WO2016019588A1

WO2016019588A1 - Oxacazone compounds to treat clostridium difficile

Info

Publication number: WO2016019588A1
Application number: PCT/CN2014/084037
Authority: WO
Inventors: Christina Scherer; Jeremy Duvall; Joseph P. Vacca; Mingliang Zhang; Zhenmin He; Huisheng XU
Original assignee: The Broad Institute, Inc.; Wuxi Apptec(Tianjin) Co., Ltd.
Priority date: 2014-08-08
Filing date: 2014-08-08
Publication date: 2016-02-11

Abstract

Compounds, compositions, and methods for treating C. difficile are provided.

Description

Oxacazone Compounds to Treat Clostridium difficile

Field Of The Invention

The present invention is directed, in part, to compounds (e. g. oxacazones) , or pharmaceutically acceptable salts thereof, for treating Clostridium difficile (C. diff. or C. difficile)

Background Of The Invention

One species of Gram-positive bacteria, Clostridium difficile (C. difficile) , is known to cause a number of serious conditions and diseases. C. difficile produces Toxin A which is an enterotoxin which stimulates infiltration of neutrophils and release of mediators of inflammation, resulting in fluid secretion, altered membrane permeability and hemorrhagic necrosis. C. difficile also produces Toxin B which is a cytotoxin. C. difficile can cause antibiotic-associated diarrhea (AAD) that can lead to pseudomembranous colitis (PMC) , asevere inflammation of the colon. These conditions often arise from the reduction or eradication of the normal gut flora by antibiotics or, less c ommonly, by cancer chemotherapy.

C. difficile-associated diarrhea (CDAD) is a disease characterized by severe and painful diarrhea. C. difficileis responsible for approximately 20％ of all cases of antibiotic-associated diarrhea (AAD) and the majority of the cases of antibiotic-associated colitis (AAC) . These diseases are typically caused by toxin producing strains of C. difficile. AAD is a significant problem in hospitals and long-term care facilities and in the community. The rising incidence of C. difficile-associated diarrhea (CDAD) has been attributed to the frequent prescription of broad-spectrum antibiotics to hospitalized patients.

The most serious form of CDAD is pseudomembranous colitis (PMC) , which is manifested histologically by colitis with mucosal plaques, and clinically by severe diarrhea, abdominal cramps, and systemic toxicity. The overall mortality rate from CDAD is low, but is much greater in patients who develop severe colitis or systemic toxicity.

There are currently several therapies for CDAD including vancomycin, metronidazole, and fidaxomicin. Vancomycin is not recommended for first-line treatment of CDAD mainly because it is the only antibiotic active against some serious life-threatening multi-drug resistant bacteria.

Metronidazole is used for treating CDAD. However, C. difficileresistance may be more than >6％ in some locations. Fidaxomicin was approved for treatment of CDAD in May, 2011. This compound is described in U. S. Pat. 7,906,489. Additionally, a new compound, LFF-571, which is a semi-synthetic thiopeptide is currently undergoing clinical trials for the treatment of patients with moderate C. difficile infections. LFF-571 is active against a variety of Gram-positive pathogens and has been shown to be more effective than vancomycin in hamsters. (Trzasko et al. , ICAAC, 9/12/2010, Boston, MA. )

However, these compounds have significant side effects, may not be effective for important strains of C. difficile, and are not sufficiently selective for inhibiting C. difficile. Thus, there is a need for enhanced methods for inhibiting C. difficile and for treating C. difficile infection.

Summary Of The Invention

Embodiments disclosed herein provided compounds, or a pharmaceutically acceptable salts thereof, of Formula I:

wherein:

R₁ and R₉ are each independently H, optionally substituted C₁-C₆ alkyl, optionally substituted C₁-C₆ alkoxy, halo, haloalkyl, hydroxy, or cyano；

R₂ R₃, R₇, and R₈ are each independently H, optionally substituted C₁-C₆ alkyl, optionally substituted C₁-C₆ alkoxy, halo, hydroxy, cyano, or haloalkyl；

Z is haloalkyl, or optionally substituted C₁-C₆ alkyl；

X is a bond, C (R₅) ₂, O, NR₅, S, [C (R₅) ₂] ₂, OC (R₅) ₂, SC (R₅) ₂, NR₅C (R₆) ₂, C (R₅) ₂O, C (R₅) ₂S, C (R₅) ₂NR₆, wherein each R₅ and R₆ are each independently H, optionally substituted C₁-C₆ alkyl.

In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, wherein the compound has a formula of Formulas (II) - (VI) :

with the variables as defined for Formula (I) or as defined herein.

