0 ° C was added dropwise 9,10-dihydrophenanthrene (0.5 g, 2.77 mmol). DCM (5 mL). The reaction mixture was stirred at 0 ° C for 30 minutes. The resulting mixture was allowed to warm to room temperature and stirred at room temperature for 2 hr. The reaction mixture was quenched by pouring onto ice. The aqueous phase was extracted with EtOAc. Using 1N NaOH, the organic phase was washed with saturated NaCl, dried over anhydrous Na ₂ SO _4, filtered and concentrated to give an oil. The crude product was dissolved in dichloromethane and taken into a 40 g silica gel cartridge eluting with a gradient of 0-100% EtOAc in hexanes over 20 min. 1,1'-(9,10-dihydrophenanthrene-2,7-diyl)dione (0.64 g) was collected as a yellow solid. LC / MS (Condition N-1): [M + H] + 265.08, R t = 3.641min. ¹ H NMR (400MHz, chloroform - d) δ ppm 7.73-7.90 (6 H, m), 2.90 (4 H, d, J = 2.26Hz), 2.55-2.64 (6 H, m).

Example N-74, step b

To a solution of 1,1'-(9,10-dihydrophenanthrene-2,7-diyl)diethyl ketone (0.64 g) in AcOH (4 mL), Br ₂ (0.274 mL) Solution in 1 mL). The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with EtOAc, ₂ SO ₃ and washed with saturated Na, and saturated aqueous NaCl. The solid which precipitated from the organic phase was filtered, washed with DCM and dried to give <RTIgt;1'''''

Example N-74, step c

To 1,1'-(9,10-dihydrophenanthrene-2,7-diyl)bis(2-bromoethylketone) (0.5g) and (S)-2-((t-butoxycarbonyl) A solution of the amino)-3-methylbutyric acid (0.540 g, 2.487 mmol) in DCM was added DIEA (0.455 mL). The reaction mixture was stirred at room temperature for 6 hours. The reaction was diluted with EtOAc, washed with saturated NaHCO _3, water and saturated NaCl, dried over anhydrous Na ₂ SO _4, filtered and concentrated to give a pale yellow solid. The crude product was dissolved in dichloromethane and taken into a 40 g silica gel cartridge eluting with a gradient of 0-80% EtOAc in hexanes. (2S,2'S)-bis(2-(t-butoxycarbonylamino)-3-methylbutyric acid) 2,2'-(9,10-dihydrophenanthrene-2) was collected as a pale yellow solid. , 7-diyl) bis(2-oxoethoxy-2,1-diyl) ester (0.68 g): LC/MS (Cond. N-1): [M+H] ⁺ 717.46, R _t = 4.436 Min.

Example N-74, step d

In the sealed tube, (2S, 2'S)-bis(2-(t-butoxycarbonylamino)-3-methylbutyric acid) 2,2'-(9,10-dihydrophenanthrene-2, A mixture of 7-diyl)bis(2-oxoethoxy-2,1-diyl)ester (0.68 g) and ammonium acetate (0.754 g) in xylene was heated at 130 ° C for 6 hours. The reaction mixture was diluted with EtOAc and water, the organic layer was washed with saturated NaHCO ₃ and saturated NaCl, dried over anhydrous Na ₂ SO _4, filtered and concentrated. The residue was taken up in dichloromethane and taken into a 40 g silica gel cartridge eluting with EtOAc from 0-100% EtOAc. (1S,1'S)-1,1'-(4,4'-(9,10-dihydrophenanthrene-2,7-diyl)bis (1H-imidazole-4,2-di) was collected as a yellow solid Base)) T-butyl bis(2-methylpropion-1,1-diyl)dicarbamic acid (0.25 g). LC / MS (Condition N-1): [M + H] + 655.55, R t = 3.381min.

Example N-74, step e

To (1S,1'S)-1,1'-(4,4'-(9,10-dihydrophenanthrene-2,7-diyl)bis(1H-imidazole-4,2-diyl)) bis ( Addition of 4M Hydrogen Chloride Dioxane (2 ml) and MeOH (0.1) to a reaction mixture of EtOAc (EtOAc) mL). The reaction was stirred at room temperature for 3 hours. The reaction mixture was concentrated to dryness to give (1S,1's)-1,1'-(4,4'-(9,10-dihydrophenanthene-2,7-diyl)bis (1H-) as a yellow solid. Imidazole-4,2-diyl))bis(2-methylpropan-1-amine) tetrahydrochloride (0.24 g). LC / MS (Condition N-1): [M + H] + 443.23, R t = 2.706min.

Example N-74

To (1S,1'S)-1,1'-(4,4'-(9,10-dihydrophenanthrene-2,7-diyl)bis(1H-imidazole-4,2-diyl)) bis ( DIEA (0.066 mL) was added to a mixture of 2-methylpropan-1-amine) tetrahydrochloride (0.038 g), pivalic acid (0.013 g) and HATU (0.053 g) in DMF (1 mL). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was purified by reverse phase HPLC to afford trifluoroacetic acid salt (0.032 g). LC / MS (Condition N-1): [M + H] + 623.55, R t = 3.355min. ¹ H NMR (400 MHz, methanol - d ₄ ) ppm 8.01 (2H, d, J = 8.03 Hz), 7.91 (2H, s), 7.73-7.71 (4H, m), 4.84-4.88 (2H, m), 3.01 (4 H, s), 2.41 (2 H, dt, J = 9.54, 6.65 Hz), 1.22-1.28 (18 H, m), 1.16 (6 H, d, J = 6.53 Hz), 0.92 (6 H,d, J =6.78 Hz).

Example N-75 to N-76

Examples N-75 to N-76 (trifluoroacetate) were prepared by starting with the procedure described for the synthesis of N-74, starting with the diamine N74e and the appropriate acid.

Example N-77

Example N-77, step a

To a solution of 1-(4-bromo-2-methylphenyl)ethanone (0.525 g, 2.464 mmol) in THF was added phenyltriethylammonium tribromide (0.926 g, 2.464 mmol). The reaction mixture was stirred at room temperature for 16 hours. The reaction was diatomaceous earth (Celite ^®) plug mixture was filtered, and the filtrate was concentrated to give a white solid of 2-bromo-1- (4-bromo-2-methyl-phenyl) - ethanone (0.61g). LC / MS (Condition N-1): [M + H] + 290.84, R t = 3.88min.

Example N-77, step b

To 2-bromo-1-(4-bromo-2-methylphenyl)ethanone (0.61 g, 2.089 mmol) and (S)-2-(t-butoxycarbonylamino)-3-methyl DIEA (0.474 mL) was added to a solution of butyric acid (0.454 g, 2.089 mmol) in DCM. The reaction mixture was stirred at room temperature for 16 hours. The crude product was dissolved in a small amount of dichloromethane and was taken in a EtOAc EtOAc. Collection of (S)-2-(t-butoxycarbonylamino)-3-methylbutanoic acid 2-(4-bromo-2-methylphenyl)-2-oxooxyl as a pale yellow oil Ethyl ester (0.9 g). LC / MS (Condition N-1): [M + H] + 451.92, R t = 4.145min.

Example N-77, step c

In the sealed tube, (S)-2-(t-butoxycarbonylamino)-3-methylbutyric acid 2-(4-bromo-2-methylphenyl)-2-oxoethoxy A mixture of the ester (1.0 g, 2.335 mmol) and ammonium acetate (1.8 g, 23.35 mmol) in xylene was heated at 130 ° C for 3 h. The reaction was diluted with EtOAc, washed with saturated NaHCO _3, water and saturated NaCl, dried over anhydrous Na ₂ SO _4, filtered and concentrated to give a yellow oil. The residue was dissolved in dichloromethane and taken up in a pad of EtOAc (EtOAc) EtOAc. (S)-1-(4-(4-Bromo-2-methylphenyl)-1H-imidazol-2-yl)-2-methylpropylcarbamic acid tert-butyl ester was collected as a yellow solid (0.52g). LC / MS (Condition N-1): [M + H] + 408.98, R t = 3.296min.

Example N-77, step d

To 4,4,4',4',5,5,5',5'-octamethyl-2,2'-linked (1,3,2-dioxaboron) (0.747g) and (S)-1-(4-(4-bromo-2-methylphenyl)-1H-imidazol-2-yl)-2-methylpropylcarbamic acid tert-butyl ester (0.58 g, prepared by 2-bromo-1-(4-bromophenyl)ethanone using the procedure described in step bc) was added potassium diacetate (0.361 g) to dioxane. Degassed for 5 minutes and hydrazine (triphenylphosphine)palladium(0) (0.085 g) was added. The reaction mixture was heated at 85 ° C for 14 hours. The reaction mixture was diluted with EtOAc, washed with saturated NaCl saturated NaHCO _3, water, dried over anhydrous Na ₂ SO _4, filtered and concentrated to give an oil. The crude product was dissolved in dichloromethane and taken into a 40 g silica gel cartridge eluting with a gradient of 0-100% EtOAc in hexanes over 20 min. (S)-2-Methyl-1-(4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborate) was collected as a yellow solid. 3-butyl)phenyl)-1H-imidazol-2-yl)propylaminocarbamic acid tert-butyl ester (0.62 g). LC / MS (Condition N-1): [M + H] + 442.19, R t = 3.53min.

Example N-77, step e

To (S)-2-methyl-1-(4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaboron) 3-butyl)phenyl)-1H-imidazol-2-yl)propylaminocarbamic acid tert-butyl ester (0.562 g) and (S)-1-(4-(4-bromo-2-methylbenzene) Addyl NaHCO ₃ (0.535 g) to a solution of DME and water, and degas for 5 minutes. And hydrazine (triphenylphosphine)palladium (0) (0.074 g) was added. The reaction mixture was heated at 80 ° C for 16 hours. The reaction mixture was diluted with EtOAc, washed with saturated NaCl saturated NaHCO _3, water, dried over anhydrous Na ₂ SO _4, filtered and concentrated to give a solid. The crude product was dissolved in dichloromethane and taken up in a EtOAc EtOAc EtOAc EtOAc. (1S,1'S)-1,1'-(4,4'-(3-methylbiphenyl-4,4'-diyl)bis (1H-imidazole-4,2-di) was collected as a yellow solid Base)) tert-butyl (2-methylpropan-1,1-diyl)dicarbamic acid (0.2 g). LC / MS (Condition N-1): [M + H] + 643.31, R t = 3.036min.

Example N-77, step f

To (1S,1'S)-1,1'-(4,4'-(3-methylbiphenyl-4,4'-diyl)bis(1H-imidazole-4,2-diyl)) bis ( Add a solution of 3M hydrogen chloride in dioxane (2 ml) and MeOH in a solution of EtOAc (EtOAc (EtOAc). (0.1 mL). The reaction was stirred at room temperature for 3 h and concentrated to dryness. (1S,1'S)-1,1'-(4,4'-(3-methylbiphenyl-4,4'-diyl)bis (1H-imidazole-4,2-di) was collected as a yellow solid Base)) bis(2-methylpropan-1-amine) tetrahydrochloride (0.2 g). LC / MS (Condition N-1): [M + H] + 443.23, R t = 2.706min.

Example N-77

To (1S,1'S)-1,1'-(4,4'-(3-methylbiphenyl-4,4'-diyl)bis(1H-imidazole-4,2-diyl)) bis ( DIEA (0.089 mL) was added to a mixture of 2-methylpropan-1-amine) tetrahydrochloride (0.05 g), pivalic acid (0.017 g) and HATU (0.071 g) in DMF. The reaction mixture was stirred at room temperature for 1 hour. The compound was purified by reverse phase HPLC to afford trifluoroacetic acid salt (0.028 g) of N. LC / MS (Condition N-1): [M + H] + 611.29, R t = 2.98min. ¹ H NMR (400 MHz, MeOD ) ppm 8.04 (1 H, dd, J =18.9, 6.7 Hz), 7.91 (1 H, s), 7.85-7.89 (3 H, m), 7.75 (1 H, s), 7.68-7.72 (1 H, m), 7.66 (1 H, s), 7.57-7.62 (1 H, m), 4.83-4.90 (2 H, m), 2.50 (3 H, s), 2.35-2.48 ( 2 H, m), 1.21-1.26 (18 H, m), 1.13-1.19 (6 H, m), 0.93 (6 H, t, J = 6.9 Hz).

Example N-78 to N-84

Examples N-78 to N-84 (trifluoroacetate) were prepared by starting with the diamine N-77f and the appropriate acid using the procedure described for the synthesis of N-77.

Example N-85 to N-100

Examples N-85 to N-100 (trifluoroacetate) were prepared by starting with the appropriate starting material using the procedure described for the synthesis of N-77.

Example N-101

N-((S)-2-methyl-1-(4-(4-(6-(2-((S)-2-methyl-1-pentylaminopropyl)-1H-imidazole) 4-yl)pyridin-3-yl)phenyl)-1H-imidazol-2-yl)propyl)-pivalamidine Example N-101, step a

To a mixture of 2,5-dibromopyridine (6 g, 25.3 mmol) in toluene was added dropwise n-BuLi (11.95 mL, 29.9 mmol) at -78 °C. The reaction mixture was stirred at -78 °C for 2 hours. Next, (2-(methoxy(methyl)amino)-2-oxoethyl)aminocarboxylic acid tert-butyl ester (2.77 g, 12.69 mmol) was added. It was stirred at -78 deg.] C the reaction mixture for 2 hours, then quenched with saturated ₄ Cl NH, diluted with EtOAc. The organic phase was washed with saturated NaCl, dried over anhydrous Na ₂ SO _4, filtered and concentrated to give an oil. The crude product was dissolved in dichloromethane and taken into a 40 g silica gel cartridge eluting with a gradient of 0-30% EtOAc in hexanes. The 3-(5-bromopyridin-2-yl)-2-oxoethylaminocarbamic acid tert-butyl ester (0.7 g) was obtained as a yellow solid. </RTI>^<RTIID=0.0>^</RTI></RTI>^<RTIID=0.0></RTI> ¹ H NMR (400 MHz, methanol - d ₄ ) ppm 8.80 (1 H, dd, J = 2.26, 0.75 Hz), 8.19 (1 H, dd, J = 8.28, 2.26 Hz), 7.96 (1 H, d, J = 8.28 Hz), 4.71 (2 H, s), 1.49 (9 H, s).

Example N-101, step b

Addition of 4M hydrogen chloride to dioxane to the reaction mixture of 2-(5-bromopyridin-2-yl)-2-oxoethylaminocarbamic acid tert-butyl ester (0.36 g, 1.142 mmol) in DCM (2 ml, 8.00 mmol) with a little MeOH. The reaction was stirred at room temperature for 3 hours. The reaction mixture was concentrated to dryness crystals crystal crystal crystal crystal crystal crystal crystal crystal LC/MS (Cond. N-1): [M+H] ⁺ 215.

Example N-101, step c

To (5-bromopyridin-2-yl)ethanone (0.16 g), (S)-2-((t-butoxycarbonyl)amino)-3-methylbutyric acid (0.133 g) and HATU ( 0.232 g) DIEA (0.340 mL) was added to the mixture in DCM. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was purified by gelatin chromatography. (S)-1-(2-(5-Bromopyridin-2-yl)-2-oxoethylethylamino)-3-methyl-1-oxobutane-2 was collected as a yellow solid. - tert-butyl carbamic acid (0.1 g). LC/MS (Cond. N-1): [M+Na] ⁺ 436.

Example N-101, step d

(S)-1-(2-(5-Bromopyridin-2-yl)-2-oxoethylethylamino)-3-methyl-1-oxobutane-2 in a sealed tube A mixture of tert-butyl carbamic acid (0.1 g) and ammonium acetate (0.186 g) in xylene was heated at 130 ° C for 3 hours. The reaction was diluted with EtOAc, washed with saturated NaHCO _3, water and saturated NaCl, dried over anhydrous Na ₂ SO _4, filtered and concentrated to give a yellow oil. The residue was purified by EtOAc (EtOAc EtOAc EtOAc) Tert-butyl 2-methyl)-2-methylpropylcarbamate (0.06 g). </RTI>^<RTIID=0.0></RTI>^</RTI>^<RTIID=0.0></RTI>

Example N-101

Example N-101 (trifluoroacetate) was prepared by starting with N-101d, N-77d and the appropriate starting material using the procedure described for the synthesis of N-77. LC/MS (Cond. N-1): [M+H] ⁺ 598. ¹ H NMR (400 MHz, methanol - d ₄ ) d ppm 9.03 (1H, dd, J = 2.26, 0.75 Hz), 8.29 (1 H, dd, J = 8.41, 2.38 Hz), 8.16 (1 H, s) , 8.00-8.07 (1 H, m), 7.90-7.97 (5 H, m), 4.84 - 4.92 (2 H, m), 2.31-2.52 (2 H, m), 1.24 (18 H, d, J = 0.75 Hz), 1.16 (6 H, dd, J = 6.65, 3.14 Hz), 0.92 (6H, dd, J = 6.78, 2.01 Hz).

Example N-102 to N-103

Examples N-102 to N-103 (trifluoroacetate) were prepared by starting with the appropriate starting material using the procedure described for the synthesis of N-101.

Example N-104

Example N-104, step a

Add 1-ethoxyvinyltri-n-butyltin (1.420 mL, 4.20 mmol) and bis(triphenylphosphine)palladium chloride to a solution of 2,5-dibromopyrazine (1 g, 4.20 mmol) in DMF. (II) (0.148 g, 0.210 mmol). The reaction mixture was heated at 100 ° C for 4 hours. The reaction mixture was diluted with EtOAc and aqueous KF. Biphasic mixture was stirred at room temperature for 20 minutes and then filtered through diatomaceous earth (Celite ^®). , Drying _3, saturated NaCl and the filtrate was washed with saturated NaHCO dried over anhydrous Na ₂ SO _4, and concentrated. The crude product was purified by EtOAc EtOAc (EtOAc:EtOAc) LC/MS (Cond. N-1): [M+H] ⁺ 229.05

Example N-104, step b

To a solution of 2-bromo-5-(1-ethoxyvinyl)pyrazine (0.65 g, 2.84 mmol) in THF and water was added NBS (0.505 g, 2.84 mmol). The reaction mixture was stirred at 0&lt;0&gt;C for 1 h then diluted with EtOAc & EtOAc. Biphasic mixture was stirred at room temperature for 20 minutes and then filtered through diatomaceous earth (Celite ^®). , Drying _3, saturated NaCl and the filtrate was washed with saturated NaHCO dried over anhydrous Na ₂ SO _4, and concentrated. The crude product was purified by EtOAc EtOAc (EtOAc) </RTI>^<RTIID=0.0></RTI>^</RTI>^<RTIID=0.0></RTI>

Example N-104

Example N-104 (trifluoroacetate) was prepared by starting with dibromo N-104b and the appropriate starting material using the procedure described for the synthesis of N-77. </RTI>^<RTIID=0.0></RTI>^</RTI>^<RTIID=0.0></RTI> ¹ H NMR (400 MHz, methanol - d ₄ ) ppm 9.30 (1 H, d, J = 1.51 Hz), 9.22 (1 H, d, J = 1.51 Hz), 8.33-8.39 (2 H, m), 8.30 ( 1 H, s), 7.99 (1 H, s), 7.91-7.97 (2 H, m), 4.99 (2 H, d, J = 14.81 Hz), 2.54-2.69 (2 H, m), 2.04-2.21 (4 H, m), 1.67-1.97 (12 H, m), 1.14 (18 H, d, J = 2.76 Hz).

Starting with the appropriate starting material by employing the procedure described for Synthesis Example N-104 To prepare Example N-105 (trifluoroacetate).

Example Y-11 to Y-12

1-(4-Bromo-2-hydroxyphenyl)ethanone (1.1 g, 5.12 mmol), sodium chlorodifluoroacetate (1.96 g, 12.89 mmol) and Cs ₂ CO ₃ (3.33 g, 10.23 mmol) in DMF The reaction mixture in (8 mL) was heated at 100-110 °C for 1.5 hours. The reaction mixture was cooled and cooled and diluted with EtOAc. Was washed with water, brine and the organic phase was dried (MgSO _4), solvent was removed, and the column on 25g silica gel (EtOAc / hexane: 0-50%) to give the residue, to give a beige solid of specified compound (1.2 g). ¹ H NMR (400MHz, CHLOROFORM -d) δ 7.69 (d, J = 8.3Hz, 1 H), 7.47 (dd, J = 8.3,1.8Hz, 1 H), 7.40-7.36 (m, 1 H), 6.63 (t, 72.78 Hz, 1 H), 2.63 (s, 3 H).

A solution of 1- (4-bromo-2- (difluoromethoxy) phenyl) ethanone (1.2g, 4.53mmol) in AcOH (5mL) of the solution was added dropwise Br ₂ (0.257mL, 4.98mmol) A solution in AcOH (1 mL). The reaction mixture was stirred at room temperature for 24 h and diluted with EtOAc. With saturated Na ₂ SO _3, water, the organic phase was washed with brine, dried (MgSO _4), and the solvent removed to give a brown viscous oil of a given compound, which is used in the next step.

To 2-bromo-1-(4-bromo-2-(difluoromethoxy)phenyl)ethanone (0.53 g, 1.541 mmol) and (S)-2-(t-butoxycarbonylamino) To a reaction mixture of -3-methylbutyric acid (0.402 g, 1.849 mmol) in EtOAc (5 mL) The reaction mixture was stirred at room temperature for 24 hours, and another portion containing (S)-2-(t-butoxycarbonylamino)-3-methylbutyric acid (0.2 g) and DIPEA (0.3 ml, 1.718) Methyl) acetonitrile (5 mL). The reaction mixture was stirred for 24 hours and concentrated. The residue was purified on a 40 g EtOAc EtOAc (EtOAc:EtOAc

In a sealed tube, ammonium acetate (3 g, 38.9 mmol) and (S)-2-((t-butoxycarbonyl)amino)-3-methylbutyric acid 2-(4-bromo-2-() The reaction mixture of difluoromethoxy)phenyl)-2-oxoethyl ester (0.6 g, 1.249 mmol) in EtOAc (3 mL) was evaporated. The reaction mixture was cooled, diluted with EtOAc, washed with saturated NaHCO _3, brine, dried (MgSO _4). The solvent was removed and the residue was purified mjjjjjjjjjjjjjj ¹ H NMR (400MHz, CHLOROFORM -d) δ 8.09 (br.s., 1 H), 7.42 (s, 1 H), 7.38 (d, J = 7.8Hz, 1 H), 7.28 (br.s., 1 H), 6.51 (t, J = 74.0 Hz, 1 H), 5.46 (br.s., 1 H), 4.49-4.33 (m, 1 H), 2.39 (d, J = 16.1 Hz, 1 H) , 1.45 (s, 9 H), 1.04 (d, J = 6.3 Hz, 3 H), 0.91 (d, J = 6.5 Hz, 3 H). LC / MS (Method YT-3): [M + H] + 461.9, R t = 2.233min.

Nitrogen was bubbled through (S)-(2-methyl-1-(5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaboron) 3-butyl)phenyl)-1H-imidazol-2-yl)propyl)carbamic acid tert-butyl ester (0.242 g, 0.547 mmol), (S)-(1-(5-(4-bromo-) T-butyl 2-(difluoromethoxy)phenyl)-1H-imidazol-2-yl)-2-methylpropyl)carbamate (0.21 g, 0.456 mmol) and sodium hydrogencarbonate (0.192 g) , 2.281 mmol), a mixture of DME (4 mL) and water (2 mL) for 5 min, then Pd(PPh ₃ ) ₄ (0.026 g, 0.023 mmol). The reaction mixture was stirred at 78 ° C for 18 hours. Allowed to cool and then diluted with EtOAc, washed with water, brine, dried (MgSO _4), and on a 25g silica gel column (EtOAc / hexanes: 0-100%) to give the residue, to give the product (0.27g). ^{1 H NMR (400MHz, MeOD)} δ 8.04 (br.s., 1 H), 7.81 (d, J = 8.3Hz, 2 H), 7.72 (d, J = 8.5Hz, 2 H), 7.62 (dd, J = 8.0, 1.8 Hz, 1 H), 7.49 (s, 2 H), 7.39 (s, 1 H), 7.20-6.77 (m, 1 H), 4.56 (t, J = 7.9 Hz, 2 H), 2.25-2.09 (m, 2 H), 1.47 (s, 9 H), 1.22 (s, 9 H), 1.02 (d, J = 6.8 Hz, 6 H), 0.92-0.88 (m, 6 H). LC / MS (Method YT-1): [M + H] + 695.49, R t = 2.66min.

To ((1S,1'S)-(5,5'-(3-(Difluoromethoxy)-[1,1'-biphenyl]-4,4'-diyl) bis(1H-imidazole-5 , 2,2-diyl)) bis(2-methylpropan-1,1-diyl))diaminocarbamic acid di-t-butyl ester (0.27 g, 0.387 mmol) in DCM (1 mL) HCl / dioxane (2.5 mL, 10.00 mmol), and the mixture was stirred at room temperature for 3 hr. It was diluted with 5 ml of toluene and the residue was evaporated in vacuo to afford product (0.248 g). LC / MS (Method YT-1): [M + H] + 495.4, R t = 2.28min.

Examples Y-11 and Y-12 in the form of bistrifluoroacetate were prepared by following the general guanamine coupling procedure using TBTU.

Example Y-11

^{1 H NMR (400MHz, MeOD)} δ ppm 7.93 (s, 1 H), 7.91-7.86 (m, 5 H), 7.81 (s, 1 H), 7.76 (d, J = 8.0Hz, 1 H), 7.68 (s, 1 H), 7.14 (t, J = 73.0 Hz, 1 H), 2.41 (br. S., 2 H), 1.24 (s, 18 H), 1.15 (d, J = 6.3 Hz, 6 H ), 0.93 (d, J = 6.8 Hz, 6 H). LC / MS (Method YT-1): [M + H] + 663.57, R t = 2.65min.

Example Y-12

LC / MS (Method YT-1): [M + H] + 743.59, R t = 2.87min.

Example N-106

Example N-106, step a

To 1,1'-([1,1'-biphenyl]-4,4'-diyl)bis(2-bromoethyl ketone) (0.073 g, 0.185 mmol) and 2-((t-butoxy) To a solution of carbonyl)amino)-3-fluoro-3-methylbutanoic acid (0.087 g, 0.370 mmol) in EtOAc (EtOAc) The reaction mixture was stirred at room temperature for 16 h and evaporated to dryness crystals crystals crystals 3-fluoro-3-methylbutyric acid) 2,2'-(biphenyl-4,4'-diyl)bis(2-oxoethoxy-2,1-diyl) ester (0.1 g) . </RTI>^<RTIID=0.0></RTI>^</RTI>^<RTIID=0.0></RTI>

Example N-106, step b

In a sealed tube, bis(2-(t-butoxycarbonylamino)-3-fluoro-3-methylbutyric acid) 2,2'-(biphenyl-4,4'-diyl) double A mixture of (2-oxoethoxyethyl-2,1-diyl) ester (0.1 g) and ammonium acetate (0.109 g, 1.419 mmol) in EtOAc (2 mL) The reaction was diluted with EtOAc, washed with saturated NaHCO _3, water and saturated NaCl, dried over anhydrous Na ₂ SO _4, filtered and concentrated to give a yellow oil. The residue was purified by EtOAc (EtOAc-EtOAc) elute Bis(butyl) of bis(1H-imidazole-4,2-diyl))bis(2-fluoro-2-methylpropan-1,1-diyl)dicarboxylate. </RTI>^<RTIID=0.0></RTI>^</RTI>^<RTIID=0.0></RTI> ¹ H NMR (400 MHz, methanol - d ₄ ) ppm 7.78 (4H, d, J = 8.28 Hz), 7.69 (4H, d, J = 8.53 Hz), 7.43 (2 H, s), 4.98 (2 H) , m), 1.44-1.55 (21 H, m), 1.41 (3 H, br.s.), 1.35 (3 H, s), 1.30 (3 H, s). By palmitic SFC (ChiralPak IC-H, 30 x 250 mm, 5 μm, mobile phase: 20% MeOH w/0.1% DEA/80% CO ₂ , pressure: 120 bar, temperature 35 ° C, flow rate: 70 mL/min The three diastereomers are separated. Diastereomer 1 : RT = 8.58 min; diastereomer 2: RT = 9.78 min; diastereomer 3: RT = 11.34 min.

Examples N-106A to N-106C

Examples N-106A to N-106C (trifluoroacetate) were prepared by starting with the respective carbamates using the appropriate starting materials and procedures for the synthesis of Example N-28.

Example N-106A (Stereoisomer-1): LC/MS (Cond. N-1): [M+H] ⁺ 757.45, RT = 3.368min. ¹ H NMR (400 MHz, methanol - d ₄ ) ppm 7.96 (2H, s), 7.85-7.91 (8H, m), 5.40 (1 H, s), 5.34 (1 H, s), 2.52-2.63 ( 2 H,m),2.05-2.19(4 H,m),1.92-2.00(2 H,m),1.70-1.91 (10 H,m),1.62(3 H,s),1.57(3 H,s ), 1.46 (3 H, s), 1.41 (3 H, s).

Example N-106B (Stereoisomer-2): LC/MS (Cond. N-1): [M+H] ⁺ 757.63, RT = 3.37 min. ¹ H NMR (400 MHz, methanol - d ₄ ) ppm 7.98 (2H, s), 7.85-7.93 (8H, m), 5.38 (1 H, s), 5.33 (1 H, s), 2.51-2.63 ( 2 H, m), 2.04-2.20 (4 H, m), 1.97 (2 H, d, J = 9.79 Hz), 1.68-1.91 (10 H, m), 1.63 (3 H, s), 1.58 (3) H, s), 1.46 (3 H, s), 1.41 (3 H, s).

Example N-106C (Stereoisomer-3): LC/MS (Cond. N-1): [M+H] ⁺ 757.5, RT = 3.38 min. ¹ H NMR (400 MHz, methanol - d ₄ ) ppm 7.96 (2 H, s), 7.85 - 7.92 (8 H, m), 5.41 (1 H, s), 5.35 (1 H, s), 2.51-2.64 ( 2 H,m),2.04-2.20(4 H,m),1.92-2.02(2 H,m),1.66-1.92(10 H,m),1.62(3 H,s),1.57(3 H,s ), 1.46 (3 H, s), 1.41 (3 H, s).

Example N-107

Example N-107, step a

Preparation of (4-(4-bromophenyl)-1H-imidazol-2-yl) (1-(trifluoromethyl) by starting with the appropriate starting material using the procedure described for the synthesis of N-77 Cyclopropyl)methylaminocarbamic acid tert-butyl ester. LC/MS (Cond. N-1): [M+H] ⁺ 460. By palmitic SFC (Chiralpak AD-H, 30 x 250 mm, 5 μm, mobile phase: 15% MeOH (0.1% DEA) in CO ₂ at 150 bar, temperature: 35 ° C, flow rate: 70 mL / Min) Separation of the two enantiomers. Enantiomer 1: RT = 4.52 min; enantiomer 2: RT = 8.31 min.

Example N-107A to N-107B

Examples N-107A to N-107B (trifluoroacetate) were prepared by starting with the individual enantiomers of bromide N-107a and the appropriate materials using the procedure described for the synthesis of N-77.

Example N-107A: LC/MS (Cond. N-1): [M+H] ⁺ 729.39, RT = 3.458 min. ¹ H NMR (400 MHz, methanol - d ₄ ) ppm 7.89-7.92 (2H, m), 7.86 (8H, s), 5.71-5.82 (2H, m), 1.17-1.32 (24 H, m), 0.97 (2 H, d, J = 7.03 Hz).

Example N-107B: LC/MS (Cond. N-1): [M+H] ⁺ 729.39. ¹ H NMR (400 MHz, methanol - d ₄ ) ppm 7.89-7.92 (2H, m), 7.83-7.89 (8H, m), 5.75-5.79 (2H, m), 1.15. ), 0.90-1.03 (2 H, m).

Examples N-108 to N-109 (trifluoroacetate) were prepared by starting with the appropriate starting material using the procedure described for the synthesis of N-107.

Example N-110

Example N-110, step a

To a solution of (R)-3-hydroxy-4,4-dimethyldihydrofuran-2(3H)-one (5 g) in EtOAc (EtOAc) The reaction mixture was cooled to -78.degree. C. and trifluoromethanesulfonic acid anhydride (7.07 mL, 41.9 mmol). The reaction mixture was stirred at -78 °C for 30 minutes, and warmed to room temperature and stirred for 1 hour. ₃ citric acid wash, water, saturated aqueous NaCl, and the reaction was diluted with EtOAc, washed with water, saturated NaHC03, dried over anhydrous Na ₂ SO _4, filtered and concentrated to give a clear oil of trifluoromethanesulfonic acid (R) - 4,4-Dimethyl-2-oxooxytetrahydrofuran-3-yl ester (10 g). LC/MS (Cond. N-1): [M+H] ⁺ 263. ¹ H NMR (400 MHz, chloroform- d ) ppm 5.09 (1H, s), 4.04 - 4.20 (2H, m), 1.32 (3H, s), 1.23 (3H, s).

Example N-110, step b

Addition of tetra-n-butylammonium azide to a solution of (R)-4,4-dimethyl-2-oxotetrahydrofuran-3-yl trifluoromethanesulfonate (10 g) in DCM (10 mL) (11.1g). The reaction mixture was stirred at room temperature for 16 hours. The reaction was diluted with EtOAc, washed with water, saturated NaHCO _3, citric acid, water and saturated NaCl, dried over anhydrous Na ₂ SO _4, filtered and concentrated to give an oil. The crude product was purified by EtOAc (EtOAc EtOAc) )-ketone. ¹ H NMR (400MHz, chloroform - d) ppm 3.87-4.02 (3 H , m), 1.17 (3 H, s), 1.02 (3 H, s).

Example N-110, step c

Under N _2, to (S) -3- azido-4,4-dimethyl-dihydro-furan -2 (3H) - one (5.52 g of) in MeOH was added 10% Pd in the (910 mL) solution of /C (0.379 g, 0.356 mmol). The reaction mixture was stirred for 16 hours under H ₂ at room temperature. Diatomaceous earth (Celite ^®) was filtered through the reaction, washed with EtOAc, and the filtrate was concentrated to give a clear oil. BOC ₂ O (9.09 mL) and TEA (13.88 mL) were added to DCM (10 mL). The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with EtOAc, washed with saturated with saturated NaHCO _3, citric acid, with aqueous NaCl, dried over anhydrous Na ₂ SO _4, filtered and concentrated to give an oil. The crude product was purified by EtOAc (EtOAc EtOAc EtOAc) T-butyl formate (3.8 g). LC/MS (Cond. N-1): [M+Na] ⁺ 252.06, RT = 2.75 min. ¹ H NMR (400 MHz, chloroform - d ) ppm 4.81-4.95 (1 H, m), 4.38 (1 H, d, J = 7.78 Hz), 3.97-4.07 (2 H, m), 1.47 (9 H, s ), 1.25 (3 H, s), 1.01 (3 H, s).

Example N-110, step d

KOH was added to a solution of (S)-4,4-dimethyl-2-oxo-tetrahydrofuran-3-ylaminocarbamic acid tert-butyl ester (0.3 g) in THF (3 mL). (0.088 g) a solution in water (1 mL). The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated to dryness crystals crystals crystals crystals The reaction mixture was stirred at room temperature for 16 hours, then diluted with EtOAc in,, washed with saturated NaCl saturated NaHCO _3, water, dried over anhydrous Na ₂ SO _4, filtered and concentrated to give an oil. The crude product was purified by EtOAc (EtOAc EtOAc EtOAc EtOAc) Acid benzyl ester (0.13 g). LC/MS (Cond. N-1): [M+Na] ⁺ 360.21.

Example N-110, step c

Add DMAP to a solution of (S)-2-(t-butoxycarbonylamino)-4-hydroxy-3,3-dimethylbutyric acid benzyl ester (0.3 g) in DCM (3 mL) 0.109 g, 0.889 mmol) and acetic anhydride (0.084 mL, 0.889 mmol). The reaction mixture was stirred at room temperature for 16 hours, then diluted with EtOAc in,, washed with saturated NaCl saturated NaHCO _3, water, dried over anhydrous Na ₂ SO _4, filtered and concentrated to give an oil. The crude product was purified by EtOAc (EtOAc-EtOAc-EtOAc) Benzyl methyl butyrate (0.31 g). </RTI>^<RTIID=0.0>^</RTI></RTI>^<RTIID=0.0></RTI>

Example N-110, step d

Under N _2, to (S) -4- acetyl-2- (tert-butoxy-carbonyl) -3,3-dimethyl butyric acid benzyl ester (0.26 g of) in MeOH (10mL 10% Pd/C (0.020 g) was added to the solution. The reaction mixture was stirred for 16 hours under H ₂ at room temperature. Through diatomaceous earth (Celite ^®) The reaction was filtered, washed with EtOAc and concentrated to give (S) -4- acetyl-2- (tert-butoxy-carbonyl) -3,3-dimethyl Butyric acid (0.18 g). </RTI>^<RTIID=0.0>^</RTI></RTI>^<RTIID=0.0></RTI>

Example N-110, step e

To 1,1'-([1,1'-biphenyl]-4,4'-diyl)bis(2-bromoethyl ketone) (0.123 g) and (S)-4-ethoxycarbonyl-2 DIEA (0.120 mL) was added to a solution of <RTI ID=0.0>(3 </RTI><RTIgt;</RTI><RTIgt;</RTI><RTIgt; The reaction mixture was stirred at room temperature for 6 hours and then diluted with EtOAc, washed with sat NaHCO _3, water and saturated NaCl, dried over anhydrous Na ₂ SO _4, filtered and concentrated to give a pale yellow oil. The crude product was purified by EtOAc (EtOAc EtOAc EtOAc) Carbonylamino)-3,3-dimethylbutyric acid 2,2'-(biphenyl-4,4'-diyl)bis(2-triethoxyethane-2,1-diyl) ester 0.18g). </RTI>^{<RTI ID} =0.0>^</RTI></RTI>^{<RTI ID} =0.0></RTI>

Example N-110, step f

In the sealed tube, (2S, 2'S)-bis(4-acetoxy-2-(t-butoxycarbonylamino)-3,3-dimethylbutyric acid) 2,2'-( Mixture of biphenyl-4,4'-diyl)bis(2-oxoethoxy-2,1-diyl) ester (0.18 g) and ammonium acetate (0.171 g) in xylene at 130 ° C 3 hours. The reaction was diluted with EtOAc, washed with saturated NaHCO _3, water and saturated NaCl, dried over anhydrous Na ₂ SO _4, filtered and concentrated to give a yellow oil. The crude product was purified by EtOAc (EtOAc-EtOAc) elute 4,4'-diyl)bis(1H-imidazole-4,2-diyl))bis(3-(t-butoxycarbonylamino)-2,2-dimethylpropane-3,1- Dibasic ester (0.1 g). LC/MS (Cond. N-1): [M+H] ⁺ 773.

Example N-110, step g

Diacetic acid (3S,3'S)-3,3'-(4,4'-(biphenyl-4,4'-diyl)bis(1H-imidazole-4,2-diyl)) bis(3- Reaction mixture of (t-butoxycarbonylamino)-2,2-dimethylpropane-3,1-diyl)ester (0.1g), THF (2mL) and 1N NaOH (0.388mL, 0.388mmol) Stir at room temperature for 3 hours. The reaction was diluted with EtOAc, washed with saturated NaHCO _3, water and saturated NaCl, dried over anhydrous Na ₂ SO _4, filtered and concentrated to give a yellow oil. The crude product was purified by EtOAc (EtOAc EtOAc EtOAc) 4'-diyl) bis(1H-imidazole-4,2-diyl)) bis(3-hydroxy-2,2-dimethylpropane-1,1-diyl)diaminecarboxylic acid tert-butyl ester (0.066g). </RTI>^<RTIID=0.0></RTI>^</RTI>^<RTIID=0.0></RTI>

Example N-110

Example N-110 (trifluoroacetate) was prepared starting from the carbamate N-110g using the procedure described for the synthesis of Example N-28 and using the appropriate material. </RTI>^<RTIID=0.0></RTI>^</RTI>^<RTIID=0.0></RTI> ¹ H NMR (400 MHz, methanol - d ₄ ) ppm 7.92 (2H, s), 7.82 - 7.91 (8H, m), 5.07-5.12 (2H, m), 3.45-3.60 (4H, m), 1.24 (18 H, s), 1.19 (6 H, s), 0.99 (6 H, s).

Example Y-13

(S)-2-methyl-1-(5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaboron) Benzyl)-2-yl)phenyl)-1H-imidazol-2-yl)propylaminocarbamate (prepared by the procedure described in US Patent Application Publication No. 2008299075 (December 4, 2008) (1.47 g, 3.33 mmol), (S)-2-(5-(4-bromophenyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylic acid benzyl ester (1.704 g, 4.00 mmol) The reaction mixture of sodium hydrogencarbonate (1.399 g, 16.65 mmol) in DME (15 mL) and water (8 mL) was purified with N _{2 for} 5 min, and Pd(PPh ₃ ) ₄ (0.192 g, 0.167 mmol) was added, and Purify with N _{2 for} 3 minutes. Was stirred at 78 deg.] C the reaction mixture was 18 hours, cooled, diluted with EtOAc, washed with water, brine, dried (MgSO _4), and on a 80g silica gel column: purified (EtOAc / hexane 0-100%), to give compound 3 (0.58g). LC-MS (retention time: 2.610 min, method P-1), m/z 661 (M+H) ⁺ .

To (S)-2-(5-(4'-(2-((S)-1-(T-butoxycarbonylamino)-2-methylpropyl)-1H-) at room temperature Addition of 4N to a solution of imidazo-5-yl)biphenyl-4-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (0.33 g, 0.499 mmol) in DCM (2 mL) Dioxane of HCl (4 ml, 16.00 mmol). After stirring at room temperature for 2 hours, the reaction mixture was evaporated to dry crystals crystals LC-MS (retention time: 2.478 min, method P-1), m/z 561 (M+H) ⁺ . ¹ H NMR (400 MHz, methanol - d ₄ ) δ ppm 7.73-8.12 (11H, m), 7.31-7.45 (2H, m), 7.04-7.20 (2H, m), 5.11-5.30 (2H, m), 4.53 (1 H, d, J = 8.53 Hz), 3.60-3.88 (4 H, m), 2.46-2.69 (2 H, m), 1.99-2.27 (3 H, m), 1.25 (3 H) , d, J = 6.53 Hz), 1.01 (3 H, d, J = 6.78 Hz).

To (S)-2-(5-(4'-(2-((S)-1-amino-2-methylpropyl)-1H-imidazol-5-yl)biphenyl-4-yl) Addition of -1H-imidazol-2-yl)pyrrolidine-1-carboxylic acid benzyl ester trihydrochloride (0.2 g, 0.298 mmol) and pivalic acid (0.034 g, 0.328 mmol) in DCM (2 mL) N-Ethyl-N-isopropylpropan-2-amine (0.309 g, 2.388 mmol) and HBTU (0.136 g, 0.358 mmol). The reaction mixture was stirred at room temperature for 1 hour. The crude reaction mixture was purified on a 12 g EtOAc EtOAc (EtOAc:EtOAc:EtOAc LC-MS (retention time: 2.641min, the method P-1), m / z 645 (M + H) +.

Add 10% Pd-C (11.97 mg, 0.011 mmol) to (S)-2-(5-(4'-(2-((S))-2-methyl-1-pentanthene) under nitrogen Aminopropyl)-1H-imidazol-5-yl)biphenyl-4-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylic acid benzyl ester (145 mg, 0.225 mmol) containing HCl A solution of dioxane (0.5 ml, 2.000 mmol) in EtOH. The suspension was stirred at room temperature under a hydrogen balloon pressure for 2 days. The suspension was filtered and the filtrate was evaporated to dryness crystals crystals LC-MS (residence time: 2.420 min, method P-1), m/z 511 (M+H) ⁺ .

To N-((S)-2-methyl-1-(5-(4'-(2-((S)-pyrrolidin-2-yl)-1H-imidazol-5-yl)biphenyl-4 -yl)-1H-imidazol-2-yl)propyl)pivalamidine trihydrochloride (40 mg, 0.065 mmol) and 3-methoxyisoquinoline-1-carboxylic acid (15.73 mg, 0.077 mmol) N-Ethyl-N-isopropylpropan-2-amine (41.7 mg, 0.323 mmol) and HBTU (29.4 mg, 0.077 mmol) were added to a solution in DCM (2 mL). After stirring at room temperature for 1.5 hours, the reaction mixture was diluted with MeOH (1 mL) and concentrated. The residue was purified by preparative EtOAc (EtOAc) LC-MS (retention time: 2.658, method P-1), m/z 696.51 (M+H) ⁺ . A mixture of rotamers was observed by ¹ H NMR (ratio 1:2). ¹ H NMR (400 MHz, MeOD) data for major rotamers: δ ppm 0.92 (d, J = 6.78 Hz, 3 H), 1.16 (d, J = 6.53 Hz, 3 H), 1.24 (s, 9 H) ), 2.09-2.49 (m, 4 H), 2.66-2.79 (m, 1 H), 3.50-3.60 (m, 1 H), 3.81-3.90 (m, 1 H), 4.10 (s, 3 H), 4.85-4.88 (m, 1 H), 5.66 (dd, J = 8.16, 6.65 Hz, 1 H), 7.34-7.42 (m, 1 H), 7.48-7.60 (m, 2 H), 7.66-7.75 (m) , 1 H), 7.84-7.98 (m, 9 H) 8.00 (s, 1 H), 8.03-8.10 (m, 1 H).

Examples Y-14 to Y-16 (Table 2)

Examples Y-14 to Y-16 (bistrifluoroacetate) were prepared by employing the procedure described in Scheme 2 for Synthesis Example Y-13.

Example Y-17 to Y-18

Compounds Y-17 and Y-18 were prepared as shown in Scheme 3.

To (1S,1'S)-1,1'-(5,5'-(biphenyl-4,4'-diyl)bis(1H-imidazole-5,2-diyl))bis(2-methyl propan-1,1-diyl) diamino acid tert-butyl ester (0.45g, 0.716mmol) was added in DMF (5mL) in a solution of _{K 2 CO 3 (0.218g, 1.574mmol} ), and cooled to - 10 ° C. The reaction mixture was stirred for 5 min then MeOH (0.098 mL, 1.. The reaction mixture was stirred at room temperature for 18 hours, diluted with EtOAc, washed with water, brine, dried (MgSO _4), filtered and evaporated to dryness. The residue was purified with EtOAc EtOAc m. LC-MS (retention time: 2.705min, the method P-1), m / z 657.48 (M + H) +. ¹ H NMR (400 MHz, chloroform-d ) δ ppm 7.80 (4H, d, J = 8.3 Hz), 7.63 (4H, d, J = 8.5 Hz), 7.10 (2 H, s), 5.39 (2 H) , d, J = 9.3 Hz), 4.59 (2 H, t, J = 8.7 Hz), 3.71 (6 H, s), 2.19-2.33 (2 H, m), 1.45 (18 H, s), 1.06 ( 6 H,d, J = 6.8 Hz), 0.92 (6 H, d, J = 6.5 Hz).

The Boc group was removed using 4N HCl-containing dioxane as described in Scheme 2 to give compound 3 (tetrahydrochloride) as a beige solid. LC-MS (retention time: 2.503min, the method P-1), MS m / z 457.35 (M + 1) +.

Examples Y-17 and Y-18 were prepared by standard guanamine coupling as shown in Scheme 3 and purified by reverse phase HPLC and isolated as bistrifluoroacetate.

Example Y-17: LC-MS (retention time: 2.616 min, method P-1), MS m/z 771.57 (M+H) ⁺ . ¹ H NMR (400 MHz, methanol - d ₄ ) δ ppm 0.94 (d, J = 6.78 Hz, 6 H), 0.98-1.03 (m, 12 H), 1.23 (d, J = 6.53 Hz, 6 H), 1.93 -2.08 (m, J = 14.24, 7.03, 6.81, 6.81 Hz, 2 H), 2.38-2.53 (m, 2 H), 3.53 (s, 6 H), 3.87 (d, J = 8.03 Hz, 2 H) , 4.05 (s, 6 H), 4.85 (d, J = 10.29 Hz, 2 H), 7.78 (s, 8 H), 7.88 (s, 2 H).

Example Y-18: LC-MS (retention time: 1.812 min, method P-2), MS m/z 625.56 (M+H) ⁺ .

Example P-48

Add pure 1-chloropyrrolidine-2,5-dione (60.5 mg, 0.444 mmol) to (1S,1'S)-1,1'-(4,4'-(biphenyl-4,4'-di Bis(1H-imidazole-4,2-diyl)) bis(2-methylpropan-1,1-diyl)dicarbamic acid tert-butyl ester (133 mg, 0.212 mmol) in DMF (2 mL) The solution was stirred and the mixture was stirred overnight at room temperature. The crude product was purified by EtOAc EtOAc (EtOAc)

A solution of 4N HCl (1.878 mL, 7.51 mmol) in EtOAc (EtOAc) The mixture was stirred at room temperature overnight, and toluene (5 mL) was evaporated.

Add HATU (78 mg, 0.205 mmol) to (1S,1'S)-1,1'-(4,4'-(biphenyl-4,4'-diyl)bis(5-chloro-1H-imidazole-4 ,2-diyl))bis(2-methylpropan-1-amine) tetrahydrochloride (60 mg, 0.093 mmol), 3-methylbutyric acid (20.96 mg, 0.205 mmol) and DIPEA (0.104 mL, 0.597) The mixture was stirred in DCM (2 mL) and the mixture was stirred at room temperature for 2 hr. The reaction mixture was evaporated to dryness then purified by EtOAc EtOAc (EtOAc) m/z 665.49 (M+H) ⁺ .

Example P-49

Addition of HATU (56.3 mg, 0.148 mmol) to 4,4'-bis(2-((1R,3S,5R)-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazole- 5-yl)biphenyltetrahydrochloride (40 mg, 0.067 mmol), 3-chloro-5-methoxyisoquinoline-1-carboxylic acid (32.0 mg, 0.135 mmol) and N-ethyl-N-isopropyl The stirred solution of propyl-2-amine (0.070 mL, 0.404 mmol) in EtOAc (EtOAc) The reaction mixture was evaporated to dryness EtOAcqqHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH 2), m/z 887.46 (M+H) ⁺ .

Example P-50

Example P-50 was prepared by the standard guanamine coupling procedure described for the preparation of Example P-49, and purified by preparative HPLC and isolated as bistrifluoroacetate: LC-MS (retention time: 1.682 min, method) P-2), m/z 887.46 (M+H) ⁺ .

Example P-51

Add HATU (76 mg, 0.200 mmol) to compound 1 (65.3 mg, 0.1 mmol), 3-methylbutyric acid (22.47 mg, 0.220 mmol) and DIPEA (0.105 mL, 0.600 mmol) in DCM (2 mL) Stir the solution. The mixture was stirred at room temperature for 2 hrs. LC-MS (retention time: 1.780min, Method P-2), m / z 621.61 (M + H) +.

Example P-52

A solution of 5-chloropentanyl chloride (533 mg, 3.30 mmol) in DCM (5 mL) was added to &lt;RTIgt;(S)-2-amino-3-methylbutyric acid benzyl ester hydrochloride (731 mg, 3 mmol) The DCM (10 mL) and water (5.00 mL) containing sodium bicarbonate (554 mg, 6.60 mmol) were stirred in a cold (0-5 ° C) two-phase solution. The mixture was stirred at room temperature for 2-3 hours, then the organic layer was separated, washed with water, brine and dried (MgSO _4). The solvent was evaporated to give EtOAc (EtOAc m.

A solution of sodium bis(trimethyldecyl)aminide (1.459 mL, 1.459 mmol) in THF (5 mL) was added dropwise to (S)-2-(5-chloropentylamino)-3-methyl The benzyl butyl ketone (490 mg, 1.459 mmol) was stirred in THF (10 mL) EtOAc (EtOAc)EtOAc. With saturated NH ₄ Cl The reaction was quenched and diluted with ether. Washed with water, the organic layer was washed with brine and dried (Na ₂ SO _4). The solvent was evaporated to give abr. EtOAc (EtOAc). Hydrogenation of intermediate 4 with 10% Pd-C in EtOAC for 16 hours under balloon pressure gave the debenzylated product 5 (157 mg, 54%).

DIPEA (0.220 mL, 1.259 mmol) was added to 1,1'-(biphenyl-4,4'-diyl)bis(2-bromoethyl ketone) (227 mg, 0.572 mmol) and (S)-3-A Base 2-(2-oxopiperidin-1-yl)butanoic acid (228 mg, 1.144 mmol) in EtOAc (3 mL) The reaction mixture was stirred with EtOAc EtOAc EtOAc. LC-MS (retention time: 2.238min, Method P-2), m / z 633.5 (M + H) +.

(2S,2'S)-bis(3-methyl-2-(2-oxopiperidin-1-yl)butyric acid) 2,2'-(biphenyl-4,4'-diyl) double (2-Ethyloxyethyl-2,1-diyl) ester (322 mg, 0.509 mmol) and ammonium acetate (785 mg, 10.18 mmol) in a stirred suspension of xylene (6 mL) at 140 ° C for 2.5 hours. . The reaction mixture was cooled to room rt and diluted with EtOAc EtOAc. With saturated NaHCO _3, water, brine and the organic phase was dried (Na ₂ SO _4), to give a brown solid, silica gel by FCC (5-10% MeOH containing of DCM) The solid was purified to give Example P-52. LC-MS (retention time: 2.192min, Method P-2), m / z 593.5 (M + H) +.

Example P-53

Add HATU (760 mg, 2.000 mmol) to (S)-2-amino-3-methylbutyric acid benzyl ester hydrochloride (487 mg, 2 mmol), (S)-2-(t-butoxycarbonyl) Amino)-4-(methylthio)butanoic acid (499 mg, 2.00 mmol) and DIPEA (0.768 mL, 4.40 mmol) in EtOAc (EtOAc) The crude product was purified by EtOAc EtOAc (EtOAc) A mixture of compound 3 (0.850 g, 1.938 mmol) and methyl iodide (4 mL, 64.1 mmol) was stirred at room temperature for 2d. Excess MeI was removed by evaporation to dryness to give compound 4 as a beige foam. LC-MS (retention time: 1.895min, Method P-2), m / z 453.34 (M + H) +.

A solution of LiHMDS (1.000 mL, 1.000 mmol) in EtOAc was added to EtOAc (EtOAc) (EtOAc) ₄ Cl reaction mixture was quenched with saturated NH, and diluted with ether. Washed with water, the organic layer was washed with brine and dried (Na ₂ SO _4). The crude product was purified by EtOAc EtOAc (EtOAc) The stirred suspension of compound 5 (142 mg, 0.364 mmol) and 10% Pd-C (38.7 mg, 0.036 mmol) in MeOH (10 mL) was stirred in a Parr shaker bottle at 50 psi. hour. The suspension was filtered, and the filtrate was evaporated to dryness to afford compound 6 (105 mg, 96%). LC-MS (retention time: 2.252min, Method P-2), m / z 299.3 (MH) -.

1,1'-(biphenyl-4,4'-diyl)bis(2-bromoethyl ketone) (69.2 mg, 0.175 mmol), compound 6 (105 mg, 0.350 mmol) and DIPEA (0.067 mL, 0.385 mmol) ) a mixture of (2mL) and CHCl ₃ (1mL) in acetonitrile was stirred overnight at room temperature. The reaction mixture was evaporated to dryness then purified eluting elut elut elut elut elut elut elut elut In a capped vial, compound 8 (126 mg, 0.151 mmol) and ammonium acetate (233 mg, 3.02 mmol) in EtOAc (4 mL). The reaction mixture was cooled to room rt and diluted with EtOAc EtOAc. With saturated NaHCO _3, water, brine and the organic phase was dried (Na ₂ SO _4), to give a brown solid, silica gel by FCC (5-10% MeOH containing of DCM) The solid was purified to give (3S, 3'S) -1 , 1'-((1S,1'S)-1,1'-(5,5'-(biphenyl-4,4'-diyl)bis(1H-imidazole-5,2-diyl)) bis ( 2-Methylpropane-1,1-diyl)) bis(2-oxopyrrolidin-3,1-diyl)dicarbamic acid tert-butyl ester (64 mg, 54%). 4N HCl (0.201 mL, 0.805 mmol) of dioxane was added to DCM (0.5 mL). The mixture was stirred for 2 hours, then evaporated to dryness to give crystals eluted eluted eluted eluted The solution was taken up in 1 mL) then EtOAc EtOAc (EtOAc:EtOAc. The mixture was stirred for 1-2 hours at room temperature, the organic layer was separated, and washed with 1N NaOH (2mL), washed with water, brine and dried (MgSO _4). The crude product was purified by preparative EtOAc EtOAc (EtOAc) LC-MS (retention time: 1.623min, Method P-2), m / z 711.59 (M + H) +.

Example P-54

DIPEA (0.123 mL, 0.705 mmol) was added to 1,1'-(biphenyl-4,4'-diyl)bis(2-bromoethyl ketone) (127 mg, 0.321 mmol) and (S)-2-( A stirred suspension of the third butoxycarbonyl(methyl)amino)-3-methylbutyric acid (74.2 mg, 0.321 mmol) in acetonitrile (2 mL) and chloroform (2 mL). The mixture was stirred at rt EtOAc then EtOAc (EtOAc)

A stirred suspension of 3 (218 mg, 0.313 mmol) and ammonium acetate (482 mg, 6.26 mmol) in EtOAc (5 mL). The reaction mixture was cooled to room temperature and diluted with EtOAc EtOAc. With saturated NaHCO _3, water, brine and the organic phase was dried (Na ₂ SO _4), to give a brown solid, silica gel by FCC (5-10% MeOH containing of DCM) The solid was purified to give Compound 4.

To a solution of 4 (70 mg, 0.106 mmol) in DCM (1 mL) The mixture was stirred for 3 hours, then evaporated to dryness to give (1S,1's)-1,1'-(4,4'-(biphenyl-4,4'-diyl)bis (1H-imidazole) as a yellow solid. -4,2-diyl))bis(N,2-dimethylpropan-1-amine) tetrahydrochloride (61 mg), suspended in DCM (3 ml), and 3-methylbutyric acid (23 mg, 0.225 mmol), DIPEA (0.106 mL, 0.607 mmol) and HATU (85 mg, 0.223 mmol). The reaction mixture was stirred at room temperature for 2 hr then evaporated to dryness crystals LC-MS (retention time: 1.885min, Method P-2), m / z 625.62 (M + H) +.

Example P-54.1

Example P-54.1 was prepared by standard guanamine coupling method, Intermediates 1-3 (see below) and isobutyric acid and isolated as bistrifluoroacetate:

LC-MS (retention time: 2.288 min, method P-2), m/z 597.5 (M+H)+.

Example V-1

Example V-1, step a

Prepared according to the following references: J. Org. Chem. 2000, 65 , p. 6984.

Example V-1, step b

Prepared from ester V-1a according to the procedure described in Tetrahedron: Asymmetry 2006, 17 , page 620.

Example V-1, step c

2-Amino-4'-bromoacetophenone hydrochloride (6.676 g, 0.031 mol), ester V-1b (5.37 g, 0.031 mol) and N,N-diisopropylethylamine (11 mL, 0.063) Add a solution of HATU (13 g, 0.034 mol) in a solution of DMF (100 mL). The reaction mixture was stirred at room temperature under N ₂ for 2 h. The volatile component was removed in vacuo and the residue was taken in ethyl acetate <RTI ID=0.0> The aqueous layer was back extracted with ethyl acetate (2 x 100 mL). The organic layer was dried over MgSO ₄ merger, filtered, and concentrated in vacuo. The residue was dissolved in CH ₂ Cl ₂ (10mL), and loaded onto Biotage silica gel column and washed with 75% ethyl acetate / hexane eluting to give a light yellow solid of Amides V-1c (10.5g). ¹ H NMR (500 MHz, DMSO-d ₆ ) δ δ 8.27 (t, J = 5.49, 1 H), 7.91 (d, J = 8.55, 2 H), 7.76 (d, J = 8.55, 2 H), 4.65 -4.46 (m, 2 H), 3.60 (s, 3 H), 3.11-2.91 (m, 2 H), 2.03-1.88 (m, 2 H), 1.77-1.68 (m, 1 H), 1.68-1.60 (m, 3 H). LC / MS: [M + H ] + C 16 H 19 79 BrNO 4 Calculated: 368.05; Found: 368.11.

Example V-1, step d

In a sealed reaction vessel, Amides V-1c (7.3g, 0.020mol) and NH ₄ OAc (9.17g, 0.119mol) in a mixture of xylene (130 mL) was heated at in the 140 ℃ 5 hours. The reaction was cooled to room temperature. Remove all solvents in a vacuum. The residue was dissolved in EtOAc ( ₃ mL)EtOAcEtOAcEtOAc The layers were separated and the aqueous extracted with EtOAc EtOAc , Washed with brine and dried over the combined organic layers over MgSO _4, and concentrated in vacuo. The resulting residue was dissolved in CH ₂ Cl ₂ and loaded onto silica gel Biotage cartridge in 25% ethyl acetate / CH ₂ Cl ₂ eluting it, to give the imidazole as a light yellow solid V-1d (3.63g). ^{1 H NMR (500MHz, DMSO-} d 6) δ ppm 12.17 / 11.93 ( two br s, 1 H), 7.69 (d , J = 8.24,2 H), 7.54 (d, J = 1.83,1 H) , 7.50 (d, J = 8.55, 2 H), 3.59 (s, 3 H), 3.44 - 3.34 (m, 1 H), 3.28-3.15 (m, 1 H), 2.17-2.02 (m, 2 H) , 1.86-1.66 (m, 4 H). LC / MS: [M + H ] + C 16 H 18 79 BrN 2 O 2 Calculated: 349.06; Found: 349.13.

Example V-1, step e

In a sealed reaction vessel, bromide V-1d (1.8 g, 5.15 mmol), diboron pinacol ester (2.61 g, 10.3 mmol) and potassium acetate (1.29 g, 13.1 mmol) in 1,4-dioxin To a mixture of the alkane (30 mL) was added bis(triphenylphosphine)palladium(0) (0.18 g, 0.16 mmol). The reaction vessel was thoroughly purged with nitrogen, sealed and heated at 80 ° C for 18 hours. Volatile components were removed in vacuo, and the residue was dissolved in CH ₂ Cl ₂ (100mL) and water (25mL) in. The layers were separated and the aqueous layer was extracted with CH ₂ Cl ₂ (2×100 mL). Dried organic layer with saturated NaHCO ₃ (aq) and the combined sum over MgSO _4, filtered, and concentrated in vacuo. The residue was loaded onto a Biotage cartridge and dissolved in 25% ethyl acetate / CH ₂ Cl _{2 to} give a white foam. Acid ester V-1e (1.9 g). LC / MS [M + H] + C 22 H 30 BN 2 O 4 Calculated: 397.23; Found: 397.33.

Example V-1, step f

In a sealed reaction vessel, to bromide V-1d (1.2 g, 3.4 mmol), Addition of hydrazine (triphenyl) to a mixture of the ester V-1e (1.86 g, 4.7 mmol) and NaHCO ₃ (0.862 g, 10.3 mmol) in 1,2-dimethoxyethane (30 mL) and water (10 mL) Palladium (0) (0.12 g, 0.10 mmol). The reaction was thoroughly purged with nitrogen, sealed, and heated at 80 ° C for 24 hours. The volatile components were removed in vacuo and the residue was taken in 20% MeOH / CHCl ₃ and washed with water. The layers were separated, and washed with 20% MeOH / CHCl aqueous layer was extracted ₃ (2 × 100mL). The organic layer was washed with saturated NaHCO ₃ solution (aq) of the combined, dried over MgSO _4, filtered, and concentrated in vacuo. The residue was dissolved in a minimal amount 5% MeOH / ₃ in CHCl, and loaded onto a Biotage silica gel cartridge and washed with 25% ethyl acetate / CH ₂ Cl ₂ eluting to give a light yellow solid of V-1f (1.3g). LC / MS [M + H] + C 32 H 35 N 4 O 4 Calculated: 539.27; Found: 539.40.

Example V-1, step g

To the V-1f (1.2g, 2.2mmol) ₂ O in the solution in MeOH / H in 1N NaOH (aq, 4.5mL, 4.5mmol), and the mixture was stirred at about 25 ℃ 19 hours. The reaction was cooled in an ice/water bath and was taken &lt;RTI ID=0.0&gt;&gt; The precipitate formed was filtered and washed with water to give EtOAc (EtOAc) ¹ H NMR (500 MHz, DMSO-d ₆ ) δ ppm 12.31 (bs, 4 H), 7.80 (d, J = 8.24, 4 H), 7.69 (d, J = 8.24, 4 H), 7.51 (s, 2) H), 3.40 (apparent quartet, J = 8.24, 2 H), 3.16 (apparent quartet, J = 8.44, 2 H), 2.19-2.01 (m, 4 H), 1.89-1.69 (m) , 8 H). LC / MS: [M + H ] + C 30 H 31 N 4 O 4 Calculated: 511.23; Found: 511.15.

Example V-1, step h

A solution of methyl carbazate (2.0 g, 22.2 mmol) and acetone (1.63 mL, 22.2 mmol) in MeOH (33 mL) The reaction was cooled to about 25 ℃, and was added _{NaBH 3 CN (1.4g, 22.3mmol)} , followed by dropwise addition of acetic acid (1mL, 17.5mmol). After stirring at about 25 ° C for 1 hour under nitrogen, all volatile components were removed in vacuo. Water was added to the residue and the product was extracted with ethyl acetate (2×100 mL). Washed with brine the organic layers were combined, dried over MgSO _4, filtered, and concentrated in vacuo to give a colorless oil of carbazate V-1h, it solidified into a white solid (2.6 g of) standing. ¹ H NMR (500MHz, CDCl ₃ ) δ ppm 6.44 (br s, 1 H), 4.23 (br s, 1 H), 3.69 (br s, 3 H), 3.15 (apparent broad singlet, 1 H), 1.01 (d, J = 6.41, 6 H).

Example V-1

To acid V-1g (0.100g, 0.196mmol), carbazate V-1h (0.155g, 1.175mmol) and N,N-diisopropylethylamine (0.150mL, 0.859mmol) in DMF (3mL HATU (0.164 g, 0.431 mmol) was added to the mixture. The reaction mixture was stirred at room temperature for 1.5 hours, followed by heating at 45 ° C for 15 hours. After allowing to cool to ambient conditions, EtOAc (EtOAc m. The solid was re-purified by a different reverse phase preparative HPLC (EtOAc/EtOAc/EtOAc). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 14.38 (apparent broad singlet, approx. 3 H), 9.78/9.46 (two broad single peaks, 2 H), 8.13 (br s, 2 H), 8.03 -7.83 (m, 8 H), 4.66-4.46 (m, 2 H), 3.91-3.72 (m, 2 H), 3.68 (s, 2 H), 3.58 (s, 4 H), 3.51-1.48 (four Overlapping multiple peaks, 12 H), 1.10-0.91 (m, 12 H). LC / MS: [M + H ] + C 40 H 51 N 8 O 6 Calculated: 739.39; Found: 739.45.

Intermediate 1-1: ((1S,1'S)-1,1'-(4,4'-(biphenyl ) was prepared by the procedure described in US Patent Application Publication No. 2008299075 (December 4, 2008) -4,4'-diyl) bis(1H-imidazole-4,2-diyl)) bis(2-methylpropan-1,1-diyl)diaminecarboxylic acid tert-butyl ester) .

Intermediate 1-2: (1S, 1'S)-1,1'-(4,4'-(biphenyl-4,4'-diyl)bis(1H-imidazole-4,2-diyl)) double (2-methylpropan-1-amine) tetrahydrochloride

Add 4N HCl (16 mL, 64.0 mmol) of dioxane to (1S,1'S)-1,1'-(4,4'-(biphenyl-4,4'-diyl)bis(1H-imidazole -4,2-diyl)) butyl (2-methylpropan-1,1-diyl)dicarbamic acid tert-butyl ester (1.42 g, 2.258 mmol) in DCM (5 mL) The resulting suspension was stirred at room temperature for 1.5 hours, then evaporated to dryness to give Intermediate 1-2 as a yellow solid. LC-MS: (Retention time: 2.348 min, Method P-1), MS m/z 429 (M+H) ⁺ . ¹ H NMR (400 MHz, MeOD ) δ ppm 8.11 (2H, br. s.), 7.95-8.03 (4H, m), 7.90 (4H, d, J = 7.0 Hz), 4.56 (2 H, br .s.), 2.64 (2H, br.s.), 1.27 (6 H, d, J = 5.8 Hz), 1.01 (6 H, d, J = 6.8 Hz).

Intermediate 1-3: Preparation of (1R, 1'R)-1,1'-(4,4'-(linked ) by following the procedure described in US Patent Application Publication No. 2008299075 (December 4, 2008) Benzene-4,4'-diyl)bis(1H-imidazole-4,2-diyl))bis(2-methylpropan-1-amine) .

Intermediate 1-4: Preparation of 4-(2-((R)-pyrrolidin-2-yl)-1H-imidazole by following the procedure described in PCT International Application 2009020825 (February 12, 2009) 5-yl)-4'-(2-((S)-pyrrolidin-2-yl)-1H-imidazol-5-yl)biphenyl .

Intermediate 1-5: Preparation of (S)-2-methyl-1-(5-(4'-(2- ) by following the procedure described in US Patent Application Publication No. 2008299075 (December 4, 2008) ((S)-Pyrrolidin-2-yl)-1H-imidazol-5-yl)biphenyl-4-yl)-1H-imidazol-2-yl)propan-1-amine .

General Method for Indirectamine Coupling: Method 1: The following procedure illustrates the use of HATU as a reagent for indole coupling.

Example Y-19

Add DIPEA (0.053 mL, 0.305 mmol), (1S, 1'S)-1,1' to a mixture of 3-methoxyisoquinoline-1-carboxylic acid (19.46 mg, 0.096 mmol) in DCM ( 1.5 mL) -(5,5'-(biphenyl-4,4'-diyl)bis(1H-imidazol-5,2-diyl))bis(2-methylpropan-1-amine)tetrahydrochloride ( 25 mg, 0.044 mmol) and HATU (36.4 mg, 0.096 mmol). The mixture was stirred at room temperature for 1.5 h and diluted with 1 mL MeOH EtOAc. The product (10.5 mg) was obtained as a bis trifluoroacetate salt. LC-MS (retention time: 2.908min, the method P-1), m / z 799.52 (M + H) +.

Method 2: The following procedure illustrates the use of HBTU as a reagent for indole coupling.

Example Y-20

To (1S,1'S)-1,1'-(5,5'-(biphenyl-4,4'-diyl)bis(1H-imidazole-5,2-diyl))bis(2-methyl N-ethyl-N- was added to a mixture of propan-1-amine) tetrahydrochloride (80 mg, 0.139 mmol) and 5-methylthiophene-2-carboxylic acid (43.6 mg, 0.306 mmol) in DCM (2 mL) Isopropylpropan-2-amine (0.2 mL, 1.145 mmol) and HBTU (116 mg, 0.306 mmol). After stirring at room temperature for 1 hour, the reaction mixture was diluted with MeOH (1 mL) and concentrated to dry. The residue was purified by preparative EtOAc (EtOAc): LC-MS: residence time: 1.933 (method P-2); m/z 677 (M+H) ⁺ . ^{1 H NMR (400MHz, MeOD)} δ ppm 7.91 (2 H, s), 7.86 (8 H, s), 7.73 (2 H, d, J = 3.76Hz), 6.87 (2 H, dd, J = 3.76, 1.00 Hz), 5.04 (2 H, d, J = 8.78 Hz), 2.42-2.55 (6 H, m), 1.20 (6 H, d, J = 6.53 Hz), 0.99 (6 H, d, J = 6.78) Hz).

Method 3: The indoleamine analog was synthesized in parallel as follows:

Preparation of (1S,1'S)-1,1'-(5,5'-(biphenyl-4,4'-diyl)bis(1H-imidazole-5,2-diyl))bis(2-methyl a stock solution of propan-1-amine) tetrahydrochloride (660 mg, 1.15 mmol) and DIPEA (1.61 ml, 9.2 mmol) in DMF (11.5 ml) and HATU (1.09 g, 2.87 mmol) in DMF (11.5 ml) The stock solution was dispensed and dispensed into each reaction vial. Add 0.5 ml to the carboxylic acid solution (0.125 mmol) in a 16 x 100 mm Wheaton vial HATU solution. The capped vial was shaken at room temperature for 10 minutes, followed by 0.5 ml of (1S,1'S)-1,1'-(5,5'-(biphenyl-4,4'-diyl)bis (1H-imidazole) -5,2-Diyl)) bis(2-methylpropan-1-amine)/DIPEA solution was added to each vial. The capped vials were shaken for 18 hours at room temperature. The reaction mixture was purified by preparative HPLC to give the corresponding decylamine analog.

Method 4: The urethane analogs were synthesized in parallel as follows:

Preparation of (2R,2'R)-N,N'-((1S,1'S)-1,1'-(5,5'-(biphenyl-4,4'-diyl)bis(1H-imidazole- 5,2-diyl))bis(2-methylpropan-1,1-diyl))bis(2-amino-3-methylbutyramine) tetrahydrochloride (460 mg, 600 μmol) and DIPEA (828 μL, 4.80 mmol) stock solution in DMF (12 mL) was partitioned into each reaction vial as follows: chloroformate (0.112 mmol) in a threaded 16 x 100 mm Wheaton tube was weighed. Add 1.0 mL of (2R,2'R)-N,N'-((1S,1'S)-1,1'-(5,5'-(biphenyl-4,4'-diyl) bis ( 1H-imidazole-5,2-diyl))bis(2-methylpropan-1,1-diyl))bis(2-amino-3-methylbutyramine)/DIPEA stock solution. The capped vials were shaken for 18 hours at room temperature. The reaction mixture was purified by preparative HPLC to give the corresponding urethane analogs (Examples S-245 to S-253 in Table 8).

Method 5: The urea analogs were synthesized in parallel as follows:

Preparation of (1S,1'S)-1,1'-(5,5'-(biphenyl-4,4'-diyl)bis(1H-imidazole-5,2-diyl))bis(2-methyl A stock solution of propan-1-amine) tetrahydrochloride (304 mg, 531 [mu]mol) and DIPEA (558 [mu]L, 3.2 mmol) in DMF (9 mL) was partitioned into each reaction vial. Add 1.0 mL (1S,1'S)-1,1'-(5,5'-(biphenyl-4,) to each of the amine formamidine chloride (0.129 mmol) in a 16×100 mm Wylton tube with a thread. 4'-Diyl) bis(1H-imidazole-5,2-diyl))bis(2-methylpropan-1-amine)/DIPEA solution. The capped vials were shaken for 18 hours at room temperature. Preparation type The reaction mixture was purified by HPLC to give the corresponding urea analog.

Example P-130

A solution of phosgene (3.17 mL, 6.00 mmol) in toluene was added to 4,4-difluoropiperidine hydrochloride (315 mg, 2 mmol) and TEA (0.669 mL, 4.80 mmol) in THF. 6 mL) in the stirred solution. The reaction mixture was allowed to warm to rt and stirred at rt overnight. Ether was added, and the reaction mixture was filtered through diatomaceous earth (Celite ^®) and the plug was washed with ether. The filtrate was evaporated to dryness to give 4,4-difluoropiperidine-1-carbonyl chloride as a pale yellow oil.

Add DIPEA (0.039 mL, 0.225 mmol) to (1S,1'S)-1,1'-(4,4'-(biphenyl-4,4'-diyl)bis(1H-imidazole-4,2- Diyl)) bis(2-methylpropan-1-amine) tetrahydrochloride (47 mg, 0.082 mmol) and 4,4-difluoropiperidine-1-carbonyl chloride (33.0 mg, 0.180 mmol) in DCM ( 3 mL) and a stirred mixture in DMF (1 mL). The mixture was stirred at room temperature overnight and then evaporated to dryness. The residue was purified by preparative EtOAc (EtOAc): LCMS (Method _{P-3): R t =} 3.24min, 723.05 [M + H] +; 1 H NMR (400MHz, methanol _{-d 4) δ 7.91 (s,} 2 H), 7.90-7.86 (m, 8 H ), 4.80 (d, J = 8.5 Hz, 2 H), 3.71-3.54 (m, J = 6.5, 5.0 Hz, 8 H), 2.45-2.31 (m, 2 H), 2.09-1.89 (m, 8 H) ), 1.18 (d, J = 6.5 Hz, 6 H), 0.96 (d, J = 6.8 Hz, 6 H).

Example P-131

LCMS (Method _{P-3): R t =} 3.03min, 719.32 [M + H] +; 1 H NMR (400MHz, methanol _{-d 4) δ 7.89 (s,} 2H), 7.89-7.84 (m, 8H), 5.35-5.25 (m, 2H), 3.88-3.79 (m, 2H), 3.69-3.60 (m, J = 7.8, 7.8 Hz, 2H), 3.58-3.45 (m, 8H), 2.63-2.50 (m, 2H) ), 2.29-2.16 (m, J = 6.0, 1.8 Hz, 2H), 2.15-2.03 (m, 8H), 2.02-1.88 (m, 4H).

Examples Y-34 to Y-37 and P-132 to P-134

PCC was added portionwise to a mixture of (1-methylcyclopropyl)methanol (1.9 g, 22.06 mmol) in DCM (30 mL) and powdered molecular sieve 4A (5 g) over 30 min. 6.18 g, 28.7 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with 60mL diethyl ether, stirred for 10 min, and diatomaceous earth over (Celite ^®) / silica gel was filtered and washed with DCM / ether (1: 2) fractions. The filtrate was concentrated carefully to give a light brown oil which was used directly in the next step.

At room temperature, under N _2, a solution of 1-methyl-cyclopropane carbaldehyde in MeOH (20mL) in a solution of 3 parts of carve was added (R) -2- amino-2-phenylethanol (3.23g, 23.54 Mm). The mixture was stirred at room temperature for 2 hours, then cooled with an ice-water bath, and trimethyl decane cyanide (5.74 mL, 42.8 mmol) was added dropwise over 5 min. The mixture was stirred for 10 minutes, the ice bath was removed, and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated and purified on a 40 g silica gel column (EtOAc/hexane: 0% to 100%) to afford (S)-2-((R)-2-hydroxy-1-phenylethylamino)- 2-(1-Methylcyclopropyl)acetonitrile. ¹ H NMR (400MHz, CHLOROFORM -d) δ 7.40-7.30 (m, 5 H), 4.08 (dd, J = 9.2,4.1Hz, 1 H), 3.82 (dd, J = 10.8,4.0Hz, 1 H) , 3.64 (t, J = 10.0 Hz, 1 H), 2.97 (s, 1 H), 1.26 (s, 3 H), 0.63-0.53 (m, 2 H), 0.51 - 0.42 (m, 2 H).

To (S)-2-((R)-2-hydroxy-1-phenylethylamino)-2-(1-methylcyclopropyl)acetonitrile (1.1 g, 4.78 mmol) in MeOH (20 mL) In a cold (0-5 ° C) solution of DCM (20 mL), lead tetraacetate (2.75 g, 6.21 mmol) was added in 5 portions. The reaction mixture was stirred at 0 ° C for 10 minutes and then at room temperature for 50 minutes. By addition of 20ml of saturated NaHCO ₃ The reaction was quenched, and the solid was filtered. The filtrate was extracted with DCM (4×). With NaHCO _3, of the combined extracts washed with brine, dried (MgSO _4), and the solvent removed to give an oil which was refluxed for 20 hours in 20ml of concentrated hydrochloric acid and cooling down. The clarified upper solution was decanted into a separate flask and concentrated to dryness to give a white solid, which was dissolved in EtOAc EtOAc (EtOAc) The mixture was cooled in ice water and BOC ₂ O (2.085 g, 9.55 mmol) was added in 5 portions. The reaction mixture was stirred at room temperature overnight (20 hours). The solvent was removed and the residue was partitioned with 10 mL 1 N EtOAc and EtOAc / hexane (~1:5). The aqueous phase was acidified with EtOAc (3x). With brine (2 ×) The combined extracts were washed, dried (MgSO _4). The solvent was removed to give (S)-2-(t-butoxycarbonylamino)-2-(1-methylcyclopropyl)acetic acid as a white solid. ¹ H NMR (400MHz, CHLOROFORM -d) δ 5.18 (br.S., 1 H), 3.76 (br.S., 1 H), 1.47 (s, 9 H), 1.09 (s, 3 H), 0.91 -0.77 (m, 1 H), 0.75-0.67 (m, 1 H), 0.52-0.44 (m, 1 H), 0.44-0.35 (m, 1 H); [α] _D = 80.95.

To (S)-2-((Tert-butoxycarbonyl)amino)-2-(1-methylcyclopropyl)acetic acid (0.81 g, 3.53 mmol) and DIPEA (0.679 mL, 3.89 mmol) in acetonitrile (1,5'-([1,1'-biphenyl]-4,4'-diyl) bis(2-bromoethyl) was added in 3 parts by stirring in (10 mL) (3-5 °C). Ketone) (0.700 g, 1.766 mmol). The suspension was stirred in an ice bath for 0.5 hour and then at room temperature for 18 hours. The reaction mixture was diluted with EtOAc, washed with NH ₄ Cl, brine. The solvent is removed to give the indicated compound. LC / MS (conditions YT-1): [M + Na] + 715.37, R t = 3.16min.

In a sealed tube, (2S,2'S)-bis(2-((t-butoxycarbonyl)amino)-2-(1-methylcyclopropyl)acetic acid) [1,1'-biphenyl -4,4'-diylbis(2-oxoethoxy-2,1-diyl) ester (1.22 g, 1.761 mmol) and ammonium acetate (4.07 g, 52.8 mmol) in xylene (5 mL) The mixture was heated at 135 ° C for 3 hours. The reaction mixture was cooled, diluted with EtOAc, washed with NaHCO _3, brine, dried (MgSO _4), concentrated, and column on 25g silica gel (EtOAc / hexane 50-100%) to give the residue, to give a yellow solid The product. LC / MS (YT-1) : [M + H] + 653.49, R t = 2.33min.

In an ice bath, to ((1S,1'S)-(5,5'-([1,1'-biphenyl]-4,4'-diyl) bis(1H-imidazole-5,2-diyl) )) bis((1-methylcyclopropyl)methylene))diamine terephthalate dicarboxylate (0.64 g, 0.980 mmol) in DCM (5 mL) Alkane (5 mL, 20.0 mmol). The reaction mixture was stirred at room temperature for 2 hr. LC / MS (Method YT-1): [M + H] + 453.3, R t = 1.58min.

Examples Y-34 to Y-37 and P-132 to P-134 were prepared by standard guanamine coupling procedures. (Table 9).

* ¹ H NMR of Y-34 (400 MHz, methanol-d ₄ ): δ ppm 7.91 (2 H, s), 7.87-7.90 (4 H, m), 7.83-7.87 (4 H, m), 4.46 (2) H, s), 2.56 (2 H, t, J = 10.29 Hz), 2.06-2.20 (4 H, m), 1.67-2.01 (12 H, m), 1.19 (6 H, s), 0.84-0.94 ( 2 H, m), 0.65-0.77 (4 H, m), 0.50-0.64 (2 H, m).

Example P-135

Add DIPEA (0.044 mL, 0.250 mmol) to (1S,1'S)-(4,4'-([1,1'-biphenyl]-4,4'-diyl) bis (1H-imidazole-4, 2-Diyl)) bis((1-methylcyclopropyl)methanamine) tetrahydrochloride (54.5 mg, 0.091 mmol) and 4,4-difluoropiperidine-1-carbonyl chloride (36.8 mg, 0.200 Methyl) in a stirred portion of the solution in DCM (2 mL) and DMF (1 mL). The mixture was stirred overnight at room temperature. The reaction mixture was evaporated to dryness crystals crystals crystals crystals LCMS (Method _{P-3): R t =} 3.186min, 747.55 [M + H] +; 1 H NMR (500MHz, methanol _{-d 4) δ 7.89 (s,} 2 H), 7.89-7.86 (m, 8 H ), 3.65 (d, J = 2.7 Hz, 8 H), 2.08-1.96 (m, 8 H), 1.19 (s, 6 H), 0.93-0.87 (m, 2 H), 0.79-0.73 (m, 2) H), 0.73-0.67 (m, 2 H), 0.60-0.53 (m, 2 H).

Example Y-38 to Y-39

At room temperature, under N _2, a solution of 1-methyl-cyclobutane-carbaldehyde (1g, 10.19mmol) in MeOH (20mL) in a solution of 3 parts of carve was added (R) -2- amino-2-phenyl Ethanol (1.538 g, 11.21 mmol). The resulting solution was stirred at room temperature for 1 hour, then cooled to -20 ° C, and trimethyl decane cyanide (2.73 mL, 20.38 mmol) was added dropwise over 5 min. The reaction mixture was then warmed to room temperature and stirred at room temperature for 18 h. The solvent was removed and the residue was purified EtOAcjjjjjjjj

To (S)-2-(((R)-2-hydroxy-1-phenylethyl)amino)-2-(1-methylcyclobutyl)acetonitrile (0.64 g, 2.62 mmol) in MeOH ( 20 mL) and DC (0-5 ° C) in DCM (20 mL) were added to a stirred solution to add lead tetraacetate (1.510 g, 3.41 mmol). The reaction mixture was stirred at 0-5 ° C for 5 min and warmed to room temperature and stirred for 3.5 h. With 20ml saturated NaHCO ₃ to quench the reaction mixture. The solid was filtered and the filtrate was extracted with DCM (4×). With NaHCO _3, of the combined extracts washed with brine, dried (MgSO _4), and the solvent removed to give an oil, it in concentrated hydrochloric acid (20mL, 240mmol) was refluxed for 17 hours. The reaction mixture was cooled to cool, and the clear solution was decanted and concentrated to dryness to give a brown solid which was dissolved in 20mL MeOH, was added 5 parts of TEA in an ice bath carve (1.095mL, 7.86mmol) and Boc ₂ O (0.858 g, 3.93 mmol), then the reaction mixture was warmed to room temperature and stirred at room temperature for 24 h. The solvent was removed, and the residue was dissolved in EtOAc and washed with ice-cooling of 1N HCl (2 ×), brine (2 ×), dried (MgSO _4), removed the solvent to obtain a given compound (0.61g). ¹ H NMR (400 MHz, chloroform-d) δ 4.97 (d, J = 8.5 Hz, 1 H), 4.40 (d, J = 9.3 Hz, 1 H), 2.43-2.22 (m, 1 H), 2.20-2.06 (m, 1 H), 2.04-1.90 (m, 1 H), 1.91-1.79 (m, 1 H), 1.80-1.60 (m, 2 H), 1.46 (d, J = 1.0 Hz, 9 H), 1.15(s,3 H);[α] _D =27.11.

To an (S)-2-((t-butoxycarbonyl)amino)-2-(1-methylcyclobutyl)acetic acid (0.61 g, 2.507 mmol) and DIPEA (0.482 mL, 2.76 mmol) of 1,1'-([1,1'-biphenyl]-4,4'-diyl) double in 3 parts of cold (0-5 ° C) in acetonitrile (10 mL) with stirring solution (2-Bromoethyl ketone) (0.497 g, 1.254 mmol). The suspension was stirred in an ice bath for 0.5 hour and then at room temperature for 3 days. The volatiles were removed in vacuo and the residue was taken directly eluted eluted eluted eluted eluted eluted LC / MS (Method YT-1): [M + H] + 743.50, R t = 3.34min. ¹ H NMR (400MHz, CHLOROFORM -d) δ 8.02 (d, J = 8.3Hz, 4 H), 7.75 (d, J = 8.5Hz, 4 H), 5.56 (d, J = 16.3Hz, 2 H), 5.29 (d, J = 16.3 Hz, 2 H), 5.05 (d, J = 9.0 Hz, 2 H), 4.54 (d, J = 9.3 Hz, 2 H), 2.44-2.32 (m, 2 H), 2.24 - 2.13 (m, 2 H), 2.05-1.82 (m, 6 H), 1.75-1.65 (m, 2 H), 1.51-1.44 (m, 18 H), 1.27 (s, 6 H).

In a sealed tube, (2S,2'S)-bis(2-((t-butoxycarbonyl)amino)-2-(1-methylcyclobutyl)acetic acid) [1,1'-biphenyl -4,4'-diylbis(2-oxoethoxy-2,1-diyl) ester (0.802 g, 1.113 mmol) and ammonium acetate (2.57 g, 33.4 mmol) in xylene (5 ml) The mixture was heated at 138 ° C for 3 hours and cooled to room temperature. The reaction mixture was diluted with EtOAc, and washed with saturated NaHCO _3, brine, dried (MgSO _4). The solvent was removed and the residue was purified EtOAcjjjjjjjjj ^{1 H NMR (400MHz, MeOD)} δ 7.83-7.74 (m, 4 H), 7.71-7.63 (m, 4 H), 7.37 (s, 2 H), 4.83 (s, 2 H), 2.29 (q, J = 9.0 Hz, 2 H), 2.14 (five peaks, J = 9.5 Hz, 2 H), 2.01-1.87 (m, 2 H), 1.86-1.74 (m, 2 H), 1.77-1.54 (m, 4) H), 1.51-1.39 (m, 18 H), 1.24-1.11 (m, 6 H). LC / MS (YT-1) : [M + H] + 681.45, R t = 2.44min.

To ((1S,1'S)-(5,5'-([1,1'-biphenyl]-4,4'-diyl)bis(1H-imidazole-5,2-diyl)) bis(( 1-Methylcyclobutyl)methylene)) Di-tert-butyl dicarbamate (0.12 g, 0.176 mmol) in DCM (3 mL) cold (0-5 ° C) 4N hydrogen chloride in dioxane (2 mL, 8.00 mmol). The reaction mixture was stirred at room temperature for 40 min and solvent was evaporated to give a yellow solid. LC / MS (YT-1) : [M + H] + 481.45, R t = 2.30min. This product was refined into the examples Y-38 to Y-39 by using a standard guanamine coupling procedure.

Example Y-38

LC/MS (method YT-1): [M+H] ⁺ 773.49, R _t = 2.528 min; ¹ H NMR (400 MHz, MeOD) δ 7.91 (s, 2 H), 7.90-7.83 (m, 8 H) , 5.12 (s, 2 H), 2.68-2.53 (m, 2 H), 2.38-2.21 (m, 2 H), 2.22-2.01 (m, 8 H), 2.01-1.82 (m, 10 H), 1.84 -1.65 (m, 8H), 1.31 (s, 6H).

Example Y-39

LC / MS (Method YT-1): [M + H] + 649.44, R t = 2.493min; 1 H NMR (400MHz, MeOD) δ 7.93 (s, 2 H), 7.91-7.84 (m, 8 H) , 5.34-5.30 (m, 2 H), 2.23 (dt, J = 11.0, 8.1 Hz, 2 H), 2.18-2.02 (m, 4 H), 1.97-1.85 (m, 4 H), 1.80-1.69 ( m, 2 H), 1.30 (s, 6 H), 1.27 (s, 18 H).

Example Y-40 to Y-48

1,1'-(biphenyl-4,4'-diyl)bis(2-bromoethyl ketone) (5 g, 12.6 mmol) and (S)-2-(third butoxy group) in 15 minutes To a solution of carbonylamino)-3-methylbutyric acid (2.74 g, 12.62 mmol) in EtOAc (40 mL) The reaction mixture was stirred at room temperature for 20 hours and diluted with EtOAc, washed with ice-cold saturated citric acid (2 ×), water, brine, dried (MgSO _4), and on a 160g silica gel column (EtOAc / hexanes: 0 The residue was purified to give the product (2.8 g). LC-MS: Retention time: 2.873 min (method YT-1); m/z 556.03 [M+Na] ⁺ ; ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 8.07-8.19 (4 H, m), 7.98(4 H,d, J =8.78Hz), 7.26(1 H,d, J =8.53Hz),5.62-5.69(1 H,m),5.51-5.57(1 H,m),5.01(2 H , s), 4.01-4.10 (1 H, m), 2.09-2.25 (1 H, m), 1.41 (9 H, s), 0.95-1.06 (6 H, m).

To (S)-2-(t-butoxycarbonylamino)-3-methylbutanoic acid 2-(4'-(2-bromoethenyl)biphenyl-4-yl)- 2-Ethyloxyethyl ester (1.0 g, 1.878 mmol) and (S)-2-(t-butoxycarbonylamino)-3,3-dimethylbutyric acid (0.5 g, 2.162 mmol) in MeCN DIPEA (0.361 mL, 2.066 mmol) was added dropwise to a solution of (5 mL) and DMF (5 mL). The reaction mixture was stirred at room temperature for 4 hours, then diluted with EtOAc, washed with ice-cold saturated citric acid (2 ×), water, brine, dried (MgSO _4), and on a 25g silica gel column (EtOAc / hexane: 20 Purification of -100%) LC-MS: Retention time = 2.173 min (method YT-3); m/z 683.20 [M+H] ⁺ ; ¹ H NMR (400 MHz, chloroform-d ) δ ppm 8.03 (4H, dd, J = 8.53, 2.01 Hz), 7.76 (4 H, d, J = 8.28 Hz), 5.50-5.64 (2 H, m), 5.27-5.39 (2 H, m), 5.15 (1 H, d, J = 9.54 Hz), 5.06 (1 H,d, J =9.54 Hz), 4.43 (1 H, dd, J = 9.16, 4.39 Hz), 4.28 (1 H, d, J = 9.79 Hz), 2.30-2.46 (1 H, m) , 1.47 (18 H, s), 1.13 (9 H, s), 1.09 (3H, d, J = 6.78 Hz), 1.05 (3H, d, J = 6.78 Hz).

In the sealed tube, (S)-2-(t-butoxycarbonylamino)-3,3-dimethylbutyric acid 2-(4'-(2-((S)-2-) Tributoxycarbonylamino)-3-methylbutyloxy)ethenyl)biphenyl-4-yl)-2-oxoethyl ester (1.1 g, 1.611 mmol) and ammonium acetate (2.5 g A mixture of 32.4 mmol) was heated at 135 ° C for 5 hours. The reaction mixture was cooled to cool, and diluted with EtOAc, washed with cold NaHCO _3, brine, dried (MgSO _4). The solvent was removed and the residue was purified mjjjjjjjjjjjjjj LC-MS: retention time = 2.413 min (method YT-1); m/z 643.34 (M+H) ⁺ .

To a solution of EtOAc (3 mL, EtOAc) The mixture was stirred at room temperature for 1.5 hr and evaporated to dryness to give product (0.568 g). LC-MS: retention time = 2.338 min (method YT-1); m/z 443.16 (M+H) ⁺ .

To (S)-1-(5-(4'-(2-((S)-1-amino-2-methylpropyl)-1H-imidazol-5-yl)biphenyl-4-yl) Add DIPEA to a mixture of -1H-imidazol-2-yl)-2,2-dimethylpropan-1-amine tetrahydrochloride (50 mg, 0.085 mmol) and EtOAc (EtOAc) (0.2 mL, 1.145 mmol) and HBTU (71 mg, 0.187 mmol). The reaction mixture was stirred at rt EtOAc (EtOAc)EtOAc.

Examples Y-49 and Y-50

To 1,1'-(biphenyl-4,4'-diyl)bis(2-bromoethyl ketone) (2.207 g, 5.57 mmol) and (S)-2-(benzyloxycarbonylamino)- A solution of 3-methylbutyric acid (1.4 g, 5.57 mmol) in EtOAc (EtOAc) (EtOAc) The reaction mixture was stirred at room temperature for 20 hours and diluted with EtOAc and washed with ice-cold citric acid (2 ×), water, brine, dried (MgSO _4), and on a 80g silica gel column (EtOAc / hexanes: 0% to The residue was purified by EtOAc (EtOAc)EtOAc. LC-MS: retention time: 2.988 min (method YT-1); m/z 590.01 (M+H) ⁺ . ¹ H NMR (400 MHz, chloroform-d ) δ ppm 8.09-8.15 (2 H, m), 8.03 (2H, d, J = 8.28 Hz), 7.72-7.82 (4H, m), 7.31-7.41 (5) H, m), 5.56 (1 H, d, J = 16.31 Hz), 5.34 (1 H, d, J = 16.06 Hz), 5.15 (2 H, s), 4.50 (2 H, s), 4.46-4.57 (1 H, m), 2.32-2.48 (1 H, m, J = 11.39, 6.79, 6.79, 6.65 Hz), 1.10 (3 H, d, J = 6.78 Hz), 1.05 (3 H, d, J = 7.03Hz).

To (S)-2-(benzyloxycarbonylamino)-3-methylbutyric acid 2-(4'-(2-bromoethenyl)biphenyl-4-yl)-2-oxooxy DIPEA was added dropwise to a solution of ethyl ester (0.98 g, 1.730 mmol) and (S)-1-(t-butoxycarbonyl)pyrrolidin-2-carboxylic acid (0.5 g, 2.323 mmol) in MeCN (10 mL) (0.332 mL, 1.903 mmol) lasted 15 minutes. The reaction mixture was stirred at rt EtOAc (EtOAc)EtOAc. LC-MS: retention time: 2.966min (Method YT-1); m / z 723.19 (M + Na) +.

In the sealed tube, (S)-pyrrolidine-1,2-dicarboxylic acid 2-(2-(4'-(2-((S)-2-(benzyloxycarbonylamino))-3-) Methylbutyronyloxy)ethinyl)biphenyl-4-yl)-2-oxoethoxyethyl ester 1-tert-butyl ester (1.05 g, 1.498 mmol) and ammonium acetate (2.5 g, 32.4 mmol) The mixture was heated at 135 ° C for 5 hours. The reaction mixture was cooled to cool to ambient temperature, diluted with EtOAc, and washed with ice-cold NaHCO _3, brine, dried (MgSO _4). The solvent was removed and the residue was purified EtOAcjjjjjjjj LC-MS: retention time = 2.373 min (method YT-1); m/z 661.30 (M+H) ⁺ .

To (S)-2-(4-(4'-(2-((S)-1-(benzyloxycarbonylamino)-2-methylpropyl)-1H-imidazol-4-yl) Add HCl-containing dioxane to a solution of tert-butyl-4-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylic acid tert-butyl ester (0.63 g, 0.953 mmol) in DCM (3 mL) 5 mL, 20.00 mmol). The mixture was stirred at room temperature for 1.5 hr. LC-MS: retention time: 2.265 min (method YT-1); m/z 561.21 (M+H) ⁺ .

To (S)-2-methyl-1-(4-(4'-(2-((S)-pyrrolidin-2-yl)-1H-imidazol-4-yl)biphenyl-4-yl) -1H-imidazol-2-yl)propylaminocarbamic acid benzyl ester trihydrochloride (0.4 g, 0.597 mmol) and (S)-2-(methoxycarbonylamino)-3-methylbutyric acid (0.125 g, 0.716 mmol) <RTI ID=0.0></RTI> The reaction mixture was stirred at room temperature for 2 hrs and then purified eluting eluting eluting eluting

The mixture (5mL) with N ₂ purge of the coupled product (0.29g, 0.404mmol) and 10% Pd-C (0.1g, 0.94mmol) in EtOH. Was added 4N HCl in dioxane of (2ml, 8.00mmol), and stirred under H ₂ balloon overnight the reaction mixture. The suspension was filtered, and the filtrate was evaporated to give purified product (0.28 g). LC-MS: residence time: 2.250 min (method YT-1); m/z 584.14 (M+H) ⁺ .

Examples Y-49 and Y-50: to (S)-1-((S)-2-(4-(4'-(2-((S)-1-amino-2-methylpropyl)) -1H-imidazol-4-yl)biphenyl-4-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylamino DIPEA (0.15 mL, 0.859 mmol) was added to a mixture of methyl formic acid trihydrochloride (60 mg, 0.087 mmol) and 4,4-difluorocyclohexanecarboxylic acid (28.4 mg, 0.173 mmol) in DCM (2 mL) HBTU (40 mg, 0.105 mmol). The reaction mixture was stirred at room temperature for 40 min and diluted with MeOH (1 mL). The solvent was removed and the residue was purified mpqqqqqqq Example Y-50 was prepared in the same manner.

Example Y-51 to Y-54

To (1S,1'S)-1,1'-(5,5'-(biphenyl-4,4'-diyl)bis(1H-imidazole-5,2-diyl))bis(2-methyl) DIMEA (2.92 ml, 16.71 mmol) was added to a mixture of EtOAc (EtOAc). The mixture was stirred for 5 minutes until the solids dissolved. Boc ₂ O (0.608 g, 2.79 mmol) was added portionwise. The reaction mixture was stirred at rt for 4 h and diluted with EtOAc EtOAc. The organic phase was washed with EtOAcq. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 7.78 (4H, d, J = 8.03 Hz), 7.68 (4H, d, J = 8.28 Hz), 7.51 (1 H, s), 7.46 (1) H, s), 6.84-6.98 (1 H, m), 3.67 (1 H, d, J = 6.78 Hz), 1.88-2.11 (2 H, m), 1.35 (9 H, s), 0.88 (6 H) , d, J = 6.78 Hz), 0.76 (3 H, d, J = 6.78 Hz), 0.72 (3 H, d, J = 6.78 Hz). LC / MS (YT 1): [M + H] + 529.23, R t = 2.363min.

To (S)-1-(5-(4'-(2-((S)-1-amino-2-methylpropyl)-1H-imidazol-5-yl)biphenyl-4-yl) a mixture of -1H-imidazol-2-yl)-2-methylpropylaminocarboxylic acid tert-butyl ester (0.46 g, 0.870 mmol) and pivalic acid (0.107 g, 1.044 mmol) in DCM (6 mL) HBTU (0.396 g, 1.044 mmol) and DIPEA (0.304 mL, 1.740 mmol) were added. The reaction mixture was stirred at room temperature for 60 min and diluted with MeOH (0.5 mL). The volatiles were removed in vacuo and the residue was crystallisjjjjjjjjjjjjjjjjjj LC / MS (YT-1) : [M + H] + 613.29, R t = 2.547min.

To a solution of EtOAc (3 mL,EtOAc) The mixture was stirred at room temperature for 1.5 hr. ¹ H NMR (400 MHz, MeOD ) δ ppm 7.77-7.97 (10 H, m), 4.84 (1 H, d, J = 9.03 Hz), 4.32 (1 H, d, J = 8.28 Hz), 2.34-2.54 ( 2 H,m), 1.23 (9 H, s), 1.18 (3H, d, J = 6.53 Hz), 1.15 (3 H, d, J = 6.53 Hz), 0.98 (3 H, s), 0.93 (3) H, d, J = 6.78 Hz). LC / MS (YT-1) : [M + H] + 513.27, R t = 2.278min.

To N-((S)-1-(5-(4'-(2-((S)-1-amino-2-methylpropyl)-1H-imidazol-5-yl)biphenyl-4 -yl)-1H-imidazol-2-yl)-2-methylpropyl)pivalamidine trihydrochloride (50 mg, 0.080 mmol) and 4,4-difluorocyclohexanecarboxylic acid (15 mg, 0.088 mmol) DIPEA (0.1 mL, 0.573 mmol) and HBTU (36.6 mg, 0.096 mmol) were added to a mixture of DCM (2 mL). The reaction mixture was stirred at room temperature for 80 minutes, and diluted with MeOH (1mL), volatile components were removed, and the residue was by purified by preparative HPLC, to give examples of ^{Y-52: 1 H NMR (} 400MHz, MeOD) δ Pills 7.91 (2 H, s), 7.83-7.90 (8 H, m), 4.88 (1 H, s), 4.86 (1 H, d, J = 2.01 Hz), 2.46-2.57 (1 H, m), 2.30-2.46(2 H,m), 2.04-2.17(2 H,m),1.83-1.97(3 H,m),1.70-1.82(3 H,m),1.24(9 H,s),1.16( 6H, d, J = 6.53 Hz), 0.97 (3H, d, J = 6.78 Hz), 0.92 (3H, d, J = 6.78 Hz).

Examples Y-53 and Y-54 were prepared from the appropriate acids by the method described in Example Y-52.

Example Y-55 to Y-57

To (1S,1'S)-1,1'-(5,5'-([1,1'-biphenyl]-4,4'-diyl)bis(1H-imidazole-5,2-diyl) a mixture of bis(2-methylpropan-1-amine) tetrahydrochloride (100 mg, 0.174 mmol) in DCM (2 mL) DIPEA (0.2 mL, 1.145 mmol) and HBTU (141 mg, 0.372 mmol) were added. The reaction mixture was stirred at rt EtOAc (EtOAc) Solvent removal The residue was purified by HPLC to give three stereoisomers, s. Dissolve-1 (Example Y-55) and Dissolve-3 (Example Y-57) did not assign absolute stereochemistry. The second dissolvate is an asymmetric stereoisomer (Example Y-56).

Example Y-58

To (1S,1'S)-1,1'-(5,5'-(biphenyl-4,4'-diyl)bis(1H-imidazole-5,2-diyl))bis(2-methyl DIPEA (0.261 mL, 1.494 mmol) and 4-methylbenzene-1-sulfonium chloride (58.4 mg) were added to a suspension of propyl-1-amine)tetrahydrochloride (80 mg, 0.139 mmol) in DCM (3 mL) , 0.306 mmol). The reaction mixture was stirred at room temperature for 1.5 h and quenched by stirring 1 mL NH ₄ Cl and stirring 20 min. The solvent was removed, and the residue was purified mjjjjjjjj LCMS (Method YT-1): [M + H] + 737.07, R t = 2.453min. ¹ H NMR (400 MHz, MeOD ) δ ppm 7.85-7.92 (4H, m), 7.70-7.81 (6H, m), 7.68 (4H, d, J = 8.28 Hz), 7.22-7.38 (4H, m), 4.19-4.41 (2 H, m), 2.25 (6 H, s), 2.06-2.24 (2 H, m, J = 13.99, 6.93, 6.93, 6.78 Hz), 1.03 (6 H, d, J =6.53 Hz), 0.81 (6 H, d, J = 6.78 Hz).

Examples Y-59 to Y-61

To (1S,1'S)-1,1'-(5,5'-([1,1'-biphenyl]-4,4'-diyl)bis(1H-imidazole-5,2-diyl) Stirring suspension of bis(2-methylpropan-1-amine) tetrahydrochloride (200 mg, 0.348 mmol) and DIPEA (0.486 mL, 2.79 mmol) in DCM (3 mL) (0-5 ° C) 2-Methylpropane-2-sulfinium chloride (0.095 mL, 0.766 mmol) was added. The reaction mixture was warmed to EtOAc EtOAc (EtOAc) The residue was purified by preparative HPLC to give three stereoisomers as listed in the following table (examples Y-59, Y-60 and Y-61):

Example L-1

(1S,1'S)-1,1'-(4,4'-([1,1'-Biphenyl]-4,4'-diyl)bis(1H-imidazole-4,2-diyl) Bis(2,2-dimethylpropan-1-amine) tetrahydrochloride (50 mg, 0.083 mmol), pivalaldehyde (0.020 mL, 0.183 mmol) and AcOH (10.45 μl, 0.183 mmol) in CH ₂ Cl ₂ (3 mL) was combined, and the resulting mixture was stirred for 5 min, then NaCNBH ₄ (20.86 mg, 0.332 mmol) was added. MeOH was added to dissolve the solid matter. The reaction mixture was stirred at room temperature for 2 hours, followed by the addition of quenched with saturated NaHCO _3, and the organic layer was separated. The aqueous layer was then extracted with DCM, and and dried (MgSO ₄₎ the organic layers were combined, filtered and concentrated. The residue was redissolved in methanol and purified _{(MeOH / H 2 O / TFA} ) by preparative HPLC, to give as a white solid of Example L-1 (30mg, trifluoroacetate). LC / MS (Condition L-1): [M + H] + 597.6, R t = 2.438min. ¹ H NMR (500 MHz, DMSO-d ₆ ) ppm 8.12 (br.s., 2 H), 7.92 (s, 8 H), 3.83 (br.s., 2 H), 2.37-2.24 (m, 4 H ), 1.02 (br.s., 18 H), 0.89 (s, 18 H).

By (1S, 1'S)-1,1'-(4,4'-([1,1'-biphenyl]-4,4'-diyl by using the procedure described for Synthesis Example L-1 Preparation of Example L-2 by bis(1H-imidazole-4,2-diyl))bis(2,2-dimethylpropan-1-amine) tetrahydrochloride and suitable starting materials obtained from commercial sources Trifluoroacetate).

Examples W-16A and W-16B

(1S,1'S)-1,1'-(4,4'-([1,1'-Biphenyl]-4,4'-diyl)bis(1H-imidazole-4,2-diyl) Bis(2,2-dimethylpropan-1-amine) tetrahydrochloride (60 mg, 0.100 mmol), 5-bromo-2-fluoropyrimidine (42.3 mg, 0.239 mmol) and DIEA (0.122 mL, 0.697 mmol) The pale yellow turbid solution in acetonitrile (1 mL) was heated in a microwave system at 65 °C for 2 hours. The reaction was purified by prep _{HPLC (MeOH / H 2 O /} TFA) mixtures to afford a white solid examples of the W-16B (11mg, trifluoroacetate), LC / MS (Condition L-1): [M + H] ⁺ 615.5, R _t = 1.23 min; and Example W-16A (36 mg, trifluoroacetate) as a white solid, LC/MS (Cond. L-1): [M+H] ⁺ 771.4, R _t =1.512min. ¹ H NMR (400 MHz, MeOD- d ₄ ) δ δ 8.40 (4H, s), 7.79-7.93 (10H, m), 4.99-5.06 (2H, m), 1.21. (18H, s).

Example W-17

Under 30psi H _2, containing examples of W-16A (20mg), 10 % Pd / C (3.41mg) and MeOH (1mL) The vial was placed in a Parr shaker (Parr shaker) for 3 hours. The reaction mixture was filtered through diatomaceous earth (Celite ^®) plug. By _{(MeOH / H 2 O / TFA} ) filtrate was purified by preparative HPLC, to give a white solid of Example W-17 The trifluoroacetate (12mg). LC / MS (Condition L-1): [M + H] + 621.4, R t = 1.105min. ¹ H NMR (400 MHz, MEOD- d ₄ ) δ ppm 7.90-7.98 (6 H, m), 7.82-7.90 (4 H, m), 3.36-3.48 (8 H, m), 1.96 (4 H, five weights Peak, J = 5.71 Hz), 1.13 (18 H, s).

Example W-31

Will contain the examples W-16A (20mg, 0.026mmol), cyclohex-1-en-1-yl A vial of acid (7.85 mg, 0.062 mmol), hydrazine (triphenylphosphine) palladium (0) (6.00 mg, 5.19 μmol) and DMA (1 mL) was heated in a microwave system at 100 ° C for 2 hours. The reaction mixture was filtered, and the filtrate was concentrated, followed by _{(CH 3 CN / H 2 O} / NH 4 OAc) was purified by preparative HPLC, to give examples of W-31. LC / MS (Condition L-1): [M + H] + 691.6, R t = 1.6min. ¹ H NMR (500 MHz, MeOD- d ₄ ) δ ppm 8.32 (2H, s), 8.28 (2H, d, J = 4.88 Hz), 7.77 (4H, dd, J = 8.39, 1.98 Hz), 7.68 (4 H, d, J = 8.54 Hz), 7.36 (2 H, d, J = 1.83 Hz), 6.62 (1 H, t, J = 4.88 Hz), 5.25 (1 H, s), 5.18 (1 H , s), 1.08 (18 H, d, J = 4.58 Hz).

Example L-3

(1S,1'S)-1,1'-(4,4'-([1,1'-Biphenyl]-4,4'-diyl)bis(1H-imidazole-4,2-diyl) Bis(2,2-dimethylpropan-1-amine) tetrahydrochloride (50 mg, 0.083 mmol), 2-((t-butoxycarbonyl)amino)-2-methylpropanoic acid (33.7) Mg, 0.166 mmol) and DIEA (0.101 mL, 0.581 mmol) were combined in DMF (2 mL) and the mixture was stirred for 5 min then HATU (66.3 mg, 0.174 mmol). The resulting solution was stirred at room temperature for 2 hours. Followed by prep _{HPLC (MeOH / H 2 O /} TFA) purification of the yellow solution to give a white solid, L-3 corresponds to an example of the trifluoroacetate (40mg). LC / MS (Condition N-1): [M + H] + 827.0, R t = 3.74min. ¹ H NMR (500 MHz, DMSO-d ₆ ) ppm 8.19 (br.s., 2 H), 8.01 - 7.83 (m, 8 H), 5.22 (br.s., 2 H), 1.46-1.21 (m, 30 H), 0.96 (s, 18 H).

By (1S, 1'S)-1,1'-(4,4'-([1,1'-biphenyl]-4,4'-diyl by using the procedure described for Synthesis Example L-3 The following examples were prepared for the bis(1H-imidazole-4,2-diyl))bis(2,2-dimethylpropan-1-amine) tetrahydrochloride and the appropriate starting materials. The product obtained is purified by preparative HPLC (MeOH/H ₂ O/TFA or CH ₃ CN/H ₂ O/NH ₄ OAc) and obtained as the corresponding trifluoroacetic acid salt or as the free base. For examples W-1, W-3, W-4, W-13, W-14, W-15, cap synthesis is disclosed in patent application WO2009146347; for examples W-67, W-68, W-69, Cap synthesis is disclosed in patent application WO2011075439.

* ¹ H NMR data: Example L-8 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.44-11.94 (m, 3H), 7.84 - 7.63 (m, 8H), 7.54 (d, J = 1.8 Hz, 1H ), 7.31 (br.s., 1H), 7.16-7.02 (m, 2H), 4.99-4.85 (m, 2H), 2.96-2.84 (m, 6H), 1.41 (s, 6H), 1.26 (s, 6H), 1.06 (br.s., 18H), 0.90 (s, 18H)

Example L-19 ¹ H NMR (500MHz, DMSO-d ₆ ) δ 12.43-12.01 (m, 2H), 7.88-7.81 (m, 3H), 7.77 (d, J = 8.4 Hz, 1H), 7.73-7.67 ( m, 4H), 7.65-7.58 (m, 1H), 7.39-7.25 (m, 2H), 5.03-4.83 (m, 2H), 3.74-3.54 (m, 5H), 3.31 (s, 8H), 3.01 2.91 (m, 6H), 1.48-1.25 (m, 4H), 1.16 (br.s., 4H), 0.89 (s, 18H)

Example L-22 ¹ H NMR (500MHz, DMSO-d ₆ ) δ 12.50-11.90 (m, 2H), 7.80 (d, J = 7.3 Hz, 4H), 7.76-7.63 (m, 6H), 7.60-7.48 ( m,3H), 7.21-7.06 (m, 2H), 5.03-4.80 (m, 2H), 3.58 (br.s., 2H), 3.43 (br.s., 3H), 2.31-2.09 (m, 2H) ), 1.99-1.71 (m, 8H), 1.51-1.24 (m, 15H), 1.04-0.88 (m, 36H)

Example L-32 ¹ H NMR (500MHz, DMSO-d ₆ ) δ 12.50-12.10 (m, 2H), 8.62 - 8.51 (m, 2H), 7.84 (d, J = 8.2 Hz, 3H), 7.78-7.63 ( m,5H), 7.62-7.56 (m, 2H), 7.43-7.27 (m, 2H), 5.39-5.19 (m, 2H), 4.93-4.82 (m, 2H), 1.47-1.36 (m, 6H), 1.13 (d, J = 9.8 Hz, 2H), 1.03 (br.s., 2H), 0.90 (s, 18H)

By (1S, 1'S)-(4,4'-([1,1'-biphenyl]-4,4'-diyl) bis (1H-) by the procedure described for Synthesis Example L-3 The following examples were prepared for imidazole-4,2-diyl))bis((1-methylcyclopropyl)methylamine) tetrahydrochloride and suitable starting materials. By prep _{HPLC (CH 3 CN / H 2} O / NH 4 OAc) The resulting product was purified and obtained in free base form.

*Example W-71 ¹ H NMR (500 MHz, DMSO- d ₆ ) δ ppm 12.28-11.89 (2 H, m), 8.16-8.10 (2 H, m), 7.86-7.35 (10 H, m), 4.72 4.62(2 H,m), 4.28-4.27(2 H,m), 3.66-3.65(2 H,m),2.85-2.84-3.40(2 H,m),2.37-2.14(4 H,m), 1.41-1.31 (19 H, m), 1.10-0.97 (13 H, m), 0.76-0.30 (8 H, m).

By (1S, 1'S)-1,1'-(4,4'-([1,1'-biphenyl]-4,4'-diyl) double by the procedure described for Synthesis Example 30 The following examples were prepared for (1H-imidazole-4,2-diyl))bis(2,2-dimethylpropan-1-amine) tetrahydrochloride and suitable starting materials. By prep _{HPLC (CH 3 CN / H 2} O / NH 4 OAc) The resulting product was purified and obtained in the free base form, except for Example W-11, which system by prep _{HPLC (MeOH / H 2 O /} TFA Purified and obtained in the form of its corresponding trifluoroacetate salt.

*Example W-24 ¹ H NMR (500 MHz, DMSO- d ₆ ) δ ppm 12.48, 12.18 (2 H, s), 9.10, 9.07, 9.05 (2H, b), 7.87-7.41 (10 H, m), 5.01, 4.99, 4.93, 4.91 (2 H, s), 3.80-3.70 (2 H, m), 3.51-3.47 (6 H, m), 2.1-1.98 (8 H, m), 1.03-0.99 (18 H) , m).