In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, wherein the compound has a formula of Formula VII

with the variables as defined for Formula (I) or as defined herein.

In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, wherein the compound has a formula of Formula VIII

with the variables as defined for Formula (I) or as defined he r ein.

In some embodiments, compounds, or a pharmaceutically acceptable salts thereof, of Formula IX are provided:

wherein

R₁ and R₉ are each indepednently H, optionally substituted C₁-C₆ alkyl, optionally substituted C₁-C₆ alkoxy, halo, haloalkyl, hydroxy, or cyano； and

In some embodiments, compounds, or a pharmaceutically acceptable salts thereof, of Formula (XI) are provided:

wherein

R₂ R₃, R₇, and R₈ are each independently H, optionally substituted C₁-C₆ alkyl, optionally substituted C₁-C₆ alkoxy, halo, hydroxy, cyano, or haloalkyl； and

In some embodiments, pharmaceutical compositions comprising one or more compounds described herein are provided. In some embodiments, the composition comprises a pharmaceutically acceptable carrier.

In some embodiments, methods of treating a Clostridium difficileinfection in a subject are provided, wherein the method comprises administering to the subject one or more compounds described herein or a pharmaceutical composition described herein.

In some embodiments, methods of inhibiting Clostridium difficilereplication or growth are provided, wherein the method comprises contacting a Clostridium difficile bacterium with one or more compounds described herein or a pharmaceutical composition described herein.

In some embodiments, methods of treating diarrhea in a subject suspected of having a Clostridium difficileinfection are provided. In some embodiments, the methods comprise administering to the subject one or more compounds described herein or a pharmaceutical composition described herein.

In some embodiments, methods of treating a subject suspected of having a Clostridium difficileinfection comprising determining whether the subject has a Clostridium difficileinfection and administering to a subject determined to have a Clostridium difficileinfection one or more compounds described herein or a pharmaceutical composition described herein.

In some embodiments, methods of specifically inhibiting Clostridium difficilereplication or growth are provided. In some embodiments, the methods comprise contacting a Clostridium difficile bacterium with one or more compounds described herein or a pharmaceutical composition described herein.

In some embodiments, methods of selectively inhibiting Clostridium difficilereplication or growth in a subject are provided. In some embodiments, the methods comprise administering to the subject one or more compounds described herein or a pharmaceutical composition described herein.

In some embodiments, methods of preventing a recurrence of a Clostridium difficileinfection are provided. In some embodiments, the methods comprise administering to a subject previously treated with a different antibiotic for aClostridium difficileinfection one or more compounds described herein or a pharmaceutical composition described herein.

In some embodiments, methods of preparing a compound described herein are provided. In some embodiments, the methods comprise preparing a compound according to a scheme of:

R₁ and R₉ are each indepednently H, optionally substituted C₁-C₆ alkyl, optionally substituted C₁-C₆ alkoxy, halo, haloalkyl, hydroxy, or cyano；

Z is haloalkyl or optionally substituted C₁-C₆ alkyl；

Brief Description of the Drawings

Figure 1 illustrates activity of various compounds MIC against C. difficile and Staphylococcus aureus.

Figure 2 illustrates activity of various compounds MIC against C. difficile and Staphylococcus aureus.

Figure 3 illustrates activity of various compounds MIC against C. difficile and Staphylococcus aureus.

Figure 4 illustrates activity of various compounds MIC against C. difficile and Staphylococcus aureus.

Figure 5 illustrates activity of various compounds MIC against C. difficile and Staphylococcus aureus.

Figure 6 illustrates activity of various compounds MIC against C. difficile and Staphylococcus aureus.

Figure 7 illustrates activity of various compounds MIC against C. difficile and Staphylococcus aureus.

Figure 8 illustrates activity of various compounds MIC against C. difficile and Staphylococcus aureus.

Description Of Embodiments.

Unless defined otherwise, all technical and scientific terms have the same meaning as is commonly understood by one of ordinary skill in the art to which the embodiments disclosed belongs.

As used herein, the terms “a” or “an” means that “at least one” or “one or more” unless the context clearly indicates otherwise.

As used herein, the term “about” means that the numerical value is approximate and small variations would not significantly affect the practice of the disclosed embodiments. Where a numerical limitation is used, unless indicated otherwise by the context, “about” means the numerical value can vary by ±5％ .

As used herein, the term “acylamino” means an amino group substituted by an acyl group (e. g. , -O-C (＝O) -H or -O-C (＝O) -alkyl) . An example of an acylamino is -NHC (＝O) H or -NHC (＝O) CH3. The term “lower acylamino” refers to an amino group substituted by a loweracyl group (e. g. , -O-C (＝O) -H or -O-C (＝O) -C₁-C₆alkyl) . An example of a lower acylamino is -NHC (＝O) H or -NHC (＝O) CH3.

As used herein, the term “alkenyl” means a straight or branched alkyl group having one or more double carbon-carbon bonds and 2-20 carbon atoms, including, but not limited to, ethenyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, and the like. In some embodiments, the alkenyl chain is from 2 to 10 carbon atoms in length, from 2 to 8 carbon atoms in length, from 2 to 6 carbon atoms in length, or from 2 to 4 carbon atoms in length.

The terms “alkoxy” , “phenyloxy” , “benzoxy” and “pyrimidinyloxy” refer to an alkyl group, phenyl group, benzyl group, or pyrimidinyl group, respectively, each optionally substituted, that is bonded through an oxygen atom. For example, the term “alkoxy” means a straight or branched -O-alkyl group of 1 to 20 carbon atoms, including, but not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, t-butoxy, and the like. In some embodiments, the alkoxy chain is from 1 to 10 carbon atoms in length, from 1 to 8 carbon atoms in length, from 1 to 6 carbon atoms in length, from 1 to 4 carbon atoms in length, from 2 to 10 carbon atoms in length, from 2 to 8 carbon atoms in length, from 2 to 6 carbon atoms in length, or from 2 to 4 carbon atoms in length.

As used herein, the term “alkyl” means a saturated hydrocarbon group which is straight-chained or branched. An alkyl group can contain from 1 to 20, from 2 to 20, from 1 to 10, from 2 to 10, from 1 to 8, from 2 to 8, from 1 to 6, from 2 to 6, from 1 to 4, from 2 to 4, from 1 to 3, or 2 or 3 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl (Me) , ethyl (Et) , propyl (e. g. , n-propyl and isopropyl) , butyl (e. g. , n-butyl, t-butyl, isobutyl) , pentyl (e. g. , n-pentyl, isopentyl, neopentyl) , hexyl, isohexyl, heptyl, 4, 4 dimethylpentyl, octyl, 2, 2, 4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2-methyl-1-pentyl, 2, 2-dimethyl-1-propyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2, 2-dimethyl-1-butyl, 3, 3-dimethyl-1-butyl, 2-ethyl-1-butyl, and the like.

As used herein, the term “alkylamino” means an amino group substituted by an alkyl group having from 1 to 6 carbon atoms. An example of an alkylamino is -NHCH₂CH3.

As used herein, the term “alkylene” or “alkylenyl” means a divalent alkyl linking group. An example of an alkylene (or alkylenyl) is methylene or methylenyl (-CH₂-) .

As used herein, the term “alkylthio” means an -S-alkyl group having from 1 to 6 carbon atoms. An example of an alkylthio group is -SCH₂CH3.

As used herein, the term “alkynyl” means a straight or branched alkyl group having one or more triple carbon-carbon bonds and 2-20 carbon atoms, including, but not limited to, acetylene, 1-propylene, 2-propylene, and the like. In some embodiments, the alkynyl chain is 2 to 10 carbon atoms in length, from 2 to 8 carbon atoms in length, from 2 to 6 carbon atoms in length, or from 2 to 4 carbon atoms in length.

As used herein, the term “amidino” means -C (＝NH) NH₂.

As used herein, the term “amino” means -NH₂.

As used herein, the term “aminoalkoxy” means an alkoxy group substituted by an amino group. An example of an aminoalkoxy is -OCH₂CH₂NH₂.

As used herein, the term “aminoalkyl” means an alkyl group substituted by an amino group. An example of an aminoalkyl is -CH₂CH₂NH₂.

As used herein, the term “aminosulfonyl” means -S (＝O) 2NH₂.

As used herein, the term “aminoalkylthio” means an alkylthio group substituted by an amino group. An example of an aminoalkylthio is -SCH₂CH₂NH₂.

As used herein, the term “animal” includes, but is not limited to, humans and non-human vertebrates such as wild, domestic, and farm animals. An animal can also be a mammal.

As used herein, the term “aryl” means a monocyclic, bicyclic, or polycyclic (e. g. , having 2, 3 or 4 fused rings) aromatic hydrocarbons. In some embodiments, aryl groups have from 6 to 20 carbon atoms or from 6 to 10 carbon atoms. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, phenanthrenyl, indanyl, indenyl, tetrahydronaphthyl, and the like. Examples of aryl groups include, but are not limited to:

As used herein, the term “arylalkyl” means a C₁-C₆alkyl substituted by aryl.