By (1S, 1'S)-(4,4'-([1,1'-biphenyl]-4,4'-diyl) bis (1H-) by the procedure described for Synthesis Example W-30 The following example (bistrifluoroacetate) was prepared from imidazole-4,2-diyl))bis((1-methylcyclopropyl)methylamine) tetrahydrochloride and the appropriate starting materials. By prep _{HPLC (CH 3 CN / H 2} O / NH 4 OAc) The resulting product was purified and obtained in the free base form, but examples of W-39, except that line by prep _{HPLC (MeOH / H 2 O /} TFA Purified and obtained in the form of its corresponding trifluoroacetate salt.

*Example W-39 ¹ H NMR (500MHz, MeOH- d ₄ ) δ ppm 7.96-7.88 (10 H, m), 4.70-4.15 (2 H, s), 3.82-3.80 (4 H, m), 3.75- 3.73(4 H,m), 2.16-2.07(8 H,m),1.20(6 H,s),0.98(2 H,m),0.81(2 H,m),0.70-0.67(4 H,m ).

Example W-13 (diastereomer 1) Example W-14 (diastereomer 2) Example W-15 (diastereomer 3)

To (1S,1'S)-1,1'-(4,4'-([1,1'-biphenyl]-4,4'-diyl)bis(1H-imidazole-4,2-diyl) Bis(2,2-dimethylpropan-1-amine) tetrahydrochloride (40 mg, 0.066 mmol), 1-((t-butoxycarbonyl)amino)-2,2-difluorocyclopropane DIEA (0.081 mL, 0.465 mmol) was added to a pad of EtOAc (EtOAc:EtOAc. The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was purified by prep _{HPLC (MeOH / H 2 O /} TFA), to give the product as the diastereomeric mixture of isomers. LC / MS (Condition W-1): [M + H] + 896.0, R t = 1.96min. The diastereomers were separated by palmitic SFC Kromasil DMB, 21.2 x 250 mm, 5 μm (15% IPA (w/0.1% DEA) / 85% CO ₂ ), and examples W-13, Example W were obtained in the order of dissolution. -14 and instance W-15.

Example W-23A (diastereomer 1) Example W-23B (diastereomer 2) Example W-23C (diastereomer 3)

To (1S,1'S)-1,1'-(4,4'-([1,1'-biphenyl]-4,4'-diyl)bis(1H-imidazole-4,2-diyl) Bis(2,2-dimethylpropan-1-amine) tetrahydrochloride (500 mg, 0.830 mmol), cis-2-((t-butoxycarbonyl)amino)cyclohexanecarboxylic acid (414 mg, 1.70 mmol), HATU (663 mg, 1.743 mmol) in EtOAc (EtOAc) The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was purified by prep _{HPLC (MeOH / H 2 O /} TFA), to give a mixture of diastereomers. LC / MS (Condition W-1): [M + H] + 908.0, R t = 1.832min. The diastereomers were separated by ChiralPak IC, 30×250 mm, 5 μm (30% EtOH (w/0.1% DEA)/70% CO ₂ ), and examples W-23A, examples W-23B and examples were obtained in the order of dissolution. W-23C.

Example W-40A (diastereomer 1) Example W-40B (diastereomer 2) Example W-40C (diastereomer 3)

To (1S,1'S)-1,1'-(4,4'-([1,1'-biphenyl]-4,4'-diyl)bis(1H-imidazole-4,2-diyl) Bis(2,2-dimethylpropan-1-amine) tetrahydrochloride (35 mg, 0.058 mmol), 2-(trans-2,6-dimethyl(N-morpholinyl)-2- To a solution of acetoxyacetic acid (23.47 mg, 0.119 mmol), EtOAc (EtOAc) The reaction mixture was stirred at room temperature for 15 hours. The reaction mixture was purified by prep _{HPLC (MeOH / H 2 O /} TFA), was obtained in the form of diastereomeric mixture of isomers (30mg). LC / MS (Condition W-1): [M + H] + 795.7, R t = 1.427min. The three diastereomers were separated by ChiralCel SFC OD-H (30% MeOH (w / 0.1% DEA) / 70% CO ₂ ). Example W-40A, Example W-40B and Example W- were obtained in the order of dissolution. 40C.

Example W-30

To (1S,1'S)-1,1'-(4,4'-([1,1'-biphenyl]-4,4'-diyl)bis(1H-imidazole-4,2-diyl) Bis(2,2-dimethylpropan-1-amine) tetrahydrochloride (150 mg, 0.249 mmol), 2-ethoxy-2-oxoacetic acid (61.5 mg, 0.510 mmol), HATU (199 mg) DIEA (0.304 mL, 1.743 mmol) was added to a EtOAc. The reaction mixture was stirred at room temperature for 18 hours. The solvent was removed and purified by prep _{HPLC (CH 3 CN / H 2} O / NH 4 OAc) residue was purified to give Example W-30: LC / MS (Condition W-1): [M + H] + 657.6 , R _t = 1.447 min. ¹ H NMR (500 MHz, MEOD- d ₄ ) δ ppm 7.95 (2 H, s), 7.85-7.92 (8 H, m), 5.19 (2 H, s), 4.40 (4 H, q, J = 7.09 Hz ), 1.39 (6 H, t, J = 7.17 Hz), 1.15 (18 H, s).

Example W-11

To (1S,1'S)-1,1'-(4,4'-([1,1'-biphenyl]-4,4'-diyl)bis(1H-imidazole-4,2-diyl) Bis(2,2-dimethylpropan-1-amine) tetrahydrochloride (100 mg, 0.166 mmol), 2-oxo-2-(piperidin-1-yl)acetic acid (56.3 mg, 0.340 mmol) DIEA (0.203 mL, 1.162 mmol) was added to a pad of EtOAc (EtOAc). The reaction mixture was stirred at room temperature for 18 hours. The solvent was removed and purified by prep _{HPLC (MeOH / H 2 O /} TFA) the residue was purified to give Example W-11 (95mg, trifluoroacetate). LC / MS (Condition W-1): [M + H] + 735.8, R t = 1.518min. ¹ H NMR (500 MHz, MeOD- d ₄ ) δ ppm 7.94-7.97 (2 H, m), 7.86-7.93 (8 H, m), 5.04 (2 H, s), 3.44 - 3.68 (8 H, m) , 1.59-1.78 (12 H, m), 1.10 - 1.24 (18 H, m).

Example W-41

To a solution of Example W-2 (100 mg, EtOAc) (EtOAc) The reaction mixture was stirred at room temperature for 3 hr then concentrated to give EtOAc EtOAc. LC / MS (Condition W-1): [M + H] + 775.8, R t = 1.508min.

Example W-41A-B

At 4 ℃, W-41 to an instance (50mg, 0.054mmol) in CH ₂ Cl ₂ (5mL) was added in the mixture of DIPEA (0.095mL) and methyl chloroformate (0.034mL). The reaction mixture was stirred at room temperature for 1 hour. Add 2M ammonia in MeOH (2mL) in the solution, and the reaction mixture was stirred at room temperature for 3 hours, then concentrated, and purified by prep _{HPLC (MeOH / H 2 O /} TFA) purification of the residue, to give a white solid Example W-41A (44 mg, trifluoroacetate). LC / MS (Condition W-1): [M + H] + 891.9, R t = 1.8min. ¹ H NMR (500 MHz, MeOD- d ₄ ) δ ppm 7.98 (2 H, s), 7.86-7.96 (8 H, m), 7.24-7.35 (5 H, m), 7.15-7.22 (5 H, m) , 5.19 (2 H, br. s.), 3.54 (6 H, br. s.), 2.89-3.05 (2 H, m), 1.98 (2 H, dd, J = 9.62, 5.83 Hz), 1.78 ( 2 H, dd, J = 7.96, 5.91 Hz), 1.16-1.12 (18 H, s); and Example W-41B. LC / MS (Condition W-1): [M + H] + 833.8, R t = 1.67min.

Example W-42

To (1S,1'S)-1,1'-(4,4'-([1,1'-biphenyl]-4,4'-diyl)bis (1H-imidazole-4, at 4 °C, a pale yellow slurry of 2-diyl))bis(2,2-dimethylpropan-1-amine) tetrahydrochloride (50 mg, 0.083 mmol) and DIEA (0.145 mL, 0.830 mmol) in DCM (5 mL) Methyl chloroformate (0.040 mL, 0.415 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 1 hour. Add 2M ammonia in MeOH (2mL) in the solution, and the reaction mixture was stirred at room temperature for 3 hours, then concentrated, and purified by prep _{HPLC (CH 3 CN / H 2} O / NH 4 OAc) residue was purified to give Example W-42 (24 mg). LC / MS (Condition W-1): [M + H] + 599.5, R t = 1.208min.

Example W-43A

Example W-43B

To (1S,1'S)-1,1'-(4,4'-([1,1'-biphenyl]-4,4'-diyl)bis(1H-imidazole-4,2-diyl) Bis(2,2-dimethylpropan-1-amine) tetrahydrochloride (702 mg, 1.166 mmol), 2-(t-butoxy)-2-oxoacetic acid (358 mg, 2.45 mmol), A solution of HATU (953 mg, 2.507 mmol) in DCM (20 mL). The reaction mixture was stirred at room temperature for 3.5 hours. The solvent was removed and purified by prep _{HPLC (CH 3 CN / H 2} O / NH 4 OAc) residue was purified to give Example W-43A (619mg), LC / MS ( Condition W-1): [M + H ] ⁺ 713.7, R _t = 1.665 min, ¹ H NMR (500 MHz, MeOD- d ₄ ) δ ppm 7.83 (3H, br.s.), 7.63-7.76 (5H, m), 7.45 (1 H, br .s.), 7.40 (1 H, br.s.), 5.06 (2 H, s), 1.59 (18 H, s), 0.97-1.11 (18 H, m); and Example W-43B (45 mg) , LC/MS (Condition W-1): [M+H] ⁺ 683.6, R _t = 1.425 min.

Example W-44

TFA (0.038 mL) was added to a solution of EtOAc (EtOAc). The resulting solution was stirred at room temperature for 2 hours. The volatiles were removed in vacuo to afford EtOAc m. LC / MS (Condition W-1): [M + H] + 601.4, R t = 1.162min.

Example W-45

Add DIEA to a solution of Example W-44 (30 mg, 0.036 mmol), cis-2,6-dimethylmorpholine (8.76 mg, 0.076 mmol), HATU (28.9 mg, 0.076 mmol) in DCM (1 mL) (0.044 mL, 0.253 mmol). The resulting solution was stirred overnight at room temperature. The volatiles were removed in vacuo, and purified by prep _{HPLC (CH 3 CN / H 2} O / NH 4 OAc) system The residue was purified to give W-45. LC / MS (Condition W-1): [M + H] + 795.9, R t = 1.43min.

Example W-46A

Add DIEA to a solution of the compound W-44 (50 mg, 0.060 mmol), 3,3-difluoropiperidine/HCl (39.0 mg, 0.247 mmol), HATU (71.1 mg, 0.187 mmol) in DCM (2 mL) 0.105 mL, 0.603 mmol). The reaction mixture was stirred at room temperature overnight. Then 2M ammonia in MeOH (2 mL) was added and the mixture was stirred at room temperature for 3 hr. The volatile components removed in vacuo, and purified by prep _{HPLC (CH 3 CN / H 2} O / NH 4 OAc) system The residue was purified to give Example W-46A (14mg), LC / MS ( conditions W- 1): [M+H] ⁺ 807.6, R _t = 1.535 min.

Examples W-47 through W-50 were prepared by the method described in Example W-45 using commercially available amines.

*Example W-47: ¹ H NMR (500 MHz, DMSO- d ₆ ) δ ppm 12.48-12.14 (2 H, m), 9.25-8.96 (2 H, m), 7.87-7.41 (10 H, m), 5.01 -4.91 (2 H, m), 4.70-4.15 (4 H, m), 3.80-3.70 (2 H, m), 3.51-3.40 (4 H, m), 1.17-1.15 (6 H, m), 0.99 -0.96 (18 H, m).

Example W-49: ¹ H NMR (500 MHz, DMSO- d ₆ ) δ ppm 12.50-12.26 (2H, m), 9.06-8.90 (2H, m), 7.85-7.40 (10 H, m), 5.01 4.93 (2H, m), 4.23-4.21 (2H, m), 1.24-1.23 (12H, m), 1.00-0.99 (18H, m), 0.77-0.47 (10H, m).

Example L-18

Example L-18 Step a

HCl (4 N in dioxane) (0.292 mL, 1.169 mmol) was added to EtOAc (EtOAc) hour. The solvent was removed under reduced pressure and a beige solid was separated, which corresponds to Example L-18 Step a (90 mg). LC / MS (Condition L-1): [M + H] + 655.65, R t = 1.576min.

(1.5mL) was added in the mixture of DIPEA (0.061mL, 0.350mmol) and methyl chloroformate (3.9μL, 0.050mmol) Example L-18 to a step in CH ₂ Cl _2. The mixture was stirred at room temperature for 1 hour. Ammonia (2 mL, 4.0 mmol, 2M in MeOH) The reaction mixture was concentrated in vacuo, and purified by prep _{HPLC (CH 3 CN / H 2} O / NH 4 OAc) residue was purified to give a white solid, corresponding to Example L-18 (40mg). ^{1 H NMR (500MHz, DMSO-} d 6) δ 12.01 (br.s., 2H), 7.81 (br.s., 4H), 7.69 (br.s., 4H), 7.57 (br.s., 1H ), 7.13 (d, J = 9.2 Hz, 2H), 4.85 (d, J = 8.2 Hz, 2H), 3.25 (br.s., 6H), 2.95 (s, 6H), 1.40 (s, 6H), 1.29 (s, 6H), 0.91 (s, 18H). LC-MS (condition L-1): [M + H] + 771.7, R t = 2.01min.

Example L-20

Example L-20 (bistrifluoroacetate) was prepared by employing the procedure described for Synthesis Example L-18. LC-MS (condition L-1): [M + H] + 835.7, R t = 2.14min.

Example L-41

Example L-41 (bis-trifluoroacetate) was prepared from Example L-40 and the appropriate starting material from commercial sources by employing the procedure described for the synthesis of Example L-18. LC-MS (Condition L-2): [M + H] + 795.65, R t = 1.268min.

Example Q-1

Example Q-1 Step a

In the example of L1 (320mg, 0.387mmol) in CH ₂ Cl ₂ (4mL), was added HCl (3mL, 12.00mmol) (4N , in dioxane). The mixture was stirred at room temperature for 1 hour. The mixture was concentrated. The residue was dissolved in MeOH and triturated with Et ₂ O to afford a pale yellow solid of Example Q-1 step a. LC / MS (conditions P-2): [M + H] + 627.63, R t = 1.64min. ¹ H NMR (500 MHz, MeOD- d ₄ ) δ ppm 7.99-8.06 (6 H, m), 7.90 (4H, d, J = 8.51 Hz), 5.38 (2 H, s), 1.81 (6 H, s ), 1.75 (6 H, s), 1.16 (18 H, s).

Was added DIPEA (0.063mL, 0.362mmol) and methyl chloroformate (0.012mL, 0.155mmol) in the ₂ Cl ₂ (2mL) mixture of Example Q-1 to step a (40mg, 0.052mmol) in CH. The mixture was stirred at room temperature for 1 hour.

Ammonia (2 mL) (2M in MeOH) was then added and the mixture was stirred at room temperature for 3 hr. The reaction mixture was then concentrated and purified by prep _{HPLC (MeOH / H 2 O /} TFA), to give a white solid as a example of the Q-1 (0.03g). LC / MS (conditions P-2): [M + H] + 743.58, R t = 1.767min. ¹ H NMR (400 MHz, MeOD- d ₄ ) δ ppm 7.93 (2 H, s), 7.89 (8 H, s), 5.10 (2 H, s), 3.66 (6 H, s), 1.50 (6 H, s), 1.44 (6 H, s), 1.11 (18 H, s).

By using the procedure described for Synthesis Example Q-1, from N,N'-((1S,1'S)-(4,4'-([1,1'-biphenyl]-4,4'- Bis(1H-imidazole-4,2-diyl))bis(2,2-dimethylpropane-1,1-diyl))bis(2-amino-2-methylpropionamide) Examples Q-2 to Q-6 (bistrifluoroacetate) were prepared as the tetrahydrochloride salt and the appropriate starting materials obtained from commercial sources.

Example Q-7

To a solution of morpholine (1.2 mL, 13.77 mmol) in EtOAc (3 mL). The resulting mixture was stirred at 80 ° C for 24 hours. The mixture was cooled to room temperature, NaOH (0.240 g, 5. The mixture was then evaporated to dryness and the product sodium 2-methyl-2-(N-morpholinyl)propionate was used without further purification.

(1S,1'S)-1,1'-(4,4'-([1,1'-Biphenyl]-4,4'-diyl)bis(1H-imidazole-4,2-diyl) Bis(2,2-dimethylpropan-1-amine) tetrahydrochloride (50 mg), sodium 2-methyl-2-(N-morpholinyl)propionate (64.8 mg) and DIEA (0.101 mL) The mixture was combined in DMF (10 mL) and the mixture was stirred for 5 min then HATU (66.3 mg, 0.174 mmol). The resulting solution was stirred at room temperature for 2 hours. The reaction mixture was concentrated and purified by prep _{HPLC (MeOH / H 2 O /} TFA), to give a white solid as a example of the Q-7 (18mg). LC / MS (conditions P-2): [M + H] + 767.57, R t = 1.657min.

Example P-137

Pure DIPEA (0.384 mL) was added to 1,1'-([1,1'-biphenyl]-4,4'-diyl)bis(2-bromoethyl ketone) (396 mg) and 1-(ethoxy carbonyl group)) in the cyclobutane carboxylic acid (362 mg) in acetonitrile (4mL) and CHCl ₃ (4mL stirred solution. The suspension was stirred at room temperature overnight and evaporated to dryness then purified EtOAc EtOAc EtOAc EtOAc O'1,O1-([1,1'-Biphenyl]-4,4'-diylbis(2-oxoethoxy-2,1-diyl))ester 1-diethyl ester (0.576g ). ¹ H NMR (500 MHz, CDCl ₃ ) ppm 8.01-8.06 (4H, m), 7.74-7.79 (4H, m), 5.43 (4H, s), 4.27 (4H, q, J = 7.12 Hz) , 2.71-2.81 (4 H, m), 2.60-2.70 (4 H, m), 1.93-2.17 (4 H, m), 1.26-1.38 (6 H, m). In a sealed tube, bis(cyclobutane-1,1-dicarboxylic acid) O'1,O1-([1,1'-biphenyl]-4,4'-diyl bis(2-sided oxy group) Ethyl-2,1-diyl))ester 1-diethyl ester (0.576 g) and ammonium acetate (1.535 g) were heated to 135 ° C in a stirred suspension in xylene (5 mL) for 3 h. The reaction mixture was diluted with DCM and saturated NaCl and washed with saturated NaHCO _3, water, and dried over anhydrous Na ₂ SO _4, filtered, and concentrated to give an orange solid silicone by FCC (DCM 3-5% MeOH containing it) to afford The solid gave 1,1'-(4,4'-(biphenyl-4,4'-diyl)bis(1H-imidazole-4,2-diyl)bicyclic as a yellow-orange solid. Diethyl butanecarboxylate (0.217 g).

1,1'-(4,4'-([1,1'-Biphenyl]-4,4'-diyl)bis(1H-imidazole-4,2-diyl))bicyclobutanecarboxylic acid Diethyl ester (217 mg, 0.403 mmol) and HCl (4.03 mL, 24.17 mmol). The resulting yellow solution was evaporated to dryness to give-1,1'-(4,4'-([1,1'-biphenyl]-4,4'-diyl) bis (1H-imidazole) as a yellow solid. 4,2-Diyl)) Dicyclobutanecarboxylic acid dihydrochloride (55.5 mg). LC / MS (conditions P-2): [M + H] + 483.3, R t = 1.73min.

Pure DIPEA (0.112 mL, 0.640 mmol) was added to 1,1'-(4,4'-([1,1'-biphenyl]-4,4'-diyl) bis (1H-imidazole-4, 2-Diyl)) Dicyclobutanecarboxylic acid dihydrochloride (55.5 mg, 0.1 mmol) and 4,4-difluoropiperidine hydrochloride (34.7 mg, 0.220 mmol) in DCM (1 mL) The mixture is stirred in a portion of the solution. The mixture was stirred overnight at room temperature. The crude reaction mixture was evaporated and purified by prep _{HPLC (MeOH / H 2 O /} TFA), to give a white solid as a example of the P-137 (bis trifluoroacetate). LC / MS (conditions P-3): [M + H] + 689.43, R t = 3.173min.

Example P-138

Add pure DIPEA (0.040 mL) to (1S,1'S)-1,1'-(4,4'-([1,1'-biphenyl]-4,4'-diyl) bis (1H-imidazole) -4,2-diyl))bis(2,2-dimethylpropan-1-amine)tetrahydrochloride (50.2 mg) and 4,4-difluorocyclohexyl chloroformate (0.40 mL, 0.20 mmol) The stirred partial solution in DCM (1 mL), acetonitrile (1 mL) and DMF (0.5 mL). The mixture was stirred overnight at room temperature. The crude mixture was evaporated to dryness, then purified by prep _{HPLC (MeOH / H 2 O /} TFA), to give as a beige solid examples of P-138 and separated (26mg) to form bis trifluoroacetate. ¹ H NMR (400 MHz, MeOD- d ₄ ) δ ppm 7.95 (2 H, s), 7.84-7.93 (8 H, m), 4.73-4.85 (2 H, m), 4.00 (2 H, s), 2.09 -1.78 (16 H, m), 1.14 (18 H, s).

Example Y-84

To an (S)-2-((t-butoxycarbonyl)amino)-3,3-dimethylbutyric acid (1.8 g, 7.78 mmol) and DIPEA (1.4 mL, 8.02 mmol) (S)-2-((Tertibutoxycarbonyl)amino)-3,3-dimethylbutyric acid (1.8 g, 7.78 mmol) was added to a solution in acetonitrile (25 mL). The suspension was stirred at room temperature for 2 hours. The reaction mixture was diluted with EtOAc, and washed with saturated aqueous NaHCO _3, NH ₄ Cl, brine, washed with water, dried (MgSO ₄₎ and concentrated to give (S) -2 - ((tertiary-butoxycarbonyl) amino) - 2-(2-chloropyrimidin-5-yl)-2-oxoethyl ester of 3,3-dimethylbutyrate. The crude product was used in the next step without purification.

(S)-2-((Tertibutoxycarbonyl)amino)-3,3-dimethylbutyric acid 2-(2-chloropyrimidin-5-yl)-2-oxoethyl ester ( A mixture of 2.5 g, 6.48 mmol) and ammonium acetate (5 g, 64.9 mmol) in xylene (20 mL) was taken in a sealed vial and heated in a 138 ° C bath for 5 hours. The reaction mixture was diluted with EtOAc, and washed with saturated NaHCO _3, brine, dried (MgSO _4), concentrated and purified by silica gel flash chromatography to give (S) - (1- (4- (2- chloro-5 (3H-Imidazol-2-yl)-2,2-dimethylpropyl)carbamic acid tert-butyl ester (0.25 g, 6.5%). LC / MS (Condition Y-1): [M + H] + 366.2, R t = 2.596min.

To the (S)-(1-(4-(2-chloropyrimidin-5-yl)-1H-imidazol-2-yl)-2,2-dimethylpropyl)carbamic acid tert-butyl ester (0.25 g, 0.683 mmol) and (S)-(2,2-dimethyl-1-(4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaboron) Addition of carbonic acid to a solution of tert-butyl (2-)-phenyl)-1H-imidazol-2-yl)propyl)carbamate (0.622 g, 1.367 mmol) in DME (10 mL) and water (4 mL) Sodium hydrogenate (0.3 g, 3.57 mmol). The reaction mixture was degassed, refilled with N _2, and was added tetrakis (triphenylphosphine) palladium (0) (0.04g, 0.035mmol) , degassed and refilled with N _2. The reaction mixture was heated to 80 ° C under N ₂ for 16 h. The reaction mixture was diluted with EtOAc, and washed with NaHCO ₃ (2 ×), washed with brine, dried (MgSO _4), concentrated and purified by silica gel flash chromatography to afford product Y-84a (0.16g, 35% ). LC / MS (Condition Y-1): [M + H] + 659.45, R t = 2.95min.

Hydrogen chloride/dioxane (2 mL, 8.00 mmol) was added to a solution of EtOAc (EtOAc). The reaction mixture was stirred at room temperature for 2 hrs and then evaporated to give (S)-1(4-(2-(4-(2-()))) 2-Dimethylpropyl)-1H-imidazol-4-yl)phenyl)pyrimidin-5-yl)-1H-imidazol-2-yl)-2,2-dimethylpropan-1-amine tetras Acid salt. LC/MS (Condition Y-1): [M+H] ⁺ 459, R _t =2.625 min.

To (S)-1-(5-(2-(4-(2-((S)-1-amino)-2,2-dimethylpropyl)-1H-imidazole-5 at 0 °C -yl)phenyl)pyrimidin-5-yl)-1H-imidazol-2-yl)-2,2-dimethylpropan-1-amine tetrahydrochloride (0.040 g, 0.066 mmol) and (R)- Add DIPEA (0.12 mL, 0.687 mmol) and HBTU to a suspension of 5,5-difluoro-2-methyltetrahydro-2H-pyran-2-carboxylic acid (0.030 g, 0.165 mmol) in DCM (1 mL) (0.06 g, 0.158 mmol). The reaction mixture was stirred for 1 h, diluted with MeOH (1 mL) and solvent was evaporated and purified by HPLC to afford (R)-N-((S)-1-(5-(2-(4-) S)-1-((R)-5,5-difluoro-2-methyltetrahydro-2H-pentan-2-carboxamido)-2,2-dimethylpropyl)-1H- Imidazo-5-yl)phenyl)pyrimidin-5-yl)-1H-imidazol-2-yl)-2,2-dimethylpropyl)-5,5-difluoro-2-methyltetrahydro- 2H-Peulran-2-carbamide (bistrifluoroacetate) was taken as an example Y-84. LC / MS (Condition Y-1): [M + H] + 783.45, R t = 2.889min.

Example N-124

According to the procedure described for Preparation Example N-28, (1S,1'S)-1,1'-(4,4'-(biphenyl-4,4'-diyl)bis(1H-imidazole-4, Starting from 2-(2,2-dimethylpropan-1-amine) tetrahydrochloride and cap N-9, examples N-124A to N-124C (trifluoroacetate) were prepared in a similar manner ). Preparative HPLC (Water Sunfire 30 x 100 mm column, 0-55% B 20 min gradient, A = H ₂ O / CH ₃ CN / TFA 90: 10: 0.1, B = CH ₃ CN / H ₂ O /TFA 90:10:0.1) Separation of the three diastereomers.

Example N-124A (Stereoisomer-1): LC/MS (Cond. N-1): [M+H] ⁺ 845.65, RT = 3.648min. ¹ H NMR (400 MHz, methanol-d ₄ ) ppm 7.94 (s, 2H), 7.93-7.85 (m, 8H), 7.45 (td, J = 7.5, 1.5 Hz, 2H), 7.34-7.23 (m, 2H) , 7.16-7.08 (m, 2H), 7.03 (dd, J = 9.9, 8.9 Hz, 2H), 5.24 - 5.15 (m, 4H), 1.20 (s, 6H), 1.15 (s, 18H), 1.13-1.05 (m, 6H).

Example N-124B (Stereoisomer-2): LC/MS (Cond. N-1): [M+H] ⁺ 845. ¹ H NMR (400 MHz, methanol-d ₄ ) ppm 7.96 (s, 1H), 7.94 (s, 1H), 7.92-7.82 (m, 8H), 7.47 (dt, J = 15.1, 7.5 Hz, 1H), 7.47 (dt, J = 15.1, 7.6 Hz, 1H), 7.37-7.25 (m, 2H), 7.22-6.98 (m, 4H), 5.24-5.16 (m, 3H), 5.04-4.99 (m, 1H), 1.27 -1.06 (m, 30H).

Example N-124C (Stereoisomer-3): LC/MS (Cond. N-1): [M+H] ⁺ 845. ¹ H NMR (400 MHz, methanol-d ₄ ) ppm 7.95-7.83 (m, 10H), 7.49 (td, J = 7.5, 1.8 Hz, 2H), 7.37-7.28 (m, 2H), 7.19 (td, J = 7.5, 1.0 Hz, 2H), 7.07 (dd, J = 10.0, 9.0 Hz, 1H), 7.07 (dd, J = 11.2, 7.7 Hz, 1H), 5.21 (s, 2H), 4.98 (s, 2H), 1.25 (s, 6H), 1.22-1.13 (m, 18H), 1.09 (s, 6H).

Example N-125

According to the procedure described for Preparation Example N-28, (1S,1'S)-1,1'-(4,4'-(biphenyl-4,4'-diyl)bis(1H-imidazole-4, Starting from 2-(2,2-dimethylpropan-1-amine) tetrahydrochloride and cap N-10, examples N-125A to N-125C (trifluoroacetate) were prepared in a similar manner ). Preparative HPLC (Water Sunfire 30 x 100 mm column, 20-minute gradient of 0-52% B, A = H ₂ O / CH ₃ CN / TFA 90: 10: 0.1, B = CH ₃ CN / H ₂ O /TFA 90:10:0.1) Separation of the three diastereomers.

Example N-125A (Stereoisomer-1): ¹ H NMR (400 MHz, methanol-d ₄ ) ppm 8.02-7.83 (m, 10H), 7.33 (dd, J = 7.7, 1.6 Hz, 2H), 7.30- 7.18 (m, 2H), 7.01-6.82 (m, 4H), 5.36 (s, 2H), 5.18-5.08 (m, 2H), 3.88-3.70 (m, 6H), 1.22--1.05 (m, 30H) .

Example N-125B (stereoisomer-2): ¹ H NMR (400 MHz, methanol-d ₄ ) ppm 8.00-7.83 (m, 10H), 7.34 (dd, J = 7.7, 1.6 Hz, 1H), 7.38 ( Dd, J = 7.7, 1.6 Hz, 1H), 7.30-7.20 (m, 2H), 7.03-6.79 (m, 4H), 5.37 (d, J = 3.5 Hz, 2H), 5.15 (s, 1H), 4.98 (s, 1H), 3.81 (s, 3H), 3.82 (s, 3H), 1.27-1.12 (m, 24H), 1.10-1.00 (m, 6H).

Example N-125C (stereoisomer-3): ¹ H NMR (400 MHz, methanol-d ₄ ) ppm 7.97-7.81 (m, 10H), 7.38 (dd, J = 7.7, 1.6 Hz, 2H), 7.31 7.19 (m, 2H), 7.04-6.90 (m, 4H), 5.37 (s, 2H), 5.01-4.93 (m, 2H), 3.89-3.73 (m, 6H), 1.23 (s, 6H), 1.20- 1.12 (m, 18H), 1.09-1.00 (m, 6H).

Example N-126

According to the procedure described for Preparation Example N-28, (1S,1'S)-1,1'-(4,4'-(biphenyl-4,4'-diyl)bis(1H-imidazole-4, Starting from 2-diyl))bis(2,2-dimethylpropan-1-amine)tetrahydrochloride and cap N-11, examples N-126A to N-126C (trifluoroacetate) were prepared in a similar manner ). Preparative HPLC (Water Sunfire 30 x 100 mm column, gradient of 5-45% B for 20 minutes, A = H ₂ O / CH ₃ CN / TFA 90: 10: 0.1, B = CH ₃ CN / H ₂ O /TFA 90:10:0.1) Separation of the three diastereomers.

Example N-126A (Stereoisomer-1): LC/MS (Cond. N-1): [M+H] ⁺ 805.6, RT = 3.538 min. ¹ H NMR (400 MHz, methanol-d ₄ ) ppm 7.93-7.80 (m, 10 H), 7.42 (d, J = 7.3 Hz, 4 H), 7.34-7.21 (m, 6 H), 5.07-5.04 (m) , 2 H), 4.94 (s, 2 H), 1.17-1.08 (m, 22 H), 0.95-0.86 (m, 2 H), 0.74-0.67 (m, 2 H).

Example N-126B (Stereoisomer-2): LC/MS (Cond. N-1): [M+H] ⁺ 805.6, RT = 3.604 min. ¹ H NMR (400 MHz, methanol-d ₄ ) 7.95-7.79 (m, 10 H), 7.58 (d, J = 8.0 Hz, 2 H), 7.46-7.34 (m, 4 H), 7.34-7.20 (m, 4 H), 5.06 (s, 1 H), 4.97-4.92 (m, 1 H), 4.76-4.71 (m, 1 H), 4.59 (s, 1 H), 1.58-1.48 (m, 1 H), 1.14-1.05 (m, 11 H), 1.00-0.82 (m, 13 H), 0.75-0.65 (m, 1 H).

Example N-126B (Stereoisomer-3): LC/MS (Cond. N-1): [M+H] ⁺ 805.6, RT = 3.638min. ¹ H NMR (400 MHz, methanol-d ₄ ) ppm 7.94-7.81 (m, 10 H), 7.58 (d, J = 7.8 Hz, 4 H), 7.44 - 7.35 (m, 4 H), 7.33 - 7.25 (m) , 2 H), 4.75-4.70 (m, 2 H), 4.58 (s, 2 H), 1.60-1.50 (m, 2 H), 1.01 - 0.84 (m, 24 H).

Example N-127

According to the procedure described for Preparation Example N-28, (1S,1'S)-1,1'-(4,4'-(biphenyl-4,4'-diyl)bis(1H-imidazole-4, 2-diyl)) bis(2,2-dimethylpropan-1-amine) tetrahydrochloride and 3-hydroxy-2,2-dimethyl-3-phenylpropionic acid starting in a similar manner Examples N-127A to N-127C (trifluoroacetate) were prepared. Preparative HPLC (Water Sunfire 30 x 100 mm column, 20-50% B 20 min gradient, A = H ₂ O / CH ₃ CN / TFA 90: 10: 0.1, B = CH ₃ CN / H ₂ O /TFA 90:10:0.1) Separation of the three diastereomers.

Example N-127A (Stereoisomer-1): LC/MS (Cond. N-1): [M+H] ⁺ 809.7, RT = 3.576 min. ¹ H NMR (400MHz, methanol _{-d 4) ppm 8.01-7.83 (m,} 10H), 7.37-7.20 (m, 10H), 5.25-5.17 (m, 2H), 4.82 (s, 2H), 1.21 (s, 6H), 1.18-1.01 (m, 24H).

Example N-127B (Stereoisomer-2): LC/MS (Cond. N-1): [M+H] ⁺ 809.7, RT = 3.. ¹ H NMR (400MHz, methanol _{-d 4) ppm 7.98-7.81 (m,} 10H), 7.40-7.15 (m, 10H), 5.22-5.16 (m, 1H), 5.00-4.92 (m, 1H), 4.79 ( d, J = 7.3 Hz, 2H), 1.29-1.01 (m, 30H).

Example N-127C (Stereoisomer-3): LC/MS (Cond. N-1): [M+H] ⁺ 809.7, RT = 3.356min. ¹ H NMR (400 MHz, methanol-d ₄ ) ppm 8.00-7.83 (m, 10H), 7.42 - 7.18 (m, 10H), 4.99 (t, J = 2.5 Hz, 2H), 4.79 (s, 2H), 1.32 -1.02 (m, 30H).

Example N-128

According to the procedure described for Preparation Example N-28, (1S,1'S)-1,1'-(4,4'-(biphenyl-4,4'-diyl)bis(1H-imidazole-4, Examples N-128A and N-128B were prepared in a similar manner starting from 2-diyl))bis(2,2-dimethylpropan-1-amine) tetrahydrochloride and cap N-12A or N-12B.

Example N-128A (Stereoisomer-1): LC/MS (Cond. N-1): [M+H] ⁺ 81. ¹ H NMR (400 MHz, methanol-d ₄ ) ppm 8.39 (br.s., 2 H), 7.84 (br.s., 4 H), 7.72 (br.s., 6 H), 7.54 (br.s .2H), 7.47 (br.s., 2 H), 7.39 (br.s., 2 H), 7.18 (br.s., 2 H), 5.08-4.99 (m, 3H), 4.79 ( s, 2H), 1.31 (s, 7H), 1.12 (s, 7H), 1.06 (s, 20H).

Example N-128B (Stereoisomer-2): LC/MS (Cond. N-1): [M+H] ⁺ 81. ¹ H NMR (400 MHz, methanol-d ₄ ) ppm 8.53-8.38 (m, 2 H), 7.84 - 7.64 (m, 10 H), 7.47-7.36 (m, 4 H), 7.27 (ddd, J = 7.5, 5.0, 1.0 Hz, 2 H), 5.04 (s, 2 H), 4.90 (br.s., 2 H), 1.18 (d, J = 3.5 Hz, 12 H), 1.10-0.95 (m, 18 H) .

Example N-129

According to the procedure described for Preparation Example N-28, (1S,1'S)-1,1'-(4,4'-(biphenyl-4,4'-diyl)bis(1H-imidazole-4, Example N-129 was prepared in a similar manner starting from 2-diyl))bis(2,2-dimethylpropan-1-amine)tetrahydrochloride and cap N-13. LC / MS (Condition N-1): [M + H] + 818.3, RT = 3.256min.

Example N-130

Example N-130 was prepared according to the procedure described for Preparation Example N-104. </RTI>^<RTIID=0.0></RTI>^</RTI>^<RTIID=0.0></RTI> ¹ H NMR (400 MHz, methanol-d ₄ ) ppm 9.10 (br.s., 1H), 9.05 (br.s., 1H), 8.12 (d, J = 8.5 Hz, 2H), 7.86 (br.s. , 2H), 7.76 (s, 1H), 7.47 (s, 1H), 5.16-5.00 (m, 2H), 3.86 (td, J = 12.7, 6.5 Hz, 2H), 3.80-3.59 (m, 2H), 2.32-2.17 (m, 2H), 2.17-2.02 (m, 2H), 1.98-1.74 (m, 4H), 1.58-1.47 (m, 6H), 1.04-0.92 (m, 18H).

Example N-131

Example N-131 was prepared according to the procedure described for Preparation Example N-74. </RTI>^<RTIID=0.0></RTI>^</RTI>^<RTIID=0.0></RTI> ¹ H NMR (400 MHz, methanol-d ₄ ) ppm 8.01 (d, J = 8.0 Hz, 2 H), 7.95-7.87 (m, 2 H), 7.76-7.63 (m, 4 H), 4.99-4.94 (m) , 2 H), 3.97-3.81 (m, 2 H), 3.70 (td, J = 13.9, 7.0 Hz, 2 H), 3.01 (s, 4 H), 2.41 (double five-fold, J = 9.8, 6.6 Hz, 2 H), 2.24 - 2.06 (m, 4 H), 2.02-1.76 (m, 4 H), 1.50 (s, 6 H), 1.21-1.08 (m, 6 H), 0.98-0.86 (m, 6 H).

Example N-132

Example N-132 was prepared according to the procedure described for Preparation Example N-77. LC/MS (Cond. N-1): [M+H] ⁺ 77. ¹ H NMR (400 MHz, methanol-d ₄ ) δ ppm 7.97 (t, J = 8.2 Hz, 1 H), 7.84 - 7.76 (m, J = 8.5 Hz, 2 H), 7.75 - 7.65 (m, J = 8.5 Hz, 2 H), 7.60-7.39 (m, 4 H), 4.90-4.81 (m, 2 H), 3.93-3.79 (m, 2 H), 3.78-3.60 (m, 2 H), 2.34-2.19 ( m,4 H), 2.16-2.01 (m, 2 H), 1.91-1.71 (m, 4 H), 1.55-1.46 (m, 6 H), 1.04 (d, J = 6.5 Hz, 6 H), 0.93 -0.80 (m, 6 H).

Example N-133

Example N-133 was prepared according to the procedure described for Preparation Example N-77. LC/MS (Cond. N-1): [M+H] ⁺ 77. ¹ H NMR (400 MHz, methanol-d ₄ ) δ ppm 8.01-7.91 (m, 2 H), 7.91-7.83 (m, 2 H), 7.82-7.76 (m, 2 H), 7.76-7.64 (m, 3) H), 5.01-4.93 (m, 2 H), 3.95-3.79 (m, 2 H), 3.77-3.61 (m, 2 H), 2.49-2.35 (m, 2 H), 2.25-2.05 (m, 4) H), 2.02-1.77 (m, 4 H), 1.57-1.39 (m, 6 H), 1.22-1.07 (m, 6 H), 1.01-0.83 (m, 6 H).

Example N-134

Example N-134 was prepared according to the procedure described for Preparation Example N-101. LC/MS (Cond. N-1): [M+H] ⁺ 754.4, RT=3.3.84 min. ¹ H NMR (400 MHz, methanol-d ₄ ) ppm 9.07 (dd, J = 2.4, 0.6 Hz, 1 H), 8.34 - 8.24 (m, 3 H), 8.17-8.11 (m, 1 H), 8.05-7.98 (m, 2 H), 7.94-7.89 (m, 2 H), 5.00-4.94 (m, 2 H), 3.96-3.81 (m, 2 H), 3.80-3.64 (m, 2 H), 2.49-2.34 (m, 2 H), 2.26-2.07 (m, 4 H), 2.04-1.78 (m, 4 H), 1.50 (s, 6 H), 1.21-1.11 (m, 6 H), 0.99-0.87 (m) , 6 H).

By (1S, 1'S)-1,1'-(4,4'-([1,1'-biphenyl]-4,4'-diyl by using the procedure described for Synthesis Example L-3 The following example (bistrifluoroacetate) was prepared as bis(1H-imidazole-4,2-diyl))bis(2,2-dimethylpropan-1-amine) tetrahydrochloride and the appropriate starting material.

* ¹ H NMR: Example P-149: ¹ H NMR (500 MHz, methanol-d ₄ ) δ 7.93 (s, 2 H), 7.92-7.84 (m, 8 H), 4.96-4.92 (m, 2 H), 2.27-2.08 (m, 4 H), 2.00-1.88 (m, 4 H), 1.87-1.73 (m, 6 H), 1.64 (d, J = 12.4 Hz, 2 H), 1.33-1.27 (m, 6) H), 1.18 (s, 6 H), 1.15 (s, 18 H).

Example P-150: ¹ H NMR (500 MHz, methanol-d ₄ ) δ 7.95 (s, 2 H), 7.92-7.87 (m, 8 H), 5.19 (t, J = 3.8 Hz, 2 H), 2.06 ( d, J = 3.7 Hz, 4 H), 1.91-1.81 (m, 2 H), 1.81-1.67 (m, 4 H), 1.62 (t, J = 14.0 Hz, 4 H), 1.37 (t, J = 12.9 Hz, 4 H), 1.24 (s, 6 H), 1.22-1.19 (m, 6 H), 1.13 (s, 18 H).

Example P-154: ¹ H NMR (500 MHz, methanol-d ₄ ) δ 7.98 (s, 2 H), 7.93-7.86 (m, 8 H), 5.33 (s, 2 H), 3.67-3.60 (m, 2) H), 3.58-3.50 (m, 4 H), 3.42 (d, J = 11.3 Hz, 2 H), 1.51 (s, 6 H), 1.17 (s, 6 H), 1.15-1.08 (m, 18 H) ), 0.79 (s, 6 H).

Example P-155: ¹ H NMR (500 MHz, methanol-d ₄ ) δ 7.96 (s, 2 H), 7.93-7.83 (m, 8 H), 5.19 (d, J = 7.3 Hz, 1 H), 5.12 ( d, J = 6.9 Hz, 1 H), 4.14 - 4.03 (m, 1 H), 4.03-3.92 (m, 1 H), 3.78-3.54 (m, 4 H), 2.33-2.16 (m, 2 H) , 2.16-1.85 (m, 4 H), 1.80-1.59 (m, 2 H), 1.33 (s, 3 H), 1.25 (d, J = 6.9 Hz, 6 H), 1.19-1.09 (m, 21 H) ).

Example Y-67A: ¹ H NMR (400 MHz, methanol-d ₄ ) δ 8.01-7.75 (m, 10 H), 5.19 (s, 2 H), 4.04-3.81 (m, 4 H), 2.27-2. , 4 H), 2.10 - 1.87 (m, 4 H), 1.46 (s, 6 H), 1.11 (s, 18 H).

Example Y-67B: ¹ H NMR (400 MHz, methanol-d ₄ ) δ 7.98 (s, 2 H), 7.94-7.85 (m, 8 H), 5.30-5.21 (m, 2 H), 4.02-3.90 (m) , 2 H), 3.89-3.78 (m, 2 H), 2.28-1.98 (m, 6 H), 1.97-1.85 (m, 2 H), 1.56 (s, 6 H), 1.11 (s, 18 H) .

By (1S, 1'S)-1,1'-(4,4'-([1,1'-biphenyl]-4,4'-diyl) bis (1H- by standard guanamine coupling procedure) The following examples were prepared for imidazole-4,2-diyl))bis(2,2-dimethylpropan-1-amine) tetrahydrochloride and suitable starting materials.

By (1S, 1'S)-(4,4'-([1,1'-biphenyl]-4,4'-diyl) bis (1H-) by the procedure described for Synthesis Example L-3 The following example (bistrifluoroacetate) was prepared from imidazole-4,2-diyl))bis((1-methylcyclopropyl)methylamine) tetrahydrochloride and the appropriate starting materials.

* ¹ H NMR: Example P-142: ¹ H NMR (500 MHz, methanol-d ₄ ) δ 7.92 (s, 2 H), 7.91 - 7.84 (m, 8 H), 4.99 - 4.94 (m, 2 H), 4.65-4.58 (m, 2 H), 4.52 (s, 2 H), 2.31 (dd, J = 12.9, 4.8 Hz, 4 H), 2.09-1.85 (m, 8 H), 1.79-1.63 (m, 4) H), 1.25-1.17 (m, 6 H), 0.85 (dt, J = 9.9, 5.1 Hz, 2 H), 0.75-0.52 (m, 6 H).

Example P-145: ¹ H NMR (500 MHz, methanol-d ₄ ) δ 7.95 - 7.92 (m, 2 H), 7.91 - 7.84 (m, 8 H), 4.78 (t, J = 2.8 Hz, 2 H), 3.78 (d, J = 11.3 Hz, 2 H), 3.70 (d, J = 11.3 Hz, 2 H), 2.32-2.19 (m, 4 H), 2.08-1.86 (m, 8 H), 1.70 (ddd, J = 14.3, 10.8, 4.0 Hz, 2 H), 1.64-1.54 (m, 2 H), 1.24-1.16 (m, 6 H), 0.97-0.87 (m, 2 H), 0.79-0.72 (m, 2) H), 0.69-0.56 (m, 4 H).

Example P-151: ¹ H NMR (500 MHz, methanol-d ₄ ) δ 7.96-7.92 (m, 2 H), 7.91 - 7.83 (m, 8 H), 4.83-4.78 (m, 2 H), 2.21-1.97 (m, 12 H), 1.88-1.76 (m, 4 H), 1.26-1.14 (m, 6 H), 0.88 (dt, J = 9.8, 4.9 Hz, 2 H), 0.74 (dt, J = 10.0, 5.0 Hz, 2 H), 0.69-0.57 (m, 4 H).

By (1S,1'S)-(4,4'-([1,1'-biphenyl]-4,4'-diyl) bis (1H-imidazole-4,2) by standard guanamine coupling procedure -diyl)) bis((1-methylcyclopropyl)methylamine) tetrahydrochloride and appropriate The starting material was prepared as the following example (bistrifluoroacetate).

By (1S,1'S)-1,1'-(4,4'-(biphenyl-4,4'-diyl)bis (1H-imidazole-4,2-di) by standard guanamine coupling procedure The following example (bistrifluoroacetate) was prepared based on the bis(2-methylpropan-1-amine) tetrahydrochloride salt and the appropriate starting material.

From 4,4'-bis(2-((S)-pyrrolidin-2-yl)-1H-imidazol-5-yl)-1,1'-biphenyltetraphosphate by standard guanamine coupling procedure The following examples (bistrifluoroacetate) were prepared from the acid salt and the appropriate starting material.

Example Y-68

The reaction mixture of 3-methylbutan-2-one (20 g, 232 mmol), triacetaldehyde (6.97 g, 232 mmol) in TFA (20 mL). The reaction mixture was allowed to cool down and the volatile solvent was removed. The residue was carefully poured in to saturated NaHCO _3, and extracted with EtOAc. Washed with water, the organic phase was washed with saturated NaCl, dried (MgSO _4), filtered and concentrated to give an oil. The crude product was dissolved in MeOH (EtOAc) (EtOAc)EtOAc. The MeOH was removed and the aqueous phase was extracted with DCM. , Saturated NaCl The organic phase was washed with water, dried (MgSO _4), filtered and concentrated to give 4-hydroxy-3,3-dimethoxy-2-one (9.7g). ¹ H NMR (400 MHz, CDCl ₃ ) δ δ δ 3.57 (2H, s), 2.18 (3H, s), 1.18 (6H, s).

Methanesulfonate was added dropwise to a solution of 4-hydroxy-3,3-dimethylbutan-2-one (9.7 g, 84 mmol) and DIPEA (16.04 mL, 92 mmol) in DCM (50 mL). Chlorochloride (7.16 mL, 92 mmol). The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with EtOAc and saturated NaCl and washed with saturated NaHCO _3, dried (MgSO _4), filtered and concentrated to give 2,2-dimethyl-3-oxo-butyl methanesulfonate (14.6g). ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 4.21. (2H, s), 3.04 (3H, s), 2.21. (3H, s), 1.25 (6H, s).

A suspension of KF (8.73 g, 150 mmol) in tetraethylene glycol (80 mL) was fed to a three-necked flask equipped with a distillation apparatus under reduced pressure. The reaction mixture was heated to 160 ° C, and tetraethylene glycol (80 mL) containing methanesulfonic acid 2,2-dimethyl-3-oxobutyl ester (14.6 g, 75 mmol) was slowly added over 80 min. The product 4-fluoro-3,3-dimethylbutan-2-one (4.1 g) was collected as a solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 4.47 (1 H, s), 4.35 (1 H, s), 2.21. (3H, d, J = 0.50 Hz), 1.19 (6 H, d, J = 1.76 Hz).

Vigorously stirred mixture of 4-fluoro-3,3-dimethylbutan-2-one (4.1 g, 34.7 mmol) in water (50 mL) and NaOH (7 mL, 70.0 mmol) cooled in ice-acetone bath Potassium permanganate (9.87 g, 62.5 mmol) was added portionwise. The internal temperature was controlled between -3 ° C and 2 ° C during the addition. After the addition was completed, the reaction mixture was stirred in an ice-acetone bath for 6 hours, and then allowed to warm. EtOH (5 mL) was added and the reaction mixture was stirred further 15 min. The reaction mixture was filtered and the solid was washed with water (~ 80 mL). The filtrate was acidified with EtOAc (EtOAc)EtOAc. With 1N HCl, saturated NaCl of the combined extracts were dried (Na ₂ SO _4), filtered and concentrated to give 4-fluoro-3,3-dimethyl-2-oxobutanoate (2.3g).

To a solution of 4-fluoro-3,3-dimethyl-2-oxobutanoic acid (2.3 g, 15.53 mmol) in DMF (30 mL), EtOAc ( _1. CO ₃ (5.36 g, 38.8 mmol). The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with EtOAc and stirred for 10 min. Filter the solids. The filtrate was partitioned between EtOAc and water. The organic phase was washed with water and saturated NaCl and concentrated. Diluted with hexane (about 100 mL) residue, and washed with water (2 × 30mL), dried over MgSO _4, filtered and concentrated to give 4-fluoro-3,3-dimethyl-2-oxo acetic acid Ester (2.3 g).

Add (S)-2-methylpropane-2 to a solution of ethyl 4-fluoro-3,3-dimethyl-2-oxobutanoate (2.3 g, 13.05 mmol) in THF (20 mL) - sulfinamide (1.899 g, 15.67 mmol) and tetraethoxytitanium (5.91 mL, 26.1 mmol). The reaction mixture was heated at 65 ° C for 6 hours. The reaction mixture was cooled with EtOAc (EtOAc)EtOAc. The solid was filtered and washed with water and EtOAc. The filtrate was separated, and washed with water, the organic layer was washed with saturated NaCl, and purified by flash chromatography (EtOAc / hexanes) and dried (MgSO _4), to give (S) -2- (tertiary-butyl sulfonylurea imino) Ethyl 4-fluoro-3,3-dimethylbutanoate (1.1 g). ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 4.46-4.53 (1H, m), 4.28 - 4.42 (3H, m), 1.59 (3H, s), 1.21-1.31 (15H, m).

To (S)-2-(t-butylsulfinium imino)-4-fluoro-3,3-dimethylbutyrate B at a rate of 6 mL/h via a syringe pump at -78 °C A solution of the ester (1.1 g, 3.94 mmol) in EtOAc (EtOAc) (EtOAc) After the addition was completed, the reaction mixture was stirred at -78 °C for 4 hours. By adding at -78 ℃ NH ₄ Cl The reaction was quenched with aqueous, diluted with EtOAc, and washed with water, brine, dried (MgSO _4), concentrated and purified by silica gel chromatography (EtOAc / hexane) to give ( S)-2-((S)-1,1-Dimethylethylsulfinamido)-4-fluoro-3,3-dimethylbutanoic acid ethyl ester (0.38 g). ¹ H NMR (400 MHz, MeOD- d ₄ ) δ ppm 4.20-4.44 (4H, m), 3.99 (1 H, s), 1.35 (3 H, t, J = 7.15 Hz), 1.13 (6 H, dd , J = 15.81, 2.01 Hz).

To (S)-2-((S)-1,1-dimethylethylsulfinamido)-4-fluoro-3,3-dimethylbutanoic acid ethyl ester (0.38 g, 1.350 mmol) HCl/dioxane (1.350 mL, 5.40 mmol) was added to a solution in MeOH (10 mL). The reaction mixture was stirred at room temperature for 30 min and concentrated to give (S)-2-amino-4-fluoro-3,3-dimethylbutanoic acid ethyl ester / HCl (0.29) g).

Add TEA (0.4 mL, 2.87) to a solution of (S)-2-Amino-4-fluoro-3,3-dimethylbutanoic acid ethyl ester / HCl (0.29 g, 1.357 mmol) in MeOH (5 mL) Methyl) and Boc ₂ O (0.58 g, 2.66 mmol). The reaction mixture was stirred at room temperature for 2 hr and concentrated. The residue was redissolved in EtOAc (EtOAc) (EtOAc) The reaction mixture was diluted with water (4 mL) andEtOAc. The aqueous layer was acidified with cold 1N EtOAc andEtOAc. Washed with water, the organic phase was washed with brine, dried (MgSO ₄₎ and concentrated to give (S) -2- (tert-butoxy carbonyl amino) -4-fluoro-3,3-dimethyl butyric acid (0.3g) . ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 12.06 (1H, br. s.), 4.06-4.36 (3H, m), 1.38-1.46 (15H, m).

To (S)-2-((t-butoxycarbonyl)amino)-4-fluoro-3,3-dimethylbutyric acid (0.3 g, 1.203 mmol) and DIPEA (0.230 mL, 1.318 mmol) To the solution in acetonitrile (5 mL) was added 1,1'-([1,1'-biphenyl]-4,4'-diyl)bis(2-bromoethyl ketone) (0.23 g, 0.581 mmol). The suspension was stirred at room temperature for 18 hours. The reaction mixture was diluted with EtOAc, and washed with saturated NaHCO _3, brine, water, dried (MgSO ₄₎ and concentrated to give a pale white solid. The product was purified by silica gel chromatography (EtOAc/hexane) to afford (2S,2's)-bis(2-((t-butoxycarbonyl)amino)-4-fluoro-3,3-dimethylbutyl Acid) [1,1'-biphenyl]-4,4'-diylbis(2-o-ethoxyethyl-2,1-diyl) ester (0.3 g). LC / MS (conditions YT-1): [M + Na] + 755.35, R t = 3.384min.

(2S,2'S)-bis(2-((t-butoxycarbonyl)amino)-4-fluoro-3,3-dimethylbutyric acid) [1,1'-biphenyl]-4, 4'-Diylbis(2-oxoethoxy-2,1-diyl) ester (0.31 g, 0.423 mmol), ammonium acetate (0.8 g, 10.38 mmol) and 1H-imidazole (0.1 g, 1.469 mmol) The mixture in toluene (5 mL) was heated to 110 ° C for 6 h. The reaction mixture was cooled with cooling and diluted with EtOAc. With saturated NaHCO _3, the organic extracts were washed with brine, dried (MgSO ₄₎ and concentrated. The product was purified by silica gel chromatography to give (1S,1'S)-1,1'-(5,5'-(biphenyl-4,4'-diyl)bis(1H-imidazole-5,2-diyl) )) tert-butyl bis(3-fluoro-2,2-dimethylpropane-1,1-diyl)diaminecarboxylate (0.21 g). LC / MS (conditions YT-1): [M + H] + 693.4, R t = 2.486min.

To ((1S,1'S)-(5,5'-([1,1'-biphenyl]-4,4'-diyl)bis(1H-imidazole-5,2-diyl)) bis (3) Adding hydrogen chloride / dioxins to a solution of difluoro-t-butyl 2,2-dimethylpropane-1,1-diyl)diamine diamine (0.21 g, 0.303 mmol) in DCM (2 mL) Alkane (2.0 mL, 8.0 mmol). The reaction mixture was stirred at room temperature for 2 hours and concentrated to give (1S,1's)-1,1'-(5,5'-([1,1'-biphenyl]-4,4' as a yellow solid. -Diyl)bis(1H-imidazole-5,2-diyl))bis(3-fluoro-2,2-dimethylpropan-1-amine) tetrahydrochloride (0.04 g). LC / MS (conditions YT-1): [M + H] + 493.4, R t = 1.84min.

To (1S,1'S)-1,1'-(5,5'-([1,1'-biphenyl]-4,4'-diyl)bis(1H-imidazole-5,2-diyl) Addition of pivalic acid to a mixture of bis(3-fluoro-2,2-dimethylpropan-1-amine) tetrahydrochloride (0.04 g, 0.063 mmol) in DCM (1 mL) and EtOAc (1 mL) 20 mg), DIPEA (0.1 mL, 0.573 mmol) and HBTU (0.052 g, 0.138 mmol). The reaction mixture was stirred at room temperature for 0.5 hr then concentrated. The residue was dissolved in MeOH and purified by prep _{HPLC (MeOH / H 2 O /} TFA), trifluoroacetate salt of Example Y-68 (10mg). LC / MS (conditions YT-1): [M + H] + 661.4, R t = 2.238min. ¹ H NMR (400 MHz, MeOD- d ₄ ) δ ppm 7.94 (2 H, s), 7.83-7.91 (8 H, m), 5.35-5.44 (2 H, m), 4.44 - 4.52 (1 H, m) , 4.33-4.43 (2 H, m), 4.15-4.31 (1 H, m), 1.26 (18 H, s), 1.08-1.18 (12 H, m).

Example Y-69

Example Y-69 was synthesized from the appropriate precursor by the method described in Example Y-68. LC / MS (conditions YT-1): [M + H] + 785.35, R t = 2.428min. ¹ H NMR (400 MHz, MeOD- d ₄ ) δ ppm 7.75-7.96 (10 H, m), 5.23 (2 H, br. s.), 4.45 (1 H, br.s.), 4.29-4.42 (2 H, m), 4.25 (1 H, br. s.), 2.49-2.65 (2 H, m), 2.09 (4 H, br. s.), 1.91 (2 H, br. s.), 1.83 ( 4 H, br.s.), 1.72 (3 H, s), 1.75 (3 H, s), 1.14 (12 H, d, J = 8.03 Hz).

Example L-34

Example L-34 step a

Example L-34 was synthesized by following the procedure described in Example Y-68 starting from commercially available (S)-2-((t-butoxycarbonyl)amino)-2-cyclopropylacetic acid. a hydrochloride salt. Treatment of 1-((methoxycarbonyl)(methyl)amino)cyclopropanecarboxylic acid (24.89 mg, 0.144 mmol) with EtOAc (56.0 mg, 0.147 mmol), mp. DIEA (0.086mL, 0.491mmol) in DMF solution (1.5mL) in, the resulting solution was stirred at room temperature for 3 hours, followed by _{(CH 3 CN / H 2 O} / NH 4 OAc) was purified by preparative HPLC, to give Example L-34 (32 mg). LC / MS (Condition L-1): [M + H] + 735.55, R t = 1.63min. ^{1 H NMR (500MHz, DMSO- d} 6) δ ppm 11.96 (2 H, br.s.), 8.01-7.63 (12 H, m), 4.56 (2 H, br.s.), 3.62 (3 H, s), 3.65 (3 H, s), 2.84-3.03 (6 H, m), 1.28-1.51 (6 H, m), 1.15 (4 H, br.s.), 0.48 (4 H, d, J = 8.24 Hz), 0.35 (4 H, d, J = 17.09 Hz).

Examples L-35 to L-37 were synthesized by following the method described in Example L-34.

Examples W-51 through W-56, W-64, and W-65 were synthesized by following the method described in Example L-34.

By (1S, 1'S)-1,1'-(4,4'-([1,1'-biphenyl]-4,4'-diyl by using the procedure described for Synthesis Example L-3 The following examples were prepared for the bis(1H-imidazole-4,2-diyl))bis(2-methylpropan-1-amine) tetrahydrochloride salt and the appropriate starting material (cap). The product obtained is purified by preparative HPLC (MeOH/H ₂ O/TFA or CH ₃ CN/H ₂ O/NH ₄ OAc) and obtained as the corresponding trifluoroacetic acid salt or as the free base.

By (1S, 1'S)-1,1'-(4,4'-([1,1'-biphenyl]-4,4'-diyl by using the procedure described for Synthesis Example L-3 The following examples were prepared for the bis(1H-imidazole-4,2-diyl))bis(2,2-dimethylpropan-1-amine) tetrahydrochloride and the appropriate starting materials (caps). The product obtained is purified by preparative HPLC (MeOH/H ₂ O/TFA or CH ₃ CN/H ₂ O/NH ₄ OAc) and obtained as the corresponding trifluoroacetic acid salt or as the free base. Examples W-80, W-102, and W-103 were prepared by methods described separately.

* Examples W-76, W-77 and W-78 were separated from the mixture of diastereomers by preparative HPLC.

** Example W-92 was prepared by employing the same procedure as described for Synthesis Example W-80.

*** Example W-114 was isolated as a secondary product during the purification of W-115.

Examples W-117 and W-118 were prepared by using the same procedures as described for Synthesis Examples W-109 and W-107, but using Example W-92 as the starting material.

The following examples were characterized by proton NMR: Example W-82 ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 12.53-11.93 (m, 1H), 8.36-7.21 (m, 6H), 5.51-5.08 (m, 1H) , 5.02-4.78 (m, 1H), 4.63-4.35 (m, 1H), 3.83-3.40 (m, 2H), 2.44-1.82 (m, 2H), 1.54-1.20 (m, 9H), 1.11 - 0.85 ( m, 9H)

Example W-116 ¹ H NMR (500MHz, DMSO-d ₆ ) δ 12.52-11.81 (m, 1H), 8.22 - 7.14 (m, 5H), 5.58-5.13 (m, 1H), 5.03-4.76 (m, 1H) ), 4.35-4.24(m,1H),4.13-4.10(m,1H),3.31-3.16(m,1H),2.36-1.68(m,2H),1.54-1.10(m,12H),1.05-0.87 (m, 9H)

Example W-184 ¹ H NMR (500MHz, DMSO-d ₆ ) δ 12.04 (br.s., 1H), 8.08-7.09 (m, 5H), 5.29-4.70 (m, 2H), 3.95-3.54 (m, 3H), 2.23-1.82 (m, 2H), 1.72-1.28 (m, 12H), 0.92 (br.s., 9H)

Example W-185 ¹ H NMR (500MHz, CD ₃ OD) δ 7.88-7.65 (m, 4H), 7.47-7.31 (m, 1H), 5.44-5.16 (m, 1H), 5.14-4.98 (m, 1H) , 4.13 - 3.73 (m, 2H), 2.63 - 2.24 (m, 2H), 1.80 - 1.58 (m, 3H), 1.39 (s, 3H), 1.13 (s, 9H), 1.07 - 0.98 (m, 9H)

Example L-66a ¹ H NMR (500MHz, DMSO-d ₆ ) δ 8.46 (br.s., 2H), 8.02-7.81 (m, 9H), 7.61 (br.s., 2H), 5.20 (br.s) .2H), 1.57 (s, 6H), 1.28-1.21 (m, 2H), 0.97 (s, 19H); ¹⁹ F NMR (471 MHz, DMSO-d ₆ ) δ -74.09 (s, 3F), -78.19 (br.s., 3F)

Example L-66b ¹ H NMR (500MHz, DMSO-d ₆ ) δ 8.43 (br.s., 2H), 8.12 (br.s., 2H), 8.02-7.81 (m, 8H), 7.62 (br.s) .1H), 7.51 (br.s., 1H), 5.20 (br.s., 2H), 1.57 (s, 3H), 1.48 (s, 3H), 1.29-1.20 (m, 2H), 0.97 ( Br.s., 9H), 0.95 (br.s., 9H); ¹⁹ F NMR (471 MHz, DMSO-d ₆ ) δ -74.10 (br.s., 6F), -78.19 (br.s., 3F) ),-78.34(br.s.,3F)

Example L-66c ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 8.43 (d,J = 19.2 Hz, 2H), 7.87 (br.s., 9H), 7.49 (br.s., 2H), 5.19 ( Br.s., 2H), 1.47 (s, 6H), 1.39 (br.s., 2H), 0.94 (br.s., 18H); ¹⁹ F NMR (471 MHz, DMSO-d ₆ ) δ -74.02 ( Br.s.,3F),-78.36(br.s.,3F)

Example L-96 ¹ H NMR (500MHz, DMSO-d ₆ ) δ 12.45-12.08 (m, 2H), 8.29-8.19 (m, 2H), 7.85 (d, J = 8.2 Hz, 3H), 7.78-7.65 ( m, 5H), 7.59-7.36 (m, 2H), 4.94-4.75 (m, 2H), 3.49-3.42 (m, 2H), 3.37 (d, J = 4.3 Hz, 2H), 3.24 - 3.12 (m, 2H), 1.7-1.08 (m, 2H), 1.05-0.98 (m, 4H), 0.94 (s, 18H)

By (1S, 1'S)-(4,4'-([1,1'-biphenyl]-4,4'-diyl) bis (1H-) by the procedure described for Synthesis Example L-34 The following examples were prepared for imidazole-4,2-diyl)) bis(cyclopropylmethylamine) tetrahydrochloride and suitable starting materials. The product obtained is purified by preparative HPLC (MeOH/H ₂ O/TFA or CH ₃ CN/H ₂ O/NH ₄ OAc) and obtained as the corresponding trifluoroacetic acid salt or as the free base.

By (1S, 1'S)-(4,4'-([1,1'-biphenyl]-4,4'-diyl) bis (1H-) by the procedure described for Synthesis Example L-3 The following examples were prepared for imidazole-4,2-diyl))bis((1-methylcyclopropyl)methylamine) tetrahydrochloride and the appropriate starting materials (caps). The product obtained is purified by preparative HPLC (MeOH/H ₂ O/TFA or CH ₃ CN/H ₂ O/NH ₄ OAc) and obtained as the corresponding trifluoroacetic acid salt or as the free base.

Example L-93 (diastereomer 1) Example L-93 (diastereomer 2) Example L-93 (diastereomer 3)

Example L-93 step a

1- (1-methylcyclopropyl) ethanone (5g, 50.9mmol), NaOH ( 10.19mL, 102mmol) and H ₂ O (150mL) fed 500ml Erlenmyer flask, and acetone - cooled in an ice bath . After the internal temperature reached -4 ° C, KMnO ₄ (14.49 g, 92 mmol) was added portionwise with vigorous stirring. The internal temperature was maintained at -3 ° C to 1 ° C during the addition for 60 minutes. The reaction mixture was then stirred in a bath for 6 hours and warmed during the process (internal temperature reached 16 ° C). EtOH (10 ml) was added and stirring was continued for a further 15 minutes. The reaction mixture was filtered to remove a solid and washed with water (~ 100 mL). The filtrate was acidified to pH < 2 with cold 6N HCl in an ice cold bath. With EtOAc (4 × 100ml and 3 × 50ml) The mixture was extracted, and washed with 1N HCl (10ml), brine (3 × 15ml) The combined extracts were washed, dried (Na ₂ SO ₄₎ and concentrated to give a clear oil It solidified upon standing under vacuum and corresponds to Example A-93, step a (3.71 g). ¹ H NMR (400 MHz, CDCl ₃ ) δ 10.21 (br.s., 1H), 1.84-1.78 (m, 2H), 1.36 (s, 3H), 1.09-1.04 (m, 2H); ¹³ C NMR (101 MHz , CDCl ₃ ) δ 197.0, 162.1 (br.s., 1C), 26.8, 20.5 (s, 2C), 19.2.

Example L-93, step b (racemate)

MeMgCl (3 M in THF) (21.23 mL, 63.7 mmol) was added dropwise to a solution of EtOAc (EtOAc) The resulting solution was then stirred at room temperature for 24 hours. The reaction mixture was then cooled to 0.degree. C. and carefully quenched with 6N EtOAc (~ 15 mL). And the aqueous layer was extracted with Et ₂ O (4 × 50mL) the organic solvent is removed under reduced pressure. Washed with brine the combined organic layers were dried (MgSO _4), filtered and concentrated under vacuum to give a white solid. The residue was then recrystallized from hot n-heptane to afford Example L-93 step b (3.15 g). ¹ H NMR (500 MHz, CDCl ₃ ) δ 1.39 (s, 3H), 1.16 (s, 3H), 0.83-0.73 (m, 2H), 0.37-0.31 (m, 1H), 0.31 - 0.25 (m, 1H) ¹³ C NMR (126 MHz, CDCl ₃ ) δ 180.6, 75.9, 21.9, 21.9, 20.7, 10.7, 9.4.

Example L-93, step c (racemic)

N -Methylpiperidine (0.843 mL, 6.94 mmol) was added to EtOAc (EtOAc m. After 10 minutes, CCl ₃ OCOCl (0.502 mL, 4.16 mmol) was added dropwise at 0 ° C, and the mixture was stirred at room temperature for 12 hours. A white precipitate formed. The solvent was removed under reduced pressure and the residue was dissolved in hexane. The solid was filtered off and washed with hexanes. The hexane solution was then concentrated under reduced pressure to give abr. EtOAc. _{^{1 H NMR (400MHz, CDCl 3}} ) δ 1.67 (s, 3H), 1.25 (s, 3H), 0.88-0.80 (m, 1H), 0.75 (dt, J = 9.6,4.6Hz, 1H), 0.59-0.47 (m, 2H); ¹³ C NMR (101 MHz, CDCl ₃ ) δ 168.6, 147.7, 89.2, 20.2, 19.7, 19.2, 10.9, 9.5.

Example L-93, step c (116 mg, 0.681 mmol) (in 0.5 mL DCM) was added to (1S,1'S)-1,1'-(4,4'-([1,1'-biphenyl]- 4,4'-diyl)bis(1H-imidazole-4,2-diyl))bis(2,2-dimethylpropan-1-amine)tetrahydrochloride (200 mg, 0.332 mmol) and DIEA ( 0.348 mL, 1.992 mmol) in DCM (2.0 mL) EtOAc. The sample was concentrated under reduced pressure and by preparative HPLC (solvent A: 5% MeCN / 95% water / 10 mM NH ₄ Ac; solvent B: 95% MeCN / 5% water / 10 mM NH ₄ Ac; column: Sunfire Prep MS C18 30×100 mmS10; Wavelength: 220 nM; Flow rate: 30 ml/min; Gradient: 0% B to 80% B over 15 minutes, hold time 5 minutes) Purify the residue to obtain the three non-pairs listed in the table below Isomerized product (example L-93a, example L-93b and example L-93c):

*Example L-93a ¹ H NMR (500MHz, DMSO-d ₆ ) δ 12.46-12.03 (m, 2H), 7.83 (d, J = 8.2 Hz, 3H), 7.78-7.64 (m, 6H), 7.60-7.53 (m, 1H), 7.61-7.31 (m, 1H), 5.44 (s, 2H), 4.92-4.79 (m, 2H), 3.32 (s, 7H), 1.23 (s, 6H), 0.92 (br.s) .18H), 0.65 (d, J = 5.2 Hz, 2H), 0.61 - 0.54 (m, 2H), 0.09 - 0.02 (m, 2H), -0.05 (s, 2H).

*Example L-93b ¹ H NMR (500MHz, DMSO-d ₆ ) δ 12.49-12.05 (m, 2H), 7.83 (d, J = 7.3 Hz, 3H), 7.78-7.62 (m, 6H), 7.60-7.29 (m, 2H), 5.56-5.33 (m, 2H), 4.84 (t, J = 10.8 Hz, 2H), 3.32 (br.s., 6H), 1.22 (d, J = 9.6 Hz, 6H), 0.96 -0.85 (m, 18H), 0.81 (br.s., 1H), 0.74 (d, J = 4.6 Hz, 1H), 0.65 (d, J = 3.6 Hz, 1H), 0.58 (d, J = 3.8 Hz) , 1H), 0.20-0.09 (m, 2H), 0.08-0.02 (m, 1H), -0.05 (dd, J = 8.7, 4.7 Hz, 1H).

Example L-94

Pure 1,1 '-carbonyldiimidazole (50.3 mg, 0.301 mmol) was added to a solution of (R)-2-hydroxy-2-phenylpropanoic acid (50.0 mg, 0.301 mmol) in THF (2 mL) The mixture was stirred overnight at room temperature. The solvent was removed under reduced pressure and the residue was crystalljjjjjjjj Then use DIPEA (0.074 mL, 0.421 mmol) and (1S,1'S)-1,1'-(4,4'-([1,1'-biphenyl]-4,4'-diyl) bis (1H -Imidazole-4,2-diyl))bis(2,2-dimethylpropan-1-amine) tetrahydrochloride (59.8 mg, 0.099 mmol) was treated with the resulting solution and the mixture was stirred at room temperature for 2 hours. . Via preparative LC/MS (column: Waters XBridge C18, 19 x 200 mm, 5 μm; mobile phase A: water and 20 mM ammonium acetate; mobile phase B: 95:5 acetonitrile: water and 20 mM ammonium acetate; gradient: over 20 minutes) 35-75% B, followed by 5 minutes at 100% B: flow rate: 20 mL/min) The crude material was purified. The fractions containing the desired product were combined and dried <RTI ID=0.0> LC / MS (Condition PS-2): [M + H] + 753.41, R t = 2.99min. ^{1 H NMR (400MHz, DMSO-} d 6) δ 7.81 (br.s., 3H), 7.69 (br.s., 5H), 7.57-7.47 (m, 6H), 7.29-7.10 (m, 6H), 6.44 (s, 2H), 4.79 (br.s., 2H), 1.70 (s, 6H), 0.94 (s, 18H).

Example L-95

Example L-95 was prepared by starting with (S)-2-hydroxy-2-phenylpropanoic acid using the procedure described for the synthesis of L-94. LC / MS (Condition PS-2): [M + H] + 756.41, R t = 3.18min. ^{1 H NMR (500MHz, DMSO-} d 6) δ 7.98-7.82 (m, 5H), 7.77-7.66 (m, 5H), 7.59 (br.s., 5H), 7.40-7.22 (m, 7H), 6.41 (br.s., 2H), 4.86-4.73 (m, 2H), 1.61 (br.s., 6H), 0.73 (br.s., 18H).

Example W-80

To a solution of W-77 in MeOH (EtOAc) (EtOAc) The resulting pale yellow solution was stirred at room temperature for 2 hours. The volatiles were removed in vacuo. The residue was triturated with EtOAc (EtOAc)EtOAc.

Example W-101

Example W-101 in the form of the tetrahydrochloride salt was prepared from Example W-181 according to the procedure described for the Synthesis Example W-80.

Example W-102 (method W-A)

To (2S,2'S,4R,4'R)-N,N'-((1S,1'S)-(4,4'-([1,1'-biphenyl]-4,4 at 4 °C '-Diyl) bis(1H-imidazole-4,2-diyl))bis(2,2-dimethylpropane-1,1-diyl))bis(4-fluoropyrrolidine-2-carboxamidine) was added DIPEA (0.105mL, 0.600mmol) and acetic anhydride (0.045mL, 0.480mmol) in the ₂ Cl ₂ (1mL) in a mixture of the amine) tetrahydrochloride (example W-101,50mg, 0.060mmol) in CH. The resulting mixture, which became a clear solution in 10 minutes, was stirred at room temperature for 1 hour. 2M ammonia in MeOH (1.000 mL, 2 mmol) was added and stirred at room temperature for 3 h. The solvent was evaporated by blowing N _2, and the residue was dissolved and _{(CH 3 CN / H 2 O} / NH 4 OAc) was purified by preparative HPLC in 1mLMeOH, obtained as the free base form of the desired product Example W-102 ( 30 mg white solid, 62% yield).

Example W-103 (method W-B)

To (2S,2'S,4R,4'R)-N,N'-((1S,1'S)-(4,4'-([1,1'-biphenyl]-4,4 at 4 °C '-Diyl) bis(1H-imidazole-4,2-diyl))bis(2,2-dimethylpropane-1,1-diyl))bis(4-fluoropyrrolidine-2-carboxamidine) Add DIPEA (0.105 mL, 0.600 mmol), O-(7-azabenzotriazol-1-yl) hexafluorophosphate to a mixture of the amine hydrochloride (50 mg, 0.060 mmol) in DMF (1 mL) -N,N,N',N'-tetramethyl (47.9 mg, 0.126 mmol) and 2-ethoxyacetic acid (0.012 mL, 0.126 mmol). For 2 h and _{(CH 3 CN / H 2 O} / NH 4 OAc) was purified by stirring at room temperature the formed solution was purified by preparative HPLC, to give the free form of the base of the desired product Example W-103 (28mg as a white solid, 54 %Yield).

The examples in the table below were prepared by the same method as described in Example W-102 (Method WA) or Example W-103 (Method WB), except for Example W-101, which is by way of example W- Prepared in the same manner as described in 80.

Example W-112 and example W-113

To (3R,3'R,5S,5'S)-5,5'-(((1S,1'S)-(4,4'-([1,1'-biphenyl]-4,4'- Bis(1H-imidazole-4,2-diyl))bis(2,2-dimethylpropan-1,1-diyl))bis(azadiyl))bis(carbonyl)) bis (3) - fluoropyrrolidine-1-carboxylic acid) di-tert-butyl ester (50 mg, 0.056 mmol) in ice-cooled solution in tetrahydrofuran, DIPEA (24.61 μl, 0.141 mmol) and diisopropyl chlorophosphate (23.74 mg, 0.118 mmol) ). The resulting mixture, which became a clear solution in 10 minutes, was stirred at room temperature for 1 hour. The contents were transferred to a vial, sealed, and heated to 80 ° C in a microwave system for 2 hours. By prep _{HPLC (CH 3 CN / H 2} O / NH 4 OAc) to give two kinds of fractions were examples, and corresponds to the example of a white solid of W-112 (4.4mg) as a white solid, and the W- 113 (5.4 mg).

Example W-112: LC/MS (Cond. W-3): 1/2 [M+H] + 526.5, R _t = 3.25 min.

Example W-113: LC/MS (Cond. W-3): 1/2 [M+H] + 608.6, R _t = 3.39 min.

Example W-135

Example W-135 Step A

Add lithium hydroxide monohydrate (0.275 g, 6.55 mmol) to a solution of the title W-126 bis trifluoroacetate (1.27 g, 1.311 mmol), water (12.00 mL) in MeOH (12 mL) Pre-formed solution in water (12.00 mL). The resulting thick paste was heated to reflux slowly for 2 hours. And an aliquot by prep _{HPLC (CH 3 CN / H 2} O / NH 4 OAc) purified for characterization, to give examples of W-133 Step A. The remaining mixture was evaporated in vacuo, diluted with EtOAc EtOAc EtOAc. The volatiles were removed under high vacuum. The residual gum was dissolved in 15.8 mL of DMA. The 0.083 M stock solution formed was used for the coupling to be carried out.

To a vial containing morpholine (15.21 mg, 0.175 mmol) and HATU (66.4 mg, 0.175 mmol) was added Example W-135 Step A dihydrochloride (1.002 mL, 0.083 mmol) in DMA 0.083 stock solution and DIEA (0.145 mL, 0.831 mmol). The resulting pale yellow solution was stirred at room temperature for 3 hours. Followed by prep _{HPLC (CH 3 CN-H 2} O-NH 4 OAc) mixture was purified to afford a white solid examples of W-135 (41mg, 59% yield).

Examples W-136 through W-158 in the table below were prepared by employing the procedure described for Synthesis Example W-135. The product obtained is purified by preparative HPLC (MeOH/H ₂ O/TFA or CH ₃ CN/H ₂ O/NH ₄ OAc) and obtained as the corresponding trifluoroacetic acid salt or as the free base.

* W-146 was isolated as a secondary product during purification example W-141.

** W-147 was isolated as a secondary product during purification example W-142.

Example W-179

Will contain (1S,1'S)-1,1'-(4,4'-([1,1'-biphenyl]-4,4'-diyl) bis(1H-imidazole-4,2-diyl) )) bis(2,2-dimethylpropan-1-amine) tetrahydrochloride (50 mg, 0.083 mmol), 4,5-dichloro-2-fluorothiazole (57.1 mg, 0.332 mmol), N, N A vial of diisopropylethylamine (0.110 mL, 0.664 mmol) and DMA (1 mL) was heated in a microwave system at 65 °C for 4 hours. By prep _{HPLC (CH 3 CN-H 2} O-NH 4 OAc) to give a white solid of the desired product. LC/MS (Condition W-2): [M+H] + 761.2, R _t = 2.25 min.

The following examples in the tables were prepared by the same method as described in Example W-179. By prep _{HPLC (CH 3 CN / H 2} O / NH 4 OAc) and the resulting product is purified to obtain the corresponding free base forms thereof.

Example W-186

To 4,4'-bis(2-((2S,3S)-3-methylpyrrolidin-2-yl)-1H-imidazol-4-yl)-1,1'-biphenyltetrahydrochloride ( 15 mg, 0.025 mmol), 2-(4,4-difluoropiperidin-1-yl)-2-oxoacetic acid (10.17 mg, 0.053 mmol), HATU (20.01 mg, 0.053 mmol) in DMA (0.5 mL) DIEA (0.031 mL, 0.175 mmol) was added to the mixture. The resulting pale yellow solution was stirred at room temperature for 2 hours. By prep _{HPLC (CH 3 CN / H 2} O / NH 4 OAc) system direct reaction mixture was purified to give examples of W-186. LC / MS (Condition W-2): [M + H] + 803.4, R t = 1.66min.

Example W-187

Example W-187 was isolated during purification example W-186 and identified as the atropisomer of example W-186. LC / MS (Condition W-2): [M + H] + 803.4, R t = 1.66min.

Example W-188

Example W-188 was prepared by the same method as described in Synthesis Example W-186, except that 4,4-difluorocyclohexanecarboxylic acid was used instead. LC / MS (Condition W-2): [M + H] + 745.5, R t = 1.54min.

Example W-189

To 4,4'-bis(2-((S)-pyrrolidin-2-yl)-1H-imidazol-4-yl)-1,1'-biphenyltetrahydrochloride (30 mg, 0.053 mmol), Add DIEA to a mixture of 2-(4,4-difluoropiperidin-1-yl)-2-oxoacetic acid (21.33 mg, 0.110 mmol), HATU (42.0 mg, 0.110 mmol) in EtOAc (1 mL) (0.064 mL, 0.368 mmol). The resulting pale yellow solution was stirred at room temperature for 2 hours. By prep _{HPLC (CH 3 CN / H 2} O / NH 4 OAc) system direct reaction mixture was purified to give examples of W-189. LC / MS (Condition W-2): [M + H] + 775.3, R t = 1.46min.

By (1S, 1'S)-1,1'-(4,4'-([1,1'-biphenyl]-4,4'-diyl by using the procedure described for Synthesis Example N-28 Bis(1H-imidazole-4,2-diyl))bis(2,2-dimethylpropan-1-amine) four The following examples were prepared for the hydrochloride salt and the appropriate starting materials.

*Example P-198: ¹ H NMR (500 MHz, methanol - d ₄ ) δ ppm -0.03-0.06 (m, 4 H) 0.29 - 0.37 (m, 2 H) 0.41 - 0.49 (m, 2 H) 0.67 - 0.77 (m, 2 H) 1.13 (s, 18 H) 1.73 (s, 6 H) 1.78 (dd, J = 14.19, 7.32 Hz, 2 H) 1.89 (dd, J = 14.27, 6.48 Hz, 2 H) 2.31 ( Wufeng, J = 7.71 Hz, 4 H) 4.00 (br.s., 4 H) 4.19 (br.s., 4 H) 7.87-7.92 (m, 8 H) 7.93 (s, 2 H).

By using the procedure described for Synthesis Example N-28, from (1S, 1'S)-(4,4'-([1,1'-biphenyl]-4,4'-diyl) bis (1H- The following examples were prepared for imidazole-4,2-diyl))bis((1-methylcyclopropyl)methylamine) tetrahydrochloride and the appropriate starting materials (caps).

Example Y-85:

To an (S)-2-((t-butoxycarbonyl)amino)-3,3-dimethylbutyric acid (3.2 g, 13.84 mmol) and DIPEA (2.4 mL, 13.74 mmol) To a solution in acetonitrile (25 mL) was added 2-bromo-1-(4-bromophenyl)ethanone (3.5 g, 12.59 mmol). The suspension was stirred at room temperature for 2 hours. The reaction mixture was diluted with EtOAc, and washed with saturated aqueous NaHCO _3, NH ₄ Cl, brine, washed with water, dried (MgSO ₄₎ and concentrated to give (S) -2 - ((tert-butoxy carbonyl) amino) - 2-(4-Bromophenyl)-2-oxoethyl ester of 3,3-dimethylbutanoic acid (5.39 g, 100%). _{^{1 H NMR (400MHz, CDCl 3}} ) δ 7.82-7.76 (m, 2H), 7.69-7.61 (m, 2H), 5.44 (s, 1H), 5.25 (d, J = 16.3Hz, 1H), 5.13 (d , J = 9.5 Hz, 1H), 4.25 (d, J = 9.5 Hz, 1H), 1.46 (s, 9H), 1.11 (s, 9H).

(S)-2-((Tertibutoxycarbonyl)amino)-3,3-dimethylbutyric acid 2-(4-bromophenyl)-2-oxoethyl ester (5.39 g, 12.59 mmol) and NH ₄ OAc (9.70g, 126mmol) of the mixture was fed into the sealed vial, and heated to 135 deg.] C, for 18 h. The reaction mixture was cooled, diluted with EtOAc, washed with NaHCO _3, brine, dried (MgSO ₄₎ and concentrated. The residue was purified by flash chromatography to give (S)-(1-(5-(4-bromophenyl)-1H-imidazol-2-yl)-2,2-dimethylpropyl) carbamic acid Third butyl ester (2.8 g, 54%). LC / MS (conditions _{YT-1): R t =} 2.804min; LC / MS: C 19 H 27 BrN 3 O 2 Calculated: 408.13; ^{Found: 408.2 [M + H] +} .

(S)-(1-(5-(4-Bromophenyl)-1H-imidazol-2-yl)-2,2-dimethylpropyl)carbamic acid tert-butyl ester (2.8 g, 6.86 Ment), KOAc (1.7 g, 17.32 mmol) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-linked (1,3,2-di Oxyboron ) Mixture (3.5g, 13.78mmol) in dioxane (30mL) was purged with in the N ₂ 15 minutes followed by addition of tetrakis (triphenylphosphine) palladium (0) (0.4g, 0.346mmol) , and then N ₂ Purify for 5 minutes. The reaction mixture was stirred at 80 ° C for 18 hours. The solvent was evaporated, and the residue was dissolved in DCM and water and the organic layer was washed with saturated NaHCO _3, dried (Na ₂ SO _4), concentrated and purified (0-100% EtOAc / Hexane) on Biotage 80g column, (S)-(2,2-Dimethyl-1-(5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaboride) was obtained as a brown foam 3-Butyl)phenyl)-1H-imidazol-2-yl)propyl)carbamic acid tert-butyl ester (3.0 g, 96%).

To (S)-2-(4-(4-bromophenyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylic acid benzyl ester (1.2 g, 2.81 mmol) and (2,2-dimethyl -1-(5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaboron) NaHCO ₃ was added to a solution of 2-methyl)phenyl)-1H-imidazol-2-yl)propyl)carbamate (1.8 g, 3.95 mmol) in DME (20 mL) and water (10 mL) 1 g, 11.90 mmol). The reaction mixture was degassed for 5 minutes and then filled with N _2, and was added tetrakis (triphenylphosphine) palladium (0) (0.05g, 0.043mmol) , degassed and refilled with N _2. Under N ₂ the reaction mixture was heated to 80 ℃, 16 h, then it was diluted with EtOAc, and washed with NaHCO ₃ (2 ×), washed with brine, dried (MgSO _4), concentrated and silica gel by FCC (80g, EtOAc /hexane: 20% to 100%) purified to give (S)-2-(4-(4'-(2-((S))-1-((t-butoxycarbonyl)amino)-2) ,2-dimethylpropyl)-1H-imidazol-4-yl)-[1,1'-biphenyl]-4-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylic acid benzoate Ester (1.6 g, 84%). LC / MS (conditions _{YT-1): R t =} 2.636min; C 40 H 47 N 6 O 4 Calculated: 675.37; ^{Found: 675.45 [M + H] +} .

In an ice bath, to (S)-2-(4-(4'-(2-((S)-1-((t-butoxycarbonyl))amino)-2,2-dimethylpropane Benzyl-1H-imidazol-4-yl)-[1,1'-biphenyl]-4-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylic acid benzyl ester (1.6 g, 2.371 mmol) HCl (10 mL, 40.0 mmol, 4N in dioxane) was added to a solution in DCM (20 mL). The reaction mixture was stirred at room temperature for 2 hours and concentrated to give (S)-2-(4-(4)-(2-(())) Propyl)-1H-imidazol-4-yl)-[1,1'-biphenyl]-4-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylic acid benzyl ester trihydrochloride . LC / MS (conditions _{YT-1): R t =} 2.477min; C 35 H 39 N 6 O 2 Calculated: 575.31; ^{Found: 575.34 [M + H] +} .

To (S)-2-(4-(4'-(2-((S)-1-amino-2,2-dimethylpropyl)-1H-imidazol-4-yl)-[1, 1'-Biphenyl]-4-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylic acid benzyl ester trihydrochloride (0.34 g, 0.497 mmol) and (R)-5,5-di To a mixture of fluoro-2-methyltetrahydro-2H-pyran-2-carboxylic acid (0.1 g, 0.555 mmol) in EtOAc (2 mL) 0.2 g, 0.527 mmol). The reaction mixture was stirred at rt for 45 min then diluted with EtOAc EtOAc The residue was diluted with EtOAc, and washed with aqueous NaHCO _3, washed with brine, dried (MgSO _4), and concentrated on a 25g silica gel cartridge: purified (EtOAc / hexane 20-100%), to give (S) -2- ( 4-(4'-(2-((S)-1-((R)-5,5-difluoro-2-methyltetrahydro-2H-pentan-2-carboxamido)-2, 2-dimethylpropyl)-1H-imidazol-4-yl)-[1,1'-biphenyl]-4-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylic acid benzyl ester (0.21 g, 57%). LC / MS (conditions _{YT-1): R t =} 2.661min; C 42 H 47 F 2 N 6 O 4 Calculated: 737.36; ^{Found: 737.4 [M + H] +} .

(S)-2-(4-(4'-(2-((S)-1-((R)-5,5-difluoro-2-methyltetrahydro-2H-pentan-2-) Methionido)-2,2-dimethylpropyl)-1H-imidazol-4-yl)-[1,1'-biphenyl]-4-yl)-1H-imidazol-2-yl)pyrrole -carboxylic acid benzyl ester (0.21g, 0.285mmol) and _{K 2 CO 3 (0.05g, 0.362mmol} ) mixture (5mL) in MeOH in the degassed and refilled with N _2. Pd/C (0.06 g, 0.056 mmol) and 2 drops of water were added, and the mixture was stirred under H ₂ (balloon pressure) for 2 hr. The solid was filtered off and the filtrate was concentrated to dry. 4M HCl/dioxane (0.5 ml, 4 M) and toluene (2 ml) were added to the residue, and the mixture was concentrated to dry to afford (R)-N-((S)-2,2 -Dimethyl-1-(4-(4'-(2-((S)-pyrrolidin-2-yl)-1H-imidazol-4-yl)-[1,1'-biphenyl]-4 -yl)-1H-imidazol-2-yl)propyl)-5,5-difluoro-2-methyltetrahydro-2H-pentan-2-carboxamide trihydrochloride (0.2 g, 100% ). LC / MS (conditions _{YT-1): R t =} 2.445min; C 34 H 41 F 2 N 6 O 2 Calculated: 603.33; ^{Found: 603.3 [M + H] +} .

In an ice bath, to (R)-N-((S)-2,2-dimethyl-1-(4-(4'-(2-((S)-pyrrolidin-2-yl))) 1H-imidazol-4-yl)-[1,1'-biphenyl]-4-yl)-1H-imidazol-2-yl)propyl)-5,5-difluoro-2-methyltetrahydro- DIPEA was added to a mixture of 2H-pyran-2-carbamide trihydrochloride (33 mg, 0.046 mmol) and 5-chloroisoquinoline-1-carboxylic acid (10.8 mg, 0.052 mmol) in DCM (1 mL) 0.15 mL, 0.859 mmol) and HBTU (20 mg, 0.053 mmol). The reaction mixture was stirred at room temperature for 1 h and then diluted with MeOH (1 mL). The volatiles were removed and the residue was purified by HPLC to afford (R)-N-((S)-1-(4-(4)-(2-((S)-1-(5-chloroisoquinoline) -1-carbonyl)pyrrolidin-2-yl)-1H-imidazol-4-yl)-[1,1'-biphenyl]-4-yl)-1H-imidazol-2-yl)-2,2- Dimethylpropyl)-5,5-difluoro-2-methyltetrahydro-2H-pentan-2-carboxamide (0.014 g, 38%); Compound Y-85.

Similar to Example Y-85, the examples described in the table below were prepared by using a suitable cap precursor.

Example Y-97

In an ice bath, to (1S,1'S)-1,1'-(5,5'-([1,1'-biphenyl]-4,4'-diyl) bis(1H-imidazole-5, 2-Diyl)) bis(2,2-dimethylpropan-1-amine) tetrahydrochloride (80 mg, 0.133 mmol) and DIPEA (0.2 mL, 1.145 mmol). Racemic cis-2-hydroxy-1-methylcyclohexanecarboxylic acid (60 mg, 0.379 mmol, racemate) and tetrafluoroborate 2-(1H-benzo[d][1,2,3] Triazol-1-yl)-1,1,3,3-tetramethyliso (95 mg, 0.296 mmol). The reaction mixture was stirred at room temperature for 1 hour. Diluted with MeOH (1 mL), solvent was removed and purified by HPLC to give product as a mixture of diastereomers with a ratio of 1:2:1. The analytical data is shown in the table below.

The examples described in the table below were prepared from the appropriate precursors according to the procedure described for Example Y-97.

The examples described in the table below were prepared from the appropriate precursors according to the procedure described for Example Y-97.

Examples Y-104, Y-105 and Y-106

In an ice bath, to (1S,1'S)-1,1'-(5,5'-([1,1'-biphenyl]-4,4'-diyl) bis(1H-imidazole-5, 2-Diyl))bis(2,2-dimethylpropan-1-amine) tetrahydrochloride (40 mg, 0.066 mmol), racemic trans-2-hydroxy-1-methylcyclohexanecarboxylic acid (25 mg, 0.158 mmol) in a mixture of DCM (2 mL), 2-(1H-benzo[d][1,2,3]triazol-1-yl)-1,1,3, 3-tetramethyliso (43 mg, 0.134 mmol) and DIPEA (0.1 mL, 0.573 mmol). The reaction mixture was stirred at room temperature for 2 hours. Diluted with MeOH (2 mL), solvent was removed and purified by reverse phase preparative HPLC to give three products. The analytical data is shown in the table below.

The examples described in the table below were prepared from the appropriate precursors according to the procedure described above for Example Y-104.

The examples described in the table below were prepared from the appropriate precursors according to the procedure described above for Example Y-104.

The examples described in the table below were prepared from the appropriate precursors according to the procedure described above for Example Y-104.

Example Y-116

Example Y-116 was prepared according to the procedure described for Synthesis Example Y-89.

Example N-135

According to the procedure described for Preparation Example N-28, (1S,1'S)-1,1'-(4,4'-(biphenyl-4,4'-diyl)bis(1H-imidazole-4, Example 2-N-135A to N-135C (Trifluoroethylene) was prepared in a similar manner from 2-diyl))bis(2,2-dimethylpropan-1-amine)tetrahydrochloride and cap N-14. Acetate). Preparative HPLC (Water Sunfire 30 x 100 mm column, gradient of 5-45% B for 20 minutes. A = H ₂ O / CH ₃ CN / TFA 90: 10: 0.1, B = CH ₃ CN / H ₂ O /TFA 90:10:0.1) Separation of the three diastereomers.

Example N-135A (Stereoisomer-1): LC/MS (Cond. N-1): [M+H] ⁺ 865.6, RT = 3.628 min. ¹ H NMR (400MHz, CDCL ₃ ) δ ppm 7.95-7.79 (m, 10H), 7.39 (dd, J = 7.7, 1.4 Hz, 2H), 7.33-7.22 (m, 2H), 7.03-6.87 (m, 4H) ), 5.63 (s, 2H), 5.00 (s, 2H), 3.85 (s, 6H), 1.23-1.04 (m, 20H), 0.87-0.70 (m, 4H), 0.31 (ddd, J = 9.3, 6.9) , 4.4 Hz, 2H).

Example N-135B (Stereoisomer-2): LC/MS (Cond. N-1): [M+H] ⁺ 865.6, RT = 3.616 min. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 7.97-7.78 (m, 10H), 7.50-7.36 (m, 2H), 7.31 (qd, J = 7.8, 1.6 Hz, 2H), 7.07-6.85 (m, 4H), 5.63 (s, 1H), 5.33 (s, 1H), 5.01 (s, 1H), 4.91 (s, 1H), 3.86 (s, 6H), 1.21-1.06 (m, 20H), 1.05-0.97 (m, 1H), 0.85-0.72 (m, 3H), 0.63-0.54 (m, 1H), 0.31 (ddd, J = 9.5, 6.9, 4.4 Hz, 1H).

Example N-135C (Stereoisomer-3): LC/MS (Cond. N-1): [M+H] ⁺ 865.6, RT = 3.659 min. _{^{1 H NMR (400MHz, CD 3}} OD) δ ppm 7.95-7.82 (m, 10H), 7.43 (dd, J = 7.7,1.4Hz, 2H), 7.35-7.28 (m, 2H), 7.05-6.93 (m, 4H), 5.32 (s, 2H), 4.90 (s, 2H), 3.86 (s, 6H), 1.15 - 1.07 (m, 20H), 1.05 - 0.98 (m, 2H), 0.81 - 0.71 (m, 2H) , 0.65-0.54 (m, 2H).

Example N-137

According to the procedure described for Preparation Example N-28, (1S,1'S)-1,1'-(4,4'-(biphenyl-4,4'-diyl)bis(1H-imidazole-4, 2-N-137) to bis(2,2-dimethylpropan-1-amine) tetrahydrochloride and cap N-16 as starting materials, in a similar manner to prepare examples N-137A to N-137C (trifluoro Acetate). Preparative HPLC (Water Sunfire 30 x 100 mm column, gradient of 5-45% B for 20 minutes. A = H ₂ O / CH ₃ CN / TFA 90: 10: 0.1, B = CH ₃ CN / H ₂ O /TFA 90:10:0.1) Separation of the three diastereomers.

Example N-137A (Stereoisomer-1): LC/MS (Cond. N-1): [M+H] ⁺ 833. _{^{1 H NMR (400MHz, CD 3}} OD) δ ppm 7.98-7.79 (m, 10H), 7.39-7.22 (m, 10H), 5.09 (s, 2H), 4.74 (s, 2H), 3.48 (s, 6H) , 1.22-1.07 (m, 19H), 1.03-0.85 (m, 5H), 0.59 (ddd, J = 9.5, 6.7, 4.4 Hz, 2H).

Example N-137B (Stereoisomer-2): LC/MS (Cond. N-1): [M+H] ⁺ 833.46, RT = 3.67 min. _{^{1 H NMR (400MHz, CD 3}} OD) δ ppm 8.02-7.77 (m, 10H), 7.51-7.23 (m, 10H), 5.09 (s, 1H), 4.84 (s, 1H), 4.73 (s, 1H) , 4.46(s,1H), 3.61(s,3H), 3.47(s,3H),1.35-1.24(m,1H),1.20-1.09(m,10H),1.07-0.81(m,14H),0.60 (ddd, J = 9.3, 6.8, 4.4 Hz, 1H).

Example N-137C (Stereoisomer-3): LC/MS (Cond. N-1): [M+H] ⁺ 833.46, RT = 3.69 min. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 7.96-7.79 (m, 10H), 7.48-7.30 (m, 10H), 4.82 (s, 2H), 4.44 (s, 2H), 3.61 (s, 6H) , 1.38-1.27 (m, 2H), 1.05-0.93 (m, 20H), 0.93-0.80 (m, 4H).

Example N-139

According to the procedure described for Preparation Example N-28, (1S,1'S)-1,1'-(4,4'-(biphenyl-4,4'-diyl)bis(1H-imidazole-4, Example 2-N-139A to N-139C (Trifluoroethylene) was prepared in a similar manner from 2-diyl))bis(2,2-dimethylpropan-1-amine)tetrahydrochloride and cap N-17. Acetate). Preparative HPLC (Water Sunfire 30 x 100 mm column, gradient of 0-25% B for 25 minutes. A = H ₂ O / CH ₃ CN / TFA 90: 10: 0.1, B = CH ₃ CN / H ₂ O /TFA 90:10:0.1) Separation of the three diastereomers.

Example N-139A (Stereoisomer-1): LC/MS (Cond. N-1): [M+H] ⁺ 665.35, RT = 3.064 min. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 7.94 (s, 2H), 7.92-7.79 (m, 8H), 5.17 (s, 2H), 4.60 (d, J = 9.5 Hz, 1H), 4.48 (d) , J = 9.3 Hz, 1H), 4.37 (d, J = 9.5 Hz, 1H), 4.25 (d, J = 9.3 Hz, 1H), 1.39 (d, J = 2.0 Hz, 6H), 1.7-1.07 (m , 18H).

Example N-139B (Stereoisomer-2): LC/MS (Cond. N-1): [M+H] ⁺ 665.45, RT=3.005 min. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 7.95 (d, J = 6.3 Hz, 2H), 7.92-7.79 (m, 8H), 5.18 (d, J = 3.3 Hz, 2H), 4.67 (d, J = 9.3 Hz, 0.5 H), 4.58 (dd, J = 15.6, 9.5 Hz, 1H), 4.48 (d, J = 9.3 Hz, 0.5H), 4.38 (dd, J = 9.5, 7.5 Hz, 1H), 4.26 (dd, J = 9.4, 7.4 Hz, 1H), 1.39 (d, J = 2.0 Hz, 3H), 1.31 (d, J = 2.0 Hz, 3H), 1.11 (d, J = 7.8 Hz, 18H).

Example N-139C (Stereoisomer-3): LC/MS (Cond. N-1): [M+H] ⁺ 665.45, RT = 3.018 min. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 7.96 (s, 2H), 7.92-7.84 (m, 8H), 5.20-5.17 (m, 2H), 4.67 (d, J = 9.3 Hz, 1H), 4.56 (d, J = 9.5 Hz, 1H), 4.39 (d, J = 9.5 Hz, 1H), 4.27 (d, J = 9.3 Hz, 1H), 1.31 (d, J = 2.0 Hz, 6H), 1.14-1.06 (m, 18H).

From (1S,1'S)-1,1'-(4,4'-([1,1'-biphenyl]-4,4'-diyl) bis(1H-imidazole-4,2-diyl) Bis(2,2-dimethylpropan-1-amine) tetrahydrochloride and appropriate starting materials The following examples were prepared and purified according to the procedure described for Preparation Example N-135.

Example N-147

To a reaction mixture of EtOAc (EtOAc) (EtOAc) The reaction mixture was stirred at room temperature for 12 hours. The reaction was concentrated, then diluted with EtOAc, washed with 1N HCl and saturated NaCl, dried over anhydrous Na ₂ SO ₄ dried and concentrated to give examples of N-147. Example N-147: LC/MS (Cond. N-1): [M+H] ⁺ 765.5, RT=3.486 min.

From (1S,1'S)-1,1'-(4,4'-([1,1'-biphenyl]-4,4'-diyl) bis(1H-imidazole-4,2-diyl) The following examples were prepared by bis(2-methylpropan-1-amine) tetrahydrochloride and appropriate starting materials, and according to the needle The procedure described in Preparation Example N-135 was purified.

From (1S,1'S)-(4,4'-([1,1'-biphenyl]-4,4'-diyl)bis(1H-imidazole-4,2-diyl))bis (1 -Methylcyclopropyl)methylamine)tetrahydrochloride and appropriate starting materials The following examples were prepared and purified according to the procedure described for Preparation Example N-135.

Example L-97

Example L-97 step a

Starting with the commercially available dicyclohexylamine (S)-3-tert-butoxy-2-(t-butoxycarbonylamino)propionate by following the procedure described in Example Y-68 The hydrochloride salt of Example L-97, step a, was synthesized. Cap Y-8b (34.7 mg, 0.193 mmol), Example L-90 Step a (57 mg, 0.094 mmol) and DIEA (0.115 mL, 0.658 mmol) in DMF (1.5 mL) solution, and the resulting solution was stirred at room temperature for 3 hours, followed by _{(CH 3 CN / H 2 O} / NH 4 OAc) was purified by preparative HPLC, to give examples of -97 (33.6mg). LC / MS (conditions of PS-3): [M + H] + 785.36, R t = 4.07min. ^{1 H NMR (500MHz, DMSO-} d 6) δ 12.04 (br.s., 2H), 7.79 (d, J = 7.9Hz, 6H), 7.67 (br.s., 6H), 5.02 (dd, J = 8.5, 4.6 Hz, 2H), 4.09 (br.s., 2H), 3.91 (br.s., 2H), 3.84 (br.s., 2H), 3.22 (s, 6H), 2.30 (br.s) .2H),2.10(br.s.,2H),1.88-1.75(m,2H),1.73-1.60(m,2H),1.41(s,6H),1.04(d, J =6.1Hz,6H ).

Examples L-91 to L-93 were synthesized by following the method described in Example L-97.

By using the procedure described for Synthesis Example L-97, from (1R, 1'R)-1,1'-(4,4'-([1,1'-biphenyl]-4,4'- The following examples were prepared for the dibasic)bis(1H-imidazole-4,2-diyl))bis(2-methoxyethylamine) tetrahydrochloride and the appropriate starting materials (caps). By prep _{HPLC (CH 3 CN / H 2} O / NH 4 OAc) The resulting product was purified and obtained in free base form.

Example L-106

Example L-106 step a

Pure DIEA (0.662 mL, 3.79 mmol) was added to 1,1'-([1,1'-biphenyl]-4,4'-diyl) bis(2-bromoethyl ketone) at 0 °C ( 0.683g, 1.724mmol) and (1R, 2S) -2 - ( ( tert-butoxy carbonyl) amino) cyclopentanecarboxylic acid (0.83g, 3.62mmol) in CH ₃ CN (15mL) and CHCl ₃ (10mL In the stirred suspension. The suspension was stirred overnight at room temperature and during this time it became a beige suspension. The solvent was removed under reduced pressure, and the residue was dissolved in CH ₂ Cl ₂ (100mL), and washed with water (50 mL), washed with 10% H ₃ PO ₄ and brine (50 mL), dried (MgSO _4), filtered, and Concentrate to give an off-white solid. The residue was purified via EtOAc (EtOAc EtOAcEtOAcEtOAcEtOAc ). LC / MS (Condition L-1): [M + Na] + 715.50, R t = 4.03min. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 8.07 (d, J = 8.5 Hz, 4H), 7.96 (d, J = 8.5 Hz, 4H), 6.72 (d, J = 8.2 Hz, 2H), 5.50 ( d, J = 16.4 Hz, 2H), 5.38 (d, J = 17.0 Hz, 2H), 4.19 - 4.08 (m, 2H), 3.02 (q, J = 7.3 Hz, 2H), 2.00-1.91 (m, 1H) ), 1.90 - 1.74 (m, 6H), 1.65-1.48 (m, 4H), 1.38 (s, 18H). ^{13 C NMR (126MHz, DMSO-} d 6) δ 192.7 (s, 2C), 172.4 (s, 2C), 155.0 (br.s., 2C), 143.6 (s, 2C), 133.5 (s, 2C), 128.5 (s, 4C), 127.5 (s, 4C), 77.6 (s, 2C), 66.3 (s, 2C), 53.8 (br.s., 2C), 47.1 (s, 2C), 30.8 (s, 2C) ), 28.2 (s, 6C), 26.4 (br.s., 2C), 21.5 (s, 2C).

Example L-106 step b

At 110 ℃, the mixture of Example L-106 step a (0.83g, 1.198mmol), NH 4 OAc (1.847g, 23.96mmol) and imidazole (0.489g, 7.19mmol) in xylene (30mL) was stirred in 20 of hour. After cooling to room temperature, diluted with EtOAc (25mL) samples, and washed with NaHCO ₃ and brine, dried (MgSO _4), filtered, and concentrated to give a brownish oily solid. The residue was purified via EtOAc (EtOAc: EtOAc:EtOAc) LC / MS (Condition L-1): [M + H] + 653.50, R t = 2.15min. ^{1 H NMR (500MHz, DMSO-} d 6) δ 12.06-11.72 (m, 2H), 7.85-7.78 (m, 4H), 7.66 (d, J = 7.9Hz, 6H), 7.53 (br.s., 2H ), 6.63 (d, J = 6.5 Hz, 2H), 4.05 (d, J = 9.9 Hz, 2H), 3.26 (d, J = 6.5 Hz, 2H), 2.14 - 2.03 (m, 3H), 2.01-1.87 (m, 6H), 1.86-1.78 (m, J = 6.9 Hz, 3H), 1.77-1.67 (m, 4H), 1.64-1.53 (m, 3H), 1.27 (s, 18H).

Example L-106 step c

Add HCl (4N in dioxane) (1 mL, 32.9 mmol) to EtOAc (EtOAc m. Liquid for 3 hours. The solvent was removed under reduced pressure and the residue was dried with Et ₂ O (15 mL). Slightly yellow solid was filtered and washed with Et ₂ O to give example L-106 of step c tetrahydrochloride (72.7% yield). It was used without further purification. LC / MS (Condition L-2): [M + H] + 453.30, R t = 0.96min. ^{1 H NMR (500MHz, DMSO-} d 6) δ 8.48 (br.s., 4H), 8.19 (br.s., 2H), 8.09 (d, J = 8.0Hz, 4H), 7.94 (d, J = 8.2 Hz, 4H), 4.09 (br.s., 2H), 3.84 (br.s., 2H), 2.44 (br.s., 2H), 2.29-2.11 (m, 4H), 2.07-1.96 (m , 2H), 1.95-1.86 (m, 2H), 1.82-1.69 (m, 2H).

Treatment of 4,4-difluorocyclohexanecarboxylic acid (22.5 mg, 0.137 mmol) with HATU (53 mg, 0.140 mmol), mp. The solution in (1.5 mL) was stirred at room temperature for 3 hours. Followed by prep _{HPLC (CH 3 CN / H 2} O / NH 4 OAc) was purified to give Example L-106 (34.4mg). LC / MS (conditions of PS-3): [M + H] + 745.40, R t = 2.68min. ^{1 H NMR (500MHz, DMSO-} d 6) δ 12.06-11.67 (m, 2H), 7.81 (br.s., 3H), 7.67 (br.s., 6H), 7.49 (br.s., 1H) , 4.34 (br.s., 2H), 3.31-3.25 (m, 2H), 2.16 (s, 4H), 2.04-1.94 (m, 4H), 1.94-1.85 (m, 5H), 1.82-1.69 (m , 5H), 1.67-1.44 (m, 10H), 1.31 (d, J = 11.9 Hz, 2H).

Example L-107

Example L-107 was prepared according to the method described in Preparation Example L-106 using pivalic acid. LC / MS (conditions of PS-3): [M + H] + 621.38, R t = 2.97min. ^{1 H NMR (500MHz, DMSO-} d 6) δ 12.21-11.88 (m, 2H), 7.95 (s, 1H), 7.84 (br.s., 4H), 7.68 (d, J = 5.8Hz, 4H), 7.56 (br.s., 3H), 4.23 (br.s., 2H), 2.17-2.07 (m, 2H), 2.05-1.89 (m, 4H), 1.85-1.69 (m, 4H), 1.60 (dd , J = 11.6, 7.9 Hz, 2H), 0.96 (br.s., 18H).

Examples L-108 through L-109 were synthesized by following the procedure described in Example L-106 and suitably synthesizing the precursor.

Examples L-110 through L-111 were synthesized by following the procedure described in Example L-106 and suitably synthesizing the precursor.

Examples L-112 through L-115 were synthesized by following the procedure described in Example L-106 and suitably synthesizing the precursor.

Example L-116

To (1S,1'S)-1,1'-(4,4'-([1,1'-biphenyl]-4,4'-diyl)bis(1H-imidazole-4,2-diyl) Add DIEA (0.153 mL, 0.876 mmol) and dimethyl to a suspension of bis(2,2-dimethylpropan-1-amine) (50 mg, 0.109 mmol) in DCM (3 mL) Chloramine sulfonium chloride (0.026 mL, 0.241 mmol). The reaction mixture was stirred at room temperature for 24 hours, followed by containing MeOH (1mL) 2N NH ₃ of treatment, and stirred for a further 16 hours at room temperature. Then the mixture was purified by prep. HPLC _{(CH 3 CN / H 2 O} / NH 4 OAc), to give examples -166 (9.7mg). LC / MS (conditions of PS-3): [M + H] + 671.31, R t = 2.97min. ^{1 H NMR (500MHz, DMSO-} d 6) δ 12.30-11.91 (m, 2H), 7.86 (br.s., 3H), 7.68 (br.s., 5H), 7.60 (br.s., 2H) , 7.41 - 7.23 (m, 2H), 4.12 (br.s., 2H), 2.39 (br.s., 12H), 0.95 (br.s., 18H).

By (1S, 1'S)-1,1'-(4,4'-([1,1'-biphenyl]-4,4'-diyl by using the procedure described for Synthesis Example L-116 The following examples were prepared for the bis(1H-imidazole-4,2-diyl))bis(2,2-dimethylpropan-1-amine) tetrahydrochloride and the appropriate starting materials. By prep _{HPLC (CH 3 CN / H 2} O / NH 4 OAc) purified product was obtained.

By (1S, 1'S)-1,1'-(4,4'-([1,1'-biphenyl]-4,4'-diyl by using the procedure described for Synthesis Example L-97 The following examples were prepared for the bis(1H-imidazole-4,2-diyl))bis(2,2-dimethylpropan-1-amine) tetrahydrochloride and the appropriate starting materials. By prep _{HPLC (CH 3 CN / H 2} O / NH 4 OAc) purified product was obtained.

By using the procedure described for Synthesis Example L-97, from 4,4'-bis(2-((S)-pyrrolidin-2-yl)-1H-imidazol-4-yl)-1,1' The following examples were prepared for the biphenyl tetrahydrochloride and the appropriate starting materials. By prep _{HPLC (CH 3 CN / H 2} O / NH 4 OAc) purified product was obtained.

By using the procedure described for Synthesis Example L-97, from 4,4'-bis(2-((2S,3S)-3-methylpyrrolidin-2-yl)-1H-imidazol-4-yl The following examples were prepared for-1,1'-biphenyl tetrahydrochloride and appropriate starting materials. By prep _{HPLC (CH 3 CN / H 2} O / NH 4 OAc) purified product was obtained.

By using the procedure described for Synthesis Example L-97, from 4,4'-bis(2-((2S,3R)-3-methylpyrrolidin-2-yl)-1H-imidazol-4-yl The following examples were prepared for-1,1'-biphenyl tetrahydrochloride and appropriate starting materials. By prep _{HPLC (CH 3 CN / H 2} O / NH 4 OAc) purified product was obtained.

By using the procedure described for Synthesis Example L-97, from 4,4'-bis(2-((1R,3S,4S)-2-azabicyclo[2.2.1]heptan-3-yl)- The following examples were prepared for 1H-imidazol-4-yl)-1,1'-biphenyl tetrahydrochloride and appropriate starting materials. By prep _{HPLC (CH 3 CN / H 2} O / NH 4 OAc) purified product was obtained.