As used herein, the term “arylamino” means an amino group substituted by an aryl group. An example of an arylamino is -NH (phenyl) .

As used herein, the term “arylene” means an aryl linking group, i. e. , an aryl group that links one group to another group in a molecule.

As used herein, the term “cancer” means a spectrum of pathological symptoms associated with the initiation or progression, as well as metastasis, of malignant tumors.

As used herein, the term “carbamoyl” means -C (＝O) -NH₂.

As used herein, the term “carbocycle” means a 5-or 6-membered, saturated or unsaturated cyclic ring, optionally containing O, S, or N atoms as part of the ring. Examples of carbocycles include, but are not limited to, cyclopentyl, cyclohexyl, cyclopenta-1, 3-diene, phenyl, and any of the heterocycles recited above.

As used herein, the term “carrier” means a diluent, adjuvant, or excipient with which a compound is administered. Pharmaceutical carriers can be liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. The pharmaceutical carriers can also be saline, gum acacia, gelatin, starch paste, talc, keratin, colloidal silica, urea, and the like. In addition, auxiliary, stabilizing, thickening, lubricating and coloring agents can be used.

As used herein, the term, “compound” means all stereoisomers, tautomers, and isotopes of the compounds described herein.

As used herein, the terms “comprising” (and any form of comprising, such as “comprise” , “comprises” , and “comprised” ) , “having” (and any form of having, such as “have” and “has” ) , “including” (and any form of including, such as “includes” and “include” ) , or “containing” (and any form of containing, such as “contains” and “contain” ) , are inclusive or open-ended and do not exclude additional, unrecited elements or method steps. While various compositions or methodsare described in terms of “comprising” various components or steps, the compositions or methods can also “consist essentially of” or “consist of” the various components and/or steps. As discussed herein, compositions include, but are not limited to, pharmaceutical compositions.

As used herein, the term “contacting” means bringing together of two elements in an in vitro system or an in vivo system. “Contacting” can also refer to the bringing together of two compounds and/or reagents in a chemical synthesis reaction under conditions sufficient to produce a third compound.

As used herein, the term “cyano” means -CN.

As used herein, the term “cycloalkyl” means non-aromatic cyclic hydrocarbons including cyclized alkyl, alkenyl, and alkynyl groups that contain up to 20 ring-forming carbon atoms. Cycloalkyl groups can include mono-or polycyclic ring systems such as fused ring systems, bridged ring systems, and spiro ring systems. In some embodiments, polycyclic ring systems include 2, 3, or 4 fused rings. A cycloalkyl group can contain from 3 to 15, from 3 to 10, from 3 to 8, from 3 to 6, from 4 to 6, from 3 to 5, or 5 or 6 ring-forming carbon atoms. Ring-forming carbon atoms of a cycloalkyl group can be optionally substituted by oxo or sulfido. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl, norpinyl, norcarnyl, adamantyl, and the like. Also included in the definition of cycloalkyl are moieties that have one or more aromatic rings fused (having a bond in common with) to the cycloalkyl ring, for example, benzo or thienyl derivatives of pentane, pentene, hexane, and the like (e. g. , 2, 3-dihydro-1H-indene-1-yl, or 1H-inden-2 (3H) -one-1-yl) .

As used herein, the term “cycloalkylalkyl” means a C₁-C₆alkyl substituted by cycloalkyl.

As used herein, the term “dialkylamino” means an amino group substituted by two alkyl groups, each having from 1 to 6 carbon atoms.

As used herein, the term “diazamino” means -N (NH₂) ₂.

As used herein, the term “guanidino” means -NH (＝NH) NH₂.

As used herein, the term “halo” means halogen groups including, but not limited to fluoro, chloro, bromo, and iodo.

As used herein, the term “haloalkoxy” means an -O-haloalkyl group. An example of an haloalkoxy group is OCF₃.

As used herein, the term “haloalkyl” means a C₁-C₆ alkyl group having one or more halogen substituents. Examples of haloalkyl groups include, but are not limited to, CF₃, C₂F₅, CHF₂, CCl₃,CHCl₂, C₂Cl₅, CH₂CF₃, and the like.

As used herein, the term “heteroaryl” means an aromatic heterocycle having up to 20 ring-forming atoms (e. g. , C) and having at least one heteroatom ring member (ring-forming atom) such as sulfur, oxygen, or nitrogen. In some embodiments, the heteroaryl group has at least one or more heteroatom ring-forming atoms, each of which are, independently, sulfur, oxygen, or nitrogen. In some embodiments, the heteroaryl group has from 3 to 20 ring-forming atoms, from 3 to 10 ring-forming atoms, from 3 to 6 ring-forming atoms, or from 3 to 5 ring-forming atoms. In some embodiments, the heteroaryl group contains 2 to 14 carbon atoms, from 2 to 7 carbon atoms, or 5 or 6 carbon atoms. In some embodiments, the heteroaryl group has 1 to 4 heteroatoms, 1 to 3 heteroatoms, or 1 or 2 heteroatoms. Heteroaryl groups include monocyclic and polycyclic (e. g. , having 2, 3 or 4 fused rings) systems. Examples of heteroaryl groups include, but are not limited to, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, furyl, quinolyl, isoquinolyl, thienyl, imidazolyl, thiazolyl, indolyl (such as indol-3-yl) , pyrryl, oxazolyl, benzofuryl, benzothienyl, benzthiazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, indazolyl, 1, 2, 4-thiadiazolyl, isothiazolyl, benzothienyl, purinyl, carbazolyl, benzimidazolyl, indolinyl, pyranyl, oxadiazolyl, isoxazolyl, triazolyl, thianthrenyl, pyrazolyl, indolizinyl, isoindolyl, isobenzofuranyl, benzoxazolyl, xanthenyl, 2H-pyrrolyl, pyrrolyl, 3H-indolyl,

4H-quinolizinyl, phthalazinyl, naphthyridinyl, quinazolinyl, phenanthridinyl, acridinyl, perimidinyl, phenanthrolinyl, phenazinyl, isothiazolyl, phenothiazinyl, isoxazolyl, furazanyl, phenoxazinyl groups, and the like. Suitable heteroaryl groups include 1, 2, 3-triazole,

1, 2, 4-triazole, 5-amino-1, 2, 4-triazole, imidazole, oxazole, isoxazole, 1, 2, 3-oxadiazole,

1, 2, 4-oxadiazole, 3-amino-1, 2, 4-oxadiazole, 1, 2, 5-oxadiazole, 1, 3, 4-oxadiazole, pyridine, and 2-aminopyridine.

As used herein, the term “heteroarylalkyl” means a C₁-C₆alkyl group substituted by a heteroaryl group.

As used herein, the term “heteroarylamino” means an amino group substituted by a heteroaryl group. An example of a heteroarylamino is -NH- (2-pyridyl) .

As used herein, the term “heteroarylene” means a heteroaryl linking group, i. e. , aheteroaryl group that links one group to another group in a molecule.

As used herein, the term “heterocycle” or “heterocyclic ring” means a 5-to 7-membered mono-or bicyclic or 7-to 10-membered bicyclic heterocyclic ring system any ring of which may be saturated or unsaturated, and which consists of carbon atoms and from one to three heteroatoms chosen from N, O and S, and wherein the N and S heteroatoms may optionally be oxidized, and the N heteroatom may optionally be quaternized, and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring. Particularly useful are rings containing one oxygen or sulfur, one to three nitrogen atoms, or one oxygen or sulfur combined with one or two nitrogen atoms. The heterocyclic ring may be attached at any heteroatom or carbon atom which results in the creation of a stable structure. Examples of heterocyclic groups include, but are not limited to, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, 2-oxoazepinyl, azepinyl, pyrrolyl, 4-piperidonyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolidinyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiazolyl, thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, thiadiazoyl, benzopyranyl, benzothiazolyl, benzoxazolyl, furyl, tetrahydrofuryl, tetrahydropyranyl, thienyl, benzothienyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, and oxadiazolyl. Morpholino is the same as morpholinyl.