Examples L-141a, L-141b, and L-141c

Example L-141 Step a (cis-racemic)

Tri-n-butylphosphine (2.465 mL, 9.99 mmol) was added to (cis)-hexahydroisobenzofuran-1,3-dione (1.54 g, 9.99 mmol) and phenylmethanol (1.551 mL, 14.98 mmol) in the in CH ₃ CN (30mL) solution, and the resulting solution was stirred for 24 hours at room temperature. The reaction mixture was filtered through a plug of hydrazine and washed with hexanes containing 20% EtOAC to remove phosphine and phosphine oxide impurities. The mixture was then dissolved in EtOAc and the residue was concentrated under reduced pressure. The remaining residue was dissolved in CH ₂ Cl _2, and extracted with _{5% NaHCO 3 (2 × 100mL} ). The sodium bicarbonate extract was washed with Et ₂ O (2×50 mL) and acidified to pH = 3 with concentrated hydrochloric acid with vigorous stirring to remove precipitated CO ₂ . Followed by _{CH 2 Cl 2 (3 × 100mL} ) and the aqueous layer was extracted, and dried (MgSO ₄₎ the organic layers were combined, filtered, and concentrated to give L-141 corresponds to an example of step a clear oil (0.58 g of), It was used without further purification. ^{1 H NMR (500MHz, DMSO-} d 6) δ 12.21 (s, 1H), 7.39-7.29 (m, 5H), 5.10 (d, J = 12.8Hz, 1H), 5.05 (d, J = 12.8Hz, 1H ), 2.87-2.74 (m, 2H), 1.97-1.81 (m, 2H), 1.79-1.72 (m, 1H), 1.72-1.63 (m, 1H), 1.45-1.29 (m, 4H). ^{13 C NMR (126MHz, DMSO-} d 6) δ 174.6,173.0,136.4,128.3 (s, 2C), 127.8,127.5 (s, 2C), 65.2,41.6 (s, 2C), 26.0,25.7,23.3,23.2 .

Example L-141, step b (cis racemate)

Under nitrogen, (2.211mL, 2.211mmol) dropwise Examples L-141 step a (0.58g, 2.211mmol) in THF (10mL) was treated in the BH ₃ .THF (1M), while cooling in an intermittent The temperature is maintained at 20-30 °C. After the addition was completed, the mixture was stirred at room temperature for 16 hours. Water (3 mL) was added dropwise to decompose any excess borane and the solvent was removed in vacuo. The residue was diluted with water (10 mL) and EtOAc was evaporated. The organic layer was dried (MgSO _4), filtered and concentrated to give L-141 corresponds to an example of the oil of step b (0.4 g of), which was used without further purification. LC / MS (Condition L-1): [M + H] + 249.15, R t = 2.65min. ¹ H NMR (500MHz, CDCL ₃ ) δ 7.43-7.31 (m, 5H), 5.16 (d, J = 12.1 Hz, 1H), 5.13 (d, J = 12.5 Hz, 1H), 3.70-3.63 (m, 1H) ), 3.62-3.56 (m, 1H), 2.07 (ddd, J = 10.0, 7.9, 3.8 Hz, 1H), 1.96-1.85 (m, 1H), 1.73-1.57 (m, 4H), 1.50-1.38 (m , 2H).

Example L-141, step c (cis-racemic)

The TBDMS-Cl (0.267g, 1.772mmol) was added to Examples L-141 step b (0.4g, 1.611mmol) and Et ₃ N (0.269mL, 1.933mmol) in CH ₂ Cl ₂ (10mL) in the solution, Catalytic DMAP (0.039 g, 0.322 mmol) was then added. The resulting solution was stirred at room temperature for 48 hours, then washed with 10% KHSO ₄ with. The organic layer was dried (MgSO _4), filtered, and concentrated in vacuo, and via Biotage (10% EtOAc / hexanes; 25g column) to afford a residue. The clear oil (37.7%) corresponding to step c of Example L-141 was recovered. _{^{1 H NMR (500MHz, CD 3}} Cl) δ 7.40-7.29 (m, 5H), 5.13 (d, J = 12.3Hz, 1H), 5.08 (d, J = 12.5Hz, 1H), 3.62-3.54 (m, 2H), 2.79 (dt, J=6.5, 4.2 Hz, 1H), 1.99 (qt, J=7.8, 4.1 Hz, 1H), 1.92-1.83 (m, 1H), 1.82-1.73 (m, 1H), 1.67 -1.53 (m, 4H), 1.51-1.39 (m, 2H), 1.39-1.29 (m, 1H), 0.88 (s, 9H), 0.01 (s, 3H), 0.00 (s, 3H). ¹³ C NMR (126 MHz, CD ₃ Cl) δ 174.4, 136.3, 128.5 (s, 2C), 128.1 (s, 2C), 128.0, 65.7, 64.0, 41.9, 40.6, 26.9, 25.9 (s, 3C), 25.4, 23.6, 23.5, 18.3, -5.4, -5.5.

Example L-141, step d (cis-racemic)

The Pd / C (0.032g, 0.030mmol) was added to Examples L-141 step c (0.22g, 0.607mmol) (10mL ) in the solution in MeOH, and blowing the resulting suspension was washed (3 times) with N _2. The mixture was then placed under 1 atm H ₂ (balloon) and stirred at room temperature for 24 hours. The suspension was filtered through a pad of celite and the solvent was removed under vacuum. A viscous oil (74.4%) corresponding to step D of Example L-141 was recovered and used without further purification. ¹ H NMR (500 MHz, CD ₃ Cl) δ 3.65 (qd, J = 10.2, 7.5 Hz, 2H), 2.80-2.74 (m, 1H), 2.01 (qt, J = 7.8, 4.1 Hz, 1H), 1.96- 1.88 (m, 1H), 1.71-1.57 (m, 5H), 1.51-1.43 (m, 2H), 1.38-1.29 (m, 1H), 0.89 (s, 9H), 0.05 (s, 3H), 0.05 ( s, 3H). ¹³ C NMR (126 MHz, CD ₃ Cl) δ 179.9 (br.s., 1 C), 64.3 (br.s., 1 C), 41.9, 40.4, 26.8 (br.s., 1C), 25.9 (s, 3C) ), 25.6, 23.8 (br.s., 1C), 23.4, 18.3, -5.5 (s, 2C).

Example L-141, step e (cis cap, mixture of diastereomers)

Example L-141, step d (120 mg, 0.440 mmol), (1S, 1 'S)-1,1'-(4,4'-([1,1'-biphenyl]-) was treated with HATU (172 mg, 0.451 mmol). 4,4'-diyl)bis(1H-imidazole-4,2-diyl))bis(2,2-dimethylpropan-1-amine)tetrahydrochloride (129 mg, 0.215 mmol) and DIEA ( A solution of 0.263 mL, 1.504 mmol) in DMF (5 mL). (15mL) samples were diluted with EtOAc, and and washed with H ₂ O (10mL) and brine (10mL). The organic layer was then dried (MgSO _4), filtered and concentrated under reduced pressure. The viscous solid (100%) corresponding to step L of Example L-141 was recovered as a mixture of diastereomers and used for the next reaction without further purification.

Example L-141 Step e (0.1 g, 0.104 mmol) was dissolved in THF (3 mL). The resulting solution was stirred at room temperature for 4 hours, then the solvent was removed under vacuum. The residue was dissolved in MeOH (2mL) and _{(CH 3 CN / H 2 O} / NH 4 OAc) was purified by preparative HPLC, to give examples of L-141a, L-141b and L-141c (by eluting order).

Example L-141a (symmetric cap, diastereomer-1): LC/MS (Cond. L-1): [M+H] ⁺ 737.47, R _t = 3.05 min. ^{1 H NMR (500MHz, DMSO-} d 6) δ 12.31-11.87 (m, 2H), 7.94 (s, 1H), 7.87-7.76 (m, 5H), 7.68 (br.s., 4H), 7.53 (br .s., 2H), 4.87 (d, J = 9.5 Hz, 2H), 4.45 (br.s., 2H), 2.64 (br.s., 2H), 1.86 (br.s., 2H), 1.82 -1.65 (m, 4H), 1.61-1.45 (m, 4H), 1.36 (br.s., 4H), 1.26 (br.s., 4H), 0.93 (br.s., 18H).

Example L-141b (symmetric cap, diastereomer-2): LC/MS (Cond. L-1): [M+H] ⁺ 737.47, R _t = 3.14 min. ^{1 H NMR (500MHz, DMSO-} d 6) δ 12.31-11.86 (m, 2H), 7.94 (s, 1H), 7.88-7.77 (m, 5H), 7.68 (br.s., 4H), 7.56-7.29 (m, 2H), 4.88 (d, J = 7.9 Hz, 2H), 4.45 (br.s., 2H), 3.27 (br.s., 3H), 2.65 (br.s., 1H), 2.54 ( s, 1H), 1.86 (br.s., 1H), 1.74 (br.s., 6H), 1.55 (br.s., 4H), 1.41-1.31 (m, 4H), 1.26 (br.s. , 3H), 0.93 (br.s., 18H).

Example L-141c (symmetric cap, diastereomer-3): LC/MS (Cond. L-1): [M+H] ⁺ 737.47, R _t = 3.28 min. ^{1 H NMR (500MHz, DMSO-} d 6) δ 12.31-11.83 (m, 2H), 7.94 (s, 1H), 7.89-7.76 (m, 5H), 7.68 (br.s., 4H), 7.53 (br .s., 2H), 4.96-4.83 (m, 2H), 4.46 (br.s., 2H), 3.26 (br.s., 4H), 1.81-1.62 (m, 8H), 1.59-1.42 (m , 4H), 1.33 (d, J = 6.1 Hz, 4H), 1.25 (br.s., 2H), 0.92 (s, 18H).

Example L-142

By (3R, 3'R, 5S, 5'S)-5,5'-(4,4'-([1,1'-biphenyl]-4, by the procedure described for Synthesis Example L-97 , 4'-Diyl) bis(1H-imidazole-4,2-diyl))bis(pyrrolidin-3-ol) tetrahydrochloride and the appropriate starting material were prepared as Example L-142. By prep _{HPLC (CH 3 CN / H 2} O / NH 4 OAc) purified product was obtained. LC / MS (Condition PS-2): [M + H] + 807.32, R t = 2.21min.

Example L-143

By using the procedure described for Synthesis Example L-97, from 4,4'-bis(2-((2S,4S)-4-methylpyrrolidin-2-yl)-1H-imidazol-4-yl -1,1'-biphenyltetrahydrochloride and an appropriate starting material were prepared as Example L-143. By prep _{HPLC (CH 3 CN / H 2} O / NH 4 OAc) purified product was obtained. LC / MS (Condition PS-2): [M + H] + 803.36, R t = 2.67min.

Example L-144

Example L-144, step a

Example L-3 (0.27 g, 0.326 mmol) was taken in EtOAc (EtOAc m. The resulting solution was stirred at room temperature for 3 hours, at which time it again precipitated to a white suspension. The solvent was removed under reduced pressure, and triturated with Et ₂ O remaining residue. The resulting solid was filtered, washed with Et ₂ O and dried in vacuo. A white solid (99%) corresponding to the mp. It was used without further purification. LC / MS (conditions P-3): [M + H] + 627.55, R t = 2.79min. ^{1 H NMR (400MHz, DMSO-} d 6) δ 9.27 (br.s., 2H), 8.32 (br.s., 6H), 8.10 (br.s., 4H), 7.94 (br.s., 4H ), 5.42 (br.s., 2H), 3.51 (br.s., 4H), 1.77-1.53 (m, 12H), 1.02 (br.s., 18H).

Add 3,3,3-trifluoropropanthene chloride (0.020 mL, 0.194 mmol) to EtOAc (1 mL, EtOAc, EtOAc (EtOAc) In the solution. The mixture was stirred at room temperature for 2 hours. After adding NH ₃ (2M in MeOH) (0.5 mL, 1.00 mmol), the mixture was stirred at room temperature for 2 hr. Examples L-144 solvent was evaporated under reduced pressure, and the resulting residue was dissolved in MeOH and _{(CH 3 CN / H 2 O} / NH 4 OAc) was purified by preparative HPLC, to give of a white solid (44.1% ). LC / MS (Condition PS-2): [M + H] + 847.40, R t = 3.17min. ^{1 H NMR (500MHz, DMSO-} d 6) δ 12.35-11.81 (m, 2H), 8.49 (s, 2H), 7.83 (d, J = 6.7Hz, 3H), 7.68 (br.s., 5H), 7.56 (br.s., 1H), 7.34 (br.s., 2H), 4.83 (d, J = 9.2 Hz, 2H), 3.34 - 3.26 (m, 4H), 1.42 (s, 6H), 1.33 ( s, 6H), 0.90 (s, 18H).

Examples L-145 through L-146 were synthesized by following the procedure described in Example L-144 and suitably synthesizing the precursor.

By (1S, 1'S)-1,1'-(4,4'-([1,1'-biphenyl]-4,4'-diyl by the procedure described for Synthesis Example L-144 The following examples were prepared for the bis(1H-imidazole-4,2-diyl))bis(2,2-dimethylpropan-1-amine) tetrahydrochloride and the appropriate starting materials. By prep _{HPLC (CH 3 CN / H 2} O / NH 4 OAc) purified product was obtained.

*Example L-149 ¹ H NMR (500MHz, DMSO-d ₆ ): δ 12.39-11.94 (m, 2H), 8.21 (s, 2H), 7.83 (d, J = 7.3 Hz, 3H), 7.69 (br. s., 5H), 7.55 (br.s., 2H), 7.49-7.31 (m, 2H), 4.78 (d, J = 8.9 Hz, 2H), 2.10 (br.s., 2H), 1.95 (br .s., 4H), 1.91-1.87 (m, 6H), 1.84-1.77 (m, 2H), 1.60 (d, J = 6.7 Hz, 8H), 0.88 (s, 18H).

*Example L-150 ¹ H NMR (500 MHz, DMSO-d ₆ ): δ 12.30-11.97 (m, 2H), 8.45 (s, 2H), 7.84 (d, J = 7.9 Hz, 3H), 7.76-7.63 ( m,5H), 7.55 (br.s., 2H), 7.40 (d, J = 9.5 Hz, 2H), 7.34 (br.s., 1H), 4.87-4.75 (m, 2H), 2.15 (dd, J = 12.8, 6.4 Hz, 2H), 1.99-1.92 (m, 2H), 1.84 (d, J = 12.2 Hz, 2H), 1.70 (br.s., 2H), 1.61 (d, J = 6.1 Hz, 8H), 0.88 (s, 18H), 0.71 - 0.55 (m, 8H).

By (1S, 1'S)-1,1'-(4,4'-([1,1'-biphenyl]-4,4'-diyl by using the procedure described for Synthesis Example L-3 The following examples were prepared for the bis(1H-imidazole-4,2-diyl))bis(2-methylpropan-1-amine) tetrahydrochloride and the appropriate starting materials. By prep _{HPLC (CH 3 CN / H 2} O / NH 4 OAc) purified product was obtained.

*Example W-215 ¹ H NMR (500MHz, DMSO-d ₆ ) δ 12.45-11.78 (m, 1H), 8.39-7.28 (m, 6H), 4.74 (br.s., 1H), 4.02-3.77 (m , 1H), 2.19 (br.s., 1H), 1.97-1.63 (m, 2H), 1.58-1.18 (m, 13H), 1.13 - 0.67 (m, 16H).

By (1S, 1'S)-(4,4'-([1,1'-biphenyl]-4,4'-diyl) bis (1H-) by the procedure described for Synthesis Example L-3 The following examples were prepared for imidazole-4,2-diyl))bis((1-methylcyclopropyl)methylamine) tetrahydrochloride and the appropriate starting materials (caps). By prep _{HPLC (CH 3 CN / H 2} O / NH 4 OAc) purified product was obtained.

*Example W-208 ¹ H NMR (500MHz, DMSO-d ₆ ) δ 12.02 (br.s., 1H), 8.05-7.24 (m, 7H), 5.51-5.18 (m, 1H), 4.97-4.48 (m) , 1H), 4.10-3.63 (m, 2H), 2.44 - 2.13 (m, 2H), 1.91 (s, 1H), 1.67-0.51 (m, 23H), 0.26 (br.s., 3H).

By (1S, 1'S)-1,1'-(4,4'-([1,1'-biphenyl]-4,4'-diyl by using the procedure described for Synthesis Example L-3 The following examples were prepared for the bis(1H-imidazole-4,2-diyl))bis(2,2-dimethylpropan-1-amine) tetrahydrochloride and the appropriate starting materials. The product obtained is purified by preparative HPLC (MeOH/H ₂ O/TFA or CH ₃ CN/H ₂ O/NH ₄ OAc) and obtained as the corresponding trifluoroacetic acid salt or as the free base.

*Example W-269 ¹ H NMR (500 MHz, CD ₃ OD) δ 7.88 (s, 10H), 5.23-5.08 (m, 2H), 2.22 (d, J = 3.6 Hz, 4H), 2.07-1.82 (m, 4H), 1.79-1.29 (m, 12H), 1.10 (s, 18H); ¹⁹ F NMR (471 MHz, CD ₃ OD) δ -76.12, 77.62.

Example W-209

To a solution of EtOAc (EtOAc) (EtOAc,EtOAc. The resulting pale yellow solution was stirred at room temperature for 1 h and purified by preparative EtOAc (EtOAc) </RTI>^<RTIID=0.0></RTI>^</RTI>^<RTIID=0.0></RTI>

Example W-210

At 4 ℃, was added to the Example W-209 (15mg, 0.013mmol) in CH ₂ Cl ₂ (0.5mL) in a mixture of DIPEA (0.022mL, 0.128mmol) and methyl chloroformate (7.89μl, 0.102mmol) . The resulting mixture was stirred at room temperature for 1 hour (which became a clear solution within 10 minutes). Add MeOH 2M NH ₃ containing the (1.0mL, 2mmol), and stirring was continued for 2 hours at room temperature. The solvent was evaporated, and the residue was crystalljjjjjjjjjjjjj </RTI>^<RTIID=0.0></RTI>^</RTI>^<RTIID=0.0></RTI> _{^{1 H NMR (400MHz, CD 3}} OD) δ 7.89-7.60 (m, 4H), 7.38 (d, J = 5.0Hz, 1H), 5.40-4.95 (m, 2H), 4.02-3.74 (m, 2H), 3.62 (s, 2H), 3.44 (s, 2H), 2.54-2.31 (m, 3H), 2.06-1.92 (m, 2H), 1.76 (d, J = 16.3 Hz, 7H), 1.16-0.90 (m, 9H).

Example W-234

The mixture of Example W-231 (30mg), Pearman's catalyst (Pearlman's Catalyst) (38.1mg, 0.054mmol), 1 drop of 1M aqueous HCl and MeOH (5mL) was placed in the Parr shaker 50psi H ₂ 16 hour. The suspension was then filtered through a pad of celite, washed with MeOH and evaporated in vacuo. The residue was dissolved and purified by prep _{HPLC (MeOH / H 2 O /} TFA) in DMF, to give a white solid of the desired product from Example W-234. </RTI>^<RTIID=0.0></RTI>^</RTI>^<RTIID=0.0></RTI>

Example W-235

A mixture of Example W-232 (30 mg), a Pielman's catalyst (31.4 mg, 0.045 mmol), 1 drop of 1M aqueous HCl and MeOH (5 mL) was placed on a &_lt;RTIgt; The suspension was then filtered through a pad of celite, washed with MeOH and evaporated in vacuo. The residue was dissolved and purified by prep _{HPLC (MeOH / H 2 O /} TFA) in DMF, to give a white solid of the desired product from Example W-235. </RTI>^<RTIID=0.0></RTI>^</RTI>^<RTIID=0.0></RTI>

Example W-237

A mixture of Example W-230 (30 mg), Pielman's catalyst (31.4 mg, 0.045 mmol), 1 drop of 1M aqueous HCl and MeOH (5 mL) was placed on a &_lt;RTIgt; The suspension was then filtered through a pad of celite, washed with MeOH and evaporated in vacuo. The residue was dissolved and purified by prep _{HPLC (MeOH / H 2 O /} TFA) in DMF, to give a white solid of the desired product from Example W-237. </RTI>^<RTIID=0.0></RTI>^</RTI>^<RTIID=0.0></RTI>

Examples W-256a, 256b, and 256c

To (1S,1'S)-1,1'-(4,4'-([1,1'-biphenyl]-4,4'-diyl)bis(1H-imidazole-4,2-diyl) Bis(2,2-dimethylpropan-1-amine) tetrahydrochloride (132 mg, 0.220 mmol), 4-(benzyloxy)-2-methoxy-2-methylbutyric acid (110 mg) DIEA (0.269 mL, 1.539 mmol) was added to a slurry of EtOAc (EtOAc). The resulting pale yellow solution was stirred at room temperature for 2 hours. It was diluted with MeOH and purified by prep _{HPLC (MeOH-H 2 O-} TFA) purification, the three main peaks.

Example W-256a: LC/MS (Cond. W-2): [M+H] ⁺ 897.8, Rt=1. Example W-256b: LC/MS (Cond. W-2): [M+H] ⁺ 897.8, Rt = 1.92 min (Asymmetric Cap, diastereomer 2). Example W-256c: LC/MS (Cond. W-2): [M+H] ⁺ 897.8, Rt = 1.99 min (symmetric cap, diastereomer 3).

Example W-257

A mixture of Example W-256a (40 mg), a Pielman's catalyst (12.48 mg, 0.018 mmol), 1 drop of 1M aqueous HCl and MeOH (3 mL) was placed on a &_lt;RTIgt; It was filtered through a pad of celite, washed with MeOH and evaporated in vacuo. The residue was dissolved and purified by prep _{HPLC (MeOH / H 2 O /} TFA) in DMF to give the desired product Example W-257. LC/MS (Cond. W-2): [M+H] ⁺ 717.6

Example W-258

Example W-258 was isolated as a minor by-product during the preparation of Example W-257 (diastereomer 2). </RTI>^<RTIID=0.0></RTI></RTI>^<RTIID=0.0></RTI></RTI>^<RTIgt;

Example W-259

Examples of the W-256c (30mg), Pearman's catalyst (12.48mg, 0.018mmol), 1 drop of 1M aqueous HCl mixture and MeOH (3mL) was placed on the Parr shaker overnight at 40psi H _2. It was filtered through a pad of celite, washed with MeOH and evaporated in vacuo. The residue was dissolved and purified by prep _{HPLC (MeOH / H 2 O /} TFA) in DMF to give the desired product Example W-259. LC/MS (Condition W-2): [M+H] ⁺ 717.6, Rt=1.40 min (symmetric cap, diastereomer 3)

Examples W-261a, 261b, and 261c

To (1S,1'S)-1,1'-(4,4'-([1,1'-biphenyl]-4,4'-diyl)bis(1H-imidazole-4,2-diyl) Bis(2,2-dimethylpropan-1-amine) tetrahydrochloride (151 mg, 0.251 mmol), 3-(benzyloxy)-2-(2-fluoroethoxy)-2-methyl DIEA (0.307 mL, 1.756 mmol) was added to a slurry of EtOAc (EtOAc, EtOAc (EtOAc). The resulting pale yellow solution was stirred at room temperature for 2 hours. It was diluted with MeOH and purified by prep _{HPLC (MeOH-H 2 O-} TFA) purification, the three main peaks. Example W-261a: LC/MS (Cond. W-2): [M+H] ⁺ 933.5, Rt = 1.85 min (y. Example W-261b: LC/MS (Cond. W-2): [M+H] ⁺ 933.5, Rt = 1.92 min Example W-261c: LC/MS (Cond. W-2): [M+H] ⁺ 933.5, Rt = 1.99 min (

Example W-270

Examples of the W-261c (47mg), Pearman's catalyst (16.93mg, 0.024mmol), the mixture solution and 1 drop of 1M HCl in methanol (5mL) was placed on the Parr shaker overnight at 40psi H _2. It was filtered through a pad of celite, washed with MeOH and evaporated in vacuo. The residue was dissolved and purified by prep _{HPLC (MeOH-H 2 O-} TFA) in DMF to afford a white solid of Example 270. LC/MS (Cond. W-2): [M+H] ⁺ 75.

Example W-271

The 47mg of the product was isolated from Example W-261a, a mixture of Pearman's catalyst (16.93mg, 0.024mmol), 1 drop of 1M aqueous HCl and methanol (5mL) was placed on the Parr shaker overnight at 40psi H _2. It was filtered through a pad of celite, washed with MeOH and evaporated in vacuo. The residue was dissolved and purified by prep _{HPLC (MeOH-H 2 O-} TFA) in DMF to afford a white solid of Example 271. LC/MS (Cond. W-2): [M+H] ⁺ 75.

Example W-217

Example W-217, step 1

To the (R)-1-(t-butoxycarbonyl)-3,3-dimethylpyrrolidine-2-carboxylic acid (129 mg, 0.530 mmol) and 1,1'-([1,1) '-Biphenyl]-4,4'-diyl) bis(2-bromoethyl ketone) (100 mg, 0.252 mmol) in EtOAc (2 mL) EtOAc (EtOAc) . The resulting pale yellow slurry was stirred overnight at room temperature. The reaction mixture was diluted with EtOAc and washed with water, 5% citric acid and brine, dried (MgSO ₄₎ and concentrated in vacuo. The residue was purified by flash chromatography eluting eluting eluting elut elut elut elut elut elut elut elut M, 90% yield). </RTI>^{<RTI ID} =0.0></RTI>^</RTI>^{<RTI ID} =0.0></RTI>

Example W-217, step 2

Examples accommodated W-217 Step 1 (276mg, 0.383mmol), NH 4 OAc (590mg, 7.66mmol), imidazole (91mg, 1.340mmol) and o-xylene (4mL) was heated in a sealed tube of 4 deg.] C oil bath at 140 hour. The reaction mixture was cooled to room temperature and concentrated in vacuo. The residue was partitioned between water (50mL) and the CHCl ₃ / between MeOH (50 / 10mL). The organic layer was separated and the aqueous solution was washed with brine, Na ₂ CO _3, dried (MgSO _4), and concentrated in vacuo. The residual solid (300mg) dissolved in DMF, and purified by prep _{HPLC (MeOH-H 2 O-} TFA), was obtained as a light yellow foam examples of W-217 Step 2 (65mg, 0.095mmol, 24.93% yield rate). LC / MS (Condition W-2): [M + H] + 681.5, Rt = 1.59min.

Example W-217, step 3

To a solution of Example W-217 Step 2 (65 mg, EtOAc, EtOAc) The resulting yellow solution was stirred at room temperature for 1 hour then evaporated in vacuo. The residue was triturated with EtOAc (EtOAc)EtOAc. </RTI>^<RTIID=0.0></RTI>^</RTI>^<RTIID=0.0></RTI>

To a mixture of EtOAc (0.5 mL) DIEA (0.020 mL, 0.112 mmol) was added. Stirring at room temperature the formed light yellow solution for 2 hours and purified by prep _{HPLC (MeOH-H 2 O-} TFA) to afford Example W-217. LC/MS (Condition W-2): [M+H] ⁺ 773.6, Rt=1.

Example W-218

Example W-218 was prepared according to the procedure described for Preparation Example W-217. </RTI>^{<RTI ID} =0.0></RTI>^</RTI>^<RTIgt;

From 4,4'-bis(2-((S)-3,3-dimethylpyrrolidin-2-yl)-1H-imidazole-4-, by the procedure described for Synthesis Example W-217 The following examples were prepared for the base-1,1'-biphenyl tetrahydrochloride and the appropriate starting materials (caps). The product obtained is purified by preparative HPLC (MeOH/H ₂ O/TFA or CH ₃ CN/H ₂ O/NH ₄ OAc) and obtained as the corresponding trifluoroacetic acid salt or as the free base.

*Example W-239 ¹ H NMR (500MHz, CD ₃ OD) δ 8.10-7.79 (m, 5H), 4.98 (s, 1H), 4.20-3.94 (m, 1H), 3.79 (dt, J = 10.7, 7.4 Hz, 1H), 2.87-2.67 (m, 2H), 2.24-1.85 (m, 2H), 1.46-1.26 (m, 3H), 1.08-0.51 (m, 10H).

Example W-241

To 4,4'-bis(2-((2S,3R)-3-methylpyrrolidin-2-yl)-1H-imidazol-4-yl)-1,1'-biphenyltetrahydrochloride ( Addition of 20 mg, 0.033 mmol), 2-(dicyclopropylamino)-2-oxoacetic acid (11.87 mg, 0.070 mmol), HATU (26.7 mg, 0.070 mmol) in DMA (0.5 mL) DIEA (0.041 mL, 0.234 mmol). The resulting pale yellow solution was stirred at room temperature for 2 hours. Followed by prep _{HPLC (CH 3 CN / H 2} O / NH 4 OAc) mixture was purified to afford a white solid examples of W-241 (free base). </RTI>^<RTIID=0.0></RTI>^</RTI>^<RTIID=0.0></RTI>

Example W-242

To (S,S)-4,4'-(2-methyl-[1,1'-biphenyl]-4,4'-diyl)bis(2-((2S,5S)-5-) Pyrrrolidin-2-yl)-1H-imidazole)tetrahydrochloride (25 mg, 0.041 mmol), 2-(4,4-difluoropiperidin-1-yl)-2-oxoacetic acid (16.56 mg DIEA (0.050 mL, 0.286 mmol) was added to a mixture of EtOAc (EtOAc). The resulting pale yellow solution was stirred at room temperature for 2 hours. Followed by prep _{HPLC (CH 3 CN / H 2} O / NH 4 OAc) mixture was purified to afford a white solid examples of W-242 (free base). </RTI>^<RTIID=0.0></RTI>^</RTI>^<RTIID=0.0></RTI>

Example W-243

To 4,4'-bis(2-((1S,3S,5S)-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-4-yl)-1,1'- Biphenyl tetrahydrochloride (25 mg, 0.042 mmol), 2-(4,4-difluoropiperidin-1-yl)-2-oxoacetic acid (17.06 mg, 0.088 mmol), HATU (33.6 mg, 0.088) Addition of DIEA (0.051 mL, 0.294 mmol) in MeOH (0.5 mL). The resulting pale yellow solution was stirred at room temperature for 2 hours. Followed by prep _{HPLC (CH 3 CN / H 2} O / NH 4 OAc) mixture was purified to afford a white solid examples of W-243 (free base). </RTI>^<RTIID=0.0></RTI>^</RTI><RTIgt;

Example W-244

To 4,4'-bis(2-((2S,3S)-3-methylpyrrolidin-2-yl)-1H-imidazol-4-yl)-1,1'-biphenyltetrahydrochloride ( Addition of 20 mg, 0.033 mmol), 2-(dicyclopropylamino)-2-oxoacetic acid (11.87 mg, 0.070 mmol), HATU (26.7 mg, 0.070 mmol) in DMA (0.5 mL) DIEA (0.041 mL, 0.234 mmol). The resulting pale yellow solution was stirred at room temperature for 2 hours. Followed by prep _{HPLC (CH 3 CN / H 2} O / NH 4 OAc) mixture was purified to afford a white solid examples of W-244 (free base). </RTI>^{<RTI ID} =0.0></RTI>^</RTI>^{<RTI ID} =0.0></RTI>

Example W-249

To 4,4'-bis(2-((2S,3S)-3-methylpyrrolidin-2-yl)-1H-imidazol-4-yl)-1,1'-biphenyltetrahydrochloride ( 20 mg, 0.033 mmol), 2-oxo-oxy-2-(2,2,6,6-tetramethylpiperidin-1-yl)acetic acid (14.97 mg, 0.070 mmol), HATU (26.7 mg, 0.070 mmol) DIEA (0.041 mL, 0.234 mmol) was added to a mixture of EtOAc (0.5 mL). The resulting pale yellow solution was stirred at room temperature for 2 hours. Followed by prep _{HPLC (CH 3 CN / H 2} O / NH 4 OAc) mixture was purified to afford a white solid examples of W-249 (free base). </RTI>^<RTIID=0.0></RTI>^</RTI>^<RTIID=0.0></RTI>

Example W-250

Example W-250, step 1

To a solution of Example L-7 ( 390 mg, 0.430 <RTI ID=0.0> The resulting solution was stirred overnight at room temperature. The volatiles were removed in vacuo to afford EtOAc m. 1H NMR (500MHz, CD ₃ OD) δ 8.16-7.99 (m, 6H), 7.90 (d, J = 8.5 Hz, 4H), 5.42 (s, 2H), 2.72-2.41 (m, 4H), 2.02-1.53 (m, 16H), 1.16 (s, 18 H). LC/MS (Cond. W-2): [M+H] ⁺ 707.7

Ethyl chloroformate (0.011 mL, 0.117 mmol) was added to DCM (0.25 mL) EtOAc. The resulting solution was stirred at room temperature for 30 minutes. Add MeOH 2M NH ₃ containing the (0.469mL, 0.938mmol), and stirred at room temperature for 2 hours. Followed by prep _{HPLC (CH 3 CN / H 2} O / NH 4 OAc) mixture was purified to afford a white solid examples of W-250 (free base). </RTI>^<RTIID=0.0></RTI>^</RTI>^<RTIID=0.0></RTI>

The following examples were prepared by the procedure described for Synthesis Example W-250, from Example W-250 Step 1 and the appropriate starting materials, while reacting with the corresponding acid chloride, anhydride or isocyanate. By prep _{HPLC (CH 3 CN / H 2} O / NH 4 OAc) and the resulting product is purified to obtain the corresponding free base forms thereof.

*Example W-252 ¹ H NMR (500MHz, DMSO-d ₆ ) δ 12.40-11.89 (m, 2H), 8.06-7.18 (m, 14H), 4.97-4.68 (m, 2H), 2.16 (d, J = 10.7 Hz, 2H), 2.03-1.85 (m, 8H), 1.72-1.33 (m, 14H), 1.19 (br.s., 2H), 0.90 (br.s., 18H).

*Example W-264 ¹ H NMR (500MHz, DMSO-d ₆ ) δ 12.39-11.87 (m, 2H), 8.34-7.26 (m, 14H), 5.05-4.48 (m, 2H), 2.21. (d, J = 12.2 Hz, 2H), 2.05-1.34 (m, 2H), 1.20 (br.s., 2H), 0.90 (br.s., 18H), 0.76-0.49 (m, 8H) 1H NMR (500 MHz, CD ₃ OD) δ 8.29-8.03 (m, 2H), 7.99-7.85 (m, 10H), 4.99-4.97 (m, 2H), 2.15 (dd, J = 19.4, 15.3 Hz, 4H), 1.96-1.74 (m, 6H), 1.72-1.47 (m, 10H), 1.41-1.29 (m, 2H), 1.11 (s, 18H), 0.97-0.73 (m, 8H).

*Example W-266 ¹ H NMR (500MHz, DMSO-d ₆ ) δ 12.42-11.79 (m, 2H), 8.00-6.95 (m, 14H), 4.98-4.62 (m, 2H), 2.62 (dt, J = 13.4, 6.6 Hz, 2H), 2.23 (d, J = 12.8 Hz, 2H), 2.00 (d, J = 11.9 Hz, 2H), 1.75-1.30 (m, 14H), 1.27-0.79 (m, 32H).

The following examples were prepared from the example W-250 Step 1 tetrahydrochloride and the appropriate starting material acid by employing the procedure described for the synthesis example L-3. By prep _{HPLC (CH 3 CN / H 2} O / NH 4 OAc) resulting purified product was obtained and its corresponding free base forms.

*Example W-268 ¹ H NMR (500MHz, DMSO-d ₆ ) δ 12.45-11.86 (m, 1H), 8.75-8.47 (m, 1H), 7.98-7.16 (m, 6H), 5.05-4.54 (m, 1H), 3.05-2.73 (m, 6H), 2.36-1.94 (m, 2H), 1.80-1.12 (m, 8H), 0.92 (s, 9H).

Example B1

Example B1, step a

At 10 ℃, 2-bromo-naphthalene (25g, 121mmol) and AlCl ₃ (19.32g, 145mmol) in nitrobenzene (227 mL) was added in the AcCl (10.78mL, 152mmol). The reaction mixture was heated to 40 ° C for 18 hours. The reaction mixture was then cooled to room temperature and poured into ice containing concentrated hydrochloric acid (400 mL). The reaction mixture was extracted with EtOAc, and washed with 1.5N HCl solution, brine, dried over Na ₂ SO ₄ and concentrated. The crude material was purified by EtOAc EtOAc EtOAc:EtOAc ¹ H NMR (CDCl ₃ , δ = 7.26 ppm, 400 MHz): δ 8.43 (s, 1 H), 8.08-8.04 (m, 2 H), 7.84 (d, J = 8.8, 1 H), 7.81 (d, J = 8.8, 1 H), 7.64 (dd, J = 8.8, 2.0, 1 H), 2.72 (s, 3 H).

Example B1, step b

At 10 ℃, of bromide B-1a (5.0g, 20.07mmol) in DCM (150mL) was added in the containing Br ₂ (0.827mL, 16.06mmol) of dioxane (50mL) over 10 minutes and The reaction mixture was stirred at 10 ° C for 2 hours. With 10% NaHCO ₃ The reaction mixture was quenched and extracted with DCM. Dried over Na ₂ SO _4, and the organic layer was concentrated to obtain a yellow solid of crude dibromide B-1b (7.0g). ¹ H NMR (CDCl ₃ , δ = 7.26 ppm, 400 MHz): δ 8.48 (s, 1 H), 8.07-8.04 (m, 2 H), 7.85 (d, J = 8.8, 1 H), 7.84 (d, J = 8.8, 1 H), 7.66 (dd, J = 8.8, 2.0, 1 H), 4.55 (s, 2 H).

Example B1, step c

To dibromide B-1b (7.0 g, 21.34 mmol) and (S)-2-((t-butoxycarbonyl)amino)-3,3-dimethylbutyric acid (4.94) at 0 °C g, 21.34 mmol) DIPEA (7.45 mL, 42.7 mmol). The reaction mixture was then concentrated and the crude was diluted with EtOAc. , Dried with 10% NaHCO _3, the organic layer was washed with brine over Na ₂ SO _4, filtered and concentrated. The crude material was purified with EtOAc EtOAc EtOAc (EtOAc) LC/MS ( Condition B-10 ): R _t = 2.43 min. ¹ H NMR (CDCl ₃ , δ = 7.26 ppm, 400 MHz): δ 8.40 (s, 1 H), 8.06 (d, J = 1.6, 1 H), 7.99 (dd, J = 8.8, 1.6, 1 H), 7.83 (d, J = 8.8, 2 H), 7.65 (dd, J = 8.8, 1.6, 1 H), 5.60 (d, J = 16.0, 1 H), 5.4 (d, J = 16.0, 1 H), 5.13 (d, J = 9.2, 1 H), 4.27 (d, J = 9.6, 1 H), 1.46 (s, 9 H), 1.12 (s, 9 H). ^{LC / MS: [MH] -} C 23 H 27 BrNO 5 Calculated: 477.38; Found: 478.0.

Example B1, step d

The ketoester B-1c (9.2g, 19.23mmol) and NH ₄ OAc (14.82g, 192mmol) in xylene (75 mL) of the reaction mixture was heated at 130 ℃ 18 hours. The reaction mixture was then cooled to room temperature and the volatile components were evaporated. The residue was then diluted with DCM, and washed with 10% NaHCO ₃ and used. The organic layer was dried over Na ₂ SO _4, filtered and concentrated. By Combiflash Isco (silica gel, 120g, Redisep, MeOH: CHCl 3, 2: 98) The crude material was purified to give the bromide as a yellow solid B-1d (6g). LC/MS ( Condition B-10 ): R _t = 2.34 min. ¹ H NMR (CDCl ₃ , δ = 7.26 ppm, 400 MHz): δ 10.05 (br s, 1 H), 8.15 (br s, 1 H), 7.94 (br s, 1 H), 7.86-7.40 (m, 4) H), 7.16 (br s, 1 H), 5.68 (d, J = 7.6, 1 H), 4.65 (br s, 1 H), 1.44 (s, 9 H), 1.08 (s, 9 H). LC / MS: [M + H ] + C 23 H 28 BrN 3 O 2 Calculated: 458.14; Found: 458.2.

Example B1, step e

Under N _2, the bromide B-1d (2.0g, 4.36mmol) and DIPEA (5.33mL, 30.5mmol) in DMF was added trimethyl silicon alkyl acetylene (6.12mL, 43.6mmol) (20mL) solution of the CuI (0.415 g, 2.182 mmol) and Pd(TPP) ₂ Cl ₂ (1.102 g, 1.571 mmol). After stirring at room temperature for 10 minutes, the reaction mixture was heated at 90 ° C for 12 hours. The reaction mixture was then diluted with EtOAc, washed with saturated NH ₄ Cl, water and brine. Through diatomaceous earth (Celite ^®) organic layer was filtered, and dried over Na ₂ SO _4, filtered and concentrated. The crude material was purified with EtOAc EtOAc (EtOAc:EtOAc) LC/MS ( Condition B-10 ): R _t = 2.72 min. ¹ H NMR (CDCl ₃ , δ = 7.26 ppm, 400 MHz): δ 9.28 (br s, 1 H), 8.22 (br s, 1 H), 7.95 (br s, 1 H), 7.78-7.00 (m, 5) H), 5.52 (br s, 1 H), 4.53 (br s, 1 H), 1.43 (s, 9 H), 1.07 (s, 9 H), 0.28 / 0.25 (s, 9 H). LC / MS: [M-Boc ] - C 23 H 28 N 3 Si Calculated: 374.21; Found: 374.2.

Example B1, step f

To a solution of (S)-(1-hydroxy-3,3-dimethylbutan-2-yl)carbamic acid tert-butyl ester (10 g, 46.0 mmol) in DCM (50 mL) Dess-Martin periodinane (39.0 g, 92 mmol) was added portionwise and the reaction mixture was stirred at room temperature for 2 h. With 10% NaHCO ₃ to quench the reaction mixture was diluted with DCM. The organic layer was separated, and washed with 10% NaHCO _3. The organic layer was then filtered through diatomaceous earth (Celite ^®), and washed with DCM. The combined filtrates were dried over Na ₂ SO ₄ and concentrated. The crude material was dissolved in diethyl ether, and filtered again through diatomaceous earth (Celite ^®), and washed with ether. The combined filtrate was concentrated and dried to give EtOAc (EtOAc). ¹ H NMR (CDCl ₃ , δ = 7.26 ppm, 400 MHz): δ 9.82 (s, 1 H), 5.13 (br s, 1 H), 4.17 (d, J = 8.4, 1 H), 1.44 (s, 9) H), 1.04 (s, 9 H).

Example B1, step g

To a solution of the aldehyde B-1f (10 g, 46.4 mmol) in MeOH (150 mL) NH ₄ OH (6 mL, 154 mmol) was then added and the mixture was stirred at 10 ° C for 24 hr. The volatile components were evaporated and the residue obtained was taken in EtOAc. Water, the organic layer was washed with brine, dried over Na ₂ SO ₄ dried and concentrated. By Combiflash Isco (silica gel, 120g, Redisep, MeOH: CHCl 3, 2: 98) The crude material was purified to give the imidazole as a white solid B-1g (9.5g). LC/MS ( Condition B-10 ): R _t = 1. 36 min. ¹ H NMR (CDCl ₃ , δ = 7.26 ppm, 400 MHz): δ 10.21 (br s, 1 H), 7.00-6.86 (m, 2 H), 5.64 (d, J = 10.0, 1 H), 4.62 (d) , J = 10.0, 1 H), 1.42 (s, 9 H), 0.99 (s, 9 H). LC / MS: [M + H ] + C 13 H 24 N 3 O 2 Calculated: 254.18; Found: 254.2.

Example B1, step h

NIS (13.50 g, 60.0 mmol) was added to a solution of the imidazole B-1 g (7.6 g, 30.0 mmol) in DCM (250 mL), and the mixture was stirred for 2 hours while warming to room temperature. , Dried with 10% NaHCO _3, the organic layer was washed with brine over Na ₂ SO _4, filtered and concentrated. The crude material was purified with EtOAc EtOAc EtOAc (EtOAc) LC/MS ( Condition B-10 ): R _t = 1.89 min. ¹ H NMR (MeOD, δ = 3.34 ppm, 400 MHz): δ 4.51 (br s, 1 H), 1.45 (s, 9 H), 0.94 (s, 9 H). LC / MS: [M + H ] + C 13 H 22 I 2 N 3 O 2 Calculated: 506.13; Found: 506.0.

Example B1 , step i

Diiodide to B-1h (13g, 25.7mmol) in EtOH (62mL) and water (62mL) was added in the _{Na 2 SO 3 (64.9g, 515mmol} ), and the reaction mixture was refluxed for 17 hours. The volatile component was then evaporated and the residue obtained was taken in EtOAc. Water, the organic layer was washed with brine, and dried over Na ₂ SO _4, filtered and concentrated. The crude material was purified with EtOAc EtOAc (EtOAc:EtOAc) LC/MS ( Condition B-10 ): R _t = 1.71 min. ¹ H NMR (CDCl ₃ , δ = 7.26 ppm, 400 MHz): δ 10.57 (br s, 1 H), 6.89 (s, 1 H), 5.70 (d, J = 9.6, 1 H), 4.57 (d, J) = 9.6, 1 H), 1.42 (s, 9 H), 0.98 (s, 9 H). LC / MS: [M + H ] + C 13 H 23 IN 3 O 2 Calculated: 380.08; Found: 380.0.

Example B1 , steps j-1 and j-2

To a solution of trimethyldecylalkylalkyne B-1e (700 mg, 1.472 mmol) and iodide B-1i (614 mg, 1.619 mmol) in DMF (50 mL) was added TEA (0.615 mL, 4.41 mmol). 28.0 mg, 0.147 mmol) and Pd(TPP) ₂ Cl ₂ (103 mg, 0.147 mmol). The reaction mixture was then heated to 70 ° C, THF (1.472 mL, 1.472 mmol) containing 1M TBAF was slowly added and stirred at 70 ° C for 10 hours. The reaction mixture was concentrated, and diluted with EtOAc, washed with saturated 10% NH ₄ Cl and brine. Diatomaceous earth (Celite ^®) organic layer was filtered, dried over Na ₂ SO ₄ filtrate was dried, filtered and concentrated. By reverse phase HPLC (ACN / water / NH ₄ OAc) and the residue was purified to obtain urethane B-1j-1 (380mg) of as a light brown solid. LC/MS ( Condition B-9 ): R _t = 2.21. min. ¹ H NMR (MeOD, δ = 3.34 ppm, 400 MHz): δ 8.18 (br s, 1 H), 8.1 (s, 1 H), 7.89-7.87 (m, 3 H), 7.55 (dd, J = 8.8, 1.6, 1 H), 7.52 (br s, 1 H), 7.34 (br s, 1 H), 4.67 (s, 1 H), 4.58 (s, 1 H), 1.47 (s, 18 H), 1.02/ 0.99 (s, 18 H). ^{LC / MS: [MH] -} C 38 H 49 N 6 O 4 Calculated: 653.39; Found: 653.3. A symmetric dimer B-1j-2 (130 mg) was obtained as a pale brown solid. LC/MS ( Condition B-9 ): R _t = 2.10 min. ¹ H NMR (MeOD, δ = 3.34 ppm, 400 MHz): δ 8.21 (br s, 2 H), 8.11 (s, 2 H), 7.94-7.87 (m, 6 H), 7.57 (dd, J = 8.4, 1.2, 2 H), 7.55 (br s, 2 H), 4.68 (s, 2 H), 1.47 (s, 18 H), 1.03 (s, 18 H). LC / MS: [M + H ] + C 50 H 57 N 6 O 4 Calculated: 805.44; Found: 805.4.

Example B1 , step k

To a solution of the carbamate B-1j-1 (200 mg, 0.305 mmol) in MeOH (10 mL), MeOH (20 mL) EtOAc. hour. The reaction mixture was then concentrated and dried to give EtOAcjjjjjjjj LC/MS ( Condition B-10 ): R _t = 1. 44 min. ¹ H NMR (MeOD, δ = 3.34 ppm, 400 MHz): δ 8.47 (br s, 1 H), 8.16-8.14 (m, 2 H), 8.04-8.01 (m, 3 H), 7.67-7.66 (m, 2 H), 4.73 (s, 1 H), 4.36 (s, 1 H), 1.23 (s, 9 H), 1.14 (s, 9 H). LC / MS: [M + H ] + C 28 H 35 N 6 Calculated: 455.28; Found: 455.3.

Example B1

Add DIPEA (0.106) to a solution of the amine B-1k (4 HCl) (80 mg, 0.152 mmol) and 4,4-difluorocyclohexanecarboxylic acid (52.3 mg, 0.318 mmol) in DMF (5 mL) mL, 0.607 mmol) followed by HATU (118 mg, 0.311 mmol). The reaction mixture was stirred at room temperature for 2 hours, then the volatile components were removed. The resulting residue was dissolved in DCM, washed with sat NH ₄ Cl, 10% NaHCO _3, brine, dried over Na ₂ SO ₄ dried and concentrated. The crude material was purified by EtOAc EtOAc (EtOAc) HPLC ( Condition B-1 and B-2 ): >97% homogeneity index. LC/MS ( Condition B-10 ): R _t = 2.06 min. ¹ H NMR (MeOD, δ = 3.34 ppm, 400 MHz): δ 8.29 (br s, 1 H), 8.17 (br s, 1 H), 8.06 (d, J = 8.8, 1 H), 8.01 (d, J) = 8.8, 1 H), 7.99 (s, 1 H), 7.89 (dd, J = 8.8, 2.0, 1 H), 7.68 (dd, J = 8.4, 1.6, 1 H), 7.64 (s, 1 H) , 4.99-4.80 (shaded, 2 H), 2.63-2.55 (m, 2 H), 2.19-2.08 (m, 4 H), 2.00-1.72 (m, 12 H), 1.17 (s, 9 H), 1.09 (s, 9 H). ^{LC / MS: [MH] -} C 42 H 49 N 6 O 2 Calculated: 745.39; Found: 745.4.

Example B2-5A

According to the procedure described for Example B1, the hydrochloride salt from B-1k and the p-valeric acid/3-chlorobenzoic acid/2-(4,4-difluoropiperidin-1-yl)-2-oxooxy group Acetic acid / 1-((methoxycarbonyl)(methyl)amino)cyclopropanecarboxylic acid/2-(4,4-difluoro-1-hydroxycyclohexyl)-2-methylpropionic acid, prepared in a similar manner Example B2-5A (trifluoroacetate).

Example B5B

To the amine B-1k (4HCl) (20 mg, 0.033 mmol) and 1-(4,4-difluoro-1-hydroxycyclohexyl)cyclopropanecarboxylic acid (15.40 mg, 0.070 mmol) in DMF (5 mL) DIPEA (0.023 mL, 0.133 mmol) was added to the solution, followed by BOP (30.2 mg, 0.068 mmol). After stirring at room temperature for 2 hours, the volatile components were removed under reduced pressure. The resulting residue was dissolved in DCM (50mL), 10% NaHCO 3 solution (50mL), washed with saturated NH ₄ Cl solution (50mL), brine (25mL), dried over Na ₂ SO _4, and concentrated in vacuo. The crude material was purified by EtOAc (EtOAc/EtOAc) HPLC ( Condition B-1 and B-2 ): >97% homogeneity index. LC/MS ( Condition B-18 ): R _t = 2.31 min. LC / MS: [M + H ] + C 48 H 59 F 4 N 6 O 4 Calculated: 859.45; Found: 859.4.

Example B6

(, 0.033mmol 25mg) in MeOH was added to Example B1 (5mL) in a solution of Pd / C (17.81mg, 0.017mmol) , and the reaction mixture was stirred under H ₂ for 2 hours at room temperature. Diatomaceous earth (Celite ^®) The reaction mixture was filtered, and washed with MeOH. The filtrate was concentrated, and EtOAc EtOAc m. HPLC ( Condition B-1 and B-2 ): >97% homogeneity index. LC/MS ( Condition B-10 ): R _t = 2. 0 min. ¹ H NMR (MeOD, δ = 3.34 ppm, 400 MHz): δ 8.20 (br s, 1 H), 7.92 (d, J = 8.4, 1 H), 7.89 (d, J = 8.4, 1 H), 7.84 ( Br s,1 H), 7.79 (dd, J=8.4,1.6,1 H), 7.64 (br s,1 H), 7.44 (dd, J=8.4,1.6,1 H), 7.14 (s, 1 H) ), 4.94 (s, 1 H), 4.72 (s, 1 H), 3.21-3.12 (m, 4 H), 2.61-2.50 (m, 2 H), 2.15-2.00 (m, 4 H), 1.90- 1.62 (m, 12 H), 1.13 (s, 9 H), 1.00 (s, 9 H). LC / MS: [M + H ] + C 42 H 55 F 4 N 6 O 2 Calculated: 751.42; Found: 751.4.

Example B7-9

Example B7-9, step a

In a similar manner from dibromide B-1b and (S)-2-((t-butoxycarbonyl)amino)-3-methylbutyric acid according to the procedure described for the preparation of bromide B-1d Preparation of bromide B7-9a. LC/MS ( Condition B-9 ): R _t = 1.83 min. LC / MS: [M + H ] + C 22 H 27 BrN 3 O 2 Calculated: 444.12; Found: 444.0.

Example B7-9, step b

Trimethyldecylalkylalkyne B7-9b was prepared in a similar manner from bromide R7-9a according to the procedure described for the preparation of trimethyldecylalkylalkyne B-1e. LC/MS ( Condition B-9 ): R _t = 2.19 min. LC / MS: [M + H ] + C 27 H 36 N 3 O 2 Si Calculated: 462.25; Found: 462.2.

Example B7-9, step c

Iodide B7 was prepared in a similar manner starting from the procedure described for the preparation of iodide B-1i starting with (S)-(1-hydroxy-3-methylbutan-2-yl)carbamic acid tert-butyl ester. -9c. LC/MS ( Condition B-13 ): R _t = 1.84 min. ¹ H NMR (CDCl ₃ , δ = 7.26 ppm, 400 MHz): δ 10.29 (br s, 1 H), 6.97 (s, 1 H), 5.34 (br s, 1 H), 4.28 (br s, 1 H) , 2.38-2.32 (m, 1 H), 1.42 (s, 9 H), 0.99 (d, J = 6.8, 3 H), 0.85 (d, J = 6.4, 3 H). LC / MS: [M + H ] + C 12 H 21 IN 3 O 2 Calculated: 366.06; Found: 366.2.

Example B7-9

Example B 7-9 (trifluoroacetate) was prepared in a similar manner starting from trimethyldecylalkylalkyne B7-9b and iodide B7-9c according to the procedure described for the preparation of Example B1-3.

Example B10

Example B10, step a

To a solution of 6-bromo-3,4-dihydronaphthalene-1(2H)-one (2.0 g, 8.89 mmol) in EtOAc (EtOAc) Then 5 mL of DCM containing Br ₂ (0.494 mL, 9.60 mmol) was added over 10 min. After stirring at room temperature for 2 hours, quenched with 10% NaHCO ₃ the reaction mixture, and extracted with DCM. The organic layer was dried over Na ₂ SO _4, filtered, concentrated and dried to give a brown solid bis bromide B-10a (2.7g). LC/MS ( Condition B-10 ): Rt = 2.05 min. LC / MS: [M + H ] + C 10 H 8 Br 2 O Calculated: 304.98; Found: 305.0.

Example B10, step b

To dibromide B-10a (2.7 g, 8.88 mmol) and (S)-2-((t-butoxycarbonyl)amino)-3,3-dimethylbutyric acid (2.054) at 0 °C g, 8.88 mmol) DIPEA (3.10 mL, 17.76 mmol) was added dropwise in a solution of ACN (50 mL), and the reaction mixture was stirred at 0 ° C for 10 min, then heated to 50 ° C for 10 s. Sex component. The resulting residue was dissolved in EtOAc, and washed with 10% NaHCO _3, brine, dried over Na ₂ SO _4, filtered and concentrated. The crude material was purified by Combiflash Isco (EtOAc, EtOAc (EtOAc) elute elute LC/MS ( Condition B-10 ): R _t = 2.37 min. _{LC / MS: [MH 2 O} ] - C 21 H 27 BrNO 5 Calculated: 453.35; Found: 454.0.

Example B10, step c

The ketoester B-10b (3.8g, 8.36mmol) , a mixture of NH ₄ OAc (3.22g, 41.8mmol) and TEA (1.749mL, 12.55mmol) in xylene (50mL) was heated at in the 130 ℃ 18 hours. After cooling to room temperature, the volatile components were removed. The residue was then diluted with DCM, washed with 10% NaHCO ₃ solution, dried over Na ₂ SO _4, filtered and concentrated. By Combiflash Isco (silica gel, 120g, Redisep, MeOH / CHCl 3, 2: 95) The crude material was purified to give the bromide as a brown solid B-10c (3.4g). ¹ H NMR (CDCl ₃ , δ = 7.26 ppm, 400 MHz): δ 10.51 / 9.45 (br s, 1 H), 7.54 - 6.53 (m, 3 H), 5.65 - 5.57 (m, 1 H), 4.60 - 4.48 (m, 1 H), 2.90-2.42 (m, 4 H), 1.44 (s, 9 H), 1.01 (s, 9 H).

Example B10, step d

To 2-amino-1-(4-bromophenyl)ethanone hydrochloride (10 g, 39.9 mmol) and (S)-2-((t-butoxycarbonyl)amine) at 0 °C HATU (16.70 g, 43.9 mmol), DIPEA (20.91 mL, 120 mmol), and at room temperature, were added sequentially to a solution of &lt;3&gt;3,3-dimethylbutyric acid (10.16 g, 43.9 mmol) in DMF (150 mL) The reaction mixture was stirred for 2 hours. Water (500 mL) was added and the mixture was extracted with EtOAc. 10% NaHCO _3, and the organic layer was washed with saturated aqueous NH ₄ Cl, washed with brine. The organic layer was dried over Na ₂ SO ₄ and concentrated. By flash chromatography (silica gel 60-120, containing the 0.6% MeOH in DCM) the crude material to give an off-white solid of one Amides B -10d (18g). LC/MS ( Condition B-12 ): R _t = 2.09 min. ¹ H NMR (CDCl ₃ , δ = 7.26 ppm, 400 MHz): δ 7.89-7.82 (m, 2 H), 7.67- 7.63 (m, 2 H), 6.65 (m, 1 H), 5.57 (br s, 1 H), 4.86-4.60 (m, 2 H), 3.97 (d, J = 9.2, 1 H), 1.44 (s, 9 H), 1.03 (s, 9 H). LC / MS: [M + H ] + C 19 H 28 BrN 2 O 4 Calculated: 428.33; Found: 428.1.

Example B10, step e

The mixture (125 mL of) the of the NH ₄ OAc (16.23g, 211mmol) and one Amides B -10d (18g, 42.1mmol) in xylene was heated overnight at 130 ℃. Evaporate volatile components. The resulting residue was diluted with EtOAc, washed with water and brine, 10% NaHCO _3,. The organic layer was concentrated, and Na ₂ SO ₄ dried under reduced pressure. By flash chromatography (silica gel 60-120, containing the ₃ CHCl 1% MeOH) to give the residue, to give an off-white solid of bromide B-10e (10.5g). LC/MS ( Condition B-14 ): R _t = 2.09 min. ¹ H NMR (CDCl ₃ , δ = 7.26 ppm, 400 MHz): δ 10.23 (br s, 1 H), 7.59 (d, J = 8.4, 2 H), 7.45 (d, J = 8.4, 2 H), 7.03 (s, 1 H), 5.67 (d, J = 9.2, 1 H), 4.61 (d, J = 9.2, 1 H), 1.43 (s, 9 H), 1.03 (s, 9 H). LC / MS: [M + H ] + C 19 H 27 BrN 3 O 2 Calculated: 408.12; Found: 408.2.

Example B10, step f

Bromide B-10e (3.0 g, 7.35 mmol), bis(pinacolyl)diboron (2.99 g, 11.76 mmol) and KOAc (2.163 g, 22.04 mmol) in 1,4-dioxane (30 mL) The mixture was purged with N _{2 for} 10 minutes. Then PdCl ₂ (dppf) (0.269 g, 0.367 mmol) was added and the reaction mixture was heated at 100 ° C overnight. Diatomaceous earth (Celite ^®) and the reaction mixture was filtered and washed. The filtrate was concentrated and the residue obtained was diluted with EtOAc. The organic layer was washed with water, brine, dried over Na ₂ SO ₄ dried and concentrated to give a dark brown solid of Acid ester B-10f (3.5 g). LC/MS ( Condition B-10 ): R _t = 2.14 min. LC / MS: [M + H ] + C 25 H 39 BN 3 O 4 Calculated: 456.3; Found: 456.4.

Example B10, steps g-1 and g-2

Add to a solution of bromide B-10c (1.7 g, 3.91 mmol) in MeOH (40 mL) Ester B-10f (1.782g, 3.91mmol) , followed by addition of _{K 2 CO 3 (1.082g, 7.83mmol} ) and _{Pd (Ph 3 P) 4 (} 0.226g, 0.196mmol). The reaction mixture was heated at 65 ° C for 12 hours. The volatile components were removed and the residue obtained was taken in EtOAc and washed with water. The organic layer was separated and aqueous layer was extracted with EtOAc. Washed with brine the organic layers were combined, dried over Na ₂ SO ₄ dried and concentrated. By reverse phase HPLC (ACN / water / NH ₄ OAc) crude material was purified to give a brown solid of urethane B-10g-1 (1.0g) . HPLC ( Condition B-1 and B-2 ): >93% homogeneity index. LC/MS ( Condition B-10 ): R _t = 2.22 min. ¹ H NMR (MeOD, δ = 3.34 ppm, 400 MHz): δ 7.76 (m, 2 H), 7.70-7.68 (m, 2 H), 7.55-7.54 (m, 3 H), 7.39 (br s, 1 H) ), 4.66 (s, 1 H), 4.62 (s, 1 H), 3.15 (t, J = 8.0, 2 H), 2.90 (t, J = 8.0, 2 H), 1.47 (s, 18 H), 1.01 (s, 18 H). ^{LC / MS: [MH] -} C 40 H 53 N 6 O 4 Calculated: 681.42; Found: 681.4. A symmetric dimer B-10g-2 (600 mg) was obtained as a brown solid. HPLC ( Conditions B-5 and B-6 ): >96% homogeneity index. LC/MS ( Condition B-10 ): R _t = 2.26 min. ¹ H NMR (MeOD, δ = 3.34 ppm, 400 MHz): δ 7.51 (br s, 6 H), 4.61 (s, 2 H), 3.13 (t, J = 8.0, 4 H), 2.88 (t, J = 8.0, 4 H), 1.47 (s, 18 H), 1.01 (s, 18 H). ^{LC / MS: [MH] -} C 42 H 55 N 6 O 4 Calculated: 707.44; Found: 707.4.

Example B10, step h

The hydrochloride salt of the amine B-10h (40 mg) was prepared according to the procedure described in the procedure of step B1. LC/MS ( Condition B-11 ): R _t = 1. 44 min. ¹ H NMR (MeOD, δ = 3.34 ppm, 400 MHz): δ 7.98-7.91 (m, 3 H), 7.83-7.76 (m, 3 H), 7.70-7.64 (m, 2 H), 4.63 (s, 1) H), 4.61 (s, 1 H), 3.35-3.20 (masked, 2 H), 3.09 (br s, 2 H), 1.19 (s, 9 H), 1.18 (s, 9 H). LC / MS: [M + H ] + C 30 H 39 N 6 Calculated: 483.32; Found: 483.4.

Example B10

The trifluoroacetate salt of Example B10 (26.6 mg) was prepared according to the procedure described in Example B1. HPLC ( Conditions B-1 and B-2 ): >98% homogeneity index. LC/MS ( Condition B-12 ): R _t = 2.16 min. ¹ H NMR (MeOD, δ = 3.34 ppm, 400 MHz): δ 7.89-7.83 (m, 5 H), 7.72-6.99 (m, 3 H), 4.94 (s, 1 H), 4.89 (s, 1 H) , 3.31-3.27 (m, 2 H), 3.08-3.04 (m, 2 H), 2.64-2.57 (m, 2 H), 2.18-2.04 (m, 4 H), 1.98-1.75 (m, 12 H) , 1.16 (s, 9 H), 1.15 (s, 9 H). LC / MS: [M + H ] + C 44 H 55 F 4 N 6 O 2 Calculated: 775.42; Found: 775.4.

Example B11-13A (trifluoroacetate) was prepared in a similar manner from the hydrochloride salt of amine B-10h and the appropriate acid according to the procedure described for Example B10.

Example B13B

Example B13B (trifluoroacetate salt) was prepared in a similar manner from the hydrochloride salt of amine B-10h and 1-(4,4-difluoro-1-hydroxycyclohexyl)cyclopropanecarboxylic acid according to the procedure described for Example B5B. ). HPLC ( Condition B-1 and B-2 ): >97% homogeneity index. LC/MS ( Condition B-18 ): R _t = 2.33 min. ¹ H NMR (MeOD, δ = 3.34 ppm, 400 MHz): δ 7.86-7.81 (m, 5 H), 7.71-7.65 (m, 3 H), 4.91 (s, 2 H), 3.32-3.28 (m, 2) H), 3.07-3.02 (m, 2 H), 2.28-2.17 (m, 4 H), 1.99-1.86 (m, 8 H), 1.65-1.54 (m, 4 H), 1.16 (s, 9 H) , 1.15 (s, 9 H), 1.09-1.02 (m, 2 H), 0.98-0.90 (m, 6 H). LC / MS: [M + H ] + C 50 H 63 F 4 N 6 O 4 Calculated: 887.48; Found: 887.4.

Example B14-16

Example B14-16, step a

In a similar manner from dibromide B-10a and (S)-2-((t-butoxycarbonyl)amino)-3-methylbutyric acid according to the procedure described for the preparation of bromide B-10c Preparation of bromide B14-16a. LC/MS ( Condition B-10 ): R _t = 2.05 min. LC / MS: [M + H ] + C 20 H 27 BN 3 O 2 Calculated: 420.12; Found: 420.2.

Example B14-16, step b

From 2-amino-1-(4-bromophenyl)ethanone hydrochloride and (S)-2-((t-butoxycarbonyl)amine according to the procedure described for the preparation of bromide B-10e Bromide B14-16b was prepared in a similar manner. LC/MS ( Condition B-9 ): R _t = 1.62 min. LC / MS: [M + H ] + C 18 H 25 BrN 3 O 2 Calculated: 394.11; Found: 394.2.

Example B14-16, step c

According to the preparation The procedure described for the ester B-10f, prepared in a similar manner from the bromide B14-16b Acid ester B14-16c. LC/MS ( Condition B-9 ): R _t = 1.83 min. LC / MS: [M + H ] + C 24 H 37 BN 3 O 4 Calculated: 442.28; Found: 442.2.

Example B14-16, step d

According to the procedure described for the preparation of urethane B-10g, bromide B14-16a and Starting with the esters B14-16c, the urethane B14-16d was prepared in a similar manner. LC/MS ( Condition B-10 ): R _t = 2.02 min. ^{LC / MS: [MH] -} C 38 H 49 N 6 O 4 Calculated: 653.39; Found: 653.4.

Example B14-16

Example B14-16 (trifluoroacetate) was prepared in a similar manner starting from the carbamate B14-16d according to the procedure described for the preparation of Example B10-12.

Example B17

Example B17, step a

To a solution of the carbamate B-10g-1 (400 mg, 0.586 mmol) in THF (75 mL), EtOAc (EtOAc (EtOAc) hour. The reaction mixture was cooled to room temperature then diluted with EtOAc. Washed with water, saturated organic layer was washed ₂ CO ₃ Na, dried over Na ₂ SO ₄ and concentrated. By reverse phase HPLC (ACN / water / NH ₄ OAc) crude material was purified to give a brown solid of urethane B-17a (280mg). HPLC ( Condition B-2 ): >97% homogeneity index. LC/MS ( Condition B-10 ): R _t = 2.24 min. ¹ H NMR (MeOD, δ = 3.34 ppm, 400 MHz): δ 8.47 (m, 1 H), 8.28 (d, J = 1.2, 1 H), 7.96 (dd, J = 8.4, 2.0, 1 H), 7.88 -7.81 (m, 5 H), 7.72 (d, J = 8.8, 1 H), 7.49 (s, 1 H), 4.90 - 4.80 (shaded, 1 H), 4.68 (s, 1 H), 1.47 ( s, 18 H), 1.09 (s, 9 H), 1.04 (s, 9 H). ^{LC / MS: [MH] -} C 40 H 51 N 6 O 4 Calculated: 679.4; Found: 679.4.

Example B17, step b

The hydrochloride salt of the amine B-17b (230 mg) was prepared according to the procedure described in the procedure of step B1. LC/MS ( Condition B-10 ): R _t = 1.49 min. ¹ H NMR (MeOD, δ = 3.34 ppm, 400 MHz): δ 8.64 (d, J = 8.4, 1 H), 8.43 (br s, 1 H), 8.12-8.01 (m, 7 H), 7.87 (d, J = 8.8, 1 H), 4.77 (s, 1 H), 4.70 (s, 1 H), 1.26 (s, 9 H), 1.24 (s, 9 H). LC / MS: [M + H ] + C 30 H 37 N 6 Calculated: 481.65; Found: 481.3.

Example B17

The trifluoroacetate salt (64 mg) of Example B17 was prepared according to the procedure described in Example B1. HPLC ( Condition B-1 and B-2 ): >99% homogeneity index. LC/MS ( Condition B-12 ): R _t = 2.671 min. ¹ H NMR (MeOD, δ = 3.34 ppm, 400 MHz): δ 8.56 (d, J = 8.0, 1 H), 8.46 (br s, 1 H), 8.14 (dd, J = 8.8, 2.0, 1 H), 8.10 (d, J = 8.8, 1 H), 8.02 (d, J = 8.8, 2 H), 7.93 (s, 1 H), 7.91 (d, J = 8.8, 2 H), 7.84 (d, J = 8.8,1 H), 5.13 (s, 1 H), 4.95 (s, 1 H), 2.68-2.55 (m, 2 H), 2.20-2.02 (m, 4 H), 2.00-1.70 (m, 12 H ), 1.21 (s, 9 H), 1.17 (s, 9 H). LC / MS: [M + H ] + C 44 H 53 F 4 N 6 O 2 Calculated: 773.41; Found: 773.8.

Example B18-19

Example B18-19 (trifluoroacetate) was prepared from the hydrochloride salt of the amine B-17b and the appropriate acid according to the procedure described for Example B17.

Example B20-22

Example B20-22 (trifluoroacetate) was prepared in a similar manner starting from the carbamate B14-16d according to the procedure described for the preparation of Example B17-19.

Example B23

Example B23, step a

The hydrochloride salt (70 mg) of the amine B-23a was prepared according to the procedure described in the procedure of step B1. LC/MS ( Condition B-10 ): R _t = 1.47 min. ¹ H NMR (MeOD, δ = 3.34 ppm, 400 MHz): δ 7.78 (d, J = 8.0, 2 H), 7.68 (br s, 2 H), 7.67 (d, J = 8.0, 2 H), 4.59 ( s, 1 H), 3.37-3.25 (masked, 4 H), 3.10-3.05 (m, 4 H), 1.21 (s, 9 H). LC / MS: [M + H ] + C 32 H 41 N 6 Calculated: 509.33; Found: 509.4.

Example B23

Example B23 (45.7 mg) was prepared according to the procedure described in Example B1. HPLC ( Condition B-1 and B-3 ): >95% homogeneity index. LC/MS ( Condition B-13 ): R _t = 2.13 min. ¹ H NMR (MeOD, δ = 3.34 ppm, 400 MHz): δ 7.69 (br s, 6 H), 4.97 - 4.80 (shaded, 2 H), 3.28 (t, J = 8.0, 4 H), 3.05 (t) , J = 8.4, 4 H), 2.65-2.57 (m, 2 H), 2.19-2.08 (m, 4 H), 1.99-1.68 (m, 12 H), 1.16 (s, 18 H). ^{LC / MS: [MH] -} C 46 H 55 F 4 N 6 O 2 Calculated: 799.44; Found: 799.4.

Example B24

Example B24, steps a-1 and a-2

The reaction mixture of the urethane B-10g-2 (300 mg, 0.423 mmol) and DDQ (96 mg, 0.423 mmol) in THF was heated at 70 ° C for 2 hours. The reaction mixture was cooled to room temperature and diluted with EtOAc. Washed with water, saturated organic layer was washed ₂ CO ₃ Na, dried over Na ₂ SO ₄ and concentrated. By reverse phase HPLC (ACN / water / NH ₄ OAc) crude material was purified to give an off-white solid of urethane B-24a-1 of the free base (73mg) of. HPLC ( Conditions B-2 and B-7 ): >94% homogeneity index. LC/MS ( Condition B-12 ): R _t = 2.62 min. ¹ H NMR (MeOD, δ = 3.34 ppm, 400 MHz): δ 8.58 (br s, 1 H), 8.24 (s, 1 H), 7.93 (dd, J = 8.8, 1.6, 1 H), 7.79 (d, J=8.8, 2 H), 7.75-7.52 (m, 3 H), 4.90-4.80 (shaded, 1 H), 4.63 (s, 1 H), 3.19 (t, J = 8.0, 2 H), 2.92 (t, J = 8.0, 2 H), 1.47 (s, 18 H), 1.09 (s, 9 H), 1.03 (s, 9 H). ^{LC / MS: [MH] -} C 42 H 53 N 6 O 4 Calculated: 705.42; Found: 705.9. The symmetrical dimer B-24a-2 (79 mg) was obtained as an off-white solid. HPLC ( Condition B-1 and B-2 ): >99% homogeneity index. LC/MS ( Condition B-12 ): R _t = 2.23 min. ¹ H NMR (MeOD, δ = 3.34 ppm, 400 MHz): δ 8.52 (br s, 2 H), 8.40 (s, 2 H), 8.10 (dd, J = 8.8, 2.0, 2 H), 7.87 (d, J = 8.8, 2 H), 7.75 (d, J = 8.8, 2 H), 4.90 - 4.80 (shaded, 2 H), 1.47 (br s, 18 H), 1.10 (br s, 18 H). ^{LC / MS: [MH] -} C 42 H 51 N 6 O 4 Calculated: 703.41; Found: 703.9.

Example B24, step b

The hydrochloride salt (60 mg) of the amine B-24b was prepared according to the procedure described in the procedure of step B1. LC/MS ( Condition B-10 ): R _t = 1.52 min. ¹ H NMR (MeOD, δ = 3.34 ppm, 400 MHz): δ 8.59 (brd, 1 H), 8.36 (br s, 1 H), 8.04 (brd, 1 H), 7.97 (d, J = 8.4, 1 H), 7.87-7.79 (m, 4 H), 4.69 (s, 1 H), 4.61 (s, 1 H), 3.52-3.32 (masked, 2 H), 3.14 (br s, 2 H), 1.23 (s, 18 H). LC / MS: [M + H ] + C 32 H 39 N 6 Calculated: 506.68; Found: 507.4.

Example B24

Example B24 (51.2 mg) was prepared according to the procedure described in Example B1. HPLC ( Condition B-2 ): >99% homogeneity index. LC/MS ( Condition B-12 ): R _t = 2.14 min. ¹ H NMR (MeOD, δ = 3.34 ppm, 400 MHz): δ 8.55 (d, J = 8.8, 1 H), 8.43 (d, J = 1.2, 1 H), 8.12 (dd, J = 8.8, 1.6, 1 H), 8.08 (d, J = 8.8, 1 H), 7.85-7.20 (m, 3 H), 7.75 (d, J = 8.0, 1 H), 5.13 (s, 1 H), 4.92-4.85 (by Shading, 1 H), 3.35-3.29 (shaded, 2 H), 3.10-3.06 (m, 2 H), 2.67-2.58 (m, 2 H), 2.20-2.11 (m, 4 H), 1.98-1.73 (m, 12 H), 1.17 (s, 9 H), 1.15 (s, 9 H). ^{LC / MS: [MH] -} C 46 H 53 F 4 N 6 O 2 Calculated: 797.95; Found: 798.1.

Example B25

Example B25, step a

The hydrochloride salt (60 mg) of the amine B-25a was prepared according to the procedure described in the procedure of step B1. LC/MS ( Condition B-10 ): R _t = 1.61 min. ¹ H NMR (MeOD, δ = 3.34 ppm, 400 MHz): δ 8.69 (d, J = 8.0, 2 H), 8.55 (s, 2 H), 8.25 (d, J = 8.0, 2 H), 8.11 (d) , J = 8.4, 2 H), 7.89 (d, J = 8.4, 2 H), 4.75 (s, 2 H), 1.27 (s, 18 H). LC / MS: [M + H ] + C 32 H 36 N 6 Analysis Calcd: 505.3; Found: 505.4.

Example B25

Example B25 (53 mg) was prepared according to the procedure described in Example B1. HPLC ( Conditions B-1 and B-8 ): >98% homogeneity index. LC/MS ( Condition B-11 ): R _t = 2.09 min. ¹ H NMR (MeOD, δ = 3.34 ppm, 400 MHz): δ 8.60 (d, J = 8.8, 2 H), 8.58 (d, J = 1.6, 2 H), 8.29 (dd, J = 8.8, 1.6, 2 H), 8.15 (d, J = 8.8, 2 H), 7.86 (d, J = 8.8, 2 H), 5.14 (s, 2 H), 2.72-2.61 (m, 2 H), 2.19-2.05 (m) , 4 H), 2.04-1.64 (m, 12 H), 1.22 (s, 18 H). ^{LC / MS: [MH] -} C 46 H 51 F 4 N 6 O 2 Calculated: 795.41; Found: 795.7.

Example B26

Example B26, step a

Under N _2, was added 1-ethoxyvinyl tri-n-butyltin (3.65 mL of medium (20mL) solution of the 2,6-dibromo-anthracene (1.2g, 3.57mmol) in 1,4-dioxane, 10.71 mmol). Then Pd(PPh ₃ ) ₂ Cl ₂ (0.251 g, 0.357 mmol) was added. The reaction mixture was heated at 100 &lt;0&gt;C for 16 h then cooled to rt and diluted with DCM &EtOAc. The organic layer was separated and the aqueous layer was extracted with DCM. The combined organic layers were dried over Na ₂ SO ₄ and concentrated. By Isco Combiflash (silica gel, 12g, Redisep, containing the 0.5% MeOH CHCl ₃₎ Purification of the crude material was washed with petroleum ether and the product was obtained as a yellow solid of 1,1 '- (anthracene-2,6- Base) Diethyl ketone (600 mg). ¹ H NMR (CDCl ₃ , δ = 7.26 ppm, 400 MHz): δ 8.67 (s, 2 H), 8.61 (s, 2 H), 8.44 - 8.04 (m, 4 H), 2.78 (s, 6 H).

Example B26, step b

To a solution of 1,1'-(indol-2,6-diyl)diethyl ketone (500 mg, 1.906 mmol) in 1,4-dioxane was added Br ₂ (0.187 mL, 3.62 mmol). The reaction mixture was stirred at room temperature for 3 hours. Water was then added to the reaction mixture and extracted with DCM. Dried over Na ₂ SO ₄ the combined organic layers were combined and concentrated under reduced pressure to give a yellow solid of dibromide B-26b (800mg).

Example B26, steps c-1 and c-2

B26 c-1

To dibromide B-26b (700 mg, 1.666 mmol) and (S)-2-((t-butoxycarbonyl)amino)-3,3-dimethylbutyric acid (848 mg, at 0 ° C, 3.67 mmol) DIPEA (1.164 mL, 6.67 mmol) was added to a solution in ACN (25 mL). The reaction mixture was stirred at room temperature for 4 hours. Water was then added to the reaction mixture and extracted with EtOAc. The organic layer was washed with 10% NaHCO ₃ and brine. The organic layer was dried over Na ₂ SO ₄ and concentrated. The crude material was purified by Combiflash Isco (EtOAc, 24 g, EtOAc, EtOAc (EtOAc): EtOAc) Mixture (650 mg). B-26c-1: LC/MS ( Condition B-10 ): R _t = 2.55 min. ^{LC / MS: [MH] -} C 40 H 51 N 2 O 10 Calculated: 719.36; Found: 719.2. B-26c-2: R _t = 2.31 min. ^{LC / MS: [MH] -} C 29 H 32 NO 6 Calculated: 490.23; Found: 490.2.

Example B26, steps d-1 and d-2

The diketo ester B-26c-1 and the single-ketoester _{NH 4 OAc B-26c-2} (650mg, 0.902mmol) (1.39g, 18.03mmol) in xylene in the reaction mixture was heated at 130 ℃ 18 hours. The volatile components are then removed. The residue was dissolved in DCM and washed with water. The aqueous layer was extracted with DCM. The combined organic layers were dried over Na ₂ SO ₄ and concentrated. Purification by reverse phase HPLC (ACN / water / NH ₄ OAc) crude material was purified to give a yellow solid of urethane B26d-1 (100mg). LC/MS ( Condition B-10 ): R _t = 2.29 min. ¹ H NMR (MeOD, δ = 3.34 ppm, 400 MHz): δ 8.44 (s, 2 H), 8.32 (br s, 2 H) 8.05 (d, J = 8.8, 2 H), 7.83 (d, J = 8) , 2 H), 7.53 (s, 2 H), 4.70 (s, 2 H), 1.48 (s, 18 H), 1.04 (s, 18 H). ^{LC / MS: [MH] -} C 40 H 51 N 6 O 4 Calculated: 679.41; Found: 679.4. The urethane B26d-2 (54 mg) was obtained as a yellow solid. LC/MS ( Condition B-13 ): R _t = 2.13 min. ¹ H NMR (MeOD, δ = 3.34 ppm, 400 MHz): δ 8.82 (s, 1 H), 8.68 (s, 1 H), 4.51 (s, 1 H), 8.41 (br s, 1 H), 8.13 ( d, J = 8.8, 1 H), 8.09 (d, J = 9.2, 1 H), 7.98 (dd, J = 8.8, 1.6, 1 H), 7.96 - 7.88 (m, 1 H), 7.59 (br s , 1 H), 4.70 (s, 1 H), 2.78 (s, 3 H), 1.47 (s, 9 H), 1.04 (s, 9 H). LC / MS: [M + H ] + C 29 H 34 N 3 O 3 Calculated: 472.25; Found: 472.2.

Example B26, step e

The hydrochloride salt of the amine B-26e (100 mg) was prepared according to the procedure described in the procedure of step b1. LC/MS ( Condition B-13 ): R _t = 1.85 min. ¹ H NMR (MeOD, δ = 3.34 ppm, 400 MHz): δ 8.60 (s, 4 H), 8.19 (d, J = 8.8, 2 H), 8.03 (s, 2 H), 7.95 (dd, J = 8.8 , 1.6, 2 H), 4.58 (s, 2 H), 1.23 (s, 18 H). LC / MS: [M + H ] + C 30 H 37 N 6 Analysis Calcd: 481.3; Found: 481.2.

Example B26

Example B26 (32 mg) was prepared according to the procedure described in Example B1. HPLC ( Conditions B-6 and B-8 ): >93% homogeneity index. LC/MS ( Condition B-12 ): R _t = 2.71 min. ¹ H NMR (MeOD, δ = 3.34 ppm, 400 MHz): δ 8.64 (s, 2 H), 8.50 (d, J = 0.4, 2 H), 8.24 (d, J = 9.2, 2 H), 8.03 (s) , 2 H), 7.86 (dd, J = 9.03, 1.6, 2 H), 5.01 (s, 2 H), 2.68-2.57 (m, 2 H), 2.21-2.07 (m, 4 H), 2.02-1.71 (m, 12 H), 1.17 (s, 18 H). LC / MS: [M + H ] + C 44 H 53 F 4 N 6 O 2 Calculated: 773.41; Found: 773.5.

Example B27

Example B27 (trifluoroacetate) was prepared in a similar manner from the hydrochloride salt of the amine B-26e and pivalic acid according to the procedure described for Example B26. HPLC ( Condition B-1 and B-2 ): >92% homogeneity index. LC/MS ( Condition B-10 ): R _t = 2.18 min. ^{LC / MS: [MH] -} C 40 H 51 N 6 O 2 Calculated: 647.42; Found: 647.4.

Example B28

Example B28, step a

The hydrochloride salt (60 mg) of the amine B-28a was prepared according to the procedure described in the procedure of step B1. LC/MS ( Condition B-13 ): R _t = 1.93 min. ¹ H NMR (D ₂ O, δ = 4.79 ppm, 400 MHz): δ 7.73-7.34 (m, 7 H), 7.18-7.15 (m, 2 H), 4.90-4.40 (shaded, 1 H), 2.29 ( s, 3 H), 1.13 (s, 9 H). LC / MS: [M + H ] + C 24 H 26 N 3 O Calculated: 372.2; Found: 372.2.

Example B28

Example B28 (36 mg) was prepared according to the procedure described in Example B1. HPLC ( Condition B-1 and B-2 ): >99% homogeneity index. LC/MS ( Condition B-12 ): R _t = 3.22 min. ¹ H NMR (MeOD, δ = 3.34 ppm, 400 MHz): δ 8.85 (s, 1 H), 8.77 (s, 1 H), 8.61 (s, 1 H), 8.47 (s, 1 H), 8. , J = 8.8, 1 H), 8.15 (d, J = 8.8, 1 H), 8.05 (s, 1 H), 8.02 (dd, J = 8.8, 1.6, 1 H), 7.84 (dd, J = 8.8 , 2.0, 1 H), 4.99 (s, 1 H), 2.79 (s, 3 H), 2.68-2.56 (m, 1 H), 2.21-2.04 (m, 2 H), 1.99-1.69 (m, 6) H), 1.18 (s, 9 H). LC / MS: [M + H ] + C 31 H 34 F 2 N 3 O 2 Calculated: 518.25; Found: 518.1.

Example B29-31

Prepared in a similar manner starting from dibromide B-26b and (S)-2-((t-butoxycarbonyl)amino)-3-methylbutyric acid according to the procedure described for Preparation Example B26 Example B29-31 (trifluoroacetate).

Example B32

Example B32, step a

Add HATU (16.25 g, 42.7 mmol) to 4-iodobenzene-1,2-diamine (10 g, 42.7 mmol), (S)-2-((t-butoxycarbonyl)amine at 0 °C A solution of -3,3-dimethylbutyric acid (9.88 g, 42.7 mmol) and DIPEA (14.93 mL, 85 mmol) The reaction mixture was diluted with water and EtOAc. Washed with water, 10% NaHCO ₃ solution, the organic layer was washed with brine, dried over Na ₂ SO ₄ dried and concentrated to give (S) - (1 - ( (2- amino-5-iodo-phenyl) amino) -3,3 -Dimethyl-1-oxobutan-2-yl)carbamic acid tert-butyl ester (20 g). LC/MS ( Condition B-10 ): R _t = 1.94 min. LC / MS: [M + H ] + C 17 H 27 IN 3 O 3 Calculated: 448.10; Found: 448.2.

AcOH (150 mL) was added to a crude urethane mixture (20 g, 44.7 mmol), and the reaction mixture was stirred at <RTIgt; The volatile components were removed; the residue was dissolved in EtOAc and neutralized with 10% EtOAc. The organic layer was separated and washed with water, brine, dried over Na ₂ SO ₄ and concentrated. The crude material was purified by flash chromatography eluting elut elut elut elut elut elut elut LC/MS ( Condition B-10 ): R _t = 1.97 min. ¹ H NMR (MeOD, δ = 3.34 ppm, 400 MHz): δ 7.91 (s, 1 H), 7.54 (d, J = 8.4, 1.6, 1 H), 7.37 (d, J = 8.4, 1 H), 4.69 (br s, 1 H), 1.47 (s, 9 H), 1.03 (s, 9 H). LC / MS: [M + H ] + C 17 H 25 IN 3 O 2 Calculated: 430.09; Found: 430.0.

Example B32, steps b-1 and b-2 and b-3

B32 b-2 B 32 b-3

Add 1,4-bis(4,4,5,5-tetramethyl-1,3,2-dioxaborate to a solution of iodide B-32a (2 g, 4.66 mmol) in MeOH (20 mL) 2-yl) benzene (3.08g, 9.32mmol), and the reaction mixture for 10 minutes with N ₂ purge. Then K ₂ CO ₃ (2.58 g, 18.64 mmol), Pd(Ph ₃ P) ₄ (0.538 g, 0.466 mmol) were added sequentially, and the reaction mixture was further purified with N _{2 for} 10 min. The reaction mixture was then heated to 85 ° C under microwave conditions for 2 hours. The volatile components were removed and the residue obtained was dissolved in EtOAc. The organic layer was washed with water and aqueous extracted with EtOAc. Washed with brine the organic layers were combined, dried over Na ₂ SO ₄ dried and concentrated. By reverse phase HPLC (ACN / water / NH ₄ OAc) crude material was purified to give a pale yellow solid of urethane B32b-1 (325mg). HPLC ( Conditions B-1 and B-2 ): >96% homogeneity index. LC/MS ( Condition B-12 ): R _t = 2.19 min. ¹ H NMR (MeOD, δ = 3.34 ppm, 400 MHz): δ 7.85 (s, 2 H), 7.79 (s, 4 H), 7.69-7.60 (m, 4 H), 4.76 (br s, 2 H), 1.47 (br s, 18 H), 1.07 (s, 18 H). ^{LC / MS: [MH] -} C 40 H 51 N 6 O 4 Calculated: 680.88; Found: 679.8. Also separated into a mixture Acid ester B32b-2 Acid B32b-3 (500 mg). B32b-2: LC/MS ( Condition B-10 ): R _t = 2.25 min. LC / MS: [M + H ] + C 29 H 41 BN 3 O 4 Calculated: 506.31; Found: 506.4; B32b-3: R t = 1.66min. LC / MS: [M + H ] + C 23 H 31 BN 3 O 4 Calculated: 424.23; Found: 424.2.

Example B32, step c

The hydrochloride salt (225 mg) of the amine B-32c was prepared according to the procedure described in the procedure of step B1. LC/MS ( Condition B-10 ): R _t = 1. 44 min. ¹ H NMR (MeOD, δ = 3.34 ppm, 400 MHz): δ 8.12 (s, 2 H), 7.94 (s, 4 H), 7.89 (s, 4 H), 4.78 (s, 2 H), 1.25 ( s, 18 H). LC / MS: [M + H ] + C 30 H 37 N 6 Analysis Calcd: 481.3; Found: 481.4.

Example B32

Example B32 (53.9 mg) was prepared according to the procedure described in Example B1. HPLC ( Conditions B-1 and B-2 ): >98% homogeneity index. LC/MS ( Condition B-12 ): R _t = 2.10 min. ¹ H NMR (MeOD, δ = 3.34 ppm, 400 MHz): δ 8.35 - 8.20 (m, 2 H), 7.93 (dd, J = 8.4, 1.6, 2 H), 7.78 (br s, 4 H), 7.86 ( d, J=8.4, 2 H), 4.99 (s, 2 H), 2.68-2.60 (m, 2 H), 2.19-2.06 (m, 4 H), 2.02-1.63 (m, 12 H), 1.20 ( s, 18 H). ^{LC / MS: [MH] -} C 44 H 51 F 4 N 6 O 2 Calculated: 771.41; Found: 771.9.

Example B33-34

Example B33-34 (trifluoroacetate) was prepared in a similar manner starting from the amine B-32c and the appropriate acid according to the procedure described for Example B32.

Example B35-37

Example B35-37, step a

4-iodobenzene-1,2-diamine and (S)-2-((t-butoxycarbonyl)amino)-3-methylbutanoic acid according to the procedure described for iodide B-32a Initially, iodide B35-37a was prepared in a similar manner.

Example B35-37, step b

Under N ₂ , to B35-37a (1 g, 2.408 mmol) and 1,4-bis(4,4,5,5-tetramethyl-1,3,2-dioxaboron 2-yl) benzene (0.397g, 1.204mmol) in toluene _{/ EtOH / H 2 O (15mL} , 1: 1: Add _{Cs 2 CO 3 (3.14g, 9.63mmol} ) 1) in the stirred solution. Next, PdCl ₂ (dppf)-DCM adduct (0.197 g, 0.241 mmol) was added, and the resulting mixture was heated at 105 ° C for 16 hours. After cooling to room temperature, the solid was filtered, and by reverse phase HPLC (ACN / water / NH ₄ OAc) The solid was purified to give an off-white solid of urethane B35-37b (80mg). HPLC ( Conditions B-1 and B-2 ): >98% homogeneity index. LC/MS ( Condition B-12 ): R _t = 2.81 min. LC / MS: [M + H ] + C 38 H 49 N 6 O 4 Calculated: 653.27; Found: 653.4.

Example B35-37

According to the procedure described for Example B32, the urethane B35-37b and the appropriate acid Starting, Example B35-37 (trifluoroacetate) was prepared in a similar manner.

Example B38

Example B38, step a

Under _{N 2, 4 (0.269g, 0.233mmol} ) in DMF was added bis (trimethylstannyl) acetylene (0.410 (10mL) in a solution of the iodide B32a (1g, 2.329mmol) and Pd (TPP) g, 1.165 mmol), and the reaction mixture was heated at 90 ° C for 12 hours. The reaction mixture was filtered through diatomaceous earth (Celite ^®), and the filtrate was concentrated. The residue was dissolved in EtOAc and washed water and brine. The organic layer was dried over Na ₂ SO ₄ and concentrated. By combiflash Isco (silica gel, 4Og, containing the ₃ CHCl 3% MeOH) to give the crude material as a white solid of urethane B38a (320mg). LC ( Condition B-2 and B-8 ): >98% homogeneity index. LC/MS ( Condition B-12 ): R _t = 2.40 min. ¹ H NMR (DMSO-d ₆ , δ = 2.50 ppm, 400 MHz): δ 12.38/12.34 (s, 2 H), 7.61/7.52 (d, J = 8.4, 2 H), 7.40-7.30 (m, 2 H) ), 7.03 (d, J = 9.6, 2 H), 4.68 (d, J = 8.8, 2 H), 1.39 (s, 18 H), 0.96 (s, 18 H). LC / MS: [M + H ] + C 36 H 49 N 6 O 4 Calculated: 629.37; Found: 629.3.

Example B38, step b

The hydrochloride salt (230 mg) of the amine B-38b was prepared according to the procedure described in the procedure of step B1. ¹ H NMR (MeOD, δ = 3.34 ppm, 400 MHz): δ 7.91 (s, 2 H), 7.74 (d, J = 8.4, 2 H), 7.61 (dd, J = 8.4, 1.1, 2 H), 4.57 (s, 2 H), 1.18 (s, 18 H).

Example B38

Example B38 (72 mg) was prepared according to the procedure described in Example B1. LC ( Condition B-1 and B-2 ): >99% homogeneity index. LC/MS ( Condition B-13 ): R _t = 2.03 min. ¹ H NMR (MeOD, δ = 3.34 ppm, 400 MHz): δ 7.94 (s, 2 H), 7.77 (d, J = 8.8, 2 H), 7.72 (dd, J = 8.8, 1.2, 2 H), 4.97 (s, 2 H), 2.65-2.58 (m, 2 H), 2.18-2.03 (m, 4 H), 1.97-1.67 (m, 12 H), 1.16 (s, 18 H). LC / MS: [M + H ] + C 40 H 49 F 4 N 6 O 2 Calculated: 721.38; Found: 721.4.

Example B39-41B

Example B39-41B (trifluoroacetate) was prepared in a similar manner starting from iodide B-38b and the appropriate acid according to the procedure described for Example B38.

Example B42-44

Example B42-44 (trifluoroacetate) was prepared in a similar manner starting from iodide B35-37a and bis(trimethylstannyl) acetylene according to the procedure described for Example B38-40.

Example B45-46 Example B45

Example B46

Example B45-46, step a

Under N _2, was added DIPEA (5.70mL, 32.6mmol) of iodide in the B-32a (2g, 4.66mmol) in DMF (20mL) solution, followed by addition of alkyl trimethyl silicon acetylene (6.54mL, 46.6mmol ), CuI (0.444 g, 2.329 mmol) and Pd(PPh ₃ ) ₂ Cl ₂ (1.177 g, 1.677 mmol). The reaction mixture was stirred at room temperature for 10 minutes and heated at 90 °C for 12 hours. The reaction mixture was then filtered through diatomaceous earth (Celite ^®). The filtrate was diluted with EtOAc, washed with water, washed with saturated NH ₄ Cl and brine. The organic layer was dried over Na ₂ SO ₄ and concentrated. By Combiflash Isco (silica gel, 12g, Redisep, containing the ₃ CHCl 3% MeOH) to give the crude material as a brown solid to give the alkyne alkyl trimethyl silicon B45-46a (860mg). LC/MS ( Condition B-10 ): R _t = 2.26 min. LC / MS: [M + H ] + C 22 H 34 N 3 O 2 Si Calculated: 400.23; Found: 400.2.

Example B45-46, step b

To a solution of trimethyldecylalkylalkyne B45-46a (944 mg, 2.312 mmol) and bromide B-10e (840 mg, 2.102 mmol) in DMF (20 mL), TEA (0.879 mL, 6.31 mmol), CuI 40.0 mg, 0.210 mmol) and Pd(PPh ₃ ) ₂ Cl ₂ (148 mg, 0.210 mmol), and the reaction mixture was heated at 70 °C. Then TBAF (1 M in THF) (2.102 mL, 2.102 mmol) was added and the mixture The reaction mixture was then filtered through Celite ^® and the filtrate was concentrated. The residue was dissolved in EtOAc and washed with water, washed with saturated NH ₄ Cl and brine. The organic layer was dried over Na ₂ SO ₄ and concentrated. By Combiflash Isco (silica gel, 24g, Redisep, 3% MeOH / CHCl 3) Purification of the crude material obtained urethane and B-45b B-46b (corresponding to 70: 30) of the mixture.

Example B45-46, step c

The hydrochloride salts of amines B-45c and B-46c were prepared according to the procedure described in step b of Example B1.

Example B45-46

Examples B45 and B46 were prepared according to the procedure described in Example B1 and isolated by preparative HPLC. Example B45: LC ( Condition B-1 and B-2 ): >95% homogeneity index. LC/MS ( Condition 15 ): R _t = 2.15 min. ¹ H NMR (MeOD, δ = 3.34 ppm, 400 MHz): δ 7.92 (s, 1 H), 7.90-7.89 (m, 1 H), 7.82-7.78 (m, 2 H), 7.76-7.70 (m, 3) H), 7.68/7.65 (d, J=1.6, 1 H), 4.99 (s, 1 H), 4.93 (s, 1 H), 2.65-2.56 (m, 2 H), 2.18-2.04 (m, 4) H), 1.96-1.68 (m, 12 H), 1.15 (s, 9 H), 1.14 (s, 9 H). LC / MS: [M + H ] + C 42 H 51 F 4 N 6 O 2 Calculated: 747.39; Found: 747.4. Example B46: LC ( Conditions B-1 and B-5 ): >91% homogeneity index. LC/MS ( Condition B-13 ): R _t = 2.13 min. ¹ H NMR (MeOD, δ = 3.34 ppm, 400 MHz): δ 7.91 (s, 2 H), 7.73 (d, J = 8.4, 2 H), 7.64 (dd, J = 8.4, 1.2, 2 H), 4.97 (s, 2 H), 2.66-2.56 (m, 2 H), 2.18-2.06 (m, 4 H), 1.99-1.65 (m, 12 H), 1.15 (s, 18 H). ^{LC / MS: [MH] -} C 42 H 47 F 4 N 6 O 2 Calculated: 743.38; Found: 743.4.

Example B47-50

Example B47-48

Example B49-50

Example B47-50 (trifluoroacetate) was prepared in a similar manner starting from a mixture of amine B-45c and amine B-46c according to the procedure described for Example B45-46.

Example B48A

Example B48A (trifluoroacetate) was prepared in a similar manner starting from pure amine B-45c and the appropriate acid according to the procedure described for Example B45-46. HPLC ( Condition B-1 and B-2 ): >97% homogeneity index. LC/MS ( Condition B-15 ): R _t = 2.25 min. ¹ H NMR (MeOD, δ = 3.34 ppm, 400 MHz): δ 7.89 (s, 1 H), 7.78 (s, 1 H), 7.78 (d, J = 8.4, 2 H), 7.72 (d, J = 8.4 , 2 H), 7.71 (d, J = 8.8, 1 H), 7.64 (d, J = 8.8, 1 H), 4.95 (s, 1 H), 4.91 (s, 1 H), 2.28-2.05 (m) , 4 H), 1.97-1.60 (m, 12 H), 1.29 (s, 3 H), 1.27 (s, 3 H), 1.20 (s, 3 H), 1.18 (s, 3 H), 1.14 (s) , 18 H). ^{LC / MS: [MH] -} C 48 H 61 F 4 N 6 O 4 Calculated: 861.48; Found: 861.4.

Example B48B

Example B48B (trifluoroacetate) was prepared in a similar manner starting from pure amine B-45c, the appropriate acid, according to the procedure described for Example B5B. ( Conditions B-1 and B-2 ): >98% homogeneity index. LC/MS ( Condition B-18 ): R _t = 2.21. ^{LC / MS: [MH] -} C 48 H 57 F 4 N 6 O 4 Calculated: 857.45; Found: 857.2.

Example B51

Example B51, step a

Was added DIPEA (2.94mL, 16.86mmol) and CuI (0.092g, 0.482mmol) in the under N _2, to iodide B35-37a (500mg, 1.29mmol) in DMF (10mL) stirred solution. Then, trimethyldecyl acetylene (1.689 mL, 12.04 mmol), Pd(PPh ₃ ) ₂ Cl ₂ (0.5 g, 0.71 mmol) was added, and the reaction mixture was stirred at 90 ° C for 12 hours. The reaction was then diluted with EtOAc, and the washed with saturated NH ₄ Cl, brine. The organic layer was dried over Na ₂ SO ₄ and concentrated. The crude material was purified with EtOAc EtOAc EtOAc (EtOAc) LC/MS ( Condition B-10 ): R _t = 2.21. LC / MS: [M + H ] + C 21 H 32 N 3 O 2 Si Calculated: 386.22; Found: 386.2.

Example B51, steps b-1 and b-2

Under N _2, the silicon of the trimethyl alkyl alkyne B-51a (0.7g, 1.815mmol) and the bromide B14-16b (0.716g, 1.815mmol) in DMF (15mL) under nitrogen was added TEA ( 0.759 mL, 5.45 mmol) followed by CuI (0.035 g, 0.182 mmol) and Pd(PPh ₃ ) ₂ Cl ₂ (0.127 g, 0.182 mmol). TBAF (1 M in THF) (0.475 g, 1.815 mmol) was slowly added at 70 ° C and the reaction mixture was stirred at 70 C for 12 hr. The reaction was then diluted with EtOAc, and the washed with saturated NH ₄ Cl, brine. The organic layer was dried over Na ₂ SO ₄ and concentrated. By reverse phase HPLC (ACN / water / NH ₄ OAc) crude material was purified to give a pale yellow solid of urethane B51b-1 (0.17g). LC/MS ( Condition B-12 ): R _t = 2.17 min. LC / MS: [M + H ] + C 36 H 47 N 6 O 4 Calculated: 627.36; Found: 627.3. The urethane B51b-2 (50 mg, 0.083 mmol) was obtained as a white solid. LC/MS ( Condition B-12 ): R _t = 2.15 min. LC / MS: [M + H ] + C 36 H 45 N 6 O 4 Calculated: 625.34; Found: 625.3.

Example B51

Example B51 (trifluoroacetate) was prepared in a similar manner starting from the carbamate B51b-1 according to the procedure described for Example B45-46. HPLC ( Condition B-1 and B-2 ): >99% homogeneity index. LC/MS ( Condition B-12 ): R _t = 2.04 min. LC / MS: [M + H ] + C 40 H 47 F 4 N 6 O 2 Calculated: 719.36; Found: 719.3.

Example B52

Example B52 (trifluoroacetate) was prepared in a similar manner starting from the carbamate B51b-2 according to the procedure described for Example B45-46. HPLC ( Conditions B-1 and B-2 ): >98% homogeneity index. LC/MS ( Condition B-14 ): R _t = 2.17 min. ^{LC / MS: [MH] -} C 40 H 43 F 4 N 6 O 2 Calculated: 715.35; Found: 715.2.

Example B53

Example B53, step a

Under N _2, was added to the bis bromide B-1d (2.0g, 4.36mmol) in 1,4-dioxane (20mL) in a solution of (roots pinacolato) diboron (1.773g, 6.98mmol) And KOAc (1.285 g, 13.09 mmol), followed by the addition of PdCl ₂ (dppf) (0.160 g, 0.218 mmol), and the reaction mixture was heated to 100 ° C under microwave conditions for 3 hours. The volatile components were removed and the residue obtained was taken in EtOAc and washed with water. The organic layer was separated and aqueous layer was extracted with EtOAc. Washed with brine the organic layers were combined, dried over Na ₂ SO ₄ dried and concentrated. The residue was washed with EtOAc EtOAc /EtOAc Acid ester B-53a (2.2 g). LC/MS ( Condition B-10 ): R _t = 2.39 min. _{^{[M + H] + C 29}} H 41 BN 3 O 4 Calculated: 506.31; Found: 506.4.

Example B53, step b

Under N _2, was added (15mL) to a solution of the iodide in the B-32a (1g, 2.329mmol) in MeOH Acid ester B-53a (1.177 g, 2.329 mmol) and K ₂ CO ₃ (0.966 g, 6.99 mmol), followed by Pd(Ph ₃ P) ₄ (0.135 g, 0.116 mmol), and the reaction mixture was heated at 80 ° C 14 hours. The volatile components were removed and the residue obtained was taken in EtOAc and washed with water. The organic layer was separated and aqueous layer was extracted with EtOAc. Washed with brine the organic layers were combined, dried over Na ₂ SO ₄ dried and concentrated. By reverse phase HPLC (ACN / water / NH ₄ OAc) crude material was purified to give an off-white solid of urethane B-53b (170mg). HPLC ( Condition B-1 and B-2 ): >95% homogeneity index. LC/MS ( Condition B-12 ): R _t = 2.21. min. ¹ H NMR (MeOD, δ = 3.34 ppm, 400 MHz): δ 8.21 (br s, 1 H), 8.12 (br s, 1 H), 8.02-7.83 (m, 5 H), 7.74-7.46 (m, 3) H), 4.76 (s, 1 H), 4.68 (s, 1 H), 1.47 (s, 18 H), 1.07 (s, 9 H), 1.03 (s, 9 H). ^{LC / MS: [MH] -} C 40 H 51 N 6 O 4 Calculated: 679.88; Found: 680.8.

Example B53, step c

The hydrochloride salt of the amine B-53c was prepared according to the procedure described in step b of Example B1. LC/MS ( Condition B-10 ): R _t = 1.56 min. ¹ H NMR (MeOD, δ = 3.34 ppm, 400 MHz): δ 8.52 (s, 1 H), 8.29 (s, 1 H), 8.19-8.13 (m, 4 H), 8.02-7.88 (m, 4 H) , 4.78 (s, 1 H), 4.65 (s, 1 H), 1.26 (s, 9 H), 1.24 (s, 9 H). ^{LC / MS: [MH] -} C 30 H 35 N 6 Analysis Calcd: 479.3; Found: 479.2.

Example B53

Example B53 was prepared according to the procedure described in Example B1. HPLC ( Condition B-1 ): >97% homogeneity index. LC/MS ( Condition B-10 ): R _t = 2.02 min. ¹ H NMR (MeOD, δ = 3.34 ppm, 400 MHz): δ 8.34 (br s, 1 H), 8.29 (br s, 1 H), 8.16 (d, J = 8.8, 1 H), 8.13 (d, J) = 8.8, 1 H), 8.10 (br s, 1 H), 8.01-7.97 (m, 3 H), 7.91-7.86 (m, 2 H), 5.01 (s, 1 H), 4.98 (s, 1 H) ), 2.64-2.57 (m, 2 H), 2.18-2.05 (m, 4 H), 1.99-1.70 (m, 12 H), 1.20 (s, 9 H), 1.18 (s, 9 H). ^{LC / MS: [MH] -} C 44 H 51 F 4 N 6 O 2 Calculated: 771.41; Found: 771.4.

Example B54

Example B54 (trifluoroacetate) was prepared in a similar manner starting from the hydrochloride salt of the amine B-53c and pivalic acid according to the procedure described for Example B53. HPLC ( Condition B-1 ): >97% homogeneity index. LC/MS ( Condition B-10 ): R _t = 2.08 min. ^{LC / MS: [MH] -} C 40 H 51 N 6 O 2 Calculated: 647.42; Found: 647.4.

Example B55

Example B55 (trifluoroacetate) was prepared in a similar manner starting from bromide B7-9a and iodide B35-37a according to the procedure described for Example B53. HPLC ( Conditions B-1 and B-2 ): >96% homogeneity index. LC/MS ( Condition B-12 ): R _t = 2.02 min. LC / MS: [M + H ] + C 42 H 49 F 4 N 6 O 2 Calculated: 745.38; Found: 745.2.

Example B56

Example B56, step a

Under N _2, the bromide was added to the B-10e (285mg, 0.698mmol) in MeOH (15mL) solution of The esters B32b-2 and 32b-3 (353 mg, 0.698 mmol) and K ₂ CO ₃ (193 mg, 1.396 mmol) were then added Pd(Ph ₃ P) ₄ (40.3 mg, 0.035 mmol). The reaction mixture was heated at 80 ° C for 14 hours. The volatile components were removed and the residue obtained was taken in EtOAc and washed with water. The organic layer was separated and aqueous layer was extracted with EtOAc. Washed with brine the organic layers were combined, dried over Na ₂ SO ₄ dried and concentrated. By reverse phase HPLC (ACN / water / NH ₄ OAc) crude material was purified to give an off-white solid of urethane B- 56a (245mg). HPLC ( Condition B-1 and B-2 ): >95% homogeneity index. LC/MS ( Condition B-10 ): R _t = 2.18 min. ¹ H NMR (MeOD, δ = 3.34 ppm, 400 MHz): δ 7.87-7.72 (m, 9 H), 7.69-7.58 (m, 2 H), 7.40 (s, 1 H), 4.76 (s, 1 H) , 4.67 (s, 1 H), 1.47 (br s, 18 H), 1.07 (s, 9 H), 1.01 (s, 9 H). ^{LC / MS: [MH] -} C 42 H 53 N 6 O 4 Calculated: 705.42; Found: 705.4.

Example B56, step c

The hydrochloride salt of the amine B-56b was prepared according to the procedure described in step b of Example B1. LC/MS ( Condition B-10 ): R _t = 1.62 min. ¹ H NMR (MeOD, δ = 3.34 ppm, 400 MHz): δ 8.10 (s, 1 H), 8.04 (br s, 1 H), 8.01 (d, J = 8.4, 2 H), 7.91 (d, J = 8.4, 2 H), 7.87-7.82 (m, 6 H), 4.74 (s, 1 H), 4.64 (s, 1 H), 1.24 (s, 9 H), 1.23 (s, 9 H). ^{LC / MS: [MH] -} C 32 H 37 N 6 Calculated: 505.32; Found: 505.3.

Example B56

Example B56 was prepared according to the procedure described in Example B1. HPLC ( Condition B-1 and B-2 ): >99% homogeneity index. LC/MS ( Condition B-12 ): R _t = 2.19 min. ¹ H NMR (MeOD, δ = 3.34 ppm, 400 MHz): δ 8.00 (s, 1 H), 7.92-7.82 (m, 11 H), 5.00 (s, 1 H), 4.94 (s, 1 H), 2.64 -2.55 (m, 2 H), 2.19-2.04 (m, 4 H), 2.00-1.65 (m, 12 H), 1.19 (s, 9 H), 1.16 (s, 9 H). LC / MS: [M + H ] + C 46 H 55 F 4 N 6 O 2 Calculated: 799.42; Found: 799.4.

Example B57

Example B57, step a

Under N ₂ 2,5-dibromothiophene (1.063 g, 4.39 mmol) and K ₂ CO ₃ (1.821 g, 13.18 mmol) were added to a solution of the acid ester B-10f (2 g, 4.39 mmol) in MeOH (5 mL). Pd(Ph ₃ P) ₄ (0.254 g, 0.220 mmol), and the reaction mixture was heated at 80 ° C for 14 hr. The volatile components were removed and the residue obtained was taken in EtOAc and washed with water. The organic layer was separated and aqueous layer was extracted with EtOAc. Washed with brine the organic layers were combined, dried over Na ₂ SO ₄ dried and concentrated. The crude material was purified with EtOAc EtOAc EtOAc (EtOAc) LC/MS ( Condition B-10 ): R _t = 2.33 min. ¹ H NMR (MeOD, δ = 3.34 ppm, 400 MHz): δ 7.79-7.62 (m, 2 H), 7.61 (d, J = 8.4, 2 H), 7.43 - 7.37 (m, 1 H), 7.22 (d) , J = 4.0, 1 H), 7.12 (d, J = 4.0, 1 H), 4.64 (s, 1 H), 1.47 (s, 9 H), 1.00 (s, 9 H). LC / MS: [M + H ] + C 23 H 29 BrN 3 O 2 S Calculated: 491.46; Found: 492.2.

Example B57, steps b-1 and b-2

Under N _2, the urethane B-57a (600mg, 1.223mmol) in 1,4-dioxane (20mL) was added in the bis (pinacolato basic frequency) diboron (652mg, 2.57mmol And K ₂ CO ₃ (516 mg, 5.26 mmol) followed by Pd(Ph ₃ P) ₄ (70.7 mg, 0.061 mmol). The reaction mixture was heated to 90 ° C under microwave conditions for 12 hours. The volatile components were removed and the residue obtained was taken in EtOAc and washed with water. The organic layer was separated and aqueous layer was extracted with EtOAc. Washed with brine the organic layers were combined, dried over Na ₂ SO ₄ dried and concentrated. The residue was washed with 5% EtOAc / petroleum ether. Acid ester B57b-1 (21%) and Mixture of acid B57b-2 (840 mg). B57b-1: LC/MS ( Condition B-10 ): R _t = 2.32 min. _{^{[M + H] + C 29}} H 41 BN 3 O 4 S Calculated: 538.28; Found: 538.3. B57b-2: R _t = 1.67 min. _{^{[M + H] + C 23}} H 31 BN 3 O 4 S Calculated: 456.21; Found: 456.2.

Example B57, step c

Under N ₂ Acid ester B57b-1 and B57b-2 mixture (850mg, 1.581mmol) in MeOH was added the acid (15mL) solution of the iodide in the B-1i (600mg, 1.581mmol) and _{K 2 CO 3 (437mg, 3.16mmol} ), followed by addition of Pd (Ph ₃ P) ₄ (91 mg, 0.079 mmol). The reaction mixture was heated at 80 ° C for 14 hours. The volatile component was then removed and the residue obtained was taken in EtOAc and washed with water. The organic layer was separated and aqueous layer was extracted with EtOAc. Washed with brine the organic layers were combined, dried over Na ₂ SO ₄ dried and concentrated. By reverse phase HPLC (ACN / water / NH ₄ OAc) crude material was purified to give an off-white solid of B-57c (120mg). HPLC ( Condition B-1 and B-2 ): >95% homogeneity index. LC/MS ( Condition B-12 ): R _t = 2.22 min. ¹ H NMR (MeOD, δ = 3.34 ppm, 400 MHz): δ 7.75-7.71 (m, 2 H), 7.68 (d, J = 8.4, 2 H), 7.39 (br s, 1 H), 7.37 (d, J = 3.6, 1 H), 7.9 (br s, 1 H), 7.7 (d, J = 3.6, 1 H), 4.65 (s, 1 H), 4.63 (s, 1 H), 1.47 (s, 18) H), 1.01 (s, 9 H), 1.00 (s, 9 H). LC / MS: [M + H ] + C 36 H 51 N 6 O 4 S Calculated: 663.36; Found: 663.2.

Example B57, step d

The hydrochloride salt of amine B-57d was prepared according to the procedure described in step b of Example B1. LC/MS ( Condition B-10 ): R _t = 1.50 min. ¹ H NMR (MeOD, δ = 3.34 ppm, 400 MHz): δ 8.04 (br s, 1 H), 7.93 (d, J = 8.0, 2 H), 7.83 (d, J = 8.0, 2 H), 7.70 ( s, 1 H), 7.53 (s, 1 H), 7.49 (s, 1 H), 4.68 (s, 1 H), 4.42 (s, 1 H), 1.21 (s, 9 H), 1.17 (s, 9 H). LC / MS: [M + H ] + C 26 H 35 N 6 S Calculated: 463.26; Found: 463.2.

Example B57

Example B57 was prepared according to the procedure described in Example B1. HPLC ( Condition B-1 and B-2 ): >99% homogeneity index. LC/MS ( Condition B-12 ): R _t = 2.21. ¹ H NMR (DMSO-d ₆ , δ = 2.50 ppm, 400 MHz): δ 14.40 (m, 2 H), 8.32 (br s, 1 H), 8.19-8.02 (m, 2 H), 7.85-7.77 (m) , 4 H), 7.60 (br s, 2 H), 7.38 (br s, 1 H), 4.91-4.82 (m, 2 H), 2.60-2.45 (shadowed, 2 H), 2.10 - 1.99 (m, 2 H), 1.95-1.67 (m, 8 H), 1.61-1.49 (m, 4 H), 1.02 (s, 9 H), 0.97 (s, 9 H). LC / MS: [M + H ] + C 40 H 51 F 4 N 6 O 2 S Calculated: 755.37; Found: 755.4.

Example B58

Example B58, step a

Under N ₂ Add Pd (PPh ₃ ) to a solution of the ester B-10f (2 g, 4.39 mmol), iodide B-32a (1.885 g, 4.39 mmol) and K ₂ CO ₃ (1.821 g, 13.18 mmol) in MeOH (25 mL) ₄ (0.254 g, 0.220 mmol). The reaction mixture was heated at 80 ° C overnight. Diatomaceous earth (Celite ^®) The reaction mixture was filtered, and washed with EtOAc. The filtrate was concentrated and the residue was crystallised eluted eluted eluting The organic layer was dried over Na ₂ SO ₄ and concentrated. By Combiflash Isco (silica gel, 40g, 2.5% MeOH / CHCl 3) and reverse phase HPLC (ACN / water / NH ₄ OAc) crude material was purified to give a pale yellow solid of urethane B-58a (225mg ). HPLC ( Conditions B-1 and B-2 ): >96% homogeneity index. LC/MS ( Condition B-12 ): R _t = 2.20 min. ¹ H NMR (MeOD, δ = 3.34 ppm, 400 MHz): δ 7.81 (s, 1 H), 7.79 (d, J = 8.4, 2 H), 7.72 (d, J = 8.4, 2 H), 7.64 (d) , J = 8.4, 1 H), 7.58 (dd, J = 8.4, 1.2, 1 H), 7.41 (s, 1 H), 4.75 (s, 1 H), 4.67 (s, 1 H), 1.47 (br) s, 18 H), 1.07 (s, 9 H), 1.02 (s, 9 H). LC / MS: [M + H ] + C 36 H 51 N 6 O 4 Calculated: 631.39; Found: 631.4.

Example B58, step b

The hydrochloride salt of amine B-58b was prepared according to the procedure described in step b of Example B1. LC/MS ( Condition B-13 ): R _t = 1.81 min. ¹ H NMR (MeOD, δ = 3.34 ppm, 400 MHz): δ 8.07 (s, 1 H), 8.1 (s, 1 H), 8.00 (d, J = 8.0, 2 H), 7.89 (d, J = 8.0 , 2 H), 7.83 (d, J = 8.4, 1 H), 7.78 (d, J = 8.4, 1 H), 4.72 (s, 1 H), 4.57 (s, 1 H), 1.23 (s, 9) H), 1.21 (s, 9 H). LC / MS: [M + H ] + C 26 H 35 N 6 Calculated: 431.28; Found: 431.2.

Example B58

Example B58 was prepared according to the procedure described in Example B1. HPLC ( Conditions B-1 and B-2 ): >98% homogeneity index. LC/MS ( Condition B-14 ): R _t = 2.04 min. ¹ H NMR (DMSO-d ₆ , δ = 2.50 ppm, 400 MHz): δ 7.23 (s, 1 H), 7.13-7.04 (m, 7 H), 4.21 (s, 1 H), 4.16 (s, 1 H) ), 1.88-1.76 (m, 2 H), 1.38-1.22 (m, 4 H), 1.19-0.86 (m, 12 H), 0.38 (s, 9 H), 0.35 (s, 9 H). LC / MS: [M + H ] + C 40 H 51 F 4 N 6 O 2 Calculated: 723.39; Found: 723.4.

Example B58A

Example B58A (trifluoroacetate) was prepared according to the procedure described in Example B1. HPLC ( Conditions B-1 and B-2 ): >96% homogeneity index. LC/MS ( Condition B-17 ): R _t = 2.40 min. LC / MS: [M + H ] + C 46 H 63 F 4 N 6 O 4 Calculated: 839.48; Found: 839.4.

Example B58B

Example B58B (trifluoroacetate) was prepared according to the procedure described in Example B5B. HPLC ( Condition B-1 and B-2 ): >98% homogeneity index. LC/MS ( Condition B-18 ): R _t = 2.06 min. ^{LC / MS: [MH] -} C 46 H 57 F 4 N 6 O 4 Calculated: 833.45; Found: 833.2.

Example B59

Example B59, step a

Under N _2, the iodide B-1i (1g, 2.64mmol) in DMF was added DIPEA (3.22mL, 18.46mmol) (20mL ) in the solution, followed by addition of alkyl trimethyl silicon acetylene (3.70mL, 26.4mmol ), CuI (0.100 g, 0.527 mmol) and Pd(PPh ₃ ) ₂ Cl ₂ (0.555 g, 0.791 mmol). The reaction mixture was stirred at room temperature for 10 minutes and heated at 90 °C for 12 hours. The reaction mixture was then concentrated. The residue was diluted with EtOAc and filtered through diatomaceous earth (Celite ^®). Washed with water, saturated NH ₄ Cl and brine filtrate. The organic layer was dried over Na ₂ SO ₄ and concentrated. The crude material was purified with EtOAc EtOAc EtOAc (EtOAc) LC/MS ( Condition B-13 ): R _t = 2.16 min. ¹ H NMR (MeOD, δ = 3.34 ppm, 400 MHz): δ 7.23 (br s, 1 H), 4.52 (s, 1 H), 1.44 (s, 9 H), 0.94 (s, 9 H), 0.23 ( s, 9 H). LC / MS: [M + H ] + C 18 H 32 N 3 O 2 Si Calculated: 350.22; Found: 350.2.

Example B59, step b

The alkyl group in the silicon-trimethyl-alkyne B-59a (660mg, 1.888mmol) and 2,5-diiodo benzene-1,4-diol (342mg, 0.944mmol) in DMF (20mL) was treated with N ₂ purge 5 minutes. Then TEA (0.790 mL, 5.66 mmol), CuI (36.0 mg, 0.189 mmol) and Pd(PPh ₃ ) ₂ Cl ₂ (133 mg, 0.189 mmol) were added and the reaction mixture was heated to 70 ° C, then TBAF (1M, (THF) (1.888 mL, 1.888 mmol), and the reaction mixture was stirred at 70 ° C overnight. Remove the solvent. The residue was dissolved in EtOAc, and filtered through diatomaceous earth (Celite ^®). Washed with water, 10% NaHCO ₃ and brine filtrate. The organic layer was dried over Na ₂ SO ₄ and concentrated. By Combiflash Isco (silica gel, 24g, Redisep, 2% MeOH / CHCl 3) and reverse phase HPLC (ACN / water / NH ₄ OAc) crude material was purified to give an off-white solid of urethane B-59b ( 190mg). HPLC ( Condition B-7 ): >92% homogeneity index. LC/MS ( Condition B-12 ): R _t = 2.18 min. ¹ H NMR (MeOD, δ = 3.34 ppm, 400 MHz): δ 7,62 (s, 2 H), 7.49 (s, 2 H), 7.05 (s, 2 H), 4.66 (s, 2 H), 1.47 (s, 18 H), 1.01 (s, 18 H). LC / MS: [M + H ] + C 36 H 49 N 6 O 6 Calculated: 661.36; Found: 661.3.

Example B59, step c

The hydrochloride salt of the amine B-59c was prepared according to the procedure described in step b of Example B1. LC/MS ( Condition B-14 ): R _t = 1.98 min. ¹ H NMR (MeOD, δ = 3.34 ppm, 400 MHz): δ 7.96 (s, 2 H), 7.79 (s, 2 H), 7.39 (s, 2 H), 4.56 (s, 2 H), 1.19 (s) , 18 H). LC / MS: [M + H ] + C 26 H 33 N 6 O 2 Calculated: 461.26; Found: 461.4.

Example B59

Example B59 was prepared according to the procedure described in Example B1. HPLC ( Condition B-1 and B-2 ): >92% homogeneity index. LC/MS ( Condition B-12 ): R _t = 2.07 min. ¹ H NMR (MeOD, δ = 3.34 ppm, 400 MHz): δ 7.92 (s, 2 H), 7.82 (s, 2 H), 7.38 (s, 2 H), 4.98 (s, 2 H), 2.64-2.55 (m, 2 H), 2.18-2.07 (m, 4 H), 1.97-1.70 (m, 12 H), 1.13 (s, 18 H). LC / MS: [M + H ] + C 40 H 49 F 4 N 6 O 4 Calculated: 753.37; Found: 753.3.

Example B60

Example B60, step a

Add TEA (0.598 mL, to a stirred solution of trimethyldecylalkylalkyne B-59a (0.5 g, 1.430 mmol) and 1,4-diiodobenzene (0.236 g, 0.715 mmol) in DMF (15 mL) 4.29 mmol) and CuI (0.027 g, 0.143 mmol). The reaction mixture was purge with N ₂ for 30 minutes and was added _{Pd (PPh 3) 2 Cl 2} (0.100g, 0.143mmol). The reaction mixture was then heated to 70 ° C, then TBAF (1M in THF) (0.374 g, 1.430 mmol). The residue was diluted with EtOAc and filtered through diatomaceous earth (Celite ^®). Washed with water, saturated NH ₄ Cl and brine filtrate. The organic layer was dried over Na ₂ SO ₄ and concentrated. By reverse phase HPLC (ACN / water / NH ₄ OAc) crude material was purified to give a pale yellow solid of urethane B-60a (0.12g). HPLC ( Condition B-1 and B-2 ): >95% homogeneity index. LC/MS ( Condition B-10 ): R _t = 2.06 min. ¹ H NMR (MeOD, δ = 3.34 ppm, 400 MHz): δ 7.50 (s, 4 H), 7.35 (s, 2 H), 4.56 (s, 2 H), 1.46 (br s, 18 H), 0.97 ( s, 18 H). LC / MS: [M + H ] + C 36 H 49 N 6 O 4 Calculated: 629.8; Found: 630.5.

Example B60, step b

The hydrochloride salt of amine B-60b was prepared according to the procedure described in step b of Example B1. LC/MS ( Condition B-10 ): R _t = 1.47 min. ¹ H NMR (MeOD, δ = 3.34 ppm, 400 MHz): δ 7.74 (s, 2 H), 7.59 (br s, 4 H), 4.43 (s, 2 H), 1.12 (s, 18 H). LC / MS: [M + H ] + C 26 H 33 N 6 Calculated: 429.27; Found: 429.3.

Example B60

Example B60 was prepared according to the procedure described in Example B1. HPLC ( Condition B-1 and B-2 ): >95% homogeneity index. LC/MS ( Condition B-12 ): R _t = 2.09 min. ¹ H NMR (MeOD, δ = 3.34 ppm, 400 MHz): δ 7.69 (s, 2 H), 7.62 (br s, 4 H), 4.81 (s, 2 H), 2.61-2.52 (m, 2 H), 2.18-2.07 (m, 4 H), 1.95-1.70 (m, 12 H), 1.09 (s, 18 H). LC / MS: [M + H ] + C 40 H 49 F 4 N 6 O 2 Calculated: 721.38; Found: 721.3.

Example B61

Example B61, step a

CuI (0.140 g, 0.735 mmol), DIPEA (4.49 mL, 25.7 mmol) was sequentially added to a solution of bromide B-10e (1.5 g, 3.67 mmol) in DMF (10 mL). Reaction mixture was purged with N ₂ for 20 min. Then, trimethyldecyl acetylene (5.15 mL, 36.7 mmol) and PdCl ₂ (TPP) ₂ (770 mg, 1.09 mmol) were added in that order. The reaction mixture was heated at 90 ° C for 12 hours. The reaction was diluted with EtOAc, and the washed with saturated NH ₄ Cl and brine. The organic layer was dried over Na ₂ SO _4, filtered and evaporated. The crude material was purified by flash chromatography eluting elut elut elut elut elut elut elut LC/MS ( Condition B-14 ): R _t = 2.25 min. ¹ H NMR (MeOD, δ = 3.34 ppm, 400 MHz): δ 7.67 (d, J = 8.4, 2 H), 7.45-7.40 (m, 3 H), 4.63 (s, 1 H), 1.45 (s, 9) H), 0.98 (s, 9 H), 0.25 (s, 9 H). ^{LC / MS: [MH] -} C 24 H 34 N 3 O 2 Si Calculated: 424.25; Found: 424.2.

Example B61, step b

Add Pd(OAc) to a solution of 5-bromo-2-iodophenol (0.48 g, 1.64 mmol) and trimethyldecylalkylalkyne B-61a (0.7 g, 1.64 mmol) in isopropyl acetate (10 mL). ₂ (7.63 mg, 0.03 mmol) and TPP (0.029 g, 0.060 mmol), followed by CuI (1.24 mg, 0.060 mmol). Reaction mixture was purged with N ₂ for 20 minutes followed by addition of DIPEA (1.51mL, 8.2mmol). The reaction mixture was then heated to 60 &lt;0&gt;C, then TBAF (1M in THF) (1.64 <RTIgt; The reaction was then quenched with water and diluted with EtOAc. Dried organic layer was washed with saturated NH ₄ Cl over Na ₂ SO _4, filtered and evaporated. The crude material was purified with EtOAc EtOAc EtOAc (EtOAc) LC/MS ( Condition B-14 ): R _t = 2.30 min. ¹ H NMR (DMSO-d ₆ , δ = 2.50 ppm, 400 MHz): δ 11.90 (br s, 1 H), 7.94-7.75 (m, 5 H), 7.66-7.58 (m, 2 H), 7.48-7.39 (m, 2 H), 6.77 (d, J = 10.0, 1 H), 4.56 (d, J = 10.0, 1 H), 1.40 (s, 9 H), 0.93 (s, 9 H). LC / MS: [M + H ] + C 27 H 31 BrN 3 O 3 Calculated: 524.15; Found: 524.2.

Example B61, step c

Add KOAc (0.28 g) to a solution of bromide B-61b (0.5 g, 1.907 mmol) and bis(pinadol) diboron (0.7363 g, 1.43 mmol) in 1,4-dioxane (15 mL) , 2.86mmol), and the reaction mixture was purged with N ₂ for 20 min. PdCl ₂ (dppf) (0.035 g, 0.045 mmol) was added and the reaction mixture was heated at 100 ° C for 12 h. After cooling to room temperature, the reaction mixture was passed through diatomaceous earth (Celite ^®) and evaporated. The resulting residue was dissolved in EtOAc, and washed with water and brine, dried over Na ₂ SO _4, filtered and evaporated. By Combiflash Isco (neutral _{Al 2 O 3, 40g, Redisep} , 15% EtOAc / petroleum ether) to afford crude material as a yellow solid of Acid ester B-61c (0.38 g). LC/MS ( Condition B-16 ): R _t = 1. 44 min. ¹ H NMR (MeOD, δ = 3.34 ppm, 400 MHz): δ 7.97 (d, J = 8.8, 2 H), 7.90 (d, J = 0.4, 1 H), 7.83 (d, J = 8.8, 2 H) , 7.66-7.59 (m, 2 H), 7.45 (s, 1 H), 7.22 (d, J = 0.8, 1 H), 4.66 (s, 1 H), 1.47 (s, 9 H), 1.22 (s) , 12 H), 1.01 (s, 9 H). LC / MS: [M + H ] + C 33 H 43 BN 3 O 5 Calculated: 572.32; Found: 572.5.

Example B61, step d

Under N ₂ Add Na ₂ CO to the stirred solution of the ester B-61c (0.38 g, 0.66 mmol) and iodide B-1i (0.22 g, 0.66 mmol) in toluene (5 mL) and EtOH (5 mL) and water (5 mL) ₃ (0.17 g, 1.75 mmol). Then PdCl ₂ (dppf)-DCM adduct (0.0480 g, 0.058 mmol) was added and the reaction mixture was heated at 85 ° C for 12 h. The reaction was then diluted with EtOAc, and washed with brine and filtered through diatomaceous earth (Celite ^®) and washed with EtOAc. The combined filtrate was evaporated. The crude material was purified with EtOAc EtOAc EtOAc (EtOAc) HPLC ( Condition B-1 and B-2 ): >97% homogeneity index. LC/MS ( Condition B-14 ): R _t = 2.18 min. ¹ H NMR (MeOD, δ = 3.34 ppm, 400 MHz): δ 7.96-7.78 (m, 5 H), 7.61 (br s, 2 H), 7.45 (br s, 1 H), 7.41 (br s, 1 H) ), 7.21 (s, 1 H), 4.66 (br s, 2 H), 1.47 (s, 18 H), 1.01 (s, 18 H). ^{LC / MS: [MH] -} 696.878C 40 H 51 N 6 O 5 Calculated: 695.4; Found: 695.3.

Example B61, step e

The hydrochloride salt of the amine B-61e was prepared according to the procedure described in step b of Example B1. LC/MS ( Condition B-16 ): R _t = 0.98 min. ¹ H NMR (MeOD, δ = 3.34 ppm, 400 MHz): δ 8.19-7.92 (m, 7 H), 7.84-7.70 (m, 2 H), 7.44 (br s, 1 H), 4.77 (s, 1 H) ), 4.73 (s, 1 H), 1.22 (s, 9 H), 1.21 (s, 9 H). LC / MS: [M + H ] + C 30 H 37 N 6 O Calculated: 497.3; Found: 497.47.

Example B61

Example B61 was prepared according to the procedure described in Example B1. HPLC ( Conditions B-1 and B-2 ): >94% homogeneity index. LC/MS ( Condition B-14 ): R _t = 2.10 min. ¹ H NMR (MeOD, δ = 3.34 ppm, 400 MHz): δ 7.95 (d, J = 8.4, 2 H), 7.89-7.77 (m, 3 H) 7.62 (br s, 2 H), 7.45 (s, 1) H), 7.41 (s, 1 H), 7.22 (s, 1 H), 5.02 (s, 1 H), 5.01 (s, 1 H), 2.52-2.48 (m, 2H), 2.18-2.04 (m, 4 H), 2.00-1.70 (m, 12 H), 1.05 (s, 9 H), 1.04 (s, 9 H). ^{LC / MS: [MH] -} C 44 H 51 F 4 N 6 O 3 Calculated: 787.40; Found: 787.3.

Example B62-63

Example B62-63 (trifluoroacetate) was prepared in a similar manner from the amine B-61e and the appropriate acid according to the procedure described for Example B61.

Example B64

Example B64, step a

Bromide B7-9a (1g, 2.250mmol) in 1,4-dioxane (20mL) in the solution was purged with N ₂ 5 minutes. Next, bis(pinacolyl)diboron (0.571 g, 2.250 mmol) was added followed by KOAc (0.663 g, 6.75 mmol) and PdCl ₂ (dppf) (0.082 g, 0.113 mmol). The reaction mixture was then heated at 100 ° C for 24 hours. Remove volatile components, and the resulting crude material was dissolved in EtOAc and water, and filtered through diatomaceous earth (Celite ^®). The filtrate was collected and the aqueous layer was separated. The organic phase was washed with brine, dried and concentrated over Na ₂ SO _4. The resulting residue was washed with petroleum ether to obtain Acid ester B-64a (443 mg). LC/MS ( Condition B-10 ): R _t = 2.19 min. LC / MS: [M + H ] + C 28 H 39 BN 3 O 4 Calculated: 492.3; Found: 492.2.

Example B64, step b

Iodide B7-9c (300 mg, 0.675 mmol) and Ester B-64a (398mg, 0.810mmol) in MeOH solution (25mL) of purifying the N ₂ 10 minutes. Then, K ₂ CO ₃ (280 mg, 2.025 mmol) and Pd(Ph ₃ P) ₄ (78 mg, 0.068 mmol) were added in that order. The reaction mixture was stirred at 85 ° C overnight. Remove volatile components, and the resulting crude material was dissolved in EtOAc in, water, and filtered through diatomaceous earth (Celite ^®). The filtrate was washed with brine, dried and concentrated over Na ₂ SO _4. By flash chromatography (silica gel 60-120,3-5% MeOH / DCM) and reverse phase HPLC (ACN / water / NH ₄ OAc) crude material was purified to give an off-white solid of urethane B-64b (42 mg). HPLC ( Condition B-1 and B-2 ): >91% homogeneity index. LC/MS ( Condition B-12 ): R _t = 2.27 min. ¹ H NMR (MeOD, δ = 3.34 ppm, 400 MHz): δ 8.22 (br s, 4 H), 8.03 - 7.93 (m, 6 H), 7.87 (dd, J = 8.4, 1.2, 2 H), 7.50 ( s, 2 H), 4.60 (s, 1 H), 4.58 (s, 1 H), 2.22-2.17 (m, 2 H), 1.48 (s, 18 H), 1.05 (d, J = 6.4, 6 H) ), 0.92 (d, J = 6.8, 6 H). LC / MS: [M + H ] + C 44 H 53 N 6 O 4 Calculated: 729.41; Found: 729.5.

Example B64, step c

The hydrochloride salt of amine 64c was prepared according to the procedure described in step b of Example B1. LC/MS ( Condition B-12 ): R _t = 1.84 min. ¹ H NMR (MeOD, δ = 3.34 ppm, 400 MHz): δ 8.51 (s, 2 H), 8.39 (s, 2 H), 8.25-7.99 (m, 10H), 4.67 (s, 1 H), 4.65 ( s, 1 H), 2.74 - 2.68 (m, 2 H), 1.31 (d, J = 6.4, 6 H), 1.05 (d, J = 6.0, 6 H). LC / MS: [M + H ] + C 34 H 36 N 6 Calculated: 529.30; Found: 529.2.

Example B64

Example B64 (16 mg) was prepared according to the procedure described in Example B1. HPLC ( Condition B-1 and B-2 ): >95% homogeneity index. LC/MS ( Condition B-12 ): R _t = 2.13 min. ¹ H NMR (MeOD, δ = 3.34 ppm, 400 MHz): δ 8.38 (s, 2 H), 8.34 (s, 2 H), 8.17 (d, J = 8.4, 2 H), 8.13 (d, J = 8.4) , 2 H), 8.09 (dd, J = 8.4, 1.6, 2 H), 7.99 (s, 2 H), 7.89 (dd, J = 8.8, 1.6, 2 H), 4.93 (s, 1 H), 4.91 (s, 1 H), 2.58-2.50 (m, 2 H), 2.45-2.34 (m, 2 H), 2.20 - 1.98 (m, 4 H), 2.00-1.72 (m, 12 H), 1.19 (d) , J = 6.4, 6 H), 1.01 (d, J = 6.8, 6 H). _{^{[M + H] + C 48}} H 53 F 4 N 6 O 2 Calculated: 821.41; Found: 821.4.

Example B65

Example B65, steps a-1 and a-2

Under N _2, the silicon of the trimethyl alkyl alkyne B-59a (0.5g, 1.430mmol) and 2,6-dibromo-naphthalene (0.409g, 1.430mmol) in DMF (10mL) was added a stirred solution of CuI (0.054 g, 0.286 mmol), TEA (0.598 mL, 4.29 mmol). Then Pd(PPh ₃ ) ₂ Cl ₂ (0.301 g, 0.429 mmol) was added and the reaction mixture was heated to 70 °C. Then TBAF (1 M in THF) (0.374 g, 1.430 mmol) was added and the mixture was stirred at <RTIgt; The reaction mixture was then diluted with EtOAc and washed with saturated NH ₄ Cl, brine, dried over Na ₂ SO _4, filtered and evaporated. By reverse phase HPLC (ACN / water / NH ₄ OAc) crude material was purified to give a pale yellow solid of the free base urethane (0.08g) B65a-1's. HPLC ( Conditions B-1 and B-2 ): >96% homogeneity index. LC/MS ( Condition B-14 ): R _t = 2.16 min. ¹ H NMR (MeOD, δ = 3.34 ppm, 400 MHz): δ 8.02 (s, 2 H), 7.85 (m, 2 H), 7.57 (m, 2 H), 7.34 (br s, 2 H), 4.56 ( s, 2 H), 1.45 (s, 18 H), 0.96 (s, 18 H). ^{LC / MS: [MH] -} C 40 H 49 N 6 O 4 Calculated: 677.39; Found: 677.2. The urethane B65a-2 (0.02 g, 0.036 mmol, 2.53%) was obtained as a pale yellow solid. LC/MS ( Condition B-14 ): R _t = 2.16 min. ¹ H NMR (MeOD, δ = 3.34 ppm, 400 MHz): δ 7.42 (s, 2 H), 4.53 (s, 2 H), 1.45 (s, 18 H), 0.95 (s, 18 H). ^{LC / MS: [MH] -} C 30 H 43 N 6 O 4 Calculated: 551.34; Found: 551.3.

Example B65, step b

The hydrochloride salt (0.07 g) of the amine B-65b was prepared according to the procedure described in the procedure of step B1. LC/MS ( Condition B-14 ): R _t = 1.99 min. ¹ H NMR (MeOD, δ = 3.34 ppm, 400 MHz): δ 8.09 (s, 2 H), 7.91 (d, J = 8.4, 2 H), 7.67 (s, 2 H), 7.61 (d, J = 8.4) , 2 H), 4.36 (s, 2 H), 1.12 (s, 18 H). ^{LC / MS: [MH] -} C 30 H 33 N 6 Calculated: 477.28; Found: 477.2.

Example B65

Example B65 (0.038 g) was prepared according to the procedure described in Example B1. HPLC ( Condition B-1 and B-2 ): >97% homogeneity index. LC/MS ( Condition B-12 ): R _t = 2.13 min. ¹ H NMR (MeOD, δ = 3.34 ppm, 400 MHz): δ 8.17 (br s, 2H), 7.97 (d, J = 8.8, 2H), 7.76 (s, 2H), 7.67 (d, J = 8.8, 2H) ), 4.86 (s, 2H), 2.64-2.54 (m, 2H), 2.19-2.05 (m, 4H), 1.98-1.70 (m, 12H), 1.11 (s, 18H). LC / MS: [M + H ] + C 44 H 51 F 4 N 6 O 2 Calculated: 771.39; Found: 771.8.

Example B66

Example B66, step a

The hydrochloride salt (0.017 g) of the amine B-66a was prepared according to the procedure described in the procedure of step B1. LC/MS ( Condition 16 ): R _t = 0.71 min. ¹ H NMR (MeOD, δ = 3.34 ppm, 400 MHz): δ 7.55 (s, 2 H), 4.20 (s, 2 H), 1.08 (s, 18 H). LC / MS: [M + H ] + C 20 H 29 N 6 Calculated: 353.24; Found: 353.35.

Example B66

Example B66 (0.010 g) was prepared according to the procedure described in Example B1. HPLC ( Conditions B-1 and B-5 ): >98% homogeneity index. LC/MS ( Condition B-12 ): R _t = 1.94 min. ¹ H NMR (MeOD, δ = 3.34 ppm, 400 MHz): δ 7.67 (s, 2 H), 4.82 (s, 2 H), 2.57-2.48 (m, 2 H), 2.18-2.04 (m, 4 H) , 1.96-1.68 (m, 12 H), 1.04 (s, 18 H). LC / MS: [M + H ] + C 34 H 45 F 4 N 6 O 2 Calculated: 645.35; Found: 645.7.

Example B67

Example B67, step a

Add HATU (1.658 g, 4.36 mmol) to 4-iodobenzene-1,2-diamine (1.021 g, 4.36 mmol), (S)-2-((t-butoxycarbonyl) at 0 °C Amino)-2-(1-methylcyclopropyl)acetic acid (1 g, 4.36 mmol) and DIPEA (1.524 mL, 8.72 mmol) in DMF (20 mL) . Water (50 mL) was added to EtOAcq. The organic layer was washed with 10% NaHCO ₃ solution (50mL) and brine (50mL) washed with water (50mL). Dried over Na ₂ SO _4, and the organic layer was concentrated under reduced pressure to give a brown solid of (S) - (2 - ( (2- amino-4-iodophenyl) amino) -1- (1- Methylcyclopropyl)-2-oxoethyl)aminocarboxylic acid tert-butyl ester (1.9 g, 4.27 mmol) and (S)-(2-((2-amino-5-iodophenyl)) A crude mixture of the aminobutyl)-1-(1-methylcyclopropyl)-2-oxooxyethyl)carbamic acid tert-butyl ester. LC/MS ( Condition B-13 ): R _t = 2.03 min. LC / MS: [M + H ] + C 17 H 25 IN 3 O 3 Calculated: 446.09; Found: 446.0. (S)-(2-((2-Amino-4-iodophenyl)amino)-1-(1-methylcyclopropyl)-2-oxoethyl)aminocarboxylic acid Butyl ester (1.9g, 4.27mmol) and (s)-(2-((2-amino-5-iodophenyl)amino)-1-(1-methylcyclopropyl)-2-oxanoxy A crude mixture of triethyl butyl carbamate was dissolved in AcOH (20 mL) and heated at 650C overnight. The AcOH was removed under reduced pressure; the crude residue was crystallised from EtOAc (EtOAc) The organic layer was separated and EtOAc (EtOAc) The combined organic layers were washed with water (200mL) and brine (100 mL) was washed, ₂ SO ₄ and dried over Na and concentrated under reduced pressure. The crude material was purified with EtOAc EtOAc (EtOAc) LC/MS ( Condition B-13 ): R _t = 2.03 min. ¹ H NMR (DMSO- d ₆ , δ = 2.50 ppm, 400 MHz): δ 12.28/12.19 (s, 1 H), 7.94/7.83 (s, 1 H), 7.47-7.26 (m, 3 H), 4.42/ 4.39 (s, 1 H), 1.40 (br s, 9 H), 0.98 (s, 3 H), 0.78-0.76 (m, 1 H), 0.60-0.58 (m, 1 H), 0.34-0.30 (m , 2 H). LC / MS: [M + H ] + C 17 H 23 IN 3 O 2 Calculated: 428.08; Found: 428.0.

Example B67, step b

Nitrogen was purged through a solution of the carbamate B-67a (900 mg, 2.106 mmol) and Pd(TPP) ₄ (243 mg, 0.211 mmol) for 5 min. Bis(trimethylstannyl)acetylene (370 mg, 1.053 mmol) was added, followed by heating the reaction mixture in a sealed tube overnight at 90 °C. The reaction mixture was filtered with EtOAc (EtOAc)EtOAc. The filtrate was washed with water (2 x 100 mL) and brine (50 mL). The organic layer was concentrated, and Na ₂ SO ₄ dried under reduced pressure. By Combiflash Isco (silica gel, 40g, Redisep, 3.5% MeOH / CHCl 3), and then the residue was purified by chiral SFC (CO ₂ / containing 0.5% of diethylamine MeOH), to give the amine as a brown solid Carbamate B-67b (230 mg). LC/MS ( Condition B-17 ): R _t = 2.14 min. ¹ H NMR (DMSO- d ₆ , δ = 2.50 ppm, 400 MHz): δ 12.30/12.28 (s, 2 H), 7.77-7.52 (m, 4 H), 7.39-7.24 (m, 4 H), 4.43 ( Br s, 2 H), 1.46 (br s, 18 H), 1.01 (s, 6 H), 0.82-0.78 (m, 2 H), 0.62-0.58 (m, 2 H), 0.39-0.22 (m, 4 H). LC / MS: [M + H ] + C 36 H 45 N 6 O 4 Calculated: 625.34; Found: 625.4.

Example B67, step c

Add HCl/MeOH (4N) (5 mL, 0.128 mmol) to a solution of carbamic acid ester B-67b (80 mg, 0.128 mmol) in MeOH (2 mL) Overnight. The reaction mixture was concentrated with EtOAc EtOAc m. LC/MS ( Condition B-17 ): R _t = 1.64 min. ¹ H NMR (MeOD, δ = 3.34 ppm, 300 MHz): δ 7.82 (br s, 2 H), 7.65 (d, J = 8.0, 2 H), 7.49 (d, J = 8.0, 2 H), 4.14 ( Br s, 2 H), 1.15-1.08 (m, 2 H), 1.06 (s, 6 H), 0.88-0.81 (m, 2 H), 0.78-0.67 (m, 4 H). LC / MS: [M + H ] + C 26 H 29 N 6 Calculated: 425.24; Found: 425.2.

Example B67

Add HATU (100 mg, 0.262 mmol) to the amine B-67c (4 HCl) (73 mg, 0.128 mmol), 4,4-difluorocyclohexanecarboxylic acid (44.1 mg, 0.269 mmol) and DIPEA (0.089) mL, 0.512 mmol) in EtOAc (3 mL) The reaction mixture was diluted with EtOAc (2 × 20mL), washed with saturated NH ₄ Cl solution (20mL), 10% NaHCO ₃ solution (20mL), water (20mL) and brine (20mL). The organic layer was concentrated, and Na ₂ SO ₄ dried under reduced pressure. The crude material was purified by EtOAcqqqqqqqq HPLC ( Conditions B-1 and B-2 ): >98% homogeneity index. LC/MS ( Condition B-17 ): R _t = 2.14 min. ¹ H NMR (MeOD, δ = 3.34 ppm, 400 MHz): δ 7.92 (s, 2 H), 7.75 (d, J = 8.8, 2 H), 7.69 (dd, J = 8.8, 1.6, 2 H), 4.61 (s, 2 H), 2.66-2.54 (m, 2 H), 2.20-2.08 (m, 4 H), 2.06-1.93 (m, 4 H), 1.91-1.70 (m, 8 H), 1.17 (s , 6 H), 0.99-0.94 (m, 2 H), 0.78-0.74 (m, 2 H), 0.67-0.58 (m, 4 H). LC / MS: [M + H ] + C 40 H 45 F 4 N 6 O 2 Calculated: 717.35; Found: 717.2.

Example B68

Example B-68 (trifluoroacetate) was prepared according to the procedure described in Example B-67. HPLC ( Conditions B-1 and B-2 ): >98% homogeneity index. LC/MS ( Condition B-19 ): R _t = 2. 0 min. LC / MS: [M + H ] + C 40 H 53 N 6 O 4 Calculated: 681.41; Found: 681.1.

Example B69

To (1S,1'S)-1,1'-(5,5'-([1,1'-biphenyl]-4,4'-diyl) bis(1H-imidazole-5, at 0 °C 2-Diyl) 2,2-dimethylpropan-1-amine tetrahydrochloride (75 mg, 0.124 mmol) was added with 3-hydroxy-2,2,3-trimethylbutyric acid ( 38.2 mg, 0.261 mmol) of DMF (3 mL), then DIPEA (0.174 mL, 0.996 mmol). Then HATU (97 mg, 0.255 mmol) was added and stirred from 0 ° C to room temperature for 6 h. The crude material was dissolved in EtOAc (50mL), washed with saturated NH _{(25mL) 4 Cl (25mL)} , 10% NaHCO 3 (25mL), brine, ₂ SO ₄ dried and concentrated under reduced pressure over Na. The crude material was purified by EtOAc EtOAc (EtOAc) HPLC ( Condition B-1 and B-2 ): >97% homogeneity index. LC/MS ( Condition B-12 ): R _t = 2.13 min. ¹ H NMR (MeOD, δ = 3.34 ppm, 400 MHz): δ 7.92-7.85 (m, 10 H), 4.94 (s, 2 H), 1.28 (s, 18 H), 1.16 (s, 12 H), 1.15 (s, 12 H). LC / MS: [M + H ] + C 42 H 61 N 6 O 4 Calculated: 713.47; Found: 713.3.

Example B70-72

Example B70 (diastereomer-1)

Example B71 (diastereomer-2)

Example B72 (diastereomer-3)

Example B-70-72 was prepared according to the procedure described in Example B-69. The crude material was purified by reverse phase HPLC (ACN / water / EtOAc) toield , white solid, diastereomer-3). SFC (CO ₂ / containing 0.3% of diethylamine MeOH) further purifying impure Example B-71 (84mg, trifluoroacetate salt, diastereomer thereof -2) by to afford the free base of Example B-71 ( 32.88 mg, white solid). Example B-70 (diastereomer-1): LC ( conditions B-1 and B-2 ): >96% homogeneity index. LC/MS ( Condition B-15 ): R _t = 1.90 min. ^{LC / MS: [MH] -} C 44 H 55 N 6 O 4 Calculated: 731.44; Found: 731.2. Example B-71 (diastereomer-2): LC ( conditions B-1 and B-2 ): > 98% homogeneity index. LC/MS ( Condition B-15 ): R _t = 1.92 min. ^{LC / MS: [MH] -} C 44 H 55 N 6 O 4 Calculated: 731.44; Found: 731.2. Example B-72 (diastereomer-3): LC ( conditions B-1 and B-2 ): >97% homogeneity index. LC/MS ( Condition B-15 ): R _t = 1.91 min. ^{LC / MS: [MH] -} C 44 H 55 N 6 O 4 Calculated: 731.44; Found: 731.2.

Example B73-75

Example B73 (diastereomer-1)

Example B74 (diastereomer-2)

Example B75 (diastereomer-3)

Example B-73-75 was prepared according to the procedure described in Example B-69. The crude material was purified by reverse phase HPLC (NH ₄ OAc / EtOAc / water) to afford a mixture of three diastereomers. Repurified SFC (CO ₂ / containing 0.3% of diethylamine MeOH) by these three diastereomers thereof, to give Example B-73 (diastereomer thereof -1,15mg, an off-white solid, the free base) Example B-74 (diastereomer-2, 25 mg, off-white solid, free base) and Example B-75 (diastereomer-3, 10 mg, off-white solid, free base). Example B-73 (diastereomer-1): LC ( conditions B-1 and B-2 ): >97% homogeneity index. LC/MS ( Condition B-19 ): R _t = 1.97 min. ^{LC / MS: [MH] -} C 40 H 51 N 6 O 4 Calculated: 679.41; Found: 678.9. Example B-74 (diastereomer-2): LC ( conditions B-1 and B-2 ): >96% homogeneity index. LC/MS ( Condition B-19 ): R _t = 1.95 min. LC / MS: [M + H ] + C 40 H 53 N 6 O 4 Calculated: 681.41; Found: 680.9. Example B-75 (diastereomer-3): LC ( conditions B-1 and B-2 ): > 98% homogeneity index. LC/MS ( Condition B-24 ): R _t = 1.33 min. ¹ H NMR (MeOD, δ = 3.34 ppm, 400 MHz): δ 7.92-7.69 (m, 8 H), 7.37 (s, 2 H), 5.03 (s, 2 H), 3.50-3.42 (m, 2 H) , 1.35 (d, J = 6.0, 6 H), 1.26-1.21 (m, 2 H), 1.0 (s, 18 H), 0.99-0.94 (m, 2 H), 0.92-0.87 (m, 2 H) , 0.60-0.53 (m, 2 H). LC / MS: [M + H ] + C 40 H 53 N 6 O 4 Calculated: 681.41; Found: 681.4.

Example B76-78

Example B76 (diastereomer-1)

Example B77 (diastereomer-2)

Example B78 (diastereomer-3)

Example B-76-78 was prepared according to the procedure described in Example B-69. The crude material was purified by reverse phase HPLC (NH ₄ OAc / EtOAc / water) to afford a mixture of three diastereomers. The three diastereomers were repurified by positive relative palm chromatography to give Example B-76 (diastereomer-1, 25 mg, pale yellow solid, free base), and Example B-77. 2, 30 mg, white solid, acetate) and Example B-78 (diastereomer-3, 40 mg, pale yellow solid, acetate). Example B-76 (diastereomer-1): LC ( conditions B-1 and B-2 ): > 98% homogeneity index. LC/MS ( Condition B-19 ): R _t = 2.03 min. ^{LC / MS: [MH] -} C 40 H 55 N 6 O 4 Calculated: 683.44; Found: 682.9. Example B-77 (diastereomer-2): LC ( conditions B-1 and B-2 ): > 98% homogeneity index. LC/MS ( Condition B-24 ): R _t = 1.40 min. ^{LC / MS: [MH] -} C 40 H 55 N 6 O 4 Calculated: 683.44; Found: 683.4. Example B-78 (diastereomer-3): LC ( conditions B-1 and B-2 ): >96% homogeneity index. LC/MS ( Condition B-19 ): R _t = 2.03 min. LC / MS: [M + H ] + C 40 H 57 N 6 O 4 Calculated: 685.44; Found: 685.0.

Example B79-81

Example B79 (diastereomer-1)

Example B80 (diastereomer-2)

Example B81 (diastereomer-3)

Examples B79-81 were prepared according to the procedure described in Example B-69. The crude material was purified by reverse phase HPLC (TFA / EtOAc / water) to afford a mixture. Repurified ₍₂ / containing 0.3% of diethylamine MeOH CO) SFC by these three diastereomers thereof, to give Example B-79 (22mg, diastereomers thereof -1, trifluoroacetate), Example B-80 (42 mg, diastereomer-2, trifluoroacetic acid salt) and imp. <RTI ID=0.0></RTI></RTI><RTIgt; Accordingly, the impure Example B-81 (diastereomer thereof -3) was dissolved in EtOAc (50mL), and washed (25mL) with 10% NaHCO ₃ (25mL), brine, dried over Na ₂ SO ₄ and Concentrate under reduced pressure. The crude material was lyophilized ( acetonitrile and water) to afford mp. Example B-79 (diastereomer-1): LC ( conditions B-1 and B-2 ): >98% homogeneity index. LC/MS ( Condition B-12 ): R _t = 1.95 min. LC / MS: [M + H ] + C 40 H 53 N 6 O 2 Calculated: 649.42; Found: 649.1. Example B-80 (diastereomer-2): LC ( conditions B-1 and B-2 ): >98% homogeneity index. LC/MS ( Condition B-12 ): R _t = 1.99 min. LC / MS: [M + H ] + C 40 H 53 N 6 O 2 Calculated: 649.42; Found: 649.1. Example B-81 (diastereomer-3): LC ( conditions B-1 and B-2 ): >94% homogeneity index. LC/MS ( Condition B-12 ): R _t = 2.10 min. LC / MS: [M + H ] + C 40 H 53 N 6 O 2 Calculated: 649.42; Found: 649.1.

Example B82-83

Example B82

Example B83

To (1S,1'S)-1,1'-(5,5'-([1,1'-biphenyl]-4,4'-diyl)bis(1H-imidazole-5,2-diyl) Addition of DCM containing 2-cyclopentyl-2-methylpropionic acid (49.0 mg, 0.314 mmol) to bis(2,2-dimethylpropan-1-amine) tetrahydrochloride (90 mg, 0.149 mmol) :DMF (1:1, 4 mL). DIPEA (0.209 mL, 1.195 mmol) was then added at 0 °C followed by HATU (116 mg, 0.306 mmol). The reaction mixture was stirred from 0 ° C to room temperature for 7 hours. ₄ Cl (25mL) The reaction mixture was quenched with saturated NH, and extracted with EtOAc (50mL) and extracted crude material. , Washed with brine (25 mL), dried organic layer was separated and washed with 10% NaHCO ₃ (25mL) over Na ₂ SO _4, and concentrated under reduced pressure. The crude material was purified by reverse phase EtOAc (EtOAc/EtOAc) (EtOAc) Example B-82: LC ( Condition B-1 and B-2 ): >93% homogeneity index. LC/MS ( Condition B-18 ): R _t = 2.671 min. ^{LC / MS: [MH] -} C 46 H 63 N 6 O 2 Calculated: 731.51; Found: 731.4. Example B-83: LC ( Conditions B-1 and B-2 ): >95% homogeneity index. LC/MS ( Condition B-18 ): R _t = 2.24 min. LC / MS: [M + H ] + C 42 H 61 N 8 O Calculated: 693.49; Found: 693.4.

Example B84-85

Example B84

Example B85

Example B-84 (12 mg, trifluoroacetate) and Example B-85 (6 mg, trifluoroacetate) were prepared according to the procedure described in Example B-82-83. Example B-84: LC ( Condition B-1 and B-2 ): >97% homogeneity index. LC/MS ( Condition B-12 ): R _t = 1.84 min. LC / MS: [M + H ] + C 48 H 65 N 6 O 6 Calculated: 821.49; Found: 821.2. Example B-85: LC (condition B-1 and B-2):> 97% homogeneity index. LC/MS ( Condition B-12 ): R _t = 1.74 min. LC / MS: [M + H ] + C 43 H 61 N 8 O 3 Calculated: 737.47; Found: 737.1.

Example B86-87

Example B86

Example B87

Example B-86 (30 mg, trifluoroacetate) and Example B-87 (5 mg, trifluoroacetate) were prepared according to the procedure described in Example B-82-83. Example B-86: LC ( Condition B-1 and B-2 ): >97% homogeneity index. LC/MS ( Condition B-13 ): R _t = 2.40 min. ^{LC / MS: [MH] -} C 48 H 63 N 6 O 2 Calculated: 755.51; Found: 755.4. Example B-87: LC ( Condition B-2 ): >92% homogeneity index. LC/MS ( Condition B-13 ): R _t = 2.06 min. ^{LC / MS: [M] +} C 43 H 61 N 8 O Calculated: 705.50; Found: 705.4.

Example B88-89

Example B88

Example B89

Example B-88 (18 mg, free base) and Example B-89 (2 mg, free base) were prepared according to the procedure described in Example B-82-83. Example B-88: LC ( Conditions B-1 and B-2 ): >96% homogeneity index. LC/MS ( Condition B-27 ): R _t = 1.80 min. LC / MS: [M + H ] + C 42 H 61 N 6 O 2 Calculated: 681.48; Found: 681.6. Example B-89: LC ( Condition B-1 and B-2 ): >97% homogeneity index. LC/MS ( Condition B-27 ): R _t = 1.56 min. LC / MS: [M + H ] + C 40 H 59 N 8 O Calculated: 667.94; Found: 668.4.

Example B90-147

According to the procedure described for Example B-69, (1S, 1'S)-1,1'-(5,5'-([1,1'-biphenyl]-4,4'-diyl) bis ( Example B-90-147 was prepared in a similar manner starting from 1H-imidazole-5,2-diyl))bis(2,2-dimethylpropan-1-amine) tetrahydrochloride and the appropriate acid.

*B90: ¹ H NMR (MeOD, δ = 3.34 ppm, 400 MHz): δ 7.92-7.86 (m, 10 H), 4.96 (s, 2 H), 2.45-2.32 (m, 4 H), 2.17-2.08 ( m, 4 H), 1.98-1.92 (m, 2 H), 1.66-1.62 (m, 2 H), 1.28 (s, 6 H), 1.25 (s, 6 H), 1.12 (s, 18 H).

*B97: ¹ H NMR (MeOD, δ = 3.34 ppm, 400 MHz): δ 7.91-7.88 (m, 10 H), 5.87 (br s, 2 H), 5.15 (s, 2 H), 4.25 (dd, J = 5.2, 2.4, 4 H), 3.87-3.81 (m, 2 H), 3.77-3.71 (m, 2 H), 2.17-2.11 (m, 2 H), 2.06-1.99 (m, 2 H), 1.37 (s, 6 H), 1.36 (s, 6 H), 1.09 (s, 18 H).

*B110: ¹ H NMR (MeOD, δ = 3.34 ppm, 400 MHz): δ 7.78 (d, J = 8.4, 4 H), 7.70 (d, J = 8.4, 4 H), 7.36 (s, 2 H), 4.95 (s, 2 H), 1.34 (s, 6 H), 1.23 (s, 6 H), 1.07 (s, 18 H), 1.06-1.02 (m, 2 H), 0.93-0.84 (m, 6 H) ).

Example B148

Add HATU (61.3 mg, 0.161 mmol) to (1S,1'S)-(5,5'-([1,1'-biphenyl]-4,4'-diyl) bis (1H) at 0 °C -imidazole-5,2-diyl))bis((1-methylcyclopropyl)methylamine) tetrahydrochloride (48 mg, 0.080 mmol), 3-hydroxy-2,2,3-trimethylbutyl A stirred solution of the acid (29.3 mg, 0.201 mmol) and EtOAc (EtOAc) The reaction mixture was diluted with EtOAc (40mL), washed with saturated NH ₄ Cl solution (20mL), 10% NaHCO ₃ solution (20mL), water (20mL) and brine (20mL). The organic layer was concentrated, and Na ₂ SO ₄ dried under reduced pressure. The crude material was purified by preparative EtOAc (EtOAc) (EtOAc) LC ( Condition B-1 and B-2 ): >98% homogeneity index. LC/MS ( Condition B-19 ): R _t = 2.06 min. LC / MS: [M + H ] + C 42 H 57 N 6 O 4 Calculated: 709.44; Found: 708.9.

Example B149

Example B-149 (23 mg, trifluoroacetate) was prepared according to the procedure described in Example B-148. LC ( Condition B-1 and B-2 ): >93% homogeneity index. LC/MS ( Condition B-26 ): R _t = 1.54 min. LC / MS: [M + H ] + C 42 H 53 N 6 O 4 Calculated: 705.41; Found: 704.9.

According to the procedure described for Example B-69, (1S, 1'S)-1,1'-(5,5'-([1,1'-biphenyl]-4,4'-diyl) bis ( Preparation of Examples B-150 to B in a similar manner using 1H-imidazole-5,2-diyl))bis(2,2-dimethylpropan-1-amine) tetrahydrochloride and the appropriate acid as starting materials -183.

*Example B-150a ¹ H NMR (CD ₃ OD, δ = 3.34 ppm, 400 MHz): δ 7.75-7.66 (m, 8 H), 7.40 (br.s., 2 H), 4.96 (s, 2 H) , 3.65 (q, J = 7.1 Hz, 4 H), 3.55 (ddd, J = 2.1, 4.2, 6.4 Hz, 2 H), 1.96-1.88 (m, 2 H), 1.23 (t, J = 7.0 Hz, 6 H), 1.19-1.09 (m, 4 H), 1.05 (s, 18 H).

*Example B-158 ¹ H NMR (CD ₃ OD, δ = 3.34 ppm, 400 MHz): δ 7.82-7.71 (m, 8 H), 7.40 (br.s., 2 H), 5.01 (s, 2 H) , 1.77-1.72 (m, 2 H), 1.54-1.36 (m, 10 H), 1.08-1.07 (m, 2 H), 1.03 (s, 18 H), 0.81 (t, J = 7.2 Hz, 6 H ).

*Example B-162 ¹ H NMR (CD ₃ OD, δ = 3.34 ppm, 400 MHz): δ 7.77-7.69 (m, 8H), 7.38 (br.s., 2H), 5.05 (s, 1H), 4.95 ( s, 1H) 1.78-1.60 (m, 3H), 1.41 (s, 3H), 1.34 (s, 3H), 1.05 (s, 18H), 0.99-0.70 (m, 3H), 0.49-0.41 (m, 3H) ), 0, 14-0.10 (m, 2H), 0.15-0.05 (m, 3H).

*Example B-171 ¹ H NMR (CD ₃ OD, δ = 3.34 ppm, 400 MHz): δ 7.89-7.66 (m, 8 H), 7.39 (d, J = 4.0 Hz, 2 H), 5.12-4.94 (m) , 2 H), 4.01 (br.s., 2 H), 3.84 (dd, J = 6.5, 9.0 Hz, 2 H), 3.79-3.72 (m, 2 H), 1.94-1.71 (m, 6 H) , 1.54-1.46 (m, 2 H), 1.31 (s, 6 H), 1.14 (s, 6 H), 1.04 (s, 18 H).

Example B-186

Example B-186 Step a

To a stirred solution of bicyclo [2.2.2] octane-1,4-dicarboxylic acid dimethyl ester (6.35 g, 28.1 mmol) in MeOH (60 mL) and water (12 mL) g, 14.03 mmol), and the reaction mixture was stirred at room temperature for 12 h. The reaction mixture was diluted with water (150 mL) andEtOAc The aqueous layer was acidified with EtOAc (EtOAc) The organic layer was dried over Na ₂ SO _4, and concentrated under reduced pressure. The residue was stirred with toluene (100 mL) and filtered. The filtrate was concentrated under reduced EtOAcqqqqqqqqqqqqqqQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQ

Example B-186, step b

Recycled suspension of 4-(methoxycarbonyl)bicyclo[2.2.2]octane-1-carboxylic acid compound (3.5 g, 16.49 mmol) and red oxidized mercury (6.07 g, 28.0 mmol) in DCM (60 mL) A solution of bromine (1.274 mL, 24.74 mmol) in DCM (25 mL). The reaction mixture was filtered through EtOAc (EtOAc)EtOAc. The organic layer was dried over Na ₂ SO _4, and concentrated under reduced pressure. The crude material was purified by EtOAc (EtOAc) elut elut elut elut elut , 11.73 mmol, 71.2% yield). ¹ H NMR (DMSO-d ₆ , δ = 2.50 ppm, 400 MHz): δ 3.56 (s, 3 H), 2.24 - 2.16 (m, 6 H), 1.92-1.85 (m, 6 H).

Example B-186 Step c

4-Bromobicyclo[2.2.2]octane-1-carboxylic acid methyl ester was added dropwise to a stirred suspension of aluminum chloride (7.04 g, 52.8 mmol) in benzene (180 mL) at -12 °C. 2.9 g, 11.73 mmol) in benzene (60 mL). The reaction mixture was gradually brought to room temperature and stirred for 12 hours, and stirred under reflux for 4 hours. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in DCM (50 mL) and poured onto ice. The layers were separated and aqueous layer was extracted with DCM (2×100 mL). Washed with 10% saturated NaHCO ₃ solution (100 mL) the organic layers were washed, dried over Na ₂ SO _4, and concentrated under reduced pressure. The crude material was purified by EtOAc (EtOAc) elut elut elut elut elut elut (1.4 g, 5.73 mmol, 48.8% yield). ¹ H NMR (DMSO-d ₆ , δ = 2.50 ppm, 400 MHz): δ 7.35-7.20 (m, 4 H), 7.19-7.12 (m, 1 H), 3.59 (s, 3 H), 1.81 (dd, J = 0.2, 2.7 Hz, 12 H).

Example B-186, step d

The 4-phenyl-bicyclo [2.2.2] octane-1-carboxylate (2.3g, 9.41mmol) and silver trifluoroacetate (2.391g, 10.83mmol) was stirred in CHCl ₃ (30mL) at -780C in the was added dropwise bromine (0.509mL, 9.88mmol) in CHCl ₃ (10mL) in the solution, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was filtered through diatomaceous earth, and the CHCl ₃ (2 × 25mL) and washed with bed. The combined filtrate was concentrated under reduced pressure. The crude residue was purified by EtOAc EtOAc (EtOAc) elute Methyl 1-carboxylate (2.6 g, 8.04 mmol, 85% yield). LC / MS (conditions _{B-12): R t =} 2.937min; LC / MS: [M + H] + C 16 H 20 BrO 2 Calculated: 323.06; ^{Found: 325.0 (M + 2, 81} Br) . ¹ H NMR (DMSO-d ₆ , δ=2.50 ppm, 300 MHz): δ 7.50-7.43 (m, 2 H), 7.32-7.25 (m, 2 H), 3.60 (s, 3 H), 1.81 (dd, J = 0.2, 2.7 Hz, 12 H).

Example B-186 step e

Methyl 4-(4-bromophenyl)bicyclo[2.2.2]octane-1-carboxylate (1.3 g, 4.02 mmol) and chloroiodomethane (1.168 mL, 16.09 mmol) in THF LDA (8.04 mL, 16.09 mmol) was added to a solution (10 mL), and the mixture was stirred at the same temperature for 2 hr. A solution of acetic acid (5 mL) in THF (15 mL) was added dropwise to the reaction mixture, and stirred at -78 °C for 10 min, then at room temperature for 30 min. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in EtOAc (75mL), and washed with 10% NaHCO ₃ solution ₍₂ × 100mL) S 2 O washed (100ml) and 10% Na _{2 3} solution. The organic layer was dried over Na ₂ SO _4, and concentrated under reduced pressure. The crude material was purified by Combiflash Isco (Redisep, 40 g of succinic acid, petroleum ether containing 45-65% chloroform) to give 1-(4-(4-bromophenyl)bicyclo[2.2.2] as an off-white solid. Oct-1-yl)-2-chloroethanone (550 mg, 1.610 mmol, 40.0% yield). ¹ H NMR (DMSO-d ₆ , δ = 2.50 ppm, 400 MHz): δ 7.46 (d, J = 8.5 Hz, 2 H), 7.29 (d, J = 8.7 Hz, 2 H), 4.77 (s, 1 H) ), 4.28 (s, 1 H), 1.81 (dd, J = 0.2, 2.7 Hz, 12 H).

Example B-186 step f

Add dimethylhydrazine to a solution of 1-(4-(4-bromophenyl)bicyclo[2.2.2]oct-1-yl)-2-chloroethanone (1 g, 2.93 mmol) in THF (10 mL) Sodium imide salt (0.668 g, 7.02 mmol) and KI (0.146 g, 0.878 mmol). The reaction mixture was stirred at room temperature for 20 hours. The reaction mixture was filtered and washed with EtOAc EtOAc. The filtrate was concentrated under reduced pressure and the residue was evaporated mjjjjjjjjjjjjjjjjjj The reaction mixture was concentrated to dryness crystals crystals crystals crystals crystals (1.05 g, 2.93 mmol, 100% yield). LC / MS (conditions _{OA LC MS): R t =} 0.95min; LC / MS: [M + H] + C 16 H 21 BrNO Calculated: 322.08; ^{Found: 324.0 (M + 2, 81} Br). ¹ H NMR (DMSO-d ₆ , (D ₂ O) δ = 2.50 ppm, 400 MHz): δ 7.46-7.43 (m, 2 H), 7.29-7.26 (m, 2 H), 4.00 (s, 2 H) , 1.78-1.73 (d, J = 20 Hz, 12 H).

Example B-186 Step g

To 2-amino-1-(4-(4-bromophenyl)bicyclo[2.2.2]oct-1-yl)ethanone hydrochloride (1.05 g, 2.93 mmol) and (S) -2 ((Tertibutoxycarbonyl)amino)-3,3-dimethylbutyric acid (0.880 g, 3.81 mmol) in DMF (15 mL) 7.32 mmol), HATU (1.336 g, 3.51 mmol), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with EtOAc (EtOAc) The organic layer was washed with 10% NaHCO ₃ solution (50mL) brine (50mL), dried over Na ₂ SO _4, and concentrated under reduced pressure. By Combiflash Isco (Redisep, 40g silicon dioxide, containing the ₃ CHCl 3% MeOH) to give the crude material as a white solid of (S) - (1 - ( (2- (4- (4- bromophenyl Bicyclo[2.2.2]oct-1-yl)-2-oxoethyl)amino)-3,3-dimethyl-1-oxobutan-2-yl)carbamic acid third Butyl ester (1.1 g, 2.054 mmol, 70.2% yield). LC/MS (Condition): Rt = 1.27 min. LC / MS: [M + H ] + C 27 H 40 BrN 2 O 4 Calculated: 535.22; ^{Found: 537.4 (M + 2, 81} Br). ¹ H NMR (DMSO-d ₆ , δ = 2.50 ppm, 400 MHz): δ 7.97 (br s, 1 H), 7.47 (dd, J = 2.0, 6.8 Hz, 2 H), 7.30 (dd, J = 2.0, 6.8 Hz, 2 H), 6.41 (d, J = 9.2 Hz, 1 H), 4.20-4.08 (m, 2 H), 3.91 (d, J = 9.6 Hz, 1 H), 1.83-1.76 (m, 12) H), 1.39 (s, 9 H), 0.92 (s, 9 H).

Example B-186 step h

In the sealed tube, to (S)-(1-((2-(4-(4-bromophenyl)bicyclo[2.2.2]oct-1-yl)-2-yloxyethyl)amine) Adding NH ₄ Ac to a solution of tert-butyl-3,3-dimethyl-1-oxobutan-2-yl)carbamate (1.1 g, 2.054 mmol) in xylene (12 mL) 4.534g, 58.8mmol), and the reaction mixture for 10 minutes with N ₂ purge. The tube was sealed and the reaction mixture was heated at 140 ° C overnight. The reaction mixture was evaporated to dryness under reduced pressure, diluted with EtOAc (100mL), 10% NaHCO ₃ was added and the solution was stirred for 30 minutes. The layers were separated and the aqueous extracted with EtOAc EtOAc. The organic layers were combined, dried and concentrated over Na ₂ SO ₄ under reduced pressure. The crude material was purified by Combiflash Isco (EtOAc, EtOAc (EtOAc) (EtOAc) [2.2.2] Octan-1-yl)-1H-imidazol-2-yl)-2,2-dimethylpropyl)carbamic acid tert-butyl ester (250 mg, 0.484 mmol, 23.56% yield). LC/MS (Condition): Rt = 1.27 min. LC / MS: [M + H ] + C 27 H 39 BrN 3 O 2 Calculated: 516.22; ^{Found: 518.4 (M + 2, 81Br} ). ¹ H NMR (DMSO-d ₆ , δ = 2.50 ppm, 400 MHz): δ 11.24 (d, J = 22.4 Hz, 1 H), 7.49-7.45 (m, 2 H), 7.34-7.30 (m, 2 H) , 6.64 (s, 1 H), 4.46-4.43 (m, 1 H), 1.86-1.83 (m, 12 H), 1.39 (s, 9 H), 0.82 (s, 9 H).

Example B-186 Step i

To (S)-(1-(5-(4-(4-bromophenyl)bicyclo[2.2.2]oct-1-yl)-1H-imidazol-2-yl)-2,2-dimethyl Addition of potassium acetate to a solution of propyl) butyl methacrylate (225 mg, 0.436 mmol) and bis(pinacolyl)diboron (221 mg, 0.871 mmol) in 1,4-dioxane (2 mL) (107 mg, 1.089 mmol). The solution was purged from N _{2 for} 5 minutes. Followed by tetrakis (triphenylphosphine) palladium (0) (25.2mg, 0.022mmol) was added to the reaction mixture, and then N ₂ purge for 5 minutes. The reaction mixture was heated at 100 ° C for 2 hours under microwave. The reaction mixture was filtered through a syringe filter and concentrated under reduced pressure. The residue was taken up in water (20 mL)EtOAc. The organic layer was washed with brine (20mL), dried over Na ₂ SO _4, and concentrated under reduced pressure. The crude material was purified by Combiflash Isco (EtOAc, EtOAc (EtOAc) EtOAc (EtOAc) 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaboron) -2-yl)phenyl)bicyclo[2.2.2]oct-1-yl)-1H-imidazol-2-yl)propyl)carbamic acid tert-butyl ester (150 mg, 0.266 mmol, 61.1% yield) . LC/MS (Condition): Rt = 1.31 min. LC / MS: [M + H ] + C 33 H 51 BN 3 O 4 Calculated: 564.40; Found: 564.5.

Example B-186 Step j

To (S)-(2,2-dimethyl-1-(5-(4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaboron) -2-yl)phenyl)bicyclo[2.2.2]oct-1-yl)-1H-imidazol-2-yl)propyl)carbamic acid tert-butyl ester (150 mg, 0.266 mmol) and (S)- (1-(5-iodo-1-((2-(trimethyldecyl)ethoxy)methyl)-1H-imidazol-2-yl)-2,2-dimethylpropyl)amino acid tert-butyl ester (136mg, 0.266mmol) in 1,4-dioxane (1 mL) was added _{K 2 CO 3 (110mg, 0.798mmol} ) and water (0.1 mL) of the solution. The stirred solution was purged by N ₂ for 10 minutes. Next, ruthenium (triphenylphosphine)palladium(0) (15.38 mg, 0.013 mmol) was added, and it was further purified with N _{2 for} 5 minutes. The reaction mixture was heated at 80 ° C for 2.5 hours under microwave. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was dissolved in EtOAc (25mL), washed with water (25mL), brine (15mL), dried over Na ₂ SO _4, and concentrated under reduced pressure. By prep _{HPLC (H 2 O / NH 4} OAc / ACN) Purification of the crude material, was obtained as a white solid of Example B-186 Step j (22mg, 0.025mmol, 9.28% yield). LC/MS (Condition): Rt = 3.03 min. LC / MS: [M + H ] + C 46 H 75 N 6 O 5 Si Calculated: 819.56; Found: 820.6. ¹ H NMR (CD ₃ OD, δ = 3.34 ppm, 400 MHz): δ 7.49 (d, J = 8.0 Hz, 2 H), 7.43 (d, J = 8.0 Hz, 2 H), 7.00 (s, 1 H) , 6.66 (s, 1 H), 5.51 (d, J = 10.8 Hz, 1 H), 5.31 (d, J = 10.8 Hz, 1 H), 3.43 (t, J = 8.0 Hz, 2 H), 2.00- 1.94 (m, 12 H), 1.46 (s, 18 H), 1.04 (s, 9 H), 0.92 (s, 9 H), 0.87-0.81 (m, 2 H), -0.03 (s, 9 H) .

Example B-186 step k

At 0 ℃, Example B-186 to step j (12mg, 0.015mmol) was added in MeOH (0.5mL) in a solution of HCl / MeOH (4M) (1mL , 0.015mmol), and stirred at room temperature for 20 hours . The reaction mixture was concentrated under reduced pressure and EtOAc mjjjjjjjjjjjjj )-1-amino-2,2-dimethylpropyl)-1H-imidazol-5-yl)bicyclo[2.2.2]oct-1-yl)phenyl)-1H-imidazol-2-yl) -2,2-Dimethylpropan-1-amine tetrahydrochloride (9.30 mg, 0.015 mmol, 100% yield). LC/MS (Condition): Rt = 1.51 min. LC / MS: [M + H ] + C 30 H 45 N 6 Calculated: 489.37; Found: 489.8. ¹ H NMR (CD ₃ OD, δ = 3.34 ppm, 400 MHz): δ 8.02 (br s, 1 H), 7.82 (br.s., 2 H), 7.57 (m, 3 H), 4.74 - 4.65 (m) , 2 H), 2.15-2.03 (m, 12 H), 1.36-1.06 (m, 18 H).

To (S)-1-(5-(4-(4-(2-((S)-1-amino)-2,2-dimethylpropyl)-1H-imidazole-5 at 0 °C -yl)bicyclo[2.2.2]oct-1-yl)phenyl)-1H-imidazol-2-yl)-2,2-dimethylpropan-1-amine tetrahydrochloride (17 mg, 0.027 mmol) DIPEA (0.019 mL) was added sequentially to a solution of (R)-5,5-difluoro-2-methyltetrahydro-2H-pyran-2-carboxylic acid (10.14 mg, 0.056 mmol) in DMF (2 mL) , 0.107 mmol), HATU (20.88 mg, 0.055 mmol), and the reaction mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with EtOAc (40mL), washed with saturated NH ₄ Cl solution (20mL), 10% NaHCO ₃ solution (20mL), water (20mL) and brine (20mL). The organic layer was dried over Na ₂ SO _4, and concentrated under reduced pressure. The crude material was purified by preparative HPLC to give (R)-N-((S)-1-(5-(4-(4-(4-(()))) -5,5-Difluoro-2-methyltetrahydro-2H-pyran-2-methylindolyl)-2,2-dimethylpropyl)-1H-imidazol-5-yl)bicyclo[ 2.2.2] Oct-1-yl)phenyl)-1H-imidazol-2-yl)-2,2-dimethylpropyl)-5,5-difluoro-2-methyltetrahydro-2H- Piper-2-carbamide (9.7 mg, 0.012 mmol, 43.4% yield). LC/MS (Condition): Rt = 2.16 min. LC / MS: [M + H ] + C 44 H 61 F 4 N 6 O 4 Calculated: 813.47; Found: 813.4. ¹ H NMR (CD ₃ OD, δ = 3.34 ppm, 400 MHz): δ 7.62 (d, J = 8.0 Hz, 2 H), 7.41 (d, J = 8.0 Hz, 2 H), 7.30 (s, 1 H) , 6.68(s,1 H),5.07(s,1 H),5.00(s,1 H),3.92-3.78(m,2 H),3.73-3.53(m,2 H),2.31-2.20(m , 2 H), 2.18-1.81 (m, 6 H), 1.52 (d, J = 5.6 Hz, 6 H), 1.01 (s, 12 H), 1.05 (s, 9 H), 0.95 (s, 9 H) ).

Example B-187

Example B-187 Step a

Add Pd(PPh ₃ ) ₂ Cl to a solution of (1S,2S)-1,2-bis(4-bromophenyl)cyclopropane (100 mg, 0.284 mmol) in 1,4-dioxane (2 mL) ₂ (19.94 mg, 0.028 mmol) and 1-ethoxyvinyltri-n-butyltin (0.290 mL, 0.852 mmol). The stirred solution was purged by N ₂ for 10 minutes. The tube was sealed and heated at 80 ° C for 15 hours. The reaction mixture was acidified with 1.5N EtOAc (2 mL). The reaction mixture was diluted with EtOAc (10 mL)EtOAcEtOAc. The organic layer was dried over Na ₂ SO _4, and concentrated under reduced pressure. By Combiflash Isco (Redisep, 4g silicon dioxide containing of 18% EtOAc in petroleum ether) to afford crude material as a white solid of Example B-187 step a (35mg, 0.126mmol, 44.3% yield). LC/MS (Condition): Rt = 0.97 min. ¹ H NMR (CDCl ₃ , δ = 7.26 ppm, 400 MHz): δ 7.90 (d, J = 8.0 Hz, 4 H), 7.21. (d, J = 8.0 Hz, 4 H), 2.59 (s, 6 H), 2.28 (t, J = 7.2 Hz, 2 H), 1.63 (d, J = 7.2 Hz, 2 H). LC / MS: [M + H ] + C 19 H 19 O 2 Calculated: 279.1; Found: 279.1.

Example B-187 step b

To a solution of the Example B-187 step a (0.4 g, 1.437 mmol) in THF (8 <RTI ID=0.0></RTI></RTI><RTIgt;</RTI><RTIgt;</RTI><RTIgt; The reaction mixture was stirred overnight under temperature. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in DCM (50 mL)EtOAc. The organic layer was dried over Na ₂ SO _4, and concentrated under reduced pressure to give a brown solid as a example of the B-187 step b (625mg, 1.433mmol). The crude material was used in the next step without further purification.

Example B-187 step c

To Example B-187, step b, and (S)-2-((t-butoxycarbonyl)amino)-3,3-dimethylbutyric acid (994 mg, 4.30 mmol) in acetonitrile at 0 °C. DIPEA (0.751 mL, 4.30 mmol) was added to a solution in 10 mL), and the mixture was stirred at room temperature for 5 hr. Water (50 mL) was then added to aq. Washed with water (50mL), the organic layer was washed with brine (50mL), dried over Na ₂ SO _4, and concentrated under reduced pressure. By Combiflash Isco (Redisep, 4g silicon dioxide, containing the 22-28% EtOAc in petroleum ether) to afford crude material as a brown solid examples of B-187 step c (620mg, 0.606mmol, 42.3% yield). LC/MS (Condition): Rt = 0.97 min. ^{LC / MS: [MH] -} C 41 H 55 N 2 O 10 Calculated: 735.4; Found: 735.7.

Example B-187 step d

Example B-187 to step c (620mg, 0.841mmol) in xylene (10 mL) was added in the _{NH 4 OAc (1297mg, 16.83mmol)} , and purge with N ₂ solution for 10 minutes. The tube was sealed and heated at 130 ° C for 15 hours. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in EtOAc (100mL), and stirred with 10% NaHCO ₃ solution for 30 minutes. Dried organic layer was separated and washed with brine (50mL) over Na ₂ SO _4, and concentrated under reduced pressure. By Combiflash Isco (Redisep, 12g silicon dioxide, of chloroform containing 2.2% MeOH) to give crude material as a brown solid examples of B-187 in step d (170mg, 0.220mmol, 26.1% yield). LC/MS (Condition): Rt = 2.41 min. LC / MS: [M + H ] + C 41 H 57 N 6 O 4 Calculated: 697.44; Found: 697.4. ¹ H NMR (CD ₃ OD, δ = 3.34 ppm, 400 MHz): δ 7.61 (d, J = 6.8 Hz, 4 H), 7.28 (s, 2 H), 7.22-7.20 (m, 4 H), 4.63 ( s, 2 H), 2.21 (t, J = 7.2 Hz, 2 H), 1.45 (s, 20 H), 1.00 (d, J = 9.6 Hz, 18 H).

Example B-187 step e

At 0 ℃, was added HCl / MeOH (4N) (5mL , 0.244mmol) (1mL) to a solution of the Example B-187 in step d (170mg, 0.244mmol) in MeOH, and the reaction mixture was stirred at room temperature for 12 hour. The reaction mixture was concentrated under reduced pressure, and the residue was co-evaporated with DCM (3 × 5mL), obtained as a brown solid examples of B-187 in step e (165mg, 0.223mmol, 92% yield). LC/MS (Condition): Rt = 1.90 min. LC / MS: [M + H ] + C 31 H 41 N 6 Calculated: 497.34; Found: 497.0. ¹ H NMR (CD ₃ OD, δ = 3.34 ppm, 300 MHz): δ 7.86 (s, 2 H), 7.68 (d, J = 7.5 Hz, 4 H), 7.25 (d, J = 8.4 Hz, 4 H) , 4.57 (s, 2 H), 2.23 (t, J = 5.7 Hz, 2 H), 1.51 (t, J = 7.2 Hz, 2 H), 1.09 (s, 18 H).

To the Example B-187 step e (55 mg, 0.086 mmol) and (R)-5,5-difluoro-2-methyltetrahydro-2H-pyran-2-carboxylic acid (38.6 mg, 0.214) DIPEA (0.060 mL, 0.342 mmol), HATU (66.7 mg, 0.175 mmol). The reaction mixture was diluted with EtOAc (40mL), washed with saturated NH ₄ Cl solution (20mL), 10% NaHCO ₃ solution (20mL), water (20mL) and brine (20mL). The organic layer was dried over Na ₂ SO _4, and concentrated under reduced pressure. The crude material was purified by EtOAc EtOAcjjjjjj LC/MS (Condition): Rt = 2.37 min. LC / MS: [M + H ] + C 45 H 57 F 4 N 6 O 4 Calculated: 821.44; Found: 821.4. ¹ H NMR (CD ₃ OD, δ = 3.34 ppm, 400 MHz): δ 7.62 (d, J = 8.0 Hz, 4 H), 7.31 (s, 2 H), 7.22 (d, J = 8.0 Hz, 4 H) , 5.06(s, 2 H), 3.93-3.81 (m, 2 H), 3.73-3.61 (m, 2 H), 2.29-2.18 (m, 4 H), 2.00-1.94 (m, 2 H), 1.88 -1.76 (m, 4 H), 1.54-1.51 (m, 8 H), 1.02 (s, 18 H).

The following examples were prepared according to the method described for Preparation Example B-187.

Example B-190

Example B-189 was prepared from (1R,2R)-1,2-bis(4-bromophenyl)cyclopropane according to the procedure described for Preparation Example B-187. LC (Condition B-39 and B-3): >96% homogeneity index. LC/MS (Condition B-26: RT = 2.26 min). LC / MS: [M + H ] C 45 H 57 F 4 N 6 O 2 Calculated: 789.54; Found: 789.4.

Example B-191

Example B-191 Step a

Add 2-amino-1-(4-) to a solution of (S)-1-((benzyloxy)carbonyl)pyrrolidin-2-carboxylic acid (3 g, 12.04 mmol) in DCM (50 mL) Bromophenyl)ethanone hydrochloride (3.02 g, 12.04 mmol), DIPEA (4.20 mL, 24.07 mmol) and HATU (4.58 g, 12.04 mmol). The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with water and extracted with DCM. , The organic layer was washed with brine, dried over Na ₂ SO _4, and concentrated under reduced pressure. The crude material was purified by Combiflash ISCO (80 g Redi-sep column and CHCl ₃ /MeOH as eluting solvent) and concentrated to give (S)-2-((2-(4-bromophenyl)-2- oxy) Ethyl)aminomethylpyridyl)pyrrolidine-1-carboxylic acid benzyl ester (4.5 g, 9.70 mmol, 81% yield). ¹ H NMR (DMSO-d6, δ=2.50 ppm, 400 MHz): δ 8.38-8.24 (m, 1 H), 7.97-7.87 (m, 2 H), 7.80-7.70 (m, 2 H), 7.42-7.21 (m, 5 H), 5.14 - 4.98 (m, 2 H), 4.62-4.46 (m, 2 H), 4.37-4.22 (m, 1 H), 3.54-3.36 (m, 2 H), 2.26-2.06 (m, 1 H), 1.97-1.76 (m, 3 H).

Example B-191 step b

To (S)-2-((2-(4-bromophenyl)-2-oxooxyethyl)aminecarboxamido)pyrrolidine-1-carboxylic acid benzyl ester (4.5 g, 10.11 mmol) in two Ammonium acetate (10.13 g, 131 mmol) was added to a solution in toluene (80 mL), and the reaction mixture was heated to 130 ° C for 18 hours. The reaction was monitored by TLC. Xylene is removed under reduced pressure, and washed with 10% NaHCO ₃ solution the reaction mixture was diluted and extracted with DCM. , The organic layer was washed with brine, dried over Na ₂ SO _4, and concentrated under reduced pressure. The crude material was purified by preparative HPLC to afford (S)-2-(5-(4-bromophenyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (3.3 g, 7.71 mmol , 76% yield). LC / MS (conditions _{B-45): R t =} 7.417min. LC / MS: [M + H ] + C 21 H 21 BrN 3 O 2 Calculated: 426.08; ^{Found: 428.0 (M + 2, 81} Br). ¹ H NMR (DMSO-d6, δ = 2.50 ppm, 400 MHz): δ 12.12-11.90 (m, 1 H), 7.71 (t, J = 8.3 Hz, 2 H), 7.63 - 7.45 (m, 3 H), 7.43-6.94 (m, 5 H), 5.16-4.86 (m, 3 H), 3.62 (br.s., 1 H), 3.46 (br.s., 1 H), 2.38-2.13 (m, 1 H) ), 2.09-1.83 (m, 3 H).

Example B-191 step c

To (S)-2-(5-(4-bromophenyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylic acid benzyl ester (3.3 g, 7.74 mmol) in dioxane (50 mL) To the solution in DMF (5 mL) was added bis(pinadol) diboron (4.91 g, 19.35 mmol), potassium acetate (2.28 g, 23.22 mmol), and the reaction mixture was purged with argon for 15 min. Next, PdCl ₂ (dppf) (0.283 g, 0.387 mmol) was added to the above reaction mixture, and heated to 110 ° C in a microwave for 1 hour. The reaction mixture was diluted with water and extracted with EtOAc. , The organic layer was washed with brine, dried over Na ₂ SO _4, and concentrated under reduced pressure. The crude material was purified by Combiflash ISCO (80 g Redisep column, hexane/ethyl acetate as solvent) and concentrated to give (S)-2-(5-(4-(4,4,5,5-4) Base-1,3,2-dioxaboron Benzyl-2-phenyl)phenyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (3.45 g, 6.56 mmol, 85% yield). LC/MS ( Condition B-16 ): R _t = 1.08 min. LC / MS: [M + H ] + C 27 H 33 BN 3 O 4 Calculated: 474.26; Found: 474.4. ¹ H NMR (CD ₃ OD, δ = 3.34 ppm, 400 MHz): δ 7.81-7.64 (m, 4 H), 7.47-7.31 (m, 3 H), 7.19-7.06 (m, 2 H), 6.99 (d) , J = 7.0 Hz, 1 H), 5.20-4.98 (m, 3 H), 3.82-3.70 (m, 1 H), 3.59 (td, J = 7.1, 10.4 Hz, 1 H), 2.41 (br.s) .1 H), 2.19-1.91 (m, 3 H), 1.38 (s, 12 H).

Example B-191 step d

To (S)-2-(5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaboron) Addyl-2-methyl)phenyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (3.45 g, 7.29 mmol) in dioxane (40 mL) and water (10 mL) (S)-(1-(5-(4-Bromophenyl)-1H-imidazol-2-yl)-2,2-dimethylpropyl)carbamic acid tert-butyl ester (2.98 g, 7.29 mmol) And Cs ₂ CO ₃ (7.12 g, 21.86 mmol). The reaction mixture was purged with argon for 15 minutes. PdCl ₂ (dppf)-CH ₂ Cl ₂ (0.298 g, 0.364 mmol) was then added to the above reaction mixture and purified with argon for 5 min. The reaction mixture was heated to 90 ° C overnight. Volatile components evaporated under reduced pressure, and the resulting residue was dissolved in EtOAc (100mL), washed with water, brine, dried over Na ₂ SO _4, and concentrated under reduced pressure. The crude material was purified by preparative HPLC to give (S)-2-(5-(4'-(2-((S))-((t-butoxycarbonyl)amino)-2,2- Dimethylpropyl)-1H-imidazol-5-yl)-[1,1'-biphenyl]-4-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylic acid benzyl ester (1.38 g, 2.022 mmol, 27.8% yield). LC/MS ( Condition B-12 ): R _t = 2.316 min. LC / MS: [M + H ] + C 40 H 47 N 6 O 4 Calculated: 675.37; Found: 675.0. ¹ H NMR (CD ₃ OD, δ = 3.34 ppm, 400 MHz): δ 7.82-7.62 (m, 8 H), 7.44-7.29 (m, 4 H), 7.19-6.97 (m, 3 H), 5.20-5.02 (m, 2 H), 4.93 (br.s., 1 H), 4.66 (s, 1 H), 3.78 (ddd, J = 5.3, 7.5, 10.3 Hz, 1 H), 3.60 (td, J = 7.1 , 10.4 Hz, 1 H), 2.40 (d, J = 8.0 Hz, 1 H), 2.18-1.94 (m, 4 H), 1.47 (s, 9 H), 1.01 (s, 9 H).

Example B-191 step e

To (S)-2-(5-(4'-(2-((S)-1-((t-butoxycarbonyl))amino)-2,2-dimethylpropane under a nitrogen atmosphere Benzyl-1H-imidazol-5-yl)-[1,1'-biphenyl]-4-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylic acid benzyl ester (0.55 g, 0.815 mmol Pd/C (100 mg, 0.940 mmol) and K ₂ CO ₃ (100 mg, 0.724 mmol) were added to a solution in methanol (10 mL). The reaction mixture was stirred overnight at room temperature and maintained under a hydrogen balloon for 6 hours. The reaction mixture was filtered through a pad of celite, washed with methanol, and concentrated under reduced pressure to give ((S)-2,2-dimethyl-1-(5-(4)-(2-(()) -pyrrolidin-2-yl)-1H-imidazol-5-yl)-[1,1'-biphenyl]-4-yl)-1H-imidazol-2-yl)propyl)carbamic acid tert-butyl Ester (0.47 g, 0.774 mmol, 95% yield). The crude material was used in the next step without purification. LC/MS ( Condition B-12 ): R _t = 1.993 min. ^{LC / MS: [MH] -} C 32 H 39 N 6 O 2 Calculated: 539.29; Found: 539.2. ¹ H NMR (CD ₃ OD, δ = 3.34 ppm, 400 MHz): δ 7.84-7.66 (m, 8 H), 7.43-7.34 (m, 2 H), 4.66 (s, 1 H), 4.36-4.24 (m) , 1 H), 3.22-3.11 (m, 1 H), 3.05-2.94 (m, 1 H), 2.34-2.22 (m, 1 H), 2.07-1.88 (m, 4 H), 1.47 (s, 9) H), 1.08-0.92 (m, 9 H).

Example B-191 step f

To ((S)-2,2-dimethyl-1-(5-(4'-(2-((S)-pyrrolidin-2-yl)-1H-imidazole-5-) at 0 °C -3,1'-Biphenyl]-4-yl)-1H-imidazol-2-yl)propyl)carbamic acid tert-butyl ester (0.47 g, 0.869 mmol) in DCM (5 mL) (S)-2-((Methoxycarbonyl)amino)-3-methylbutyric acid (0.152 g, 0.869 mmol), DIPEA (0.228 mL, 1.304 mmol) and HATU (0.661 g, 1.738mmol). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with water and extracted with DCM. , Dried over Na ₂ SO ₄ organic layer was washed with brine, filtered and concentrated in vacuo. By crude material was purified by preparative HPLC to give Example B-190 step f (0.08g, 0.110mmol, 12.66% yield). LC/MS ( Condition B-12 ): R _t = 2.302 min. ^{LC / MS: [MH] -} C 39 H 50 N 7 O 5 Calculated: 696.4; Found: 696.2. ¹ H NMR (CD ₃ OD, δ = 3.34 ppm, 400 MHz): δ 7.87-7.62 (m, 8 H), 7.44-7.28 (m, 2 H), 5.40-5.14 (m, 1 H), 4.70-4.55 (m,1 H), 4.25 (d, J = 7.5 Hz, 1 H), 4.16-3.97 (m, 1 H), 3.92-3.81 (m, 1 H), 3.73-3.59 (m, 3 H), 2.47-2.15 (m, 3 H), 2.13 - 2.01 (m, 2 H), 1.43 (d, J = 5.5 Hz, 9 H), 1.05 - 0.88 (m, 15 H).

Example B-191 step g

To a solution of Example B-191, step f (0.08 g, 0.115 mmol), EtOAc (EtOAc) The reaction mixture was concentrated in vacuo. The residue obtained is the obtained syrup which is washed with diethyl ether and dried in vacuo to give ((S)-1-((S)-2-(5-(4'-(2-((S)))) -2,2-dimethylpropyl)-1H-imidazol-5-yl)-[1,1'-biphenyl]-4-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl Methyl 3-methyl-1-oxobutan-2-yl)carbamate trihydrochloride (0.08 g, 0.110 mmol, 96% yield). LC/MS ( Condition B-12 ): R _t = 1.961 min. LC / MS: [M + H ] + C 34 H 44 N 7 O 3 Calculated: 598.35; Found: 598.2. ¹ H NMR (CD ₃ OD, δ = 3.34 ppm, 400 MHz): δ 8.04-7.98 (m, 3 H), 7.96-7.83 (m, 8 H), 5.28 (t, J = 7.8 Hz, 1 H), 4.65 (s, 1 H), 4.26 (d, J = 7.0 Hz, 1 H), 4.14 (br.s., 1 H), 3.97-3.86 (m, 1 H), 3.68 (s, 3 H), 3.57-3.47 (m, 1 H), 2.68-2.53 (m, 1 H), 2.35-2.17 (m, 3 H), 2.14-2.01 (m, 1 H), 1.25-1.18 (m, 9 H), 1.01-0.88 (m, 6 H).

To ((S)-1-((S)-2-(5-(4'-(2-((S)-1-amino-2,2-dimethylpropyl)-1H-imidazole- 5-yl)-[1,1'-biphenyl]-4-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2- DIPEA (0.030 mL, 0.170 mmol), boc-L-proline acid (DIPEA (0.030 mL, 0.170 mmol) was added to a solution of methyl carbamic acid methyl ester trihydrochloride (0.03 g, 0.042 mmol) in DCM (3 mL) 9.13 mg, 0.042 mmol) and HATU (0.016 g, 0.042 mmol). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with water and extracted with DCM. , The organic layer was washed with brine, dried over Na ₂ SO _4, filtered and concentrated in vacuo to give Example B-191, which was purified by reverse phase preparative HPLC. LC ( Condition B-40 and B-41 ): >97% homogeneity index. LC/MS ( Condition B-12 ): R _t = 2.196 min. ^{LC / MS: [MH] -} C 44 H 57 N 8 O 6 Calculated: 793.44; Found; 793.2.

The following examples were prepared from Example B-191, step g, and the appropriate starting materials (caps) by employing the procedure described for Synthesis Example B-190. The product obtained is purified by preparative HPLC (MeOH/H ₂ O/TFA or CH ₃ CN/H ₂ O/NH ₄ OAc) and obtained as the corresponding trifluoroacetic acid salt or as the free base.

Example B-200

Example B-200 step a

K _{2 was} added sequentially to a solution of (S)-2-((t-butoxycarbonyl)amino)-3-methylbutyric acid (30 g, 138 mmol) in DMF (100 mL). CO ₃ (38.2 g, 276 mmol), CH ₃ I (12.95 mL, 207 mmol), and stirred overnight. The reaction mixture was quenched with water and extracted with EtOAc EtOAc. , The organic layer was washed with brine, dried over Na ₂ SO _4, and concentrated in vacuo. The crude material was purified by EtOAc (EtOAc):EtOAc (EtOAc:EtOAc:EtOAc Methyl 3-methylbutanoate (18 g, 78 mmol, 85% yield). ¹ H NMR (CDCl ₃ , δ = 7.26 ppm, 400 MHz): δ 5.01 (d, J = 8.03 Hz, 1 H) 4.16 - 4.28 (m, 1 H) 3.73 (s, 3 H) 2.12 (d, J = 5.52 Hz, 1 H) 1.40-1.48 (m, 9 H) 0.96 (d, J = 7.03 Hz, 3 H) 0.89 (d, J = 7.03 Hz, 3 H).

Example B-200 step b

(S)-2-((Tertidinoxycarbonyl)amino)-3-methylbutyrate was added dropwise to a suspension of LAH (4.10 g, 108 mmol) in THF (120 mL). A solution of the acid methyl ester (25 g, 108 mmol) in THF (50 mL). The reaction mixture was allowed to warm to rt and stirred overnight. The reaction mixture was quenched with water (10 mL) and filtered over EtOAc. The filtrate was washed with brine and the organic layer was extracted with EtOAc (2 × 100mL),, dried over Na ₂ SO _4, and concentrated in vacuo. The crude material was purified by EtOAc (EtOAc):EtOAc (EtOAc:EtOAc Tributyl methacrylate (18 g, 89 mmol, 82% yield). ¹ H NMR (CDCl ₃ , δ = 7.26 ppm, 400 MHz): δ 4.62 (br.s., 1 H), 3.57-3.75 (m, 2 H), 3.39-3.47 (m, 1 H), 2.25 (br) .s., 1 H), 1.76-1.89 (m, 1 H), 1.45 (s, 9 H), 0.95 (d, J = 7.78 Hz, 6 H).

Example B-200 step c

Adding dichromic acid to a solution of (S)-(1-hydroxy-3-methylbutan-2-yl)carbamic acid tert-butyl ester (18 g, 89 mmol) in DCM (100 mL) Pyridine (66.6 g, 177 mmol) and stirred overnight. The reaction mixture was diluted with DCM (100 mL) and filtered over EtOAc. , The filtrate was washed with brine, dried over Na ₂ SO _4, and concentrated in vacuo. The crude material was purified by EtOAc (EtOAc):EtOAc (EtOAc:EtOAc -Base) tert-butyl carbamic acid (6 g, 29.8 mmol, 33.7%). ¹ H NMR (CDCl ₃ , δ = 7.26 ppm, 400 MHz): δ 9.65 (s, 1H), 5.07 (br.s., 1 H), 4.25 (br.s., 1 H), 2.26-2.30 (m) , 1 H), 1.45 (s, 9 H), 1.03 (d, J = 8 Hz, 3H), 0.95 (d, J = 7.2 Hz, 3 H).

Example B-200 step d

To a solution of (S)-(3-methyl-1-oxobutan-2-yl)carbamic acid tert-butyl ester (6 g, 29.8 mmol) in methanol (20 mL) at room temperature A solution of 2M ammonia in methanol (67.1 mL, 134 mmol), hexahydro-[1,4]dioxine[2,3-b][1,4]dioxine- 2,3,6,7-Tetraol (2.87 g, 13.66 mmol) and stirred overnight. The volatile components were removed in vacuo and the obtained residue was taken in water (30 mL) andEtOAc. , The organic layer was washed with brine, dried over Na ₂ SO _4, and concentrated in vacuo. The crude material was purified by EtOAc (EtOAc):EtOAc (EtOAc:EtOAc T-butyl 2-methylpropyl)carbamate (5 g, 20.89 mmol, 70.1% yield). ¹ H NMR (DMSO-d6, δ=2.50 ppm, 300 MHz): δ 11.51-11.67 (m, 1 H), 6.82-6.89 (m, 3 H), 4.30-4.46 (m, 1 H), 1.94-2.08 (m, 1 H), 1.37 (s, 9 H), 0.84 (d, J = 6.80 Hz, 3 H), 0.71 (d, J = 6.80 Hz, 3 H).

Example B-200 step e

(S)-(1-(1H-imidazol-2-yl)-2-methylpropyl group was added dropwise to a suspension of NaH (0.877 g, 21.94 mmol) in THF (20 mL). A solution of tert-butyl carbamic acid (5 g, 20.89 mmol) in THF (10 mL). The reaction mixture was allowed to warm to rt for 30 min. Methyl iodide (8.11 mL, 130 mmol) was then added and stirred at room temperature for 8 h. (10 mL) The reaction mixture was quenched with saturated NH ₄ Cl solution, and extracted with EtOAC (2 × 100mL). The organic phase was washed with brine, dried over Na ₂ SO ₄ dried, and concentrated in vacuo. The crude material was purified by EtOAc (EtOAc):EtOAc (EtOAc:EtOAc -1H-Imidazol-2-yl)propyl)carbamic acid tert-butyl ester (4 g, 15.79 mmol, 76% yield). ¹ H NMR (DMSO-d ₆ , δ = 2.50 ppm, 300 MHz): δ 6.98-7.09 (m, 2 H), 6.79 (s, 1 H), 4.35 (s, 1 H), 3.61 (s, 3 H) ), 2.13 - 2.25 (m, 1 H), 1.35 (s, 9 H), 0.95 (d, J = 7.03 Hz, 3 H), 0.73 (d, J = 6.53 Hz, 3 H).

Example B-200 step f

To (S)-(2-methyl-1-(1-methyl-1H-imidazol-2-yl)propyl)carbamic acid tert-butyl ester (4 g, 15.79 mmol) in DCM NBS (2.81 g, 15.79 mmol) was added to the solution in (10 mL), and stirred at the same temperature for 2 hr. The reaction mixture was quenched with EtOAc (EtOAc)EtOAc. , The organic layer was washed with brine, dried over Na ₂ SO _4, and concentrated in vacuo. The crude material was purified by EtOAc (EtOAc):EtOAc (EtOAc:EtOAc T-butyl 2-methylpropyl)carbamate (5 g, 20.89 mmol, 70% yield). ¹ H NMR (DMSO-d ₆ , δ = 2.50 ppm, 300 MHz): δ 7.19 (d, J = 9.04 Hz, 1 H), 6.94 (s, 1 H), 4.38 (t, J = 8.78 Hz, 1 H ), 3.55 (s, 3 H), 2.14 - 2.27 (m, 1 H), 1.37 (s, 9 H), 0.95 (d, J = 7.03 Hz, 3H), 0.73 (d, J = 6.53 Hz, 3H) ).

Example B-200 step g

Add n-butyllithium (1.0 M solution) to a solution of 4,4'-dibromo-1,1'-biphenyl (5.00 g, 16.03 mmol) in anhydrous THF (100 mL) at -78 °C. , 40.1 mL, 64.1 mmol) in hexanes, and stirred for 1 hour. The reaction mixture was warmed to -30 ° C, and trimethyl borate (4.83 mL, 43.3 mmol) was added dropwise and stirred at room temperature for 1 hour. The reaction mixture was then acidified to pH = 2 with 1.5N HCl. The precipitate was filtered to obtain [1,1'-biphenyl]-4,4'-diyl 2 as an off-white solid. Acid (2.5 g, 10.34 mmol, 64.5% yield). ¹ H NMR (DMSO-d ₆ , δ = 2.50 ppm, 400 MHz): δ 8.06 (br. s., 4 H), 7.78 (d, J = 8. s Hz, 4 H), 7.65 (d, J = 8.4 Hz) , 4 H).

Example B-200 step h

To [1,1'-biphenyl]-4,4'-diyl 2 Add (S)-(1-(5-bromo-1-methyl-1H-imidazol-2-yl)-2-methylpropyl to a solution of the acid (0.65 g, 2.419 mmol) in DMF (2 mL) Tributyl methacrylate (1.688 g, 5.08 mmol), tripotassium phosphate (2.054 g, 9.68 mmol) and PdCl ₂ (dppf) (0.177 g, 0.242 mmol). The reaction mixture was degassed and heated to 90 ° C overnight. The volatile components are removed in a vacuum. The resulting residue was dissolved in EtOAc (EtOAc)EtOAc. , The filtrate was washed with brine, dried over Na ₂ SO _4, and concentrated in vacuo. By ISCO, using silicon dioxide 40g Redisep column _{(MeOH: CHCl 3, 3:} 97) The crude material was purified, and further purified by reverse phase prep HPLC, was obtained as an off-white solid of ((1S, 1'S) - (5,5'-([1,1'-biphenyl]-4,4'-diyl) bis(1-methyl-1H-imidazole-5,2-diyl)) bis(2-methyl Propyl-1,1-diyl))di-tert-butyl diamine (0.2 g, 0.304 mmol, 12.59% yield). ^{1 H NMR (DMSO-d6,} δ = 2.50ppm, 300MHz): δ 7.81 (d, J = 8.31Hz, 4 H), 7.56 (d, J = 8.1Hz, 4 H), 7.18 (s, 2 H) , 7.04(s, 2 H), 4.42-4.51 (m, 2 H), 3.83 (s, 6 H), 2.21-2.33 (m, 2 H), 1.39 (s, 18 H), 0.99 (d, J = 6.52 Hz, 6 H), 0.84 (d, J = 6.61 Hz, 6H). LCMS: (Condition B12) R _t : 2.45.

Example B-200 step i

To ((1S,1'S)-(5,5'-([1,1'-Biphenyl]-4,4'-diyl)bis(1-methyl-1H-imidazole-5,2-diyl) Add) 4M HCl in a solution of di-tert-butyl bis(2-methylpropion-1,1-diyl))diaminecarboxylate (0.2 g, 0.304 mmol) in dioxane (5 mL) Dioxane (10 mL, 40.0 mmol) was stirred at room temperature for 1 hour. The volatile component was removed in vacuo to give (1S,1'S)-1,1'-(5,5'-([1,1'-biphenyl]-4,4'-two as an off-white solid. Bis(2-methyl-1H-imidazol-5,2-diyl))bis(2-methylpropan-1-amine) dihydrochloride (0.15 g, 0.283 mmol, 93% yield). ¹ H NMR (DMSO-d6, δ = 2.50 ppm, 300 MHz): δ 7.93 (d, J = 8.31 Hz, 4H) 7.68 (d, J = 8.21 Hz, 6H) 4.62-4.65 (m, 2H), 3.83 ( s, 6H) 3.46-3.51 (m, 2H) 1.12 (d, J = 6.61 Hz, 6H) 0.91 (d, J = 6.70 Hz, 6H).

To (1S,1'S)-1,1'-(5,5'-([1,1'-biphenyl]-4,4'-diyl)bis(1-methyl-1H-imidazole-5, Addition of 4,4-difluorocyclohexanecarboxylic acid to a solution of bis(2-methylpropan-1-amine) dihydrochloride (30 mg, 0.057 mmol) in DMF (2 mL) (20.46 mg, 0.125 mmol), DIPEA (0.040 mL, 0.227 mmol) and HATU (47.4 mg, 0.125 mmol). After stirring at room temperature for 2 hours, the volatile components removed in vacuo, and the residue was dissolved in DCM (10mL), washed with saturated NH ₄ Cl solution, 10% NaHCO ₃ solution, brine, dried over Na ₂ sulfate SO _4, and concentrated in vacuo. The crude material was purified by reverse phase HPLC (ACN / water / NH ₄ OAc) to afford Example B-200. LC (Condition B4): >99% homogeneity index. LC/MS ( Condition 12 ): R _t = 2.22 min. LC / MS: [M + H ] + C 42 H 53 F 4 N 6 O 2 Calculated: 749.42; Found: 749.4.

The following examples were prepared from Example B-200, step i, and the appropriate starting materials (caps) by employing the procedure described for Synthesis Example B-199. By prep _{HPLC (CH 3 CN / H 2} O / NH 4 OAc) purified product was obtained.

Example B-206

Example B-206 step a

To (S)-2-((t-butoxycarbonyl)amino)-3,3-dimethylbutyric acid (3 g, 12.97 mmol) in anhydrous DMF (20 mL) NaH (2.59 g, 64.9 mmol) was added to the solution and the mixture was warmed to room temperature over 30 min. Methyl iodide (8.11 mL, 130 mmol) was then added and stirred at room temperature for 8 h. The reaction mixture was quenched with EtOAc (EtOAc)EtOAc. The organic phase was washed with brine, dried over Na ₂ SO _4, filtered and concentrated under reduced pressure, to give (3g, 89% yield) as a colorless liquid of (S) -2 - ((tert-butoxy carbonyl) Methyl (methyl)amino)-3,3-dimethylbutanoate was taken to the next step without further purification. ¹ H NMR (CDCl ₃ , δ = 7.26 ppm, 300 MHz): δ 4.75 (s, 1 H), 3.70 (s, 3 H), 2.93 (s, 3 H), 1.47 (s, 9 H), 1.07 ( s, 9 H).

Example B-206 step b

a mixture of (S)-2-((t-butoxycarbonyl)(methyl)amino)methyl-3,3-dimethylbutanoate (1.5 g, 5.78 mmol) in THF / MeOH / water LiOH (0.693 g, 28.9 mmol) was added to the solution (1:1:1, 30 mL), and stirred at room temperature for 8 hours. The solvent was removed in vacuo and aq. EtOAc (EtOAc) (EtOAc) Washed with brine the organic layers were combined, dried over Na ₂ SO _4, filtered and concentrated under reduced pressure to give a colorless gum mucus-like body of (S) -2 - ((tert-butoxy carbonyl) (methyl Amino)-3,3-dimethylbutyric acid (1.1 g, 78%) was taken to the next step without further purification. ¹ H NMR (CDCl ₃ , δ = 7.26 ppm, 300 MHz): δ 4.48 (s, 1H), 2.96 (s, 3 H), 1.48 (s, 9 H), 1.11 (s, 9 H).

Example B-206 step d

To 1,1'-([1,1'-biphenyl]-4,4'-diyl)bis(2-bromoethyl ketone) (0.8 g, 2.02 mmol) at 0 ° C under N ₂ atmosphere And a solution of (S)-2-((t-butoxycarbonyl)(methyl)amino)-3,3-dimethylbutyric acid (1.14 g, 4.65 mmol) in anhydrous DMF (30 mL) DIPEA (1.411 mL, 8.08 mmol) was added and the mixture was stirred at room temperature for 4 hr. The volatiles were removed in vacuo and EtOAcqqqqq Dried organic layer was washed with 10% NaHCO ₃ solution, brine over Na ₂ SO _4, and concentrated in vacuo. The crude material was purified with EtOAc (EtOAc) elute Further separation of the mixture of diastereomers by SFC gave (2S,2'S)-bis(2-((t-butoxycarbonyl)(methyl)amino)-3,3- as a brown solid. Dimethylbutyric acid) [1,1'-biphenyl]-4,4'-diylbis(2-o-ethoxyethyl-2,1-diyl) ester (812 mg, 54% yield). ¹ H NMR (CD ₃ OD, δ = 3.34 ppm, 400 MHz): δ 8.10 (d, J = 8.5 Hz, 4 H), 7.89 (d, J = 8.5 Hz, 4 H), 5.52 (s, 4 H) , 4.84 (br.s., 2 H), 3.01 (s, 6 H), 1.48 (s, 18 H), 1.14 (s, 18 H).

Example B-206 step e

To (2S,2'S)-bis(2-((t-butoxycarbonyl)(methyl)amino)-3,3-dimethylbutyric)[1,1'-biphenyl]-4, Ammonium acetate (1295 mg, 16.80 mmol) was added to a solution of 4'-diylbis(2-oxoethoxy-2,1-diyl) ester (812 mg, 1.120 mmol) in anhydrous xylene (5 mL). The reaction mixture was purged with argon for 30 minutes. The reaction mixture was heated at 130 ° C for 8 hours in a sealed tube. The volatiles were removed in vacuo and EtOAcqqqqq Dried organic layer was washed with 10% NaHCO ₃ solution, brine over Na ₂ SO _4, and concentrated in vacuo. The crude material was purified by preparative HPLC to give ((1S,1'S)-(5,5'-([1,1'-biphenyl]-4,4'-diyl) bis (1H) as a brown solid. -imidazole-5,2-diyl))bis(2,2-dimethylpropane-1,1-diyl))bis(methylaminocarbamic acid) di-t-butyl ester (183 mg, 24% yield ). ¹ H NMR (CD ₃ OD, δ = 3.34 ppm, 400 MHz): δ 7.95-7.62 (m, 8 H), 7.45-7.32 (m, 2 H), 5.22 (br.s, 2 H), 3.08-2.98 (m, 6 H), 1.56 (s, 18 H), 1.14 (s, 18 H).

Example B-206 step f

To ((1S,1'S)-(5,5'-([1,1'-biphenyl]-4,4'-diyl)bis(1H-imidazole-5,2-diyl)) bis (2) Add a solution of HCl in methanol to a solution of 2-dimethylpropane-1,1-diyl)) bis(methylaminocarbamic acid) di-t-butyl ester (40 mg, 0.058 mmol) in anhydrous MeOH (10 mL) (20 mL, 60.0 mmol). The reaction was stirred at room temperature for 8 hours. The volatile components are removed in a vacuum. The obtained solid was dried under vacuum to give (1S,1's)-1,1'-(5,5'-([1,1'-biphenyl]-4,4'-diyl) double as a brown solid. (1H-Imidazole-5,2-diyl))bis(N,2,2-trimethylpropan-1-amine) tetrahydrochloride (50 mg, 91% yield). ¹ H NMR (CD ₃ OD, δ = 3.34 ppm, 300 MHz): δ 7.99-7.95 (m, 4 H), 7.91 (s, 2 H), 7.83 (d, J = 8.7 Hz, 4 H), 4.48 ( s, 2 H), 2.73 (s, 6 H), 1.21 (s, 18 H).

To (1S,1'S)-1,1'-(5,5'-([1,1'-biphenyl]-4,4'-diyl) bis(1H-imidazole-5, at 0 °C 2-Diyl)) bis(N,2,2-trimethylpropan-1-amine) tetrahydrochloride (60 mg, 0.095 mmol) in 4 D of 4M in anhydrous DMF (2 mL) Difluorocyclohexanecarboxylic acid (62.5 mg, 0.381 mmol), DIPEA (0.083 mL, 0.476 mmol) and HATU (90 mg, 0.238 mmol). After stirring at room temperature for 2 hours, the volatile components removed in vacuo, and the residue was dissolved in DCM (100mL), washed with saturated NH ₄ Cl solution (30mL), 10% NaHCO ₃ solution (30 mL), washed with brine (30mL), dried over Na ₂ SO _4, and concentrated in vacuo. The crude material was purified by reverse phase HPLC (ACN / water / NH ₄ OAc), obtained as a pale yellow solid of Example B-206 (50mg). LC/MS ( Condition B-12 ): R _t = 2.759 min. LC / MS: [M + H ] + C 44 H 57 F 4 N 6 O 2 Calculated: 777.45; Found: 777.0. LC ( Condition B-1 and B-2 ): R _t = 8.879 (B-1) and R _t = 7.962 (B-2).

Example B-207

Example B-207 was prepared according to the method described for Preparation Example B-206. LC ( Condition B-1 and B-2 ): >98% homogeneity index. LC/MS ( Condition B-12 ): R _t = 2.985 min. LC / MS: [M + H ] + C 40 H 57 N 6 O 2 Calculated: 653.45; Found: 653.0. LC ( Condition B-1 and B-2 ) R _t = 8.591 (B-1) and R _t = 7.289 (Condition B-2).

Example B-209

Example B-209 step a

To (S)-2-((t-butoxycarbonyl)amino)-3,3-dimethylbutyric acid (2 g, 8.65 mmol) in anhydrous methanol at 0 ° C under N ₂ atmosphere ( SOCl ₂ (6.31 mL, 86 mmol) was added dropwise to a solution in 20 mL). After the addition, the reaction was heated to 80 ° C for 8 hours. The volatile components were removed in vacuo and the residue was evaporated with dry diethyl ether (3×5 mL). The resulting salt was exposed to a high vacuum to give (S)-2-amino-3,3-dimethylbutyric acid methyl ester hydrochloride (1.2 g, 76%) Go to the next step. ¹ H NMR (DMSO-D ₆ , δ = 2.50 ppm, 400 MHz): δ 8.75 (br.s., 2 H), 3.83 (s, 3 H), 3.18 (br.s., 1H), 1.02 (s) , 9 H).

Example B-209 step b

Under N ₂ atmosphere, to (S) -2- amino-3,3-dimethylbutanoate hydrochloride (2g, 11.01mmol) in dry DMF (10mL) was added sequentially a solution of the K _{2 CO 3 (6.09g, 44.0mmol)} , ((2- iodoethoxy) methyl) benzene (3.46g, 13.21mmol). The reaction was heated at 70 ° C for 8 hours. The volatile components removed in vacuo, and the residue was dissolved in ethyl acetate (250 mL), washed with water (100 mL), washed with brine (100 mL), dried (Na ₂ SO _4), filtered, and concentrated in vacuo. The crude material was purified by flash chromatography (EtOAc (EtOAc) elute Methyl-3,3-dimethylbutanoate (1.6 g, 52%). ¹ H NMR (CDCl ₃ , δ = 7.26 ppm, 300 MHz): δ 7.36-7.34 (m, 5 H), 4.53 (d, J = 2.3 Hz, 2 H), 3.70 (s, 3 H), 3.59-3.53 (m, 2 H), 2.94 (s, 1 H), 2.84 (ddd, J = 5.1, 6.9, 12.2 Hz, 1 H), 2.63-2.55 (m, 1 H), 0.97 (s, 9 H).

Example B-209 step c

Under N ₂ atmosphere, to (S) -2 - ((2- ( benzyloxy) ethyl) amino) -3,3-dimethoxy butyric acid methyl ester (1g, 3.58mmol) in dry diethyl (BOC) ₂ O (4.16 mL, 17.90 mmol) was added to a solution of methylene chloride (10 mL). The reaction was heated to 130 ° C for 8 hours. The volatile components removed in vacuo, and the residue was dissolved in ethyl acetate (500 mL), washed with water (100 mL), washed with brine (100 mL), dried (Na ₂ SO _4), filtered, and concentrated in vacuo. The crude material was purified by flash chromatography (EtOAc, EtOAc (EtOAc) elute Ethyl)(t-butoxycarbonyl)amino)methyl-3,3-dimethylbutanoate (980 mg, 72%). ¹ H NMR (CDCl ₃ , δ = 7.26 ppm, 300 MHz): δ 7.37-7.32 (m, 5 H), 4.53 (d, J = 1.9 Hz, 3 H), 3.69-3.61 (m, 6 H), 3.58 (br.s., 1 H), 1.49-1.42 (m, 9 H), 1.07 (s, 9 H).

Example B-209 step d

Water (7.5 mL) containing LiOH (1.893 g, 79 mmol) was added to (S)-2-((2-(benzyloxy)ethyl)(t-butoxycarbonyl)amino)-3, A solution of methyl 3-dimethylbutanoate (3 g, 7.91 mmol) in THF (15 mL) EtOAc. The reaction mixture was stirred at room temperature overnight. The reaction was monitored by LCMS. Only 50% completed. LiOH (0.947 g, 39.5 mmol) was added to the above reaction mixture, and the reaction mixture was stirred at room temperature overnight.

LCMS showed only 85% completion. LiOH (0.379 g, 15.81 mmol) was again added to the reaction mixture and stirred overnight. The reaction was monitored by LCMS. The solvent is removed in vacuo, and extracted with ethyl acetate (2 × 20ml) acidified with acetic acid, dried and concentrated over Na ₂ SO _4. The crude material was chromatographed by SFC to give (S)-2-((2-(benzyloxy)ethyl)(t-butoxycarbonyl)amino)-3 as an off-white solid. 3-Dimethylbutyric acid (2.2 g, 5.89 mmol, 74.5%). ¹ H NMR (CDCl ₃ , δ = 7.26 ppm, 300 MHz): δ 7.28 (br.s., 4 H), 7.22 - 7.18 (m, 1 H), 4.48 (br.s., 2 H), 3.72 ( Td, J = 7.0, 12.2 Hz, 4 H), 2.01 (br.s., 2 H), 1.37 (br.s., 9 H), 1.02 (bs, 9 H).

Example B-209 step e

To 1,1'-([1,1'-biphenyl]-4,4'-diyl)bis(2-bromoethyl ketone) (340 mg, 0.858 mmol) at 0 ° C under N ₂ atmosphere And (S)-2-((2-(benzyloxy)ethyl)(t-butoxycarbonyl)amino)-3,3-dimethylbutyric acid (784 mg, 2.146 mmol) in anhydrous DMF DIPEA (0.600 mL, 3.43 mmol) was added to the solution and the mixture was stirred at room temperature for 8 hr. The volatiles were removed in vacuo, and the residue was dissolved in ethyl acetate (500 mL), washed with 10% sodium bicarbonate solution (150ml), brine (20mL), dried (Na ₂ SO _4), in vacuo concentrate. The crude material was purified by combi flash (24 g of cerium oxide, Redisep 24% ethyl acetate: petroleum ether) to give (2S,2'S)-bis(2-((2-(phenyloxy)) as a colorless liquid. Ethyl)ethyl)(t-butoxycarbonyl)amino)-3,3-dimethylbutyric acid)[1,1'-biphenyl]-4,4'-diyl bis(2-side oxygen Base ethyl-2,1-diyl) ester (364 mg, 39%). ¹ H NMR (CD ₃ OD, δ = 3.34 ppm, 400 MHz): δ 8.03 (d, J = 8.0 Hz, 4 H), 7.91-7.80 (m, 4 H), 7.37-7.22 (m, 10 H), 5.49(s,2 H), 5.23 (d, J = 16.6 Hz, 2 H), 4.64 - 4.38 (m, 6 H), 3.81-3.56 (m, 6 H), 3.52-3.37 (m, 2 H) , 1.53-1.37 (m, 18 H), 1.19-1.01 (m, 18 H).

Example B-209 step f

In the sealed tube, to (2S,2'S)-bis(2-((2-(benzyloxy)ethyl))(t-butoxycarbonyl)amino)-3,3-dimethylbutyric acid [1,1'-biphenyl]-4,4'-diylbis(2-oxoethoxy-2,1-diyl) ester (364 mg, 0.377 mmol) in anhydrous xylene (5 mL) Ammonium acetate (436 mg, 5.66 mmol) was added to the solution and the reaction was heated to 130 ° C overnight. Volatile components were evaporated under reduced pressure, and the residue was dissolved in DCM (500mL), and washed with water (100mL), 10% saturated sodium bicarbonate solution (100 mL), washed with brine (100 mL), dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. The crude material was purified by reverse phase HPLC (ACN / water / ammonium acetate) to afford a pale yellow solid of Example B-209 step f (60mg, 17% yield). ¹ H NMR (CD ₃ OD, δ = 3.34 ppm, 400 MHz): δ 8.03 (d, J = 8.0 Hz, 4 H), 7.91-7.80 (m, 6 H), 7.37-7.22 (m, 10 H), 5.49 (s, 2 H), 4.64 - 4.38 (m, 4 H), 3.8 l - 3.56 (m, 6 H), 3.52-3.37 (m, 2 H), 1.53-1.37 (m, 18 H), 1.19 -1.01 (m, 18 H).

Example B-209 step g

Add HCl containing methanol (10 mL, 0.540 mmol) to ((1S,1'S)-(5,5'-([1,1'-biphenyl]-4,4'-diyl) bis (1H-imidazole) -5,2-diyl))bis(2,2-dimethylpropane-1,1-diyl))bis((2-(benzyloxy)ethyl)carbamic acid) di-third The ester (0.5 g, 0.540 mmol) was added and the reaction mixture was stirred at room temperature overnight. The reaction was monitored by LCMS. The solvent was removed in vacuo, washed with EtOAc EtOAc EtOAcjHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH ,4'-diyl)bis(1H-imidazole-5,2-diyl))bis(N-(2-(benzyloxy)ethyl)-2,2-dimethylpropan-1-amine Trihydrochloride (0.41 g, 0.491 mmol, 91% yield). ¹ H NMR (DMSO-d ₆ , δ = 2.50 ppm, 400 MHz): δ 9.07-8.38 (m, 1 H), 8.28-8.11 (m, 2 H), 8.09-7.73 (m, 8 H), 7.47- 7.12 (m, 11 H), 4.81 (br.s., 2 H), 4.69-4.45 (m, 4 H), 3.94-3.66 (m, 4 H), 3.38 (d, J = 7.2 Hz, 2 H ), 3.08-2.97 (m, 2 H), 1.16-1.00 (m, 18 H).

Example B-209 step h

To (1S,1'S)-1,1'-(5,5'-([1,1'-biphenyl]-4,4'-diyl)bis(1H-imidazole-5,2-diyl) a solution of bis(N-(2-(benzyloxy)ethyl)-2,2-dimethylpropan-1-amine)tetrahydrochloride (0.09 g, 0.103 mmol) in DCM (10 mL) DIPEA (0.181 mL, 1.034 mmol), 4,4-difluorocyclohexanecarboxylic acid (0.170 g, 1.034 mmol) and HATU (0.196 g, 0.517 mmol) were added. The reaction mixture was stirred at room temperature overnight. The reaction was monitored by LCMS. The reaction mixture was diluted with EtOAc (EtOAc)EtOAc. The organic layer was dried over NaSO ₄ and concentrated merger. The crude material was purified by ISCO using a 24 g Redisep column and CHCl ₃ /MeOH as a solvent to give N,N'-((1S,1'S)-(5,5'-([1,1'-biphenyl) ]-4,4'-diyl)bis(1H-imidazole-5,2-diyl))bis(2,2-dimethylpropane-1,1-diyl))bis(N-(2-) (Benzyloxy)ethyl)-4,4-difluorocyclohexanecarbamide (0.07 g, 0.065 mmol, 62.6% yield). LC / MS (conditions _{B-25): R t =} 3.206min; LC / MS: [M + H] + C 60 H 73 F 4 N 6 O 4 Calculated: 1017.56; Found: 1017.0.