As used herein, the term “heterocycloalkyl” means non-aromatic heterocycles having up to 20 ring-forming atoms including cyclized alkyl, alkenyl, and alkynyl groups, where one or more of the ring-forming carbon atoms is replaced by a heteroatom such as an O, N, or S atom. Heterocycloalkyl groups can be mono or polycyclic (e. g. , fused, bridged, or spiro systems) . In some embodiments, the heterocycloalkyl group has from 1 to 20 carbon atoms or from 3 to 20 carbon atoms. In some embodiments, the heterocycloalkyl group contains 3 to 14 ring-forming atoms, 3 to 7 ring-forming atoms, or 5 or 6 ring-forming atoms. In some embodiments, the heterocycloalkyl group has 1 to 4 heteroatoms, 1 to 3 heteroatoms, or 1 or 2 heteroatoms. In some embodiments, the heterocycloalkyl group contains 0 to 3 double bonds. In some embodiments, the heterocycloalkyl group contains 0 to 2 triple bonds. Examples of heterocycloalkyl groups include, but are not limited to, morpholino, thiomorpholino, piperazinyl, tetrahydrofuranyl, tetrahydrothienyl, 2, 3-dihydrobenzofuryl, 1, 3-benzodioxole, benzo-1, 4-dioxane, piperidinyl, pyrrolidinyl, isoxazolidinyl, oxazolidinyl, isothiazolidinyl, pyrazolidinyl, thiazolidinyl, imidazolidinyl, pyrrolidin-2-one-3-yl, and the like. In addition, ring-forming carbon atoms and heteroatoms of a heterocycloalkyl group can be optionally substituted by oxo or sulfido. For example, a ring-forming S atom can be substituted by 1 or 2 oxo (form a S (O) or S (O) 2) . For another example, a ring-forming C atom can be substituted by oxo (form carbonyl) . Also included in the definition of heterocycloalkyl are moieties that have one or more aromatic rings fused (having a bond in common with) to the nonaromatic heterocyclic ring including, but not limited to, pyridinyl, thiophenyl, phthalimidyl, naphthalimidyl, and benzo derivatives of heterocycles such as indolene, isoindolene, 4, 5, 6, 7-tetrahydrothieno [2, 3-c] pyridine-5-yl, 5, 6-dihydrothieno [2, 3-c] pyridin-7 (4H) -one-5-yl, isoindolin-1-one-3-yl, and 3, 4-dihydroisoquinolin-1 (2H) -one-3yl groups. Ring-forming carbon atoms and heteroatoms of the heterocycloalkyl group can be optionally substituted by oxo or sulfido.

As used herein, the term “heterocycloalkylalkyl” refers to a C₁-C₆alkyl substituted by heterocycloalkyl.

As used herein, the term “hydoxy” or “hydroxyl” means an -OH group.

As used herein, the term “hydroxyalkyl” or “hydroxylalkyl” means an alkyl group substituted by a hydroxyl group. Examples of a hydroxylalkyl include, but are not limited to, -CH₂OH and -CH₂CH₂OH.

As used herein, the term “individual” or “patient, ” used interchangeably, means any animal, including mammals, such as mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, or primates, such as humans.

As used herein, the phrase “in need thereof” means that the animal or mammal has been identified as having a need for the particular method or treatment. In some embodiments, the identification can be by any means of diagnosis. In any of the methods and treatments described herein, the animal or mammal can be in need thereof. In some embodiments, the animal or mammal is in an environment or will be traveling to an environment in which a particular disease, disorder, or condition is prevelant.

As used herein, the phrase “integer from X to Y” means any integer that includes the endpoints. For example, the phrase “integer from 1 to 5” means 1, 2, 3, 4, or 5.

As used herein, the term “isolated” means that the compounds described herein are separated from other components of either (a) a natural source, such as a plant or cell, or (b) a synthetic organic chemical reaction mixture, such as by conventional techniques.

As used herein, the term “mammal” means a rodent (i. e. , amouse, a rat, or a guinea pig) , a monkey, a cat, a dog, a cow, a horse, a pig, or a human. In some embodiments, the mammal is a human.

As used herein, the term “nitro” means -NO₂.

As used herein, the term “n-membered” , where n is an integer, typically describes the number of ring-forming atoms in a moiety, where the number of ring-forming atoms is n. For example, pyridine is an example of a 6-membered heteroaryl ring and thiophene is an example of a 5-membered heteroaryl ring.

As used herein, the phrase “optionally substituted” means that substitution is optional and therefore includes both unsubstituted and substituted atoms and moieties. A “substituted” atom or moiety indicates that any hydrogen on the designated atom or moiety can be replaced with a selection from the indicated substituent groups, provided that the normal valency of the designated atom or moiety is not exceeded, and that the substitution results in a stable compound. For example, if a methyl group is optionally substituted, then 3 hydrogen atoms on the carbon atom can be replaced with substituent groups.

As used herein, the phrase “pharmaceutically acceptable salt (s) , ” includes, but is not limited to, salts of acidic or basic groups. Compounds that are basic in nature are capable of forming a wide variety of salts with various inorganic and organic acids. Acids that may be used to prepare pharmaceutically acceptable acid addition salts of such basic compounds are those that form non-toxic acid addition salts, i. e. , salts containing pharmacologically acceptable anions including, but not limited to, sulfuric, thiosulfuric, citric, maleic, acetic, oxalic, hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, bisulfite, phosphate, acid phosphate, isonicotinate, borate, acetate, lactate, salicylate, citrate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, bicarbonate, malonate, mesylate, esylate, napsydisylate, tosylate, besylate, orthophoshate, trifluoroacetate, and pamoate (i. e. , 1, 1′-methylene-bis- (2-hydroxy-3-naphthoate) ) salts. Compounds that include an amino moiety may form pharmaceutically acceptable salts with various amino acids, in addition to the acids mentioned above. Compounds that are acidic in nature are capable of forming base salts with various pharmacologically acceptable cations. Examples of such salts include, but are not limited to, alkali metal or alkaline earth metal salts and, particularly, calcium, magnesium, ammonium, sodium, lithium, zinc, potassium, and iron salts. The present invention also includes quaternary ammonium salts of the compounds described herein, where the compounds have one or more tertiary amine moiety.