To N,N'-((1S,1'S)-(5,5'-([1,1'-biphenyl]-4,4'-diyl) bis(1H-imidazole-5,2-diyl) )) bis(2,2-dimethylpropane-1,1-diyl))bis(N-(2-(benzyloxy)ethyl)-4,4-difluorocyclohexanecarboxamide (60 mg, 0.059 mmol) <RTI ID=0.0></RTI></RTI><RTIgt;</RTI><RTIgt;</RTI><RTIgt_; The reaction was monitored by LCMS. The reaction mixture was filtered through a pad of Celite and washed with methanol. The combined filtrates were concentrated, and the crude material was purified eluting with EtOAc EtOAc EtOAc EtOAc -((1S,1'S)-(5,5'-([1,1'-biphenyl]-4,4'-diyl) bis(1H-imidazole-5,2-diyl)) bis (2 ,2-dimethylpropan-1,1-diyl))bis(4,4-difluoro-N-(2-hydroxyethyl)cyclohexanecarbamamine) (7.89 mg, 9.43 μmol, 15.98% Yield). LC ( Condition B-30 ): >98% homogeneity index. LC/MS ( Condition B-12 ): R _t = 2.360 min. LC / MS: [M + H ] + C 46 H 61 F 4 N 6 O 4 Calculated: 837.47; Found: 837.4. _{^{1 H NMR (CD 3 OD,}} δ = 3.34ppm, 400MHz): δ 7.97-7.63 (m, 8 H), 7.49 (br.s., 2 H), 5.79 (br.s., 2 H), 4.32 - 3.92 (m, 2 H), 3.85-3.56 (m, 2 H), 3.13 - 2.79 (m, 6 H), 2.27-1.70 (m, 16 H), 1.25 - 1.04 (m, 18 H).

Preparation of intermediate acid: Cap-1:1-methoxycyclobutanecarboxylic acid

Cap-1 was prepared by following the procedure described in Organometallics, 6 (10), 2079-85; 1987.

Cap-2: 4-fluorobicyclo[2.2.2]octane-1-carboxylic acid

Cap-2 was prepared by following the procedure described in Journal of Organic Chemistry, 57 (10), 2850-5, 1992.

Cap-3: 1-(fluoromethyl)cyclopropanecarboxylic acid

Pure trifluoro(diethylamino)sulfide (419 mg, 2.60 mmol) was added to ethyl 1-(hydroxymethyl)cyclopropanecarboxylate (288 mg, 2 mmol) in DCM (-78 ° C) The solution was allowed to warm to room temperature and stirred at room temperature overnight. The reaction mixture was cooled with ice and quenched with saturated NaHCO _3. The organic layer was separated, and with 1N HCl, water, brine and dried (MgSO _4). The <RTI ID=0.0></RTI></RTI><RTIID=0.0></RTI></RTI><RTIgt; The homogenous mixture was stirred overnight at rt, then acidified and extracted with diethyl ether to give abr. ¹ H NMR (400 MHz, chloroform-d) δ 4.53 (d, J = 46.9 Hz, 2 H), 1.51-1.45 (m, 2 H), 1.13-1.07 (m, 2 H).

Cap-4: 3-Fluoro-2,2-dimethylpropionic acid

In a capped vial, methyl 3-hydroxy-2,2-dimethylpropanoate (0.264 g, 2 mmol) and tris[bis(2-methoxyethyl)amino]sulfide (0.531 g) The pure stirred mixture of 2.400 mmol) was heated at 70 ° C for 18 hours. The reaction mixture was cooled and quenched with ice and DCM was added. With 1N HCl, water, brine and the organic layer was dried (MgSO _4). The <RTI ID=0.0></RTI></RTI><RTIID=0.0></RTI><RTIID=0.0> A homogeneous mixture was stirred overnight at room temperature, and acidified with 1N HCl and extracted with EtOAc, washed with water, brine and dried (MgSO _4). The solvent was evaporated to give a pale brown oil of the cap -4: ¹ H NMR (400MHz, CHLOROFORM -d) δ 4.43 (d, J = 47.1Hz, 2 H), 1.28 (d, J = 1.0Hz, 6 H) .

Cap-5: 4,4-difluoro-1-methylcyclohexanecarboxylic acid

A solution of n-butyllithium (1.250 mL, 2.000 mmol) was added to a solution of diisopropylamine (0.283 mL, 2.00 mmol) in THF (-78 ° C), and the mixture was stirred at -78 ° C under nitrogen. 1 hour. A solution of ethyl 4,4-difluorocyclohexanecarboxylate (192 mg, 1 mmol) in THF (1 mL) was obtained. The reaction mixture was stirred at -78 °C for 1 hour, then gradually warmed to -20 °C over 2 hours. Pure methyl iodide (0.138 mL, 2.200 mmol) was added at -78.degree. C., and the mixture was warmed to room temperature and stirred at room temperature overnight. With saturated NH ₄ Cl The reaction was quenched and extracted with EtOAc, and washed with water, the organic phase was washed with brine, dried (Na ₂ SO _4). The solvent was evaporated to give ethyl 4,4-difluoro-1-methylcyclohexanecarboxylate ( 222 mg) as a pale brown oil, which was dissolved in EtOH and KOH (112 mg, 2.00 mmol) in water (2.00) Solution in mL). The reaction mixture was heated to EtOAc (EtOAc m. ¹ H NMR (400MHz, CHLOROFORM -d) δ 2.26-2.17 (m, 2 H), 2.07-1.95 (m, 2 H), 1.94-1.83 (m, 2 H), 1.63-1.54 (m, 2 H) , 1.31 (s, 3 H).

Cap-6: 4,4-difluoro-1-(hydroxymethyl)cyclohexanecarboxylic acid

Under N _2, a solution of butyllithium (2.000mL, 2.80mmol) was added diisopropylamine (0.396mL, 2.80mmol) (5mL) in the cold (-78 deg.] C) in a solution of THF, at -78 deg.] C and The mixture was stirred for 1 hour. A solution of ethyl 4,4-difluorocyclohexanecarboxylate (384 mg, 2 mmol) in THF (2 mL) was added at -78 ° C, and the mixture was stirred for 1 hour, then gradually warmed to -20 ° C over 2 hours, then Cool again to -78 °C. Pure ((chloromethoxy)methyl)benzene (0.226 mL, 2.200 mmol) was added, and the mixture was warmed to room temperature over 2 hr. With saturated NH ₄ Cl The reaction was quenched and extracted with EtOAc and washed with water, brine, dried (Na ₂ SO _4). Evaporation of the solvent afforded EtOAc (EtOAc: EtOAc) 4-difluorocyclohexanecarboxylate.

Add pure methanesulfonic acid (1.102 mL, 16.97 mmol) to ethyl 1-((benzyloxy)methyl)-4,4-difluorocyclohexanecarboxylate (106 mg, 0.339 mmol) in DCM (2 mL) The mixture was stirred and the mixture was stirred at room temperature for 2 hours. Washed with water, saturated NaHCO _3, brine and dried the reaction mixture (MgSO _4), was obtained as an oil of 4,4-difluoro-1- (hydroxymethyl) cyclohexanecarboxylate. ¹ H NMR (400MHz, CHLOROFORM -d) δ 4.25 (q, J = 7.3Hz, 2H), 3.67 (s, 2 H), 2.28-2.17 (m, 2 H), 2.08-1.93 (m, 2 H) , 1.86-1.80 (m, 2 H), 1.67-1.56 (m, 2 H), 1.31 (t, J = 1.0 Hz, 3 H).

Add 1N NaOH (0.994 mL, 0.994 mmol) to EtOAc (EtOAc (EtOAc) The solution was stirred and the mixture was stirred at room temperature for 3-4 hours. The reaction mixture was acidified, and extracted with EtOAC, washed with brine and dried (MgSO _4). The solvent was evaporated to give a cap-6 as a beige solid. ¹ H NMR (400 MHz, chloroform-d) δ 3.74 (s, 2 H), 2.30-2.20 (m, J = 13.3 Hz, 2 H), 2.13-1.85 (m, 4 H), 1.71-1.60 (m, 2 H).

Cap-7: 4,4-difluoro-1-(fluoromethyl)cyclohexanecarboxylic acid

The pure stirred mixture of Deoxo-Fluor® (196 mg, 0.887 mmol) and 4,4-difluoro-1-(hydroxymethyl)cyclohexanecarboxylate (98.6 mg, 0.444 mmol) was heated at 70 °C. Overnight. The reaction was cooled to room temperature and quenched with ice, and extracted with DCM, washed with saturated NaHCO _3, water, brine and dried (MgSO _4). The DCM was evaporated to give abr. EtOAc (EtOAc:EtOAc) Ethyl hexanecarboxylate. ¹ H NMR (400MHz, CHLOROFORM -d) δ 4.42 (d, J = 47.2Hz, 2 H), 4.25 (q, J = 7.0Hz, 2 H), 2.33-2.19 (m, 2 H), 2.15-2.01 (m, 2 H), 2.01-1.81 (m, 2 H), 1.69-1.56 (m, 2 H), 1.31 (t, J = 7.0 Hz, 3 H).

Add 1N NaOH (0.994 mL, 0.994 mmol) to 4,4-difluoro-1-(fluoromethyl)cyclohexanecarboxylate (73.6 mg, 0.331 mmol) in THF (1 mL) The solution was stirred and the mixture was stirred at room temperature for 3-4 hours. The reaction mixture was acidified, and extracted with EtOAC, washed with brine and dried (MgSO _4). The solvent was evaporated to give a cap-7 as a beige solid. ¹ H NMR (400MHz, CHLOROFORM -d) δ 4.38 (d, J = 47.1Hz, 2 H), 2.30-2.16 (m, 2 H), 2.11-1.98 (m, 2 H), 1.96-1.76 (m, 2 H), 1.65-1.51 (m, 2 H).

Cap-8: 4,4-difluoro-1-(methoxymethyl)cyclohexanecarboxylic acid

Add NaH (60%, 29.4 mg, 0.736 mmol) to ethyl 4,4-difluoro-1-(hydroxymethyl)cyclohexanecarboxylate (109 mg, 0.490 mmol) in THF (2 mL) °C) The solution was allowed to warm to room temperature over 30 minutes. Then pure dimethyl sulfate (0.070 mL, 0.736 mmol) was added and the mixture was stirred at room temperature overnight. The excess of Me ₂ SO _{4 was} quenched with EtOAc (EtOAc) (EtOAc)EtOAc. Ethyl fluoro-1-(methoxymethyl)cyclohexanecarboxylate (47 mg). The ethyl ester was saponified (1 N NaOH, MeOH-THF) to give a white solid: -8: ¹ H NMR (400 MHz, chloroform-d) δ 3.47 (s, 2 H), 3.39 (s, 3 H), 2.25 (br.d, J = 13.1 Hz, 2 H), 2.10 - 1.95 (m, 3 H), 1.69 - 1.55 (m, 3 H).

Cap-9: 4,4-difluoro-1-hydroxycyclohexanecarboxylic acid Cap-10: 4,4-difluoro-1-methoxycyclohexanecarboxylic acid

Add butyl lithium solution (1.600 mL, 4.00 mmol) to diisopropylamine (0.565 mL, 4.00 mmol) in THF (5 mL) cold (-78 ° C) and at -78 ° C The mixture was stirred for 1 hour. A solution of ethyl 4,4-difluorocyclohexanecarboxylate (384 mg, 2 mmol) in THF (2 mL) was evaporated. The mixture was gradually warmed to -20 ° C over 2 hours, then cooled again to -78 ° C, and attached to an oxygen balloon and stirred at -78 ° C for 1 hour. A saturated NaHSO ₃ solution (5 mL) was added and the mixture was warmed to room temperature and stirred at room temperature overnight. The reaction mixture was diluted with ether, and the organic layer was separated, washed with water, brine, dried (Na ₂ SO _4). Evaporation of the solvent gave EtOAc (EtOAc md. ¹ H NMR (400MHz, CHLOROFORM -d) δ 4.28 (q, J = 7.3Hz, 2 H), 2.23 (br.s, 1 H), 2.19-1.99 (m, 6 H), 1.83-1.73 (m, 2 H), 1.33 (t, J = 1.0 Hz, 3 H).

Add 1N NaOH (0.382 mL, 0.382 mmol) to a solution of ethyl 4,4-difluoro-1-hydroxycyclohexanecarboxylate (26.5 mg, 0.127 mmol) in THF (0.5 mL) The mixture was stirred overnight at room temperature. The reaction mixture was acidified with 2N HCl, and extracted with EtOAc, washed with brine and dried (MgSO _4). The solvent was evaporated to give a cap-9 as a white solid. ¹ H NMR (400MHz, CHLOROFORM -d) δ 2.21-2.01 (m, 5 H), 1.92-1.87 (m, J = 6.8,3.2,3.2Hz, 2 H), 1.86-1.79 (m, J = 6.7, 3.1 Hz, 2 H).

Add NaH (60%, 2.2 eq.) to 4,4-difluoro-1-hydroxycyclohexanecarboxylic acid (1 eq.) in THF (2 mL) EtOAc (EtOAc) To room temperature (30 minutes). Pure dimethyl sulfate (2.4 eq.) was then added at 0&lt;0&gt;C, and the mixture was warmed to room temperature and stirred at room temperature overnight. Excess Me ₂ SO _{4 was} quenched with TEA and the mixture was acidified with EtOAc (EtOAc) eluting with diethyl ether to afford methyl 4,4-difluoro-1-methoxycyclohexanecarboxylate (1N NaOH, THF - MeOH) to give a cap - 10 as a beige semi-solid. ¹ H NMR (400 MHz, chloroform-d) δ 3.36 (s, 3 H), 2.17.98 (m, 8H).

Cap-11: 3,3-difluoro-2,2-dimethylpropionic acid

PCC (808 mg, 3.75 mmol) was added to a solution of 4-hydroxy-2,2-dimethylpropanoic acid benzyl ester (521 mg, 2.5 mmol) in powdered 4 Å molecular sieves (about 0.5 g) in DCM (5 mL) The mixture was stirred overnight at room temperature. The reaction mixture was filtered with EtOAc (EtOAc) elute

Add Deoxo-Fluor® (0.789 ml, 4.28 mmol) to a solution of benzyl 2,2-dimethyl-3-oxopropionate (401 mg, 1.944 mmol) in DCM (5 mL) Catalytic amount of EtOH (0.034 mL, 0.583 mmol). The resulting solution was stirred overnight at room temperature. The reaction was _quenched with saturated NaHCO, and the mixture was extracted with DCM (2 ×). Washed with water, brine, and the combined organic layers were dried (MgSO _4), filtered and dried to give a yellow - orange oil, silicone by FCC (2: 1 hexanes-DCM) The oil was purified to give a colorless Oily benzyl 3,3-difluoro-2,2-dimethylpropanoate (340 mg).

A stirred suspension of 3,3-difluoro-2,2-dimethylpropanoic acid benzyl ester (340 mg, 1.49 mmol) and 10% Pd-C (42 mg, 0.04 mmol) in EtOAc (20 mL) Hydrogenated overnight under balloon pressure. The suspension was filtered, and the filtrate was evaporated to dry crystals crystals ¹ H NMR (400MHz, CHLOROFORM -d) δ 6.01 (t, J = 1.0Hz, 1 H), 2.07 (br.s, 1 H), 1.34 (t, J = 1.0Hz, 6 H).

Cap-12:5,5-difluorooctahydrocyclopentadiene-2-carboxylic acid

Add NaH (60%, 0.480 g) to a cold (0 ° C) solution of diethyl 2-allylmalonate (2.002 g) in DMF (10 mL). temperature. A solution of 3-bromopropan-1-yne (1.487 g) in DMF (3 mL) was then evaporated. The reaction mixture was diluted with diethyl ether, followed by quenching with saturated NH ₄ Cl, washed with water, brine and dried (Na ₂ SO _4). The crude product was purified by silica gel FCC (1:1 DCM-hexane) toield diethyl 2-ethyl <RTIgt;

Pure octacarbonyldicobalt (718 mg, 2.100 mmol) was added to diethyl 2-allyl-2-(prop-2-yn-1-yl)malonate (477 mg, 2 mmol) under N ₂ The stirred solution in DCM (25 mL) was stirred at room temperature for 1 hour. The in situ formed alkenyl-Co ₂ (CO) ₆ complex was diluted with DCM (25 mL) and pure trimethylamine N-oxide (451 mg) was added in one portion at -78 °C under an O ₂ balloon. The reaction mixture was allowed to warm to rt and stirred at rt overnight. Evaporation of the reaction mixture to dryness, then purified by silica gel eluting eluting eluting eluting eluting eluting eluting Ethylene-2,2(1H)-dicarboxylic acid diethyl ester. ¹ H NMR (400MHz, CHLOROFORM -d) δ 5.95 (br.s., 1 H), 4.35-4.15 (m, 4 H), 3.44-3.32 (m, 1 H), 3.32-3.21 (m, 1 H ), 3.12 (br.s., 1 H), 2.81 (dd, J = 12.7, 7.7 Hz, 1 H), 2.65 (dd, J = 17.8, 6.3 Hz, 1 H), 2.15 (d, J = 17.6) Hz, 1 H), 1.75 (t, J = 12.8 Hz, 1 H), 1.37-1.18 (m, 6 H).

5-Phenoxy-3,3a,4,5-tetrahydrocyclopentadiene-2,2(1H)-dicarboxylic acid diethyl ester (322 mg, 1.209 mmol) and 10% Pd-C (129 mg, The stirred suspension in EtOH (40 mL) was hydrogenated under balloon pressure overnight. The suspension was filtered, and the filtrate was evaporated to dryness to give crystals of 5-- oxy hexahydro-cyclo-cyclopentadiene-2,2(1H)-dicarboxylate as a clear oil.

The stirred mixture of 5-oxo hexahydrocyclopentadienyl-2,2(1H)-dicarboxylic acid diethyl ester (0.651 g, 2.426 mmol) and 6N HCl (10 mL, 60.0 mmol) was heated to reflux. After maintaining for 3-4 hours, then evaporating to dryness to give a mixture of the mixture of the 5-oxooxy octahydrocyclopentadiene-2-carboxylic acid as a viscous oil, which was used without further purification. In the next step.

Pure (bromomethyl)benzene (531 mg) was added to 5-oxooxy octahydrocyclopentadiene-2-carboxylic acid (435 mg) and DIPEA (0.542 mL) in acetonitrile (2.5 mL) and CHCl ₃ (2.5 mL) The mixture was stirred and the mixture was stirred overnight at room temperature. The reaction mixture was evaporated to dryness and purified by silica gel FCC (EtOAc EtOAc EtOAc EtOAc The mixture of structures is isolated.

Add pure Deoxo-Fluor® (0.771 mL) to a cold (0 ° C) solution of 5-sided oxy octahydrocyclopentadienyl-2-carboxylate (450 mg) in DCM (6 mL). EtOH (0.031 mL) was added. The resulting yellowish solution was stirred at room temperature overnight. The reaction was _quenched with saturated NaHCO, and the mixture was extracted with DCM (2 ×). Washed with water, brine, and the combined organic layers were dried (MgSO _4), filtered and dried to give a yellow - orange oil. The residue was purified by silica gel FCC (1:1 hexane-DCM) to give a mixture of the mixture of the 5,5-difluoro octahydrocyclopentadiene-2-carboxylic acid benzyl ester as a colorless oil. (262 mg).

A stirred suspension of 10% Pd-C (12.53 mg) in benzyl 5,5-difluorooctahydrocyclopentadienyl-2-carboxylate (33 mg) in EtOAc (5 mL) Hydrogenation under pressure for 2-3 hours. The suspension was filtered and evaporated to dryness to give a mixture of &lt ¹ H NMR (400MHz, CHLOROFORM -d) δ 3.04-2.93 (m, 1 H), 2.88-2.76 (m, 2 H), 2.40-2.26 (m, 2 H), 2.15-2.04 (m, 2 H) , 1.87-1.71 (m, 4 H).

Cap-13:6,6-difluorospiro[3.3]heptane-2-carboxylic acid

Added (bromomethyl) benzene (564mg) in CHCl ₃ (1mL) in the solution to 6-oxo-spiro [3.3] heptane-2-carboxylic acid (462 mg) and DIPEA (0.576mL) in acetonitrile (2mL) and in the CHCl ₃ (2mL) stirred solution, and the mixture was stirred overnight at room temperature. The reaction mixture was evaporated to dryness then purified EtOAc EtOAc EtOAc EtOAc

Deoxo-Fluor® (1.456 g) was added to a cold (0 ° C) solution of 6-side oxo[3.3]heptane-2-carboxylic acid benzyl ester (0.670 g) in DCM (6 mL). EtOH (0.048 mL). The resulting solution was stirred overnight at room temperature. The reaction was _quenched with sat NaHCO and extracted with DCM (2 ×). Washed with water, brine, and the combined organic layers were dried (MgSO _4), filtered and evaporated to give a yellow - orange oil, silicone by FCC (1: 1 hexanes-DCM) The oil was purified to give a colorless Oily 6,6-difluorospiro[3.3]heptane-2-carboxylic acid benzyl ester (619 mg).

A stirred suspension of 10% Pd-C (40.6 mg) in EtOAc (10 mL) EtOAc (EtOAc) 2 hours. The suspension was filtered and the filtrate was evaporated to dryness to afford a cap-----. ¹ H NMR (400 MHz, chloroform-d) δ 3.18-3.08 (m, 1 H), 2.69-2.55 (m, 4H), 2.52-2.37 (m, 4H).

Cap-14:8,8-difluorobicyclo[3.2.1]octane-3- endo- formic acid

A solution of methyl 2-(bromomethyl)acrylate (531 mg) in acetonitrile (3 mL) was added dropwise to 1-(cyclopent-1-en-1-yl)pyrrolidine (407 mg) in acetonitrile (3 mL) A portion of the TEA was added to the stirred solution, followed by heating the mixture to reflux for 5 hours. Hydrolysis of the iminium ion intermediate was achieved by adding 5% aqueous AcOH (2 mL) followed by refluxing the mixture for 0.5 hours. The solvent was evaporated, and the residue was extracted with ether, washed with 1N HCl, saturated NaHCO _3, water, brine, then dried (Na ₂ SO _4). Evaporation of the ether afforded EtOAc (EtOAc: EtOAc) Internal type - methyl formate.

Add Deoxo-Fluor® (411 mg) to a cold (0 ° C) solution of 8-oxo-bicyclo[3.2.1]octane-3- endo- formic acid methyl ester (141 mg) in DCM (2 mL) Then EtOH (0.014 mL) was added. The resulting solution was stirred overnight at room temperature. The reaction was _quenched with saturated NaHCO, and the mixture was extracted with DCM (2 ×). Washed with water, brine, and the combined organic layers were dried (MgSO _4), filtered and dried to give oil, silicone by FCC (1: 1 hexanes-DCM) The oil was purified to give colorless oil of 8,8-Difluorobicyclo[3.2.1]octane-3-endo-formate (98 mg).

Methyl 8,8-difluorobicyclo[3.2.1]octane-3-endo-formic acid (98 mg) and lithium hydroxide monohydrate (60.4 mg) in THF (1 mL), MeOH (1 mL) The stirred solution was sonicated for 2 hours in 1 mL). The volatiles were evaporated, EtOAc (EtOAc m. ¹ H NMR (500 MHz, chloroform - d ) δ δ 2.65-2.76 (1 H, m), 2.32 (2H, dd, J = 6.26, 3.66 Hz), 2.09 (2H, t, J = 12.74 Hz), 1.95-2.03 (2 H, m), 1.83-1.92 (2 H, m), 1.52-1.62 (2 H, m).

Cap-15:8,8-difluorobicyclo[3.2.1]octane-3- exo -formic acid

(4mL) in methyl formate (67.7 mg) in MeOH - Sodium methoxide (0.5ml, 0.250mmol) was added to 8,8-difluoro-diazabicyclo the solution in MeOH [3.2.1] octan-3-endo The mixture was stirred and the mixture was heated at 70 ° C for 1 hour. The reaction was cooled, and acidified with 5% AcOH solution and extracted with diethyl ether, to give 8,8-difluoro-bicyclo [3.2.1] octane-outer -3--- acid methyl ester, as described for the synthesis of Cap -14 saponification allowed (1 N NaOH, THF-MeOH) afforded a cap -15 as a white solid. ¹ H NMR (400 MHz, chloroform-d) δ 2.77-2.64 (m, J =11.9, 6.1, 6.1 Hz, 1H), 2.32 (dd, J = 6.3, 3.5 Hz, 2 H), 2.15-2.04 (m, 2 H), 2.03-1.95 (m, 2 H), 1.94-1.84 (m, 2 H), 1.62-1.54 (m, 2 H).

Cap Y-1: (1R, 5S, 6r)-3,3-difluorobicyclo[3.1.0]hexane-6-carboxylic acid

a solution of cyclopent-3-en-1-yl benzoate (1.6 g) and ruthenium (II) acetate dimer (0.225 g) in DCM (20 mL) via a syringe pump at a rate of 0.8 mL/h A solution of 2-diazoacetate (3.53 mL) in 20 mL DCM was added. Speed at 0.2 mL/h via syringe pump Another portion of pure 2-diazoacetic acid ethyl acetate (4.0 mL) was added. After the addition, the reaction mixture was concentrated and purified on a pad of EtOAc (EtOAc / hexanes 0% to 25%).

The above product was dissolved in 5 mL THF, 20 mL MeOH and 30 mL 2N NaOH. The mixture was stirred for one day and partially concentrated. The residue was acidified with EtOAc (EtOAc) Washed with water, brine of the combined extracts were dried (MgSO ₄₎ and evaporated to dryness. In an ice bath, the residue was dissolved in EtOH (30mL) and was added SOCl ₂ (1mL, 13.70mmol). The resulting clear solution was stirred at room temperature for 2 days, the solvent was removed, and the residue was purified on a 25 g silica gel column (MeOH / DCM 0% to 25%) to afford product.

Add a molecular sieve (1.5 g, powder) to a solution of (1R,5S,6r)-3-hydroxybicyclo[3.1.0]hexane-6-carboxylate (0.59 g) in DCM (20 mL) PCC (0.971 g) was added in three portions. The reaction mixture was stirred at room temperature for 3 hours and filtered through silica gel (to diatomaceous earth (Celite ^®) and cap from 5% to 100% EtOAc / hexanes eluting), and concentrated to give the product as a viscous oil (0.5 g). ¹ H NMR (400 MHz, chloroform-d) δ 4.16 (q, J = 7.3 Hz, 2 H), 2.73 - 2.59 (m, 2 H), 2.34 - 2.24 (m, 2 H), 2.19 (td, J = 3.5, 1.6 Hz, 2 H), 1.33-1.19 (m, 4 H).

Add Deoxo-Fluor® (1.206 mL) to a solution of (1R,5S,6r)-3-oxo-bicyclo[3.1.0]hexane-6-carboxylate (0.5 g) in DCM (5 mL) Then EtOH (0.052 mL) was added. The resulting solution was stirred at room temperature for 16 hours. Another portion of Deoxo-Fluor® (0.3 mL) was added, and the reaction mixture was stirred for another day, and another portion of Deoxo-Fluor® (0.5 mL) was added, and the reaction mixture was stirred at room temperature for 7 hours. The reaction mixture was partitioned between diethyl ether and saturated NaHCO _3. , And dried with saturated NaHCO _3, water, saturated NaCl The organic phase was dried over anhydrous MgSO _4, filtered and the solvent removed to give a yellow oil (0.5g). ¹ H NMR (400MHz, CHLOROFORM -d) δ 4.13 (q, J = 7.0Hz, 2 H), 2.54-2.37 (m, 2 H), 2.35-2.21 (m, 2 H), 1.96 ( quintet, J = 3.3 Hz, 2 H), 1.66 (q, J = 3.0 Hz, 1 H), 1.30-1.24 (m, 3 H).

To a solution of 3,3-difluorobicyclo[3.1.0]hexane-6-carboxylic acid ethyl ester (0.5 g) in THF (10 mL) MeOH (10 mL) The reaction mixture was stirred at room temperature for 18 hours, concentrated and diluted with EtOAc, with 1N HCl, brine, dried (Na ₂ SO _4). The solvent was removed to give a cap Y-1 (0.43 g) as a brown solid. ¹ H NMR (400MHz, CHLOROFORM -d) δ 2.57-2.40 (m, 2 H), 2.39-2.25 (m, 2 H), 2.07-2.02 (m, J = 3.2,3.2,3.2,3.2Hz, 2 H ), 1.69 (q, J = 3.0 Hz, 1 H).

Cap Y-2: (1R, 3s, 5S)-6,6-difluorobicyclo[3.1.0]hexane-3-carboxylic acid Cap Y-3: (1R, 3r, 5S)-6,6-difluorobicyclo[3.1.0]hexane-3-carboxylic acid

2-Chloro-2 was added to a solution of methyl cyclopent-3-enecarboxylate (0.41 g) in diethylene glycol dimethyl ether (6 mL) via a syringe pump at 0.5 mL/h in a 180 ° C bath. A solution of sodium 2-difluoroacetate (2.5 g, 16.40 mmol) in 15 mL of diethylene glycol dimethyl ether. Next, another portion of 18 mL of diethylene glycol dimethyl ether containing sodium 2-chloro-2,2-difluoroacetate (2.5 g) was added at a rate of 1.0 mL/h. After the addition, the solution was cool down, and the reaction mixture was diluted with ether, washed with water (3 ×), washed with brine and dried (MgSO _4), and the solvent removed. The residue was dissolved in MeOH (5 mL) and 1N EtOAc (15 mL). The reaction mixture was extracted with EtOAc (EtOAc)EtOAc. With 1N HCl, water (2 ×), washed with brine and the combined the EtOAc extracts were dried (MgSO _4). The trans and cis isomers were separated by gel chromatography.

Cap Y-2: ¹ H NMR (400 MHz, chloroform-d) δ 3.08-2.78 (m, 1 H), 2.47-2.19 (m, 4 H), 2.05 (d, J = 13.8 Hz, 2 H).

Cap-Y-3: ¹ H NMR (400MHz, chloroform-d) δ 3.31-3.16 (m, 1 H), 2.50-2.40 (m, 2 H), 2.40-2.28 (m, 2 H), 2.10-1.98 (m, 2 H).

Cap Y-4: 2-(2-fluoroethoxy)-2-methylpropionic acid

To a stirred solution of 2-fluoroethanol (2 g) in acetone (60 mL) (0-5 ° C), NaOH (5.0 g) was added, and then chloroform (10 mL) was added dropwise over 10 min. The reaction mixture was stirred in an ice bath for 1 hour, then stirred at room temperature for 16 hours. The solid was filtered and washed with MeOH. The filtrate was concentrated, and the residue was diluted with EtOAc, washed with ice cold 1N HCl, brine and dried (MgSO _4). The crude product was dissolved in sulfuric acid (30 mL) and heated at 60 ° C for 4 hr and cooled to cool. The reaction mixture was extracted with EtOAc, and the washed with water, brine, dried (MgSO _4). The solvent was removed on a 25g silica gel column and (MeOH / DCM) and the residue was purified to afford Cap ^{Y-4: 1 H NMR (} 400MHz, CHLOROFORM -d) δ 4.73-4.59 (m, 1 H), 4.59-4.45 (m, 1 H), 3.81-3.68 (m, 2 H), 1.51 (s, 6 H).

Cap Y-5 to Cap Y-7 were prepared according to the procedure described for Synthetic Cap Y-4.

Cap Y-5: 2-(2,2-difluoroethoxy)-2-methylpropionic acid

¹ H NMR (400MHz, CHLOROFORM -d) δ ppm 5.75-6.15 (1 H , m), 3.74 (2 H, td, J = 13.49,4.14Hz), 1.53 (6 H, s).

Cap Y-6: 2-methyl-2-(2,2,2-trifluoroethoxy)propionic acid

¹ H NMR (400MHz, CHLOROFORM -d) δ 3.94 (q, J = 8.4Hz, 2 H), 1.54 (s, 6 H).

Cap Y-7: 2-(2-fluorophenoxy)-2-methylpropionic acid

¹ H NMR (400 MHz, chloroform-d) δ 7.18 - 7.00 (m, 4H), 1.59 (s, 6H).

Cap N-1: 2-(4,4-difluorocyclohexyl)acetic acid

Deoxo-Fluor® (0.881 mL) and EtOH (0.038 mL) were added to a solution of ethyl 2-(4-oxocyclohexyl)acetate (0.4 g) in DCM (5 mL). The reaction mixture was stirred for 16 hours at room temperature, then diluted with saturated NaHCO ₃ and EtOAc. Water, the organic phase was washed with saturated NaCl, and dried over anhydrous Na ₂ SO _4, filtered, and dried to give 2- (4,4-difluoro-cyclohexyl) acetate (0.4g). To a solution of ethyl 2-(4,4-difluorocyclohexyl)acetate in THF / MeOH (2 mL) EtOAc (1 mL). The reaction mixture was concentrated with EtOAc EtOAc EtOAc. The organic phase was washed with saturated NaCl, dried over anhydrous Na ₂ SO _4, filtered and concentrated to give a yellow solid of 2- (4,4-difluoro-cyclohexyl) acetic acid. ¹ H NMR (400 MHz, DMSO- d ₆ ) ppm 12.13 (1H, br.s.), 2.06-2.28 (3H, m), 1.92-2.03 (1H, m), 1.72-1.91 (4H, m), 1.31-1.48 (1 H, m), 1.10 - 1.31 (2 H, m).

Cap N-2: 3,3-difluorocyclopentanecarboxylic acid

(S)-1-Phenylethanol (1.281 g), DCC ( slowly added) to a solution of the racemic 3-oxocyclopentanecarboxylic acid (1.28 g) in DCM (5 mL). 2.061 g) and DMAP (0.122 g) in DCM (5 mL). The reaction mixture was then diluted with EtOAc, solid filtered off, and _3, water, citric acid, water, saturated NaCl and the filtrate was washed with saturated NaHCO, and dried over anhydrous Na ₂ SO _4, and concentrated to give the crude product. The crude product was purified by EtOAc (EtOAc) (EtOAc) LC/MS (Cond. N-1): [M+Na] ⁺ 255. ¹ H NMR (400 MHz, chloroform - d ) ppm 7.27-7.40 (5 H, m), 5.91 (1 H, qd, J = 6.61, 2.26 Hz), 3.06-3.24 (1 H, m), 2.43-2.52 ( 2 H, m), 2.27-2.41 (2 H, m), 2.13 - 2.25 (2H, m), 1.56 (3H, dd, J = 6.53, 1.00 Hz).

Deoxo-Fluor® (1.746 mL) and EtOH (0.075 mL) were added to a solution of (S)-1-phenylethyl 3- oxycyclopentanecarboxylate (1 g) in DCM. The reaction mixture was stirred for 16 hours at room temperature, then diluted with saturated NaHCO ₃ and EtOAc. Water, the organic phase was washed with saturated NaCl, and dried over anhydrous Na ₂ SO _4, filtered, and dried to give a yellow oil. The crude product was purified by silica gel chromatography to give (S)-1-phenylethyl 3,3-difluorocyclopentanecarboxylate. LC/MS (Cond. N-1): [M+Na] ⁺ 277. ¹ H NMR (400 MHz, chloroform - d ) ppm 7.29-7.41 (5 H, m), 5.91 (1 H, q, J = 6.69 Hz), 2.97-3.12 (1 H, m), 2.30-2.51 (2 H , m), 1.96-2.26 (4 H, m), 1.53-1.58 (3 H, m). Separation of two non-pairs by chiral column chromatography (ChiralCel OJ-H, 4.6 x 100 mm, 5 μm, mobile phase: 90% heptane / 0.1% DEA/10% EtOH, flow rate: 1.0 mL/min) Opposite: diastereomer-1: _Rt = 3.58 min; diastereomer-2: _Rt = 4.06 min.

(S)-1-Phenylethyl 3,3-difluorocyclopentanecarboxylate (diastereomer-1 or diastereomer-2, 0.15 g) in ethanol (5 mL) 10% Pd-C was added to the solution. The reaction mixture was stirred for 16 hours under H ₂ at room temperature. The reaction mixture was filtered, and the filtrate was concentrated to give the corresponding enantiomer of 3,3-difluorocyclopentanecarboxylic acid. ¹ H NMR (400 MHz, methanol - d ₄ ) ppm 2.97-3.08 (1H, m), 2.28-2.41 (2H, m), 1.93 - 2.23 (4H, m).

Cap W-1

Cap W-1 step a

To N-ethyl-2,2,2-trifluoroethylamine hydrochloride (211 mg, 1.290 mmol) and N,N-diethylpropylethylamine (0.674 mL, 3.87 mmol) in DCM A solution of methylglyoxime chloride (0.124 mL, 1.290 mmol) in DCM (5 mL) was added dropwise. The reaction mixture was stirred at room temperature for 1 hour, then water (50 mL) was added. The organic layer was separated, and washed with 1N HCl and brine, dried over MgSO _4, filtered and evaporated in vacuo to give a colorless oil cap of W-1 in step a (239mg).

To a solution of this oil in MeOH (4 mL) EtOAc (4 mL). The reaction mixture was stirred at room temperature for 1.5 hours. The solution was then acidified with 2M HCl (2 mL). Remove volatiles. The remaining aqueous layer was saturated with brine and extracted with EtOAc. Washed with brine the organic layers were combined, dried over MgSO _4, filtered, and evaporated to give the cap W-1 (219mg). ¹ H NMR (500 MHz, MeOD- d ₄ ) δ ppm 4.18 (2H, q, J = 9.14 Hz), 3.51-3.61 (2H, m), 1.24-1.31 (3H, m).

Cap W-2

Cap W-2 was prepared using the appropriate starting materials by employing the procedure described for Synthetic Cap W-1.

Cap W-3

Cap W-3 was prepared by starting with N-isopropylcyclopropylamine using the procedure described for Synthetic Cap W-1. LC / MS (Condition W-1): [M + H] + 172.1, R t = 0.76min.

Cap W-4

Cap W-4 was prepared by starting with 4,4-difluoropiperidine/hydrochloride using the procedure described for synthetic cap W-1. ¹ H NMR (500 MHz, CDCl ₃ ) δ ppm 7.99 (1 H, br. s.), 3.97-4.11 (2 H, m), 3.72-3.90 (2 H, m), 2.12 (4 H, dtt, J = 18.69, 12.57, 12.57, 6.23, 6.23 Hz).

Cap W-5

Add LiOH (8.36 mmol) to a solution of methyl 2-oxo-2-(4-(trifluoromethyl)piperidin-1-yl)acetate (1.00 g, 4.18 mmol) in MeOH and THF A solution in water. The reaction mixture was stirred at room temperature for 1.5 h then acidified with 2M EtOAc. The volatiles were removed in vacuo. The remaining aqueous layer was saturated with brine and extracted with EtOAc. Washed with brine the organic layers were combined, dried over MgSO _4, filtered and evaporated to afford the cap W-5 (806mg). LC / MS (Condition W-1): [M + H] + 226.1, R t = 0.743min.

Cap W-6

Cap W-6 step a

To a solution of oxetan-3-one (290 mg, 4.02 mmol) and 4,4-difluoropiperidine hydrochloride (1268 mg, 8.05 mmol) in acetic acid (4 mL) 1.073 mL, 8.05 mmol). It was heated at 60 deg.] C the reaction mixture for 5 h, diluted with DCM (20mL), and poured into saturated Na ₂ CO ₃ (40mL). Dried the organic layer was separated and washed with 1M NaOH and brine over MgSO _4, filtered and evaporated in vacuo. The residual oil was purified by flash chromatography to give the desired product, w. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 4.84 (2H, d, J = 6.35 Hz), 4.67 (2H, d, J = 6.55 Hz), 2.54 (4H, t, J = 5.65 Hz), 2.02-2.22 (4 H, m).

The reaction mixture of the cap W-6 step a (481 mg, 2.379 mmol) and water containing sodium hydroxide (19.0 ml, 95 mmol) was heated at 100 ° C for 12 hours, cooled and cooled, and diluted with water (20 mL). 20 mL) extraction. The aqueous layer was separated with EtOAc (EtOAc)EtOAc. , Washed with brine and dried over the combined organic layers over MgSO _4, filtered, and evaporated to give a white solid of the cap W-6 (167mg). ¹ H NMR (400 MHz, MeOD- d ₄ ) δ ppm 4.79 (2H, d, J = 6.35 Hz), 4.61 (2H, d, J = 6.53 Hz), 2.64 (4 H, t, J = 5.65 Hz ), 1.93 - 2.14 (4 H, m).

Cap W-7

Cap W-7 was prepared by starting with N-(2,2,2-trifluoroethyl)propan-2-amine hydrochloride using the procedure described for synthetic cap W-1. LC / MS (Condition W-1): [M + H] + 214.1, R t = 0.645min.

Cap W-8

Cap W-8 was prepared by starting with cis-2,6-dimethylmorpholine using the procedure described for synthetic cap W-1. ¹ H NMR (500 MHz, MeOD- d ₄ ) δ ppm 4.23-4.33 (1 H, m), 3.54-3.71 (3H, m), 2.89-2.98 (1 H, m), 2.51 (1 H, dd, J = 13.08, 10.72 Hz), 1.22 (3 H, d, J = 6.15 Hz), 1.15 - 1.20 (3 H, m).

Cap W-9

Cap W-9 step a

2,6-Dimethylmorpholine (mixture of cis and trans, 5.08 mL, 40 mmol) and N,N-diisopropylethylamine (15.33 mL, 88 mmol) in DCM (50 mL) A solution of methylglyoxime chloride (3.84 mL, 40.0 mmol) in DCM (50 mL) was added dropwise. The reaction mixture was stirred at room temperature for 30 minutes and then quenched with water. Dried the organic layer was separated and washed with 1N HCl and brine over MgSO _4, filtered, and evaporated. The residual oil was purified by Biotag system (240 g cartridge) eluting with a gradient of 30%-60% acetone-hexane to give cap W-9 step a (cis) as the first eluting peak (main) product And cap W-9 step a (trans) as the second dissolved (secondary) product. Cap W-9, step a (cis): ¹ H NMR (500 MHz, CDCl ₃ ) δ ppm 4.34-4.38 (1 H, m), 3.90 (3 H, s), 3.61-3.64 (2 H, m), 3.50-3.54 (1 H, m), 2.87-2.92 (1 H, m), 2.46-2.51 (1 H, m), 1.20-1.24 (6 H, m).

Cap W-9, step a (trans): ¹ H NMR (500 MHz, CDCl ₃ ) δ ppm 4.02-4.12 (2 H, m), 3.90 (3 H, s), 3.77 (1 H, dd, J = 13.08) , 3.47 Hz), 3.52 (1 H, dd, J = 13.24, 3.31 Hz), 3.30 (1 H, dd, J = 13.24, 6.46 Hz), 3.19 (1 H, dd, J = 13.24, 5.67 Hz), 1.20-1.30 (6 H, m).

A pre-formed solution of lithium hydroxide monohydrate (0.621 g) in water was added to a solution of Cap W-9 step a (trans) (1.49 g) in MeOH and THF. The reaction mixture was stirred at room temperature for 1.5 hours. The solution was concentrated and then acidified with 2M HCl. The aqueous layer was saturated with brine and extracted with EtOAc. Washed with brine the organic layers were combined, dried over MgSO _4, filtered, and evaporated to give the cap W-9 (trans) (1.43g). ¹ H NMR (500 MHz, MeOD- d ₄ ) δ ppm 4.00-4.09 (2 H, m), 3.70 (1 H, dd, J = 13.16, 3.39 Hz), 3.60 (1 H, dd, J = 13.32, 3.39 Hz), 3.22-3.32 (2 H, m), 1.21 (6 H, d, J = 6.46 Hz).

Cap W-10

Cap W-10 step a

A three-necked flask containing methyl 2-(benzyloxycarbonylamino)acrylate (6.80 g, 28.9 mmol), sodium fluoride (0.121 g, 2.89 mmol) and toluene (150 mL) was heated to reflux. A solution of 2,2-difluoro-2-(fluorosulfonyl)acetic acid trimethyldecane ester (14.24 mL, 72.3 mmol) in toluene (150 mL) was added dropwise over 4 hr. The reaction mixture was heated for 3 hours and then cooled to room temperature, saturated Na ₂ CO ₃ was quenched with the at 0 ℃. The separated aqueous layer was extracted with EtOAc. , Washed with brine and dried over the combined organic layers over MgSO _4, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography to afford m.j. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 7.32-7.47 (5 H, m), 5.54 (1 H, br.s.), 5.17 (2H, s), 3.68-3.89 (3 H, m), 2.56-2.84 (1 H, m), 1.98 (1 H, br. s.).

Cap W-10 step b

A solution of cap W-10 step a (7.12 g, 24.96 mmol), dibutyl succinate (6.54 g, 30.0 mmol) and 4-dimethylaminopyridine (0.610 g, 4.99 mmol) in THF Stir at room temperature for 18 hours. The reaction mixture was quenched with EtOAc (EtOAc)EtOAc. The separated aqueous layer was saturated with brine and extracted with EtOAc. , Washed with brine and dried over the combined organic layers over MgSO _4, filtered and concentrated. The residue was purified by silica gel chromatography to afford vis. LC / MS (Condition W-1): [M + Na] + 408.12, R t = 2.077min.

A mixture of Cap W-10 Step b (9.44 g, 24.50 mmol), EtOAc (EtOAc) The remaining solution was diluted with water (50 mL), filtered, and then filtered. The aqueous layer was acidified to pH 2 with 2N EtOAc. Washed with brine the organic layers were combined, dried over MgSO _4, filtered, and concentrated to afford the cap W-10 (5.43g). ¹ H NMR (400 MHz, MEOD- d ₄ ) δ δ 2.39-2.59 (1H, m), 1.73-1.93 (1H, m), 1.43-1.52 (9H, m).

Cap W-11

Cap W-11 step a

Add a solution of 3,3-difluoroazetidine hydrochloride (0.775 g, 5.98 mmol) in DCM (5 mL) DCM (5 mL) containing methyl 2-chloro-2-oxoacetate (0.806 g, 6.58 mmol) was added dropwise. The reaction was stirred at room temperature for 18 hours. With 1N HCl (2 × 25mL), saturated NaHCO ₃ (2 × 25mL) The reaction solution is washed, then dried (MgSO _4), filtered, and concentrated to give a white crystalline solid cap of W-11 step a (1.015g) . ¹ H NMR (500 MHz, CDCl ₃ ) δ δ 4.84 (2H, td, J = 11.67, 1.98 Hz), 4.46 (2H, td, J = 11.83, 1.98 Hz), 3.88 (3H, s).

To a solution of the cap W-11 step a (0.850 g, 4.75 mmol) in EtOAc (5 mL) EtOAc. The reaction was stirred for 1 hour then acidified with cone. HCl. The resulting mixture was concentrated and the solid was washed with DCM. The filtrate was concentrated to give a cap W-11 (0.205 g). ^{1 H NMR (500MHz, DMSO- d} 6) δ ppm 14.08 (1 H, br.s.), 4.82 (2 H, td, J = 12.44,0.76Hz), 4.41 (2 H, td, J = 12.44, 0.76Hz).

Cap W-12

Cap W-12(S)-2-(3-fluoropyrrolidine-1- was prepared by starting with (S)-3-fluoropyrrolidinium hydrochloride using the procedure described for the synthetic cap W-10. Base)-2-oxoacetic acid. ¹ H NMR (500 MHz, DMSO- d ₆ ) δ ppm 14.08 (1 H, br. s.), 5.36 (1 H, d, J = 53.10 Hz), 3.46-3.93 (4 H, m), 2.12-2.22 (2 H,m).

Cap W-13

Cap W-13 was prepared by starting with 4-fluoropiperidine hydrochloride using the procedure described for Synthetic Cap W-10. ¹ H NMR (500 MHz, CDCl ₃ ) δ ppm 7.62 (1 H, br. s.), 4.93 (1 H, d, J = 47.90 Hz), 4.36-4.46 (1 H, m), 4.02-4.11 (1) H, m), 3.79-3.89 (1 H, m), 3.45-3.53 (1 H, m), 1.78-2.09 (4H, m).

Cap W-14

Cap W-14 was prepared starting with 2,5-dihydro-1H-pyrrole using the procedure described for Synthetic Cap W-10. ¹ H NMR (400 MHz, MeOD- d ₄ ) δ ppm 5.77-6.00 (2H, m), 4.50-4.60 (2H, m), 4.18-4.36 (2H, m).

Cap W-15

Cap W-15 was prepared by starting with 2,2-dimethylmorpholine using the procedure described for Synthetic Cap W-10. ¹ H NMR (500 MHz, MEOD- d ₄ ) δ ppm 3.70-3.84 (2 H, m), 3.56-3.63 (1 H, m), 3.47-3.54 (1 H, m), 3.45 (1 H, s) , 3.36 (1 H, s), 1.20-1.30 (6 H, m).

Cap L-1

Cap L-1 step a

Add methyl chloroformate (0.127 mL, 1.644 mmol) to benzyl 1-(methylamino)cyclopropanecarboxylate trifluoroacetate (0.35 g, 1.096 mmol) and DIEA (0.574 mL, 3.29 mmol) _{In a} solution of ₂ Cl ₂ (5 mL). The resulting solution was stirred at room temperature for 2 hours. The mixture was diluted with CH ₂ Cl ₂ (15mL), then washed with NaHCO ₃ and brine, dried (MgSO ₄₎ and concentrated. The residue was purified by silica gel chromatography to afford m. LC / MS (Condition L-1): [M + H] + 264.2, R t = 2.58min. ¹ H NMR (400 MHz, CDCl ₃ ) ppm 7.43-7.28 (m, 5 H), 5.15 (s, 2 H), 3.75-3.56 (m, 3 H), 3.00-2.87 (m, 3 H), 1.76 -1.56 (m, 2 H), 1.26 (br.s., 2 H).

Cap L-1 step a (180 mg) was dissolved in MeOH (5 mL) and was taken in 10% Pd/C (36.4 mg). Purged with N ₂ suspension, and stirred at room temperature under H ₂ 16 hours. The reaction mixture was filtered, and the solvent was evaporated under reduced pressure to give a m. _{^{1 H NMR (500MHz, CDCl 3}} ) 10.65 (br.s., 1 H), 3.70 (s, 3 H), 2.93 (d, J = 5.2Hz, 3 H), 1.85-1.41 (m, 2 H) , 1.40-1.09 (m, 2 H).

Cap L-2

Cap L-2 step a

Add Deoxo-Fluor® (0.473 mL, 2.57 mmol) to (S)-4-Sideoxypiperidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (300 mg, 1.166 mmol) in DCM EtOH (0.020 mL) was added to the solution in (5 mL), and the obtained solution was stirred at room temperature for 16 hours.

The reaction mixture DCM (10mL) diluted, and washed with saturated NaHCO ₃ (20mL), washed with water (20mL) and brine (20mL), dried (MgSO ₄₎ and concentrated. The residue was purified by silica gel chromatography to afford mp. ¹ H NMR (500 MHz, CDCl ₃ ) δ ppm 5.15-4.81 (m, 1H), 4.24 - 4.01 (m, 1H), 3.76 (br.s., 3H), 3.38-3.12 (m, 1H), 2.72 ( Br.s., 1H), 2.27-1.97 (m, 2H), 1.97-1.77 (m, 1H), 1.54-1.39 (m, 9H).

A solution of LiOH (34.3 mg, 1.432 mmol) in water (3.00 mL) was added to (S)-4,4-difluoropiperidine-1,2-dicarboxylic acid 1-t-butyl ester 2-methyl ester ( 200 mg) in a solution of THF (3 mL), and the mixture was stirred at room temperature for 3 hr. The reaction mixture was diluted with water and washed with EtOAc. The aqueous layer was then acidified with EtOAc (EtOAc)EtOAc. Washed with brine the combined organic layers were dried (MgSO _4), filtered and concentrated to afford the cap L-2. ^{1 H NMR (500MHz, DMSO-} d 6) δ ppm 13.00 (br.s., 1 H), 4.90-4.69 (m, 1 H), 4.19-3.91 (m, 1 H), 3.22-2.98 (m, 1 H), 2.49-2.14 (m, 2 H), 1.98 (dd, J = 12.2, 3.5 Hz, 1 H), 1.48-1.33 (m, 9 H).

Cap L-3

(S)-2-Methylpyrrolidine-2-carboxylic acid (0.5 g, 3.87 mmol) and Na ₂ CO ₃ (0.240 g) were dissolved in 1N NaOH (3.87 mL, 3.87 mmol) and the solution was cooled to 0 ° C . Methyl chloroformate (0.315 mL) was added dropwise, and the solution was stirred at room temperature for 2 hr. The reaction mixture was diluted with water and washed with Et ₂ O. The organic layer was acidified with EtOAc ₍ EtOAc ₎ EtOAc. Dried (MgSO ₄₎ the organic layers were combined, filtered and concentrated to afford the cap L-3 (0.41g). ^{1 H NMR (500MHz, DMSO-} d 6) δ ppm 12.43 (s, 1 H), 3.55 (s, 3 H), 3.48-3.37 (m, 2 H), 2.16-1.99 (m, 1 H), 1.96 -1.80 (m, 3 H), 1.43 (m, 3 H).

Cap L-4

Add Et ₃ N (0.680) to a stirred solution of (S)-2-methylpyrrole-2-carboxylic acid (0.42 g, 3.25 mmol) and BOC ₂ O (0.906 mL, 3.90 mmol) in DCM (10 mL) mL, 4.88 mmol), and the resulting suspension was stirred at room temperature for 16 h. The reaction was partitioned between water and EtOAc. Remove the organic layer. The aqueous layer was with EtOAc (10mL) mixing, pH, 10% KHSO ₄ and the biphasic mixture was acidified with. The layers were separated and the aqueous extracted with EtOAc. Dried (MgSO ₄₎ the organic layers were combined and concentrated to give a white solid of the cap L-4 (0.57g). ^{1 H NMR (500MHz, DMSO-} d 6) ppm 12.36 (s, 1 H), 3.45-3.28 (m, 2 H), 2.13-1.98 (m, 1 H), 1.91-1.74 (m, 3 H), 1.40 (s, 3 H), 1.39-1.29 (m, 9 H).

Cap L-5

A mixture of ethyl 1-((2-hydroxyethyl)amino)cyclopropanecarboxylate (0.180 g, 1.039 mmol) and CDI (0.177 g, 1.91 mmol) in THF (5 mL) Then, it was heated to reflux for 15 hours. The solvent was removed and the residue was purified using EtOAc EtOAc (EtOAc) Add a solution of LiOH (0.048 g) in water (3 mL) EtOAc (EtOAc &lt;RTIgt; The solution was stirred vigorously at room temperature for 16 hours. The reaction mixture was then diluted with water and washed with EtOAc. The aqueous layer was then acidified with EtOAc (EtOAc)EtOAc. Dried (MgSO ₄₎ the organic layers were combined, filtered and concentrated to afford the cap L-5 (60mg). ^{1 H NMR (500MHz, DMSO-} d 6) ppm 12.83 (br.s., 1 H), 4.30-4.20 (m, 2 H), 3.65-3.56 (m, 2 H), 1.41-1.33 (m, 2 H), 1.25-1.19 (m, 2 H).

Cap L-6

Cap L-6 step a

Add 1,3-difluoro-2-methylpropan-2-ylpyridin-2-yl carbonate (0.5 g, 4.54 mmol) to a suspension of NaH (0.200 g, 5.00 mmol) in THF (5 mL) ). After stirring for 1 hour, the solution was transferred to a solution of dipyridin-2-yl carbonate (0.982 g, 4.54 mmol) in THF (5 mL). The resulting slurry was stirred overnight at room temperature. It was diluted with EtOAc, washed with brine, dried over MgSO _4, filtered, and concentrated to afford an oily residue in the form of a cap L-6 step a.

1-Aminocyclopropanecarboxylic acid benzyl ester hydrochloride (118 mg) and cap L-6 step a (180 mg) were combined in DCM (0.1 mL) in DCM (5 mL) and stirred at room temperature The solution was 16 hours. The solvent was removed under reduced pressure and the residue was purified using EtOAc EtOAc (EtOAc) _{^{1 H NMR (500MHz, CDCl 3}} ) δ ppm 7.43-7.28 (m, 5H), 5.58 (br.s., 1H), 5.13 (s, 2H), 4.72-4.42 (m, 4H), 1.56 (br. s., 2H), 1.46 (br.s., 3H), 1.19 (d, J = 1.7 Hz, 2H).

Cap L-6 step b

Cap L-6 step b (150 mg) was dissolved in MeOH (5 mL) and 10% Pd/C (24.4 mg) was fed. The reaction mixture was stirred for 16 hours under H ₂ at room temperature. The catalyst was filtered and the volatiles removed to give cap L-6 (105 mg). ^{1 H NMR (500MHz, DMSO-} d 6) δ ppm 12.28 (br.s., 1 H), 7.84 (br.s., 1 H), 4.73-4.49 (m, 4 H), 1.39 (br.s .3 H), 1.27 (d, J = 2.8 Hz, 2 H), 0.96 (br.s., 2 H).

Cap L-7

Cap L-7 step a

Piperidine-1-carbonyl chloride (1.599 mL) was added to a solution of methyl 1-hydroxycyclopropanecarboxylate (1 mL) and DIEA (3.04 mL) The resulting solution was stirred at room temperature for 2 hours, followed by diluted with DCM, and the organic layer was washed with 1N HCl, water and brine, dried (MgSO _4), filtered and concentrated. The residue was purified using oxime to give mp.

A solution of LiOH (0.158 g, 6.60 mmol) in water (5 mL) EtOAc (EtOAc) The resulting two phase mixture was vigorously stirred at room temperature for 16 hours. The reaction mixture was then diluted with water and washed with EtOAc. The aqueous layer was acidified with EtOAc EtOAc. Dried (MgSO ₄₎ the organic layers were combined, filtered and concentrated to afford the cap L-7 (0.65g). ¹ H NMR (500 MHz, DMSO-d ₆ ) δ ppm 12.58 (br.s., 1 H), 3.31 (br.s., 4 H), 1.58-1.50 (m, 2 H), 1.48-1.40 (m) , 4 H), 1.34-1.28 (m, 2 H), 1.15 - 1.10 (m, 2 H).

Cap L-8

Cap L-8 was prepared by starting with dimethylamine formazan chloride using the procedure described for synthetic cap L-7. ¹ H NMR (500 MHz, DMSO-d ₆ ) ppm 12.48 (br.s., 1 H), 2.82 (d, J = 9.0 Hz, 6 H), 1.34-1.29 (m, 2 H), 1.15-1.10 ( m, 2 H).

Cap L-9

Cap L-9 step a

To a solution of methyl 1-hydroxycyclopropanecarboxylate (0.741 mL, 8. <RTI ID=0.0></RTI></RTI><RTIgt;</RTI><RTIgt;</RTI><RTIgt;</RTI><RTIgt;</RTI><RTIgt; The resulting solution was stirred at room temperature for 2 hours, followed by diluted with DCM, and the organic layer was washed with 1N HCl, water and brine, dried (MgSO _4), filtered and concentrated. The residue was purified via EtOAc (EtOAc: EtOAc:EtOAc)

A solution of LiOH (0.130 g, 5.43 mmol) in EtOAc (3 mL) The yellow mixture was 3 hours then diluted with EtOAc and water. The aqueous layer was acidified to pH 2 with 1N EtOAc then EtOAc (3x). Dried (MgSO ₄₎ the organic layers were combined, filtered and concentrated to afford the cap L-9 (0.12g). ^{1 H NMR (400MHz, DMSO-} d 6) δ ppm 12.49 (br.s., 1 H), 3.90 (br.s., 1 H), 3.77 (br.s., 1 H), 1.36-1.27 ( m, 2 H), 1.18-1.08 (m, 14 H).

Cap L-10

Under N _2, l - stirring the (((tert-butoxy carbonyl) amino) methyl) cyclopropanecarboxylic acid (0.5g, 2.323mmol) in THF (10mL) and was cooled (ice bath) of NaH (60% oil suspension) (0.465 g, 11.61 mmol) was added to the solution, followed by MeI (1.16 mL, 18.58 mmol), and the mixture was stirred at room temperature under N ₂ for 3 days. The mixture was diluted with EtOAc (20 mL). The aqueous phase was acidified with citric acid and extracted with EtOAc. With 1M Na ₂ S ₂ O _3, the organic extracts were washed with brine, dried (Na ₂ SO _4), filtered, and concentrated to give the cap L-10 (0.37g). ^{1 H NMR (400MHz, DMF)} ppm 11.84 (s, 1 H), 3.02 (s, 2 H), 2.34 (d, J = 16.6Hz, 3 H), 0.92 (s, 9 H), 0.63 (br. s., 2 H), 0.39 (br.s., 2 H).

Cap L-11

Cap L-11 was prepared by starting with (R)-1,1,1-trifluoropropan-2-ol using the procedure described for Synthetic Cap L-6. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 12.49 (s, 1 H), 8.25-7.89 (m, 1 H), 5.26 (seven peaks, J = 6.7 Hz, 1 H), 1.35-1.27 (m) , 5 H), 1.08-0.95 (m, 2 H).

Cap L-12

Cap L-12 step a

To a mixture of Cap L-2 Step a (0.3 g, 1.074 mmol) in EtOAc (EtOAc) The resulting suspension was stirred at room temperature for 2 hours. The volatiles were removed to give cap L-12 step a (0.23 g). ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 10.11 (br.s., 2 H), 4.44 (dd, J =11.2, 3.9 Hz, 1 H), 3.85-3.75 (m, 3 H), 3.50 -3.38 (m, 1 H), 3.17-3.00 (m, 1 H), 2.68-2.51 (m, 2 H), 2.48-2.25 (m, 2 H).

Cap L-12 step b

Methyl chloroformate (0.030 mL, 0.383 mmol) was added to a solution of EtOAc EtOAc (EtOAc (EtOAc). The resulting solution was 16 hours. Diluted with EtOAc (10mL) the reaction mixture, and washed with H ₂ O and brine, dried (MgSO _4), filtered, and concentrated to afford the cap L-12 step b (80mg).

A solution of LiOH (16.15 mg, 0.675 mmol) in water (0.5 mL) was added to a solution of EtOAc. hour. The reaction mixture was diluted with H ₂ O (10mL) and washed with Et ₂ O (15mL). The aqueous layer was then acidified to pH ~2 with 1N EtOAc and extracted with EtOAc. Dried (MgSO ₄₎ the organic layers were combined, filtered and concentrated to afford the cap L-12 (48mg). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 13.09 (1 H, br. s.), 4.75-4.93 (1 H, m), 3.95-4.14 (1 H, m), 3.55-3.70 (3 H , m), 3.20-3.10 (1 H, t, J = 12.17 Hz), 2.52-2.36 (2 H, d, J = 12.55 Hz), 2.29 (1 H, br. s.), 2.03 (1 H, d, J = 14.05 Hz).

Cap L-13

Add 60% sodium hydride (1.004 g, 25.10 mmol) to a stirred and cooled solution of 1-(t-butoxycarbonylamino)cyclopropanecarboxylic acid (1.01 g, 5.02 mmol) in THF (20 mL) Methyl iodide (5.70 g, 40.2 mmol), and the mixture was stirred at room temperature under N ₂ for 3 days. The mixture was diluted with water and EtOAc. The aqueous phase was acidified with citric acid and extracted with EtOAc. With 1M Na ₂ S ₂ O _3, the organic extracts were washed with brine, dried (Na ₂ SO _4), filtered and concentrated to give a white crystalline solid of the cap L-13. ¹ H NMR (500 MHz, CDCl ₃ ) δ ppm 2.79-2.94 (3 H, m), 1.70 (2 H, br. s.), 1.36-1.50 (9 H, m), 1.11-1.34 (2 H, m ).

Cap L-14

Cap L-14 step a

Reaction mixture of cap L-13 (1.05 g, 4.88 mmol), K ₂ CO ₃ (1.348 g, 9.76 mmol) and (bromomethyl)benzene (0.876 g, 5.12 mmol) in DMF (5 mL) Stir for 18 hours. The mixture was partitioned between EtOAc and water, and the organic extracts were washed with brine, dried (Na ₂ SO ₄₎ and concentrated to give L-14 cap step a (1.44g). ¹ H NMR (500 MHz, CDCl ₃ ) δ ppm 7.26-7.40 (5 H, m), 5.05-5.23 (2 H, m), 2.82-2.90 (3 H, m), 1.49-1.82 (2 H, m) , 1.32-1.46 (9 H, m), 1.06-1.28 (2 H, m).

Cap L-14 step b

To a solution of Cap L-14 Step a (1.40 g, 4.58 mmol) in EtOAc (EtOAc)EtOAc. b (1.96g).

Cap L-14 step c

To a cooled solution of the cap L-14 step b (0.93 g) and TEA (1.52 mL) in DCM (5 mL), EtOAc (EtOAc) 2.5 hours. The mixture was diluted with DCM and washed with water, 1N HCl, saturated NaHCO _3, washed with brine, dried (Na ₂ SO ₄₎ and concentrated to give L-14 cap step c (0.89g).

Was added 10% Pd-C (80mg, 0.075mmol) to cap benzyl L-14 step c (440mg, 1.050mmol) in EtOH (10mL) and EtOAc (10.00mL) in the solution and at 1 atm H ₂ The mixture was hydrogenated for 72 hours. The mixture was filtered and washed with EtOH. The combined filtrate was concentrated to dryness to give abr. ¹ H NMR (500 MHz, CDCl ₃ ) δ ppm 10.29 (1H, br. s.), 2.95 (3H, s), 2.04-2.19 (3H, m), 1.85-1.93 (1 H, m), 1.56-1.68 (1 H, m), 1.33-1.43 (1 H, m), 1.26-1.33 (1 H, m).

Cap L-15

Cap L-15 was prepared from the appropriate starting materials by employing the procedure described for Synthetic Cap L-13. ^{1 H NMR (500MHz, DMSO-} d 6) δ ppm 12.50 (br.s., 1 H), 2.83-2.65 (m, 3 H), 2.42-2.20 (m, 4 H), 2.02-1.89 (m, 1 H), 1.71 (d, J = 8.8 Hz, 1 H), 1.42-1.23 (m, 9 H).

Cap L-16

Cap L-16 was prepared from the appropriate starting materials by employing the procedure described for Synthetic Cap L-14. ¹ H NMR (500 MHz, CDCl ₃ ) δ ppm 7.02 (1H, br.s.), 2.92 (3H, s), 2.55-2.67 (2H, m), 2.21-2.32 (2 H, m), 2.07-2.10 (3 H, m), 2.00-2.07 (1 H, m), 1.67-1.82 (1 H, m).

Cap L-17

Cap L-17 step a

At 0 deg.] C, under N ₂ on added triazol-1-yl (5mL) of a solution of the 2,4-dibromo-butyric acid methyl ester (2.60g, 10.00mmol) in DMF Sodium (1.012 g, 10.00 mmol). The reaction mixture was stirred at 0-5 ° C for 30 minutes and then at room temperature for 18 hours. The reaction mixture was concentrated, and the residue was washed with water, brine and diluted with EtOAc, dried (Na ₂ SO ₄₎ and concentrated. The crude oil was purified by EtOAc (EtOAc) elute elute ¹ H NMR (500 MHz, CDCl ₃ ) δ ppm 1.46-1.61 (2H, m, 3a, 4a-CH ₂ ), 1.71-1.82 (2H, m, 3b, 4b-CH ₂ ), 3.57 (3H, s, 7 -OCH ₃ ), 7.80 (1H, s, 6-CH), 8.13 (1H, s, 5-CH).

1N NaOH (1.041 mL) was added to a solution of EtOAc (EtOAc m. The mixture was concentrated and the residue was taken &lt ¹ H NMR (500 MHz, MEOD-d ₄ ) δ δ 8.54 (s, 1 H), 7.92 (s, 1 H), 1.77-1.67 (m, 2 H), 1.47-1.36 (m, 2 H).

Cap N-3

To a solution of ethyl 4-methylenecyclohexanecarboxylate (0.05 g) in EtOAc (2 mL) The resulting solution was stirred at room temperature for 16 hours. The reaction mixture was diluted with 1N HCl and EtOAc. The organic phase was washed with saturated NaCl, and dried over anhydrous Na ₂ SO _4, filtered and dried to give a yellow oil of the cap N-3 (0.042g). ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 4.62-4.73 (2 H, m), 2.50 (1 H, tt, J = 11.01, 3.54 Hz), 2.30-2.41 (2 H, m), 1.98-2.14 ( 4 H,m), 1.54-1.69 (2 H,m).

Cap N-4

Under N ₂ was added to diethyl ether (10 mL) of LiAlH ₄ (0.369g, 9.73mmol), under N ₂ and then added dropwise -en- containing carboxylic acid ethyl ester (1g, 6.48mmol) at 0 ℃ of Ether (4 mL). After the addition, the reaction mixture was stirred at 0 ° C for 1 hour, followed by stirring at room temperature for 18 hours. The reaction mixture was carefully quenched by the sequential addition of 6 mL EtOAc and 3 mL water. The solid was filtered and washed with DCM. The filtrate was concentrated to give an oil. The crude product was poured into a 40 g silica gel cartridge eluting with a gradient of 0-80% EtOAc in hexanes to afford a cyclohexane-1-en-1-ylmethanol (0.66 g) as a clear oil. ¹ H NMR (400 MHz, DMSO- d ₆ ) ppm 5.57 (1H, tt, J = 3.51, 1.63 Hz), 4.60 (1 H, t, J = 5.65 Hz), 3.70-3.81 (2H, m), 1.97 (2H, dtt, J = 7.84, 3.86, 3.86, 1.88, 1.88 Hz), 1.87-1.94 (2H, m), 1.46-1.64 (4H, m).

To a solution of cyclohex-1-en-1-ylmethanol (0.6 g, 5.35 mmol) in DCC (5 mL), hexane (1. The mixture was stirred for 10 min then chloroiodomethane (1.242 mL, 17.12 mmol). The reaction mixture was stirred at 0 ° C for 1 hour and then at room temperature for 16 hours. Diluted with EtOAc and 1N HCl reactant, the organic phase washed with saturated NaCl, dried over anhydrous Na ₂ SO _4, filtered and concentrated to give an oil. The crude product was poured into a 25 g silica gel cartridge eluting with a gradient of 0-40% EtOAc in hexanes to afford bicyclo[4.1.0]hept-1-ylmethanol (0.12 g). ¹ H NMR (400 MHz, CDCl ₃ ) ppm 3.27-3.38 (2 H, m), 1.81-1.92 (2H, m), 1.54-1.78 (2H, m), 1.11-1.37 (4H, m), 0.81 (1 H, dddd, J = 9.16, 7.22, 5.46, 1.51 Hz), 0.46 (1 H, dd, J = 9.29, 4.52 Hz), 0.24 (1 H, t, J = 5.02 Hz).

[4.1.0] hept-1-ylmethanol (0.12 g of) in acetonitrile (3mL) and CCl ₄ (3mL) was added water-containing sodium periodate (0.610g, 2.85mmol) of (4mL) in a solution of the bicyclic Then, ruthenium (III) chloride (4.14 mg, 0.020 mmol) was added as a solid. The reaction mixture was stirred vigorously at room temperature for 16 hours. The reaction was diluted with water and extracted with DCM (3x). Through diatomaceous earth (Celite ^®) organic phase was filtered, then washed with saturated NaCl, dried over anhydrous Na ₂ SO _4, filtered and concentrated to give an oil. The residue was fed into a 12 g silica gel cartridge eluting with a gradient of 0-15% MeOH in dichloromethane for 20 min to afford cap N-4 (0.06 g). ¹ H NMR (400 MHz, CDCl ₃ ) ppm 2.46-2.58 (1 H, m), 1.86-2.00 (1 H, m), 1.69-1.77 (1 H, m), 1.59-1.69 (1 H, m), 1.45 (1 H, dd, J = 9.79, 4.02 Hz), 1.24-1.37 (3 H, m), 1.13-1.24 (1 H, m), 0.86-0.94 (1 H, m), 0.73 (1 H, Dd, J = 7.03, 4.02 Hz).

Cap N-5

At room temperature, under N _2, to the but-3-enoate (1.0g, 10mmol) and zinc - copper couple agent (zinc-copper couple) (2.0g , 15.5mmol) in DME (5mL) and Trichloroethane chloride (2.98 mL, 26.7 mmol) was added to the reaction mixture in diethyl ether (30 mL). The reaction mixture was stirred at room temperature for 2.5 days. Diatomaceous earth (Celite ^®) The reaction mixture was filtered, and washed with DCM. The filtrate was concentrated and purified by EtOAc (EtOAc) eluting 1.0g). ¹ H NMR (400 MHz, CDCl ₃ ) ppm 3.66-3.70 (3 H, m), 3.42-3.55 (1 H, m), 3.23 - 3.39 (1 H, m), 3.05 (1 H, dd, J = 17.82) , 8.78 Hz), 2.90 (1 H, dd, J = 16.94, 6.65 Hz), 2.67 (1 H, dd, J = 16.94, 8.16 Hz).

Zinc powder (0.929 g) was added to the reaction mixture of methyl 2-(2,2-dichloro-3-oxocyclobutyl)acetate (0.6 g) in AcOH (5 mL). The reaction mixture was stirred at 100 ° C for 15 hours.

The reaction mixture was cooled to room temperature and then diluted with EtOAc, and a solution of saturated NaHCO ₃ was carefully neutralized at 0 ℃. The aqueous phase was extracted with EtOAc, washed with saturated NaCl and of the combined organic phases were dried over anhydrous Na ₂ SO _4, filtered and concentrated. The crude material was purified by EtOAc (EtOAc) eluting ¹ H NMR (400 MHz, CDCl ₃ ) ppm 3.63 (3H, s), 3.12-3.27 (2H, m), 2.68-2.81 (3H, m), 2.56-2.64 (2H, m).

Add Deoxo-Fluor® (0.485mL, 2.63mmol) and EtOH (0.021mL solution of 2- (3-oxo-cyclobutyl) acetate (0.17 g of) in CH ₂ Cl ₂ (3.6mL) in a solution of ). The resulting solution was stirred at room temperature for 16 hours.

The reaction mixture was diluted with saturated NaHCO ₃ and DCM. Washed with water, the organic phase was washed with saturated NaCl, and dried over anhydrous Na ₂ SO _4, filtered, and dried to give 2- (3,3-difluoro-cyclobutyl) acetate (0.19g). ¹ H NMR (400 MHz, CDCl ₃ ) ppm 3.69 (3H, s), 2.70-2.85 (2H, m), 2.47-2.58 (3H, m), 2.17-2.35 (2H, m).

To a solution of methyl 2-(3,3-difluorocyclobutyl)acetate (0.19 g) in EtOAc (2 mL) The resulting solution was stirred at room temperature for 13 hours. The reaction mixture was diluted with 1N HCl and EtOAc. The organic phase was washed with saturated NaCl, and dried over anhydrous Na ₂ SO _4, filtered and dried to afford the cap N-5 (0.17g). ¹ H NMR (400 MHz, CDCl ₃ ) ppm 10.28 (1 H, br. s.), 2.69-2.86 (2 H, m), 2.56-2.60 (2 H, m), 2.44-2.56 (1 H, m) , 2.19-2.35 (2 H, m).

Cap N-6

At 0 deg.] C, under N ₂ to a solution of 4-oxo-cyclohexanecarboxylic acid ethyl ester (0.47mL, 2.94mmol) and dibromodifluoromethane (0.54mL, 5.88mmol) in N, N- dimethyl Triethylphosphine (1.54 g, 5.88 mmol) of N,N-dimethylacetamide (3.5 mL) was added dropwise to a solution of acetamide (3.5 mL) over 15 min. The reaction mixture was stirred at ambient temperature for 1 hour, then zinc (0.384 g, 5.88 mmol) was added over 1 min. The mixture was stirred at room temperature for 20 minutes, followed by heating at 70 ° C for 16 hours. The reaction was diluted with DCM, dried diatomaceous earth (Celite ^®) was filtered, and _3, and saturated aqueous NaHCO filtrate was washed with saturated NaCl, dried over anhydrous Na ₂ SO _4, filtered and concentrated to an oil. The crude product was poured into a 40 g silica gel cartridge eluting with a gradient of 0-20% EtOAc in hexanes to give ethyl 4-(difluoromethylene)cyclohexanecarboxylate (0.015 g). ¹ H NMR (400 MHz, CDCl ₃ ) ppm 4.10-4.20 (2H, m), 2.35-2.52 (3H, m), 1.95-2.05 (2H, m), 1.79-1.93 (2H, m), 1.48-1.63 (3 H, m), 1.25-1.31 (3 H, m).

To a solution of ethyl 4-(difluoromethylene)cyclohexanecarboxylate (0.015 g) in EtOAc (2 mL) The resulting solution was stirred at room temperature for 16 hours. The reaction mixture was diluted with 1N HCl and EtOAc. The organic phase was washed with saturated NaCl, and dried over anhydrous Na ₂ SO _4, filtered and dried to give a white solid of the cap N-6 (0.013g).

Cap N-7

Add 2 to a solution of 4-methylenecyclohexanecarboxylate (0.15 g, 0.892 mmol) in diethylene glycol dimethyl ether (3 mL) via a syringe pump at 150 ° C. A solution of sodium chloro-2,2-difluoroacetate (0.544 g, 3.57 mmol) in 5 ml of diethylene glycol dimethyl ether. The reaction was cooled to room temperature, followed by diluted with DCM, and washed with water, brine, dried over Na ₂ SO _4, filtered and concentrated. The residue was poured into a 40 g silica gel cartridge which was eluted with a gradient of 0-20% EtOAc in hexanes for 20 min to afford ethyl 1,1-difluorospiro[2.5]octane-6-carboxylate. ¹ H NMR (400 MHz, CDCl ₃ ) ppm 4.09-4.19 (2 H, m), 2.29-2.45 (1 H, m), 1.89-2.03 (2H, m), 1.55-1.72 (5 H, m), 1.45-1.54 (1 H, m), 1.31-1.39 (1 H, m), 1.21-1.30 (3 H, m), 0.84-0.94 (1 H, m).

To a solution of ethyl 1,1-difluorospiro[2.5]octane-6-carboxylate (0.015 g, 0.069 mmol) in THF (2 mL) The resulting solution was stirred at room temperature for 16 hours. The reaction mixture was diluted with 1N HCl and EtOAc. The organic phase was washed with saturated NaCl, and dried over anhydrous Na ₂ SO _4, filtered and dried to give a white solid of the cap N-7 (0.015g).

Cap N-8

Add chloroiodomethane (0.110 mL, 1.522 mmol) to a solution of ethyl 4-methylenecyclohexanecarboxylate (0.08 g) in DCM (1 mL). Hexane (0.761 mL, 0.761 mmol). The reaction was stirred at 0 ° C for 1 hour and then at room temperature for 18 hours. And the reaction mixture was diluted with EtOAc 1N HCl, the organic phase washed with saturated NaCl, dried over anhydrous Na ₂ SO _4, filtered and concentrated. The crude product was poured into a 25 g silica gel cartridge which was eluted with a gradient of 0-6% EtOAc in hexanes for 20 min to afford succinate. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 4.08-4.18 (2 H, m), 2.32 (1 H, tq, J = 11.01, 3.53 Hz), 1.85-1.93 (2 H, m), 1.53-1.74 ( 4 H,m), 1.28-1.35 (2 H,m), 1.22-1.28 (3 H,m), 0.28 (2 H,ddd, J =8.53,5.52,1.51 Hz), 0.17-0.25 (2 H, m).

To a solution of spiro[2.5]octane-6-carboxylic acid ethyl ester (0.03 g, 0.165 mmol) in THF (3 mL) MeOH (1 mL) The reaction was stirred at room temperature for 18 hours. The reaction mixture was diluted with 1N HCl and EtOAc. The organic phase was washed with saturated NaCl, and dried over anhydrous Na ₂ SO _4, filtered and dried to afford the cap N-8 (0.02g).

Cap P-16

Pure 4,4-difluorocyclohexanol (136 mg, 0.999 mmol) was added to a cold (-20 ° C) solution of phosgene (2.0 mL, 3.80 mmol) in toluene, and the mixture was allowed to warm to room temperature and stirred. Overnight. Excess phosgene was carefully removed to give cap P-16 as a toluene solution and was used without further purification.

Cap P-17

4,4-Difluoropiperidine/HCl (158 mg), 2-bromo-2-methylpropionic acid benzyl ester (257 mg) and TEA (0.279 mL) in acetonitrile (1.5 mL). The stirred mixture was heated at 85 ° C overnight. The reaction mixture was evaporated to dryness, and the residue was dissolved in diethyl ether, washed with saturated NaHCO _3, water, brine and dried (MgSO _4). The crude product was purified by silica gel FCC (EtOAc EtOAc EtOAc EtOAc) Ester (33.7 mg). ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 7.31-7.46 (5 H, m), 5.18 (2 H, s), 2.66 (4 H, t, J = 5.40 Hz), 1.86-2.08 (4 H, m ), 1.36 (6 H, s). The benzyl group was removed from the benzyl 2-(4,4-difluoropiperidin-1-yl)-2-methylpropanoate by hydrogenation (10%EtOAc /EtOAc) Cap P-16. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 3.00 (4H, br. s.), 2.18-2.43 (4H, m), 1.45 (6H, s).

Cap P-18

Will be pure BF ₃ . OEt ₂ (1.014 mL, 8.00 mmol) was added dropwise to 4,4-difluorocyclohexanone (0.671 g, 5 mmol) and ((1-methoxy-2-methylprop-1-en-1-yl) The oxy)trimethyl decane (1.937 g, 10.00 mmol) was cooled (-78 ° C) in EtOAc (EtOAc)EtOAc. ₃ (10mL) The reaction mixture was quenched with saturated NaHCO, and diluted with DCM (20mL). The organic layer was separated, and washed with an aqueous solution of 0.25M HF, water, brine and dried (MgSO _4). The solvent was evaporated to give EtOAc (EtOAc:EtOAc. Methyl-hydroxycyclohexyl)-2-methylpropanoate (1.14 g).

Methyl 2-(4,4-difluoro-1-hydroxycyclohexyl)-2-methylpropanoate (1.137 g, 4.81 mmol) in THF (4 mL) MeOH (3 mL) The stirred solution was heated overnight at 60 °C. Of THF and MeOH was evaporated, and the aqueous residue was acidified and extracted with EtOAc, washed with water, brine and dried (MgSO _4). Evaporation of solvent

Cap P-18 (0.997 g) in the form of a white solid. ¹ H NMR (500 MHz, CDCl ₃ ) δ ppm 2.12-2.30 (2 H, m), 1.92-2.03 (2 H, m), 1.78-1.87 (2 H, m), 1.66-1.75 (2 H, m) , 1.32 (6 H, s).

Cap P-19

A solution of LDA in THF prepared from diisopropylamine (304 mg, 3.00 mmol) and butyllithium (1.20 mL, 3.00 mmol) was added to butyl cyclopropanecarboxylate (427 mg, 3.00 mmol) in THF (2 mL) The mixture was cooled (-78 ° C) and the mixture was stirred at -78 ° C for 1 hour. A solution of 4,4-difluorocyclohexanone (268 mg, 2 mmol) in THF (0.5 mL) was added dropwise and the mixture was stirred at -78 °C for 2 hr and warmed to room temperature overnight. The crude product was purified by EtOAc (EtOAc) (EtOAc) ¹ H NMR (500 MHz, CDCl ₃ ) δ ppm 2.12-2.30 (2H, m), 1.79-1.96 (4H, m), 1.48-1.53 (2H, m), 1.41-1.47 (9 H, m) , 1.21-1.34 (1 H, m), 1.11-1.17 (2 H, m), 0.90-0.97 (2 H, m).

Pure TFA (0.446 mL, 5.79 mmol) was added to a solution of &lt;RTI ID=0.0&gt;&gt; The mixture was stirred at room temperature for 1-2 hours. The reaction was evaporated to dryness to give mp. ¹ H NMR (500 MHz, CDCl ₃ ) δ ppm 2.09-2.29 (2 H, m), 1.84-2.00 (4H, m), 1.57 (2H, td, J = 13.85, 3.43 Hz), 1.34-1.40 ( 2 H,m), 1.10 - 1.15 (2 H, m).

Cap P-20

To a solution of 1-(methoxycarbonyl)cyclopropanecarboxylic acid (144 mg, 1 mmol) was added 2M EtOAc (1. The reaction mixture was stirred until the gas ceased to be released (about 1 hour). Excess ethyl ruthenium chloride and DCM were evaporated to give methyl 1-(chlorocarbonyl)cyclopropanecarboxylate. Add 4,4-difluoropiperidine/HCl (173 mg) and DIPEA (0.384 mL) to a solution of methyl 1-(chlorocarbonyl)cyclopropanecarboxylate in DCM (2 mL). The mixture was warmed to room temperature. The reaction mixture was purified by silica gel FCC to give cap P-20. ¹ H NMR (500 MHz, CDCl ₃ ) δ ppm 3.77-3.82 (2H, m), 3.75 (3H, s), 3.64 (2H, t, J = 5.42 Hz), 1.96-2.09 (4 H, m ), 1.51-1.57 (2 H, m), 1.33-1.39 (2 H, m). Hydrolysis of methyl 1-(4,4-difluoropiperidine-1-carbonyl)cyclopropanecarboxylate (2 mL, EtOAc (1 mL) EtOAc) ¹ H NMR (500 MHz, CDCl ₃ ) δ ppm 3.78-3.73 (4H, m), 1.97-2.10 (4H, m), 1.59-1.65 (2H, m), 1.42-1.48 (2 H, m) .

Cap P-21

Was added 2-methyl-2- (4-oxo-cyclohexyl) propanoic acid (0.184g, 1mmol) and DIPEA (0.192mL, 1.100mmol) in acetonitrile (1 mL) and CHCl ₃ (1mL) solution of the Benzyl bromide (0.131 mL, 1.100 mmol), and the mixture was stirred at room temperature overnight. Evaporation of the reaction mixture to dryness and purification with EtOAc (EtOAc-EtOAc (EtOAc) 184mg), which was dissolved in CH ₂ Cl ₂ (2mL), was treated with Deoxo-Fluor® (0.442mL, 2.40mmol) , followed by addition of EtOH (5.8μL). The resulting yellowish solution was stirred at room temperature overnight. The reaction mixture was diluted with saturated NaHCO ₃ and EtOAc. The organic phase was separated and washed with water, washed with saturated NaCl, dried over anhydrous MgSO _4, filtered and dried to give a yellow oil. The crude product was purified by silica gel FCC (1:1 hexane-DCM) to afford phenyl 2-(4,4-difluorocyclohexyl)-2-methylpropanoate (143 mg) It was hydrogenated under balloon pressure (0.053 g of 10% Pd-C, EtOAc) for 4 h. The suspension was filtered and evaporated to dryness to give cap P-21. ¹ H NMR (500 MHz, CDCl ₃ ) δ ppm 2.08-2.23 (2 H, m), 1.64-1.85 (5 H, m), 1.36-1.54 (2 H, m), 1.12-1.29 (6 H, m) .

Cap P-22

Add to a solution of 5-oxooxyhexahydrocyclopentadienyl-2,2(1H)-dicarboxylic acid 2-tributyl ester 2-ethyl ester (0.8 g, 2.70 mmol) in DCM (4 mL) TFA (2.080 mL), and the mixture was stirred at room temperature for 4 hr. The reaction mixture was evaporated to dryness and the residue was crystalljjjjjjjjjjjjj The pyridine was evaporated, and the residue was purified EtOAcjjjjjjjjj a mixture of isomers). ¹ H NMR (500 MHz, CDCl ₃ ) δ ppm 4.10-4.18 (2H, m), 2.85-3.02 (2H, m), 2.69-2.80 (1 H, m), 2.44-2.56 (2 H, m) , 2.20-2.36 (2 H, m), 2.10-2.20 (1 H, m), 2.04 (1 H, dd, J = 19.45, 4.65 Hz), 1.66-1.80 (2 H, m), 1.22-1.31 ( 3 H,m).

Slowly add trifluoromethanesulfonate to a solution of 5-oxo-octahydrocyclopentadienyl-2-carboxylate (210 mg) in DCM (5 mL) cooled to -78 ° C under N2. Alkanoate (11.89 mg, 0.054 mmol) and 2,2,7,7-tetramethyl-3,6-dioxa-2,7-dioxaoctane (287 mg, 1.391 mmol). After stirring at -78 ° C for 30 minutes, the reaction mixture was warmed to room temperature and stirred at room temperature for 16 hours. At -78 deg.] C with anhydrous pyridine The reaction was quenched, and then quenched with saturated NaHC03 _3, followed by extraction with EtOAc. ₄ combined organic layers were dried over anhydrous MgSO and concentrated in vacuo. The residue was purified by flash chromatography to give hexahydro-1'H-spiro[[1,3]dioxol-2,2'-cyclopentadiene]-5' as a clear oil. - ethyl formate (a mixture of endo/exo isomers).

Add hexahydro-1' to a solution of LDA, HMPA (0.217 mL, 1.248 mmol) prepared from diisopropylamine (0.176 mL, 1.248 mmol) and butyllithium (0.499 mL, 1.248 mmol) at -78 °C A solution of H-spiro[[1,3]dioxol-2,2'-cyclopentadienyl]-5'-carboxylic acid ethyl ester (200 mg, 0.832 mmol) in THF (1 mL). The reaction mixture was stirred at -78.degree. C. for 2 hr then EtOAc (EtOAc &EtOAc. The reaction mixture was stirred at -78 °C for 2 hours, then allowed to warm to 0 °C over 3 hours. ₄ Cl reaction mixture was quenched with saturated NH, and extracted with diethyl ether. The combined organic layers were dried and concentrated in vacuo. The residue was purified by flash chromatography (EtOAc /EtOAc) The major isomer product isolated was (3a'R,5's,6a'S)-5'-methylhexahydro-1'H-spiro[[1,3]dioxol-2,2'- Cyclopentadienyl]-5'-carboxylic acid ethyl ester (89 mg). ¹ H NMR (500 MHz, CDCl ₃ ) δ ppm 4.10-4.18 (2H, m), 3.86-3.95 (4H, m), 2.62- 2.74 (2 H, m), 1.97-2.05 (2 H, m) , 1.83-1.96 (4 H, m), 1.60-1.69 (2 H, m), 1.25-1.29 (3 H, m), 1.21 (3 H, s).

(3a'R,5's,6a'S)-5'-methylhexahydro-1'H-spiro[[1,3]dioxol-2,2'-cyclopentadiene]-5 The mixture of '-ethyl formate (89 mg, 0.350 mmol) and PPTS (22 mg, 0.088 mmol) in acetone (3 mL) and water (1 mL) was heated to reflux for 4 hours. Acetone was evaporated, and extracted with EtOAc and saturated NaHCO ₃ diluted with the residue. The organic phase was washed with saturated NaCl, and dried over MgSO _4, filtered and concentrated. The residue was purified by EtOAc EtOAc (EtOAc) elute Ethyl formate. ¹ H NMR (500 MHz, CDCl ₃ ) δ ppm 4.13 (2 H, q, J = 7.12 Hz), 2.82-2.93 (2H, m), 2.44-2.54 (2H, m), 2.11-2.19 (2 H m), 1.90-2.02 (4 H, m), 1.28-1.31 (3 H, m), 1.23-1.28 (3 H, m).

To (2s, 3aR, 6aS)-2-methyl-5-oxooxy octahydrocyclopentadienyl-2-carboxylate (63 mg, 0.300 mmol) in DCM (2 mL) Deoxo-Fluor® (133 μL) was added to the solution, followed by EtOH (3 μL). The resulting yellowish solution was stirred at room temperature for 18 hours. The reaction was _quenched with sat NaHCO and extracted with DCM. Washed with water, brine, and the combined organic layers were dried (MgSO _4), filtered and evaporated to give a yellow - orange oil by flash chromatography on silica gel (EtOAc / hexane) to give the oil, to give (2s, 3aR, 6aS)-5,5-Difluoro-2-methyl octahydrocyclopentadiene-2-carboxylic acid ethyl ester (58 mg). ¹ H NMR (500 MHz, CDCl ₃ ) δ ppm 4.11-4.20 (2 H, m), 2.71-2.84 (2 H, m), 2.28 (2H, qd, J = 13.58, 9.31 Hz), 1.86-1.99 ( 6 H,m), 1.26-1.31 (3 H,m), 1.7-1.25 (3 H,m).

Add LiOH to a solution of (2s,3aR,6aS)-5,5-difluoro-2-methyloctahydrocyclopentadiene-2-carboxylate in THF (1 mL) and MeOH (1 mL) 25.1 mg) solution in water (0.5 mL). The mixture was stirred at room temperature for 2 hours. Standard acid treatment and separation by extraction gave a cap P-22 (42 mg) as a white solid. ¹ H NMR (500MHz, CDCl ₃ ) δ ppm 2.72-2.85 (2 H, m), 2.21-2.36 (2 H, m), 1.88-2.01 (6 H, m), 1.25-1.27 (3 H, m) .

Cap P-23

Benzyl 2-bromo-2-methylpropanoate (0.748 g, 2.91 mmol), tetrahydro-2H-pipetan-2-one (0.260 g, 2.60 mmol) and indium (0.341 g, 2.97 mmol) The stirred suspension in THF (3 mL) was sonicated for 6 hours. The reaction was _quenched with sat NaHCO and extracted with diethyl ether, and then concentrated. The residue was purified by flash chromatography eluting EtOAc (EtOAc) ¹ H NMR (500 MHz, CDCl ₃ ) δ ppm 7.30-7.43 (5 H, m), 5.18 (2 H, s), 3.51-3.61 (2 H, m), 2.41 (2 H, t, J = 7.10 Hz ), 1.56-1.66 (2 H, m), 1.35-1.47 (8 H, m). Dissolving 2-methyl 2-(2-hydroxytetrahydro-2H-piperidin-2-yl)-2-methylpropanoate in triethyldecane (0.415 mL, 2.60 mmol) eluting with TFA (0.200 mL) Treated with 2.60 mmol), and the reaction mixture was stirred at room temperature for 16 hr then evaporated to dryness to give &lt;EMI&gt; 2-methyl-2-(tetrahydro-2H-pyran-2-yl)propanoate. ¹ H NMR (500 MHz, CDCl ₃ ) δ ppm 7.30-7.41 (5 H, m), 5.22 (1 H, d, J = 12.66 Hz), 5.10 (1 H, d, J = 12.51 Hz), 3.91-4.01 (1 H,m), 3.53 (1 H, dd, J = 11.22, 1.75 Hz), 3.39 (1 H, td, J = 11.56, 2.37 Hz), 1.82-1.92 (1 H, m), 1.44-1.59 (4 H, m), 1.30 - 1.41 (1 H, m), 1.19-1.25 (3 H, m), 1.11-1.19 (3 H, m). 10% Pd-C (16.63 mg) and benzyl 2-methyl-2-(tetrahydro-2H-pyran-2-yl)propanoate (82 mg, 0.313 mmol) the suspension was stirred for 6 hours with stirring under H _2, then filtered and concentrated to afford the cap P-23 (54mg). ¹ H NMR (500 MHz, CDCl ₃ ) δ ppm 4.09-4.19 (1 H, m), 3.48-3.57 (1 H, m), 3.33 - 3.42 (1 H, m), 1.88-1.97 (1 H, m) , 1.71 (1 H, d, J = 13.12 Hz), 1.47-1.65 (3 H, m), 1.29-1.40 (1 H, m), 1.23-1.27 (3 H, m), 1.14 - 1.20 (3 H , m).

Cap P-24

Ethyl 2-oxopropionate (0.581 g, 5 mmol) and 2,2-dimethylpropane-1,3-diol (0.521 g, 5.00 mmol) cooled to 0 ° C in acetonitrile (5 mL) Add BF _{3 to} the solution. OEt ₂ (0.063 mL, 0.500 mmol), and the mixture was warmed to room temperature and stirred at room temperature for 18 hours. ₃ (5mL) The reaction mixture was quenched with saturated NaHCO, and extracted with ether / hexane: dilution (1 1,20mL). Washed with water, the organic layer was washed with brine and dried (MgSO _4). The solvent was evaporated to give 2,5,5-trimethyl-1,3-dioxane-2-carboxylic acid ethyl ester (681 mg). ¹ H NMR (500 MHz, CDCl ₃ ) δ ppm 4.31 (2H, q, J = 7.07 Hz), 3.48-3.58 (4 H, m), 1.55 (3 H, s), 1.35 (3 H, t, J =7.17 Hz), 1.22 (3 H, s), 0.69-0.75 (3 H, m). Ethyl 2,5,5-trimethyl-1,3-dioxane-2-carboxylate (90 mg) was saponified (1N EtOAc, MeOH-THF). ¹ H NMR (500 MHz, CDCl ₃ ) δ ppm 3.53-3.64 (4H, m), 1.63 (3H, s), 1.23 (3H, s), 0.78 (3H, s).

Cap P-25

60% NaH (81 mg, 2.02 mmol) was added to a solution of 6-methoxytetrahydro-2H-pentan-3-ol (222 mg, 1.680 mmol) in DMF (2 mL). The mixture was warmed to room temperature and stirred at room temperature for 30 minutes. A solution of (bromomethyl)benzene (345 mg, 2.016 mmol) in DMF (1 mL) was evaporated. The reaction mixture was diluted with ether and quenched with water. The crude product was purified by EtOAc (EtOAc EtOAc) elute ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 7.29-7.41 (5 H, m), 4.53-4.64 (3 H, m), 3.90 (1 H, dd, J = 12.05, 2.51 Hz), 3.56-3.65 ( 1 H,m), 3.46-3.53 (1 H,m), 3.43 (3 H,s), 1.97-2.14 (2 H,m), 1.69-1.81 (1 H,m), 1.48-1.60 (1 H , m).

A solution of 5-(benzyloxy)-2-methoxytetrahydro-2H-pyran (317 mg, 1.426 mmol) in AcOH (10 mL) and water (5 mL) Evaporation to dryness gave 5-benzyloxyoxytetrahydropyran-2-ol (300 mg). 5-Benzyloxytetrahydropyran-2-ol was dissolved in DCM (3 mL) eluting with EtOAc (EtOAc:EtOAc: The mixture was stirred at room temperature for 4 hours, quenched with saturated NaHC03 _3, and extracted with DCM. Washed with water, the organic phase was washed with brine, dried (MgSO ₄₎ and concentrated to give a clear oil of acetic acid 5- (phenylmethoxy) -2H- tetrahydro-pyran-2-yl ester (281mg).

5-(Benzyloxy)tetrahydro-2H-pyran-2-yl acetate (281 mg, 1.123 mmol) and ((1-methoxy-2-methylpropan-1) at -78 °C Add BF _{3 to a} solution of 1-en-1-yloxy)trimethylnonane (783 mg, 4.49 mmol) in DCM (5 mL). OEt ₂ (0.228 mL, 1.796 mmol). The reaction mixture was gradually warmed to room temperature and stirred at room temperature for 18 hours. ₃ (5mL) The reaction mixture was quenched with saturated NaHCO, and diluted with DCM (20mL). The organic layer was separated, washed with water, brine, dried (MgSO ₄₎ and concentrated. The crude product was purified by EtOAc (EtOAc (EtOAc) elute Methyl methacrylate (253 mg). Add 10% Pd- to a solution of methyl 2-(5-(benzyloxy)tetrahydro-2H-piperidin-2-yl)-2-methylpropanoate (250 mg) in MeOH (20 mL) C (59.7 mg), and the reaction mixture was hydrogenated overnight at 40 psi. The suspension was filtered, and the filtrate was evaporated to dry crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal

To a solution of methyl 2-(5-hydroxytetrahydro-2H-piperidin-2-yl)-2-methylpropanoate (187 mg, 0.925 mmol) in DCM (5 mL) PCC (259 mg, 1.202 mmol) was added to the stirred solution. The reaction mixture was stirred at room temperature for 3 hours, then loaded onto a silica gel column and eluted with 10-20%EtOAcEtOAc eluted to afford 2-methyl-2-(5-s. Methyl-2H-piperid-2-yl)propanoate (105 mg). ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 4.18 (1H, dd, J = 16.56, 1.76 Hz), 3.87-4.01 (2H, m), 3.73 (3H, s), 2.59-2.69 (1H m), 2.48 (1 H, dt, J = 17.13, 8.63 Hz), 1.93-2.04 (2H, m), 1.27 (3H, s), 1.15-1.24 (3H, m).

Add Deoxo- to a cold solution of methyl 2-methyl-2-(5-oxo-tetrahydro-2H-piperidin-2-yl)propanoate (98.5 mg, 0.492 mmol) in DCM (2 mL) Fluor® (261 mg, 1.181 mmol) and EtOH (4.31 μl, 0.074 mmol). The reaction mixture was allowed to warm to rt and stirred overnight. The reaction was _quenched with sat NaHCO and extracted with DCM (2 ×). Washed with water, brine, and the combined organic layers were dried (MgSO _4), filtered and concentrated. The residue was purified by EtOAc EtOAc (EtOAc) ¹ H NMR (500 MHz, CDCl ₃ ) δ ppm 3.92-4.01 (1 H, m), 3.69-3.72 (3 H, m), 3.61 (1 H, dd, J = 10.30, 2.21 Hz), 3.44-3.56 ( 1 H,m), 2.21-2.32 (1 H,m),1.83-2.02 (1 H,m),1.65-1.78 (2 H,m),1.22-1.26 (3 H,m),1.14-1.19 ( 3 H,m). Saponification of methyl 2-(5,5-difluorotetrahydro-2H-piperidin-2-yl)-2-methylpropanoate (LiOH.H ₂ O, MeOH/THF/H ₂ O) affords cap P-25 (48 mg). ¹ H NMR (500 MHz, CDCl ₃ ) δ ppm 3.94-4.07 (1 H, m), 3.44-3.67 (2H, m), 2.21-2.35 (1 H, m), 1.83-2.01 (1 H, m) , 1.71-1.83 (2 H, m), 1.7-1.27 (6 H, m).

Cap Y-8a and Y-8b

In a sealed tube, a reaction mixture of hydroquinone (150 mg), acrolein (3.225 mL) and 2-methyl-3,4-dihydro-2H-pentan-2-carboxylic acid benzyl ester (2.5 g) was Heat at 180 ° C for 18 hours. The reaction mixture was cooled and cooled and purified directly on a silica gel column to give 2-methyl-3,4-dihydro-2H-pyran-2-carboxylic acid benzyl ester (1 g) (Thomson 80g column, EtOAc / hexane Alkane: 0% to 10%). ¹ H NMR (400 MHz, CDCl ₃ ) ppm 7.30-7.44 (5 H, m), 6.41 (1 H, dt, J = 6.27, 1.88 Hz), 5.12-5.27 (2 H, m), 4.67-4.81 (1) H, m), 2.27 (1 H, dt, J = 13.11, 4.49 Hz), 1.87-2.03 (2H, m), 1.72-1.83 (1H, m), 1.51 (3H, s).

To a solution of 2-methyl-3,4-dihydro-2H-pentan-2-carboxylic acid benzyl ester (1.0 g, 3.44 mmol) in THF (10 mL) BH _{3 was} added dropwise to the solution. THF (2.07 mL, 2.07 mmol). The reaction mixture was stirred in a bath for 4 hours. The reaction mixture was quenched by the addition of sodium acetate (0.283 g, 3.44 mmol) in water (3 mL). After stirring for 10 minutes, H ₂ O ₂ (0.3 mL, 4.89 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with EtOAc, and washed with saturated NH ₄ Cl, washed with brine and dried (MgSO _4). The solvent was removed in vacuo to give benzyl 5-hydroxy-2-methyltetrahydro-2H-pyran-2-carboxylate.

To benzyl 5-hydroxy-2-methyltetrahydro-2H-pentan-2-carboxylate (1.1 g, 3.52 mmol) and molecular sieve (4 Å, 2 g, powder) in DCM (20 mL) PCC (1.137 g, 5.27 mmol) was added in two portions in the mixture. The reaction mixture was stirred at room temperature for 17 hours. The reaction mixture was directly loaded and purified on a 40 g silica gel cartridge (EtOAc / hexanes: 0% to 40%) to give 2-methyl-5-oxooxytetrahydro-2H-pyran-2-carboxylic acid benzyl ester ( 0.47g). ¹ H NMR (400 MHz, CDCl ₃ ) ppm 7.45-7.31 (m, 5 H), 5.25 (s, 2 H), 4.27 (d, J = 17.6 Hz, 1 H), 4.07 (d, J = 17.3 Hz, 1 H), 2.59-2.34 (m, 3 H), 2.14 - 2.04 (m, 1 H), 1.56 (s, 3 H).

To methyl-5-oxo-tetrahydro -2H--pyran-2-carboxylic acid benzyl ester (0.47g, 1.893mmol) in CH of the ₂ Cl ₂ (5mL) was added Deoxo-Fluor® ( 0.838 mL, 4.55 mmol), followed by the addition of EtOH (5 μL). The resulting yellow solution was stirred at room temperature for 18 h, then partitioned between saturated NaHCO ₃ and EtOAc. , And dried with saturated NaHCO _3, water, saturated NaCl The organic phase was dried over anhydrous MgSO _4, filtered and dried to give a yellow oil. The crude product contained a vinyl by-product as judged by ¹ H NMR. The mixture was dissolved in EtOAc (2 mL) EtOAc (EtOAc) (EtOAc) Ice bath was removed, and the mixture was stirred for 40 hours at room temperature, then diluted with EtOAc, and washed with water, washed with NH ₄ Cl, brine, and dried (MgSO _4). The crude material was purified on a 12 g EtOAc EtOAc (EtOAc:EtOAc:EtOAc ¹ H NMR (400 MHz, CDCl ₃ ) ppm 7.35-7.43 (5H, m), 5.25 (2H, s), 3.68-3.90 (2H, m), 2.36-2.45 (1 H, m), 2.07- 2.18 (1 H, m), 1.72-1.89 (2 H, m), 1.43-1.51 (3 H, m).

Add 10% Pd/C to a suspension of benzyl 5,5-difluoro-2-methyltetrahydro-2H-pentan-2-carboxylate (0.22 g, 0.814 mmol) in MeOH (5 mL) 0.12g). The reaction mixture was stirred under H ₂ for 1 hour. The reaction was filtered and concentrated to dryness to give 5,5-difluoro-2-methyltetrahydro-2H-pyran-2-carboxylic acid (100 mg). ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 3.79-3.91 (2 H, m), 2.29-2.42 (1 H, m), 2.12-2.26 (1 H, m), 1.85-2.08 (2 H, m) , 1.54 (3 H, s).

Pyridin-2-ylmethanol (91 mg, 0.833 mmol), 5,5-difluoro-2-methyltetrahydro-2H-pyran-2-carboxylic acid (100 mg, 0.555 mmol), HBTU (274 mg, 0.722 mmol) A mixture of DIEA (0.2 mL, 1.145 mmol) in DCM (2 mL) The reaction mixture was diluted with EtOAc, and washed with NaHCO _3, brine, dried (MgSO _4), concentrated and chromatographed by silica gel (EtOAc / hexanes) the residue to give the racemic form of 5,5 Difluoro-2-methyltetrahydro-2H-pentan-2-carboxylic acid pyridin-2-ylmethyl ester. By palmitic SFC (Chiralpak AD-H preparative column, 20 x 250 mm, 5 μm, mobile phase: 10% 2:1 heptane: EtOH, in CO ₂ , 150 bar; temperature: 35 ° C; flow rate : 45 mL/min, UV: 258 nm) The two enantiomers were separated (Solution-1: 4.04 min, and Eluent-2: 4.61 min).

A mixture of Dissolve-1 (collected at 4.04 min) (25 mg, 0.092 mmol), EtOAc (1 N, 1 mL, 1 mmol), THF (3mL) and MeOH (2mL) The reaction mixture was diluted with EtOAc, and washed with HCl (1N, 2 × 5mL) , brine (2 ×), dried (MgSO _4), filtered and the solvent removed to give (R) -5,5- difluoro-2- Methyltetrahydro-2H-pentan-2-carboxylic acid (14 mg).

A mixture of Dissolve-2 (collected at 4.61 min) (21 mg, 0.077 mmol), EtOAc (1 N, 1 mL, 1 mmol), THF (3mL) and MeOH (2mL) The reaction mixture was diluted with EtOAc, and washed with HCl (1N, 2 × 5mL) , brine (2 ×), dried (MgSO _4), filtered and the solvent removed to give (S) -5,5- difluoro-2- Methyltetrahydro-2H-pentan-2-carboxylic acid (13 mg).

Cap Y-8b

n-Butyllithium (51.0 mL, 128 mmol) was added dropwise to a solution of phenylmethanol (15 mL, 144 mmol) in THF (100 mL). The resulting solution was stirred for 20 minutes, followed by dropwise addition of (2S,5R)-5-allyl-2-(t-butyl)-5-methyl-1,3-dioxane at 0 °C. Cyclopentan-4-one (25.3 g, 128 mmol, prepared by the method described in HELVETICA CHIMICA ACTA - Vol. 70 (1987), page 1194) in THF (80 mL). The reaction mixture was stirred for 18 hours at room temperature and the cold quenched with aqueous NH ₄ Cl. The mixture was extracted with EtOAc (2×). Washed with brine the combined organic solution was dried (MgSO ₄₎ and purified by silica gel flash chromatography to give the product (21.1g, 75%). ¹ H NMR (400MHz, CHLOROFORM -d) ppm 7.43-7.33 (m, 5H ), 5.74 (ddt, J = 17.2,10.2,7.3Hz, 1H), 5.20 (s, 2H), 5.13-4.99 (m, 2H ), 2.57-2.48 (m, 1H), 2.45-2.36 (m, 1H), 1.45 (s, 3H).

To a solution of (R)-2-hydroxy-2-methylpent-4-enoic acid benzyl ester (11 g, 49.9 mmol) in THF (100 mL) at -78 °C A solution of potassium hexamethyldioxane/toluene (120 mL, 60 mmol) was added. The reaction mixture was stirred at -78 °C for 15 min and allyl bromide (5.5 mL, 63.6 mmol) was added. The reaction mixture was stirred in a bath for 18 hours and allowed to warm to room temperature during this. The reaction mixture was quenched with EtOAc (EtOAc)EtOAc. Washed with water, brine and the organic solution was combined, dried (MgSO _4), solvent was removed and purified by flash chromatography on silica gel to give the product (9.4g, 72.3%). ¹ H NMR (400MHz, CHLOROFORM -d) ppm 7.40-7.34 (m, 5H ), 6.06-5.87 (m, 1H), 5.87-5.69 (m, 1H), 5.36-5.27 (m, 1H), 5.26-5.03 (m, 5H), 4.00-3.89 (m, 2H), 2.63-2.48 (m, 2H), 1.44 (s, 3H).

The (R & lt) -2- (allyloxy) -2-methyl-pent-4-enoic acid benzyl ester (4.3g, 16.52mmol) in toluene (150 mL) in the solution was purged with N ₂ 5 minutes, followed by Grubbs I (0.26 g, 0.311 mmol) was added. The reaction mixture was stirred at room temperature for 1.5 hours. The reaction mixture was purge with N _2, and was added CuCl (20mg, 0.202mmol), stirred at room temperature for 10 minutes. Grubbs I (0.26 g, 0.311 mmol) and trimethyldecane (2.2 mL, 13.77 mmol) were added. The reaction mixture was heated in a EtOAc (EtOAc) EtOAc (EtOAc)EtOAc. . ¹ H NMR (400MHz, CHLOROFORM -d) ppm 7.42-7.32 (m, 5H ), 6.41 (dt, J = 6.3,1.9Hz, 1H), 5.21 (s, 2H), 4.75-4.69 (m, 1H), 2.30-2.23 (m, 1H), 1.98-1.88 (m, 2H), 1.82-1.72 (m, 1H), 1.52 (s, 3H).

To (R)-2-methyl-3,4-dihydro-2H-pentan-2-carboxylic acid benzyl ester (3.5 g, 15.07 mmol) in THF (30 mL) BH _{3 was} added dropwise to the solution. THF (10.55 ml, 10.55 mmol). The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was re-cooled in EtOAc (EtOAc)EtOAc. The reaction mixture was stirred at this temperature for 10 minutes, hydrogen peroxide (3 mL, 48.9 mmol) was added, and stirred at room temperature for 1 hour. The reaction mixture was diluted with EtOAc, and washed with NH ₄ Cl, washed with brine, dried (MgSO _4), solvent was removed to give the crude product (3.4g, 90%). The crude product was used in the next reaction without purification.

In an ice bath, to (2R)-5-hydroxy-2-methyltetrahydro-2H-pentan-2-carboxylic acid benzyl ester (3.4 g, 13.58 mmol) and MS (4 Å, 15 g, powder) PCC (4 g, 18.56 mmol) was added in two portions in DCM (30 mL). The reaction mixture was stirred at room temperature for 20 hr then diluted with EtOAc EtOAc (EtOAc)

To a solution of Deoxo-Fluor® (4.27 mL, 23.16 mmol) in DCM (15 mL) EtOAc. The mixture was stirred at room temperature for 1 hour. (R)-2-Methyl-5-oxooxytetrahydro-2H-pentan-2-carboxylic acid benzyl ester (2.3 g, 9.26 mmol) in DCM (5 mL) Solution. The reaction mixture was stirred at room temperature overnight. Another portion of Deoxo-Fluor® (3.6 mL, 19.53 mmol) was added dropwise at 0 °C. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was carefully poured into ice with stirring of aqueous NaHCO _3, and the (2 ×) and extracted with EtOAc. With NaHCO _3, the organic extracts were washed with brine, dried (MgSO _4). The crude product was dissolved in EtOAc (4 mL) EtOAc (EtOAc) (EtOAc) The reaction mixture was stirred at room temperature for 3 days. The reaction mixture was diluted with EtOAc, and washed with water, NH ₄ Cl, washed with brine, dried (MgSO ₄₎ and purified by flash chromatography on silica gel to give the product (1.5g, 59.9%).

(R)-5,5-Difluoro-2-methyltetrahydro-2H-pentan-2-carboxylic acid benzyl ester (0.51 g, 1.887 mmol) and Pd/C (0.05 g, 0.047 mmol) in MeOH the mixture (20mL) was degassed and refilled in the H _2. The reaction mixture was stirred at room temperature under H ₂ balloon pressure for 1 day. The reaction mixture was filtered, and the filtrate was evaporated mjjjjjj

Cap Y-9

A mixture of KO-tBu (7.4 g, 65.9 mmol) and bromo (methyl)triphenylphosphane (21.6 g, 60.5 mmol) in diethyl ether (100 mL) A solution of 1,4-dioxaspiro[4.5]decan-8-one (6.24 g, 40.0 mmol) in diethyl ether (100 mL) was then added dropwise over 1.5 hr. The reaction mixture was stirred for 2 h, cooled to rt then filtered and filtered. The residue was purified by EtOAc EtOAc (EtOAc) elute ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 4.62-4.74 (2H, m), 3.98 (4 H, s), 2.30 (4H, dd, J = 7.03, 6.02 Hz), 1.66-1.77 (4 H , m).

A solution of diethyl hydrazine oxime (0.14 g, 0.317 mmol) and 8-methylene-1,4-dioxaspiro[4.5] decane (1.5 g, 9.73 mmol) in DCM (20 mL) To reflux, a solution of 2-dinitroacetic acid ethyl ester (2.018 mL, 19.45 mmol) in DCM (6 mL). After the addition was completed, the reaction mixture was stirred for 2 hr, cooled to room temperature and concentrated. By silica gel chromatography (EtOAc / hexanes) the residue to give (1 S) -6- oxo-spiro [2.5] octane-1-carboxylate (1.9g). ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 4.08-4.18 (2H, m), 3.94-3.99 (4H, m), 1.83 (4H, m), 1.59-1.67 (2 H, m), 1.49 -1.58(2 H,m),1.35-1.46(1 H,m),1.23-1.30(3 H,m),1.15(1 H,t, J =4.89Hz),0.90(1 H,dd, J =7.91, 4.39Hz).

Add PPTS (0.1g to (1 S) -6- oxo-spiro [2.5] octane-1-carboxylate (1.9g, 7.91mmol) in acetone (20mL) and water (5mL) in the solution, 0.398 mmol). The reaction mixture was heated at 60 ° C for 5 hours, followed by stirring at room temperature for 45 hours. The reaction mixture was diluted with EtOAc, washed with water, brine, dried (MgSO ₄₎ and concentrated to give an oil of 6- oxo-spiro [2.5] octane-1-carboxylate (1.32g). ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 4.13-4.21 (2 H, m), 2.35-2.51 (3H, m), 2.19-2.30 (1 H, m), 2.00-2.09 (3 H, m) , 1.86 (1 H,ddd, J = 13.68, 8.16, 5.27 Hz), 1.64-1.77 (2 H, m), 1.23-1.35 (3 H, m), 1.08 (1 H, dd, J = 8.16, 4.64 Hz).

Solution of 6-oxo-spiro [2.5] octane-1-carboxylate (1.32g, 6.73mmol) was added in CH Deoxo-Fluor® (2.7mL, 14.64mmol) in the ₂ Cl ₂ (5mL) and a solution of EtOH (5 μL). The resulting yellowish solution was stirred at room temperature for 18 hours. The reaction mixture was partitioned between EtOAc and ₃ saturated NaHCO. , And dried with saturated NaHCO _3, water, saturated NaCl The organic phase was dried over anhydrous MgSO _4, filtered and dried to give 6,6-difluoro-spiro [2.5] octane-1-carboxylate (0.72g).