As used herein, the term “phenyl” means -C₆H₅. A phenyl group can be unsubstituted or substituted with one, two, or three suitable substituents.

As used herein, the terms “prevention” or “preventing” mean a reduction of the risk of acquiring a particular disease, condition, or disorder.

As used herein, the term “prodrug” means a derivative of a known direct acting drug, which derivative has enhanced delivery characteristics and therapeutic value as compared to the drug, and is transformed into the active drug by an enzymatic or chemical process.

As used herein, the term “purified” means that when isolated, the isolate contains at least 90％ , at least 95％ , at least 98％ , or at least 99％ of a compound described herein by weight of the isolate.

As used herein, the phrase “substantially isolated” means a compound that is at least partially or substantially separated from the environment in which it is formed or detected.

As used herein, the phrase “suitable substituent” or “substituent” means a group that does not nullify the synthetic or pharmaceutical utility of the compounds described herein or the intermediates useful for preparing them. Examples of suitable substituents include, but are not limited to: C₁-C₆alkyl, C₁-C₆alkenyl, C₁-C₆alkynyl, C₅-C₆aryl, C₁-C₆alkoxy, C₃-C₅heteroaryl, C₃-C₆cycloalkyl, C₅-C₆aryloxy, -CN, -OH, oxo, halo, haloalkyl, -NO₂, -CO₂H, -NH₂, -NH (C₁-C₈alkyl) , -N (C₁-C₈alkyl) ₂, -NH (C₆aryl) , -N (C₅-C₆aryl) ₂, -CHO, -CO (C₁-C₆alkyl) , -CO ( (C₅-C₆) aryl) , -CO₂ ( (C₁-C₆) alkyl) , and -CO₂ ( (C₅-C₆) aryl) . One of skill in art can readily choose a suitable substituent based on the stability and pharmacological and synthetic activity of the compounds described herein.

As used herein, the phrase “therapeutically effective amount” means the amount of active compound or pharmaceutical agent that elicits the biological or medicinal response that is being sought in a tissue, system, animal, individual or human by a researcher, veterinarian, medical doctor or other clinician. The therapeutic effect is dependent upon the disorder being treated or the biological effect desired. As such, the therapeutic effect can be a decrease in the severity of symptoms associated with the disorder and/or inhibition (partial or complete) of progression of the disorder, or improved treatment, healing, prevention or elimination of a disorder, or side-effects. The amount needed to elicit the therapeutic response can be determined based on the age, health, size and sex of the subject. Optimal amounts can also be determined based on monitoring of the subject’ sresponse to treatment.

As used herein, the terms “treat, ” “treated, ” or “treating” mean both therapeutic treatment and prophylactic or preventative measures wherein the object is to prevent or slow down (lessen) an undesired physiological condition, disorder or disease, or obtain beneficial or desired clinical results. Beneficial or desired clinical results include, but are not limited to, alleviation of symptoms； diminishment of extent of condition, disorder or disease； stabilized (i. e. , not worsening) state of condition, disorder or disease； delay in onset or slowing of condition, disorder or disease progression； amelioration of the condition, disorder or disease state or remission (whether partial or total) , whether detectable or undetectable； an amelioration of at least one measurable physical parameter, not necessarily discernible by the patient； or enhancement or improvement of condition, disorder or disease. Treatment includes eliciting a clinically significant response without excessive levels of side effects. Treatment also includes prolonging survival as compared to expected survival if not receiving treatment. Thus, “treatment of cancer” or “treating cancer” means an activity that prevents, alleviates or ameliorates any of the primary phenomena (initiation, progression, metastasis) or secondary symptoms associated with the cancer.

At various places in the present specification, substituents of compounds may be disclosed in groups or in ranges. It is specifically intended that embodiments include each and every individual subcombination of the members of such groups and ranges. For example, the term “C₁-C₆alkyl” is specifically intended to individually disclose methyl, ethyl, propyl, C₄alkyl, C₅alkyl, and C₆alkyl.