To a solution of 6,6-difluorospiro[2.5]octane-1-carboxylate (0.72 g, 3.30 mmol) in THF (5 mL) MeOH (2.5 mL) Lithium oxide (1.108 g, 26.4 mmol). The reaction mixture was stirred at room temperature for 32 hours. The reaction mixture was diluted with EtOAc, and washed with 1N HCl (30mL), washed with brine, dried (MgSO ₄₎ and concentrated to dryness to afford the cap Y-9 (0.627g). _{^{1 H NMR (400MHz, CDCl 3}} ) δ ppm 2.37-2.19 (m, 1 H), 2.08-1.77 (m, 4 H), 1.61 (s, 2 H), 1.57-1.36 (m, 1 H), 1.35 - 1.19 (m, 2 H), 1.11 - 1.00 (m, 1 H).

Cap Y-10

To the dry flask was added Pd ₂ (dba) ₃ CHCl ₃ adduct (0.1 g, 0.097 mmol), N,N'-((1S,2S)-cyclohex-1,2-diyl) bis(2- (Diphenylphosphino)benzamide (0.2 g, 0.290 mmol). The flask was degassed and purged with N _2. Add DCM (200mL), then degassed and purged with N _2. Was added allyl alcohol (3 mL, 44.1 mmol), and degassed, refilled with N _2. The mixture was stirred at room temperature for 20 minutes and the color turned orange. Triethylborane/hexane (0.4 mL, 0.400 mmol) was added and stirred for 2 min then 2-methyl-2-vinyl oxirane (4 mL, 40.8 mmol). The reaction mixture was stirred at room temperature for 17 h and concentrated to dryness to give crystals. The crude product was used in the next step without purification. ¹ H NMR (400MHz, CHLOROFORM -d) ppm 5.98-5.77 (m, 2H ), 5.35-5.22 (m, 3H), 5.15 (dq, J = 10.4,1.5Hz, 1H), 3.90 (dt, J = 5.3 , 1.5 Hz, 2H), 3.57-3.42 (m, 2H), 1.32 (s, 3H).

To a solution of (R)-2-(allyloxy)-2-methylbut-3-en-1-ol (5.8 g, 40.8 mmol) in DCM (100 mL) DIPEA (8.6 ml, 49.2 mmol) and benzamidine chloride (5.2 mL, 44.8 mmol) were added. The reaction mixture was stirred at room temperature for 5 hours. Diethyl ether (100 mL) and TEA (5 mL, 35.9 mmol) were then evaporated and The reaction mixture was diluted with EtOAc and hexanes, with HCl (1N, 2 ×), NaOH (1N, 2 ×), washed with brine, dried (MgSO _4), solvent was removed and purified by silica gel flash chromatography to give the product ( 5.4g, 54%). ¹ H NMR (400MHz, CHLOROFORM -d) ppm 8.11-8.02 (m, 2H ), 7.62-7.55 (m, 1H), 7.49-7.41 (m, 2H), 5.99-5.86 (m, 2H), 5.39-5.28 (m, 3H), 5.14 (dq, J = 10.5, 1.6 Hz, 1H), 4.38-4.30 (m, 2H), 4.01-3.96 (m, 2H), 1.43 (s, 3H).

A solution of (R)-2-(allyloxy)-2-methylbut-3-en-1-ylbenzoate (5.4 g, 21.92 mmol) in DCM (200 mL) ₂ Purify for 5 minutes. Grubbs II (0.16 g, 0.188 mmol) was added and the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated and purified with EtOAc EtOAc EtOAc (EtOAc:EtOAc ¹ H NMR (400MHz, CHLOROFORM -d) ppm 8.08-8.01 (m, 2H ), 7.63-7.53 (m, 1H), 7.49-7.36 (m, 2H), 5.96 (dt, J = 6.2,1.5Hz, 1H ), 5.77 (dt, J = 6.3, 2.5 Hz, 1H), 4.75-4.68 (m, 2H), 4.40 (d, J = 11.3 Hz, 1H), 4.26 (d, J = 11.3 Hz, 1H), 1.42 (s, 3H).

To a solution of (R)-(2-methyl-2,5-dihydrofuran-2-yl)methyl benzoate (3.6 g, 16.49 mmol) in THF (40 mL) A borane-methyl sulfide complex (6 mL, 12.00 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was cooled in an ice-bath, and a solution of sodium acetate (1.353 g, 16.49 mmol) in water (15 mL) was carefully added to the reaction mixture. The reaction mixture was stirred at room temperature for 25 min then hydrogen peroxide (1.516 mL, 24.74 mmol). The reaction mixture was stirred at room temperature overnight. Another portion of hydrogen peroxide (1.516 mL, 24.74 mmol) was added and stirred at room temperature for 2 h. The reaction mixture was diluted with EtOAc and washed with water, brine, dried (MgSO _4), solvent was removed to give the product (3.9g, 100%). The crude product was used in the next reaction without purification.

To (5R)-5-((benzyloxy)methyl)-5-methyltetrahydrofuran-3-ol (3.9 g, 17.55 mmol) and MS (4 Å, 6 g, powder) at ice bath temperature PCC (5.29 g, 24.56 mmol) was added in two portions. The reaction mixture was stirred at room temperature for 20 h and diluted with EtOAc EtOAc (EtOAc) ¹ H NMR (400MHz, CHLOROFORM -d) ppm 8.02-7.94 (m, 2H ), 7.62-7.54 (m, 1H), 7.50-7.38 (m, 2H), 4.42-4.32 (m, 2H), 4.21 (d , J =17.1 Hz, 1H), 4.13 (d, J = 17.1 Hz, 1H), 2.69 (d, J = 18.1 Hz, 1H), 2.45 (d, J = 17.8 Hz, 1H), 1.52 (s, 3H) ).

To a solution of Deoxo-Fluor® (3.8 mL, 20.61 mmol) in DCM (10 mL) EtOAc. The mixture was stirred at room temperature for 1 hour. The reaction mixture was cooled to 0 ° C, and triethylamine trihydrofluoride (0.2 mL, 1.228 mmol), containing (R)-(2-methyl-4-oxo-tetrahydrofuran-2-yl)methyl benzoate (1.6 g, 6.83 mmol) in DCM (5 mL). The reaction mixture was stirred for 20 hours at room temperature and carefully poured into ice with stirring of an aqueous solution of NaHCO _3, extracted with EtOAc. With NaHCO _3, the organic extracts were washed with brine, dried (MgSO _4), and concentrated on a 25g silica gel cartridge: purified (EtOAc / hexanes 0-30%) to give product (1.1g, 63%). ¹ H NMR (500MHz, CHLOROFORM -d) ppm 8.12-8.03 (m, 2H ), 7.61 (tt, J = 7.4,1.3Hz, 1H), 7.51-7.41 (m, 2H), 4.40-4.27 (m, 2H ), 4.20-4.04 (m, 2H), 2.63 (dt, J = 16.1, 14.1 Hz, 1H), 2.33 (dddd, J = 17.4, 14.3, 9.6, 0.9 Hz, 1H), 1.48 (s, 3H).

(R)-(4,4-Difluoro-2-methyltetrahydrofuran-2-yl)methyl benzoate (1.1 g, 4.29 mmol) in THF (10 mL), MeOH (10.00 mL) The mixture in 1N, 25.00 mmol) was stirred at room temperature overnight. The reaction mixture was partially concentrated and the residue was partitioned between 1N EtOAc and diethyl ether. The aqueous layer was extracted with diethyl ether (2×). With 1N NaOH, water, brine and the combined the organic solution was dried (MgSO _4), solvent was removed to give the product (0.65g, 100%). ¹ H NMR (400MHz, CHLOROFORM -d) ppm 4.13-4.00 (m, 2H ), 3.66-3.42 (m, 2H), 2.73-2.49 (m, 1H), 2.25-2.08 (m, 1H), 1.32 (s , 3H).

Add Jones reagent (Jones) to a solution of (R)-(4,4-difluoro-2-methyltetrahydrofuran-2-yl)methanol (0.65 g, 4.27 mmol) in acetone (10 mL). 'Reagent) (2.5 M, 3.4 mL, 8 mmol). The reaction mixture was stirred in a bath for 18 hours and allowed to warm to room temperature during this. The reaction mixture was diluted with EtOAc and washed with water, brine, dried (MgSO _4), and the solvent was removed (MeOH / DCM: 0% to 20%) on 25g silica gel cartridge to afford Cap Y-10 (0.16g, 23 %). ^<1> H NMR (500 MHz, chloroform-d) ppm: </ RTI></RTI></RTI></RTI></RTI></RTI></RTI></RTI></RTI></RTI><RTIgt;

Cap Y-11

To the dry flask was added Pd ₂ (dba) ₃ CHCl ₃ adduct (0.15 g, 0.145 mmol), N,N'-((1S,2S)-cyclohex-1,2-diyl) bis(2- (Diphenylphosphino)benzamide (0.3 g, 0.434 mmol). The flask was degassed under vacuum and purged with N _2. Repeat the procedure twice. Add DCM (200mL), and then degassed under vacuum and purged with N _2. Was added but-3-en-1-ol (4.4 mL, 51.9 mmol), and degassed and refilled with N _2. The mixture was stirred at room temperature for 20 minutes. The color turns orange. Triethylborane/hexane (0.8 mL, 0.800 mmol) was added. After stirring for 2 minutes, 2-methyl-2-vinyloxirane (4 mL, 40.8 mmol) was added at room temperature. The reaction mixture was stirred at room temperature for 19 hours. The reaction mixture was concentrated to dryness to give the product. The crude product was used in the next reaction without purification (6.37 g, 100%).

(R)-2-(But-3-en-1-yloxy)-2-methylbut-3-en-1-ol (6.4 g, 41.0 mmol) in DCM (80 mL) DIPEA (9.30 mL, 53.3 mmol) and benzamidine chloride (6 mL, 51.7 mmol) were added dropwise to the solution. The reaction mixture was stirred at room temperature for 1 day. Ethyl ether (150 mL) and TEA (8 mL, 57.4 mmol), benzinium chloride (6 mL, 51.7 mmol) were added to the reaction mixture. The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with EtOAc and hexanes, with NaOH (1N, 2 ×), washed with brine, dried (MgSO _4), and the solvent was removed by a plug (plugged through) silica gel pad, and in the 160 silica gel cartridge (EtOAc /hexane: 0% to 15%) purified to give the product (10.5 g, 79%). ¹ H NMR (400MHz, CHLOROFORM -d) ppm 8.14-8.00 (m, 2H ), 7.61-7.52 (m, 1H), 7.51-7.38 (m, 2H), 6.00-5.79 (m, 2H), 5.38-5.27 (m, 2H), 5.11-4.96 (m, 2H), 4.31 (d, J = 4.0 Hz, 2H), 3.46 (td, J = 6.9, 4.5 Hz, 2H), 2.32 (dt, J = 6.8, 1.4) Hz, 2H), 1.45-1.37 (m, 3H).

(R)-2-(But-3-en-1-yloxy)-2-methylbut-3-en-1-yl benzoate (10.5 g, 32.3 mmol) in DCM (600 mL) the solution was degassed for 5 minutes and purified N _2. Grubbs II (0.18 g, 0.212 mmol) was added, and the reaction mixture was stirred at room temperature for 3 days. The reaction mixture was concentrated and purified EtOAc EtOAcjjjjjj ¹ H NMR (400MHz, CHLOROFORM -d) ppm 8.11-8.05 (m, 2H ), 7.61-7.54 (m, 1H), 7.50-7.41 (m, 2H), 6.05-5.96 (m, 1H), 5.69 (dt , J = 10.3, 2.0 Hz, 1H), 4.42 (d, J = 11.3 Hz, 1H), 4.18 (d, J = 11.3 Hz, 1H), 3.92 (dd, J = 11.3, 5.5 Hz, 1H), 3.84 (dd, J = 11.2, 5.6 Hz, 1H), 2.16-2.08 (m, 2H), 1.36 (s, 3H).

(R)-(2-methyl-5,6-dihydro-2H-pyran-2-yl)methyl benzoate (5.9 g, 25.4 mmol) in THF over 10 min. BH _{3 was} added dropwise to the solution in (60 mL). THF (15.3 mL, 15.30 mmol). The reaction mixture was stirred at room temperature for 1 hour. Add another portion of BH ₃ at 0 °C. THF (15.3 ml, 15.30 mmol), and the mixture was stirred at room temperature for 0.5 h. The reaction mixture was re-cooled in EtOAc (EtOAc)EtOAc. After stirring for 10 minutes, hydrogen peroxide (4.67 mL, 76 mmol) was added and stirred at room temperature for 1 hour. The reaction mixture was diluted with EtOAc, and washed with NH ₄ Cl, saturated _{Na 2 S 2 O 3 (2} ×), washed with brine, dried (MgSO _4), removed the solvent and purified on a 160g silica gel column, to give the product (1.6g , 25%).

In an ice bath, ((2R)-4-hydroxy-2-methyltetrahydro-2H-pyran-2-yl)methyl benzoate (1.6 g, 6.39 mmol) and MS (4 Å, 3 g, powder PCC (2 g, 9.28 mmol) was added in two portions in a mixture. The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was filtered with EtOAc EtOAc (EtOAc) ¹ H NMR (400MHz, CHLOROFORM -d) ppm 8.08-8.01 (m, 2H ), 7.63-7.57 (m, 1H), 7.51-7.43 (m, 2H), 4.34 (s, 2H), 4.25-4.14 (m , 1H), 4.13-4.00 (m, 1H), 2.67 (d, J = 14.3 Hz, 1H), 2.62-2.53 (m, 1H), 2.51-2.40 (m, 2H), 1.38 (s, 3H).

To a solution of Deoxo-Fluor® (1.5 mL, 8.14 mmol) in DCM (5 mL) EtOAc. The mixture was stirred at room temperature for 1 hour. Add (R)-(2-methyl-4-oxo-tetrahydro-2H-piperidin-2-yl)methyl benzoate (0.7 g, 2.82 mmol) in DCM (5 mL) Solution and triethylamine trihydrofluoride (0.1 mL, 0.614 mmol). The reaction mixture was stirred at room temperature for 18 hr and the reaction mixture was further evaporated and evaporated and evaporated. The reaction mixture was stirred for a further 2 hours at room temperature. The reaction mixture was carefully poured into a stirred solution of ice cold aqueous NaHCO ₃ solution, and (2 ×) and extracted with EtOAc. With NaHCO _3, the organic was washed with brine and the combined extracts were dried (MgSO _4), and the solvent was removed on a 25g silica gel cartridge: purified (EtOAc / hexanes 0-20%) to afford the vinyl contamination of the byproduct product. The product was dissolved in EtOAc (4 mL) EtOAc (EtOAc) (EtOAc) The reaction mixture was stirred at room temperature for 3 days, and diluted with EtOAc, washed with water, NH ₄ Cl, washed with brine, dried (MgSO ₄₎ and purified by silica gel flash chromatography to give benzoic acid (R) - (4,4- Difluoro-2-methyltetrahydro-2H-piperidin-2-yl)methyl ester (0.48 g, 63%). ¹ H NMR (400MHz, CHLOROFORM -d) ppm 8.13-8.04 (m, 2H ), 7.60 (tt, J = 7.4,1.3Hz, 1H), 7.52-7.39 (m, 2H), 4.42-4.34 (m, 1H ), 4.24 (d, J = 11.5 Hz, 1H), 4.00 - 3.84 (m, 2H), 2.21-1.93 (m, 4H), 1.46-1.36 (m, 3H).

(R)-(4,4-difluoro-2-methyltetrahydro-2H-pyran-2-yl)methyl benzoate (0.45 g, 1.665 mmol) in THF (5 mL) MeOH (4 mL) A mixture of sodium hydroxide (4 mL, 4.00 mmol) was stirred at room temperature for 5 hr. The reaction mixture was diluted with diethyl ether, and washed with 1N NaOH, washed with brine, dried (MgSO _4), solvent was removed to give the product as a liquid (0.22g, 80%). ¹ H NMR (400MHz, CHLOROFORM -d) ppm 3.92-3.84 (m, 2H ), 3.50-3.37 (m, 2H), 2.27-2.09 (m, 1H), 2.08-1.78 (m, 3H), 1.27-1.21 (m, 3H).

a solution of (R)-(4,4-difluoro-2-methyltetrahydro-2H-pyran-2-yl)methanol (0.22 g, 1.324 mmol) in acetone (10 mL) Jones reagent (1.1 mL, 2.75 mmol) was added. The reaction mixture was stirred in a bath for 18 hours and allowed to warm to room temperature during this. The mixture was diluted with EtOAc and EtOAc (EtOAc)EtOAc. ¹ H NMR (400 MHz, chloroform-d) ppm 4.15 - 3.91 (m, 2H), 2.78 - 2.64 (m, 1H), 2.11-1.88 (m, 3H), 1.56 (s, 3H).

Cap Y-12

n-Butyllithium (2.9 mL, 7.25 mmol) was added dropwise to a solution of DIPEA (1.220 mL, 8.56 mmol) in 10 mL THF over EtOAc. . The reaction mixture was re-cooled in a EtOAc (EtOAc) (EtOAc). The resulting solution was stirred at -78 ° C for 0.5 hours. A solution of N-fluorobenzenesulfonimide (2.249 g, 7.13 mmol) in THF (15 mL) was added dropwise over 5 min. The reaction mixture was stirred in a bath for 18 hours and allowed to warm to room temperature during this. The reaction mixture was diluted with EtOAc, and washed with saturated aqueous NH ₄ Cl (2 ×), water, brine, dried (MgSO _4), removed the solvent and purified on a 25g silica gel cartridge to give the product (0.8g, 60%). ¹ H NMR (400MHz, CHLOROFORM -d) ppm 4.75 (t, J = 1.5Hz, 2H), 4.26 (q, J = 7.3Hz, 2H), 2.49-2.37 (m, 2H), 2.32-2.23 (m, 2H), 2.16-2.06 (m, 2H), 2.05-1.82 (m, 2H), 1.37-1.30 (m, 3H).

a mixture of ethyl 1-fluoro-4-methylenecyclohexanecarboxylate (0.2 g, 1.074 mmol) in THF (5 mL), MeOH (4 mL) It was stirred for 5 h and was acidified with EtOAc (2×). Washed with brine the combined organic solvent was dried (MgSO _4), solvent was removed to afford the cap Y-12 (0.17g, 100% ). ¹ H NMR (500MHz, CHLOROFORM -d) ppm 4.77 (t, J = 1.5Hz, 2H), 2.49-2.35 (m, 2H), 2.35-2.27 (m, 2H), 2.22-2.13 (m, 2H), 2.09-1.88 (m, 2H).

Cap Y-13

Under N _2, a solution of 4-methylene-cyclohexanecarboxylic acid ethyl ester (2g, 11.89mmol) in diethyl ether (40 mL) in added portionwise a solution of LAH (0.5g, 13.17mmol). The reaction mixture was refluxed for 1 h and was carefully quenched with EtOAc EtOAc EtOAc. The reaction mixture was cooled and cooled, and 3 mL 1N NaOH was added and stirred for 5 min, and the solid was filtered and washed with diethyl ether. Washed with water, the filtrate was washed with brine, dried (MgSO _4), and the solvent removed to give (4-methylcyclohexyl) methanol.

To a solution of (4-methylenecyclohexyl)methanol (1.1 g, 8.72 mmol) in EtOAc (40 mL)EtOAc. The reaction mixture was stirred at 0 °C for 3 hours. The reaction mixture was diluted with EtOAc, and washed with aqueous ₂ S ₂ O ₃ Na, 1N NaOH, brine, and dried on 40g silica gel cartridge (MgSO _4): purified (EtOAc / hexanes 0-20%) to afford the product ( 0.53g, 24%). ¹ H NMR (400MHz, CHLOROFORM -d) ppm 3.94 (s, 2H ), 3.14 (s, 2H), 2.01-1.93 (m, 2H), 1.90-1.80 (m, 2H), 1.75-1.66 (m, 5H ).

Potassium acetate (1.5 g, 15.28 mmol) was added to a solution of 1-(iodomethyl)-2-oxabicyclo[2.2.2] octane (0.53 g, 2.102 mmol) in DMF (15 mL). The reaction mixture was stirred in a 110 ° C bath for 63 hours and at 125 ° C for 46 hours. The reaction mixture was diluted with ether, and washed with water (3 ×), washed with brine, dried (MgSO _4), solvent was removed to give the crude product (0.3g, 80%). The crude product was used directly in the next reaction. ¹ H NMR (400MHz, CHLOROFORM -d) ppm 3.96-3.92 (m, 2H ), 3.90 (s, 2H), 2.11 (s, 3H), 2.00-1.77 (m, 4H), 1.75-1.49 (m, 5H ).

To a solution of 2-oxabicyclo[2.2.2]oct-1-ylmethyl acetate (0.3 g, 1.628 mmol) in EtOAc (4 mL) The reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated and partitioned between diethyl ether and water. Washed with water, the organic solution was washed with brine, dried (MgSO _4), and the solvent removed to give the product (0.23g, 79%). The crude product was used in the next reaction.

To a solution of 2-oxabicyclo[2.2.2]oct-1-ylmethanol (0.23 g, 1.617 mmol) in EtOAc (4 mL) EtOAc. The reaction mixture was stirred in a bath and allowed to warm to room temperature during the process. The reaction mixture was stirred for 18 h and diluted with EtOAc EtOAc EtOAc EtOAc (EtOAc) . ¹ H NMR (400MHz, CHLOROFORM -d) ppm 4.07-4.00 (m, 2H ), 2.52 (dt, J = 14.7,5.6Hz, 2H), 2.47-2.33 (m, 2H), 2.34-2.19 (m, 2H ), 2.20 - 1.65 (m, 3H).

Cap Y-14

Add Deoxo-Fluor® (1.0 ml, 5.42 mmol) to a solution of methyl 4-carboxymethylcyclohexanecarboxylate (0.37 g, 2.174 mmol) in DCM (5 mL). 0.086 mmol). The resulting yellowish solution was stirred at room temperature for 18 hours. The reaction mixture was partitioned between EtOAc and ₃ saturated NaHCO. , Dried with saturated NaHCO _3, washed with water, brine and the organic phase was dried over anhydrous MgSO _4, filtered and concentrated to dryness to give a yellow oil, 25g on a silica gel column: purified (EtOAc / hexane 0-50%), A product is obtained in the form of a mixture of the same formula and trans.

To a solution of methyl 4-(difluoromethyl)cyclohexanecarboxylate (0.18 g, <RTI ID=0.0></RTI><RTIID=0.0> The reaction mixture was stirred at rt EtOAc (3 mL). The aqueous layer was acidified to pH < 2 and extracted with EtOAc. Dried (MgSO ₄₎ extracts were dried and concentrated to afford Cap Y-14 (0.12g, 72% ). ¹ H NMR (500 MHz, chloroform-d) mp. 5.96 - 5.40 (m, 1H).

Cap N-9

n-BuLi/hexane (9.29 mL, 23.22 mmol) was added dropwise to a solution of diisopropylamine (3.31 mL, 23.22 mmol) in THF (5 mL). The reaction mixture was stirred at -78 °C for 5 min and then stirred in an ice-bath for 20 min. A solution of isobutyric acid (1.055 mL, 11.61 mmol) in THF (5 mL) was added dropwise at EtOAc. The reaction mixture was stirred at 0 ° C for 30 minutes and at 60 ° C for 2 hours. The flask was again cooled to 0 ° C, and a solution of 2-fluorobenzaldehyde (1.441 g, 11.61 mmol) in THF (5 mL). The solution was then allowed to warm to room temperature and stirred for 16 hours. The reaction was quenched with 1N EtOAc to EtOAc (EtOAc). The combined organic layers were washed with 1 N NaOH. The combined basic washes were acidified with EtOAc and EtOAc evaporated. The organic phase was washed with a saturated then NaCl, dried over anhydrous MgSO ₄ and concentrated to give 3- (2-fluorophenyl) -3-hydroxy-2,2-dimethyl-propionic acid (1.5g, 60.9% yield) as Cap N-9. ¹ H NMR (400 MHz, DMSO-d ₆ ) ppm 7.50 (td, J = 7.5, 1.8 Hz, 1H), 7.32 (tdd, J = 7.7, 5.4, 1.8 Hz, 1H), 7.22 (td, J = 7.5, 1.0 Hz, 1H), 7.14 (ddd, J = 10.5, 8.3, 1.3 Hz, 1H), 5.28-5.11 (m, 1H), 3.33 (br.s., 1H), 1.06-0.97 (m, 3H), 0.93 (d, J = 2.8 Hz, 3H).

Cap N-10

Cap N-10 was prepared in a similar manner starting from 2-methoxybenzaldehyde isobutyric acid according to the procedure described for the preparation of cap N-9. ¹ H NMR (400 MHz, DMSO-d ₆ ) ppm 7.40 (dd, J = 7.5, 1.8 Hz, 1H), 7.28-7.18 (m, 1H), 7.00-6.89 (m, 2H), 5.47-5.35 (m, 1H), 3.80 (d, J = 5.5 Hz, 3H), 1.00-0.94 (m, 3H), 0.92-0.79 (m, 3H).

Cap N-11

n-BuLi/hexane (3.38 mL, 8.44 mmol) was added dropwise to a solution of diisopropylamine (1.203 mL, 8.44 mmol) in THF (10 mL). The reaction mixture was stirred in a bath for 5 minutes and then stirred in an ice bath for 30 minutes. A solution of tributyl butyl propanecarboxylate (1 g, 7.03 mmol) in THF (5 mL) was added dropwise to the reaction mixture at -78. The reaction mixture was stirred at -78 °C for 2 hours. A solution of benzaldehyde (0.746 g, 7.03 mmol) in THF (2 mL) was added dropwise at -78. The solution was then allowed to warm to room temperature and stirred for 1 hour. Quenched with NH ₄ Cl The reaction was then diluted with EtOAc. Followed by saturated NaHCO _3, water, the organic phase was washed with saturated NaCl, dried over anhydrous Na ₂ SO _4, and concentrated to give an oil. The crude material was purified by EtOAc (EtOAc) elute elut Yield). ¹ H NMR (400MHz, CHLOROFORM -d) ppm 7.48-7.40 (m, 2 H), 7.38-7.23 (m, 3 H), 4.70 (d, J = 7.5Hz, 1 H), 3.55 (d, J = 7.8 Hz, 1 H), 1.43-1.33 (m, 10 H), 1.17 (ddd, J = 9.6, 6.6, 3.9 Hz, 1 H), 0.99-0.79 (m, 2 H).

To a solution of 1-(hydroxy(phenyl)methyl)cyclopropanecarboxylic acid in the butyl ester (0.56 g, 2.255 mmol) in THF (4 mL) MeOH (1 mL) ). The reaction mixture was stirred at room temperature for 12 hours. And extracted with 1N HCl The reaction was diluted with 2 × EtOAc, washed with saturated NaCl and of the combined organic phase was dried (anhydrous Na ₂ SO _4), filtered, and concentrated to give 1- (hydroxy (phenyl) methyl) ring Propanecarboxylic acid (0.35 g, 81% yield) was taken as cap N-11. ¹ H NMR (400MHz, CHLOROFORM -d) ppm 7.48-7.26 (m, 5 H), 4.94 (s, 1 H), 1.46 (ddd, J = 9.8,7.0,4.3Hz, 1 H), 1.38-1.30 ( m, 1 H), 1.08 (ddd, J = 9.5, 7.1, 4.3 Hz, 1 H), 0.93-0.84 (m, 1 H).

Cap N-12

To a solution of diisopropylamine (1.675 mL, 11.75 mmol) in THF (10 mL), EtOAc (EtOAc) The reaction mixture was stirred in a bath for 5 minutes and then stirred in an ice bath for 30 minutes. A solution of methyl isobutyrate (1 g, 9.79 mmol) in THF (5 mL) was added dropwise at -78 °C. The reaction mixture was stirred at -78 °C for 2 hours. A solution of pyridinecarboxaldehyde (1.258 g, 11.75 mmol) in THF (2 mL) was added dropwise at -78. The solution was then allowed to warm to room temperature and stirred for 1 hour. Quenched with NH ₄ Cl The reaction was then diluted with EtOAc. Followed by saturated NaHCO _3, water, the organic phase was washed with saturated NaCl, dried over anhydrous Na ₂ SO _4, and concentrated to give an oil. The crude material was purified by EtOAc (EtOAc/EtOAc) elute Ester (1.0 g). ¹ H NMR (400MHz, CHLOROFORM -d) ppm 8.61-8.44 (m, 1 H), 7.66 (td, J = 7.7,1.8Hz, 1 H), 7.26-7.12 (m, 2 H), 4.96 (d, J = 7.5 Hz, 1 H), 4.67 (d, J = 7.5 Hz, 1 H), 3.74 (s, 3 H), 1.18 (s, 3 H), 1.10 (s, 3 H).

By solvent HPLC (chiralpak AD, 21 × 250 mm, 10 μ, UV = 254 nm, flow rate = 15 mL / min, 30% B, etc. for 17 minutes, solvent A: 0.1% diethylamine / heptane, solvent B: 100% ethanol) Separation of methyl 3-hydroxy-2,2-dimethyl-3-(pyridin-2-yl)propanoate (0.42 g) gave two enantiomers. Enantiomer 1: RT = 6.071 min, enantiomer 2: RT = 9.356 min. Each enantiomer was subjected to NaOH hydrolysis to obtain caps N-12A and N-12B, respectively.

Cap N-13

Cap N-13 was prepared in a similar manner starting from 2-methoxybenzaldehyde isobutyric acid and 1-methyl-1H-pyrazole-5-carbaldehyde according to the procedure described for the preparation of cap N-11.

Cap P-26

A solution of methyl 2-methoxypropionate (177 mg, 1.5 mmol) in THF (1 mL) was added to diisopropylamine (0.212 mL, 1.50 mmol) Lithium (0.60 mL, 1.50 mmol) of a solution of LDA in THF (2 mL). The mixture was gradually warmed to -20 ° C over 1 h then cooled to -78 ° C then EtOAc EtOAc (EtOAc) The mixture was allowed to warm to room temperature over 2 hours and stirred overnight. With sat NaHCO ₃ (5mL) The reaction was quenched, diluted with DCM (10mL). The organic layer was separated, washed with water, brine and dried (MgSO _4). Evaporation of the solvent afforded EtOAc (EtOAc (EtOAc (EtOAc)) In the steps.

Will be pure BF ₃ . OEt ₂ (0.152 mL, 1.200 mmol) was added dropwise to 4,4-difluorocyclohexanone (0.134 g, 1 mmol) and tert-butyl ((1,2-dimethoxyprop-1-ene-1) To a stirred solution of dimethyl oxane (0.311 g, 1.338 mmol) in dry EtOAc (EtOAc) The reaction was _quenched with saturated NaHCO, diluted with DCM (10mL). The organic layer was separated, washed with water, brine and dried (MgSO _4). Evaporation of the solvent gave EtOAc (EtOAc: EtOAc Compound: Methyl cyclohexyl)-2-methoxypropionate (177 mg). ¹ H NMR (500MHz, CHLOROFORM -d) δ ppm 3.79 (s, 3H), 3.34 (s, 3H), 2.89 (br.s., 1H), 2.26-2.03 (m, 2H), 2.00-1.91 (m , 2H), 1.87-1.60 (m, 4H), 1.45 (s, 3H).

A small sample of the methyl ester (about 37 mg) was saponified (LiOH.H ₂ O, MeOH-THF-water) to afford to afford a pale white semi-solid. ¹ H NMR (500MHz, CHLOROFORM -d) δ ppm 3.40 (s, 3H), 2.25-2.06 (m, 2H), 2.05-1.95 (m, 2H), 1.94-1.67 (m, 4H), 1.47 (s, 3H).

Cap P-27

A solution of Deoxo-Fluor® (0.737 mL, 4.00 mmol) in DCM (4 mL) was added to (3as,6as)-tetrahydrocyclopentadiene-2,5(1H,3H)-dione (276 mg, 2 mmol) in a cold (0 ° C) solution in DCM (20 mL), followed by a catalytic amount of EtOH (0.035 mL, 0.600 mmol). The resulting yellowish solution was stirred at room temperature overnight. With saturated aqueous NaHCO ₃ The reaction was quenched, and the mixture was extracted with DCM (2 ×). Washed with water, brine, and the combined organic layers were dried (MgSO _4), filtered and dried to give a yellow - orange oil. The desired difluorinated monoketone (3aR,6aS)-5,5-difluorohexahydrocyclopentadienyl-2(1H)-one was obtained as a colorless oil by separation of EtOAc (DCM).

Will be pure BF ₃ . OEt ₂ (0.104 ml, 0.819 mmol) was added dropwise to (3aR,6aS)-5,5-difluorohexahydrocyclopentadienyl-2(1H)-one (82 mg, 0.512 mmol) and ((1- Methoxy-2-methylprop-1-en-1-yloxy)trimethyldecane (198 mg, 1.024 mmol) in cold (-78 ° C) The mixture was gradually warmed to room temperature and stirred overnight. With sat NaHCO ₃ (5mL) The reaction was quenched, diluted with DCM (10mL), the organic layer was separated, and washed with 0.25M HF solution, water, brine and dried (MgSO _4). The solvent was evaporated to give abr. EtOAc (EtOAc). The main isomer of 2-((2s,3aR,6aS)-5,5-difluoro-2-hydroxy octahydrocyclopentadien-2-yl)-2-methylpropane was isolated as a colorless oil. Methyl ester.

Methyl 2-((3aR,6aS)-5,5-difluoro-2-hydroxyoctahydrocyclopentadien-2-yl)-2-methylpropanoate (58 mg, 0.221 mmol) and monohydrate Lithium hydroxide (27.8 mg, 0.663 mmol) was heated in THF (0.5 mL), MeOH (0.5 mL) and water (0.5 mL). Acid treatment and EtOAc extraction gave cap P-27 as a white solid.

Cap P-28 and P-29

A solution of zinc (0.981 g, 15.01 mmol) in cyclohexanone (0.491 g, 5.0 mmol) and ethyl 2-bromo-2,2-difluoroacetate (2.031 g, 10.01 mmol) in anhydrous THF (5 mL) The stirred suspension is sonicated for 4-5 hours, then heated to reflux for 1-2 hours. The reaction mixture was cooled and diluted with diethyl ether, and washed with 1N HCl, saturated NaHCO _3, water, brine and dried (MgSO _4). Evaporation of the solvent to give the title compound mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj Ethyl acetate (770 mg, ca. 70%). ¹ H NMR (500MHz, CHLOROFORM -d) δ ppm 4.37 (q, J = 7.2Hz, 2H), 2.10-2.01 (m, J = 3.4Hz, 1H), 1.82-1.69 (m, 3H), 1.68-1.54 (m, 6H), 1.38 (t, J = 7.2 Hz, 3H), 1.20 (br.s, 1H).

Ethyl ester was saponified (1 N NaOH, THF-MeOH, EtOAc). ¹ H NMR (500 MHz, chloroform-d) δ 4.34 (br.s., 2H), 1.89-1.53 (m, 8H), 1.32-1.17 (m, 1H).

60% NaH (88 mg, 2.204 mmol) was added to a cold (0 ° C) solution of cap P-28 (194.5 mg, 1.002 mmol) in THF (2 mL), and the mixture was stirred for about 30 minutes, followed by the addition of dimethyl sulfate Ester (0.227 mL, 2.404 mmol). The mixture was allowed to warm to room temperature and stirred overnight. The crude product was purified by silica gel FCC (DCM) to afford methyl 2,2-difluoro-2-(1-methoxycyclohexyl)acetate as a clear oil. ¹ H NMR (500MHz, CHLOROFORM -d) δ ppm 3.90 (s, 3H), 3.39 (t, J = 1.7Hz, 3H), 2.04-1.97 (m, 2H), 1.73-1.66 (m, J = 13.0, 1.5, 1.5 Hz, 1H), 1.66-1.59 (m, J = 8.5, 2.7 Hz, 2H), 1.54-1.44 (m, 4H), 1.27-1.17 (m, J = 12.8 Hz, 1H).

The methyl ester intermediate was saponified (1 N NaOH, THF-MeOH, EtOAc) to afford to afford a white solid.

Cap P-30

Cap P-31

Cap P-32

Caps P-30, P-31, and P-32 were prepared by the method described in Cap P-28.

Cap P-33

Add 10% Pd-C (80 mg, 0.753 mmol) to methyl 2-((benzyloxy)methyl)tetrahydrofuran-2-carboxylate (377 mg, 1.506 mmol) in a pad shaker under nitrogen. It was hydrogenated overnight at 30 psi in MeOH (20 mL). The suspension was filtered, and the filtrate was evaporated to dry crystal crystal crystal crystal crystal crystal crystal crystal ¹ H NMR (500MHz, CHLOROFORM -d) δ ppm 4.10-3.98 (m, 2H), 3.85 (d, J = 11.4Hz, 1H), 3.78 (s, 3H), 3.69 (d, J = 11.4Hz, 1H ), 2.19-2.12 (m, 1H), 2.09-2.02 (m, 1H), 2.01-1.93 (m, 2H).

A pure stirred mixture of Deoxo-Fluor® (800 mg, 1.808 mmol) and 4,4-difluoro-1-(hydroxymethyl)cyclohexanecarboxylate (224 mg) was heated at 70 ° C overnight. The reaction was cooled to room temperature and quenched with ice and extracted with DCM, washed with saturated NaHCO _3, water, brine and dried (MgSO _4). The DCM was evaporated to give EtOAc (EtOAc md. 184 mg, 82%).

Will LiOH. H ₂ O (42mg, 1mmol) in water (0.5mL) was added to a solution of the 4,4-difluoro-1- (fluoromethyl) cyclohexanecarboxylic acid ethyl ester (180mg, 0.80mmol) in THF (1mL) In a solution of MeOH (1 mL), and the mixture was stirred at room temperature overnight. After the acid treatment, the product was extracted with EtOAc, washed with brine and dried (MgSO _4). The solvent was evaporated to give a cap P-33 as a white solid.

Cap P-34

Zinc (294 mg, 4.50 mmol) in 2-ethyloxypropanoate (348 mg, 3 mmol) and 3-bromo-3,3-difluoroprop-1-ene (565 mg, 3.60 mmol) in dry THF (3 mL The stirred suspension in the solution was sonicated for about 30 minutes, followed by heating at 40 °C overnight. The reaction mixture was cooled with EtOAc EtOAc m. The layers were separated, and washed with water, saturated NaHCO _3, washed with water, brine and the organic phase was dried (Na ₂ SO _4). The crude product was purified by silica gel FCC (DCM) to afford ethyl 3,3-difluoro-2-hydroxy-2-methylpent-4-enoate as a clear oil.

Add 60% NaH (48.5 mg, 1.212 mmol) to ethyl 3,3-difluoro-2-hydroxy-2-methylpent-4-enoate (214 mg, 1.102 mmol) in DMF (2 mL) (-20 ° C) in the solution, and the mixture was allowed to warm to room temperature (about 30 minutes), followed by 3-bromoprop-1-ene (0.113 mL, 1.323 mmol). The mixture was stirred at room temperature overnight, diluted with ether (20 mL), and washed with water, brine and dried (MgSO _4). The crude product was purified by silica gel FCC (2:1 DCM-hexane) to give 2-(allyloxy)-3,3-difluoro-2-methylpent-4-enoate as a clear oil. ester.

Ethyl 2-(allyloxy)-3,3-difluoro-2-methylpent-4-enoate (165 mg, 0.704 mmol) and Grubbs II (29.9 mg, 0.035 mmol) in DCM (20 mL) The stirred degassed solution was stirred overnight at room temperature. Evaporation of the reaction mixture to dryness eluting with EtOAc EtOAc EtOAc Ethyl 2-carboxylate (about 138 mg, 95%). ¹ H NMR (500MHz, CHLOROFORM -d) δ ppm 6.26-6.20 (m, J = 10.5,2.4,2.4Hz, 1H), 5.96-5.87 (m, 1H), 4.57-4.48 (m, 1H), 4.36- 4.26 (m, 3H), 1.60 (s, 3H), 1.33 (t, J = 7.2 Hz, 3H).

10% Pd-C (37.5 mg, 0.035 mmol) in ethyl 3,3-difluoro-2-methyl-3,6-dihydro-2H-pyran-2-carboxylate in EtOAc (10 mL) The stirred suspension in the solution was hydrogenated under balloon pressure for 1 hour. The suspension was filtered and evaporated to dryness crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal ¹ H NMR (400MHz, CHLOROFORM -d) δ ppm 4.35-4.24 (m, 2H), 3.89-3.80 (m, 1H), 3.78-3.69 (m, 1H), 2.34-2.09 (m, 2H), 2.03- 1.90 (m, 1H), 1.85-1.75 (m, 1H), 1.57-1.51 (m, J = 1.5, 0.5 Hz, 3H), 1.34 (t, J = 7.2 Hz, 3H).

The ethyl ester intermediate was dissolved in THF (2 mL) and MeOH (1. 5 mL) and EtOAc (EtOAc) hour. The reaction mixture was evaporated, EtOAc (EtOAc m. ¹ H NMR (500MHz, CHLOROFORM -d) δ ppm 3.96-3.89 (m, 1H), 3.88-3.80 (m, 1H), 2.29-2.18 (m, 1H), 2.17-2.07 (m, 1H), 2.00- 1.87 (m, 2H), 1.64 (t, J = 1.2 Hz, 3H).

Cap P-35

Pure 1,2-dibromoethane (0.094 g, 0.500 mmol) was added to a suspension of zinc (1.308 g, 20.00 mmol) in THF (7 mL). The reaction mixture was sonicated for 3 hours and cooled to room temperature, and titanium dichloride (0.062 g, 0.250 mmol) was added and stirred for 10-15 minutes. A solution of tetrahydro-2H-pipetan-2-one (0.501 g, 5 mmol) in EtOAc (3 mL) A solution in THF (3 mL) and the mixture was stirred at room temperature overnight. Cooled (0 deg.] C) and the reaction was diluted with ether and with 1N HCl, water, brine and dried (MgSO _4). Evaporation of the solvent gave EtOAc (EtOAc md. Ethyl 2H-piperidin-2-yl)acetate (365 mg, 32.5%). Ethyl 2,2-difluoro-2-(2-hydroxytetrahydro-2H-piperidin-2-yl)acetate (about 200 mg), triethyldecane (0.799 mL, 5.00 mmol) and TFA (0.385 mL) , 5.00 mmol) of the pure mixture was heated at 60 ° C for 3 hours and evaporated to dryness to give crystals, which was purified from EtOAc (EtOAc) Ethyl 2-(tetrahydro-2H-pyran-2-yl)acetate (145 mg, 78%) eluted eluted elute (75 mg, 83%). ¹ H NMR (500MHz, CHLOROFORM -d) δ ppm 7.35-7.13 (m, 1H), 4.14-4.05 (m, J = 11.2,4.3Hz, 1H), 3.95-3.82 (m, 1H), 3.57-3.47 ( m, J =11.7, 11.7, 2.3 Hz, 1H), 2.05-1.94 (m, 1H), 1.86-1.76 (m, 1H), 1.73-1.50 (m, 4H).

Cap P-36

A solution of zinc (0.981 g, 15.00 mmol) in benzaldehyde (0.531 g, 5 mmol) and ethyl 2-bromo-2,2-difluoroacetate (1.522 g, 7.50 mmol) in anhydrous THF (10 mL) The stirred suspension was sonicated for 4-5 hours, followed by stirring at room temperature overnight. The reaction was cooled and diluted with diethyl ether and with 1N HCl, water, brine and dried (MgSO _4). The solvent was evaporated to give aq.qqqqqqqqqqq Ethyl propionate (619 mg, ca. 54%). ¹ H NMR (500MHz, CHLOROFORM -d) δ ppm 7.49-7.44 (m, 2H), 7.43-7.39 (m, 3H), 5.23-5.12 (m, J = 15.3,8.0,5.5Hz, 1H), 4.32 ( q, J = 7.1 Hz, 2H), 2.87-2.76 (m, 1H), 1.31 (t, J = 7.2 Hz, 3H).

The ethyl ester intermediate was saponified (LiOH.H ₂ O, THF-MeOH-water) to afford a cap P-36 as a white solid. ¹ H NMR (500 MHz, chloroform-d) δ δ </ RTI></RTI></RTI> 7.52 - 7.47 (m, 2H), 7.46 - 7.41 (m, 3H), 5.22 (dd, J = 16.0, 7.2 Hz, 1H).

Cap P-37

60% NaH (0.233 g, 5.81 mmol) was added to a cold (0 ° C) solution of thiophenol (0.566 mL, 5.54 mmol) in DMSO (6 mL) and the mixture was warmed to room temperature over 30 min. Then, pure ethyl 2-bromo-2,2-difluoroacetate (1.236 g, 6.09 mmol) was added, and the mixture was stirred at room temperature overnight. With saturated NH ₄ Cl The reaction was quenched and extracted with diethyl ether, washed with water, brine and dried (MgSO _4). The crude isolate was purified by silica gel FCC (1:1 DCM-hexane) to afford ethyl 2,2-difluoro-2-(phenylthio)acetate (1.076 g, 84%) as a clear oil: ¹ H NMR (500MHz, chloroform-d) δ 7.67-7.62 (m, 2H), 7.52-7.46 (m, 1H), 7.45-7.39 (m, 2H), 4.27 (q, J = 7.2 Hz, 2H), 1.28 (t, J = 7.2 Hz, 3H).

The ethyl ester intermediate was saponified (1N NaOH, MeOH-THF) to afford abr. ¹ H NMR (500 MHz, chloroform-d) δ δ δ δ δ δ δ δ δ δ δ δ δ δ δ δ δ δ δ δ δ δ 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。

Cap P-38

Pure dibromo (16.78 g, 105 mmol) was added dropwise to the stirred mixture of ε-caprolactone (11.41 g, 100 mmol) and tribromophosphine (0.05 ml, 100 μmol) at 100 ° C while Br ₂ The rate of addition kept the pot temperature below 120 °C. Heating is continued until HBr stops releasing. The crude mixture was cooled with EtOAc (EtOAc)EtOAc. Excess MeOH was evaporated, and washed with 1: 1 ether - hexanes residue was extracted and dried over MgSO _4, concentrated and distilled under reduced pressure, to give a clear oil of 2,6-dibromo-hexanoate (about 1 Torr, boiling point 75-80 ° C).

To a solution of methyl 2,6-dibromohexanoate (1440 mg, 5 mmol) in DMSO (5 mL), EtOAc. The reaction was quenched with water, and extracted with diethyl ether, washed with water, brine and dried (MgSO _4). The crude isolate was purified by silica gel FCC (DCM) to give methyl 2-(ethyithio)-6-bromohexanoate as a clear oil.

Potassium pure methanol (133 mg, 1.893 mmol) was added to a solution of methyl 2-(ethyithio)-6-bromohexanoate (536 mg, 1.893 mmol) in anhydrous THF (18 mL) The mixture was stirred under nitrogen for 2 days. The crude isolate was purified by silica gel FCC (DCM) to afford methyl 4-hydro-2H-thiopyran-2-carboxylate as a clear oil, which was saponified (1N NaOH, MeOH-THF) to afford cap P- 38.

Cap P-39

Ethyl 2-bromo-2-methylpropanoate (0.975 g, 5 mmol), cyclohexylamine (0.496 g, 5.00 mmol), potassium carbonate (1.382 g, 10.00 mmol) and sodium iodide (0.600 g, 4.00 mmol) The stirred suspension in acetonitrile (10 ml) was heated at 90 ° C overnight under nitrogen. The reaction mixture was cooled, filtered and evaporated to dryness crystals crystals crystalsssssssssssssssssssssssssssss , about 20%). ¹ H NMR (500MHz, CHLOROFORM -d) δ ppm 4.16 (q, J = 7.2Hz, 2H), 2.38-2.29 (m, 1H), 1.86-1.78 (m, 2H), 1.74-1.67 (m, J = 13.5, 3.4, 3.4 Hz, 2H), 1.66-1.55 (m, 2H), 1.31 (s, 6H), 1.30-1.27 (m, 3H), 1.27-1.19 (m, 2H), 1.15- 1.04 (m, 2H).

The ethyl ester intermediate was hydrolyzed by refluxing for 3 hours in concentrated hydrochloric acid, followed by evaporation to dryness to afford cap P-39. ¹ H NMR (500MHz, CHLOROFORM -d) δ ppm 3.02 (br.s., 1H), 2.27-2.17 (m, 2H), 1.89-1.83 (m, 2H), 1.83-1.78 (m, 1H), 1.76 (s, 6H), 1.73-1.63 (m, 2H), 1.34-1.16 (m, 4H).

Cap P-40

Add 1 M solution of potassium tert-butoxide (3.00 mL, 3.00 mmol) in THF to 2-bromo-N-(t-butyl)-2-methylpropanamide (0.666 g, 3 mmol) in dry diethyl ether (30 ° C) was cooled (0 ° C) in a stirred solution, and the mixture was stirred at 0 ° C for 2-3 hours. A second equivalent of potassium third butoxide (3.00 mL, 3.00 mmol) was then added and the mixture was warmed to room temperature and stirred overnight. With saturated NH ₄ Cl The reaction was quenched, and the organic layer was separated and washed with water, brine and dried (Na ₂ SO _4). The crude isolate was purified by EtOAc (EtOAc EtOAc) &lt; ¹ &gt ^; H NMR (500 MHz, chloroform-d) &lt ^; RTI ID=0.0&gt ^; &gt ^; &gt;

The third butyl ester intermediate was dissolved in DCM and treated with TFA for 1 hour then evaporated to dryness to afford cap P-40. ¹ H NMR (500 MHz, chloroform-d) δ mp. 1.98 - 1.92 (m.p., s.

Cap P-41

In a Parr shake flask, 10% Pd-C (45.8 mg, 0.043 mmol) in (R)-2-methyl-3,4-dihydro-2H-pentan-2-carboxylic acid benzyl ester (200 mg) The stirred suspension in a solution of EtOAc (10 mL) was hydrogenated at 50 psi overnight. Filter the suspension and Evaporation to dryness gave a cap P-41 as a clear oil.

Cap P-42

In a stainless steel Hoke cylinder, by stirring a solution of 2-ethyloxymalonate (5 g, 28.7 mmol) and a little BHT crystals in acetonitrile (50 mL) (-60 ° C) The butadiene-1,3-diene (9.68 g, 179 mmol) gas was condensed. The cylinder was capped and sealed and heated at 140 °C for 24 hours. The reaction mixture was cooled to room temperature and concentrated to half volume, then 25 mL of ethanol was added. The solid which precipitated was filtered off, and the filtrate was evaporated to dryness to crystals crystals crystalsssssssssssssssssssssssssss , 2(3H,6H)-dicarboxylic acid diethyl ester. ¹ H NMR (400MHz, CHLOROFORM -d) δ ppm 5.85 (ddt, J = 10.3,4.0,2.0Hz, 1H), 5.77-5.67 (m, 1H), 4.45-4.37 (m, 2H), 4.35-4.23 ( m, 4H), 2.76-2.67 (m, 2H), 1.33-1.28 (m, 6H).

10% Pd-C (0.511 g, 0.480 mmol) in EtOAc (50 mL) EtOAc. The stirred suspension was hydrogenated under balloon pressure for 3 hours. The suspension was filtered, and the filtrate was evaporated to dryness to give diethyldichloro-2H-pyran-2,2-dicarboxylate as a clear oil. ¹ H NMR (400MHz, CHLOROFORM -d) δ ppm 4.33-4.24 (m, 4H), 3.88-3.81 (m, 2H), 2.15-2.08 (m, 2H), 1.79-1.69 (m, 2H), 1.67- 1.57 (m, 2H), 1.33-1.28 (m, 6H).

1M hydrogenated lithium tri-butoxide aluminum lithium solution (8.79 mL, 8.79 mmol) was added dropwise to tetrahydro-2H-pyran-2,2-dicarboxylic acid diethyl ester (0.810 g, 3.52 mmol) in dry THF The cold (0 ° C) in (9 mL) was stirred in the solution. After the addition was complete, the mixture was allowed to warm to room temperature and heated to reflux for 4-5 hours. The reaction mixture was cooled, diluted with ether, and washed with 20% NaHSO ₄ solution was quenched with vigorous stirring. The organic layer was separated, washed with brine and dried over MgSO _4. The crude isolate was purified by EtOAc (EtOAc EtOAc) ¹ H NMR (400 MHz, chloroform-d) δ ppm 4.29 (q, J = 7.0 Hz, 2H), 3.95-3.87 (m, 2H), 3.71 (dd, J = 11.2, 8.2 Hz, 1H), 3.62 (dd , J =11.2, 5.1 Hz, 1H), 2.24 - 2.16 (m, J = 8.0, 5.3 Hz, 1H), 2.14 - 2.06 (m, 1H), 1.84-1.72 (m, 1H), 1.64-1.50 (m , 4H), 1.37-1.29 (m, 3H).

Ethyl 2-(hydroxymethyl)tetrahydro-2H-pentan-2-carboxylate (52 mg, 0.276 mmol) and lithium hydroxide monohydrate (39 mg, 0.929 mmol) in THF (1 mL) The solution was sonicated in water (0.5 mL) for 1-2 hours. The solvent was evaporated, and the (0.5mL) aqueous residue was acidified with 6N HCl and extracted with EtOAc, washed with brine and dried (MgSO _4). The solvent was evaporated to give a cap P-42 in the form of a viscous oil. ¹ H NMR (400 MHz, chloroform-d) δ ppm 3.98-3.83 (m, 2H), 3.83- 3.69 (m, 2H), 2.38 (s, 1H), 2.16-2.05 (m, 1H), 1.79 (br. s., 1H), 1.66-1.47 (m, 4H).

Cap P-43

Pure Deoxo-Fluor® (342 mg, 1.546 mmol) was added to cold (0 ° C) stirred ethyl 2-(hydroxymethyl)tetrahydro-2H-pyran-2-carboxylate (194 mg, 1.031 mmol) And the mixture was heated overnight at 70 °C. The reaction was quenched with ice and saturated aqueous NaHCO ₃ solution and extracted with with DCM (2 ×). Washed with water, brine, and the combined organic layers were dried (MgSO _4), filtered and dried to give a yellow - orange oil, silicone by FCC (DCM 0-5% EtOAc containing it) The oil was purified to afford Ethyl 2-(fluoromethyl)tetrahydro-2H-pentan-2-carboxylate (125 mg, 63%) saponified (LiOH.H ₂ O, MeOH-THF-H ₂ O, sonic Treatment), a cap P-43 (82 mg, 77%) was obtained as a viscous oil. ¹ H NMR (400MHz, CHLOROFORM -d) δ ppm 4.66-4.54 (m, 1H), 4.54-4.41 (m, 1H), 4.02-3.84 (m, 2H), 1.98-1.84 (m, 1H), 1.84- 1.72 (m, 2H), 1.69-1.52 (m, 4H).

Cap P-44

Pure PCC was added to a solution of powdered 4Å molecular sieve (about 0.5g) in ethyl 2-(hydroxymethyl)tetrahydro-2H-pyran-2-carboxylate (165mg, 0.877mmol) in DCM (6mL) The stirred suspension was stirred and the mixture was stirred at room temperature for 5 hours. The suspension was filtered through a pad of EtOAc (EtOAc) elute elute ¹ H NMR (400MHz, CHLOROFORM -d) δ ppm 9.53 (s, 1H), 4.35-4.20 (m, 2H), 3.97-3.77 (m, 2H), 2.23-2.12 (m, 1H), 1.90-1.77 ( m, 1H), 1.77-1.69 (m, 1H), 1.64-1.56 (m, 3H), 1.32 (t, J = 7.2 Hz, 3H).

Add Pure Deoxo-Fluor® (196 mg, 0.886 mmol) to a solution of ethyl 2-carbazinotetrahydro-2H-pyran-2-carboxylate (55 mg, 0.295 mmol) in DCM (1 mL) The mixture was stirred overnight at room temperature. With ice cold saturated NaHCO ₃ The reaction was quenched and extracted with DCM, and washed with water, brine and dried (MgSO _4). The crude isolate was purified by silica gel FCC (DCM) to afford ethyl 2-(difluoromethyl)tetrahydro-2H-pyran-2-carboxylate as a clear oil. ¹ H NMR (500MHz, CHLOROFORM -d) δ ppm 5.70 (t, J = 1.0Hz, 1H), 4.33 (q, J = 7.2Hz, 2H), 4.03-3.93 (m, 1H), 3.73 (td, J = 12.1, 2.7 Hz, 1H), 2.26-2.17 (m, 1H), 1.91-1.80 (m, 1H), 1.73-1.62 (m, 2H), 1.59-1.47 (m, 2H), 1.38-1.30 (m , 3H).

The ethyl ester intermediate was saponified (LiOH.H ₂ O, MeOH-THF-H ₂ O, sonication) to give a cap P-44 as a viscous oil.

Cap P-45

Add 60% NaH (40.3 mg, 1.007 mmol) to ethyl 2-(hydroxymethyl)tetrahydro-2H-pyran-2-carboxylate (158 mg, 0.839 mmol) in THF (3 mL) °C) The solution was allowed to warm to room temperature over about 30 minutes. Pure dimethyl sulfate (127 mg, 1.007 mmol) was added at 0 ° C, and allowed to warm to room temperature and stirred overnight. TEA was quenched with an excess of dimethyl sulfate, and then acidified with 1N HCl, the product extracted with ether, washed with water, brine and dried (MgSO _4). The crude isolate was purified by EtOAc (EtOAc EtOAc) ¹ H NMR (400MHz, CHLOROFORM -d) δ ppm 4.34-4.22 (m, J = 7.2,7.2,7.2,4.1Hz, 2H), 3.96-3.87 (m, 1H), 3.86-3.77 (m, 1H), 3.55-3.43 (m, 2H), 3.36 (s, 3H), 2.17-2.07 (m, 1H), 1.80-1.70 (m, 1H), 1.69-1.56 (m, 2H), 1.55-1.42 (m, 3H) ), 1.32 (t, J = 7.2 Hz, 3H).

The ethyl ester intermediate was saponified (LiOH.H ₂ O, THF-MeOH-H ₂ O) to give a viscous oily cap P-45 (59 mg, 40%). ¹ H NMR (400MHz, CHLOROFORM -d) δ ppm 3.99-3.88 (m, 1H), 3.87-3.76 (m, 1H), 3.69-3.58 (m, 1H), 3.58-3.48 (m, 1H), 3.41 ( s, 3H), 2.16-2.02 (m, 1H), 1.80-1.69 (m, 1H), 1.67-1.47 (m, 4H).

Cap L-18

Cap L-18 step a

Was added dropwise in the benzyl ((tert-butoxy carbonyl) amino) cyclopropanecarboxylic acid (2,9.94mmol) and Et ₃ N (3.32mL, 23.85mmol) in DMF (40mL) solution of - 1 to Bromine (2.84 mL, 23.85 mmol), and the mixture was stirred at room temperature for 16 hr. After diluting with EtOAc (40 mL) EtOAc (EtOAc) With saturated NH ₄ Cl, washed with water and brine and the organic layers were combined, dried (MgSO _4), filtered and concentrated to give an off-white solid. The residue was purified by EtOAcqqqqqqqq _{^{1 H NMR (400MHz, CDCl 3}} ) δ 7.45-7.28 (m, 5H), 5.14 (s, 2H), 1.56 (br.s., 2H), 1.42 (br.s., 9H), 1.19 (br. s., 2H); ¹³ C NMR (101 MHz, CDCl ₃ ) δ 172.9, 155.9, 135.7, 128.5 (3C), 128.1, 127.9, 80.0, 67.0, 34.4, 28.2 (3C), 17.9 (2C).

Cap L-18 step b

HCl (7.77 mL, 31.1 mmol, 2N in dioxane) was added to a solution of EtOAc EtOAc (EtOAc m. 2 hours. The volatiles were removed under reduced pressure, and triturated with Et ₂ O remaining residue. Isolated as an off-white solid, corresponding to mp. ^{1 H NMR (400MHz, DMSO-} d 6) δ 9.11 (br.s., 3H), 7.47-7.30 (m, 5H), 5.20 (s, 2H), 1.54-1.47 (m, 2H), 1.46-1.39 (m, 2H); ¹³ C NMR (101 MHz, DMSO-d ₆ ) δ 169.5, 135.3, 128.5 (2C), 128.3, 127.9 (2C), 67.1, 33.6, 13.4 (2C).

Cap L-18 step c

Add 1-Ethoxy-2,2,2-trifluoroethanol (0.172 mL, 1.318 mmol) to Cap L-18 Step B hydrochloride (300 mg, 1.318 mmol) and MgSO ₄ (1063 mg, 8. In a suspension in DCM (10 mL), TFA (0.531 mL, 6.. The white suspension was then stirred at room temperature for 16 hours. Was added followed by NaCNBH ₃ (166mg, 2.64mmol) and stirring was continued for 3 hours. The reaction was filtered, the filtrate was washed and diluted with water (50mL) and brine (50mL) with EtOAc in (50mL), dried over MgSO _4, filtered, and concentrated in vacuo. A clear oil is recovered. The residue was purified by EtOAc (EtOAc) elute _{^{1 H NMR (400MHz, CDCl 3}} ) δ 7.45-7.30 (m, 5H), 5.15 (s, 2H), 3.44-3.30 (m, 2H), 2.45 (br.s., 1H), 1.40-1.34 (m , 2H), 1.16-1.10 (m, 2H); ¹⁹ F NMR (376MHz, CDCl ₃ ) δ -73.13 (s, 3F); ¹³ C NMR (101MHz, CDCl3) δ 174.8, 128.6 (2C), 128.3, 128.0 (2C), 125.0 (q, J = 278.2 Hz, 1C), 66.8, 49.5 (q, J = 32.4 Hz, 1C), 41.3, 18.1 (2C).

(, 0.366mmol 100mg) in the in MeOH (3mL) was added 10% Pd-C to cap benzyl L-18 step c (20mg, 0.019mmol), and the mixture was hydrogenated 1 atm H ₂ at 16 hours. The mixture was filtered and washed with MeOH. The combined filtrate was concentrated to dryness to give abr. ¹ H NMR (400 MHz, DMSO-d6) δ 3.38 (q, J =10.5 Hz, 2H), 1.16-1.10 (m, 2H), 0.91 (q, J = 3.8 Hz, 2H); ¹⁹ F NMR (376 MHz, DMSO-d ₆ ) δ -71.30 (br.s., 3F); ¹³ C NMR (101 MHz, DMSO-d ₆ ) δ 176.2, 125.7 (q, J = 276.7 Hz, 1 C), 48.5 (q, J = 30.8) Hz, 1C), 40.4, 17.0 (2C).

Cap L-19

Cap L-19 step a

Starting with (R)-1,1,1-trifluoropropan-2-ol and 1-aminocyclopropanecarboxylic acid ethyl ester hydrochloride by the procedure described for the synthetic cap L-6 step a Prepare cap L-19 step a. _{^{1 H NMR (500MHz, CDCl 3}} ) δ 5.46 (br.s., 1H), 5.29-5.18 (m, 1H), 4.16 (q, J = 6.9Hz, 2H), 1.57 (br.s., 2H) , 1.41 (d, J = 6.6 Hz, 3H), 1.30-1.12 (m, 5H); ¹⁹ F NMR (376 MHz, CDCl ₃ ) δ -79.02 (br.s., 3F); ¹³ C NMR (126 MHz, CDCl) ₃ ) δ 172.3, 154.7, 123.6 (q, J = 280.4 Hz, 1C), 67.6 (q, J = 34.3 Hz, 1C), 61.6, 34.6, 17.6 (br.s., 2C), 14.0, 13.7.

Cap L-19 step b

KOtBu (0.173 g, 1.538 mmol) was added to a solution of EtOAc EtOAc (EtOAc m. With saturated NaCO ₃ (10mL) The reaction was quenched, followed by (3 ×) mixture was extracted with Et ₂ O. Washed with brine the combined organic layers were dried (MgSO _4), filtered and concentrated. The residue was purified by EtOAc (EtOAc) elute _{^{1 H NMR (400MHz, CDCl 3}} ) δ 5.31-5.18 (m, 1H), 4.20-4.11 (m, 2H), 2.96 (s, 3H), 1.59 (br.s., 1H), 1.45-1.32 (m , 4H), 1.24 (t, J = 7.0 Hz, 3H), 1.31-1.13 (m, 5H); ¹⁹ F NMR (376 MHz, CDCl ₃ ) δ -79.13 (br.s., 3F) ^{body: -78.96; 13 C NMR (101MHz} , CDCl 3) δ 172.2 (s, 2C), 155.6,124.2 (q, J = 267.4Hz, 1C), 68.67-67.71 (m, 1C), 61.4,41.3,35.3 , 21.2, 17.3 (br.s., 1C), 14.0, 13.8 (br.s., 1C) minor rotamers: 172.0, 155.3, 67.9, 42.2.

A solution of LiOH (36 mg, 1.48 mmol) in water (3 mL) was added to a solution of m. . The reaction mixture was diluted with H ₂ O (7mL) with, and washed with Et ₂ O (10mL). The aqueous layer was then acidified to pH ~2 with 1N EtOAc and extracted with EtOAc. Dried (MgSO ₄₎ the organic layers were combined, filtered and concentrated to afford the cap L-19 (0.18g). ¹ H NMR (500 MHz, CDCl ₃ ) δ 5.27 - 5.20 (m, 1H), 2.97 (s, 3H), 1.45-1.35 (m, 7H).

Cap L-20

Cap L-20 was prepared by starting with 1,1,1-trifluoro-2-methylpropan-2-ol using the procedure described for Synthetic Cap L-6. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.92 (br.s., 1H), 1.60 (s, 6H), 1.26 (br.s., 2H), 0.97 (br.s., 2H).

Cap L-21

Cap L-21 step a

Add Deoxo-Fluor ^® (0.449 mL, 2.433 mmol) to methyl 1-((t-butoxycarbonyl)amino)-4-oxocyclohexanecarboxylate (300 mg, 1.106 mmol) in DCM (15 mL) In the solution, a catalytic amount of EtOH (0.032 mL, 0.553 mmol) was added, and the resulting solution was stirred at room temperature for 16 hours. The reaction was _quenched with sat NaHCO and extracted with DCM (2 ×). Washed with water, brine, and the combined organic layers were dried (MgSO _4), filtered and evaporated to give a yellow - orange oil which was purified by flash chromatography (20% EtOAc / hexanes) to give the oil, to give a colorless Oily cap L-21 step a (619 mg). _{^{1 H NMR (400MHz, CDCl 3}} ) δ 3.72 (s, 3H), 2.18-2.07 (m, 4H), 2.07-1.88 (m, 4H), 1.41 (s, 9H); 19 F NMR (376MHz, CDCl 3 δ -94.27 (d, J = 227.3 Hz, 1F), -101.43 (d, J = 227.1 Hz, 1F); ¹³ C NMR (101 MHz, CDCl ₃ ) δ 174.0, 155.2 (s, 2C), 122.2 (t) , J = 242.0 Hz, 2C), 80.4 (br.s., 1C), 57.6, 52.4, 29.75-29.47 (m, 2C), 29.4, 29.1, 28.2 (s, 3C).

A solution of LiOH (22.86 mg, 0.955 mmol) in EtOAc (3 mL) hour. The mixture was diluted with H ₂ O (10mL), and washed with E ₂ O (10mL). The aqueous layer was then acidified with EtOAc (EtOAc) (EtOAc) Dried (MgSO ₄₎ the organic layers were combined, filtered and concentrated to give a white solid, corresponding to the cap L-21 (50mg), which was used without further purification. ^{1 H NMR (400MHz, DMSO-} d 6) δ 12.48 (br.s., 1H), 7.45-7.21 (m, 1H), 2.10 (br.s., 2H), 1.98-1.78 (m, 6H), 1.38 (s, 9H).

Cap L-22

Cap L-22 was prepared by starting with (2-((t-butoxycarbonyl)amino)-2-methylpropanoic acid using the procedure described for the synthetic cap L-18. ¹ H NMR ( 500MHz, DMSO-d ₆ ) δ 7.41 (br.s., 1H), 3.18 (q, J = 10.1 Hz, 2H), 1.19 (s, 6H); ¹⁹ F NMR (376 MHz, DMSO-d ₆ ) δ - 71.13(s, 3F).

Cap L-23

Cap L-23 step a

(S)-Piperidine-2-carboxylic acid methyl ester hydrochloride (0.5 g, 2.78 mmol), 2,2,2-trifluoroethyl trifluoromethanesulfonate (0.802 mL, 5.57 mmol) and DIEA (1.458) A solution of mL, 8.35 mmol) in DMF (20 mL) was heated to 50 &lt;0&gt;C for 24 h. The volatiles were removed under reduced pressure and purified EtOAcqqqq The clear oil was isolated, corresponding to cap L-23 step a (0.385 g). ¹ H NM R (400MHz, CDCl ₃ ) δ 3.71 (s, 3H), 3.55 (t, J = 4.8 Hz, 1H), 3.22-3.03 (m, 3H), 2.71 (dt, J = 11.2, 4.4 Hz, 1H), 1.98 (dq, J = 13.3,4.4Hz, 1H), 1.87-1.77 (m, 1H), 1.64-1.48 (m, 3H), 1.33-1.23 (m, 1H); 19 F NMR (376MHz, CDCl ₃ ) δ -71.28 (s, 3F); ¹³ C NMR (101MHz, CDCl ₃ ) δ 173.5, 125.7 (q, J = 279.7 Hz, 1 C), 62.8, 57.0 (q, J = 30.8 Hz, 1 C), 51.5, 50.3, 28.8, 25.5, 20.9.

Water (3 mL) containing LiOH (0.082 g, 3.42 mmol) was added to a solution of Cap L-23 Step a (0.385 g, 1.710 mmol) in THF (10 mL) at EtOAc. The resulting mixture was stirred for 3 hours. The mixture was then diluted with H ₂ O (10mL), and washed with Et ₂ O (10mL). The aqueous layer was then acidified with EtOAc (EtOAc) Dried (MgSO ₄₎ the organic layers were combined, filtered and concentrated under reduced pressure to give a white solid, corresponding to the cap L-23 (0.35g), which was used without further purification. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.51 (br.s., 1H), 3.50 (t,J=4.3 Hz, 1H), 3.44 - 3.16 (m, 3H), 3.00 (t, J = 10.7) Hz, 1H), 2.63 (d, J = 11.3 Hz, 1H), 2.00-1.83 (m, 1H), 1.73-1.59 (m, 1H), 1.57-1.40 (m, 3H), 1.24-1.07 (m, ^{1H); 19 F NMR (376MHz} , DMSO-d 6) δ -70.03 (s, 3F); 13 C NMR (101MHz, DMSO-d 6) δ 174.0,129.59-117.32 (m, J = 234.3,234.3,234.3 Hz, 1C), 61.8, 56.0 (q, J = 29.3 Hz, 1 C), 49.4, 28.3, 25.2, 20.6.

Cap L-24

Cap L-24 was prepared by starting with (S)-pyrrolidine-2-carboxylic acid benzyl ester hydrochloride using the procedure described for the synthetic cap L-22. ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.37 (br.s., 1H), 3.54 (dd, J = 9.4, 3.6 Hz, 1H), 3.43-3.18 (m, 3H), 2.83-2.68 (m, 1H) ), 2.31-2.17 (m, 1H), 2.14-2.01 (m, 1H), 1.99-1.77 (m, 2H); ¹⁹ F NMR (376 MHz, CDCl ₃ ) δ -70.35 (s, 3F); ¹³ C NMR (101 MHz, CDCl ₃ ) δ 175.7, 124.8 (q, J = 276.7 Hz, 1 C), 66.7, 55.8 (q, J = 31.6 Hz, 1 C), 55.2, 30.2, 24.5.

Cap L-25

Add a solution of LiOH (0.046 g, 1.928 mmol) in water (2 mL) to (S)-2,2-dimethyloxazolidine-3,4-dicarboxylic acid 3-tert-butyl ester 4-methyl ester (0.5 g, 1.928 mmol) in THF (6 mL). The resulting mixture was stirred at room temperature for 48 hr. Dried (MgSO ₄₎ of the combined organic phases were filtered and concentrated under vacuum to give a yellow oil of the cap L-25 (0.2g). Used without further purification. ¹ H NMR (400 MHz, DMSO-d ₆ , s. J = 9.0, 3.3 Hz, 1H), 1.56-1.51 (m, 3H), 1.42 (s, 7H), 1.39-1.33 (m, 6H); ¹³ C NMR (101 MHz, DMSO-d ₆ , rotamer Mixture) δ 172.32-171.83 (m), 150.7, 93.76-93.42 (m), 79.66-79.01 (m), 65.94-65.54 (m), 58.79-58.57 (m), 28.05-27.74 (m, 3C), 24.93 -24.75 (m), 24.16-23.99 (m).

Cap L-26

Cap L-26 was prepared by starting with 3-aminooxetane-3-carboxylic acid using the procedure described for synthetic cap L-3. _{^{1 H NMR (400MHz, CDCl 3}} ) δ 5.04 (d, J = 6.5Hz, 2H), 4.81 (d, J = 8.0Hz, 2H), 3.73 (s, 3H); 13 C NMR (101MHz, CDCl 3) δ 174.1, 152.8, 76.6, 58.2, 54.5.

Cap L-27

Cap L-27 was prepared by starting with 2-((t-butoxycarbonyl)(methyl)amino)-2-methylpropanoic acid using the procedure described for the synthetic cap L-18. ^{1 H NMR (400MHz, DMSO-} d 6) δ 3.30-3.22 (m, 2H), 2.42 (s, 3H), 1.26 (s, 6H); 19 F NMR (376MHz, DMSO-d 6) δ -70.48 ( s, 3F); ¹³ C NMR (101MHz, DMSO-d ₆ ) δ 176.9, 126.0 (q, J = 268.2 Hz, 1C), 62.1, 53.0 (d, J = 30.1 Hz, 1C), 39.00-38.91 (m , 1C), 24.8 (s, 2C).

Cap L-28

Cap L-28 step a

TMS-diazomethane (2M in Et ₂ O) (2.011 mL, 4.02 mmol) was added dropwise to (S)-4-(t-butoxycarbonyl)morpholine-3-carboxylic acid (0.93 g, 4.02 mmol) in a solution of benzene (20 mL) and MeOH (15 mL) until the solution remained yellow and no gas evolution was observed. The solvent was removed under reduced pressure and isolated to give a clear oil, corresponding to Cap L-28 Step a (0.96 g). Used without further purification. ¹ H NMR (400 MHz, CDCl ₃ , mixture of rotamers) δ 4.60-4.21 (m, 2H), 3.89 (d, J = 10.5 Hz, 1H), 3.77 (s, 3H), 3.74 - 3.66 (m, 1H), 3.63 (dd, J = 11.8, 3.8 Hz, 1H), 3.53-3.41 (m, 1H), 3.36-3.13 (m, 1H), 1.46 (d, J = 15.1 Hz, 9H); ¹³ C NMR (101MHz, CDCl ₃ , mixture of rotamers) δ 170.98-170.37 (m, 1C), 155.7 (br.s., 1C), 80.6, 68.09-66.99 (m, 1C), 66.81-66.19 (m, 1C) ), 55.71-53.50 (m, 1C), 52.3, 42.46-39.94 (m, 1C), 28.2 (br.s., 3C).

Cap L-28 step b

HCl (5.10 mL, 20.39 mmol) was added dropwise to a solution of EtOAc (EtOAc m. The solvent was removed under reduced pressure and a white solid was obtained, corresponding to mp. Used without further purification. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 4.37 (dd, J = 7.5, 3.5 Hz, 1H), 4.08 (dd, J = 12.4, 3.9 Hz, 1H), 3.94 - 3.84 (m, 2H), 3.82 - 3.75 (m, 4H), 3.28-3.20 (m, 1H), 3.15 - 3.03 (m, 1H); ¹³ C NMR (101 MHz, DMSO-d ₆ ) d 166.6, 64.5, 62.9, 53.7, 53.0, 41.6.

Cap L-28 is then prepared by employing the procedure described for synthetic cap L-23. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.75 (br.s., 1H), 4.03 (d, J = 11.3 Hz, 1H), 3.71 (d, J = 10.8 Hz, 1H), 3.66 - 3.57 ( m,1H), 3.54-3.27 (m, 4H), 3.23-3.09 (m, 1H), 2.56 (d, J = 9.8 Hz, 1H); ¹⁹ F NMR (376 MHz, DMSO-d ₆ ) δ -70.22 ( Br.s., 3F); ¹³ C NMR (101 MHz, DMSO-d ₆ ) δ 172.3, 132.72-118.59 (q, J=277.4, Hz, 1C), 68.5, 66.5, 61.2, 56.22-55.26 (t, J = 30.1 Hz, 1 C), 48.3.

Cap L-29

2-D-oxypropionic acid (1.200 mL, 17.03 mmol), propane-1,3-diol (1.834 mL, 25.6 mmol) and Amberlite 15 in a Dean-Stark apparatus A mixture of (2 g, 17.03 mmol) in EtOAc (50 mL) After cooling, the reaction mixture was filtered and concentrated under reduced pressure. The residue was redissolved in 2M aqueous NaOH (10 mL) and warm to reflux for 2 hr. Followed by ice-cold ₄ 6M H ₃ PO aqueous reaction mixture was acidified to pH = 1, and quickly extracted with EtOAc (3 ×). Dried (MgSO ₄₎ the organic layers were combined, filtered and concentrated in vacuo to give a yellowish oil corresponding to the cap L-29, which solidified on standing. _{^{1 H NMR (400MHz, CDCl 3}} ) δ 4.08-3.98 (m, 2H), 3.97-3.88 (m, 2H), 2.18-2.07 (m, 1H), 1.57 (s, 2H), 1.41 (dd, J = 13.6, 1.5 Hz, 1H); ¹³ C NMR (101 MHz, CDCl ₃ ) δ 175.2, 98.1, 63.2 (s, 2C), 26.0, 24.4.

Cap L-30

Cap L-30 was prepared by starting with cycloprop-1,1-diyldimethanol using the procedure described for synthetic cap L-29. ^{1 H NMR (400MHz, DMSO-} d6) δ 13.10 (br.s., 1H), 4.06 (d, J = 11.8Hz, 2H), 3.07 (d, J = 12.0Hz, 2H), 1.38 (s, 3H ), 0.62-0.51 (m, 2H), 0.33-0.27 (m, 2H); ¹³ C NMR (101 MHz, DMSO-d6) δ 171.4, 97.7, 69.0 (s, 2C), 25.6, 16.5, 12.8, 4.4.

Cap L-31

Cap L-31 step a

To a solution of methyl 2-oxopropionate (0.867 mL, 9.60 mmol) and (2S,4S)-pentane-2,4-diol (0.5 g, 4.80 mmol) in MeCN (15 mL) BF ₃ .OEt ₂ (1.217 mL, 9.60 mmol) was added, and the mixture was stirred at room temperature for 24 hr. Carefully with saturated aqueous NaHCO ₃ The reaction was quenched, and stirred at room temperature for 30 minutes. The volume of the reaction under vacuum and the mixture was reduced to one third of its original volume, then extracted with _{CH 2 Cl 2 (3 × 10mL} ), and dried (MgSO ₄₎ the organic layers were combined, filtered and concentrated in vacuo . The yellow oil was recovered and purified by flash chromatography (10%EtOAcEtOAc A clear oil was recovered corresponding to cap L-31 step a (0.32 g). _{^{1 H NMR (400MHz, CDCl 3}} ) δ 4.20-4.03 (m, 2H), 3.76 (s, 3H), 1.73-1.64 (m, 1H), 1.59-1.50 (m, 1H), 1.48 (s, 3H) , 1.23 (dd, J = 6.3, 2.0 Hz, 6H); ¹³ C NMR (101 MHz, CDCl ₃ ) δ 172.0, 97.1, 65.6, 64.7, 52.3, 38.4, 25.0, 21.6, 20.2.

The cap L-31 step a (0.27g, 1.434mmol) and NaOH (0.258g, 6.46mmol) in a solution of THF (10 mL) and H ₂ O (5mL) was stirred at room temperature for 3 hours. The reaction mixture was concentrated in vacuo, and treated with cold 6N H ₃ PO ₄ The remaining aqueous layer was acidified to pH = 2, and quickly extracted with EtOAc (3 ×). Dried (MgSO ₄₎ the organic layers were combined, filtered and concentrated to give a yellow oil, a cap corresponding to the L-31 (0.22g). Used without further purification. ^{1 H NMR (400MHz, DMSO-} d 6) δ 4.17-4.00 (m, 2H), 1.63-1.53 (m, 1H), 1.53-1.45 (m, 1H), 1.32 (s, 3H), 1.16 (d, J = 6.8 Hz, 3H), 1.11 (d, J = 6.3 Hz, 3H); ¹³ C NMR (101 MHz, DMSO-d ₆ ) δ 172.7, 96.1, 65.1, 63.8, 37.7, 25.0, 21.6, 20.2.

Cap L-32

Cap L-32 step a

Add DBU (1.021 mL, 6.77 mmol) to (R)-2-hydroxy-3-methylbutyric acid (0.8 g, 6.77 mmol) and benzyl bromide (1.390 g, 8.13 mmol) in DMF (10 mL) The resulting yellowish solution was stirred at room temperature for 16 hours. The mixture was then dissolved in EtOAc (50 mL) and water (30 mL). The aqueous layer was extracted with EtOAc, washed with brine and the combined organic layers were dried (MgSO _4), filtered, and concentrated to give a clear oil. The residue was purified by flash chromatography (10%EtOAcEtOAc A clear oil was recovered corresponding to cap L-32 step a (1.3 g). _{^{1 H NMR (400MHz, CDCl 3}} ) δ 7.44-7.31 (m, 5H), 5.30-5.17 (m, 2H), 4.10 (dd, J = 6.1,3.4Hz, 1H), 2.73 (dd, J = 6.1, 1.9 Hz, 1H), 2.11 (dtd, J = 13.8, 6.9, 3.5 Hz, 1H), 1.02 (d, J = 7.0 Hz, 3H), 0.84 (d, J = 7.0 Hz, 3H); ¹³ C NMR ( 101 MHz, CDCl ₃ ) δ 174.8, 135.2, 128.6 (s, 2C), 128.5, 128.4 (s, 2C), 75.0, 67.3, 32.2, 18.8, 15.9.

Cap L-32 step b

The silver oxide (I) (1.113g, 4.80mmol) was added to the cap L-32 step a (0.5g, 2.401mmol) and MeI (0.751mL, 12.00mmol) in in the E ₂ O (10mL) solution, and The suspension was stirred at 40 ° C for 72 hours. The suspension was filtered through a glass fiber filter to remove the silver salt and concentrated under reduced pressure. The clear oil was recovered and purified by flash chromatography (2%EtOAcEtOAc A clear oil was recovered corresponding to cap L-32 step b (0.14 g). _{^{1 H NMR (400MHz, CDCl 3}} ) δ 7.42-7.30 (m, 5H), 5.26-5.16 (m, 2H), 3.56 (d, J = 5.5Hz, 1H), 3.38 (s, 3H), 2.07 ( bis Wufeng, J=6.8, 5.5 Hz, 1H), 0.95 (d, J=4.5 Hz, 3H), 0.93 (d, J=4.3 Hz, 3H); ¹³ C NMR (101 MHz, CDCl ₃ ) δ 172.1, 135.7, 128.5 (s, 2C), 128.3 (s, 2C), 128.3, 85.9, 66.3, 58.5, 31.5, 18.6, 17.5.

Pd/C (0.029 g, 0.027 mmol) was added to a solution of EtOAc EtOAc (EtOAc) _{&lt;RTI ID} =0.0&gt _; (mmol) under a balloon and stirred at room temperature for 3 hours. The catalyst was filtered through a pad of celite and concentrated under vacuum. A clear oil was recovered corresponding to cap L-32 (0.07 g). _{^{1 H NMR (400MHz, CDCl 3}} ) δ 8.78 (br.s., 1H), 3.56 (d, J = 4.8Hz, 1H), 3.41 (s, 3H), 2.09 (dq, J = 11.8,6.8Hz, 1H), 1.00 (d, J = 7.0 Hz, 3H), 0.95 (d, J = 6.8 Hz, 3H); ¹³ C NMR (101 MHz, CDCl ₃ ) δ 177.3, 85.4, 58.8, 31.3, 18.6, 17.2.

Cap L-33

Cap L-33 step a

Add solid (1s, 4s)-1-methyl-2,5,7-trioxabicyclo[2.2. to a mixture of ethanol (15 mL) and NaOEt (21% in ethanol, 1.619 mL, 4.34 mmol). 2] Oct-6-one (2.5 g, 17.35 mmol, obtained according to the method of Gellas and Thiallier, Carbohydrate Research , 1973 , 20 , 21, obtained from methyl pyruvate and glycerol) to form a clear solution. The mixture was stirred at room temperature for 16 hours. To this ethanol solution was added 2.5 mL of a wet volume of dowex resin (50W 8X-200) in an acidic form at room temperature, and stirring was continued for 30 minutes, followed by removal by filtration. The filtrate was dried under high vacuum to give a yellow mp. mp. _{^{1 H NMR (400MHz, CDCl 3}} ) δ 4.79-4.76 (m, 1H), 4.29 (q, J = 7.3Hz, 2H), 4.12-4.10 (m, 1H), 4.07-4.01 (m, 2H), 3.93 -3.84 (m, 1H), 3.52-3.43 (m, 2H), 1.50 (s, 3H), 1.33 (t, J = 7.2 Hz, 3H); ¹³ C NMR (101 MHz, CDCl ₃ ) δ 170.0, 97.8, 67.5 (s, 2C), 61.9, 61.1, 24.3, 14.1.

Cap L-33 step b

Ethylene dichloride dichloride (1.376 mL, 15.77 mmol) was added to 250 mL of RBF containing DCM (25 mL) at -78. The mixture was again cooled to -78 ° C, and DMSO (1.213 mL, 17.09 mmol) was added dropwise at a rate that was slow enough to allow the evolution of the evolved gas. The mixture was stirred at -78.degree. C. for 30 min then EtOAc (EtOAc &lt Stirring continued for 45 minutes at -78 ℃, the reaction mixture was then treated with _{Et 3 N (4.40mL, 31.5mmol)} . The resulting white suspension was stirred at -78 °C for 30 minutes and then at 0 °C for a further 30 minutes. With 50ml of saturated aqueous NaHCO ₃ The reaction was quenched, and the aqueous layer was extracted with DCM (4 × 20mL). Dried (MgSO ₄₎ the organic layers were combined and concentrated under reduced pressure to give a clear yellow oil. The residue was purified by EtOAc (EtOAc) elute _{^{1 H NMR (400MHz, CDCl 3}} ) δ 4.42-4.34 (m, 2H), 4.28 (q, J = 7.2Hz, 2H), 4.29-4.23 (m, J = 1.0Hz, 2H), 1.62 (s, 3H ), 1.33 (t, J = 7.2 Hz, 3H).

Cap L-33 step c

(0.882mL, 4.78mmol) was treated with Deoxo-Fluor ^® L-33 containing cap step b (0.36g, 1.913mmol) of DCM (10mL), and the yellow solution was stirred at room temperature for 2 hours. The reaction mixture was cooled to 0 ℃, diluted with CH ₂ Cl ₂ (5mL), and washed with saturated aqueous NaHCO ₃ was carefully quenched. The mixture was stirred for 15 minutes until gas ceased to be evolved, and (2 ×) the aqueous layer was extracted with CH ₂ Cl _2. Dried (MgSO ₄₎ the organic layers were combined, filtered and concentrated. A yellow oil was recovered which corresponds to the crude cap L-33 step c (0.1 g) and was used without further purification. _{^{1 H NMR (400MHz, CDCl 3}} ) δ 4.31 (q, J = 7.0Hz, 2H), 4.06-3.88 (m, 4H), 1.58 (s, 3H), 1.35 (t, J = 7.0Hz, 3H); ¹⁹ F NMR (376 MHz, CDCl ₃ ) δ - 112.09 (d, J = 251.4 Hz, 1F), -116.34 (d, J = 251.4 Hz, 1F); ¹³ C NMR (101 MHz, CDCl ₃ ) δ 168.6, 113.3 ( t, J = 243.5 Hz, 1 C), 98.3, 65.7 (d, J = 27.7 Hz, 1 C), 65.2 (d, J = 28.5 Hz, 1 C), 62.2, 24.2, 14.1.

The LiOH.H ₂ O (23.96mg, 0.571mmol) in the in H ₂ O (1.5mL) was added to the cap L-33 step c (60mg, 0.285mmol) in the in THF (5mL) solution, and the The resulting mixture was stirred at room temperature for 3 hours. The reaction mixture was then acidified until pH ₄ with 6M H ₃ PO value of about 2, and the aqueous layer was extracted with EtOAc (3 ×). Dried (MgSO ₄₎ the organic layers were combined, filtered and concentrated to give a brown oil of the cap L-33 (50mg). Used without further purification. _{^{1 H NMR (400MHz, CDCl 3}} ) δ 8.31 (br.s., 1H), 4.14-3.95 (m, 4H), 1.66 (s, 3H); 19 F NMR (376MHz, CDCl 3) δ -111.89 (d , J = 250.4 Hz, 1F), -116.17 (d, J = 250.4 Hz, 1F); ¹³ C NMR (101 MHz, CDCl ₃ ) δ 173.4, 114.6 (d, J = 242.8 Hz, 1 C), 112.1 (d, J = 243.5 Hz, 1 C), 98.1, 65.8 (d, J = 28.5 Hz, 1 C), 65.4 (d, J = 28.5 Hz, 1 C), 24.0.

Cap L-34

Cap L-34 was prepared starting with (2R,4R)-pentane-2,4-diol using the procedure described for synthetic cap L-31. ¹ H NMR (400 MHz, CDCl ₃ ) δ 10.08 (br.s., 1H), 4.15 (dq, J = 13.2, 6.4 Hz, 1H), 4.11-4.02 (m, 1H), 1.75-1.59 (m, 2H) ), 1.55 (s, 3H), 1.29 (d, J = 6.5 Hz, 3H), 1.25 (d, J = 6.3 Hz, 3H); ¹³ C NMR (101 MHz, CDCl ₃ ) δ 175.5 (br.s., 1C), 97.5, 65.5 (s, 2C), 38.8, 24.2, 21.6, 20.7.

Cap W-16

To the ice-cooled solution of N,N-diisopropylethylamine (6.11 mL, 35.1 mmol) in DCM (50 mL) was added (1R, 2S, 5S)-3-azabicyclo[3.1. 0] Hexane-2-carboxylic acid (3.715 g, 29.2 mmol). A solution of di-tert-butyl dicarbonate (8.29 g, 38.0 mmol) in DCM (25.00 mL) was added dropwise to this mixture. The final mixture was stirred overnight at room temperature. Washed with 5% aqueous citric acid, the organic phase was washed with saturated aqueous NaCl, dried over MgSO ₄ and evaporated to give 7.6g viscous oil, solidified on standing failure in a freezer. The residue was redissolved in EtOAc (EtOAc) (EtOAc)EtOAc. , The organic layer was washed with brine, dried over MgSO _4, filtered and evaporated in vacuo to give a foamy cap of W-16 (3.90g). _{^{1 H NMR (400MHz, CDCl 3}} ) δ 4.53-4.27 (m, 1H), 3.72-3.52 (m, 2H), 2.00-1.83 (m, 1H), 1.67 (dd, J = 6.7,3.4Hz, 1H) , 1.56-1.34 (m, 9H), 0.90-0.64 (m, 2H).

Cap W-17

Cap W-17 Step A

To (S)-4,4-difluoropyrrolidine-1,2-dicarboxylic acid 1-t-butyl ester 2-methyl ester (1.552 g, 5.68 mmol) in THF (50 mL) at -78 °C THF (3.12 mL, 6.24 mmol) containing 2M lithium diisopropylamide was added dropwise. After stirring the pale yellow solution at -78 °C for 30 minutes (when it became a pale brown solution), iodomethane (0.389 mL, 6.24 mmol) was added dropwise via a syringe. After stirring at -78 °C for 2 hours, the reaction mixture was stirred at EtOAc (EtOAc) The combined organic extracts were washed with brine, dried (MgSO4 The residual oil was purified by EtOAc (EtOAc: EtOAc) _{^{1 H NMR (400MHz, CDCl 3}} ) δ 3.98-3.81 (m, 2H), 3.80-3.74 (m, 3H), 2.81-2.57 (m, 1H), 2.48-2.26 (m, 1H), 1.75-1.60 ( m, 3H), 1.53-1.40 (m, 9H).

Will contain 4,4-difluoro-2-methylpyrrolidine-1,2-dicarboxylic acid 1-tributyl ester 2-methyl ester (118 mg, 0.423 mmol), THF (4 mL) and 1 M sodium hydroxide (4.23) The vial of mL, 4.23 mmol) was sealed and heated in a microwave system at 80 °C for 2 hours. The volatiles were removed in vacuo. The remaining aqueous layer was extracted with EtOAc (EtOAc)EtOAc. , Washed with brine and dried over the combined organic layers over MgSO _4, filtered and evaporated in vacuo to give a colorless viscous oil cap of W-17 (100mg, 0.377mmol, 89% yield), which workbench Solidified when standing. _{^{1 H NMR (400MHz, CD 3}} OD) δ 3.93-3.77 (m, 2H), 2.86-2.61 (m, 1H), 2.60-2.42 (m, 1H), 1.71-1.59 (m, 3H), 1.54-1.42 (m, 9H).

Cap W-18

Cap W-18 Step A

To a solution of 1-((t-butoxycarbonyl)amino)-4-oxocyclohexanecarboxylic acid (988 mg, 3.72 mmol) in methanol (15 mL) Hexyldiazomethane in hexane (7.45 mL, 14.90 mmol) until the solution turned pale yellow. It was stirred overnight at room temperature. The volatiles were removed in vacuo. The residue (1.2 g) was purified eluting elut elut elut elut elut elut eluting ¹ H NMR (400 MHz, CDCl ₃ ) δ 4.93 (s, 1H), 3.84 - 3.73 (m, 3H), 2.59 - 2.19 (m, 8H), 1.56-1.39 (m, 9H).

Cap W-18 Step B

Cap W-18 Step A (1.00 g, 3.69 mmol) and THF (20 mL) were applied to a 100 mL 3-neck RBF and cooled with a dry ice-acetone bath. To the solution was added dropwise 1 M THF (4.43 mL, 4.43 mmol) of tri-isobutylborohydride (completed over 5 min). Was stirred at -78 ℃ 3 hours, followed by the addition of saturated aqueous NH ₄ Cl at -78 ℃ (20mL) The reaction was quenched then diluted with EtOAc (20mL) and water (20 mL), at room temperature and the It was stirred for 1 hour. The separated organic layer was washed with brine, dried MgSO ₄ The residual oil was purified by flash chromatography (30% to 70%EtOAc-hexane). The combined fractions were concentrated in vacuo to give the desired product, m.j. _{^{1 H NMR (400MHz, CDCl 3}} ) δ 4.74 (br.s., 1H), 3.96 (d, J = 2.8Hz, 1H), 3.81-3.67 (m, 4H), 2.38-2.09 (m, 2H), 1.96-1.63 (m, 6H), 1.62-1.39 (m, 9H).

Cap W-18 Step C

To the ice-cooled solution of Cap W-18 Step B (890 mg, 3.26 mmol) and N,N-diisopropylethylamine (0.851 mL, 4.88 mmol) in DCM (20 mL) Chlorofluorene (0.302 mL, 3.91 mmol). The resulting pale yellow solution was stirred at room temperature for 2 hours. ₃ quenched with saturated NaHCO. , Dried the organic layer was separated and washed with brine, 5% citric acid over MgSO _4, filtered and evaporated in vacuo. The residual solid was purified by EtOAc (EtOAc) elute elute ¹ H NMR (400 MHz, CDCl 3 ) δ 4.96 (br.s., 1H), 4.81-4.57 (m, 1H), 3.82-3.70 (m, 3H), 3.12-2.99 (m, 3H), 2.32-1.76 ( m, 8H), 1.61 (s, 1H), 1.46 (s, 8H).

Cap W-18 Step D

THF (3.27 mL, 3.27 mmol) containing 1 M potassium tert-butoxide was added dropwise to a solution of EtOAc (EtOAc, EtOAc) The resulting pale yellow solution was stirred overnight at room temperature (it became cloudy after one hour). The reaction was quenched with EtOAc (EtOAc)EtOAc. The aqueous layer was separated with EtOAc (EtOAc)EtOAc. , Washed with brine and dried over the combined organic layers over MgSO _4, filtered and evaporated in vacuo. The residue was purified by flash chromatography eluting elut elut elut elut elut elut elut ¹ H NMR (500 MHz, CDCl ₃ ) δ 4.33 (t, J = 4.8 Hz, 1H), 3.89 (s, 3H), 2.28-2.11 (m, 2H), 2.05-1.88 (m, 2H), 1.77 (ddd , J = 11.5, 9.2, 4.5 Hz, 2H), 1.58-1.39 (m, 9H).

A vial containing Cap W-18 Step C (128 mg, 0.5 mmol), THF (5 mL) and 1M sodium hydroxide (5.00 mL, 5 mmol) was sealed and heated at 100 ° C for 2 hours in a microwave system. The volatiles were removed in vacuo and EtOAc EtOAc m. The separated aqueous layer was acidified with EtOAc (EtOAc) (EtOAc) , Washed with brine and dried over the combined organic layers over MgSO _4, filtered and evaporated in vacuo to give a white solid cap of W-18 (85mg). ¹ H NMR (500 MHz, CD ₃ OD) δ 4.28 (t, J = 4.8 Hz, 1H), 2.21-2.09 (m, 2H), 1.97-1.85 (m, 2H), 1.79 (ddd, J = 11.4, 9.2 , 4.5 Hz, 2H), 1.57 (ddd, J = 11.5, 9.1, 4.3 Hz, 2H), 1.50-1.42 (m, 9H).

Cap W-19

Cap W-19 Step A

Add (2S,4S)-1-(t-butoxycarbonyl) as a solid to the ice-cooled mixture of sodium hydride (228 mg, 5.71 mmol) (pre-washed with hexane) and DMF (10 mL) 4-hydroxypyrrolidine-2-carboxylic acid (600 mg, 2.59 mmol). The resulting slurry was stirred at this temperature for 30 minutes, then methyl iodide (0.485 mL, 7.78 mmol) was added dropwise. The final reaction mixture was stirred at room temperature over the weekend. It was poured into water (100 mL) and EtOAc (20 mL, , Washed with water and brine and dried over combined organic layers were over MgSO _4, filtered and evaporated in vacuo. The residue was purified by EtOAc (EtOAc:EtOAc) ¹ H NMR (500 MHz, CD ₃ OD) δ 4.38 (td, J = 8.6, 3.2 Hz, 1H), 3.99 (dt, J = 5.1, 2.4 Hz, 1H), 3.81-3.68 (m, 3H), 3.64 3.53 (m, 1H), 3.50-3.40 (m, 1H), 2.45-2.21 (m, 2H), 1.55-1.40 (m, 9H).

Add a solution of Cap W-19 Step A (140 mg, 0.540 mmol) in MeOH (2 mL) Solution. The resulting cloudy solution was stirred overnight at room temperature. The volatiles were removed in vacuo. The remaining aqueous layer was diluted with water (10 mL) andEtOAc. The aqueous phase was separated with EtOAc (EtOAc)EtOAc. , Washed with brine and dried over the combined organic layers over MgSO _4, filtered and evaporated in vacuo to give a colorless oil cap of W-19 (123mg), which solidified on standing. ¹ H NMR (500 MHz, CD ₃ OD) δ 4.42-4.22 (m, 1H), 4.05-3.93 (m, 1H), 3.69-3.56 (m, 1H), 3.45 (dd, J=11.5, 2.5 Hz, 1H ), 3.31-3.24 (m, 3H), 2.47-2.17 (m, 2H), 1.56-1.37 (m, 9H).

Cap W-20

To a solution of (S)-1-(t-butoxycarbonyl)-4-oxoxypyrrolidin-2-carboxylic acid (229 mg, 0.999 mmol) in THF (5 mL) A 3 M solution of methylmagnesium bromide in diethyl ether (0.832 mL, 2.497 mmol) was added. The mixture was stirred at this temperature for 1 hour, and cooled with an ice bath and stirred overnight. The mixture was then poured into ice cold 1M EtOAc and extracted with EtOAc. , Dried the organic layer was separated and washed with brine over MgSO _4, filtered and evaporated in vacuo to give a white solid, which was 4: 1 hexanes-EtOAc (5 mK) wet-milled to give a white powder of the desired product as a cap W -20 (156 mg). _{^{1 H NMR (500MHz, CD 3}} OD) δ 4.43-4.25 (m, 1H), 3.52-3.35 (m, 2H), 2.38-2.07 (m, 2H), 1.59-1.42 (m, 11H), 1.40-1.30 (m, 3H).

Intermediate W-1

Sodium hydride (183 mg, 4.58 mmol) pre-washed (with hexanes) was suspended in THF (20 mL) and then 1-methylcyclopropanol (300 mg, 4.16 mmol) was slowly added at 4 °C. The resulting pale yellow turbid solution was stirred at this temperature for 30 minutes, followed by the addition of bis(pyridin-2-yl) carbonate ( 899 mg, 4.16 mmol). The final mixture was stirred at room temperature overnight, poured into ice cold water and extracted with EtOAc. The organic layer was washed with water and brine, dried over MgSO _4, filtered and evaporated in vacuo. The residue was purified with EtOAc EtOAc EtOAcjjjjj ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.50-8.38 (m, 1H), 7.92-7.76 (m, 1H), 7.36-7.22 (m, 1H), 7.19-7.08 (m, 1H), 1.82-1.63 ( m, 3H), 1.19-1.04 (m, 2H), 0.83-0.68 (m, 2H).

Cap W-21

A mixture of 4-bromobicyclo[2.2.2]octane-1-carboxylic acid methyl ester (183 mg, 0.741 mmol) and 0.25 M sodium hydroxide (15 mL, 3.75 mmol) in an oil bath at 100 ° C in an oil bath Heat in 24 hours. The mixture was extracted with EtOAc (EtOAc)EtOAc. , Washed with brine and dried over the combined organic layers over MgSO _4, filtered and evaporated to give a white solid cap of W-21 (110mg). ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 11.97 (br.s., 1H), 4.29 (s, 1H), 1.98-1.65 (m, 6H), 1.61-1.36 (m, 6H).

Cap W-22

Cap W-22 Step A

A mixture of tetrahydro-2H-pentan-4-carboxylic acid (1.36 g, 10.45 mmol) and sulfinium chloride (7.63 mL, 105 mmol) was warmed to reflux and maintained for 2.5 h. The mixture was then cooled to room temperature and evaporated in vacuo. To this -2H- tetrahydro-pyran-4-carbonyl chloride in DCM (15mL) in the solution was added dropwise Et ₃ N (4.36mL, 31.4mmol) and benzyl alcohol (1.622mL, 15.68mmol), simultaneously with an ice The bath is cooled. The resulting slurry was stirred under cooling for 30 minutes, followed by stirring at room temperature for 30 minutes. The mixture was washed successively with water, 5% citric acid and a saturated aqueous solution of sodium chloride. The organic solution was dried over MgSO ₄ and then evaporated. The resulting residue was purified by EtOAc EtOAc EtOAc EtOAc _{^{1 H NMR (500MHz, CDCl 3}} ) δ 7.52-7.31 (m, 5H), 5.16 (s, 2H), 3.99 (dt, J = 11.5,3.6Hz, 2H), 3.45 (td, J = 11.2,2.9Hz , 2H), 2.69-2.49 (m, 1H), 2.03-1.73 (m, 4H).

Cap W-22 Step B

To a solution of bis(isopropyl)amine (0.308 mL, 2.197 mmol) in THF (10 mL), hexane (1.373 mL, 2.97) Mm). After stirring the resulting solution for 30 minutes at -78 °C, cap W-22 Step A (440 mg, 1.998 mmol) was added, and the resulting yellow solution was stirred for further 30 min. Thereafter, methyl iodide (0.149 mL, 2.397 mmol) was added dropwise via a syringe. After stirring at -78 °C for 30 minutes, the reaction mixture was stirred with EtOAc. The organic extracts were washed with brine, dried (MgSO _4), filtered, and concentrated in vacuo. The residual oil was purified by EtOAc (EtOAc EtOAc) LC / MS (Condition W-2): [M + H] + 235.2, R t = 1.95min.

Under H ₂ (40psi), a mixture of the W-22 cap Step B (100mg, 0.427mmol) and Pd / C (45.4mg, 0.043mmol) in MeOH (2mL) was placed in a Parr shaker for 4 hours. The mixture was filtered through celite and evaporated in vacuo. The residue was triturated with EtOAc (EtOAc)EtOAc. The hexane wash solution was slowly evaporated by N ₂ blowing to give another 28 mg product as a white solid. ¹ H NMR (500 MHz, CD ₃ OD) δ 3.80 (dt, J = 11.9, 4.2 Hz, 2H), 3.53 (ddd, J = 11.8, 10.4, 2.5 Hz, 2H), 2.13-1.95 (m, 2H), 1.50 (ddd, J = 14.0, 10.2, 4.3 Hz, 2H), 1.25 (s, 3H).

Cap W-23

Cap W-23 Step A

In a capped vial, cis-2,6-dimethylmorpholine (460 mg, 4.00 mmol), 2-bromo-2-methylpropionic acid benzyl ester (514 mg, 1.999 mmol) and N,N-di A mixture of isopropylethylamine (1.393 mL, 8.00 mmol) in acetonitrile (10 mL) was heated in a microwave oven. The solvent was removed in vacuo and the residue was taken in EtOAc. The mixture was washed with water and brine, dried MgSO ₄ By prep _{HPLC (MeOH-H 2 O-} TFA) and the residue was purified. The collected fractions were concentrated to give the trifluoroacetate as a product as a solid. The residue was dissolved in MeOH, poured in to saturated NaHCO _3, and extracted with EtOAc. , Dried the organic layer was separated and washed with brine over MgSO _4, filtered and evaporated to give an off-white oil cap of W-23 Step A (286mg). _{^{1 H NMR (400MHz, CDCl 3}} ) δ 7.54-7.32 (m, 5H), 5.27 (s, 2H), 4.08 (ddd, J = 10.7,6.3,1.9Hz, 2H), 3.40 (d, J = 11.3Hz , 2H), 2.74 (t, J = 11.2 Hz, 2H), 1.72 (s, 6H), 1.19 (d, J = 6.3 Hz, 6H).

Under 50psi H _2, containing 10% Pd / C (53.3mg, 0.050mmol), the cap W-23 Step A (286mg, 0.932mmol) and MeOH (4mL) the vessel was placed on a Parr shaker overnight. The suspension was filtered through EtOAc (EtOAc) (EtOAc) _{^{1 H NMR (400MHz, CD 3}} OD) δ 4.10-3.86 (m, 2H), 3.35-3.30 (m, 2H), 2.71 (t, J = 11.4Hz, 2H), 1.49 (s, 6H), 1.25 ( d, J = 6.5 Hz, 6H).

Cap W-24

Cap W-24 Step A

Add 0.5 M ethynyl magnesium bromide dropwise to a solution of 6-methylhept-5-en-2-one (5.05 g, 40 mmol) in THF (100 mL) at EtOAc. THF (96 mL, 48.0 mmol). The resulting white slurry was allowed to warm to room temperature and stirred for 2 hours. ₄ Cl was quenched with saturated NH, extracted with diethyl ether. The separated organic layer was washed with brine, dried over Na ₂ CH ₄ , filtered and evaporated. The residual oil was purified by EtOAc (EtOAc:EtOAc) ¹ H NMR (500 MHz, CDCl ₃ ) δ 5.28-5.12 (m, 1H), 2.48 (s, 1H), 2.39 - 2.26 (m, 1H), 2.24 - 2.15 (m, 1H), 2.09 (br.s. , 1H), 1.79-1.65 (m, 8H), 1.56-1.50 (m, 3H).

Cap W-24 Step B

The mixture of Cap W-24 Step A (3.87 g, 25.4 mmol) and Amberlyst (R) 15 (1.00 g, 25.4 mmol) in DCM (50 mL) was warmed to reflux and maintained for 6 hr. The mixture was cooled to room temperature, filtered, and the resin was washed with DCM. , Dried over MgSO ₄ and saturated NaHCO ₃ filtrate was washed with brine, filtered and without heating in vacuo evaporated. The residual oil was purified by distillation under a house vacuum, and the fraction distilled between 90 ° C and 95 ° C was collected to give a cap W-24 step B (3.50 g) as a colorless oil. _{^{1 H NMR (500MHz, CDCl 3}} ) δ 2.37 (s, 1H), 2.03 (qt, J = 13.5,3.4Hz, 1H), 1.91-1.82 (m, 1H), 1.70-1.54 (m, 2H), 1.53 - 1.47 (m, 6H), 1.45-1.31 (m, 2H), 1.23-1.18 (m, 3H).

Cap W-24 Step C

Potassium permanganate (711 mg, 4.50 mmol) in water (8 mL) was added dropwise to a solution of Cap W-24 Step B (228 mg, 1.5 mmol) Pre-formed solution. The resulting mixture was stirred at rt EtOAc (EtOAc)EtOAc. The remaining aqueous layer was diluted with 1 M EtOAc and EtOAc. , Dried the organic layer was separated and washed with brine over MgSO _4, filtered and evaporated in vacuo to give a colorless oil of the desired product as a cap W-24 (265mg). ¹ H NMR (500MHz, CDCl ₃ ) δ 2.06-1.98 (m, 1H), 1.73 (five-peak, J = 6.1 Hz, 2H), 1.63-1.44 (m, 6H), 1.29 (d, J = 16.6 Hz) , 6H).

Cap W-25 and cap W-26

Cap W-25/Cap W-26 Step A

3-sided oxycyclobutanecarboxylic acid (2.15 g, 18.84 mmol), benzyl alcohol (2.145 mL, 20.73 mmol) and N 1-((ethylimino)methylene) -N 3 , N 3- A mixture of dimethylpropane-1,3-diamine hydrochloride (5.42 g, 28.3 mmol) in DCM (100 mL The reaction mixture was washed with water (3x), and the combined aqueous layer was extracted with DCM. , Washed with brine and dried combined organic layers were dried over anhydrous MgSO _4, and concentrated in vacuo. The crude product was purified by EtOAc (EtOAc:EtOAc) ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.39 (m, 5H), 5.21. (s, 2H), 3.49 - 3.41 (m, 2H), 3.36 - 3.28 (m, 3H).

Cap W-25/Cap W-26 Step B

To a solution of Cap W-25 / Cap W-26 Step A (613 mg, 3 mmol) in THF (10 mL), EtOAc. 4.2 mmol). The resulting brown solution was stirred at this temperature for 4 hours and poured into ice cold 1M HCl. Then the mixture was saturated with NaCl, extracted with EtOAc, the organic layer was separated and washed with brine, dried over MgSO _4, filtered and evaporated in vacuo. By prep _{HPLC (CH 3 CN-H 2} O-NH 4 OAc) residual oil was purified to afford the major product as a colorless oil, which corresponds to the W-25 cap Step B (160mg). _{^{1 H NMR (500MHz, CDCl 3}} ) δ 7.50-7.32 (m, 5H), 5.15 (s, 2H), 2.90-2.67 (m, 1H), 2.48-2.27 (m, 4H), 2.24-2.09 (m, 2H), 1.40 (s, 3H). A more polar and minor product was also isolated and corresponds to Cap W-26 Step B (60 mg). _{^{1 H NMR (500MHz, CDCl 3}} ) δ 7.50-7.30 (m, 5H), 5.16 (s, 2H), 3.23 (tt, J = 9.7,6.8Hz, 1H), 2.50-2.30 (m, 4H), 1.48 -1.36 (m, 3H).

Under 30psi H _2, the cap containing the W-25 Step B (80mg, 0.363mmol), Pd / (38.7mg, 0.036mmol) and MeOH (5mL) of container 5 hours was placed on a Parr shaker. The suspension was filtered through a pad of celite and evaporated in vacuo to afford abr. ¹ H NMR (500 MHz, CD ₃ OD) δ 3.69 (s, 1H), 2.84-2.60 (m, 1H), 2.41-2.21 (m, 4H), 1.48-1.29 (m, 3H).

Cap W-26 was prepared by the same procedure as described above for Cap W-25. ¹ H NMR (400 MHz, CD ₃ OD) δ 3.20-2.99 (m, 1H), 2.41-2.21. (m, 4H), 1.43-1.27 (m, 3H).

Cap W-27

Cap W-27 was prepared by the same procedure as described in Cap W-25. ¹ H NMR (500 MHz, CD ₃ OD) δ 2.44-2.28 (m, 1H), 1.98-1.88 (m, 2H), 1.75-1.58 (m, 4H), 1.57-1.45 (m, 2H), 1.22 (s) , 3H).

Cap W-28

Cap W-28 Step A

Feeding Cap W-25/Cap W-26 Step A (2g, 9.79mmol), Polyethylene Glycol (1.638mL, 29.4mmol) into 250 ml RBF equipped with a Dean-Stork trap ), p-toluenesulfonic acid monohydrate (0.186 g, 0.979 mmol) and toluene (50 mL). The mixture was heated to reflux slowly for 2 hours and the water formed was separated. The solvent is removed in vacuo, and the remaining residue was dissolved in EtOAc (50mL), dried and washed with saturated NaHCO ₃ and brine, dried over Na ₂ SO _4, filtered and evaporated in vacuo. The residual oil was purified by EtOAc (EtOAc:EtOAc) _{^{1 H NMR (500MHz, CDCl 3}} ) δ 7.49-7.31 (m, 5H), 5.16 (s, 2H), 4.01-3.85 (m, 4H), 3.08-2.91 (m, 1H), 2.79-2.65 (m, 2H), 2.63-2.51 (m, 2H).

Cap W-28 was hydrogenated by the same procedure as described in Cap W-25. ¹ H NMR (500 MHz, CD ₃ OD) δ 3.98-3.82 (m, 4H), 2.87 (t,J = 8.7 Hz, 1H), 2.65-2.46 (m, 4H).

Cap W-29 and cap W30

Cap W-29/ Cap W-30 Step A

(2S,4S)-1-(Tertoxycarbonyl)-4-hydroxypyrrolidin-2-carboxylic acid (5.22 g, 22.57 mmol), cesium carbonate (16.18 g, 49.7 mmol) and benzyl bromide ( A mixture of 3.22 mL, 27.1 mmol) in DMF (70 mL) was warm. The mixture was poured into ice cold water (500 mL) andEtOAcEtOAc Water, 0.2M NaOH and the organic layer was washed with brine, dried over MgSO _4, filtered and evaporated in vacuo. The residual oil was purified by FCC (20% to 60%EtOAc-hexanes) to afford abr. _{^{1 H NMR (400MHz, CDCl 3}} ) δ 7.54-7.31 (m, 5H), 5.42-5.27 (m, 1H), 5.27-5.11 (m, 2H), 4.40-4.26 (m, 1H), 3.80-3.51 ( m, 2H), 2.36 (dtd, J = 14.4, 9.8, 4.6 Hz, 1H), 2.22 - 2.03 (m, 1H), 1.57-1.41 (m, 5H), 1.37 (s, 5H).

Cap W-29/ Cap W-30 Step B

To a cap W-29/ cap W-30 Step A (2.98 g, 9.27 mmol), imidazole (3.16 g, 46.4 mmol) and 4-dimethylaminopyridine (0.113 g, 0.927 mmol) in DMF (20 mL) A solution of butyl dimethyl dimethyl decane chloride (2.59 mL, 20.40 mmol) in DMF (10.00 mL) was added dropwise. The resulting solution was stirred at rt EtOAc (EtOAc)EtOAc. The separated organic layer was washed with water and brine, dried over MgSO _4, filtered and evaporated in vacuo. The residual oil was purified by FCC (EtOAc to EtOAc) elute _{^{1 H NMR (400MHz, CDCl 3}} ) δ 7.49-7.31 (m, 5H), 5.36-5.00 (m, 2H), 4.56-4.23 (m, 2H), 3.79-3.52 (m, 1H), 3.48-3.24 ( m,1H), 2.49-2.25 (m,1H), 2.14 (dt, J = 12.9, 4.7 Hz, 1H), 1.48 (s, 3H), 1.41-1.30 (m, 6H), 0.98-0.79 (m, 9H), 0 (s, 6H).

Cap W-29/ Cap W-30 Step C

To a solution of bis(isopropyl)amine (1.281 mL, 9.14 mmol) in THF (40 mL), hexane (5.45 mL, 8.73 mmol). After the resulting solution was stirred at -78 °C for 30 min, a solution of EtOAc (EtOAc m. Methyl iodide (0.673 mL, 10.80 mmol) was then added dropwise via a syringe. After stirring at -78 °C for 2 hours, the reaction mixture was stirred at EtOAc (EtOAc) The organic extracts were washed with brine, dried (MgSO _4), filtered, and concentrated in vacuo. The residual oil was purified by EtOAc (EtOAc to EtOAc) elute ¹ H NMR (500MHz, CDCl ₃ ) δ 7.49-7.32 (m, 5H), 5.38-4.93 (m, 2H), 4.54-4.25 (m, 1H), 3.92-3.57 (m, 1H), 3.52-3.20 ( m,1H), 2.41-1.84 (m, 2H), 1.81-1.54 (m, 5H), 1.52-1.30 (m, 10H), 1.03-0.68 (m, 9H), 0.20--0.01 (m, 6H) .

Cap W-29 Step D

THF (4.23 mL, 4.23 mmol) containing 1 M tetrabutylammonium fluoride was added dropwise to an ice-cooled solution of EtOAc (EtOAc). After the resulting solution was stirred at rt EtOAc (EtOAc) (EtOAc) The organic extracts were washed with brine, dried (MgSO _4), filtered, and concentrated in vacuo. The residual oil was purified by FCC (0% to 50%EtOAc-hexanes) to afford to afford a vis. _{^{1 H NMR (400MHz, CDCl 3}} ) δ 7.50-7.31 (m, 5H), 5.38-4.96 (m, 2H), 4.48 (d, J = 2.3Hz, 1H), 3.88-3.65 (m, 1H), 3.62 -3.42(m,1H), 2.98-2.97(m,1H), 2.47-2.29(m,1H),2.16-1.96(m,1H),1.87-1.61(m,5H),1.55-1.30(m, 9H).

Cap W-29/ Cap W-30 Step E

To a solution of Cap W-29/ Cap W-30 Step D (540 mg, 1.610 mmol) in DCM (5 mL), EtOAc (EtOAc) ). The resulting solution was stirred at room temperature for 3 days. It was cooled with an ice bath and diluted with DCM, washed with saturated aqueous Na ₂ HPO ₄ The reaction was quenched. , Dried over MgSO ₄ organic layer was separated and washed with brine, filtered and evaporated in vacuo. The residue was purified by FCC (0% to 30%EtOAcEtOAc). The first dissolved compound in the form of an oil was collected from the column as a diastereomerically pure cap W-29 step E (124 mg, the absolute stereochemistry of alpha carbon was assigned to 2-( S )). _{^{1 H NMR (400MHz, CD 3}} OD) δ 7.44-7.27 (m, 5H), 5.31-5.02 (m, 3H), 3.88-3.56 (m, 2H), 2.53-2.19 (m, 2H), 1.64 (s , 3H), 1.43-1.32 (m, 9H).

A second dissolving compound in the form of a pale yellow oil was collected from the column as a diastereomerically pure cap W-30 step E (280 mg, the absolute stereochemistry of alpha carbon was assigned to 2-( R )), which was allowed to stand. solidification. _{^{1 H NMR (400MHz, CD 3}} OD) δ 7.42-7.27 (m, 5H), 5.25-5.03 (m, 3H), 3.92-3.62 (m, 2H), 2.67-2.50 (m, 1H), 2.39-2.15 (m, 1H), 1.65 (d, J = 18.1 Hz, 3H), 1.43-1.31 (m, 9H).

Under 30psi H _2, the cap containing the W-29 Step E (100mg, 0.296mmol), 10 % Pd / C (63mg, 0.059mmol) and MeOH (5mL) The vessel was placed on a Parr shaker 24 hours. The suspension was filtered through a pad of celite and evaporated in vacuo. The residue was triturated with EtOAc (EtOAc)EtOAc. ¹ H NMR (400 MHz, CD ₃ OD) δ 5.40-5.12 (m, 1H), 3.90-3.55 (m, 2H), 2.64 - 2.13 (m, 2H), 1.72-1.57 (m, 3H), 1.54-1.39 (m, 9H). (The absolute stereochemistry was confirmed by the NOE study.) Cap W-30

Cap W-30 was obtained by hydrogenation according to the procedure used to synthesize cap W-29. _{^{1 H NMR (500MHz, CD 3}} OD) δ 5.29-5.04 (m, 1H), 3.93-3.59 (m, 2H), 2.72-2.53 (m, 1H), 2.41-2.12 (m, 1H), 1.73-1.57 (m, 3H), 1.54-1.41 (m, 9H). (The absolute stereochemistry was confirmed by the NOE study.)

Cap B-1

Cap B-1, step a

To -butanone (500 mg, 7.13 mmol) and ((1-methoxy-2-methylprop-1-en-1-yl)oxy)trimethylnonane (2487 mg, 14.27) at -78 °C Methyl) BF _{3 was} added dropwise to a solution of DCM (10 mL). OEt ₂ (1.446 mL, 11.41 mmol), and the reaction mixture was stirred for 5 hr then warmed to room temperature. ₃ (50mL) The reaction mixture was quenched with saturated NaHCO, diluted with DCM (50mL). , Washed with brine (50mL), dried organic layer was separated and washed with 10% NaHCO ₃ solution (50mL) over Na ₂ SO _4, filtered and concentrated under reduced pressure. The crude material was purified by EtOAc EtOAc EtOAc (EtOAc:EtOAc ¹ H NMR (CDCl ₃ , δ = 7.26 ppm, 400 MHz): δ 3.67 (s, 3 H), 3.22 (s, 1 H), 2.34-2.20 (m, 2 H), 2.02-1.89 (m, 3 H) ), 1.63-1.48 (m, 1 H), 1.24 (s, 6 H).

Cap B-1

To a solution of hydroxyester B-1a (50 mg, 0.290 mmol) in THF (3 mL), MeOH ( 1.5 mL) Stir at room temperature for 12 hours. The reaction mixture was then cooled to 0 ° C, and the pH of the reaction mixture was adjusted to (about 3) with a 1.5 N HCl solution. The reaction is then extracted with DCM (2 × 50mL) mixture, and the organic layer was washed with brine (25 mL), dried over Na ₂ SO _4, filtered, and concentrated under reduced pressure to obtain the cap B-1 (22mg). ¹ H NMR (DMSO- d ₆ , δ = 2.50 ppm, 400 MHz): δ 2.40-2.29 (m, 2 H), 1.87-1.75 (m, 3 H), 1.47-1.38 (m, 1 H), 1.05 ( s, 6 H).

Cap B-2

Cap B-2, step a

To -cyclohexanone (10.0 g, 102 mmol) and ((1-methoxy-2-methylprop-1-en-1-yl)oxy)trimethylnonane (35.5 g, at -78 ° C, Pure BF ₃ .OEt ₂ (20.66 mL, 163 mmol) was added dropwise to a solution of EtOAc (EtOAc). ₃ (50mL) The reaction mixture was quenched with saturated NaHCO, diluted with DCM (250mL). , Washed with brine (50 mL), dried organic layer was separated and washed with 10% NaHCO ₃ solution (3 × 50mL) over Na ₂ SO _4, filtered and concentrated under reduced pressure. The crude material was purified by EtOAc EtOAc EtOAc EtOAc EtOAc ¹ H NMR (CDCl ₃ , δ = 7.26 ppm, 400 MHz): δ 3.69 (s, 3 H), 3.14 (s, 1 H), 1.75-1.59 (m, 3 H), 1.56-1.32 (m, 7 H) ), 1.21 (s, 6 H).

Cap B-2, step b

DAST (1.319 mL, 9.99 mmol) was added to a solution of hydroxy ester B-2a (2 g, 9.99 mmol) in DCM (10 mL). The reaction mixture was poured into 10% NaHCO ₃ (50mL), and the extracted with DCM (50mL). The organic layer was washed with brine (50mL), dried over Na ₂ SO _4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography eluting EtOAc EtOAc EtOAc ¹ H NMR (CDCl ₃ , δ = 7.26 ppm, 400 MHz): δ 5.59-5.54 (m, 1 H), 3.65 (s, 3 H), 2.09-2.03 (m, 2 H), 1.94-1.87 (m, 2 H), 1.63-1.52 (m, 4 H), 1.28 (s, 6 H).

Cap B-2, step c

To a solution of the ester B-2b (650 mg, 3.57 mmol) in MeOH (10 mL) EtOAc. AcOH (0.204 mL, 3.57 mmol) was then added and the reaction mixture was purified with nitrogen for 2 min. The reaction mixture was then hydrogenated at ambient temperature for 2 hours. The reaction mixture was filtered with EtOAc (EtOAc)EtOAc. The filtrate was then concentrated under reduced pressure to give EtOAc m. ¹ H NMR (CDCl ₃ , δ = 7.26 ppm, 400 MHz): δ 3.65 (s, 3 H), 2.00-1.50 (m, 6 H), 1.28-1.14 (m, 3 H), 1.12 (s, 6 H) ), 1.10-0.90 (m, 2 H).

Cap B-2

Add LiOH (65.0 mg, 2.71 mmol) to a solution of the ester B-2b (50 mg, 0.271 mmol) in EtOAc (3 mL) Heat at °C for 12 hours. The reaction mixture was then cooled to 0 ° C, and the pH of the reaction mixture was adjusted to (about 3) with a 1.5 N HCl solution. The reaction is then extracted with EtOAc (2 × 50mL) mixture, and the organic layer was washed with brine (25 mL), dried over Na ₂ SO _4, filtered, and concentrated under reduced pressure to obtain a white solid of the cap B-2 (20mg ). ¹ H NMR (CDCl ₃ , δ = 7.26 ppm, 400 MHz): δ 1.82-1.57 (m, 6 H), 1.30-1.15 (m, 3 H), 1.13 (s, 6 H), 1.11-0.95 (m, 2 H).

Cap B-3 and B-4

Caps B-3 and B-4, step a

To (1-ethoxycyclopropoxy)trimethylnonane (500 mg, 2.87 mmol) and ((1-methoxy-2-methylprop-1-en-1-yl) at -78 °C Pure BF ₃ .OEt ₂ (0.582 mL, 4.59 mmol) was added dropwise to a solution of oxy)trimethyl decane (1.163 mL, 5.74 mmol) in DCM (10 mL). To room temperature. ₃ (50mL) The reaction mixture was quenched with saturated NaHCO, diluted with DCM (50mL). , Washed with brine (50mL), dried organic layer was separated and washed with 10% NaHCO ₃ solution (50mL) over Na ₂ SO _4, filtered and concentrated under reduced pressure. The crude material was purified by EtOAc EtOAc EtOAc EtOAc EtOAc ¹ H NMR (CDCl ₃ , δ = 7.26 ppm, 400 MHz): δ 3.73 (s, 3 H), 3.20 (s, 1 H), 1.16 (s, 6 H), 0.74-0.68 (m, 4 H).

Cap B-3 and B-4

To a solution of hydroxyester B-3a (50 mg, 0.316 mmol) in THF (3 mL), MeOH ( 1.5 mL) Stir for 12 hours at room temperature. The reaction mixture was then cooled to 0 ° C, and the pH of the reaction mixture was adjusted to (about 3) with a 1.5 N HCl solution. The reaction is then extracted with DCM (2 × 50mL) mixture, and the organic layer was washed with brine (25 mL), dried over Na ₂ SO _4, filtered, and concentrated under reduced pressure to obtain a yellow liquid of cap B-3 to B a mixture of -4 (40 mg). Cap B-4: ¹ H NMR (CDCl ₃ , δ = 7.26 ppm, 400 MHz): δ 2.58 (q, J = 7.2, 2 H), 1.20 (s, 6 H), 1.08 (t, J = 7.2, 3) H).

Cap B-5

Cap B-5, step a

Dihydro-2H-piperan-4(3H)-one (1.887 mL, 19.98 mmol) and ethyl 2-(triphenylphosphinyl)acetate (13.92 g, 40.0 mmol) in toluene (50 mL) The solution was heated at 90 ° C for 12 hours. The reaction mixture was cooled to room temperature and concentrated under vacuum. The crude material was purified by Combi-flash (EtOAc,EtOAcEtOAcEtOAc ¹ H NMR (CDCl ₃ , δ = 7.26 ppm, 300 MHz): δ 5.68-5.67 (m, 1 H), 4.15 (q, J = 7.2, 3 H), 3.75 (dt, J = 13.6, 5.6, 4 H) ), 3.00 (dt, J = 6.0, 1.2, 2 H), 2.32 (dt, J = 6.0, 1.2, 2 H), 1.27 (t, J = 7.2, 3 H).

Cap B-5

To a solution of the ester B-5a (500 mg, 2.94 mmol) in EtOAc (3 mL) Stir under 12 hours. The reaction mixture was then cooled to 0 ° C, and the pH of the reaction mixture was adjusted to (about 3) with a 1.5 N HCl solution. The reaction is then extracted with DCM (2 × 50mL) mixture, and the organic layer was washed with brine (25 mL), dried over Na ₂ SO _4, filtered, and concentrated under reduced pressure to obtain a colorless liquid of the cap B-5 (300mg ). ¹ H NMR (CDCl ₃ , δ = 7.26 ppm, 400 MHz): δ 5.73 (s, 1 H), 3.86-3.72 (m, 4 H), 3.05-2.99 (m, 2 H), 2.41-2.36 (m, 2 H).

Cap B-6

Cap B-6, step a

A solution of trimethylsulfoxonium iodide (800 mg, 3.63 mmol) and NaH (60% in mineral oil, 153 mg, 6.37 mmol) in DMSO (10 mL) was stirred for 20 min. The reaction mixture was then cooled to 0.degree. C. and EtOAc (5 mL). The reaction mixture was quenched with EtOAc (EtOAc) Washed with water (2 × 50mL), the organic layer was washed with brine (50mL), dried over Na ₂ SO _4, filtered and concentrated under reduced pressure. The crude material was purified by EtOAc EtOAc EtOAc EtOAc EtOAc ¹ H NMR (CDCl ₃ , δ = 7.26 ppm, 400 MHz): δ 4.13 (q, J = 7.2, 2 H), 3.74-3.56 (m, 4 H), 1.77-1.73 (m, 2 H), 1.56- 1.42 (m, 3 H), 1.27 (t, J = 7.2, 3H), 1.17-1.15 (m, 1 H), 0.93-0.88 (m, 1 H).

Cap B-6

Add LiOH (65.0 mg, to a solution of the ester B-6a (50 mg, 0.271 mmol) in (2:1:1) THF (3 mL), MeOH (1.5 mL) 2.71 mmol) and stirred at room temperature for 12 hours. The reaction mixture was then cooled to 0 ° C, and the pH of the reaction mixture was adjusted to (about 3) with a 1.5 N HCl solution. The reaction is then extracted with DCM (2 × 50mL) mixture, and the organic layer was washed with brine (25 mL), dried over Na ₂ SO _4, filtered, and concentrated under reduced pressure to obtain a colorless liquid of the cap 35mg B-6 ( ). ¹ H NMR (CDCl ₃ , δ = 7.26 ppm, 300 MHz): δ 3.83-3.68 (m, 4 H), 1.85-1.81 (m, 2 H), 1.62-1.42 (m, 3 H) 1.21 (t, J) = 6.4, 1 H), 1.07-1.01 (m, 1 H).

Cap B-7

To a solution of Cap B-5 (100 mg, 0.703 mmol) in MeOH (5 mL)EtOAc. The reaction mixture was then hydrogenated at ambient temperature for 12 hours. The reaction mixture was filtered with EtOAc (EtOAc)EtOAc. The filtrate was concentrated under reduced pressure to give abr. ¹ H NMR (CDCl ₃ , δ = 7.26 ppm, 400 MHz): δ 3.98-3.94 (m, 2 H), 3.45-3.41 (m, 2 H), 2.30 (d, J = 6.8, 2 H), 2.05- 1.95 (m, 1 H), 1.71-1.66 (m, 2 H), 1.43-1.28 (m, 2 H).

Cap B-8

Cap B-8, step a

To a stirred solution of methyl cyclobutanecarboxylate (250 mg, 2.190 mmol) in THF (3 mL), EtOAc (EtOAc, EtOAc) The reaction mixture was stirred at -78 °C for 1 hour. A solution of cyclohexanone (150 mg, 1.533 mmol) in THF (2 mL) was added dropwise to the reaction mixture, and stirring was continued at -78 °C for 2 hr and stirred overnight at room temperature. The ice-cold saturated NH ₄ Cl solution (10 mL) was added to the reaction mixture, and extracted with EtOAc (2 × 10mL). The organic layer was washed with water (20mL) brine (20mL), dried over Na ₂ SO ₄ dried and concentrated under reduced pressure. The crude material was purified by EtOAc EtOAc EtOAc:EtOAc ¹ H NMR (CDCl ₃ , δ = 7.26 ppm, 400 MHz): δ 3.75 (s, 3 H), 2.76 (s, 1 H), 2.41-2.23 (m, 4 H), 1.87-1.73 (m, 2 H) ), 1.71-1.55 (m, 8 H), 1.45-1.33 (m, 2 H).

Cap B-8

LiOH (56.4 mg, 2.355 mmol) was added to a stirred solution of hydroxy ester B-8a (50 mg, 0.236 mmol) in THF (0.5 mL) and water (0.5 mL) at rt. The reaction mixture was stirred overnight. The reaction mixture was concentrated under reduced pressure. Water (10 mL) was added to EtOAc EtOAc. The aqueous layer was acidified with EtOAc (EtOAc)EtOAc. Concentrated under reduced pressure and the organic layer was dried over Na ₂ SO _4, to give an off-white solid of cap B-8 (16mg). ¹ H NMR (MeOD, δ = 3.34 ppm, 400 MHz): δ 2.41-2.25 (m, 4 H), 1.89-1.51 (m, 9 H), 1.49-1.37 (m, 2 H), 1.18-1.11 (m) , 1 H).

Cap B-9

Cap B-9, step a

To a solution of methyl cyclobutanecarboxylate (200 mg, 1.752 mmol) in THF (2 mL) EtOAc (EtOAc) The reaction mixture was stirred at -78 °C for 1 hour. A solution of 4,4-difluorocyclohexanone (165 mg, 1.227 mmol) in THF (2 mL) was added dropwise to the reaction mixture; stirring was continued at -78 °C for 2 hr and stirred overnight at room temperature. The ice-cold saturated NH ₄ Cl solution (10 mL) was added to the reaction mixture, and extracted with EtOAc (2 × 10mL). The organic layer was washed with water (20mL) and brine (20mL), ₂ SO ₄ and dried over Na and concentrated under reduced pressure. The crude material was purified by EtOAc EtOAc EtOAc EtOAc EtOAc ¹ H NMR (CDCl ₃ , δ = 7.26 ppm, 400 MHz): δ 3.79 (s, 3 H), 3.26 (s, 1 H), 2.46-2.35 (m, 2 H), 2.28-2.10 (m, 4 H) ), 2.01-1.63 (m, 8 H).

Cap B-9

LiOH (48.2 mg, 2.014 mmol) was added to a stirred solution of hydroxy ester B-9a (50 mg, 0.201 mmol) in THF (0.5 mL) and water (0.5 mL) at rt. The reaction mixture was stirred overnight. LiOH (48.2 mg, 2.014 mmol) was again added to the reaction mixture and stirring was continued for a further 24 hours. The volatile components were removed under reduced pressure. Water (10 mL) was added to EtOAc EtOAc. The aqueous layer was acidified with EtOAc (EtOAc)EtOAc. Concentrated under reduced pressure and the organic layer was dried over Na ₂ SO _4, to give an off-white solid of cap B-9 (32mg). ¹ H NMR (CDCl ₃ , δ = 7.26 ppm, 400 MHz): δ 2.53-2.42 (m, 2 H), 2.32-2.09 (m, 4 H), 2.05-1.92 (m, 3 H), 1.89-1.72 ( m, 5 H).

Cap B-10

Cap B-10, step a

To a solution of methyl cyclobutanecarboxylate (200 mg, 1.752 mmol) in THF (2 mL) EtOAc (EtOAc) The reaction mixture was stirred at -78 °C for 1 hour. A solution of dihydro-2H-piperidin-4(3H)-one (123 mg, 1.227 mmol) in THF (1 mL) was added dropwise to the reaction mixture; stirring was continued at -78 ° C for 2 hours and at room temperature Stir under night. The ice-cold saturated NH ₄ Cl solution (10 mL) was added to the reaction mixture, and extracted with EtOAc (2 × 10mL). The organic layer was washed with water (20mL) and brine (20mL), ₂ SO ₄ and dried over Na and concentrated under reduced pressure. The crude material was purified by EtOAc EtOAc EtOAc (EtOAc:EtOAc ¹ H NMR (CDCl ₃ , δ = 7.26 ppm, 400 MHz): δ 3.85-3.79 (m, 4 H), 3.77 (s, 3 H), 3.20 (s, 1 H), 2.44-2.34 (m, 2 H) ), 2.31-2.20 (m, 2 H), 1.96-1.77 (m, 4 H), 1.45-1.38 (m, 2 H).

Cap B-10

LiOH (168 mg, 7.00 mmol) was added to a stirred solution of hydroxy ester B-10a (150 mg, 0.700 mmol) in THF (1 mL) and water (1 mL) and stirred at room temperature. The mixture was 48 hours. The reaction mixture was concentrated under reduced pressure. Water (10 mL) was added to EtOAc EtOAc. The aqueous layer was acidified with EtOAc (EtOAc)EtOAc. Dried over Na ₂ SO _4, and the organic layer was concentrated under reduced pressure, to give a white solid of the cap B-10 (28mg). ¹ H NMR (MeOD, δ = 3.34 ppm, 400 MHz): δ 3.79-3.75 (m, 4 H), 2.39-2.32 (m, 4 H), 1.93-1.74 (m, 4 H), 1.53-1.47 (m) , 2 H).

Cap B-11

Cap B-11, step a

To dihydro-2H-piperidin-4(3H)-one (2g, 19.98mmol) and ((1-methoxy-2-methylprop-1-en-1-yl) at -78 °C yloxy) of the trimethyl Silane (6.96g, 40.0mmol) in DCM (20mL) under nitrogen was added dropwise _{BF 3 .OEt 2 (4.05mL, 32.0mmol} ), and the reaction mixture was gradually warmed to room temperature . The ice-cold saturated NH ₄ Cl solution (100 mL) was added to the reaction mixture, and extracted with EtOAc (2 × 100mL). Washed with water (100mL), the organic layer was washed with brine (100mL), dried over Na ₂ SO _4, filtered and concentrated under reduced pressure. The crude material was purified by EtOAc EtOAc EtOAc:EtOAc ¹ H NMR (CDCl ₃ , δ = 7.26 ppm, 400 MHz): δ 3.87-3.75 (m, 4 H), 3.72 (s, 3 H), 3.51-3.50 (m, 1 H), 1.88-1.75 (m, 2 H), 1.37-1.31 (m, 2 H), 1.24 (s, 6 H).

Cap B-11, step b

DAST (1.307 mL, 9.89 mmol) was added to a stirred solution of hydroxy ester B-11a (1 g, 4.94 mmol) in DCM (10 mL). hour. The reaction mixture was cooled to 0 ℃ and treated with 10% NaHCO ₃ the solution was cooled (50mL) and quenched. The reaction mixture was extracted with DCM (2×50 mL) The organic layer was concentrated, and Na ₂ SO ₄ dried under reduced pressure. The crude material was purified by EtOAc EtOAc EtOAcjEtOAc ¹ H NMR (CDCl ₃ , δ = 7.26 ppm, 400 MHz): δ 5.59-5.57 (m, 1 H), 4.19 (dd, J = 2.8, 2.4, 2 H), 3.76 (t, J = 5.4, 2 H) ), 3.65-3.67 (s, 3 H), 2.08-2.02 (m, 2 H), 1.31 (s, 6 H).

Cap B-11

LiOH (195 mg, 8.14 mmol) was added to a stirred solution of EtOAc (EtOAc) (EtOAc) The volatile components were removed under reduced pressure. Water (10 mL) was added to EtOAc EtOAc. The aqueous layer was acidified with EtOAc (EtOAc)EtOAc. Dried over Na ₂ SO _4, and the organic layer was concentrated under reduced pressure to give a brown oil of the cap B-11 (80mg). ¹ H NMR (MeOD, δ = 3.34 ppm, 400 MHz): δ 5.67 - 5.65 (m, 1 H), 4.19 (dd, J = 2.8, 2.4, 2 H), 3.78 (t, J = 5.4, 2 H) , 2.17-2.01 (m, 2 H), 1.32 (s, 6 H).

Cap B-12

Add AcOH (0.05 mL), Pd/C (15.63 mg, 0.015 mmol) to a stirred solution of Cap B-11 (25 mg, 0.147 mmol) in MeOH (1.5 mL). The reaction mixture was stirred overnight under a hydrogen atmosphere (5 kg/cm ² ). The reaction mixture was filtered through EtOAc (EtOAc) (EtOAc) The combined filtrate was concentrated under reduced pressure to give abr. ¹ H NMR (MeOD, δ = 3.34 ppm, 400 MHz): δ 3.99 (dd, J = 11.2, 4.4, 2 H), 3.41 (dt, J = 11.6, 2.4, 2 H), 1.90 to 10.81 (m, 1) H), 1.56-1.41 (m, 4 H), 1.14 (s, 6 H).

Cap B-13

Cap B-13, step a

To a stirred solution of tributyl butyl propanecarboxylate (350 mg, 2.461 mmol) in THF (2 mL), EtOAc (EtOAc, EtOAc. The reaction mixture was stirred at -78 °C for 1 hour. Then, THF (1 mL) containing dihydro-2H-piperidin-4(3H)-one (172 mg, 1.723 mmol) was added dropwise, and the mixture was stirred at -78 °C for 1 hour and stirred at room temperature overnight. The ice-cold saturated NH ₄ Cl solution (10 mL) was added to the reaction mixture, and extracted with EtOAc (2 × 20mL). Washed with water (20 mL), the organic layer was washed with brine (20 mL), dried over Na ₂ SO _4, filtered, and concentrated under reduced pressure. The crude material was purified with EtOAc EtOAc (EtOAc) ¹ H NMR (CDCl ₃ , δ = 7.26 ppm, 400 MHz): δ 4.51-4.48 (m, 1 H), 3.84 (dt, J = 11.6, 2.4, 2 H), 3.78-3.72 (m, 2 H), 1.62-1.48 (m, 4 H), 1.42 (s, 9 H), 1.12 - 1.08 (m, 2 H), 0.95 - 0.91 (m, 2 H).

Cap B-13

To a stirred solution of hydroxy ester B-13a (100 mg, 0.413 mmol) in EtOAc (EtOAc:EtOAc) The reaction mixture was stirred for 2 hours. The reaction mixture was concentrated to dryness under reduced pressure. The residue was co-evaporated with DCM (3.times. ¹ H NMR (MeOD, δ = 3.34 ppm, 400 MHz): δ 3.81-3.75 (m, 4 H), 2.20-2.11 (m, 2 H), 1.49-1.45 (m, 2 H), 1.14-1.11 (m , 2 H), 1.08-1.05 (m, 2 H).

Cap B-14

Cap B-14, step a

DAST (0.109 mL, 0.825 mmol) was added to a stirred solution of hydroxy ester B-13a (100 mg, 0.413 mmol) in DCM (2 mL). hour. The reaction mixture was cooled with ice to 0 ℃ and 10% NaHCO ₃ solution (10 mL) and quenched. The reaction mixture was extracted with DCM (2×20 mL The organic layer was concentrated, and Na ₂ SO ₄ dried under reduced pressure. The crude material was purified by EtOAc EtOAc EtOAc EtOAc EtOAc ¹ H NMR (CDCl ₃ , δ = 7.26 ppm, 400 MHz): δ 3.86 (dd, J = 11.6, 6.0, 2 H), 3.66 (dt, J = 11.2, 2.0, 2 H), 2.62-2.43 (m, 2 H), 1.65-1.56 (m, 2 H), 1.46 (s, 9 H), 1.10-1.01 (m, 4 H).

Cap B-14

Add a solution of TFA (0.378 mL, 4.91 mmol) in DCM (0.3 mL) EtOAc (EtOAc) The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated to dryness under reduced pressure. The residue was co-evaporated with DCM (3.times. ¹ H NMR (CDCl ₃ , δ = 7.26 ppm, 400 MHz): δ 3.92 (dd, J = 11.6, 5.6, 2 H), 3.69 (dt, J = 11.2, 2.0, 2 H), 2.67-2.46 (m, 2 H), 1.65-1.53 (m, 2 H), 1.34-1.20 (m, 4 H).

Cap B-15

BF ₃ .OEt ₂ (1.111 mL, 8.77 mmol) was added dropwise to a stirred solution of Cap B-14 (330 mg, 1.753 mmol) in DCM (1 mL) and stirred at 0 ° C. The mixture was stirred for 1 hour and at room temperature for 12 hours. The reaction mixture was concentrated under reduced pressure at room temperature. The (15mL) water was added to the residue, followed by addition of 10% NaHCO ₃ solution (25 mL), and extracted with 10% EtOAc / petroleum ether (50mL). The aqueous layer was acidified with EtOAc (EtOAc) The organic layer was washed with brine (50 mL), dried over Na ₂ SO ₄ and concentrated under reduced pressure to give a brown solid of the cap B-15 (200mg). ¹ H NMR (MeOD, δ = 3.34 ppm, 400 MHz): δ 5.67 - 5.64 (m, 1 H), 4.14 - 4.11 (m, 2 H), 3.82-3.77 (m, 2 H), 2.31-2.26 (m) , 2 H), 1.32-1.28 (m, 2 H), 1.02-0.95 (m, 2 H).

Cap B-16

Add AcOH (0.01 mL), Pd/C (26.9 mg, 0.025 mmol) to a stirred solution of Cap B-15 (85 mg, 0.505 mmol) in MeOH (2 mL). The reaction mixture was stirred under a hydrogen atmosphere (5 kg/cm ² ) for 12 hours in a pressure reactor. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The 10% NaHCO ₃ solution (20mL) was added to the residue, and the 10% EtOAc in petroleum ether (20mL) containing extracted. The aqueous layer was acidified with EtOAc (EtOAc) The organic layer was washed with brine (20 mL), dried over Na ₂ SO ₄ and concentrated under reduced pressure to give a brown sticky solid plastic cap of the B-16 (65mg). ¹ H NMR (DMSO- d ₆ , δ = 2.50 ppm, 300 MHz): δ 3.89 - 3.80 (m, 2 H), 3.30 - 3.12 (m, 2 H), 1.59-1.38 (m, 5 H), 0.95- 0.70 (m, 4 H).

Cap B-17

Cap B-17, step a

To a stirred solution of tributyl butyl propanecarboxylate (0.5 g, 3.52 mmol) in THF (4 mL), EtOAc (EtOAc) Next, cyclohexanone (0.207 g, 2.110 mmol) was added dropwise at -78 ° C and stirred at the same temperature for 2 hours, and the reaction mixture was slowly brought to ambient temperature and stirred for 12 hours. Washed with water (50mL) The reaction was quenched and extracted with EtOAc (250mL), washed with brine, dried over Na ₂ SO _4, filtered and evaporated under reduced pressure. The crude material was purified by flash chromatography eluting elut elut elut elut elut elut ¹ H NMR (DMSO- d ₆ , δ = 2.50 ppm, 400 MHz): δ 3.82 (s, 1 H), 2.03 (dt, J = 13.2, 4.4, 2 H), 1.65-1.49 (m, 3 H), 1.46-1.32 (m, 4 H), 1.37 (s, 9 H), 1.13-1.10 (m, 1 H), 0.97-0.94 (m, 2 H), 0.80-0.77 (m, 2 H).

Cap B-17

TFA (0.5 mL, 6.49 mmol) was added dropwise to a stirred solution of hydroxy ester B-17a (0.1 g, 0.416 mmol) in DCM (1 mL) The volatile component was evaporated under reduced pressure to give abr. B-17 (0.08 g). ¹ H NMR (DMSO- d ₆ , δ = 2.50 ppm, 400 MHz): δ 12.08 (s, 1 H), 5.55-5.53 (m, 1 H), 2.07-2.05 (m, 2 H), 1.97-1.95 ( m, 2 H), 1.58-1.48 (m, 4 H), 1.13-1.08 (m, 2 H), 0.84-0.80 (m, 2 H).

Cap B-18

Cap B-18, step a

To a stirred solution of tributyl butyl 1-(4,4-difluoro-1-hydroxycyclohexyl)cyclopropanecarboxylate (0.2 g, 0.724 mmol) in DCM (4 mL) DAST (0.096 mL, 0.724 mmol) was added and the reaction mixture was slowly taken to ambient temperature and stirred for 1 hour. The reaction mixture was then saturated with NaHCO ₃ (25mL), and extracted with DCM (200mL). The organic layer was dried over Na ₂ SO _4, filtered and evaporated under reduced pressure. The crude material was purified by flash chromatography eluting elut elut elut elut elut elut ¹ H NMR (CDCl ₃ , δ = 7.26 ppm, 400 MHz): δ 2.70-2.49 (m, 2 H), 2.10-1.92 (m, 4 H), 1.87-1.78 (m, 2 H), 1.43 (s, 9 H), 1.12-1.09 (m, 2 H), 1.06-1.03 (m, 2 H).

Cap B-18

TFA (0.083 mL, 1.078 mmol) was added to a stirred solution of EtOAc EtOAc (EtOAc). The reaction mixture was evaporated with EtOAc EtOAc m. ¹ H NMR (CDCl ₃ , δ = 7.26 ppm, 400 MHz): δ 2.75-2.50 (m, 2 H), 2.09-1.97 (m, 4 H), 1.85-1.78 (m, 2 H), 1.24-1.21 ( m, 2 H), 1.12-1.05 (m, 2 H).

Cap B-19

Cap B-19, step a

LDA (0.496 g, 4.63 mmol) was added dropwise to a stirred solution of methyl cyclobutanecarboxylate (0.44 g, 3.85 mmol) in THF (2 mL). The mixture was 2 hours. Then, anhydrous acetone (0.198 mL, 2.70 mmol) was added dropwise at -78 °C; the reaction mixture was slowly brought to ambient temperature and stirred for 12 hr. The reaction mixture was quenched with crushed ice, and extracted with EtOAc (100mL), dried over Na ₂ SO _4, filtered and evaporated under reduced pressure. The crude material was purified with EtOAc (EtOAc:EtOAc:EtOAc ¹ H NMR (DMSO- d ₆ , δ = 2.50 ppm, 400 MHz): δ 4.63 (s, 1 H), 3.62 (s, 3 H), 2.40-2.34 (m, 2 H), 2.18-2.12 (m, 2 H), 1.67-1.63 (m, 2 H), 1.01 (s, 6 H).

Cap B-19

Add LiOH (0.083 g, 3.48 mmol) to a stirred solution of hydroxy ester B-19a (0.12 g, 0.697 mmol) in THF (2 mL), MeOH (2 mL) The resulting reaction mixture was stirred for 12 hours. The volatile components were then evaporated under reduced pressure. The resulting residue was dissolved in water (50 mL) and the pH was adjusted to 4-5 with 0.5N HCl solution. Aqueous solution was extracted with DCM (250mL), dried over Na ₂ SO _4, filtered and evaporated under reduced pressure to give a colorless liquid of the cap B-19 (0.065g). ¹ H NMR (CDCl ₃ , δ = 7.26 ppm, 300 MHz): δ 2.55-2.44 (m, 2 H), 2.28-2.17 (m, 2 H), 2.05-1.84 (m, 2 H), 1.37 (s, 6 H).

Cap B-20

Cap B-20, step a

K ₂ CO ₃ (3.19 g, 23.05 mmol) was added to a stirred solution of _3- ethyloxybutyrate (1 g, 7.68 mmol) in DMSO (10 mL) at room temperature, followed by dropwise addition 1 2-Dibromoethane (3.61 g, 19.2 mmol). The reaction mixture was stirred at ambient temperature for 48 h and quenched with water (50 mL). The reaction was extracted with EtOAc (200mL) the mixture was washed with brine (50 mL), dried over Na ₂ SO _4, filtered and evaporated under reduced pressure. The crude material was purified by flash chromatography eluting elut elut elut elut elut elut ¹ H NMR (CDCl ₃ , δ = 7.26 ppm, 400 MHz): 4.20 (q, d = 7.2, 2 H), 2.46 (s, 3 H), 1.46 (s, 4 H), 1.28 (t, J = 7.2) , 3 H).

Cap B-20

To a stirred solution of ketone ester B-20a (0.3 g, 1.921 mmol) in MeOH (4 mL), EtOAc (EtOAc) The volatile components were evaporated under reduced pressure and diluted with water (50 mL). The pH of the reaction mixture was adjusted to 3-4 with 1N EtOAc andEtOAc. The organic layer was dried over Na ₂ SO _4, filtered and evaporated under reduced pressure to afford the cap B-20 (0.07g). ¹ H NMR (CDCl ₃ , δ = 7.26 ppm, 300 MHz): δ 2.12 (s, 3 H), 2.01-1.98 (m, 2 H), 1.76-1.73 (m, 2 H).

Cap B-21

Cap B-21, step a

Add K _{2 to the} stirred solution of 3-(((3-oxobutylbutylidene)oxy)methyl)benzene-1-ylindole (1 g, 5.23 mmol) in DMSO (10 mL) CO ₃ (2.168 g, 15.69 mmol) followed by dropwise addition of 1,2-dibromoethane (2.456 g, 13.08 mmol). The reaction mixture was stirred at ambient temperature for 24 hours, then heated to 80 ° C for 24 hours. The reaction was quenched with EtOAc (EtOAc)EtOAc. The organic layer was washed with brine (50mL), dried over Na ₂ SO _4, filtered and evaporated under reduced pressure. By reverse phase HPLC (ACN / water / NH ₄ OAc) crude material was purified to give the ketoester B-21a (0.3g). ¹ H NMR (MeOD, δ = 3.34 ppm, 400 MHz): δ 7.39-7.33 (m, 5 H), 5.20 (s, 2 H), 2.40 (s, 3 H), 1.50-1.42 (m, 4 H) .

Cap B-21, step b

MeMgBr (0.273 g, 2.291 mmol) was added to a stirred solution of the ketoester B-21a (0.5 g, 2.291 mmol) in THF (10 mL), and the mixture was slowly brought to ambient temperature and stirred 12 hour. The reaction was quenched with EtOAc (EtOAc)EtOAc. The organic layer was washed with brine (50mL), dried over Na ₂ SO _4, filtered and evaporated under reduced pressure. The crude material was purified by flash chromatography eluting elut elut elut elut elut elut elut elut ¹ H NMR (MeOD, δ = 3.34 ppm, 400 MHz): δ 7.38-7.33 (m, 5 H), 5.08 (s, 2 H), 1.39 (s, 6 H), 1.10-1.09 (m, 4 H) ).

Cap B-21

Pd/C (0.018 g, 0.017 mmol) was added to a stirred solution of EtOAc (EtOAc) (EtOAc) The reaction mixture was filtered through EtOAc (EtOAc) (EtOAc) The filtrate was evaporated under reduced pressure to give abr. ¹ H NMR (MeOD, δ = 3.34 ppm, 400 MHz): δ 1.37 (s, 6 H), 1.09-1.05 (m, 4H).

Cap B-22

Cap B-22, step a

DAST (0.135 mL, 1.024 mmol) was added dropwise to a stirred solution of hydroxy ester B-21b (0.2 g, 0.854 mmol) in DCM (5 mL). Stir for 2 hours. The reaction was cooled to 0 ℃, and washed with saturated NaHCO ₃ (50mL) was quenched and extracted with DCM (200mL). The organic layer was dried over Na ₂ SO _4, filtered and evaporated under reduced pressure to give a brown liquid ester of cap B-22a (0.15g). ¹ H NMR (CDCl ₃ , δ = 7.26 ppm, 400 MHz): δ 7.36-7.28 (m, 5 H), 5.07 (s, 2H), 1.58 (d, J = 23.6, 6 H), 1.22-1.19 (m) , 2 H), 1.15 - 1.13 (m, 2 H).

Cap B-22

Pd/C (0.018 g, 0.017 mmol) was added to a stirred solution of EtOAc EtOAc (EtOAc,EtOAc. The reaction mixture was filtered through a pad of EtOAc (EtOAc) (EtOAc) The filtrate was evaporated under reduced pressure to give abr. ¹ H NMR (MeOD, δ = 3.34 ppm, 400 MHz): δ 1.58 (d, J = 23.6, 6 H), 1.17-1.15 (m, 2 H), 1.10-1.08 (m, 2 H).

Cap B-23

Cap B-23, step a

NaBH ₄ (0.069 g, 1.833 mmol) was added portionwise to a stirred solution of ketone ester cap B-21a (0.4 g, 1.833 mmol) in MeOH (10 mL). The mixture was 1 hour. The solvent was evaporated under reduced pressure and the obtained crude material was dissolved in water (20mL). The pH of the reaction mixture was adjusted to 5-6 with 1.5 N HCl. (200mL) and the aqueous layer was extracted with DCM, and the combined organic layer and dried over Na ₂ SO _4, filtered and evaporated under reduced pressure, to obtain hydroxy ester B-23a (0.3g). ¹ H NMR (CDCl ₃ , δ = 7.26 ppm, 400 MHz): δ 7.38-7.25 (m, 5 H), 5.12 (ABq, J = 12.4, 2 H), 3.63 (q, J = 6.4, 1 H), 1.32-1.22 (m, 2 H), 1.26 (d, J = 6.4, 3 H), 0.97-0.92 (m, 1 H), 0.86-0.82 (m, 1 H).

Cap B-23

Pd/C (0.966 g, 0.908 mmol) was added to a stirred solution of EtOAc EtOAc (EtOAc,EtOAc. The reaction mixture was filtered through a pad of EtOAc (EtOAc) (EtOAc) The filtrate was evaporated under reduced pressure to give abr.br. ¹ H NMR (CDCl ₃ , δ = 7.26 ppm, 400 MHz): δ 3.61-3.57 (m, 1 H), 1.37-1.21 (m, 2 H), 1.28 (d, J = 6.4, 3 H), 1.00- 0.95 (m, 1 H), 0.87-0.81 (m, 1 H).

Cap B-24

Cap B-24, step a

DAST (0.144 mL, 1.090 mmol) was added dropwise to a stirred solution of hydroxy ester B-23a (0.2 g, 0.908 mmol) in DCM (5 mL). Stir for 2 hours. The reaction was cooled to 0 ℃, and washed with saturated NaHCO ₃ (50mL) and quenched. With DCM (200mL) the reaction mixture was extracted, dried over Na ₂ SO ₄ and evaporated under reduced pressure to give a pale yellow liquid ester of cap B-24a (0.15g). ¹ H NMR (CDCl ₃ , δ = 7.26 ppm, 400 MHz): δ 7.38-7.28 (m, 5 H), 5.12 (dq, J = 47.2, 6.4, 1 H), 5.11 (s, 2 H), 1.37 ( Dd, J = 27.6, 6.4, 3 H), 1.31-1.20 (m, 2 H), 1.14-1.08 (m, 1 H), 0.98-0.92 (m, 1 H).

Cap B-24

Pd/C (0.718 g, 0.675 mmol) was added to a stirred solution of EtOAc (EtOAc) (EtOAc) The reaction mixture was filtered through a pad of EtOAc (EtOAc) (EtOAc) The filtrate was evaporated under reduced pressure to give cap B-24 (0.06 g). ¹ H NMR (CDCl ₃ , δ = 7.26 ppm, 300 MHz): δ 7.53 (br s, 1 H), 5.55 (dq, J = 47.2, 6.4, 1 H), 1.38 (dd, J = 24.4, 6.4, 3 H), 1.36-1.24 (m, 2 H), 1.7-1.12 (m, 1 H), 1.02-0.98 (m, 1 H).

Cap B-25

Cap B-25, step a

Add K ₂ CO ₃ (6.47 g, 46.8 mmol) to a stirred solution of benzyl 3-butoxybutyrate (3 g, 15.61 mmol) in DMSO (30 mL) at room temperature, followed by dropwise addition MeI (2.93 mL, 46.8 mmol). The reaction mixture was then stirred at ambient temperature for 24 hours. The reaction was quenched with EtOAc (EtOAc)EtOAc. The organic layer was washed with brine (50mL), dried over Na ₂ SO ₄ and evaporated under reduced pressure. By reverse phase HPLC (ACN / water / NH ₄ OAc) crude material was purified to give the ketoester B-25a (3g). ¹ H NMR (CDCl ₃ , δ = 7.26 ppm, 400 MHz): 7.36-7.31 (m, 5 H), 5.17 (s, 2 H), 2.08 (s, 3 H), 1.38 (s, 6H).

Cap B-25, step b

MeMgBr (0.271 g, 2.270 mmol) was added to the stirred solution of the ketoester B-25a (0.5 g, 2.270 mmol) in THF (10 mL), and the mixture was slowly brought to ambient temperature and stirred 12 hour. The reaction was quenched with EtOAc (EtOAc)EtOAc. The organic layer was washed with brine (50mL), dried over Na ₂ SO ₄ and evaporated under reduced pressure. The crude material was purified by flash chromatography eluting elut elut elut elut elut elut elut ¹ H NMR (CDCl ₃ , δ = 7.26 ppm, 400 MHz): δ 7.38-7.33 (m, 5 H), 5.16 (s, 2 H), 3.59 (s, 1H), 1.26 (s, 6 H), 1.17 (s, 6 H).

Cap B-25, step c

DAST (0.134 mL, 1.016 mmol) was added dropwise to a stirred solution of hydroxy ester B-25b (0.2 g, 0.846 mmol) in DCM (5 mL). Stir for 2 hours. The reaction was cooled to 0 ℃, and washed with saturated NaHCO ₃ (50mL) was quenched and extracted with DCM (200mL). The organic layer was washed with brine (50 mL), dried over Na ₂ SO ₄ and evaporated under reduced pressure to give a brown liquid ester of the B-25c (0.12g). ¹ H NMR (CDCl ₃ , δ = 7.26 ppm, 400 MHz): 7.37-7.30 (m, 5 H), 5.12 (s, 2 H), 1.33 (s, 6 H), 1.31-1.10 (m, 6 H) .

Cap B-25

Pd/C (0.018 g, 0.017 mmol) was added to a stirred solution of EtOAc EtOAc (EtOAc,EtOAc. The reaction mixture was filtered through a pad of EtOAc (EtOAc) (EtOAc) The filtrate was evaporated under reduced pressure to give cap B-25 (0.04 g). ¹ H NMR (CDCl ₃ , δ = 7.26 ppm, 400 MHz): δ 1.43 (d, J = 22.4, 6 H), 1.27 (s, 6H).

Cap B-26

Cap B-26, step a

NaBH ₄ (0.137 g, 3.63 mmol) was added portionwise to a stirred solution of ketone ester B-25a (0.8 g, 3.63 mmol) in MeOH (10 mL), and the mixture was stirred at the same temperature. 1 hour. The solvent was evaporated under reduced pressure and the obtained crude material was dissolved in water (20mL). The pH of the reaction mixture was adjusted to 5-6 with 1.5 N HCl. (200mL) and the aqueous layer was extracted with DCM, and the combined organic layer and dried over Na ₂ SO _4, filtered and evaporated under reduced pressure to give a pale yellow liquid of hydroxy ester B-26a (0.7g). ¹ H NMR (CDCl ₃ , δ = 7.26 ppm, 400 MHz): 7.39-7.31 (m, 5 H), 5.15 (s, 2 H), 3.90-3.87 (m, 1 H), 2.54 (br s, 1 H) ), 1.20 (s, 6 H), 1.13 (d, J = 6.4, 3 H).

Cap B-26

Pd/C (2.394 g, 2.249 mmol) was added to a stirred solution of hydroxy ester B-26a (0.5 g, 2.449 mmol) in EtOAc (5 mL). The reaction mixture was filtered through a pad of EtOAc (EtOAc) (EtOAc) The filtrate was evaporated under reduced pressure to give abr. B-26 (0.2 g). ¹ H NMR (CDCl ₃ , δ = 7.26 ppm, 300 MHz): 3.92-3.87 (m, 1 H), 1.24 (s, 6 H), 1.21. (d, J = 6.4, 3 H).

Cap B-27

Cap B-27, step a

At room temperature, in the in Et ₂ O (5mL) to a stirred ketoester B-21a (0.5g, 2.291mmol) was added portionwise methylene triphenyl phosphine (0.760g, 2.75mmol), and Stir for 4 hours. The reaction was quenched with EtOAc (EtOAc)EtOAc. The organic layer was dried over Na ₂ SO _4, filtered and evaporated under reduced pressure. The crude material was purified by flash chromatography eluting elut elut elut elut elut elut ¹ H NMR (CDCl ₃ , δ = 7.26 ppm, 400 MHz): δ 7.38-7.29 (m, 5 H), 5.12 (s, 2 H), 4.94-4.89 (m, 2 H), 1.88 (dd, J = 1.2, 0.8, 3 H), 1.37-1.35 (m, 2 H), 0.97-0.94 (m, 2 H).

Cap B-27

To a stirred solution of the ester B-27a (0.2 g, 0.925 mmol) in MeOH (5 mL), EtOAc (EtOAc) The volatile component was evaporated under reduced pressure and the obtained residue was diluted with water (25mL). The pH of the reaction mixture was adjusted to 3-4 with EtOAc (EtOAc) The organic layer was dried over Na ₂ SO _4, filtered and evaporated under reduced pressure to give a brown solid of the cap B-27 (0.045g). ¹ H NMR (CDCl ₃ , δ = 7.26 ppm, 400 MHz): δ 4.98 - 4.91 (m, 2 H), 1.90 (dd, J = 1.2, 0.8, 3 H), 1.42-1.39 (m, 2 H), 1.03-1.00 (m, 2 H).

Cap B-28

Cap B-28, step a

At room temperature, in the in Et ₂ O (5mL) to a stirred ketoester B-25a (0.5g, 2.270mmol) was added portionwise methylene triphenyl phosphine (0.753g, 2.72mmol), and Stir for 4 hours. The reaction was quenched with EtOAc (EtOAc)EtOAc. The organic layer was dried over Na ₂ SO _4, filtered and evaporated under reduced pressure. The crude material was purified by flash chromatography eluting elut elut elut elut elut elut ¹ H NMR (CDCl ₃ , δ = 7.26 ppm, 400 MHz): δ 7.35-7.29 (m, 5 H), 5.12 (s, 2 H), 4.88 - 4.86 (m, 2 H), 1.70 (dd, J = 1.2, 0.8, 3 H), 1.35 (s, 6 H).

Cap B-28

To a stirred solution of the ester B-28a (0.2 g, 0.916 mmol) in MeOH (5 mL) and water (3mL), LiOH (0.110 g, 4.58 mmol) was added and the mixture was stirred at ambient temperature for 14 hours. The volatile component was evaporated under reduced pressure and the obtained residue was diluted with water (25mL). The pH of the reaction mixture was adjusted to 3-4 with EtOAc (EtOAc) The organic layer was dried over Na ₂ SO _4, filtered and evaporated under reduced pressure to give a pale yellow liquid of the cap B-28 (0.035g). _{^{1 H NMR (CDCl 3, δ}} = 7.26ppm, 400MHz): δ 4.95-4.92 (m, 2 H), 1.80 (dd, J = 1.2,0.8,3 H), 1.35 (s, 6 H).

Cap B-29

Pd/C (0.059 g, 0.550 mmol) was added to a stirred solution of EtOAc (EtOAc) (EtOAc (EtOAc) 12 hours. The reaction mixture was filtered through a pad of EtOAc (EtOAc) (EtOAc) The filtrate was evaporated under reduced pressure to give abr. ¹ H NMR (MeOD, δ = 3.34 ppm, 400 MHz): δ ppm 2.02-1.95 (m, 1 H), 1.10 (s, 6 H), 0.90 (d, J = 8.0, 6 H).

Cap B-30

Cap B-30, step a

To propan-2-one (0.5 g, 8.61 mmol) and ((1-methoxy-2-methylprop-1-en-1-yl)oxy)trimethylnonane at -78 °C 3.00 g, 17.22 mmol) BF ₃ .OEt ₂ (1.745 mL, 13.77 mmol) was added dropwise to a stirred solution in DCM (15 mL). The reaction mixture was stirred for 6 hours while warming to ambient temperature. With 10% NaHCO ₃ (50mL) The reaction mixture was quenched, and the reaction mixture was dissolved in EtOAc (50mL). The organic layer was separated and washed with brine (25mL), ₂ SO ₄ dried and concentrated under reduced pressure over Na. The crude material was purified by flash chromatography eluting elut elut elut elut elut elut elut ¹ H NMR (DMSO-d ₆ , δ = 2.50 ppm, 400 MHz): δ 4.33 (s, 1 H), 3.58 (s, 3 H), 1.12 (s, 6 H), 1.11 (s, 6 H).

Cap B-30

To a solution of the hydroxyester B-30a (800 mg, 4.99 mmol) in THF (10 mL) and water (10 mL) EtOAc. The crude material was extracted with diethyl ether (25 mL) and organic layer was evaporated. The aqueous layer was acidified to pH 3-4 with 1.5 N HCl. Followed by 5% MeOH / DCM (3 × 25mL) aqueous phase was extracted, dried over Na ₂ SO _4, filtered and concentrated under reduced pressure to give an off-white solid of cap B-30 (496mg). ¹ H NMR (DMSO-d ₆ , δ = 2.50 ppm, 400 MHz): δ 1.15 (s, 6 H), 1.10 (s, 6 H).

Cap B-31

Cap B-31, steps a-1 and a-2

To a cyclopentanone (5 g, 59.4 mmol) and ((1-methoxy-2-methylprop-1-en-1-yl)oxy)trimethylnonane (20.72 g, at -78 ° C, 119 mmol) in DCM (150mL) in the stirred solution was added dropwise BF _3. OEt ₂ (12.05 mL, 95 mmol). The reaction mixture was stirred for 6 hours while warming to ambient temperature. With 10% NaHCO ₃ (300mL) was quenched reaction mixture, and the organic layer was separated, dried over Na ₂ SO ₄ dried and concentrated under reduced pressure. The crude material was purified by flash chromatography eluting EtOAc EtOAc EtOAc Colorless oil). B-31a-1: ¹ H NMR (DMSO-d ₆ , δ = 2.50 ppm, 300 MHz): δ 4.18 (s, 1 H), 3.56 (s, 3 H), 1.72-1.65 (m, 4 H), 1.51-1.44 (m, 4 H), 1.14 (s, 6 H). B-31a-2: ¹ H NMR (DMSO-d ₆ , δ = 2.50 ppm, 300 MHz): δ 5.48 (t, J = 2.1, 1 H), 3.59 (s, 3 H), 2.30-2.18 (m, 4 H), 1.85-1.71 (m, 2 H), 1.24 (s, 6 H).

Cap B-31

To a solution of the hydroxyester B-31a-1 (320 mg, 1.718 mmol) in THF (3 mL) and water (3 mL) The crude material was extracted with diethyl ether (25 mL) and organic layer was evaporated. The aqueous layer was acidified to pH 3-4 with 1.5 N HCl. Then extracted with 5% MeOH / DCM (2 × 25mL) aqueous phase, washed with water (25mL), dried over Na ₂ SO _4, filtered and concentrated under reduced pressure to give a pale yellow solid of the cap B-31 (261mg ). The crude material was used in the next step without further purification. ¹ H NMR (DMSO-d ₆ , δ = 2.50 ppm, 400 MHz): δ 1.77-1.67 (m, 4 H), 1.56-1.42 (m, 4 H), 1.12 (s, 6 H).

Cap B-32

To a stirred solution of the ester B-31a-2 (110 mg, 0.654 mmol) in THF (3 mL) and water (3 mL) The reaction mixture was stirred for 3 days. The crude material was extracted with diethyl ether (25 mL) and organic layer was evaporated. The aqueous layer was acidified to pH 3-4 with 1.5 N HCl. Then extracted with 5% MeOH / DCM (3 × 25mL) aqueous phase, washed with water (25mL), dried over Na ₂ SO _4, filtered and concentrated under reduced pressure to give the gluing cap-like substance B-32 (67mg ). This material was used as such in the next step without any further purification. ¹ H NMR (MeOD, δ = 3.34 ppm, 400 MHz): δ 5.56 (dd, J = 4.0, 2.0, 1 H), 2.36-2.31 (m, 4 H), 1.92-1.85 (m, 2 H), 1.33 (s, 6 H).

Cap B-33

A solution of Cap B-32 (70 mg, 0.454 mmol) in MeOH (3 mL) Pd/C (50 mg, 0.047 mmol) was then added and a vacuum was applied to remove nitrogen. The reaction mixture was then stirred overnight under a hydrogen atmosphere (balloon pressure) at ambient temperature. The catalyst was filtered through a syringe filter and washed with MeOH (4×10 mL). The filtrate was concentrated under reduced pressure to give abr. The crude material was used in the next step without further purification. ¹ H NMR (MeOD, δ = 3.34 ppm, 400 MHz): δ 2.20-2.15 (m, 1 H), 1.69-1.53 (m, 6 H), 1.38-1.29 (m, 2 H), 1.14 (s, 6) H).

Cap B-34

Cap B-34, step a

A stirred solution of benzyl 1-(2-hydroxypropan-2-yl)cyclopropanecarboxylate (750 mg, 3.20 mmol) in THF (15 mL). 4.80 mmol) and stirred at room temperature for 30 minutes. MeI (4.00 mL, 64.0 mmol) was then added dropwise to the reaction mixture at the same temperature and heated to 50 ° C for 12 h. After completion of the reaction mixture, EtOAc (3×50 mL). With brine (50mL) The combined organic layers were washed, dried over anhydrous Na ₂ SO _4, and the solvent removed under reduced pressure. The crude material was purified with EtOAc (EtOAc) eluting ¹ H NMR (CDCl ₃ , δ = 7.26 ppm, 400 MHz): δ 7.35-7.29 (m, 5H), 5.07 (s, 2H), 3.14 (s, 3H), 1.35 (s, 6H), 1.10-1.06 ( m, 4H).

Cap B-34

Benzyl 1-(2-methoxypropan-2-yl)cyclopropanecarboxylate (215 mg, 0.866 mmol) was dissolved in MeOH (8 mL) and placed in a micro-pressure reaction kettle to which 10% Pd was added. /C (46.1 mg, 0.043 mmol). The mixture was stirred at room temperature under a H ₂ atmosphere (2.5 kg/cm ² ) for 2.5 hours. The catalyst was filtered through a pad of celite and the bed was washed with MeOH (15 mL). The combined filtrate was concentrated under reduced vacuo afforded mjjjjjjj ¹ H NMR (CD ₃ OD, δ = 3.34 ppm, 400 MHz): δ 3.22 (s, 3H); 1.36 (s, 6H); 1.08 (s, 4H).

Cap B-35

Cap B-35, step a

Chloroiodomethane (0.798 mL, 10.99 mmol) was slowly added dropwise to a stirred suspension of diethylzinc (5.50 mL, 5.50 mmol) in toluene (2 mL) at -20 ° C and stirred for 1 hour. A solution of 2,2,3-trimethylbut-3-enoic acid benzyl ester (0.4 g, 1.832 mmol) in toluene (2 mL) was added dropwise to the reaction mixture at -20 ° C, and Stirring was continued for 6 hours at the same temperature, and then allowed to reach 25 °C. After completion of the reaction, it was cooled to 0 ℃ and (25mL) ₄ Cl was quenched with aqueous saturated NH. The product was extracted into EtOAc (3×50 mL)EtOAc. The crude residue thus obtained was purified by column chromatography (yield: EtOAc, EtOAc (EtOAc): EtOAc (EtOAc) Yield). ¹ H NMR (CDCl ₃ , δ = 7.26 ppm, 300 MHz): δ 7.40-7.31 (m, 5H), 5.15 (s, 2H), 1.11 (s, 6H), 0.99 (s, 3H), 0.68-0.64 ( m, 2H), 0.23-0.21 (m, 2H).

Cap B-35

To a stirred solution of benzyl 2-methyl-2-(1-methylcyclopropyl)propanoate (150 mg, 0.646 mmol) in MeOH (3 mL) 51.6 mg, 1.291 mmol), and stirred for 48 hours. The solvent was evaporated under reduced pressure. The residue was dissolved in water (20 mL)EtOAc. The pH of the aqueous layer was adjusted to 3-4 with 1.5N HCl and extracted with DCM (3×50mL). After evaporation of the solvent <RTI ID=0.0></RTI></RTI><RTIID=0.0> ¹ H NMR (CDCl ₃ , δ = 7.26 ppm, 400 MHz): δ 1.08 (s, 6H), 1.06 (s, 3H), 0.69-0.67 (m, 2H), 0.23-0.20 (m, 2H).

Cap B-36

Cap B-36, step a

Chloroiodomethane (0.805 mL, 11.10 mmol) was slowly added dropwise to a stirred suspension of diethylzinc (5.55 mL, 5.55 mmol) in toluene (2 mL) at -20 ° C and stirred 1 hour. A solution of benzyl 1-(prop-1-en-2-yl)cyclopropanecarboxylate (0.4 g, 1.849 mol) in toluene (2 mL) was added dropwise to this mixture at -20 ° C, and It was stirred at the same temperature for 6 hours and brought to 25 °C. After completion of the reaction, it was cooled again to 0 ℃ ₄ Cl and with aqueous saturated NH (20mL) quenched and extracted with EtOAc (2 × 50mL), dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue was purified by EtOAc EtOAcjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj 35.2% yield). ¹ H NMR (CDCl ₃ , δ = 7.26 ppm, 400 MHz): δ 7.37-7.30 (m, 5 H), 5.14 (s, 2 H), 1.20 (s, 3 H), 1.11 (applied quartet, J 3.6 Hz, 2 H), 0.70 (apparent quadruple peak, J 3.6 Hz, 2 H), 0.39-0.31 (m, 4 H).

Cap B-36

To a stirred solution of dicyclopropylbenzyl ester B-36a (200 mg, 0.868 mmol) in MeOH (5 mL), EtOAc (EtOAc) The solvent was evaporated under reduced pressure and the~~~~~~ The pH of the aqueous layer was adjusted to 3-4 using 1.5N HCl and extracted with dichloromethane (3×50 mL). The organic layer was evaporated under reduced pressure to give di-dichloropropyldithioacetate B-36 (0.03 mg, 0.214. ¹ H NMR (CDCl ₃ , δ ppm = 7.26, 400 MHz): δ 1.22 (s, 3 H), 1.19 (applied quartet, J 3.6 Hz, 2 H), 0.70 (apparent quadruple peak, J 3.6 Hz, 2 H), 0.33 (s, 4 H).

Cap B-37

Cap B-37, step a

Ethyl 2-oxopropionate (1 g, 8.61 mmol) was dissolved in DCM (5M) and cooled to -78. Titanium tetrachloride (8.61 mL, 8.61 mmol) in dichlorohexane (5 mL) was added thereto, and the reaction mixture was stirred at this temperature for 30 minutes. To the reaction mixture was added dropwise allyltrimethylnonane (1.279 g, 11.20 mmol) at -78 °C, and stirring was continued for 2 hr. It was then allowed to reach 0 ° C, and was quenched with aq. The residue was purified by EtOAc (EtOAc-EtOAc-EtOAcEtOAc (0.8 g, 5.06 mmol, 58.7% yield). ¹ H NMR (CDCl ₃ , δ = 7.26 ppm, 400 MHz): δ 5.84 - 5.72 (m, 1 H), 5.15 - 5.09 (m, 2 H), 4.29 - 4.19 (m, 2 H), 2.56 - 2.37 ( m, 2 H), 1.43 (s, 3 H), 1.31 (t, J = 9.6 Hz, 3 H).

Cap B-37

Add LiOH (0.378 g, 15.80 mmol) to a stirred solution of ethyl 2-hydroxy-2-methylpent-4-enoate (0.5 g, 3.16 mmol) in MeOH (3 mL). hour. The solvent was evaporated under reduced pressure and the residue was crystallised from water The aqueous portion was treated with diethyl ether (50 mL). The pH of the aqueous layer was then adjusted to 6 with HCl (1.5N) and extracted to dichloromethane (250 mL). The organic layer obtained was dried with sodium sulfate and evaporatedEtOAcjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj ¹ H NMR (CDCl ₃ , δ = 7.26 ppm, 400 MHz): δ 5.91-5.81 (m, 1 H), 5.14-5.08 (m, 2 H), 2.51 (dd, J = 14, 7.2 Hz, 1H), 2.40 (dd, J = 14, 7.2 Hz, 1H), 1.39 (s, 3 H).

Cap B-38

Cap B-38, step a

Deoxo-Fluor (837 μl, 4.54 mmol) and a catalytic amount of ethanol (1.060 μl, 0.018 mmol) were added to a 10 mL round bottom flask containing ketoester B-25a (200 mg, 0.908 mmol) at 0 ° C under an inert atmosphere. ). The reaction mixture was heated at 50 ° C overnight.

It was cooled to 0 ° C and a saturated NaHCO ₃ solution (10 mL) was added. The mixture was extracted with (3 x 15 mL) dichloromethane. The combined organic layers were washed with brine, dried over anhydrous sodium The liquid was purified to give the difluoro ester B-38a (135 mg) as a pale yellow liquid. ¹ H NMR (CDCl ₃ , δ = 7.26 ppm, 400 MHz): δ 7.40-7.29 (m, 5H), 5.2 (s, 2H), 1.64 (t, J _HF = 19.2 Hz, 3H), 1.35 (s, 6) H); ¹⁹ F NMR (CDCl ₃ , 376 MHz): δ = -97.5 (s, 2 F)

Cap B-38

Add Pd-C (10%) (57.1 mg) to a stirred solution of benzyl 3,3-difluoro-2,2-dimethylbutanoate (130 mg, 0.537 mmol) in ethyl acetate (5 mL) , 0.537 mmol), and the resulting mixture (under balloon pressure) was hydrogenated at room temperature for 4 hours. The reaction mixture was filtered through a pad of Celite, and washed with EtOAC (3×5 mL). The filtrate was evaporated under reduced pressure to give abr.br. ¹ H NMR (CDCl ₃ , δ = 7.26 ppm, 400 MHz): δ 1.72 (t, J _HF = 19.2 Hz, 3H), 1.36 (s, 6H); ¹⁹ F NMR (CDCl ₃ , 376 MHz): δ=-97.6 (s, 2 F).

Cap B-39

Cap B-39, step a

Ethyl alcohol (3.34 μl, 0.057 mmol) was added to a solution of cyclopropyl ketone ester B-21a (250 mg, 1.145 mmol) in Deoxo-Fluor (2 mL, 11.45 mmol). The mixture was allowed to warm to room temperature and heated at 50 °C for 36 hours. At 0 ℃ cooled and diluted with 25mL DCM and washed with saturated aqueous NaHCO ₃ (10 mL) and quenched. The aqueous layer was extracted with DCM (2×50 mL). , Dried with brine the combined organic layers over Na ₂ SO _4, and concentrated under reduced pressure. The crude material was purified with EtOAc EtOAc (EtOAc:EtOAc: ¹ H NMR (CDCl ₃ , δ = 7.26 ppm, 400 MHz): δ 7.38-7.30 (m, 5 H), 5.14 (s, 2 H), 1.89 (t, J _HF = 18.4 Hz, 3 H), 1.29 (m, 2 H), 1.27-1.23 (m, 2 H); ¹⁹ F NMR (CDCl ₃ , 376 MHz): δ=-93.8 (s, 2 F).

Cap B-39

10% Pd/C (20.00 mg, 0.019 mmol) was added to a solution of B-39a (200 mg, 0.832 mmol) in ethyl acetate (10 mL), and the mixture was stirred at ambient temperature under a hydrogen atmosphere (balloon pressure) 3 hours. The reaction mixture was filtered with EtOAc EtOAc EtOAc (EtOAcjjjjjjjj 95% yield). _{^{1 H NMR (CDCl 3, δ}} = 7.26ppm, 400MHz): δ 1.95 (t, J = 37.0Hz, 3 H), 1.40-1.36 (m, 2 H), 1.33-1.30 (m, 2 H); 19 F NMR (CDCl ₃ , 376 MHz): δ 94.14 (s, 2 F).

Cap B-40

Cap B-40, step a

Pyridine (0.459 mL, 5.67 mmol), PBr ₃ (0.535 mL, 5.67) were added sequentially to a solution of hydroxy ketone ester 23a (500 mg, 2.270 mmol) in benzene (10 mL) at a temperature of -5 ° C to 0 ° C. Methyl) and stirred for 1 hour. The reaction mixture was allowed to warm to 25 ° C and stirring was continued for 12 h. After completion of the reaction, and the aqueous portion was extracted with DCM (3 × 50mL) with 10mL of saturated aqueous Na ₂ CO ₃ which was quenched. The organic layer was washed with 10% NaHCO ₃ solution (50 mL), dried over anhydrous sodium sulfate and the solvent removed under reduced pressure to give crude material. This crude material was dissolved in DBU (1.711 mL, 11.35 mmol) and warmed to 100 ° C for 4 hr. The reaction mixture was cooled with EtOAc EtOAc m. This was filtered and the solvent was removed under reduced pressure to give a crude material which was purified eluting with EtOAc (EtOAc, EtOAc (EtOAc) Base B-40a (110 mg, 0.544 mmol, 23.96% yield). ¹ H NMR (CDCl ₃ , δ = 7.26 ppm, 300 MHz): δ 7.39-7.31 (m, 5 H), 6.56 (dd, J = 17.4, 10.8 Hz, 1 H), 5.16 (s, 2 H), 4.99 (dd, J = 10.8, 0.9 Hz, 1H), 4.93 (dd, J = 17.4, 0.9 Hz, 1H), 1.51 (apparent quadruple, J 3.7 Hz, 2 H), 1.10 (apparent quadruple peak, J 3.7 Hz, 2 H).

Cap B-40

Dissolving benzyl 1-vinylcyclopropanecarboxylate 40a (50 mg, 0.247 mmol) in MeOH (2.5 mL)-water (0.5 mL), then EtOAc (1N) . The mixture was stirred for 10 minutes and warmed to 25 ° C and stirring was continued for a further 12 hours. After the reaction was completed, the solvent was completely removed, and 5 mL of water was added. This mixture was extracted with diethyl ether (2 x 10 mL). The aqueous layer was acidified (pH ~2) with 1.5N EtOAc (EtOAc) , Dried with brine solution (10 mL) the combined organic layers were washed with dried over anhydrous Na ₂ SO _4, filtered and the organic solvent was removed under reduced pressure to obtain a colorless liquid of the cap B-40 (42mg, 0.375mmol, 152% Yield). ¹ H NMR (CDCl ₃ , δ = 7.26 ppm, 300 MHz): δ 6.51 (dd, J = 17.4, 10.8 Hz, 1 H), 5.01 (dd, J = 10.8, 0.9 Hz, 1 H), 4.94 (dd, J = 17.4, 0.9 Hz, 1 H), 1.56 (apparent quadruple, J 4.1 Hz, 2 H), 1.16 (apparent quadruple peak, J 4.0 Hz, 2 H).

Cap B-41

Cap B-41, step a

15% diethylzinc toluene (4.49 mL, 4.94 mmol) and chloroiodomethane (0.538 mL, 7.42 mmol) in toluene (5 mL) were placed in a 25 mL single-neck round bottom flask at -20 ° C Stir for 30 minutes. To the mixture was added toluene (2 mL) containing 1-methylcyclopropanecarboxylate 40a (250 mg, 1.263 mmol), and stirred at -20 ° C for 6 hr. With 10% NaHCO ₃ (10mL) The reaction was quenched and diluted with DCM (25mL). The organic layer was washed with aqueous 10% NaHCO ₃ (50mL) saline solution (50mL), dried over anhydrous Na ₂ SO _4, filtered and concentrated under reduced pressure. The crude material was purified by EtOAc EtOAc (EtOAc:EtOAc:EtOAc , ¹ H NMR (CDCl ₃ , δ = 7.26 ppm, 400 MHz): δ 7.36-7.30 (m, 5 H), 5.14 (s, 2 H), 1.56-1.49 (m, 1 H), 1.10 (apparent four Heavy peak J = 3.6 Hz, 2 H), 0.57 (apparent quadruple peak, J 3.6 Hz, 2 H), 0.48-0.44 (m, 2 H), 0.03- -0.01 (m, 2 H).

Cap B-41

To a solution of the ester B-41a (100 mg, 0.462 mmol) in MeOH (2.5 mL) EtOAc (EtOAc:EtOAc. After stirring at ° C for 10 minutes, the temperature was raised to 25 ° C and stirred for 12 hours. The volatile components were completely removed under reduced pressure. Water (5 mL) was added and extracted with diethyl ether (2×10 mL). The aqueous layer was acidified (pH ~ 2) with 1.5N HCl and extracted with a 10% MeOH / DCM mixture (3 x 10 mL). Brine solution (10 mL) was washed and the combined organic layers were dried over anhydrous Na ₂ SO _4. The solvent was removed under reduced pressure afforded EtOAc m. ¹ H NMR (CDCl ₃ , δ = 7.26 ppm, 400 MHz): δ 1.49-1.46 (m, 1 H), 1.15 (applied quartet J = 3.6 Hz, 2 H), 0.62 (apparent quartet J = 3.6 Hz, 2 H), 0.49 - 0.44 (m, 2 H), 0.04 - -0.008 (m, 2 H).

Cap B-42

Cap B-42, step a

To a solution of benzyl 1-vinylcyclopropanecarboxylate B-40a (100 mg, 0.494 mmol) in ethyl acetate (10 mL), EtOAc (EtOAc) The reaction mixture was stirred at 25 ° C under a hydrogen atmosphere (balloon pressure) for 1 hour. After the reaction was completed, it was filtered over a pad of celite, and the bed was washed with EtOAc (2×20 mL). The solvent was removed under reduced pressure to give &lt;RTI ID=0.0&gt;&gt;&gt; ¹ H NMR (CDCl ₃ , δ = 7.26 ppm, 400 MHz): δ 7.36-7.30 (m, 5 H), 5.10 (s, 2 H), 1.59 (q, J = 7.2 Hz, 2 H), 1.21. View of the Four Peaks, J 3.6 Hz, 2 H), 0.99 (t, J = 7.2 Hz, 3 H), 0.69 (apparent quadruple, J 3.6 Hz, 2 H).

Cap B-42

Add NaOH aqueous solution (1 N) (1 mL, 0.247 mmol) to a solution of EtOAc (EtOAc (EtOAc) Stir for 10 minutes. It was allowed to warm to room temperature and stirred for 12 hours. The volatile components were removed under reduced pressure. Water was added to the residue and extracted with diethyl ether (2×10 mL). The aqueous layer was acidified with aq. EtOAc (~~~~~~~~~ Brine solution (10 mL) the combined organic fractions are washed, dried over anhydrous Na ₂ SO ₄ and removing the organic solvent under reduced pressure to yield a colorless liquid of the cap B-42 53mg, 0.464mmol, 47.4 % yield ( ). ¹ H NMR (CDCl ₃ , δ = 7.26 ppm, 300 MHz): δ = 1.56 (q, J = 7.2 Hz, 2 H), 1.26 (applied quartet, J 3.6 Hz, 2 H), 1.01 (t, J = 7.2 Hz, 3 H), 0.75 (apparent quadruple, J 3.6 Hz, 2 H).

Cap B-43

Cap B-43, step a

A solution of potassium tert-butoxide (15.93 g, 142 mmol) and 2-oxopropionic acid (5 g, 56.8 mmol) in tetrahydrofuran (30 mL) was stirred at -70 °C for 10 min. Tetrahydrofuran (10 mL) containing HMPA (19.76 mL, 114 mmol) was added to the reaction mixture and stirred at -70 °C for 20 min. To the mixture was added n-butyllithium (89 mL, 142 mmol) and stirred at -70 ° C for 1 hour, followed by diethyl sulfate (26.3 g, 170 mmol). It was stirred at -70 ° C for 10 minutes, and slowly warmed to 25 ° C and stirring was continued for 12 hours. The reaction mixture was quenched with water (20 mL). The organic layer (2 × 20mL), dried and extracted with CHCl ₃ (2 × 100mL) and the combined water layer was extracted with water. The aqueous layer was acidified (pH ~ 2) with 1.5N HCl and extracted with diethyl ether (2×100 mL). The organic layer was dried over anhydrous Na ₂ SO _4, filtered and the solvent removed under reduced pressure to give a colorless liquid of 2- ethoxyacrylate B-43a (3.8g, 32.7mmol, and 57.6% yield). This crude material was used in the next step without purification. ¹ H NMR (CDCl ₃ , δ = 7.26 ppm, 300 MHz): δ 5.49 (d, J = 2.7 Hz, 1 H), 4.71 (d, J = 2.7 Hz, 1 H), 3.87 (q, J = 7.0 Hz) , 2 H), 1.41 (t, J = 7.0 Hz, 3 H).

Cap B-43, step b

To a solution of 2-ethoxyacrylic acid B-43a (1 g, 8.61 mmol) in DMF (10 mL) was added (bromomethyl)benzene (1.620 g, 9.47 mmol), 1.309 g, 9.47 mmol) and stirred at 25 ° C for 12 hours. The reaction mixture was quenched with EtOAc (EtOAc)EtOAc. Sequentially washed with water (3 × 50mL), brine solution (50mL) was washed and the combined organic layers were dried over anhydrous Na ₂ SO _4. It was filtered and concentrated under reduced pressure. The crude material was purified by Combiflash (EtOAc, EtOAc/EtOAc (EtOAc:EtOAc) rate). ¹ H NMR (CDCl ₃ , δ = 7.26 ppm, 400 MHz): δ 7.39-7.31 (m, 5 H), 5.36 (d, J = 2.8 Hz, 1 H), 5.25 (s, 2 H), 4.61 (d) , J = 2.4 Hz, 1 H), 3.82 (q, J = 7.0 Hz, 2 H), 1.39 (t, J = 7.0 Hz, 3 H).

Cap B-43, step c

To a solution of 15% diethylzinc in toluene (9.70 mL, 10.67 mmol) was added toluene (5 mL) containing chloroiodomethane (1.161 mL, 16.00 mmol), and stirred at -20 ° C for 30 min. To the mixture was added toluene (2 mL) containing 2-ethyl ethoxy acrylate B-43b (550 mg, 2.67 mmol), and the mixture was further stirred at -20 ° C for 6 hours. The reaction mixture was allowed to warm to ambient temperature and stirring was continued for 12 h. With 10% NaHCO ₃ solution (10 mL) The mixture was quenched and diluted with DCM (30mL). Sequentially with 10% NaHCO ₃ solution (50mL), brine solution (50mL) The organic portion was washed, and dried over anhydrous Na ₂ SO _4. It was filtered and concentrated under reduced pressure. By reverse phase HPLC (ACN / water / NH ₄ OAc) Purification of the residue, a colorless liquid was obtained as the benzyl ester B-43c (55mg, 0.250mmol, 9.36% yield) (free base). ¹ H NMR (CDCl ₃ , δ = 7.26 ppm, 300 MHz): δ 7.37-7.31 (m, 5 H), 5.17 (s, 2 H), 3.64 (q, J = 7.0 Hz, 2 H), 1.33-1.30 (m, 2 H), 1.25-1.15 (m, 5 H).

Cap B-43

To a solution of methanol (2.5 mL) and water (0.5 mL), EtOAc-EtOAc (EtOAc,EtOAc. Aqueous NaOH (1 N) (1 mL, 0.247 mmol) was then added and stirred for 10 min. The reaction mixture was allowed to warm to rt and stirring was continued for 12 h. The volatile components were removed under reduced pressure and water was added to a residue and ethyl ether (2×10 mL). The aqueous layer was acidified with aq. EtOAc (~~~~~~~~~ Dried with brine and Na ₂ SO solution (10 mL) the combined organic layers were washed with dried over _anhydrous, filtered and the solvent removed under reduced pressure to give a colorless liquid of the cap B-43 (25mg, 0.192mmol, 77% yield rate). ¹ H NMR (CDCl ₃ , δ = 7.26 ppm, 400 MHz): δ 3.65 (q, J = 7.0 Hz, 2 H), 1.38-1.35 (m, 2 H), 1.27-1.18 (m, 5 H).

Cap B-44

To a solution of benzyl 2-ethoxy acrylate B-43a (100 mg, 0.485 mmol) in ethyl acetate (10 mL) was added 10% Pd / C (5.00 mg, 4. 2 minutes. It was then hydrogenated at ambient temperature for 1 hour. The reaction mixture was filtered with EtOAc (EtOAc)EtOAc. The filtrate was concentrated under reduced EtOAcqqqqqqqqqqqqqQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQ ¹ H NMR (CDCl ₃ , δ = 7.26 ppm, 300 MHz): δ 4.03 (q, J = 6.9 Hz, 1 H), 3.68-3.55 (m, 2 H), 1.48-1.46 (d, J = 6.9 Hz, 3 H), 1.28 (t, J = 6.9 Hz, 3 H).

Cap B-45

A solution of 1-phenylcyclopropanecarboxylic acid (100 mg, 0.617 mmol) and PtO ₂ (7.00 mg, 0.031 mmol) in EtOH (5 mL) and AcOH (0.035 mL, 0.617 mmol) was stirred for 2 hr. The reaction mixture was filtered through a pad of celite, and the bed was washed with EtOH (2×10 mL). The filtrate was concentrated under reduced pressure to give abr. ¹ H NMR (MeOD, δ = 3.34 ppm, 400 MHz): δ 1.77-1.66 (m, 5 H), 1.14-1.18 (m, 6 H), 1.10-1.08 (m, 2 H), 0.76-0.74 (m) , 2 H).

Cap B-46

Add LiOH (12.3 mg, 0.514 mmol) to a solution of the ester B-2b (100 mg, 0.549 mmol) in MeOH (1 mL) The reaction mixture was stirred for 12 hours. The reaction mixture was then cooled to 0 ° C, and the pH of the reaction mixture was adjusted to (about 3) with a 1.5 N HCl solution. The reaction is then extracted with EtOAc (2 × 100mL) mixture, and the organic layer was washed with brine (25 mL), dried over Na ₂ SO _4, filtered, and concentrated under reduced pressure to obtain a colorless liquid of the cap B-46 (10mg ). ¹ H NMR (CDCl ₃ , δ = 7.26 ppm, 400 MHz): 5.63-5.60 (m, 1 H), 2.10-2.03 (m, 2 H), 2.00-1.94 (m, 2 H), 1.64-1.52 (m) , 4 H), 1.31 (s, 6 H).

Cap P-43

Trifluoromethanesulfonic anhydride (3.60 g, 12.75 mmol) was added to ethyl 2-(hydroxymethyl)tetrahydro-2H-pentan-2-carboxylate (1.6 g, 8.50 mmol) and 2,6-dimethyl Pyridine (1.980 mL, 17.00 mmol) in DCM (16 mL) EtOAc. The reaction mixture was diluted with DCM, washed with 2N HCl, water, brine, and dried (MgSO _4). The crude isolate was purified by silica gel FCC (EtOAc EtOAc EtOAc EtOAc) Ethyl 2H-pyran-2-carboxylate (1.79 g).

Pure sodium azide (1.035 g, 15.92 mmol) was added to ethyl 2-((((trifluoromethyl)sulfonyl)oxy)methyl)tetrahydro-2H-pyran-2-carboxylate ( 1.7 g, 5.31 mmol) in a cold (0 ° C) solution in dry DMF (12 mL), and the mixture was warmed to room temperature and stirred for 2 hours, then heated at 60 ° C for 2 hours. The reaction mixture was cooled and water was added, and the product was extracted with ether (2 × 30ml), washed with water, brine and dried (MgSO _4). The crude was purified by EtOAc (EtOAc) (EtOAc)

Added trimethylphosphine (1782μl, 1.782mmol) in THF to a solution of 2- (azidomethyl) -2H- tetrahydro-pyran-2-carboxylate (190mg, 0.891mmol) and H ₂ O (150 μl, 8.33 mmol) in EtOAc (EtOAc)EtOAc. Evaporation of the reaction mixture to dryness afforded ethyl <RTI ID=0.0>(</RTI><RTIgt;</RTI><RTIgt;</RTI><RTIgt; 265 μl, 1.515 mmol) and methyl chloroformate (103 μl, 1.337 mmol). The mixture was allowed to warm to room temperature and stirred overnight and the crude was purified eluted eluted eluted eluted eluted eluted -2H-Peuro-2-carboxylic acid ethyl ester (133 mg), which was saponified (LiOH.H ₂ O, THF-MeOH-H ₂ O) to give 2-((((methoxycarbonyl)) as a viscous oil. Amino)methyl)tetrahydro-2H-pyran-2-carboxylic acid ( cap P-43 ) (94.5 mg): ¹ H NMR (400 MHz, CDCL ₃ ) δ ppm 1.50-1.70 (m, 4 H) 1.72 - 1.86 (m, 1 H) 2.09 - 2.20 (m, 1 H) 3.44 (dd, J = 13.80, 5.27 Hz, 1 H) 3.62 (dd, J = 13.80, 7.03 Hz, 1 H) 3.69 (s, 3) H) 3.76-3.87 (m, 1 H) 3.87-3.97 (m, 1 H).

Cap P-44

Pure methanesulfonium chloride (0.084 mL, 1.083 mmol) was added to ethyl 2-(aminomethyl)tetrahydro-2H-pyran-2-carboxylate (156 mg, 0.833 mmol) and DIPEA (0.218 mL, 1.250 mmol) The mixture was stirred in a cold (0 ° C) solution in DCM (2 mL) and the mixture was stirred overnight. The crude isolate was purified by silica gel FCC (DCM containing 10-20% EtOAC) to afford 2-(methylsulfonamidomethyl)tetrahydro-2H-pyran-2-carboxylic acid as a clear viscous oil. The ethyl ester (93 mg) was saponified (LiOH.H ₂ O, THF-MeOH-H ₂ O) to give 2-(methylsulfonamidomethyl)-tetrahydro-2H as a viscous oil. Piperidine-2-carboxylic acid ( cap P-44 ) (86 mg): ¹ H NMR (400 MHz, CDCL ₃ ) δ ppm 1.51-1.68 (m, 4 H) 1.74-1.86 (m, 1 H) 2.08-2.16 (m) , 1 H) 3.01 (s, 3 H) 3.44 (dd, J = 6.15, 1.38 Hz, 2 H) 3.90 (dd, J = 5.90, 4.64 Hz, 2 H) 5.11 (t, J = 6.15 Hz, 1 H ).

Cap P-45

Add pure acetic anhydride (0.111 mL, 1.178 mmol) to ethyl 2-(aminomethyl)tetrahydro-2H-pyran-2-carboxylate (147 mg, 0.785 mmol) and DIPEA (0.233 mL, 1.435 mmol) The solution was cooled (0 ° C) in DCM (3 mL) and the mixture was stirred overnight at room temperature. The crude isolate was purified by silica gel FCC (DCM containing 20-30% EtOAC) to give 2-(ethylaminomethyl)-tetrahydro-2H-pyran-2-carboxylate as a transparent viscous oil. The ester is saponified (LiOH.H ₂ O, THF-MeOH-H ₂ O) to give 2-(ethylaminomethyl)tetrahydro-2H-pyran-2-carboxylic acid as a viscous oil. Cap P-45 ) (65 mg).

Cap P-46

A solution of chloroiodomethane (5.29 g, 30.0 mmol) in toluene (12 mL) was added dropwise to diethylzinc (13.64 mL, 15.00 mmol) in toluene (-25 ° C) in a stirred solution over time. 10 minutes. The resulting mixture was stirred at -20 ° C for 1 hour, followed by dropwise addition of a solution of (R)-2-hydroxy-2-methylpent-4-enoic acid benzyl ester (1.101 g, 5 mmol) in toluene (6 mL) It lasted 15 minutes. The reaction mixture was stirred at -20 °C for 2-3 hours, then allowed to warm to room temperature and stirred overnight. Cooled (0 deg.] C) ₄ Cl and the reaction mixture was quenched with saturated NH, and silica gel and purified by FCC (DCM 2-3% EtOAc containing of) the product was extracted with EtOAc, to give a clear oil of (R) -3- Benzyl cyclopropyl-2-hydroxy-2-methylpropanoate (1.018 g, 87%): ¹ H NMR (500 MHz, CDCL ₃ ) δ ppm -0.05 (m, J = 9.50, 4.80, 4.80, 4.80 Hz,1 H)0.06-0.15(m,1 H)0.31-0.40(m,1 H)0.42-0.51(m,1 H)0.70-0.82(m,1 H)1.46(s,3 H)1.56- 1.64 (m, 1 H) 1.74 (dd, J = 14.11, 6.18 Hz, 1 H) 3.28 (s, 1 H) 5.18 (d, J = 12.36 Hz, 1 H) 5.27 (d, J = 12.36 Hz, 1 H) 7.31 - 7.46 (m, 5 H).

10% Pd-C (21.80 mg, 0.020 mmol) in benzyl (R)-3-cyclopropyl-2-hydroxy-2-methylpropanoate (160 mg, 0.683 mmol) The stirred suspension in solution was hydrogenated under balloon pressure for 30 minutes. The suspension was filtered and evaporated to dryness crystals crystal crystal crystal crystal crystal crystal crystal Add NaH (60% in mineral oil, 82 mg, 2.049 mmol) to (R)-3-cyclopropyl-2-hydroxy-2-methylpropanoic acid (98 mg) in cold THF (2 mL) (-20 ° C) in the solution, and the mixture was allowed to warm to room temperature (about 30 minutes). Pure methyl iodide was added and the mixture was stirred at room temperature overnight. The reaction was quenched with water (1 mL) EtOAc (EtOAc)EtOAc. (R)-3-Cyclopropyl-2-methoxy-2-methylpropanoic acid ( cap P-46 ) (96 mg).

Cap P-47

Sodium hydride (60%, 192 mg, 4.80 mmol) was added to EtOAc (MeOH (EtOAc) Room temperature (about 30 minutes). Pure (bromomethyl)cyclopropane (648 mg, 4.80 mmol) and sodium iodide (120 mg, 0.800 mmol) were added, and the mixture was stirred at room temperature overnight. The crude product was isolated by aqueous work-up and purified by EtOAc (EtOAc (EtOAc) 468mg).

1M hydrogenated lithium tri-butoxide aluminum lithium solution (5.32 mL, 5.32 mmol) was added dropwise to dimethyl 2-(cyclopropylmethyl)-2-methoxymalonate (460 mg, 2.127 mmol) It was cooled (0 ° C) in anhydrous THF (9 mL). After the addition was complete, the mixture was allowed to warm to rt and heated to reflux overnight. The reaction mixture was cooled, diluted with ether, and washed with 20% NaHSO ₄ solution was quenched with vigorous stirring. The organic layer was washed with brine and dried over MgSO ₄ The crude isolate was purified by silica gel FCC (EtOAc EtOAc EtOAc EtOAc , 61%), saponified (LiOH.H ₂ O, MeOH-THF-water) to give 3-cyclopropyl-2-(hydroxymethyl)-2-methoxypropane as a transparent viscous oil Acid ( cap P-47 ) (211 mg, 57%): ¹ H NMR (400 MHz, CDCL ₃ ) δ ppm 0.07-0.23 (m, 2 H) 0.47-0.56 (m, 2 H) 0.75 (ddd, J = 7.91) , 5.27, 2.64 Hz, 1 H) 1.59 (dd, J = 14.81, 7.78 Hz, 1 H) 1.88 (dd, J = 14.81, 5.77 Hz, 1 H) 2.07 (s, 1 H) 3.48 (s, 3 H ) 3.92 (s, 2 H).

Cap P-48

2-bromoacetic acid benzyl ester (5.50 g, 24.00 mmol), dihydrofuran-2(3H)-one (1.722 g, 20 mmol) and indium (2.76 g, 24.00 mmol) in anhydrous THF (12 mL) The stirred suspension was heated overnight at 65-70 °C. Quenched with saturated NaHCO ₃ The reaction was extracted with diethyl ether, to give a clear oil, which was purified by silica gel FCC (containing the DCM 10-20% EtOAc) to afford keto - form the lactol mixture of the desired product (1.09 g).

Pure TEA (1.711 mL, 12.28 mmol) was added to the above keto-lactitol mixture (0.967 g, 4.09 mmol) and 2,4,6-triisopropylbenzene-sulfonium azide (1.393 g, 4.50 mmol) In ice-cold solution in THF (15 mL), mixture was warmed to room temperature and stirred overnight. Evaporation of the reaction mixture to dryness afforded EtOAc (EtOAc) ^{0.95g, 79%): 1 H} NMR (400MHz, CDCL 3) δ ppm 1.83 (br.t, J = 5.40,5.40Hz, 1 H) 1.89-2.00 (m, 2 H) 3.01 (t, J = 7.03 Hz, 2 H) 3.70 (m, J = 5.90, 5.90, 5.90 Hz, 2 H) 5.29 (s, 2 H) 7.34-7.47 (m, 5 H).

A solution of 2-diazo-6-hydroxy-3-oxo-hexanoic acid benzyl ester (0.934 g, 3.56 mmol) in dry benzene (35 mL) was added to yttrium acetate (ii) dimer. The suspension (0.079 g, 0.178 mmol) in benzene (35 mL) was stirred for 30-35 min. The stirred mixture was then maintained at reflux for 1 h and evaporated to dryness to give 3- <RTI ID=0.0>#</RTI> </RTI> <RTIgt; The crude product was used in the next step without further purification.

Add NaH (60%, 148 mg, 3.71 mmol) to benzyl 3-hydroxytetrahydro-2H-pyran-2-carboxylate (724 mg, 3.09 mmol) in cold DMF (3 mL) °C) The solution was stirred and the mixture was allowed to warm to room temperature (15 min). Pure methyl iodide (0.290 mL, 4.64 mmol) was added at 0 ° C, and the mixture was stirred at room temperature overnight. To the reaction mixture was added water and diethyl ether, and the ether layer was separated and washed with brine and dried (Na ₂ SO _4). The crude isolate was purified by EtOAc (EtOAc EtOAc (EtOAc) 323mg, 42%): ¹ H NMR (500MHz, CDCL ₃ ) δ ppm 1.52 (s, 3 H) 1.98-2.06 (m, 1 H) 2.10-2.22 (m, 1 H) 2.42-2.51 (m, 1 H 2.54-2.61 (m, 1 H) 3.88-4.01 (m, 2 H) 5.19-5.32 (m, 2 H) 7.32-7.43 (m, 5 H).

Add sodium borohydride (50.0 mg, 1.321 mmol) to 2-methyl-3-oxo-tetrahydro-2H-pentan-2-carboxylate (164 mg, 0.661 mmol) in dry methanol (5 mL) In a cold (-20 ° C) solution, the mixture was allowed to warm to room temperature and stirred for 1-2 hours. The reaction was quenched with dilute AcOH was washed and product was extracted with EtOAc, washed with saturated NaHCO _3, water, brine, and dried (Na ₂ SO _4). By silicone FCC (DCM 5% EtOAc containing of) the crude isolate was purified, to give a clear oil of 2-methyl-3-hydroxy-piperidin-tetrahydro -2H- pyran-2-carboxylic acid benzyl ester (128mg): ¹ H NMR (500MHz, CDCL ₃ ) δ ppm 1.56 (s, 3 H) 1.66-1.76 (m, 2 H) 2.00-2.10 (m, 1 H) 3.32 (d, J = 11.44 Hz, 1 H) 3.40 (m) , J = 12.10, 9.70, 4.20 Hz, 1 H) 3.48 (m, J = 11.00, 11.00, 4.00 Hz, 1 H) 3.72-3.82 (m, 1 H) 5.28 (s, 2 H) 7.32-7.45 (m , 5 H).

10% Pd-C (16 mg, 0.015 mmol) in EtOAc (3 mL) The stirred suspension was hydrogenated under balloon pressure for 30-45 minutes. The suspension was filtered and evaporated to dryness to give a white semi-solid of 3-hydroxy-2-methyl-piperidin-tetrahydro -2H- pyran-2-carboxylic acid (the cap P-48) (79mg, 100 %): 1 H NMR (500MHz, CDCL ₃ ) δ ppm 1.57 (s, 3 H) 1.61-1.74 (m, 2 H) 1.84 (m, J = 13.00, 6.00, 3.40 Hz, 1 H) 2.01-2.08 (m, 1 H) 3.65 -3.74 (m, 2 H) 3.83 (m, J = 11.90, 5.90, 4.20 Hz, 1 H).

Cap P-49

Lithium hydrogenated tri-tert-butoxide aluminum (25.03 mL, 25.03 mmol) was added dropwise to 2H-pyran-2,2(3H,6H)-dicarboxylic acid diethyl ester (2.285 g, 10.01 mmol) in dry THF The cold (0 ° C) in (24 mL) was stirred in the solution. After the addition was complete, the mixture was allowed to warm to room temperature and heated to reflux for 4-5 hours. The reaction mixture was cooled, diluted with ether, and washed with 20% NaHSO ₄ solution was quenched with vigorous stirring. The organic layer was separated, washed with brine and dried over MgSO _4. The crude isolate was purified by silica gel FCC (EtOAc EtOAc EtOAc EtOAc) (0.892 g, 48%).

Pure benzamidine chloride (0.770 g, 5.48 mmol) was added to 2-(hydroxymethyl)-3,6-di Hydrogen-2H-pentan-2-carboxylic acid ethyl ester (0.85 g, 4.56 mmol) and EtOAc (EtOAc:EtOAc. The crude product was extracted by aqueous treatment and purified by silica gel FCC (DCM) to give 2-((benzylideneoxy)methyl)-3,6-dihydro-2H-pyran-2 as a transparent oil. Ethyl formate (1.3 g, 98%).

The 2 - ((benzoyl) methyl) -3,6-dihydro -2H--pyran-2-carboxylate (1.3g, 4.48mmol) in toluene (50mL) was treated with N ₂ in the Purification was carried out for 5 minutes, followed by the addition of triethyldecane (1.073 mL, 6.72 mmol), copper (I) chloride (0.016 g, 0.157 mmol) and Grubbs-I catalyst (0.075 g, 0.090 mmol). The reaction vessel was capped and heated at 110 °C for 72 hours. Evaporation of the mixture to dryness and purification with EtOAc (EtOAc) (EtOAc) Ester (0.89 g, 69%).

To a solution of ethyl 2-((benzylideneoxy)methyl)-3,4-dihydro-2H-pyran-2-carboxylate (0.85 g, 2.93 mmol) in THF (12 mL) BH ₃ .THF (2.050 ml, 2.050 mmol) was added dropwise over a period of 10 min. The reaction mixture was allowed to warm to room temperature and stirred for 3-4 hours. The reaction mixture was re-cooled (0 ° C) and was purified eluting with EtOAc EtOAc After about 10 minutes, hydrogen peroxide (0.583 ml, 9.52 mmol) was added and stirred at room temperature for 1 hour. The reaction mixture was diluted with ether, and washed with NH ₄ Cl, washed with brine, dried (MgSO _4). The crude isolate was purified by silica gel FCC (EtOAc EtOAc EtOAc EtOAc) Ethyl 2-formate (724 mg, 80%).

Pure PCC (0.319 g, 1.479 mmol) was added to a 4Å molecular sieve (about 1 g) in ethyl 2-((benzylideneoxy)methyl)-5-hydroxytetrahydro-2H-pyran-2-carboxylate ( 0.304 g, 0.986 mmol) in a stirred suspension in EtOAc (EtOAc)EtOAc. The reaction mixture was plugged with EtOAc (EtOAc) elute The eluate was evaporated to dryness to give 2-((benzylideneoxy) A as a clear oil. Ethyl 5-aminooxy-2H-pyran-2-carboxylate (237 mg).

To a cold (0 ° C) solution of Deoxofluo (R) (439 mg, 1.986 mmol) in DCM (4 mL), and the mixture was warmed to room temperature and stirred. 1 hour and cooled to 0 °C. Add a solution of ethyl 2-((benzylideneoxy)methyl)-5-oxo-tetrahydro-2H-pyran-2-carboxylate (234 mg, 0.764 mmol) in DCM (4 mL) Triethylamine trihydrofluoride (0.041 mL, 0.252 mmol), and the mixture was stirred at room temperature for 18 hr. The reaction was quenched with ice and carefully neutralized with saturated NaHCO ₃ and, and the product was extracted with DCM. The crude isolate was dissolved in acetone (4 mL), t-BuOH (2 mL) and water (2mL), and 4-methylmorpholine 4-oxide (179 mg, 1.528mmol) The mixture was treated with mg, 7.64 μmol), and the mixture was stirred at room temperature for 2 days. The reaction mixture was evaporated to dryness, and washed with EtOAc in product was extracted, washed with water, brine, and dried (Na ₂ SO _4). The crude isolate was purified by silica gel FCC (DCM) to afford pure 2-((benzylideneoxy)methyl)-5,5-difluorotetrahydro-2H-pyran-2-carboxylic acid as a clear oil. Ethyl ester (195 mg): ¹ H NMR (500 MHz, CDCL ₃ ) δ ppm 1.30 (t, J = 7.10 Hz, 3 H) 1.86-2.10 (m, 2 H) 2.19 - 2.31 (m, 1 H) 2.38-2.49 (m,1 H)3.92-4.05(m,2 H)4.25-4.35(m,2 H)4.46-4.54(m,2 H)7.42-7.52(m,2 H)7.59(tt, J =7.44, 1.34 Hz, 1 H) 7.99-8.08 (m, 2 H).

Ethyl 2-((benzylideneoxy)methyl)-5,5-difluorotetrahydro-2H-pentan-2-carboxylate (192 mg, 0.496 mmol) and hydrogenated monohydrate at room temperature A mixture of lithium (128 mg, 3.06 mmol) in THF (2 mL), MeOH (2 mL) The crude isolate was purified by EtOAc (EtOAc) elute elute elute ( Cap P-49 ) (96.7 mg, 65%).

Cap P-50

The general procedure for preparing the urethane cap acid is represented by the following procedure for preparing cap P-50 :

Add pure triphosgene (26.7 mg, 0.090 mmol) to 4,4-difluoro-1-hydroxycyclohexanecarboxylic acid ethyl ester (50 mg, 0.240 mmol) and DMAP (95 mg, 0.780 mmol) in DCM (2 mL) The solution was cooled (-20 ° C) and the mixture was gradually warmed to room temperature (about 30 minutes) and stirred for 30 minutes. The resulting white suspension was cooled (EtOAc) EtOAc (EtOAc) The reaction was diluted with DCM, washed with 2N HCl, water, brine, and dried (MgSO _4). The crude isolate was purified by EtOAc (EtOAc EtOAc EtOAc) ester ^{(63mg): 1 H NMR (} 500MHz, CDCL 3) δ ppm 1.24-1.34 (m, 3 H) 1.92-2.16 (m, 6 H) 2.31-2.42 (m, 2 H) 2.92 (br.s,. 3 H) 2.99 (br.s., 3 H) 4.16-4.29 (m, 2 H).

Ethyl 1-((dimethylaminocarbamido)oxy)-4,4-difluorocyclohexanecarboxylate (63 mg) was saponified (LiOH.H ₂ O, THF-MeOH-H ₂ O, 23 ° C There was obtained 1-((dimethylaminocarbamido)oxy)-4,4-difluorocyclohexanecarboxylic acid ( cap P-50 ) (50 mg) as a white solid.

Cap P-51

Cerium oxide (VIII) (4% by weight solution in t-BuOH, 0.826 g, 0.130 mmol) was added to benzyl methacrylate (1.762 g, 10 mmol) and 4-methylmorpholine 4-oxide ( 2.401 g, 20.50 mmol) in a solution of acetone (16 mL), t-BuOH (4 mL) and water (4 mL). With 10% NaHSO ₃ was quenched reaction mixture was extracted with EtOAC, washed with saturated brine. The crude isolate was purified by EtOAc (EtOAc EtOAc)

Pure tert-butyl chlorodimethyl decane (1.640 g, 10.88 mmol) was added to 2,3-dihydroxy-2-methylpropionic acid benzyl ester (1.83 g, 8.70 mmol) and imidazole (0.770 g, 11.32). Methyl) in a solution of anhydrous DMF (12 mL). Excess TBDMSCl was quenched with methanol (about 30 min), diluted with ether and water was added. Water, the organic layer was washed with brine, and dried (MgSO _4). Evaporation of the solvent gave benzyl 3-((t-butyldimethylmethyl)alkyl)-2-hydroxy-2-methylpropanoate (2.72 g, 96%).

Triphosgene (55.6 mg, 0.187 mmol) was added to 3-((t-butyldimethylmethylalkyl)oxy)-2-hydroxy-2-methylpropanoic acid benzyl ester (162.2 mg, 0.500 mmol) And a cold (-20 ° C) solution of DMAP (198 mg, 1.625 mmol) in DCM (3 mL), and the mixture was gradually warmed to room temperature (30 min) and stirred for 30 min. The resulting white suspension was cooled (EtOAc) EtOAc (EtOAc) Washed with water, the reaction was diluted with DCM, brine, and dried (MgSO _4). The crude isolate was purified by silica gel FCC (EtOAc EtOAc EtOAc EtOAc) Benzyl-2-methylpropionate (162 mg, 82%). Under balloon pressure for removal of benzyl (10% Pd-C, H 2, EtOAc), to give a clear oil of 3 - ((tert-butyl dimethyl silicone alkyl) oxy) -2 - (( Dimethylamine-mercapto)oxy)-2-methylpropanoic acid ( cap P-51 ) (141 mg, 92%).

Cap P-52

Pure (bromomethyl)benzene (262 mg, 1.532 mmol) was added to (+/-)-2-hydroxy-1-methylcyclohexanecarboxylic acid (202 mg, 1.277 mmol) and DMAP (507 mg, 4.15 mmol) in DCM (2 mL) and a solution in acetonitrile (2 mL), and the mixture was stirred at room temperature for 3 hr. The solvent was evaporated, and the residue was extracted with diethyl ether, washed with 1N HCl, saturated NaHCO _3, water, brine, and dried (MgSO _4). Ether was evaporated to give (+/-)-2-hydroxy-1-methylcyclohexanecarboxylic acid benzyl ester (219 mg). To a cold (-20 ° C) solution of crude benzyl ester (219 mg) and DMAP (507 mg, 4.15 mmol) in EtOAc (EtOAc) Stir and stir for 30 minutes. A solution of dimethylamine (2M in THF, 1.915 mL, 3.. The crude isolate was purified by EtOAc (EtOAc EtOAc) Benzoyl hexanecarboxylate (207 mg). Under balloon pressure for removal of benzyl (10% Pd-C, H 2, EtOAc), to give a white solid of (+/-) - 2 - ((dimethylamino methyl acyl) oxy) - 1-methylcyclohexanecarboxylic acid ( cap P-52 ) (148 mg, 51%).

Cap Y-15

To the dry flask was added Pd ₂ (dba) ₃ CHCl ₃ adduct (0.1 g, 0.097 mmol), N,N'-((1R,2S)-cyclohex-1,2-diyl) bis(2- (Diphenylphosphino)benzamide (0.2 g, 0.290 mmol). The flask was degassed under vacuum and purged with N _2. This procedure was repeated twice. Was added DCM (150ml), and then degassed under vacuum and purged with N _2. Was added allyl alcohol (3mL, 44.1mmol), and the mixture was degassed and purged with N _2. The mixture was stirred at room temperature for 20 minutes. The color turns orange. Triethylborane/hexane (0.4 mL, 0.400 mmol) was added and stirred for 2 min. 2-Methyl-2-vinyloxirane (4 mL, 40.8 mmol) was added. The reaction mixture was stirred overnight and concentrated to give crystals crystals crystals crystals crystals _{^{1 H NMR (400MHz, CDCl 3}} ) δ 6.00-5.76 (m, 2H), 5.34-5.22 (m, 3H), 5.18-5.10 (m, 1H), 3.90 (dt, J = 5.3,1.6Hz, 2H) , 3.62-3.38 (m, 2H), 2.05 (dd, J = 7.2,5.9Hz, 1H), 1.32 (s, 3H).

Add DIPEA to a solution of (S)-2-(allyloxy)-2-methylbut-3-en-1-ol (5.2 g, 36.6 mmol) in DCM (30 mL) and ACN (60 mL) (8 ml, 45.8 mmol), then benzamidine chloride (5.2 ml, 44.8 mmol) was added dropwise while the flask was kept in an ice bath. The reaction mixture was stirred at room temperature for 18 h then EtOAc (5 mL, 35.9 mmol) The reaction mixture was stirred at room temperature for 4 hours, and diluted with EtOAc and hexanes, with HCl (1N, 2 ×), NaOH (1N, 2 ×), washed with brine, dried (MgSO _4), concentrated and silica gel by FCC Purification gave (S)-2-(allyloxy)-2-methylbut-3-en-1-yl benzoate (5.4 g, 60%). _{^{1 H NMR (400MHz, CDCl 3}} ) δ 8.08-8.04 (m, 2H), 7.62-7.54 (m, 1H), 7.49-7.41 (m, 2H), 5.99-5.87 (m, 2H), 5.38-5.27 ( m, 3H), 5.14 (dd, J = 10.5, 1.8 Hz, 1H), 4.38-4.29 (m, 2H), 3.98 (dt, J = 5.3, 1.3 Hz, 2H), 1.43 (s, 3H).

A solution of (S)-2-(allyloxy)-2-methylbut-3-en-1-yl benzoate (6.7 g, 27.2 mmol) in DCM (200 mL) N _{2 was} purged for 5 minutes. Grubbs II catalyst (0.01 g, 0.012 mmol) was added. The reaction mixture was stirred at room temperature for 16 hours, concentrated and purified with EtOAc EtOAc (EtOAc:EtOAc:EtOAc -Dihydrofuran-2-yl)methyl ester (4.7 g, 79%). _{^{1 H NMR (400MHz, CDCl 3}} ) δ 8.07-8.02 (m, 2H), 7.60-7.54 (m, 1H), 7.49-7.39 (m, 2H), 5.97 (dt, J = 6.2,1.5Hz, 1H) , 5.77 (dt, J = 6.1, 2.5 Hz, 1H), 4.75-4.70 (m, 2H), 4.40 (d, J = 11.3 Hz, 1H), 4.26 (d, J = 11.3 Hz, 1H), 1.42 ( s, 3H).

BH ₃ .SMe was added dropwise to a solution of (S)-(2-methyl-2,5-dihydrofuran-2-yl)methyl benzoate (4.7 g, 21.54 mmol) in THF (40 mL) ₂ (7 mL, 14.00 mmol), and stirred at room temperature for 2 hr. The reaction mixture was cooled in an ice-bath, and a solution of sodium acetate (1. <RTI ID=0.0></RTI></RTI><RTIgt; The reaction mixture was stirred at room temperature for 25 min then H ₂ O ₂ (4 mL, 65.3 mmol). The mixture was stirred overnight at room temperature and diluted with EtOAc, washed with water, brine, dried (MgSO ₄₎ and concentrated to give benzene with an acid ((2S) -4- hydroxy-2-methyl-tetrahydrofuran-2-yl) methyl Ester (5 g, 98%). The crude product was used directly in the next reaction.

In an ice bath, benzoic acid ((2S)-4-hydroxy-2-methyltetrahydrofuran-2-yl)methyl ester (5 g, 21.16 mmol) and MS (4 Å, 10 g, powder) in DCM (100 mL) PCC (5.47 g, 25.4 mmol) was added in two portions in the mixture. The reaction mixture was stirred at room temperature for 20 h and diluted with EtOAc (EtOAc) (EtOAc) 4-Phenoxytetrahydrofuran-2-yl)methyl ester (2.2 g, 44%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.01-7.94 (m, 2H), 7.64 - 7.56 (m, 1H), 7.51 - 7.42 (m, 2H), 4.41 (d, J = 11.7 Hz, 1H), 4.37 (d, J = 11.7 Hz, 1H), 4.23 (d, J = 17.0 Hz, 1H), 4.14 (d, J = 17.0 Hz, 1H), 2.70 (d, J = 17.8 Hz, 1H), 2.46 (d) , J = 17.8 Hz, 1H), 1.53 (s, 3H).

In an ice bath, was added the Deoxo-Fluor® to the BF ₃ .Et ₂ O (1,7.89mmol) in DCM (10mL) solution (1.6mL, 8.68mmol). The reaction mixture was stirred at room temperature for 1 hour and cooled in an ice bath. A solution of (S)-(2-methyl-4-oxo-tetrahydrofuran-2-yl)methyl benzoate (0.8 g, 3.42 mmol) in DCM (8 mL) The reaction mixture was made for 18 hours. Thereafter, the mixture was poured carefully to a stirred solution of saturated NaHCO _3, and extracted with EtOAc. The organic solution was washed with brine, dried (MgSO _4), concentrated and purified on a silica gel cartridge to give benzoic acid (S) - (4,4- difluoro-2-methyl-tetrahydrofuran-2-yl) methyl ester (0.26g , 30%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.08-8.04 (m, 2H), 7.62-7.57 (m, 1H), 7.50-7.43 (m, 2H), 4.37-4.33 (m, 1H), 4.33-4.28 ( m, 1H), 4.19-4.04 (m, 2H), 2.69-2.53 (m, 1H), 2.32 (dddd, J = 17.5, 14.3, 9.6, 0.8 Hz, 1H), 1.46 (s, 3H).

(S)-(4,4-Difluoro-2-methyltetrahydrofuran-2-yl)methyl benzoate (0.26 g, 1.015 mmol) in THF (5 mL), MeOH (5 mL) The mixture in sodium hydroxide (4 ml, 4.00 mmol) was stirred for 3 hr. The reaction mixture was partially concentrated and extracted with diethyl ether (2). Washed with brine the combined extracts were dried (MgSO ₄₎ and concentrated to give (S) - (4,4- difluoro-2-methyl-tetrahydrofuran-2-yl) methanol (0.15g, 97%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 4.06 (t, J =12.7 Hz, 2H), 3.61-3.46 (m, 2H), 2.69-2.51 (m, J = 17.1, 14.7, 14.7 Hz, 1H), 2.16 (ddd, J = 16.9, 14.1, 8.7 Hz, 1H), 1.32 (s, 3H).

Add Jones reagent (1 mL) to a solution of (S)-(4,4-difluoro-2-methyltetrahydrofuran-2-yl)methanol (0.15 g, 0.986 mmol) in acetone (5 mL). , 2.500mmol). The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with EtOAc EtOAc EtOAc m. ¹ H NMR (400 MHz, CDCl ₃ ) δ s.sup.ssssssssssssssssssssssssssssssssssssssssssssssssssssss

Cap Y-16

At 0 deg.] C, under N ₂ on, added to nBuLi in the DIPEA (0.6mL, 4.21mmol) in THF (6mL) solution (0.35mL, 3.50mmol), and stirred at 0 ℃ 15 minutes. The reaction mixture was cooled to -78.degree. C., EtOAc (EtOAc, EtOAc (EtOAc) The mixture was stirred for 0.5 hours, then (chloromethoxy)methyl)benzene (0.5 mL, 3.51 mmol) was added dropwise. The reaction mixture was stirred at -78 °C for 1 hour and at room temperature for 1 hour. The reaction mixture was diluted with EtOAc, with NH ₄ Cl (2 ×), washed with brine, dried (MgSO _4), and concentrated on a 12g silica gel cartridge: purified (EtOAc / hexanes 0-40%) to give 2 - (( Methyl benzyloxy)methyl)tetrahydrofuran-2-carboxylate (0.42 g, 55%). _{^{1 H NMR (400MHz, CDCl 3}} ) δ 7.41-7.28 (m, 5H), 4.72 (d, J = 6.0Hz, 1H), 4.61 (q, J = 12.3Hz, 2H), 4.06-3.97 (m, 2H ), 3.76 (s, 3H), 3.62 (d, J = 10.0 Hz, 1H), 2.22 (dd, J = 7.2, 6.4 Hz, 1H), 2.00-1.88 (m, 3H).

Methyl 2-((benzyloxy)methyl)tetrahydrofuran-2-carboxylate (0.42 g, 1.678 mmol) in THF (5 mL) MeOH (5 mL) The mixture in mmol) was stirred overnight. The reaction mixture was diluted with EtOAc and with 1N HCl, brine, dried (MgSO _4), and concentrated to dryness to give 2 - ((benzyloxy) methyl) tetrahydrofuran-2-carboxylic acid (0.25g, 63%). _{^{1 H NMR (400MHz, CDCl 3}} ) δ 7.40-7.29 (m, 5H), 4.61 (s, 2H), 4.16-4.07 (m, 1H), 4.05-3.95 (m, 1H), 3.81 (d, J = 10.0 Hz, 1H), 3.59 (d, J = 10.0 Hz, 1H), 2.37-2.25 (m, 1H), 2.03-1.82 (m, 3H).

2 - degassed solution of ((benzyloxy) methyl) tetrahydrofuran-2-carboxylic acid (0.25g, 1.058mmol) in MeOH (10mL), refilled and N _2. Pd/C (0.1 g, 0.094 mmol) was added and the mixture was degassed. At 50psi H ₂ with stirring overnight the reaction mixture, and the solid was filtered off. The remaining solution was concentrated to dryness to give 2-(hydroxymethyl)tetrahydrofuran-2-carboxylic acid (0.15 g, 100%). _{^{1 H NMR (400MHz, CDCl 3}} ) δ 4.15-4.07 (m, 1H), 4.07-3.98 (m, 1H), 3.91 (d, J = 11.5Hz, 1H), 3.69 (d, J = 11.5Hz, 1H ), 2.34 - 2.23 (m, 1H), 2.10 - 1.89 (m, 3H).

Cap Y-17

Pd ₂ (dba) ₃ CHCl ₃ adduct (0.06 g, 0.058 mmol) and N,N' -((1S,2S)-cyclohex-1,2-diyl) bis(2-) were added to the dry flask. (Diphenylphosphino)benzamide (0.12 g, 0.174 mmol). The flask was degassed under vacuum and purged with N _2. This procedure was repeated twice. Was added DCM (100ml), and then degassed under vacuum and purged with N _2. Pent-4-en-1-ol was added (2.4mL, 23.24mmol), degassed and purged with N _2. The mixture was stirred at room temperature for 20 minutes during which time the color turned orange. Triethylborane/hexane (0.3 mL, 0.300 mmol) was added, and the mixture was stirred for 2 min, then 2-methyl-2-vinyl oxirane (2.3 mL, 23.43 mmol). The reaction mixture was stirred at room temperature for 19 hours. The reaction mixture was concentrated to dryness to give crude <RTI ID=0.0>(</RTI><RTIgt;</RTI><RTIgt;</RTI><RTIgt;</RTI><RTIgt; Used without further purification. _{^{1 H NMR (400MHz, CDCl 3}} ) δ 5.89-5.77 (m, 2H), 5.33-5.20 (m, 2H), 5.08-4.95 (m, 2H), 3.53-3.40 (m, 2H), 3.39-3.29 ( m, 2H), 2.21-2.10 (m, 2H), 2.04 (dd, J = 6.8, 6.0 Hz, 1H), 1.73-1.61 (m, 2H), 1.28 (s, 3H).

To (R)-2-methyl-2-(pent-4-en-1-yloxy)but-3-en-1-ol (3.7 g, 26.0 mmol) in DCM (30 mL) TEA (4.5 mL, 32.3 mmol) and benzamidine chloride (3.5 mL, 30.2 mmol) were slowly added to the solution. The reaction mixture was stirred at room temperature for 1.5 hours. The reaction mixture was diluted with hexane, and washed with 1N HCl, NaHCO _3, washed with brine, dried (MgSO _4), and purified on a silica gel cartridge to give benzoic acid (R) -2- methyl-2- (pent-4 Alken-1-yloxy)but-3-en-1-yl ester (2.2 g, 31%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.10-8.00 (m, 2H), 7.62-7.54 (m, 1H), 7.50-7.42 (m, 2H), 6.00-5.71 (m, 2H), 5.36-5.25 ( m, 2H), 5.05-4.90 (m, 2H), 4.34-4.25 (m, 2H), 3.47-3.31 (m, 2H), 2.38-2.02 (m, 2H), 1.71-1.58 (m, 2H), 1.41 (s, 3H).

(R)-2-Methyl-2-(pent-4-en-1-yloxy)but-3-en-1-ylbenzoate (2.2 g, 8.02 mmol) in DCM (150 mL) the solution was degassed for 5 minutes and purifying N _2. Grubbs II catalyst (0.1 g, 0.118 mmol) was added and the reaction mixture was stirred at room temperature for 18 h. The reaction mixture was concentrated and purified by silica gel FCC (EtOAc / hexane: 0% to 20%) to afford benzoic acid (R)-(2-methyl-2,5,6,7-tetrahydrogen Indole-2-yl)methyl ester (0.9 g, 46%). _{^{1 H NMR (400MHz, CDCl 3}} ) δ 8.12-8.03 (m, 2H), 7.57 (tt, J = 7.4,1.3Hz, 1H), 7.51-7.41 (m, 2H), 5.85-5.75 (m, 1H) , 5.44 (dt, J = 11.7, 1.4 Hz, 1H), 4.42 (d, J = 11.3 Hz, 1H), 4.21 (d, J = 11.3 Hz, 1H), 3.96-3.77 (m, 2H), 2.44- 2.22 (m, 2H), 1.92-1.84 (m, 2H), 1.40 (s, 3H).

(R)-(2-methyl-2,5,6,7-tetrahydroindol-2-yl)methyl benzoate (0.9 g, 3.65 mmol) in THF (4 mL) A mixture of MeOH (5 mL) and sodium hydroxide (15 mL, 15.00 mmol) was stirred overnight. The reaction mixture was partially concentrated, and diluted with ether, washed with 1N NaOH, washed with brine, dried (MgSO ₄₎ and concentrated to give a liquid of (R) - (2- methyl-2,5,6,7 Oxan-2-yl)methanol (0.52 g, 100%). ¹ H NMR (500 MHz, CDCl ₃ ) δ 5.76 (dt, J =11.7, 5.8 Hz, 1H), 5.32 (dt, J =11.7, 1.5 Hz, 1H), 3.89-3.77 (m, 2H), 3.58 (dd , J =11.0, 4.4 Hz, 1H), 3.40 (dd, J = 10.8, 7.3 Hz, 1H), 2.43-2.33 (m, 1H), 2.28-2.18 (m, 1H), 2.13 - 2.07 (m, 1H) ), 1.91-1.79 (m, 2H), 1.29 (s, 3H).

The (R) - degassed solution of (2-methyl-2,5,6,7-Boom four hydroxyl-2-yl) methanol (0.3g, 2.110mmol) in MeOH (15mL) and treated with N ₂ Purification. Was added Pd / C (0.090g, 0.084mmol) , and the suspension was degassed and refilled with H _2. The reaction mixture was stirred under H ₂ (balloon pressure) for 3 hours. The solid was filtered off and the residue was concentrated to dryness to give product (0.3 g, 99%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 3.71-3.46 (m, 4H), 1.74-1.41 (m, 9H), 1.24-1.14 (m, 3H).

Add a Jones reagent (1.5 mL, 3.75) to a solution of (R)-(2-methyloxepane-2-yl)methanol (0.28 g, 1.942 mmol) in acetone (10 mL). Mm). The reaction mixture was stirred in an ice bath and allowed to warm to room temperature over 18 hours. The reaction mixture was diluted with EtOAc and washed with water, brine, dried (MgSO ₄₎ and concentrated to dryness, to give (R) -2- methyl oxetane heptane-2-carboxylic acid (0.2g, 65%). _{^{1 H NMR (400MHz, CDCl 3}} ) δ 3.89-3.78 (m, 1H), 3.64-3.53 (m, 1H), 2.43-2.30 (m, 1H), 1.85-1.49 (m, 7H), 1.41 (s, 3H).

Cap Y-18

60% of a solution of ethyl 2-hydroxypent-4-enoate (3 g, 20.81 mmol, reference: Org. Lett., 2009, 11, 2019-2022) in THF (20 mL) at 0 ° C sodium hydride (0.92g, 23.00mmol) and benzyl bromide (2.72mL, 22.89mmol), and the reaction mixture was stirred for 2 hours, diluted with hexane, dried NHCl _4, washed with brine, dried (MgSO _4), and concentrated in Purification on a 120 g silica gel cartridge gave ethyl 2-(benzyloxy)pent-4-enoate (1.4 g, 29%). _{^{1 H NMR (400MHz, CDCl 3}} ) δ 7.45-7.30 (m, 5H), 5.85 (ddt, J = 17.1,10.2,7.0Hz, 1H), 5.19-5.08 (m, 2H), 4.73 (d, J = 11.8 Hz, 1H), 4.46 (d, J = 11.8 Hz, 1H), 4.23 (dtt, J = 10.8, 7.2, 3.7 Hz, 2H), 4.01 (t, J = 6.3 Hz, 1H), 2.59-2.50 ( m, 2H), 1.30 (t, J = 7.2 Hz, 3H).

Ethyl 2-(benzyloxy)pent-4-enoate was added dropwise to a suspension of LiAlH ₄ (0.5 g, 13.17 mmol) in diethyl ether (30 mL) over 10 min. 1.4 g, 5.98 mmol) in diethyl ether (20 mL) and the mixture was maintained at this temperature for 90 min. The reaction was quenched by EtOAc / EtOAc (EtOAc) (EtOAc) The mixture was stirred for 0.5 h and filtered, EtOAcqqqqqqqqqqqQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQQ _{^{1 H NMR (400MHz, CDCl 3}} ) δ 7.45-7.29 (m, 5H), 5.84 (ddt, J = 17.1,10.1,7.2Hz, 1H), 5.20-5.06 (m, 2H), 4.69 (d, J = 11.5 Hz, 1H), 4.56 (d, J = 11.5 Hz, 1H), 3.70 (d, J = 10.0 Hz, 1H), 3.65-3.50 (m, 2H), 2.50-2.39 (m, 1H), 2.39- 2.29 (m, 1H).

To the dry flask was added 2-(benzyloxy)pent-4-en-1-ol (1.3 g, 6.76 mmol), Pd ₂ (dba) ₃ CHCl ₃ adduct (0.07 g, 0.068 mmol) and N , N'-((1S,2S)-cyclohexyl-1,2-diyl)bis(2-(diphenylphosphino)benzamide) (0.15 g, 0.217 mmol). The flask was degassed under vacuum and purged with N _2. This procedure was repeated twice. Was added DCM (100ml), and then degassed under vacuum and purged with N _2. The mixture was stirred at room temperature for 20 minutes during which time the color turned orange. Triethylborane/hexane (0.3 mL, 0.300 mmol) was added, and after stirring for 2 min, 2-methyl-2-vinyl oxirane (0.7 mL, 7.13 mmol) was added at room temperature. The mixture was stirred at room temperature for 3 days, then concentrated and purified on a pad of EtOAc (EtOAc/hexane: 0% to 60%) to afford (2. Base pent-4-en-1-yl)oxy)-2-methylbut-3-en-1-ol (1.4 g, 75%). _{^{1 H NMR (400MHz, CDCl 3}} ) δ 7.42-7.29 (m, 5H), 5.97-5.76 (m, 2H), 5.38-5.18 (m, 2H), 5.18-4.99 (m, 2H), 4.69-4.60 ( m, 2H), 3.65-3.36 (m, 5H), 2.48-2.23 (m, 2H), 1.30-1.26 (m, 3H).

To (2R)-2-((1-(benzyloxy)pent-4-en-1-yl)oxy)-2-methylbut-3-en-1-ol (at 0 ° C) TEA (1 mL, 7.17 mmol) and benzamidine chloride (0.8 mL, 6.89 mmol) were slowly added to a solution of EtOAc (EtOAc). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with hexane, and washed with 1N HCl, NaHCO _3, washed with brine, dried (MgSO _4), and on 40g silica gel cartridge: purified (EtOAc / hexanes 0-50%) to give benzoic acid (2R) 2-((2-(Benzyloxy)pent-4-en-1-yl)oxy)-2-methylbut-3-en-1-yl ester (1.63 g, 85%).

(2R)-2-((2-(Benzyloxy)pent-4-en-1-yl)oxy)-2-methylbut-3-en-1-yl benzoate (1.63g) , 4.28mmol) in DCM solution (200mL) was degassed and purified in the 5 minutes N _2. Grubbs II catalyst (0.1 g, 0.118 mmol) was added and the reaction mixture was stirred at room temperature for 1 day. The reaction mixture was concentrated and purified on EtOAc (hexanes: EtOAc: EtOAc: EtOAc: EtOAc: EtOAc 2,5,6,7-Tetrahydroindol-2-yl)methyl ester (1.2 g, 79%).

((2R)-6-(Benzyloxy)-2-methyl-2,5,6,7-tetrahydrooxan-2-yl)methyl benzoate (1.2 g, 3.40 mmol) in MeOH (15mL) in a solution of degassed and purged with N _2. Was added Pd / C (0.2g, 0.188mmol) , and degassed and refilled with H _2. The reaction mixture was stirred at 50 PSI H ₂ for 20 hr then filtered and filtered and filtered to give &lt;RTI ID=0.0&gt; , 100%).

To benzoic acid ((2R)-6-hydroxy-2-methyloxaheptan-2-yl)methyl ester (0.9 g, 3.41 mmol) and MS (4 Å, 2 g, powder) in DCM (30 mL) PCC (1.1 g, 5.10 mmol) was added in two portions while maintaining the reaction at ice bath. The reaction mixture was stirred at room temperature overnight then diluted with 30 mL hexanes and purified EtOAc EtOAc EtOAc EtOAc -6-Sideoxyoxepane-2-yl)methyl ester (0.82 g, 72%). _{^{1 H NMR (400MHz, CDCl 3}} ) δ 8.13-8.01 (m, 2H), 7.66-7.55 (m, 1H), 7.50-7.42 (m, 2H), 4.37 (d, J = 11.3Hz, 1H), 4.27 (d, J =11.5 Hz, 1H), 4.18-4.10 (m, 1H), 4.10-4.03 (m, 1H), 2.82-2.66 (m, 2H), 1.97-1.72 (m, 4H), 1.37 (s) , 3H).

At 0 ℃, (, 7.89mmol 1mL) was added in CH Deoxo-Fluor® to BF ₃ .Et ₂ O in the ₂ Cl ₂ (10mL) solution (1.6mL, 8.68mmol). The reaction mixture was stirred at room temperature for 1 hour, cooled again in an ice bath, and (R)-(2-methyl-6-oxoxyoxepane-2-) was added dropwise at this temperature. A solution of methyl ester (0.82 g, 3.13 mmol) in DCM (5 mL). The reaction mixture was stirred for 18 hours at room temperature, then it was carefully poured into a stirred solution of NaHCO _3. The aqueous layer was extracted with EtOAc, and the organic solution was washed with brine, dried (MgSO ₄₎ and concentrated to give the crude acid product (R) - (6,6- difluoro-2-methyl-2-oxepan Methyl ester (0.8 g, 90%). _{^{1 H NMR (400MHz, CDCl 3}} ) δ 8.09-8.03 (m, 2H), 7.59 (tt, J = 7.4,1.3Hz, 1H), 7.51-7.43 (m, 2H), 4.36 (d, J = 11.5Hz , 1H), 4.18 (d, J = 11.5 Hz, 1H), 3.90-3.69 (m, 2H), 2.13-1.84 (m, 3H), 1.79-1.68 (m, 3H), 1.34 (s, 3H).

(R)-(6,6-Difluoro-2-methyloxaheptan-2-yl)methyl benzoate (0.8 g, 2.81 mmol) in THF (10 mL), MeOH A mixture of (10 mL) and sodium hydroxide (5 mL, 5.00 mmol) was stirred overnight. The reaction mixture was partially concentrated and extracted with EtOAc (2). With 1N NaOH, washed with brine and the combined the organic solution was dried (MgSO ₄₎ and concentrated to give (R) - (6,6- difluoro-2-methyl-oxepan-2-yl) methanol (0.42 g, 83%). _{^{1 H NMR (400MHz, CDCl 3}} ) δ 3.78-3.70 (m, 2H), 3.59 (d, J = 11.3Hz, 1H), 3.38-3.31 (m, J = 11.2,6.4Hz, 1H), 2.12-1.85 (m, 3H), 1.81-1.58 (m, 3H), 1.23 (s, 3H).

Add to a solution of (R)-(6,6-difluoro-2-methyloxaheptan-2-yl)methanol (0.42 g, 2.331 mmol) in acetone (10 mL) Jones reagent (2 mL, 5.00 mmol). The reaction mixture was stirred in a bath and allowed to warm to room temperature for 18 h. The mixture was re-cooled in an ice-bath, and another portion of Jones reagent (2 mL, 5.00 mmol) was added and the mixture was stirred at room temperature for one day. The reaction mixture was diluted with EtOAc and washed with water, brine, dried (MgSO ₄₎ and concentrated to give (R) -6,6- difluoro-2-methyl-oxepane 2-carboxylic acid (0.3g, 66 %). _{^{1 H NMR (400MHz, CDCl 3}} ) δ 3.90-3.78 (m, 2H), 2.37 (dd, J = 15.6,9.3Hz, 1H), 2.23-2.02 (m, 1H), 1.99-1.69 (m, 3H) , 1.67-1.50 (m, 1H), 1.48 (s, 3H).

Cap Y-19, Y-20

Compound A (synthetic cap Y-9 precursor; 11.2 g, 46.6 mmol) and hydrated lithium hydroxide (4.2 g, 100 mmol) in THF (50 mL), MeOH (50 mL) and water (50 mL) The mixture was stirred for 3 days. The reaction mixture was cooled with EtOAc (EtOAc)EtOAc. The organic layer was washed with brine, dried (MgSO ₄₎ and concentrated to give the product (8.2g, 83%). _{^{1 H NMR (400MHz, CDCl 3}} ) δ 3.97 (s, 4H), 1.86-1.81 (m, 2H), 1.79-1.55 (m, 6H), 1.52-1.42 (m, 1H), 1.20 (t, J = 4.9 Hz, 1H), 1.00 (dd, J = 7.8, 4.5 Hz, 1H).

The above product (6g, 28.3mmol), pyridin-2-ylmethanol (4.1g, 37.6mmol), DCC (7.6g, 36.8mmol) and DMAP (0.345g, 2.83mmol) in DCM (100mL) The mixture was stirred for 20 h and diluted with EtOAc (EtOAc) ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.61 (d, J = 4.5 Hz, 1H), 7.72 (td, J = 7.7, 1.8 Hz, 1H), 7.37 (d, J = 8.0 Hz, 1H), 7.24 ( Dd, J = 7.3, 5.0 Hz, 1H), 5.30-5.25 (m, 1H), 5.24 - 5.18 (m, 1H), 3.97 (s, 4H), 1.90 - 1.64 (m, 6H), 1.59 - 1.51 ( m,1H), 1.51-1.40 (m, J = 6.3 Hz, 1H), 1.29-1.24 (m, 1H), 1.21 (t, J = 5.0 Hz, 1H), 0.98 (dd, J = 7.9, 4.4 Hz) , 1H).

PPTS (0.7 g, 2.79 mmol) was added to a solution of EtOAc (EtOAc,EtOAc. The reaction mixture was heated in a 65 ° C bath for 4 days. The reaction mixture was cooled and diluted with EtOAc, washed with water, brine, dried (MgSO _4), concentrated and purified by silica gel FCC, to give as a form of racemic 6-oxo-spiro [2.5] octane-1 Pyridin-2-ylmethyl formate (2.85 g, 48%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.65-8.56 (m, 1H), 7.72 (td, J = 7.7, 1.8 Hz, 1H), 7.37 (d, J = 7.8 Hz, 1H), 7.25 (ddd, J =6.9, 5.5, 1.1 Hz, 1H), 5.32-5.18 (m, 2H), 2.56-2.41 (m, 2H), 2.40-2.30 (m, 1H), 2.30-2.22 (m, 1H), 2.09-2.00 (m, 1H), 1.92-1.81 (m, 2H), 1.75-1.66 (m, 2H), 1.38 (t, J = 5.0 Hz, 1H), 1.14 (dd, J = 8.0, 4.8 Hz, 1H).

On ChiralPak IC (20% ACN / 80 % CO 2) was further purified racemate outer product thereof to give two fractions. The optical rotation of Dissolve-1 corresponds to (-)-6-side oxyspiro[2.5]octane-1-carboxylic acid pyridin-2-ylmethyl ester and the optical rotation of Dissolve-2 corresponds to (+)-6. - oxospiro[2.5]octane-1-carboxylic acid pyridin-2-ylmethyl ester.

In an ice bath, (, 6.94mmol 0.880mL) was added in CH Deoxo-Fluor® to BF ₃ .Et ₂ O in the ₂ Cl ₂ (10mL) solution (1.6mL, 8.68mmol). The reaction mixture was stirred at room temperature for 1 hour and cooled to 0 °C. A solution of (+)-6-oxooxyspiro[2.5]octane-1-carboxylic acid pyridin-2-ylmethyl ester (solvent-2, 0.9 g, 3.47 mmol) in DCM (8 mL). The reaction mixture was stirred at room temperature for 20 hours and cautiously poured into cold NaHCO ₃ solution, and extracted with EtOAc (2 times). With NaHCO _3, washed with brine and the combined the organic solution was dried (MgSO ₄₎ and concentrated to give the crude product. The crude product was dissolved in acetone (3mL), THF (6mL) , water (3mL), and the added NMO (0.813g, 6.94mmol) and OsO ₄ (0.436mL, 0.035mmol), and the mixture was stirred for 2 days. The solvent was removed, and the residue was partitioned between dilute NH ₄ Cl and EtOAc. The organic solution was washed with brine, dried (MgSO _4), concentrated and purified on a 40g silica gel cartridge to give 6,6-difluoro-spiro [2.5] octane-1-carboxylic acid pyridin-2-ylmethyl ester (0.41g, 42 %). ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.65-8.58 (m, 1H), 7.72 (td, J = 7.7, 1.9 Hz, 1H), 7.36 (d, J = 7.8 Hz, 1H), 7.27-7.21 (m) , 1H), 5.26 (s, 2H), 2.05-1.78 (m, 5H), 1.77-1.63 (m, 3H), 1.53-1.43 (m, 1H), 1.25 (t, J = 5.0 Hz, 1H), 1.01 (dd, J = 8.0, 4.8 Hz, 1H).

6,6-Difluorospiro[2.5]octane-1-carboxylic acid pyridin-2-ylmethyl ester (0.41 g, 1.458 mmol) in THF (5 mL), MeOH (5 mL) and sodium hydroxide The mixture in (4 ml, 4.00 mmol) was stirred for 5 hours. The reaction mixture was partially concentrated, acidified to pH <2, and extracted with EtOAc (2times). With 1H HCl, washed with brine and the combined organic extracts the solution, dried (MgSO ₄₎ and concentrated to give (+) - 6,6-difluoro-spiro [2.5] octane-1-carboxylic acid (0.25g, 90%) .

In a similar manner, (-)-6,6-difluorospiro[2.5] was prepared from autolyzed-1(-)-6-oxooxyspiro[2.5]octane-1-carboxylic acid pyridin-2-ylmethyl ester. Octane-1-carboxylic acid.

Cap Y-21

Add NaOEt (9.6 ml, 25.7 mmol) and MeI (1.7 ml, 27.2) to a solution of 2-ethyloxycyclohexanecarboxylate (4 g, 23.50 mmol) in ethanol (30 mL). (mmol), and the reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was partially concentrated, and the residue was diluted with EtOAc, washed with 5N NaOH, water, brine, dried (MgSO ₄₎ and concentrated to give 1-methyl-2-oxo-cyclohexanecarboxylic acid ethyl ester (4.0 g of, 92%). ¹ H NMR (500MHz, CDCl ₃ ) δ 4.32-4.10 (m, 2H), 2.57-2.43 (m, 3H), 2.08-1.98 (m, 1H), 1.82-1.64 (m, 3H), 1.51-1.42 ( m, J =13.7, 11.9, 4.4 Hz, 1H), 1.30 (s, 3H), 1.28 (t, J = 7.1 Hz, 3H).

Cap Y-22

Add NaBH ₄ (0.16 g, 4.23 mmol) to a solution of 1-methyl-2-oxocyclohexanecarboxylate (0.8 g, 4.34 mmol) in MeOH (10 mL). ). The reaction was stirred at 0 ℃ mixture was 2.5 hours, diluted with EtOAc, and washed with NH ₄ Cl, washed with brine, dried (MgSO _4), on 40g silica gel cartridge: purified (EtOAc / hexanes 0-40%) to give cis Ethyl 2-hydroxy-1-methylcyclohexanecarboxylate (0.46 g, 57%). _{^{1 H NMR (400MHz, CDCl 3}} ) δ 4.26-4.12 (m, 2H), 3.48 (d, J = 10.0Hz, 1H), 3.39-3.29 (m, 1H), 2.23-2.11 (m, 1H), 1.94 -1.86 (m, 1H), 1.78-1.68 (m, 1H), 1.58-1.46 (m, 2H), 1.32 (s, 3H), 1.29 (t, J = 7.2 Hz, 3H).

Hydrogen fluoride was added to a mixture of (1R,2S)-2-hydroxy-1-methylcyclohexanecarboxylic acid ethyl ester (0.2 g, 1.074 mmol) in THF (4 mL), MeOH (4 mL) Lithium oxide (0.3 g, 7.15 mmol). The reaction mixture was stirred at room temperature overnight, then it was diluted with EtOAc, washed with dilute hydrochloric acid, washed with brine, dried (MgSO ₄₎ and concentrated to give cis-1-methyl-cyclohexanecarboxylic acid 2-hydroxy (0.14 g of, 82%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 3.48 (dd, J =10.5, 3.8 Hz, 1H), 2.30-2.18 (m, 1H), 1.96-1.87 (m, 1H), 1.76 (td, J = 4.5, 3.1 Hz, 1H), 1.66-1.50 (m, 2H), 1.38 (s, 3H), 1.35-1.12 (m, 3H).

Cap Y-23, Y-24

(-) Cap Y-23 was prepared using a similar procedure as described for the synthesis of compound Y-22 using (R)-1-methyl-2-oxocyclohexanecarboxylate as the starting material (Tetrahedron 1993) , 49, 1579-1588), (-)-(1R,2S)-2-hydroxy-1-methylcyclohexanecarboxylic acid ((-)-cap Y-23) was obtained.

To 1-methyl-2-oxocyclohexanecarboxylic acid (0.7 g, 4.48 mmol) and 2-(methyl(pyridin-2-yl)amino)ethanol (0.819 g, 5.38 mmol) at 0 °C Add N-ethyl-N-isopropylpropan-2-amine (0.695 g, 5.38 mmol) and 2-(1H-benzo[d][1, tetrafluoroborate in a solution in DCM (10 mL) 2,3]triazol-1-yl)-1,1,3,3-tetramethyliso (1.583 g, 4.93 mmol). The reaction mixture was stirred at room temperature for 18 hours, and diluted with EtOAc, washed with saturated NaHCO _3, water, brine, dried (MgSO _4), concentrated and purified on a 40g silica gel cartridge to give an oil of 1-methyl - 2-(Methyl(pyridin-2-yl)amino)ethyl 2-oxocyclohexanecarboxylate (1.1 g, 85%). _{^{1 H NMR (400MHz, CDCl 3}} ) δ 8.14 (ddd, J = 4.9,1.9,0.8Hz, 1H), 7.47 (ddd, J = 8.7,6.9,2.0Hz, 1H), 6.57 (ddd, J = 7.2, 4.9, 0.8 Hz, 1H), 6.51 (d, J = 8.5 Hz, 1H), 4.35 (td, J = 5.6, 1.8 Hz, 2H), 3.91-3.83 (m, 2H), 3.05 (s, 3H), 2.52-2.44(m,1H),2.44-2.36(m,2H),2.00-1.90(m,1H),1.75-1.60(m,3H), 1.49-1.37(m,1H),1.27(s,3H ).

2-(Methyl(pyridin-2-yl)amino)ethyl 1-methyl-2-oxocyclohexanecarboxylate (1.1 g, 3.79 mmol) in MeOH (10 mL) NaBH ₄ (0.4 g, 10.57 mmol) was added to the solution. The reaction mixture was stirred in a bath for 0.5 hour and then at 0 ° C for 2 hours. The reaction mixture was diluted with EtOAc, and washed ₄ Cl saturated aqueous NH, water, brine, dried (MgSO _4), and on 80g silica gel cartridge: purified (EtOAc / hexane 5-100%), to give cis-2- 2-(Methyl(pyridin-2-yl)amino)ethyl hydroxy-1-methylcyclohexanecarboxylate. _{^{1 H NMR (400MHz, CDCl 3}} ) δ 8.16 (ddd, J = 5.0,1.9,0.9Hz, 1H), 7.47 (ddd, J = 8.8,7.0,2.0Hz, 1H), 6.58 (ddd, J = 7.0, 5.0, 0.8 Hz, 1H), 6.53 (d, J = 8.5 Hz, 1H), 4.43-4.25 (m, 2H), 3.90 (t, J = 5.5 Hz, 3H), 3.08 (s, 3H), 1.80- 1.67 (m, 3H), 1.51-1.33 (m, 4H), 1.30-1.21 (m, 1H), 1.17 (s, 3H).

Further purification of the racemic cis-2-hydroxy-1-methylcyclohexanecarboxylic acid 2-(methyl(pyridin-2-yl) on a Chiralpak AD (ethanol/heptane: 17%, 35 min) column Amino)ethyl ester To the two dissolved fractions. Dissolve-1(1S,2R)-2-hydroxy-1-methylcyclohexanecarboxylic acid 2-(methyl(pyridin-2-yl)amino)ethyl ester and the solvate-2(1R,2S)- 2-(methyl(pyridin-2-yl)amino)ethyl 2-hydroxy-1-methylcyclohexanecarboxylate.

Ether-1 (1S,2R)-2-hydroxy-1-methylcyclohexanecarboxylic acid 2-(methyl(pyridin-2-yl)amino)ethyl ester (0.2 g, 0.684) at room temperature A mixture of THF (5 mL), MeOH (5 mL) and EtOAc. The reaction mixture was acidified to mp EtOAc (EtOAc) (EtOAc) Washed with brine the combined organic solution was dried (MgSO ₄₎ and concentrated to give (+) - (1S, 2R ) -2- hydroxy-1-methyl-cyclohexanecarboxylic acid (0.08g, 74%).

Hydrolysis of the dissolvate-2(1R,2S)-2-hydroxy-1-methylcyclohexanecarboxylic acid 2-(methyl(pyridin-2-yl)amino)ethyl ester using the same method gave (-)-( 1R, 2S)-2-hydroxy-1-methylcyclohexanecarboxylic acid.

Cap Y-25

Under N _2, to SmI ₂ (2.8g, 6.93mmol) in THF (120mL) was added in the containing methyl-2-oxo-cyclohexanecarboxylic acid 2- (methyl (pyridin-2 Ethyl)ethyl ester (0.8 g, 2.76 mmol) in THF (120 mL) and MeOH (0.6 mL, 14.. The reaction mixture was stirred at room temperature for 3 hours and diluted with EtOAc, washed with water, brine, dried (MgSO _4), and concentrated on a 24g silica gel cartridge: purified (EtOAc / hexanes 2-80%) to afford trans - 2-(Methyl(pyridin-2-yl)amino)ethyl 2-hydroxy-1-methylcyclohexanecarboxylate (0.25 g, 31%). _{^{1 H NMR (400MHz, CDCl 3}} ) δ 8.16 (ddd, J = 4.9,2.0,0.9Hz, 1H), 7.47 (ddd, J = 8.7,6.9,2.0Hz, 1H), 6.58 (ddd, J = 7.2, 5.0, 0.9 Hz, 1H), 6.53 (dd, J = 8.5, 0.8 Hz, 1H), 4.45-4.26 (m, 2H), 3.95-3.82 (m, 3H), 3.11-3.04 (m, 3H), 1.78 -1.63 (m, 3H), 1.52-1.35 (m, 3H), 1.31 - 1.22 (m, 2H), 1.17 (s, 3H).

To 2-(methyl(pyridin-2-yl)amino)ethyl p -trans -2-hydroxy-1-methylcyclohexanecarboxylate (0.25 g, 0.855 mmol) in THF (5 mL) NaOH (2 mL, 2.000 mmol) was added to the mixture and stirred at room temperature for 18 h. The reaction mixture was acidified to pH ~2 at EtOAc (EtOAc). With 1N HCl, the combined organic was washed with brine solution, dried (MgSO ₄₎ and concentrated to give trans -2-hydroxy-1-methyl-cyclohexanecarboxylic acid (0.135g, 100%). ¹ H NMR (400 MHz, CDCl ₃ ) δ 3.98 (dd, J = 10.8, 4.3 Hz, 1H), 1.91-1.68 (m, 3H), 1.68-1.31 (m, 5H), 1.27 (s, 3H).

Cap Y-26 (racemate)

To a solution of 7-methyl-8-oxo-1,4-dioxaspiro[4.5]decane-7-carboxylate (1.1 g, 4.54 mmol) at -15 ° C (ice/methanol) in MeOH (20mL) in a solution of 3 parts of carve was added NaBH ₄ (0.08g, 2.115mmol). Stirred at this temperature for 2 hours the reaction mixture, and the reaction mixture was diluted with EtOAc, washed with NH ₄ Cl (2 ×), washed with brine, dried (MgSO ₄₎ and concentrated to dryness to give (7S, 8R) -8- hydroxy - Ethyl 7-methyl-1,4-dioxaspiro[4.5]decane-7-carboxylate (1.1 g, 99%). _{^{1 H NMR (500MHz, CDCl 3}} ) δ 4.28-4.11 (m, 2H), 4.02-3.84 (m, 4H), 3.49-3.39 (m, 2H), 2.36 (dd, J = 13.9,2.9Hz, 1H) , 2.04-1.91 (m, 1H), 1.84-1.74 (m, 1H), 1.73-1.62 (m, J = 12.5, 12.5, 4.7 Hz, 1H), 1.46 (d, J = 14.0 Hz, 1H), 1.35 (s, 3H), 1.32-1.29 (m, 3H).

To (7S,8R)-8-hydroxy-7-methyl-1,4-dioxaspiro[4.5]decane-7-carboxylic acid ethyl ester (1.1 g, 4.50) at 0 ° C under N ₂ Addition of NaH (0.26 g, 6.50 mmol) in EtOAc (EtOAc) Benzyl bromide (0.81 mL, 6.81 mmol) was added and the reaction mixture was stirred at room temperature overnight. The reaction mixture was then diluted with EtOAc, and washed with NH ₄ Cl, washed with brine, dried (MgSO _4), concentrated and purified by silica gel by FCC to give (7S, 8R) -8- (benzyloxy) -7-methyl -1,4-Dioxaspiro[4.5]decane-7-carboxylic acid ethyl ester (1.2 g, 80%). _{^{1 H NMR (400MHz, CDCl 3}} ) δ 7.35-7.20 (m, 5H), 4.58 (d, J = 11.5Hz, 1H), 4.41 (d, J = 11.8Hz, 1H), 4.21-4.04 (m, 2H ), 4.01-3.87 (m, 4H), 3.78-3.71 (m, 1H), 2.35 (d, J = 14.1 Hz, 1H), 2.00-1.86 (m, 2H), 1.85-1.77 (m, 1H), 1.74-1.67 (m, 1H), 1.55-1.47 (m, 1H), 1.32 (s, 3H), 1.20 (t, J = 7.2 Hz, 3H).

To (7S,8R)-8-(benzyloxy)-7-methyl-1,4-dioxaspiro[4.5]decane-7-carboxylic acid ethyl ester (1.2 g, 3.59 mmol) in acetone ( PPTS (0.1 g, 0.398 mmol) was added to a solution of 20 mL) and water (5 mL). The reaction mixture was heated in a 60 ° C bath for 5 hours and at room temperature for 18 hours. The reaction mixture was diluted with EtOAc, and washed with NaHCO _3, brine, dried (MgSO _4), and concentrated on a 40g silica gel cartridge: purified (EtOAc / hexanes 0-40%) to give a colorless oil form the (1S, 2R)-2-(Benzyloxy)-1-methyl-5-oxocyclohexanecarboxylate (0.8 g, 77%). _{^{1 H NMR (400MHz, CDCl 3}} ) δ 7.43-7.28 (m, 5H), 4.68 (d, J = 11.8Hz, 1H), 4.54 (d, J = 11.5Hz, 1H), 4.24-4.06 (m, 2H ), 3.97 (br.S., 1H), 3.15 (d, J = 14.3 Hz, 1H), 2.63 (td, J = 13.8, 6.5 Hz, 1H), 2.38-2.31 (m, 1H), 2.29-2.15 (m, 2H), 1.97-1.87 (m, 1H), 1.23 (t, J = 7.2 Hz, 3H), 1.16 (s, 3H).

To an aqueous solution of (1S,2R)-2-(benzyloxy)-1-methyl-5-oxocyclohexanecarboxylate (0.34 g, 1.171 mmol) in CH ₂ Cl ₂ Deoxo-Fluor® (1 mL, 5.42 mmol) and BF ₃ .Et ₂ O (0.2 mL, 1.478 mmol) were added to the solution in 1 mL). The reaction mixture was stirred at room temperature for three days, then it was carefully poured into a stirred solution of NaHCO _3, and extracted with EtOAc. The organic solution was washed with brine, dried (MgSO _4), concentrated and the silicone tube 25g: purified (EtOAc / hexanes 0-35%) to give (1S, 2R) -2- (benzyloxy) -5, Ethyl 5-difluoro-1-methylcyclohexanecarboxylate (0.28 g, 77%). _{^{1 H NMR (400MHz, CDCl 3}} ) δ 7.37-7.20 (m, 5H), 4.57 (d, J = 11.8Hz, 1H), 4.43 (d, J = 11.5Hz, 1H), 4.22-4.03 (m, 2H ), 3.82 (br.S., 1H), 2.62-2.44 (m, 1H), 2.17-1.95 (m, 3H), 1.95-1.84 (m, 1H), 1.84-1.73 (m, 1H), 1.28 ( d, J = 1.8 Hz, 3H), 1.22 (t, J = 7.0 Hz, 3H).

Ethyl (1S,2R)-2-(benzyloxy)-5,5-difluoro-1-methylcyclohexanecarboxylate (0.28 g, 0.896 mmol) and lithium hydroxide hydrate (0.5 g, 11.92) A mixture of THF (5 mL), MeOH (5 mL) and water (5 mL) The reaction mixture was acidified to pH <2 and extracted with EtOAc. Washed with water, the organic solution was washed with brine, dried (MgSO ₄₎ and concentrated to give (1S, 2R) -2- (benzyloxy) -5,5-difluoro-1-methyl-cyclohexanecarboxylic acid (0.14 g of, 55%). _{^{1 H NMR (400MHz, CDCl 3}} ) δ 7.37-7.14 (m, 5H), 4.61-4.56 (m, 1H), 4.51-4.45 (m, 1H), 3.81 (br.S., 1H), 2.65-2.46 (m, 1H), 2.12-1.97 (m, 3H), 1.96-1.87 (m, 1H), 1.87-1.75 (m, 1H), 1.36-1.31 (m, 3H).

In the H ₂ 50PSI, the (1S, 2R) -2- (benzyloxy) -5,5-difluoro-1-methyl-cyclohexanecarboxylic acid (0.14g, 0.492mmol) and Pd (OH) ₂ /C (0.04 g, 0.057 mmol) <RTI ID=0.0> The mixture was filtered, and the filtrate was evaporated to dry crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal _{^{1 H NMR (400MHz, CDCl 3}} ) δ 3.80 (t, J = 4.8Hz, 1H), 2.65-2.48 (m, 1H), 2.26-2.09 (m, 1H), 2.03-1.78 (m, 4H), 1.40 (s, 3H).

Cap Y-27

Add DIPEA (1.5 mL, 8.59 mmol) and benzyl bromide to a solution of 5,6-dihydro-2H-pyran-3-carboxylic acid (1 g, 7.80 mmol) in DCM (10 mL) (1.1 mL, 9.25 mmol). The reaction mixture was stirred at room temperature for 18 hours, then it was diluted with EtOAc, and washed with aqueous NH ₄ Cl and brine, and concentrated on a 40g silica gel cartridge: purified (EtOAc / hexanes 0-60%) to give 5 , 6-Dihydro-2H-pyran-3-carboxylate (1.6 g, 94%). _{^{1 H NMR (400MHz, CDCl 3}} ) δ 7.42-7.33 (m, 5H), 7.13 (tt, J = 4.1,1.9Hz, 1H), 5.21 (s, 2H), 4.40-4.32 (m, 2H), 3.77 (t, J = 5.5Hz, 2H ), 2.39-2.25 (m, J = 5.5,5.5,4.1,2.8,2.8Hz, 2H).

At 0 deg.] C, under N ₂ on added BuLi (1.3ml, 2.080mmol) to the sum DIPEA (0.31ml, 2.175mmol) in THF (4mL) solution. The reaction mixture was stirred at 0 °C for 0.5 h and cooled to -78 °C. HMPA (0.26 ml, 1.494 mmol) was added and stirred for 15 min then a solution of EtOAc (3 g, EtOAc. The mixture was stirred at -78 °C for 1 hr then EtOAc (0.12 mL, 1.19 mmol). The reaction mixture was stirred for 2 hours and allowed to warm to room temperature during this. The reaction mixture was diluted with EtOAc and with 1N HCl, brine, dried (MgSO _4), concentrated and purified by silica gel by FCC to give 3-methyl-3,6-dihydro-pyran-3-carboxylic acid benzyl -2H- Methyl ester (0.19 g, 60%). _{^{1 H NMR (500MHz, CDCl 3}} ) δ 7.47-7.31 (m, 5H), 6.00-5.89 (m, 1H), 5.86-5.79 (m, 1H), 5.24-5.11 (m, 2H), 4.20 (d, J = 11.1Hz, 1H), 4.19-4.08 (m, 2H), 3.56-3.46 (m, 1H), 1.30 (s, 3H).

3-methyl-3,6-dihydro -2H- pyran-3-carboxylic acid benzyl ester piperidine (0.19g, 0.818mmol) in MeOH solution (15mL) of the degassed and purged with N _2. Was added Pd / C (0.08g, 0.075mmol) , and the mixture was degassed and refilled with H _2. The reaction mixture was stirred at 40 PSI H ₂ for 3 days and then filtered. The filtrate was concentrated to dryness to give 3-methyltetrahydro-2H-pyran-3-carboxylic acid (0.09 g, 76%). _{^{1 H NMR (400MHz, CDCl 3}} ) δ 4.12 (d, J = 11.3Hz, 1H), 3.87-3.77 (m, 1H), 3.56-3.44 (m, 1H), 3.28 (d, J = 11.3Hz, 1H ), 2.28-2.11 (m, 1H), 1.84-1.67 (m, 1H), 1.60 (td, J = 9.0, 4.0 Hz, 1H), 1.51-1.38 (m, 1H), 1.18 (s, 3H).

Cap Y-28

At 0 deg.] C, under N ₂ on, BuLi was added to the medium of DIPEA (0.55mL, 3.86mmol) in THF (10mL) solution (0.35mL, 3.50mmol). The reaction mixture was stirred at this temperature for 15 minutes. The reaction mixture was cooled in a -78 ° C bath, and HMPA (0.47 mL, 2.70 mmol) was added dropwise, followed by dropwise addition of benzyl 5,6-dihydro-2H-pyran-3-carboxylate (0.6 g, 2.75) Methyl) solution in THF (6 mL). The mixture was stirred at -78 °C for 0.5 h, then ((chloromethoxy)methyl)benzene (0.5 mL, 3.51 mmol). Stirring the reaction mixture at -78 deg.] C for 1 hour and stirred at room temperature for 1 hour before it was diluted with EtOAc, and washed with NH ₄ Cl (2 ×) and brine, dried (MgSO _4), and concentrated in 40g Purification on a silica gel cartridge (EtOAc / hexanes: 0% to 40%) afforded 3-((benzyloxy)methyl)-3,6-dihydro-2H-pyran-3-carboxylate. 0.63g, 68%). _{^{1 H NMR (400MHz, CDCl 3}} ) δ 7.37-7.20 (m, 10H), 5.96-5.87 (m, 2H), 5.23-5.19 (m, 1H), 5.19-5.14 (m, 1H), 4.53-4.49 ( m, 1H), 4.49-4.44 (m, 1H), 4.16-4.06 (m, 3H), 3.94 (d, J = 11.3 Hz, 1H), 3.68-3.65 (m, 1H), 3.65-3.62 (m, 1H).

A solution of 3-((benzyloxy)methyl)-3,6-dihydro-2H-pyran-3-carboxylate (0.63 g, 1.862 mmol) in MeOH (10 mL) Refill with N ₂ . Pd/C (0.1 g, 0.094 mmol) was added and the suspension was degassed. The reaction mixture was stirred for 3 days at 50psi H _2, and the solid was filtered off. The filtrate was concentrated to dryness to give 3-(hydroxymethyl)tetrahydro-2H-pyran-3-carboxylic acid (0.22 g, 74%). _{^{1 H NMR (400MHz, CDCl 3}} ) δ 4.05 (d, J = 11.5Hz, 1H), 3.77-3.66 (m, 2H), 3.64 (d, J = 11.5Hz, 1H), 3.83-3.60 (m, 2H ), 2.11-1.97 (m, 1H), 1.77-1.62 (m, 3H).

Cap Y-29

To a solution of benzyl 5,6-dihydro-2H-pyran-3-carboxylate (1 g, 4.58 mmol) in EtOAc (EtOAc) The reaction mixture was stirred at 65 ° C for 4 hours. The reaction mixture was cooled, diluted with DCM, washed with 1N NaOH (3 ×), brine (2 ×), dried (MgSO _4), concentrated and silica gel in the cartridge: purified (EtOAc / hexanes 0-50%) to give Methyl 3,7-dioxabicyclo[4.1.0]heptane-1-carboxylate (0.62 g, 58%). _{^{1 H NMR (400MHz, CDCl 3}} ) δ 7.43-7.31 (m, 5H), 5.25 (d, J = 12.3Hz, 1H), 5.18 (d, J = 12.3Hz, 1H), 4.62 (d, J = 13.6 Hz, 1H), 3.96 (d, J = 13.6 Hz, 1H), 3.71-3.63 (m, 1H), 3.59-3.44 (m, 2H), 2.15 - 1.98 (m, 2H).

Add MgI ₂ (0.4 g, 1.438) to a solution of 3,7-dioxabicyclo[4.1.0]heptane-1-carboxylic acid benzyl ester (0.24 g, 1.025 mmol) in diethyl ether (10 mL) Mm). The reaction mixture was stirred at room temperature for 0.5 hours and diluted with EtOAc, and washed with 1N HCl (2 ×), brine (2 ×), dried (MgSO ₄₎ and concentrated to give 3-hydroxy-4-iodo-tetrahydro -2H - Piperonyl-3-carboxylic acid benzyl ester (0.37 g, 100%). _{^{1 H NMR (400MHz, CDCl 3}} ) δ 7.49-7.35 (m, 5H), 5.39-5.34 (m, 1H), 5.33-5.26 (m, 1H), 4.27 (dd, J = 11.3,5.3Hz, 1H) , 4.24.4.04 (m, 1H), 3.83 (dt, J = 11.4, 3.6 Hz, 1H), 3.53-3.41 (m, 2H), 2.80-2.65 (m, 1H), 2.35-2.25 (m, 1H) .

3-Hydroxy-4-iodo-tetrahydro-pyran-3-carboxylic acid -2H- benzyl ester (0.21g, 0.580mmol) and Pd / C (0.08g, 0.075mmol) the mixture was degassed, and the H ₂ ( Stir for 3 hours at 50 PSI pressure). Another portion of Pd/C (0.5 g) was added and the reaction mixture was stirred at 55 PSI for 3 days. The solid was filtered off and the filtrate was concentrated to dryness to give 3-hydroxytetrahydro-2H-pyran-3-carboxylic acid. _{^{1 H NMR (400MHz, CD 3}} OD) δ 3.91-3.76 (m, 2H), 3.62-3.44 (m, 2H), 2.15-2.05 (m, 1H), 2.03-1.87 (m, 1H), 1.78-1.67 (m, 1H), 1.59 - 1.46 (m, 1H).

Cap N-14

Cap N-14 was prepared in a similar manner starting from 2-methoxybenzaldehyde and tributyl butyl cyclopropanecarboxylate according to the procedure described for the preparation of cap N-11. LC/MS (Cond. N-1): [M-OH] ⁺ 205.1, RT = 2.994 min.

Cap N-15

To a solution of methyl 3-hydroxy-2,2-dimethyl-3-phenylpropanoate (0.2 g, 0.960 mmol) in THF (4 mL) at -78 °C THF (1.152 mL, 1.0 M) containing hexamethyldioxane was added. The reaction mixture was stirred at -78 °C for 15 min then EtOAc (0.273 g). The reaction mixture was stirred at -78 °C for 0.5 hr and slowly warmed to room temperature over 1 hour then stirred at room temperature for 18 h. The reaction mixture was poured into saturated NH ₄ Cl, and the extracted with EtOAc. The organic solution was washed with brine, dried (Na ₂ SO ₄₎ and concentrated to give a pale yellow liquid of 2,2-dimethyl-3-methoxy-3-phenyl-propionic acid methyl ester (0.19g). _{^{1 H NMR (400MHz, CDCl 3}} ) δ ppm 7.44-7.24 (m, 5H), 4.51 (s, 1H), 3.73 (s, 3H), 3.22 (s, 3H), 1.14 (s, 3H), 1.04 ( s, 3H).

Add 1N NaOH (2.6 mL) to a solution of methyl 3-methoxy-2,2-dimethyl-3-phenylpropanoate (0.19 g, 0.855 mmol) in THF (4 mL) / MeOH (1 mL) ). The reaction mixture was stirred at room temperature for 16 hours. The reaction was diluted with water and EtOAc. The organic phase was extracted with 1N EtOAc then EtOAc (EtOAc)EtOAc. It was washed with water and saturated NaCl of the combined organic phases were dried (Na ₂ SO _4), filtered and concentrated to afford Cap N-15. LC/MS (Cond. N-1): [M+Na] ⁺ 231.1, RT = 3.59 min.

Cap N-16

Cap N-16 was prepared according to the procedure described for the preparation of cap N-15. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 7.43-7.28 (m, 5H), 4.94 (s, 1H), 3.37-3.32 (m, 3H), 1.35-1.30 (m, 1H), 1.21-1.14 (m , 1H), 1.05 (ddd, J = 9.5, 7.1, 4.0 Hz, 1H), 0.60 (ddd, J = 9.5, 7.1, 4.0 Hz, 1H).

Cap N-17

A solution of 1-fluoropropan-2-one (1 g, 13.15 mmol) in diethyl ether (3 mL) was added to EtOAc EtOAc. Next, a solution of sodium cyanide (0.723 g, 14.76 mmol) in water (2.5 mL) was added to the obtained mixture, and the mixture was stirred at room temperature for 18 hr. The reaction was diluted with water and diethyl ether. The combined washed with water and brine and the organic phases were dried (Na ₂ SO _4), filtered and concentrated to give a yellow oil of 3-fluoro-2-methyl-propionitrile (0.56g). ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 4.53-4.40 (m, 1H), 4.37 - 4.31 (m, 1H), 1.48 (d, J = 2.3 Hz, 3H).

3-Fluoro-2-hydroxy-2-methylpropanenitrile (0.56 g) was heated to reflux with aq. The reaction was then cooled to room temperature and diluted with water and EtOAc. The aqueous phase was extracted with 2x EtOAc. Washed with brine the combined organic phases were dried (Na ₂ SO _4), filtered and concentrated to afford Cap N-17 (0.08g). ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 4.71-4.60 (d, J = 9.3 Hz, d, J = 9.3 Hz, 1H), 4.47 - 4.35 (d, J = 9.3 Hz, d, J = 9.3 Hz, 1H), 1.47 (d, J = 2.3 Hz, 3H).

Cap N-18

Add DIPEA (3.13 mL, 17.89 mmol), benzene to a solution of 3-hydroxy-2-(hydroxymethyl)-2-methylpropanoic acid (2 g, 14.91 mmol) in EtOAc (15 mL) Methyl bromide (1.862 mL, 15.66 mmol) and DMAP (0.100 g, 0.820 mmol). The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated, then diluted with EtOAc, and washed with saturated NaHCO _3, citric acid, water, brine, dried (Na ₂ SO _4), and purified by silica gel chromatography (0-100% EtOAc in hexane of), Benzo 3-hydroxy-2-(hydroxymethyl)-2-methylpropanoate (2.02 g) was obtained. _{^{1 H NMR (400MHz, CDCl 3}} ) δ 7.44-7.31 (m, 5H), 5.23 (s, 2H), 3.95 (dd, J = 10.9,6.4Hz, 2H), 3.75 (dd, J = 11.3,6.3Hz , 2H), 2.83 (t, J = 6.7 Hz, 2H), 1.10 (s, 3H).

Add Deoxo-Fluor® (0.370 mL, 2.007 mmol) to a solution of benzyl 3-hydroxy-2-(hydroxymethyl)-2-methylpropanoate (0.45 g, 2.007 mmol) in DCM (10 mL) Then, EtOH (0.035 mL) was added. The resulting yellowish solution was stirred at room temperature for 16 hours. The reaction mixture was diluted with saturated NaHCO ₃ and EtOAc. Water, the organic phase was washed with saturated NaCl, and dried over anhydrous Na ₂ SO _4, filtered, and dried to give a yellow oil. The crude product was purified by EtOAc EtOAc (EtOAc:EtOAc) _{^{1 H NMR (400MHz, CDCl 3}} ) δ ppm 7.44-7.32 (m, 5H), 5.21 (s, 2H), 4.75 (d, J = 9.0Hz, 0.5H), 4.69-4.51 (m, 1H), 4.45 (d, J = 9.0 Hz, 0.5H), 3.85 (ddd, J = 11.3, 6.5, 0.8 Hz, 1H), 3.76 (ddd, J = 11.3, 6.8, 1.8 Hz, 1H), 1.27-1.19 (m, 3H).

To a solution of benzyl 3-fluoro-2-(hydroxymethyl)-2-methylpropanoate (0.09 g) in THF (5 mL) and MeOH (1. The reaction mixture was stirred at room temperature for 5 hours. The reaction was concentrated, then diluted with water and washed with diethyl ether. The aqueous phase was then acidified with EtOAc (EtOAc)EtOAc. The organic phase was washed with saturated NaCl, dried (Na ₂ SO _4), filtered and concentrated to give a white solid of the cap N-18. ¹ H NMR (400 MHz, CDCl ₃ ) δ 4.81-4.52 (m, 2H), 3.95 - 3.72 (m, 2H), 1.37-1.25 (m, 3H).

Cap N-19

Cap N-19 was prepared according to the procedure described for the preparation of cap N-17. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 4.85-4.74 (m, 1H), 4.72-4.62 (m, 2H), 4.61-4.52 (m, 1H).

Cap N-20

Cap N-20 was prepared in a similar manner starting from 4,4-difluorocyclohexanecarbaldehyde and methyl isobutyrate according to the procedure described for the preparation of cap N-11.

Cap N-21

Methyl 3,3-difluorocyclobutanecarboxylate (1.2 g, 7.99 mmol), indium (III) iodide (0.198 g, 0.400 mmol), (1-methoxy-2- at room temperature Methylpropan-1-en-1-yloxy)trimethyldecane (1.811 g, 10.39 mmol), dimethyl (phenyl) decane (1.593 mL) was added to a stirred solution in DCM (10 mL). 10.39mmol). The reaction mixture was stirred at room temperature for 16 hours. The reaction was diluted with EtOAc (EtOAc)EtOAc. The aqueous phase was extracted twice with diethyl ether. The organic phase was washed with water and brine, dried (Na ₂ SO _4), filtered and concentrated to give a yellow oil. The crude product was purified by EtOAc (EtOAc:EtOAc) _{^{1 H NMR (400MHz, CDCl 3}} ) δ ppm 3.74-3.68 (m, 3H), 3.64 (t, J = 5.9Hz, 1H), 2.91 (d, J = 6.5Hz, 1H), 2.67-2.40 (m, 4H), 2.37-2.24 (m, 1H), 1.22-1.18 (m, 3H), 1.16 (s, 3H).

Add 1N to a solution of methyl 3-(3,3-difluorocyclobutyl)-3-hydroxy-2,2-dimethylpropanoate (0.16 g) in THF (4 mL) MeOH (1 mL) NaOH (2.160 mL). The solution was then stirred at room temperature for 16 hours. The reaction was concentrated with EtOAc (EtOAc)EtOAc. The organic phase was washed with saturated NaCl, dried over anhydrous Na ₂ SO _4, filtered and concentrated to afford the cap N-21. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 3.73 (d, J = 5.8 Hz, 1H), 2.66-2.54 (m, 1H), 2.54-2.39 (m, 3H), 2.37-2.24 (m, 1H) , 1.22-1.15 (m, 3H), 1.11 (s, 3H).

Cap N-22

To a solution of diethyl cyclohexane-1,1-dicarboxylate (1 g, 4.38 mmol) in THF (5 mL) . The reaction mixture was stirred at room temperature for 5 hours. The reaction mixture was concentrated, then diluted with water and washed with diethyl ether. The aqueous phase was then acidified with EtOAc (EtOAc)EtOAc. The organic phase was washed with saturated NaCl, dried (Na ₂ SO _4), filtered and concentrated to afford Cap N-22. ¹ H NMR (400 MHz, CDCl ₃ ) δ 4.22 (q, J = 7.2 Hz, 2H), 2.09 - 1.93 (m, 4H), 1.64-1.40 (m, 6H), 1.32-1.23 (m, 3H).

Cap N-23

Cap N-23 was prepared according to the procedure described for the preparation of cap N-21. _{^{1 H NMR (400MHz, CDCl 3}} ) δ ppm 3.03 (d, J = 9.0Hz, 1H), 1.34-1.26 (m, 6H), 1.05-0.93 (m, 1H), 0.69-0.61 (m, 1H), 0.58-0.49 (m, 1H), 0.43-0.29 (m, 2H).

Cap N-24

Cap N-24 was prepared according to the procedure described for the preparation of cap N-21.

Cap N-25

To a solution of diisopropylamine (0.548 mL) in THF (10 mL), EtOAc. The reaction mixture was stirred at -78 °C for 5 minutes and then stirred for 30 minutes in an ice bath. A solution of benzyl cyclohexanecarboxylate (0.7 g, 3.21 mmol) in THF (5 mL) was added dropwise. The reaction mixture was stirred at -78 °C for 2 hours. A solution of acetaldehyde (0.283 g, 6.41 mmol) in THF (2 mL) was added dropwise at -78. The solution was then allowed to warm to room temperature and stirred at room temperature for 16 hours. Quenched with NH ₄ Cl The reaction was then diluted with EtOAc. Followed by saturated NaHCO _3, water, the organic phase was washed with saturated NaCl, dried over anhydrous Na ₂ SO ₄ dried and concentrated to give an oil. The crude product was purified by EtOAc (EtOAc) elute </RTI>^<RTIID=0.0></RTI>^</RTI>^<RTIID=0.0></RTI>

To a solution of benzyl 1-(1-hydroxyethyl)cyclohexanecarboxylate (0.07 g) in MeOH (5 mL)EtOAc. Followed by stirring at room temperature under H ₂ was 16 hours. The reaction was filtered with EtOAc (EtOAc)EtOAcEtOAc _{^{1 H NMR (400MHz, CDCl 3}} ) δ ppm 3.78 (q, J = 6.5Hz, 1H), 2.26-2.17 (m, 1H), 2.11-2.01 (m, 1H), 1.75-1.61 (m, 3H), 1.61-1.50 (m, 1H), 1.47-1.33 (m, 2H), 1.30-1.20 (m, 5H).

Cap N-26

TFA (2 mL, 26.0 mmol) was added to a flask containing DCM (2OmL). The mixture was stirred at room temperature. After stirring at room temperature for 2.5 hours, the mixture was diluted with ethyl acetate. Washed sequentially with water, saturated NaHCO _3, the organic phase was washed with brine, and dried over Na ₂ SO _4, filtered, and concentrated to give 3-oxo-cyclobutane-1,1-dicarboxylate (1.2g). ¹ H NMR (400 MHz, CDCl ₃ ) δ δ 5.13 (dt, J =12.5, 6.3 Hz, 2H), 3.64-3.53 (m, 4H), 1.32-1.24 (m, 12H).

Add Deoxo-Fluor® (1.370 mL, 7.43 mmol) to a solution of 3-oxocyclobutane-1,1-dicarboxylic acid diisopropyl ester (1.2 g) in DCM (15 mL). 0.087 mL). The resulting yellowish solution was stirred at room temperature for 16 hours. The reaction mixture was diluted with saturated NaHCO ₃ and EtOAc. Water, the organic phase was washed with saturated NaCl, and dried over anhydrous Na ₂ SO _4, filtered, and dried to give a yellow oil. The crude product was purified by EtOAc EtOAc (EtOAc:EtOAc) ¹ H NMR (400 MHz, CDCl ₃ ) δ δ 5.10 (dt, J =12.5, 6.3 Hz, 2H), 3.11 (t, J = 11.9 Hz, 4H), 1.32-1.20 (m, 12H).

To a stirred solution of 3,3-difluorocyclobutane-1,1-dicarboxylic acid diisopropyl ester (0.4 g, 1.514 mmol) in THF (6 mL) Lithium third butoxide aluminum solution (3.78 mL, 3.78 mmol). The reaction mixture was then warmed to room temperature and heated to 70 ° C for 15 h. The reaction mixture was cooled to room temperature, diluted with ether and washed with aqueous ₄ Cl NH quenched. The organic layer was separated and washed with water, saturated NaHCO _3, water, citric acid, brine, and dried over Na ₂ SO _4, to give 3,3-difluoro-1- (hydroxymethyl) cyclobutane-carboxylic acid isopropyl ester ( 0.3g). _{^{1 H NMR (400MHz, CDCl 3}} ) δ ppm 5.15-5.04 (m, 1H), 3.85 (d, J = 1.5Hz, 2H), 3.02-2.88 (m, 2H), 2.86-2.75 (m, 1H), 2.67-2.53 (m, 2H), 1.32-1.30 (m, 3H), 1.29 (s, 3H).

To a solution of isopropyl 3,3-difluoro-1-(hydroxymethyl)cyclobutanecarboxylate (0.2 g) in THF (4 mL) MeOH (1 mL) The solution was then stirred at room temperature for 16 hours. The reaction was concentrated and diluted with water and ethyl ether. Then the aqueous phase was acidified with 1N HCl, extracted with EtOAc (2 times), saturated organic phase was washed with NaCl, dried over anhydrous Na ₂ SO _4, filtered and concentrated to afford Cap N-26. ¹ H NMR (400 MHz, CDCl ₃ ) δ 3.94 (d, J = 1.5 Hz, 2H), 3.15 - 2.99 (m, 2H), 2.75 - 2.61 (m, 2H).

Cap N-27

Add 60% sodium hydride (0.315 g) to a cold (0 ° C) solution of dimethyl 2-methoxymalonate (0.902 mL, 6.56 mmol) in DMF (10 mL). Warm, maintain for 30 minutes. Then, 1-bromo-2-fluoroethane (0.587 mL) and sodium iodide (0.197 g) were added, and the mixture was stirred at room temperature for 16 hours. With EtOAc and the reaction was diluted with saturated NaHCO _3, the organic phase was washed with saturated NaCl, dried over anhydrous NaSO _4, filtered and concentrated to give the crude product. The crude product was purified by EtOAc EtOAc (EtOAc:EtOAc) ¹ H NMR (500MHz, CDCl ₃ ) δ ppm 4.64 (t, J = 5.8 Hz, 1H), 4.55 (t, J = 5.8 Hz, 1H), 3.83 (s, 6H), 3.43 (s, 3H), 2.56 (t, J = 5.9 Hz, 1H), 2.51 (t, J = 5.8 Hz, 1H).

To a stirred solution of 2-(2-fluoroethyl)-2-methoxymalonic acid dimethyl ester (0.73 g) in THF (6 mL) Lithium butoxide aluminum solution (8.77 mL, 8.77 mmol). After the addition was completed, the mixture was allowed to warm to room temperature and heated to 77 ° C for 6 hours. The reaction mixture was cooled, diluted with EtOAc and NH ₄ Cl solution under vigorous stirring. The organic layer was separated, washed with water, saturated NaHCO _3, water, citric acid, brine, and dried over anhydrous Na ₂ SO _4, to give 4-fluoro-2- (hydroxymethyl) -2-methoxy-methylbutanoate ( 0.16g). ¹ H NMR (400MHz, CDCl ₃ ) δ ppm 4.02-3.88 (m, 4H), 3.81-3.76 (m, 3H), 3.34-3.25 (m, 3H), 2.37 (dt, J = 13.2, 7.9 Hz, 1H ), 2.26-2.16 (m, 1H).

To a solution of methyl 4-fluoro-2-(hydroxymethyl)-2-methoxybutanoate (0.16 g) in THF (4 mL) MeOH (1 mL) The solution was then stirred at room temperature for 16 hours. The reaction was concentrated, diluted with EtOAc and 1N HCl, the organic phase washed with saturated NaCl, dried over anhydrous Na ₂ SO _4, filtered and concentrated to afford Cap N-27. ¹ H NMR (400 MHz, CD ₃ OD) δ 4.00 - 3.87 (m, 4H), 2.43 - 2.33 (m, 1H), 2.28 - 2.16 (m, 1H).

Cap N-28

Add 60% sodium hydride (0.257 g) to a cold (0 ° C) solution of dimethyl 2-methoxymalonate (0.737 mL) in DMF (10 mL). 30 minutes. Then, 1-bromo-2-methylpropane (0.7 mL) and sodium iodide (0.161 g) were added, and the mixture was stirred at room temperature for 16 hours. With EtOAc and the reaction was diluted with saturated NaHCO _3, the organic phase was washed with saturated NaCl, dried over anhydrous NaSO _4, filtered and concentrated to give the crude product. The crude product was purified by EtOAc EtOAc (EtOAc:EtOAc) _{^{1 H NMR (400MHz, CDCl 3}} ) δ ppm 3.79-3.67 (m, 6H), 3.28 (s, 3H), 2.00-1.92 (m, 2H), 1.66 (dt, J = 13.2,6.6Hz, 1H), 0.85 (d, J = 6.5 Hz, 6H).

To a stirred solution of 2-isobutyl-2-methoxymalonate (0.52 g, 2.383 mmol) in THF (6 mL) Lithium aluminum oxide solution (5.96 mL, 5.96 mmol). After the addition was completed, the mixture was allowed to warm to room temperature and heated to 70 ° C for 15 hours. The reaction mixture was cooled, diluted with EtOAc, and washed with NH ₄ Cl solution was quenched with vigorous stirring. The organic layer was separated and washed with water, saturated NaHCO _3, water, citric acid, brine, and dried over anhydrous Na ₂ SO _4, to give 2- (hydroxymethyl) -2-methoxy-4-carboxylic acid Ester (0.4 g). _{^{1 H NMR (400MHz, CDCl 3}} ) δ ppm 3.84 (s, 2H), 3.80 (s, 3H), 3.38 (s, 3H), 1.83-1.76 (m, 1H), 1.76-1.64 (m, 2H), 0.96 (d, J = 6.5 Hz, 3H), 0.94 - 0.90 (m, 3H).

To a solution of methyl 2-(hydroxymethyl)-2-methoxy-4-methylpentanoate (0.21 g) in EtOAc (4 mL) The solution was then stirred at room temperature for 16 hours. The reaction was concentrated, diluted with EtOAc and 1N HCl, the organic phase washed with saturated NaCl, dried over anhydrous Na ₂ SO _4, filtered and concentrated to afford Cap N-28 (0.15g). ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 3.80-3.74 (m, 2H), 3.34 (s, 3H), 1.82-1.66 (m, 2H), 1.63-1.55 (m, 1H), 0.98-0.88 ( m, 6H).

Cap W-31

Cap W-31, step 1

(2S,4S)-4-fluoropyrrolidine-2-carboxylic acid (2.68 g, 20.13 mmol), p-toluenesulfonic acid monohydrate (3.91 g, 20.53 mmol), benzyl alcohol (20.93 mL, 201 mmol) in toluene (20 mL) The mixture in the mixture is heated to a gentle reflux. Water was removed by means of a Dean-Stark apparatus for 4 hours (about 1 ml of water was separated). The reddish solution was allowed to cool to room temperature and toluene was removed in vacuo. The remaining solution was then diluted with 200 mL of dry Et ₂ O and placed at room temperature for 4 h. The formed precipitate was filtered and washed thoroughly with Et ₂ O and dried in vacuo to afford an off-white fine powder cap of W-31 Step 1 pTSA (6.856g, 17.34mmol, 86 % yield). ¹ H NMR (400 MHz, CD ₃ OD) δ 7.72 (d, J = 8.3 Hz, 1H), 7.51-7.34 (m, 2H), 7.25 (d, J = 8.0 Hz, 1H), 5.58-5.23 (m, 1H), 4.73 (dd, J = 9.9, 4.1 Hz, 1H), 3.87-3.47 (m, 2H), 2.87-2.54 (m, 2H), 2.39 (s, 3H).

Cap W-31, step 2

To an ice-cooled solution of DIPEA (9.06 mL, 52.0 mmol) and D.sub.3 (0.106 g, <RTI ID=0.0></RTI></RTI><RTIgt; A solution of di-tert-butyl dicarbonate (7.57 g, 34.7 mmol) in DCM (25.00 mL) was added dropwise to the obtained mixture. The final mixture was stirred overnight at room temperature. Washed with water, 5% aqueous citric acid and saturated Na ₂ CO ₃ solution and the organic phase was washed with saturated aqueous NaCl, dried over MgSO ₄ and evaporated to give 7.1g viscous oil, by FCC (300g silica gel cartridge, 50 to 10% Purification of % EtOAc-hexanes afforded EtOAc EtOAc (EtOAc: EtOAc: _{^{1 H NMR (400MHz, CD 3}} OD) δ 7.54-7.20 (m, 5H), 5.36-5.05 (m, 2H), 4.65-4.38 (m, 1H), 3.87-3.49 (m, 2H), 2.71-2.26 (m, 2H), 1.63-1.23 (m, 9H).

Cap W-31, step 3a / step 3b

To a solution of Cap W-31 Step 2 (1.675 g, 5.18 mmol) in THF (20 mL), THF (1. <RTIgt; , 5.70 mmol). The resulting solution was stirred at this temperature for 30 minutes, followed by the addition of MeI (0.645 mL, 10.36 mmol). The final solution was stirred at this temperature for 2 hours, followed by stirring at 0 °C for 2 hours. ₄ Cl was quenched with saturated aqueous NH, and extracted with EtOAc. , Dried the organic layer was separated and washed with brine, 5% citric acid over Na ₂ SO _4, filtered and evaporated in vacuo. The residue was purified by FCC (EtOAc (EtOAc)EtOAc The first elution peak (minor) was assigned as Cap W-31 Step 3a (300 mg, 0.889 mmol, 17.17% yield); ¹ H NMR (400 MHz, CD ₃ OD) δ 7.53-7.22 (m, 5H), 5.34 5.02 (m, 3H), 3.92-3.49 (m, 2H), 2.31 (br.s., 2H), 1.66 (s, 3H), 1.49-1.27 (m, 9H).

The second dissolving peak (mainly) was assigned as Cap W-31 Step 3b (1.25 g, 3.70 mmol, 71.5% yield). ¹ H NMR (400 MHz, CD ₃ OD) δ 7.50-7.28 (m, 5H), 5.32-5.02 (m, 3H), 3.95-3.59 (m, 2H), 2.75-2.49 (m, 1H), 2.44-2.14 (m, 1H), 1.67 (d, J = 17.6 Hz, 3H), 1.50-1.26 (m, 9H).

The W-31 cap receiving step 3b (500mg, 1.482mmol), 10 % Pd / C (315mg, 0.296mmol) and MeOH (10mL) was placed in the vessel under H ₂ (50psi) 24 hours on a Parr shaker. The suspension was then filtered through a bed of diatomaceous earth and evaporated in vacuo. The residue was triturated with EtOAc (EtOAc)EtOAc. ¹ H NMR (400 MHz, CD ₃ OD) δ 5.30-5.01 (m, 1H), 3.79 (dd, J = 6.3, 4.5 Hz, 2H), 2.62 (d, J = 2.0 Hz, 1H), 2.29 (s, 1H), 1.73-1.58 (m, 3H), 1.55-1.41 (m, 9H).

Cap W-32

Cap W-32 is obtained from cap W-31a according to the procedure described for cap W-31. _{^{1 H NMR (400MHz, CD 3}} OD) δ 5.39-5.11 (m, 1H), 3.87-3.56 (m, 2H), 2.31 (br.s., 2H), 1.70-1.59 (m, 3H), 1.55- 1.39 (m, 9H).

Cap W-35

To (R)-3,3-dimethylpyrrolidine-2-carboxylic acid hydrochloride (prepared according to known literature procedures: J. Org. Chem. 2008 , 73 , 3946-3949) (1.50 g, 7.59 mmol) 1M NaOH aqueous solution (15.94 mL, 15.94 mmol) was added to ice-cooled solution in water (25 mL) and dioxane (12.50 mL), and dibutyl succinate (1.822 g) was added dropwise via an addition funnel. , 8.35 mmol) of a pre-formed solution in dioxane (25.00 mL). The resulting mixture was stirred at this temperature for 30 minutes and then stirred at room temperature overnight. The mixture was then partitioned by the addition of Et ₂ O (20 mL). The organic layer was separated and discarded. The aqueous layer was cooled with EtOAc EtOAc (EtOAc) Washed with brine the combined organic layers were dried (MgSO ₄₎ and concentrated to give a white solid cap of W-35 (1.36g, 5.53mmol, 72.9% yield), which was used without further purification. _{^{1 H NMR (400MHz, CD 3}} OD) δ 4.87 (br.s., 1H), 3.89-3.76 (m, 1H), 3.63-3.39 (m, 2H), 3.33 (dt, J = 3.3,1.6Hz, 1H), 2.00-1.78 (m, 1H), 1.68 (ddd, J = 12.2, 7.4, 3.8 Hz, 1H), 1.56-1.38 (m, 9H), 1.25-1.16 (m, 3H), 1.14-1.07 ( m, 3H).

Cap W-36

Cap W-36 is obtained according to the procedure described for cap W-35. ¹ H NMR (400 MHz, CD ₃ OD) δ 4.87 (br.s., 1H), 3.91-3.75 (m, 1H), 3.63-3.38 (m, 2H), 3.33 (dt, J = 3.3, 1.6 Hz, 1H), 1.98-1.80 (m, 1H), 1.68 (ddd, J = 12.00, 7.3, 3.8 Hz, 1H), 1.57-1.39 (m, 9H), 1.26-1.16 (m, 3H), 1.13-1.05 ( m, 3H).

Cap W-37

Cap W-37, step 1

To a solution of (1R,2S)-2-hydroxycyclopentanecarboxylic acid ethyl ester (1.00 g, 6.32 mmol) in THF (10 mL), dropwise. Lithium hydride THF (13.91 mL, 13.91 mmol). The resulting solution was stirred at this temperature for 10 minutes, followed by heating in an ice bath for 30 minutes. After cooling back to -78 ° C, MeI (0.590 mL, 9.48 mmol) was added, and the final solution was stirred at this temperature for 1 hour, followed by stirring at room temperature for 3 hours. ₄ Cl was quenched with saturated aqueous NH, and extracted with EtOAc. , Dried the organic layer was separated and washed with brine, 5% citric acid over Na ₂ SO _4, filtered and evaporated in vacuo. The residue was purified by EtOAc EtOAcjjjjjjj _{4H NMR (500MHz, CDCl 3)} δ 4.21 (q, J = 7.2Hz, 2H), 4.01 (dd, J = 5.8,3.2Hz, 1H), 2.24 (ddd, J = 13.0,9.8,7.0Hz, 1H) , 2.10 - 1.96 (m, 1H), 1.93-1.82 (m, 1H), 1.77-1.65 (m, 2H), 1.63-1.56 (m, 1H), 1.30 (t, J = 7.2 Hz, 3H), 1.21. (s, 3H).

The cap W-37 Step 1 (210mg, 1.219mmol), 1M sodium hydroxide (9.75mL, 9.75mmol), THF ( 10mL) and _{H 2 O 2 (0.125mL, 1.341mmol} ) the mixture was slowly heated to reflux, Maintain for 3 hours. The volatiles were removed in vacuo and the remaining aqueous layer was extracted with diethyl ether. The separated aqueous layer was acidified with EtOAc (EtOAc)EtOAc. , Washed with brine and dried over the combined organic layers over MgSO _4, filtered and evaporated in vacuo to give a colorless viscous oil cap of W-37 (140mg, 0.961mmol, 79% yield) without further purification That is to use. ¹ H NMR (400 MHz, CD ₃ OD) δ 3.97 (dd, J = 5.6, 3.4 Hz, 1H), 2.31 (ddd, J = 13.0, 9.9, 7.5 Hz, 1H), 2.12-1.97 (m, 1H) , 1.95-1.80 (m, 1H), 1.77-1.61 (m, 2H), 1.57-1.45 (m, 1H), 1.25-1.15 (m, 3H).

Cap W-38

Cap W-38, step 1

Under nitrogen, the mixture was added dropwise DBU (4.11g, 22.53mmol) and CHCl ₃ (3.63ml, 45.1mmol) in the solution of 1- (benzyloxy) propan-2-one (4.07ml, 27.0mmol). The reaction mixture was stirred at rt overnight, then diluted with CHCl ₃ (50mL), and washed with 1N HCl (3 × 20mL) to remove the catalyst used. The organic phase was then dried (Na ₂ SO ₄ ) and evaporated. The residual oil (4.8 g) was purified by EtOAcjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj _{^{1 H NMR (500MHz, CDCl 3}} ) δ 7.50-7.31 (m, 5H), 4.82-4.55 (m, 2H), 3.99 (d, J = 9.9Hz, 1H), 3.77 (d, J = 9.9Hz, 1H ), 3.53-3.19 (m, 1H), 1.68 (s, 3H).

A solution of KOH (1.599 g, 28.5 mmol) in water (1. <RTI ID=0.0></RTI></RTI><RTIID=0.0></RTI><RTIgt; ). After 15 minutes the ice bath was removed and the resulting pale yellow solution was stirred at room temperature for 2 h then the contents were transferred to a sealed vial and heated in a microwave system at 85 °C for 4 hours. The reaction was cooled to room temperature and the solid was removed by filtration and rinsed with methanol. The filtrate was concentrated in vacuo and aq. The separated aqueous phase was brought to pH = 0 by addition of concentrated aqueous hydrochloric acid, and then extracted with ethyl acetate (30×2 mL). Dried (Na ₂ SO ₄₎ and concentrated in vacuo of the combined extracts to give 1.80g cap W-38, which was used without further purification in the next reaction. _{^{1 H NMR (500MHz, CDCl 3}} ) δ 7.48-7.25 (m, 5H), 4.69-4.52 (m, 2H), 3.76-3.58 (m, 2H), 3.40 (s, 3H), 1.53-1.35 (m, 3H).

Cap W-39

Cap W-39, step 1

To a solution of dicyclopropylamine hydrochloride (300 mg, 2.245 mmol) and DIPEA (1.173 mL, 6.74 mmol) in DCM (5 mL) 4.49 mL, 2.245 mmol) of a pre-formed solution in DCM (5 mL). The resulting pale yellow solution was stirred at room temperature for 3 h then quenched with water (50 mL). Dried the organic layer was separated and washed with 1M HCl and brine over MgSO _4, filtered and evaporated in vacuo to give a brown oil cap of W-39 Step 1 (364mg, 1.987mmol, 88% yield). This material was used without further purification. _{^{1 H NMR (500MHz, CDCl 3}} ) δ 3.96-3.82 (m, 3H), 2.75-2.52 (m, 2H), 0.99-0.74 (m, 8H).

Add a pre-formed solution of LiOH.H ₂ O (167 mg, 3.97 mmol) in water (4.00 mL) to a solution of EtOAc (EtOAc (EtOAc) . The resulting cloudy solution was stirred overnight at room temperature. The solution was cooled with EtOAc (EtOAc) (EtOAc) , Washed with brine and dried over the combined organic layers over MgSO _4, filtered and evaporated in vacuo. Cap W-39 (258 mg, 1.51 mmol, EtOAc) elute ¹ H NMR (500 MHz, CDCl ₃ ) δ 7.64 (br.s., 1H), 2.87 (tt, J = 7.1, 3.7 Hz, 1H), 2.74-2.53 (m, 1H), 1.07 - 0.75 (m, 8H) ).

Cap W-40

Cap W-40 was obtained from 2,2,6,6-tetramethylpiperidine according to the procedure described for cap W-39. ¹ H NMR (500 MHz, CDCl ₃ ) δ 9.19 (br.s., 1H), 1.89-1.39 (m, 18H).

Cap W-41

Cap W-41 was obtained from 2-methylbutan-2-amine according to the procedure described for cap W-39. </RTI>^{<RTI ID} =0.0></RTI>^</RTI>^{<RTI ID} =0.0></RTI>

Cap W-42

Cap W-42 was obtained from 4-(benzyloxy)butan-2-one according to the procedure described for cap W-38. _{^{1 H NMR (400MHz, CDCl 3}} ) δ 7.45-7.22 (m, 5H), 4.50 (s, 2H), 3.69-3.48 (m, 2H), 3.35 (s, 3H), 2.26 (dt, J = 14.5, 7.2 Hz, 1H), 2.08 (dt, J = 14.6, 6.0 Hz, 1H), 1.49 (s, 3H).

Cap W-43

Cap W-43 was prepared from 2-fluoroethanol and cap W-38, step 1, according to the procedure used to prepare cap W-38. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.46-7.30 (m, 5H), 4.75 - 4.45 (m, 4H), 3.95 - 3.62 (m, 4H), 1.47 (s, 3H).

Cap W-44

To a 0 ° C solution of 1-aminocyclohexanecarboxylic acid (300 mg, 2.095 mmol) in EtOAc (2 mL) EtOAc (EtOAc) The resulting solution was stirred at this temperature for 1 hour, followed by stirring at room temperature overnight. All volatiles were removed in vacuo and the residue was triturated with warm water and filtered. The filter cake was washed with water and dried <RTI ID=0.0> This material was used without further purification. ¹ H NMR (500 MHz, CD ₃ OD) δ 8.95 (br.s., 1H), 2.32 - 0.74 (m, 11H); ¹⁹ F NMR (471 MHz, CD ₃ OD) δ - 76.97.

Cap W-45

3,3,3-trifluoropropionyl chloride (767 mg, 5.24 mmol) was added to a pressure vessel containing 1-aminocyclohexanecarboxylic acid (500 mg, 3.49 mmol) and anhydrous THF (50 mL) at 0 °C. The resulting mixture was sealed and heated in a 70 ° C oil bath for 2 hours. The reaction mixture was cooled to room temperature and filtered. The volatiles were removed under reduced pressure, and the residual solid (700 mg) was then evaporated from warm water (40ml) and filtered. The filter cake was washed with 1 M HCl and water (10 mL) and dried to give abr. This material was used for the next coupling without further purification. ¹ H NMR (500 MHz, CD ₃ OD) δ 8.32 (br. s., 1H), 3.23 (q, J = 10.8 Hz, 2H), 2.10 (d, J = 13.7 Hz, 2H), 1.95-1.77 (m) , 2H), 1.74-1.23 (m, 6H); ¹⁹ F NMR (471 MHz, CD ₃ OD) δ -64.56 (t, J = 11.0 Hz).

Cap W-46

Cap W-46, step 1

Heating a mixture of 1-aminocyclohexanecarboxylic acid (7.00 g, 48.9 mmol), p-toluenesulfonic acid monohydrate (10.23 g, 53.8 mmol) and benzyl alcohol (50.8 mL, 489 mmol) in toluene (50 mL) Slow reflux. Water was removed by means of a Dean-Stark apparatus for 6 hours (about 2 ml of water was separated). The pale yellow solution was allowed to cool to room temperature and toluene was removed in vacuo. The remaining solution was then diluted with 400 mL TBME and placed at room temperature overnight. The resulting white thick paste was filtered, washed thoroughly with TBME and dried in vacuo. The obtained white fine powder cap W-46 step 1 pTSA (18.11 g, 44.7 mmol, 91% yield) was suspended in CHCl ₃ (400 ml) with stirring, and MeOH was added until it became a clear solution (20 ml MeOH) ). Add 400ml of saturated NaHCO _3, the organic layer was separated and washed with 0.1M NaOH and brine, dried over MgSO _4, filtered and evaporated in vacuo. The oil-like cap W-46, step 1 (10.4 g, 44.6 mmol, 91% yield) was recovered and used without further purification. ¹ H NMR (500 MHz, CDCl ₃ ) δ 7.47-7.31 (m, 5H), 5.18 (s, 2H), 2.08-1.29 (m, 12H).

Cap W-46, step 2

Benzyl chloroformate (0.268 mL, 2.143 mmol) was added to an ice-cooled solution of EtOAc EtOAc (EtOAc). The resulting solution was stirred at room temperature for 1 hour, then poured into ice-water and partitioned. Extract the aqueous phase (2 times) with DCM and use 5% citric acid and salt The combined organics were washed with EtOAc EtOAc m.

Cap W-46, step 3

A vial of cap 2 (220 mg, 0.623 mmol) and MeOH (2801 μl, 5.60 mmol) containing 2M Me ₂ NH was heated to 80 ° C under microwave irradiation for 2 hours. The reaction mixture was then cooled to room rt, poured over water and EtOAc. , Washed with 5% citric acid and dried, 0.5M NaOH and brine The organic layer over MgSO _4, and evaporated in vacuo. The residue was purified by EtOAc EtOAcjjjjjjjj _{^{1 H NMR (500MHz, CDCl 3}} ) δ 7.51-7.30 (m, 5H), 5.18 (s, 2H), 4.51 (s, 1H), 2.98-2.88 (m, 6H), 2.18-2.02 (m, 2H) , 1.90 (td, J = 12.9, 3.7 Hz, 2H), 1.78-1.59 (m, 4H), 1.56-1.40 (m, 1H), 1.37-1.24 (m, 1H).

A mixture of Cap W-46 Step 3 (110 mg, 0.361 mmol), Piern's catalyst (10.15 mg, 0.072 mmol), 1 drop of 1M aqueous HCl and MeOH (5 mL) was placed in _&lt; RTIgt _; 2 hours on the device. The suspension was filtered through a pad of celite, washed with MeOH and evaporated in vacuo. The residue recovered was triturated with hexanes and dried to give abr. ¹ H NMR (500 MHz, CD ₃ OD) δ 3.37 (s, 1H), 3.03 - 2.86 (m, 6H), 2.08 (d, J = 13.7 Hz, 2H), 1.85 (d, J = 3.2 Hz, 2H) , 1.71-1.50 (m, 5H), 1.44-1.32 (m, 1H).

Cap B-47 and cap B-48

Cap B-47 and cap B-48, step a

Ethyl ethoxide (7.01 mL, 69.3 mmol) and ruthenium (II) acetate dimer (0.153 g, 0.347 mmol) were suspended in diethyl ether (5 mL) by a syringe pump under argon at room temperature. Ethyl 2-diazoacetate (3.65 mL, 34.7 mmol) was slowly added to the mixture over 6 hr. The resulting mixture was stirred at the same temperature overnight. The mixture was then filtered through celite and the solvent was removed in vacuo. The crude material (brown liquid, 5.2 g, 1:1 cis: trans mixture) was purified by Combiflash (EtOAc, 40 g, EtOAc, EtOAc: petroleum ether 90:10). , UV activity) 2-ethoxycyclopropanecarboxylic acid ethyl ester (1.1 g, 6.95 mmol, 10.03% yield) and a colorless liquid in the form of a fraction 2 (UV inactive, KMnO ₄ active) 2-ethoxy ring Ethyl propanecarboxylate (1.4 g, 8.85 mmol, 12.76% yield).

NB did not determine the exact stereochemistry of Dissolved Part 1 and Dissolved Part II at this stage.

Dissolved fraction 1 : ¹ H NMR (CDCl ₃ , δ = 7.26 ppm, 400 MHz): δ 4.15-4.07 (m, 2 H), 3.63-3.54 (m, 3 H), 1.74 (ddd, J = 2.1, 6.1, 9.5 Hz, 1 H), 1.29-1.16 (m, 8 H)

Dissolved Part II : ¹ H NMR (CDCl ₃ , δ = 7.26 ppm, 400 MHz): δ 4.17 (q, J = 7.1 Hz, 2 H), 3.63-3.52 (m, 2 H), 3.44 (dq, J = 7.1 , 9.5 Hz, 1 H), 1.69 (td, J = 6.6, 8.6 Hz, 1 H), 1.58-1.52 (m, 1 H), 1.27 (t, J = 7.1 Hz, 3 H), 1.18 (t, J = 7.1 Hz, 3 H), 1.11-1.02 (m, 1 H).

Add LiOH (757 mg, 31.6 mmol) to a solution of ethyl 2-ethoxycyclopropanecarboxylate (500 mg, 3.16 mmol) (isomer 1) in MeOH (5 mL) ) and stirred overnight at room temperature. The MeOH was removed in vacuo and EtOAc (EtOAc)EtOAc. The aqueous portion was acidified with 1.5N HCl (pH 2-3) and extracted with (3×15 mL) DCM. With DCM layer collected was washed with brine, and dried over anhydrous Na ₂ SO ₄ and evaporated to dryness in vacuo to give 2-ethoxy-cyclopropanecarboxylic acid (250 mg, 1.921mmol, 60.8% yield).

Cap B-47 obtained from autodissolved I : ¹ H NMR (CDCl ₃ , δ = 7.26 ppm, 400 MHz): δ 3.71-3.52 (m, 3 H), 1.81-1.67 (m, 1 H), 1.36-1.29 (m, 2 H), 1.21 (t, J = 7.0 Hz, 3 H). 2-Ethoxycyclopropanecarboxylic acid was obtained following a similar procedure as described above.

Cap B-48 obtained from autolyzed fraction II : ¹ H NMR (CDCl ₃ , δ = 7.26 ppm, 400 MHz): δ 3.70-3.61 (m, 2 H), 3.56 (dq, J = 7.1, 9.5 Hz, 1 H ), 1.73 (td, J = 6.5, 8.9 Hz, 1 H), 1.56 (dt, J = 4.8, 6.5 Hz, 1 H), 1.22 (t, J = 7.1 Hz, 3 H), 1.22-1.17 (m) , 1 H).

Cap B-49

Cap B-49, step a

Trichloroisocyanuric acid (3.26 g, 14.01) was added sequentially to a solution of ethyl 1-(hydroxymethyl)cyclopropanecarboxylate (2.0 g, 13.87 mmol) in DCM (25 mL). Methyl) and TEMPO (0.217 g, 1.387 mmol). The reaction mixture was stirred at -5 °C for 1 hour. The mixture was filtered through celite and diluted with DCM (50 mL). With saturated _{Na 2 CO 3 (50mL),} 1N HCl (50mL), brine (50mL) and saturated ₄ Cl (3 × 50mL) solution was washed with NH. The organic layer was dried over Na ₂ SO _4, filtered, and concentrated under reduced pressure to obtain a colorless liquid of 1-acyl cyclopropanecarboxylate (1.5g, 10.55mmol, 76% yield); product without Purification was used in the next step. ¹ H NMR (CDCl ₃ , δ = 7.26 ppm, 300 MHz): δ 10.40 (s, 1 H), 4.28 (q, J = 7.1 Hz, 2 H), 1.72-1.56 (m, 4 H), 1.32 (t) , J = 7.1 Hz, 3 H).

Cap B-49, step b

To a solution of ethyl 1-carbylcyclopropanecarboxylate (1.8 g, 12.66 mmol) in DCM (25 mL) The reaction mixture was allowed to warm to room temperature and stirred for 12 h. The reaction mixture was then quenched with EtOAc EtOAc (EtOAc) The organic layer was washed with 10% NaHCO ₃ solution (50mL) brine (50mL), dried over Na ₂ SO _4, filtered and concentrated to give a brown liquid of 1- (difluoromethyl) cyclopropanecarboxylate (800 mg of , 4.87 mmol, 38.5% yield). The crude material was used in the next step without purification. ¹ H NMR (CDCl ₃ , δ = 7.26 ppm, 400 MHz): δ 6.43 (t, J = 57.2 Hz, 1 H), 4.20 (q, J = 7.1 Hz, 2 H), 1.33-1.20 (m, 7 H) F19 NMR (CDCl ₃ , δ 7.26 ppm, 400 MHz): δ-123.09 (s, 2 F).

To a solution of ethyl 1-(difluoromethyl)cyclopropanecarboxylate (1 g, 6.09 mmol) in MeOH (10 mL) EtOAc (EtOAc. After stirring for 10 minutes, the reaction mixture was allowed to warm to room temperature and stirred for 12 hr. The reaction mixture was concentrated and EtOAc EtOAc m. The aqueous layer was acidified with 1N EtOAc EtOAc (EtOAc)EtOAc. The organic layer was dried over Na ₂ SO _4, filtered and concentrated to give a brown liquid of 1- (difluoromethyl) cyclopropanecarboxylic acid (250mg, 1.837mmol, 30.2% yield). The crude material was used without further purification. ^{_{1 H NMR (CDCl 3, δ}} = 7.26ppm, 400MHz): δ 6.42 (t, J = 57.2Hz, 1 H), 1.43-1.36 (m, 2 H), 1.35-1.28 (m, 2 H); 19 F NMR (CDCl ₃ , δ = 7.26 ppm, 400 MHz): δ-123.24 (s, 2 F).

Cap B-50

Cap B50 step a

Pd/C (0.025 g, added to a stirred solution of ethyl 2-hydroxy-2-methylpent-4-enoate (0.25 g, 1.580 mmol) in ethyl acetate (5 mL) 0.237 mmol) and the resulting mixture was hydrogenated under balloon pressure for 12 hours. The reaction was filtered through EtOAc (EtOAc)EtOAc. ¹ H NMR (CDCl ₃ , δ = 7.26 ppm, 400 MHz): δ 4.28-4.21 (m, 2 H), 3.17 (s, 1 H), 2.10-1.11 (m, 2 H), 1.51 (s, 3 H) ), 1.50-1.48 (m, 4 H) 1.46-1.45 (m, 1 H), 1.44-1.41 (t, J = 4 Hz, 3 H).

Add LiOH (0.112 g, 4.68 mmol) to a stirred solution of 2-hydroxy-2-methylpentanoate (0.15 g, 0.936 mmol) in MeOH (3 mL). The reaction was carried out for 12 hours. The solvent was evaporated <RTI ID=0.0></RTI> The pH of the aqueous layer was adjusted to 6 with H.sub.2 (.sub.1N), and extracted with dichloromethane (2×100 mL), dried over sodium sulfate and evaporated under reduced pressure to give 2-hydroxy-2-methyl Valeric acid (0.03 g, 0.227 mmol, 24.25% yield). ¹ H NMR (CD ₃ OD, δ = 3.34 ppm, 400 MHz): δ 1.76-1.72 (m, 1 H), 1, 60-1.47 (m, 2 H), 1.37 (s, 3 H), 1.32-1.26 (m, 1 H), 0.95-0.91 (t, J = 8 Hz, 3 H).

Cap B51

Cap B51 step a

To a stirred suspension of diethylzinc (5.69 mL, 5.69 mmol) in toluene (2 mL) was slowly added dropwise with chloroiodomethane at -20 ° C in a single neck RB flask equipped with a nitrogen inlet. 0.826 mL, 11.38 mmol), and the resulting mixture was stirred for 1 hour, and ethyl 2-hydroxy-2-methylpent-4-enoate (0.3 g, 1.89 mol) in toluene (2 mL) was added dropwise at the same temperature. Solution in the middle. The resulting mixture was stirred at the same temperature for 12 hours. The reaction was cooled to 0 ℃, and (25mL) was quenched with saturated NH ₄ Cl solution and extracted with EtOAc (2 × 100mL), dried over sodium sulfate and evaporated at reduced pressure. The crude material was used as it is for the next step.

Add LiOH (0.209 g, 8.71 mmol) to a stirred solution of ethyl 3-cyclopropyl-2-hydroxy-2-methylpropanoate (0.3 g, 1.742 mmol) in MeOH (3 mL) 12 hours. The solvent was evaporated <RTI ID=0.0></RTI> The pH of the aqueous layer was adjusted to 6 with EtOAc (EtOAc) (EtOAc) -2-Methylpropionic acid (0.1 g, 0.694 mmol, 39.8% yield). ¹ H NMR (CD ₃ OD, δ = 3.34 ppm, 400 MHz): δ 1.74-1.69 (m, 1 H), 1.59-1.54 (m, 1 H), 1.42 (s, 3 H), 0.89-0.81 (m) , 1 H), 0.54-0.39 (m, 2 H), 0.14-0.10 (m, 2 H).

Cap B52

Cap B52, step a

In a single neck RB flask equipped with a nitrogen inlet, 2,3-dihydrofuran (0.2 g, 2.85 mmol) and cerium (II) acetate dimer (1.261 mg, 2.85 μmol) at 25 ° C using a syringe pump ) in the in Et ₂ O (10mL) stirred solution was slowly added dropwise ethyl (0.592mL, 5.71mmol) in the in Et ₂ O (10mL) was added dropwise over a period of 5 hours, and stirred for 12 hours. The reaction mixture was filtered through celite and evaporated under reduced pressure to give crude material. The crude material was taken to the next step without purification.

Add LiOH to the stirred solution of 2-oxabicyclo[3.1.0]hexane-6-carboxylate (0.4 g, 2.56 mmol) in MeOH / THF / H ₂ O (2 mL / 2 mL / 2 mL) 0.307 g, 12.81 mmol), and the resulting mixture was stirred at 25 ° C for 12 hours. The solvent was evaporated under reduced pressure and the residue was crystallisjjjjjjjjjj The aqueous layer was extracted with dichloromethane (3×50 mL)EtOAc. %Yield).

Cap B53

Cap B53, step a

To a solution of diethylamine (6.26 mL, 59.9 mmol) in dry THF (30 mL) EtOAc. The solution was stirred at 0 ° C for 30 minutes. The reaction mixture was cooled to -78 ℃, and a solution of (E) -2- methylbut-2-enoic acid (3g, 30.0mmol) in anhydrous solution (10 mL) in of THF, and stirred at 0 ℃ 30 minutes . The reaction mixture was again cooled to -78.degree. C., and a solution of dimethyl sulfate (2.86 mL, 30.0 mmol) in anhydrous THF (10 mL). The reaction mixture was stirred at -78 °C for 1 hour and at room temperature for 1 hour. The reaction mixture was quenched with EtOAc (EtOAc)EtOAc. The aqueous layer was acidified with EtOAc (EtOAc) (EtOAc) The combined organic layers were washed with EtOAc EtOAc m. ¹ H NMR (CDCl ₃ , δ = 7.26 ppm, 300 MHz): δ 6.05 (dd, J = 10.6, 17.4 Hz, 1 H), 5.21-5.01 (m, 2 H), 1.33 (s, 6 H).

Cap B53 step b

Under N ₂ atmosphere, was added K ₂ CO ₃ a solution of 2,2-dimethoxy-3-enoic acid (0.5g, 4.38mmol) in dry DMF (10mL) in a stirred solution of (1.211g, 8.76mmol ) and stirred at room temperature for 5 minutes. (Bromomethyl)benzene (0.574 mL, 4.82 mmol) was then added to the above reaction mixture and stirred at room temperature overnight. The volatile component was evaporated under reduced pressure and EtOAcqqqqqq Washed with water (20 mL), the organic layer was washed with brine (30 mL), dried over Na ₂ SO _4, and concentrated under reduced pressure, to obtain brown liquid (700mg, 78% yield). ¹ H NMR (CDCl ₃ , δ = 7.26 ppm, 400 MHz): δ 7.35-7.33 (m, 5 H), 6.09-6.01 (m, 1 H), 5.13-5.05 (m, 4 H), 1.33 (s, 6 H).

Cap B53 step c

Add a freshly prepared weight to a solution of 2,2-dimethylbut-3-enoic acid benzyl ester (0.1 g, 0.490 mmol) in dry diethyl ether (50 mL) at -20 ° C. Nitrogen methane was added followed by Pd(OAc) ₂ (10.99 mg, 0.049 mmol), and the mixture was stirred overnight at room temperature. The reaction mixture was passed through a pad of celite and concentrated under reduced pressure. The crude material was purified by Combiflash Isco (EtOAc, EtOAc (EtOAc:EtOAc) Yield). ¹ H NMR (CDCl ₃ , δ = 7.26 ppm, 400 MHz): δ 7.37-7.33 (m, 5 H), 5.13 (s, 2 H), 1.09 (s, 7 H), 0.39-0.27 (m, 4 H) ).

Add Pd/C (25.8 mg, 0.243 mmol) to a solution of benzyl 2-cyclopropyl-2-methylpropanoate (53 mg, 0.243 mmol) in dry MeOH (10 mL) Stir under a hydrogen atmosphere for 8 hours. The reaction mixture was taken through a pad of celite and concentrated under reduced pressure, dried and evaporated. ¹ H NMR (CDCl ₃ , δ = 7.26 ppm, 300 MHz): δ 5.81-5.22 (bs, 1 H), 1.21-0.94 (m, 7 H), 0.49-0.25 (m, 4 H).

Cap B54

Cap B54 step a

n-Butyllithium (3.23 mL, 5.17 mmol) was added to a solution of diisopropylamine (0.736 mL, 5.17 mmol) in anhydrous THF (30 mL). The reaction mixture was cooled to -78.degree. C., and a solution of ethyl i-butyrate (0.5 mg, 4.30 mmol) in anhydrous THF (30 mL). A solution of 3-iodotetrahydrofuran (1.28 g, 6.46 mmol) in THF (30 mL) was then evaporated. The reaction mixture was quenched with EtOAc EtOAc (EtOAc) The combined organic layers were washed with EtOAcq. The crude material was purified by vacuum distillation. The fractions in the form of a yellow liquid (68 mg, 8.48% yield) were collected at <RTIgt; ¹ H NMR (CDCl ₃ , δ = 7.26 ppm, 300 MHz): δ 4.17-4.08 (m, 2 H), 3.88-3.80 (m, 2 H), 3.77-3.70 (m, 1 H), 3.69-3.55 ( m, 1 H), 2.61-2.52 (m, 1 H), 1.97-1.84 (m, 1 H), 1.74-1.66 (m, 1 H), 1.29-1.22 (m, 3 H), 1.17 (s, 6 H).

Add LiOH (87 mg, 3.65 mmol) to a solution of ethyl 2-methyl-2-(tetrahydrofuran-3-yl)propanoate (68 mg, 0.365 mmol) in EtOAc The reaction mixture was stirred at room temperature for 8 hours. The solvent was removed under reduced pressure and the aqueous layer was washed with ethyl acetate (50mL). The aqueous layer was acidified with EtOAc (EtOAc)EtOAc. The solvent was removed under reduced pressure to give 2-methyl-2-(tetrahydrofuran-3-yl)propanoic acid (21 mg, 36.4% yield). ¹ H NMR (CDCl ₃ , δ = 7.26 ppm, 300 MHz): δ 3.91-3.60 (m, 4 H), 2.64-2.53 (m, 1 H), 2.01-1.90 (m, 1 H), 1.80-1.67 ( m, 1 H), 1.21 (d, J = 0.8 Hz, 6 H).

Cap B55

Cap B55 step a

To a solution of 1-methoxy-1-trimethyldecyloxy-2-methyl-1-propene (1.914 mL, 9.42 mmol) in DCM (10 mL) ) and stirred at -35 ° C for 30 minutes. Then 2-(phenylsulfonyl)tetrahydrofuran (1 g, 4.71 mmol) was added and stirred at the same temperature for 4 hours. The reaction mixture was quenched with EtOAc EtOAc (EtOAc) The organic layer was separated and washed with water (100 mL The solvent was removed under reduced pressure and purified by distillation. The fractions collected at 6 Torr (120 ° C) were the product, 117 mg, as a colorless liquid. ¹ H NMR (CDCl ₃ , δ = 7.26 ppm, 300 MHz): δ 4.08-4.03 (m, 1 H), 3.85-3.70 (m, 3 H), 3.68 (s, 3 H), 1.88-1.84 (m, 3 H), 1.83 (d, J = 1.5 Hz, 1 H), 1.37 (s, 1 H), 1.19 (s, 3H), 1.13 (s, 3 H).

To a solution of methyl 2-methyl-2-(tetrahydrofuran-2-yl)propanoate (117 mg, 0.679 mmol) in THF (5 mL) / water (2 mL) The reaction mixture was stirred at room temperature for 8 hours. The solvent was removed under reduced pressure and the aqueous layer was washed with ethyl acetate (50mL). The aqueous layer was acidified with EtOAc EtOAc (EtOAc) The solvent was removed under reduced pressure to give 2-methyl-2-(tetrahydrofuran-2-yl)propionic acid (76 mg). ¹ H NMR (CDCl ₃ , δ = 7.26 ppm, 400 MHz): δ 4.04-3.97 (m, 1 H), 3.91-3.84 (m, 2 H), 2.04-1.94 (m, 4 H), 1.65-1.56 ( m, 1 H), 1.30 (s, 3 H), 1.19 (s, 3 H).

Cap B56

To a solution of tetrahydrofuran-3-ol (0.1 g, 1.135 mmol) in acetonitrile (5 mL), bis(2,5-di-oxypyrrolidin-1-yl) carbonate (0.436 g, 1.703 mmol) TEA (0.237 mL, 1.703 mmol). The reaction mixture was stirred at room temperature for 18 hours. The solvent was removed and the reaction mixture was diluted with DCM, washed with 10% NaHCO _3, brine, dried over Na ₂ SO ₄ and concentrated to give 2,5-carbonate-oxo-pyrrolidin-1-yl ester (tetrahydrofuran -3 -Base)ester (0.08 g, 0.349 mmol, 30.8% yield). ¹ H NMR (DMSO-d ₆ , δ = 2.50 ppm, 400 MHz): δ 5.44-5.38 (m, 1 H), 3.88-3.65 (m, 5 H), 2.82 (s, 3 H), 2.31-2.21. m, 1 H), 2.07-1.98 (m, 1 H).

Cap B57

To a solution of oxetan-3-ol (0.1 g, 1.350 mmol) in acetonitrile (5 mL), bis(2,5-di-oxypyrrolidin-1-yl) carbonate (0.519 g, 2.025) Methyl) and TEA (0.282 mL, 2.025 mmol). The reaction mixture was stirred at room temperature for 18 hours. The solvent was removed under reduced pressure, and the reaction mixture was diluted with DCM, washed with 10% NaHCO _3, brine, dried over Na ₂ SO ₄ dried and concentrated to give 2,5-carbonate-oxo-pyrrolidin-1-yl ester Oxetane-3-yl ester (0.18 g, 0.837 mmol, 62.0% yield). ¹ H NMR (DMSO-d ₆ , δ = 2.50 ppm, 400 MHz): δ 5.69-5.61 (m, 1 H), 4.86 (ddd, J = 1.0, 6.0, 8.0 Hz, 2 H), 4.63-4.56 (m) , 2 H), 2.78 (s, 4 H).

Cap B58

To a solution of tetrahydro-2H-piperidin-4-ol (0.15 g, 1.469 mmol) in acetonitrile (5 mL) was added bis(2,5-di-oxypyrrolidin-1-yl) carbonate (0.376 g, 1.469 mmol) and TEA (0.205 mL, 1.469 mmol). The reaction mixture was stirred at room temperature for 18 hours. The solvent was removed under reduced pressure, and the reaction mixture was diluted with DCM, washed with 10% NaHCO _3, brine, dried over Na ₂ SO ₄ and concentrated to give Example -23: 2,5-carbonate-oxo-pyrrolidin-- 1-yl ester (tetrahydro-2H-pyran-4-yl) ester (0.26 g, 1.069 mmol, 72.8% yield). ¹ H NMR (DMSO-d ₆ , δ = 2.50 ppm, 400 MHz): δ 4.98 (dd, J = 4.5, 8.8 Hz, 1 H), 3.86-3.73 (m, 2 H), 3.48 (ddd, J = 3.0) , 9.3, 11.8 Hz, 2 H), 2.82 (s, 4 H), 2.03-1.93 (m, 2 H), 1.75-1.62 (m, 2 H).

Cap B59

Cap B59 step a

To a solution of ethyl-1,2-diol (0.5 g, 8.06 mmol) and (E)-3-ethoxyethyl acrylate (1.9 g, 13.18 mmol), sodium hydrogen sulfate (0.001 g, 8.33 μmol) was added. And the reaction mixture was heated to 200 ° C for 1 hour. The reaction mixture was then cooled to room temperature, water was added andEtOAc was evaporated. , The organic layer was washed with brine, dried over Na ₂ SO _4, and concentrated in vacuo. The crude material was purified by EtOAc (EtOAc:EtOAcEtOAcEtOAc , 28% yield). ¹ H NMR (CDCl ₃ , δ = 7.26 ppm, 400 MHz): δ 5.29 (t, J = 5.21 Hz, 1 H), 4.18 (q, J = 7.15 Hz, 2 H), 3.79-4.04 (m, 4 H) ), 2.68 (d, J = 5.21 Hz, 2 H), 1.7-1.37 (m, 3 H).

To a solution of ethyl 2-(1,3-dioxolan-2-yl)acetate (0.3 g, 1.873 mmol) in THF (5 mL) and water (5 mL) 0.236 g, 5.62 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was then concentrated in vacuo, water was added and washed with EtOAc EtOAc. The aqueous layer was acidified to pH = 3 from a citric acid solution and extracted with ethyl acetate (100 mL x 2). Washed with water (50mL), the organic layer was washed with brine (50mL), dried over Na ₂ SO _4, and concentrated in vacuo. ¹ H NMR (CDCl ₃ , δ = 7.26 ppm, 400 MHz): δ 5.28 (t, J = 5.15 Hz, 1 H), 3.83-4.02 (m, 4 H), 2.64-2.80 (m, 2 H).

Cap B60

Cap B60 step a

Add cerium (II) acetate dimer (1.298 mg, 2.94 μmol) to a solution of methylene cyclobutane (1 g, 14.68 mmol) in DCM (6 mL) at -20 ° C, then add A solution of ethyl 2-diazoacetate (0.463 mL, 4.40 mmol) in DCM (EtOAc) The reaction mixture was allowed to warm to rt and stirred overnight. Then diluted with DCM (200mL) the reaction mixture was washed with water (50 mL), washed with brine (50 mL), dried over Na ₂ SO _4, and concentrated in vacuo. The crude material was purified by EtOAc (EtOAc:EtOAcEtOAcEtOAcEtOAc , 17.67%). ¹ H NMR (CDCl ₃ , δ = 7.26 ppm, 300 MHz): δ 4.04-4.26 (m, 2 H), 2.13 - 2.33 (m, 3 H), 1.93 - 2.12 (m, 3 H), 1.53-1.61 ( m, 1 H), 1.23-1.34 (m, 3 H), 1.19 (t, J = 4.91 Hz, 1 H), 1.02 (dd, J = 8.31, 4.53 Hz, 1 H).

To a solution of spiro[2.3]hexane-1-carboxylic acid ethyl ester (0.4 g, 2.59 mmol) in THF / water (1:1, 10 mL), &lt;RTI ID=0.0&gt; Stir overnight at room temperature. The volatile component was removed in vacuo and the obtained residue was taken in water (30mL) The aqueous layer was acidified to pH = 3 from citric acid and extracted with EtOAc (2.times.100 mL). The organic layer was washed with water (50mL) brine (50mL), dried over Na ₂ SO _4, and concentrated in vacuo to give an off-white solid of spiro [2.3] hexane-1-carboxylic acid (0.2g, 1.585mmol, 61.1 %Yield). ¹ H NMR (DMSO-d ₆ , δ = 2.50 ppm, 300 MHz): δ 1.81-2.27 (m, 6 H), 1.40-1.53 (m, 1 H), 0.98 (d, J = 0.76 Hz, 2 H) .

Cap B61

Add LiOH (270 mg, 11.27 mmol) to a solution of ethyl 2-methyl-2-(methylsulfonyl)propanoate (500 mg, 2.57 mmol) in THF (4 mL) The reaction mixture was stirred at room temperature for 18 hours. The reaction was further diluted with water (20 mL) thenEtOAc. The basic aqueous layer was cooled in an ice-bath and acidified to pH 2 with 1M aqueous HCI. The acidic aqueous layer was extracted with isopropyl alcohol / chloroform (1/1, 3×, 20 mL). , Washed with brine and dried the combined organic extracts were dried over Na ₂ SO _4, filtered and concentrated under reduced pressure to give an off-white solid of 2-methyl-2- (methyl-sulfo acyl) propanoic acid (390 mg of, 2.347 mmol, 91% yield). ¹ H NMR (DMSO-d ₆ , δ = 2.50 ppm, 400 MHz): δ 1.48 (s, 6 H), 3.09 (s, 3 H).

Biological activity

The NS5A synergistic inhibitory effect of the test compound can be determined using various amounts of the NS5A targeting compound under titration of the relevant second compound. It is understood that the NS5A targeting compound and the related second compound are substantially inactive or less active when tested individually for HCV variants, and recover 3 or 3 times only when tested against the HCV variant in combination. The synergistic inhibition potency of the above inhibition. In one embodiment, Compound BMS-790052, which is a NS5A targeting compound, can be maintained at a fixed concentration of 200 nM, followed by titration of the test compound against the HCV variant. In one embodiment, the HCV genotype strain can be genotype 1a, which contains a change in the composition of glutamic acid to glutamic acid at the amino acid 30 of the NS5A protein. The test compound can be selected from the compounds listed above or selected from the additional compounds presented in the literature. Skilled in the art can readily previously been shown in the art, as is the effective concentration of the cell-based HCV replicon analysis of the son of a test compound, and I may be readily determined by 50% inhibition of the specific compound (EC _50).

To illustrate, Compound P-55 can be titrated in an HCV-based replicon cell-based assay consisting of the NS5A protein in which the glutamic acid 30 is changed to the glutamate genotype-1a variant. BMS-790052 alone titration resulting EC ₅₀ values of about 200nM, P-55 alone resulting titration> EC ₅₀ values of 200nM. At a fixed amount of a presence of 200nM BMS-790052 P-55 titration of the resulting ₅₀ EC P-55 value of about 2nM, show synergistic inhibitory effect of the combination of> 100 fold. Similarly, titration of EC BMS-790052 BMS-790052 obtained in a fixed amount of a presence of 200nM P-55 ₅₀ value of about 2nM, showing a combination of mutually cooperating inhibition of about 100 times (PCT / US2011 / 043785,2011 Application on July 13, 2003, Table 3). Additional compounds can be tested in a similar manner and the level of potentiator activity determined; the selected compounds are shown for these grades for genotype 1a Q→E variants.

It is to be understood that genotypes are not limited to genotype 1a variants, but may encompass all genotype variants of HCV, including but not limited to those shown in PCT/US2011/043785 (filed July 13, 2011). HCV variants of 1b, 2a, 3a, 4a, 5a, 6a. It will also be appreciated that synergy is not limited to the BMS-790052 or P-55 combination, but may be derived from other combinations of NS5A targeting compounds that have lower potency or ineffective ability to HCV variants.

A method has been described to identify compounds that exhibit synergistic inhibition of HCV replicon activity when combined with an NS5A targeting compound, such as BMS-790052 (PCT/US2011/043785, filed on Jul. 13, 2011). Briefly, titration of test compounds in the presence of a fixed concentration of BMS-790052 was used to identify NS5A potentiators. The potentiator compound was then used to identify other NS5A targeting inhibitors (shown in the table below) that have synergistic activity when combined.

It is understood that each compound is substantially inactive or much less active when tested individually for some HCV variants, and has only a synergistic inhibitory effect of 3 or more times when tested in combination. A variety of putative NS5A targeting compounds and a variety of test compounds can be used to examine the synergistic activity of the combination. In one embodiment, the compound N47 (a kind of wild type lines, Y93H L31V variants of genotype 1a and virtually no activity (EC ₅₀ values> 1,000nM) of known synergists NS5A) can be kept constant in the fixing 200nM Test compounds were then titrated against HCV variants at concentrations. The test compound can be selected from the compounds exemplified below (which are prepared by methods known in the art) or other compounds selected from the literature. Those skilled in the art readily previously been demonstrated based on the analysis of HCV replication in daughter cells of the test compound, and I can be readily determined effective concentration (EC ₅₀₎ upon the particular compound in 50% inhibition of the related art.

For purposes of illustration, in the analysis of HCV replicon cells consisting of the genotype 1a L31V variant of niaminic acid 31 in the NS5A protein, titration of the compound BMS alone and in combination with a fixed amount of compound N47 -790052. BMS-790052 alone titration resulting EC ₅₀ values of about 56nM; Similarly, the individual titration resulting compound N47> 1,000nM of value. Titration 200nM N47 fixed amount of a compound in combination with BMS-790052 obtained EC BMS-790052 ₅₀ values of <0.5nM, demonstrated synergistic inhibition of the combination of> 100 fold. Similarly, in HCV replicon cell-based assays consisting of tyrosine 93 in his NS5A protein to histidine-type genotype 1a Y93H variant, BMS-790052 was tested separately and in combination with a fixed amount of compound N47. . Titration BMS-790052 alone will give about 69nM of EC _50; similarly, the individual titration resulting compound N47> 1,000nM the EC _50. Titration 200nM N47 fixed amount of a compound in combination with BMS-790052 obtained EC BMS-790052 ₅₀ values of <0.5nM, demonstrated synergistic inhibition of the combination of> 100 fold. Other compounds can be titrated in combination with Compound N47 maintained at 200 nM and fractionated according to synergistic activity; the fold variation of the selected compounds against genotype 1a L31V and Y93H variants is shown in the table below.

It should be understood that genotypes are not limited to genotype 1a variants, but may cover all genotypic variants of HCV, including but not limited to those as demonstrated in PCT/US2011/043785 (filed on July 13, 2011). HCV variants of 1b, 2a, 3a, 4a, 5a, 6a. It will also be appreciated that synergy is not limited to the combination of compound N47 or BMS-790052, but may be derived from other combinations of compounds that have lower potency or ineffective ability to specific HCV variants.

It is obvious to those skilled in the art that the present invention is not limited to the foregoing illustrative examples, and may be embodied in other specific forms without departing from the basic attributes thereof. Therefore, the present invention is to be considered as illustrative and not restrictive, and the scope of the accompanying claims Changes are intended to be included.

Claims (7)

A combination comprising an NS5A targeting compound and an NS5A potentiator, when administered, provides synergistic anti-HCV activity against a variant comprising a mutation that confers resistance to a NS5A targeting compound alone, wherein the NS5A synergist Selected from: Or a pharmaceutically acceptable salt thereof. A combination comprising a NS5A targeting compound and an NS5A potentiator, when administered, provides synergistic anti-HCV activity against a variant comprising a mutation that confers resistance to a NS5A targeting compound alone, wherein the NS5A targeting compound Selected from: Or a pharmaceutically acceptable salt thereof. A composition comprising a combination of claim 1 or 2, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. The composition of claim 3, which additionally comprises one or two amounts having anti-HCV activity External compound. The composition of claim 4, wherein at least one of the additional compounds is an interferon or ribavirin. A use as claimed in claim 1 or 2, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of HCV infection in a patient. The use of claim 6, wherein the medicament additionally comprises one or two additional compounds having anti-HCV activity, or is used before, after or simultaneously with one or two additional compounds having anti-HCV activity.