For compounds in which a variable appears more than once, each variable can be a different moiety selected from the Markush group defining the variable. For example, where a structure is described having two R groups that are simultaneously present on the same compound, the two R groups can represent different moieties selected from the Markush groups defined for R. In another example, when an optionally multiple substituent is designated in the form, for example,

then it is understood that substituent R can occur s number of times on the ring, and R can be a different moiety at each occurrence. Further, in the above example, where the variable T¹ is defined to include hydrogens, such as when T¹ is CH₂, NH, etc. , any H can be replaced with a substituent.

It is further appreciated that certain features described herein, which are, for clarity, described in the context of separate embodiments, can also be provided in combination in a single embodiment. Conversely, various features which are, for brevity, described in the context of a single embodiment, can also be provided separately or in any suitable subcombination.

It is understood that the present invention encompasses the use, where applicable, of stereoisomers, diastereomers and optical stereoisomers of the compounds of the invention, as well as mixtures thereof. Additionally, it is understood that stereoisomers, diastereomers, and optical stereoisomers of the compounds of the invention, and mixtures thereof, are within the scope of the invention. By way of non-limiting example, the mixture may be a racemate or the mixture may comprise unequal proportions of one particular stereoisomer over the other.

Additionally, the compounds can be provided as a substantially pure stereoisomers, diastereomers and optical stereoisomers (such as epimers) .

The compounds described herein can be asymmetric (e. g. , having one or more stereocenters) . All stereoisomers, such as enantiomers and diastereomers, are intended to be included within the scope of the invention unless otherwise indicated. Compounds that contain asymmetrically substituted carbon atoms can be isolated in optically active or racemic forms. Methods of preparation of optically active forms from optically active starting materials are known in the art, such as by resolution of racemic mixtures or by stereoselective synthesis. Many geometric isomers of olefins, C＝N double bonds, and the like can also be present in the compounds described herein, and all such stable isomers are contemplated in the present invention. Cis and trans geometric isomers of the compounds are also included within the scope of the invention and can be isolated as a mixture of isomers or as separated isomeric forms. Where a compound capable of stereoisomerism or geometric isomerism is designated in its structure or name without reference to specific R/Sor cis/trans configurations, it is intended that all such isomers are contemplated.

Resolution of racemic mixtures of compounds can be carried out by any of numerous methods known in the art, including, for example, fractional recrystallizaion using a chiral resolving acid which is an optically active, salt-forming organic acid. Suitable resolving agents for fractional recrystallization methods include, but are not limited to, optically active acids, such as the D and L forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid, and the various optically active camphorsulfonic acids such as β-camphorsulfonic acid. Other resolving agents suitable for fractional crystallization methods include, but are not limited to, stereoisomerically pure forms of α-methylbenzylamine (e. g. , Sand R forms, or diastereomerically pure forms) , 2-phenylglycinol, norephedrine, ephedrine, N-methylephedrine, cyclohexylethylamine, 1, 2-diaminocyclohexane, and the like. Resolution of racemic mixtures can also be carried out by elution on a column packed with an optically active resolving agent (e. g. , dinitrobenzoylphenylglycine) . Suitable elution solvent compositions can be determined by one skilled in the art.

Compounds may also include tautomeric forms. Tautomeric forms result from the swapping of a single bond with an adjacent double bond together with the concomitant migration of a proton. Tautomeric forms include prototropic tautomers which are isomeric protonation states having the same empirical formula and total charge. Examples of prototropic tautomers include, but are not limited to, ketone-enol pairs, amide-imidic acid pairs, lactam-lactim pairs, amide-imidic acid pairs, enamine-imine pairs, and annular forms where a proton can occupy two or more positions of a heterocyclic system including, but not limited to, 1H-and 3H-imidazole, 1H-, 2H-and 4H-1, 2, 4-triazole, 1H-and 2H-isoindole, and 1H-and 2H-pyrazole. Tautomeric forms can be in equilibrium or sterically locked into one form by appropriate substitution.

Compounds also include hydrates and solvates, as well as anhydrous and non-solvated forms.

Compounds can also include all isotopes of atoms occurring in the intermediates or final compounds. Isotopes include those atoms having the same atomic number but different mass numbers. For example, isotopes of hydrogen include tritium and deuterium.

In some embodiments, the compounds, or salts thereof, are substantially isolated. Partial separation can include, for example, a composition enriched in the compound of the invention. Substantial separation can include compositions containing at least about 50％ , at least about 60％ , at least about 70％ , at least about 80％ , at least about 90％ , at least about 95％ , at least about 97％ , or at least about 99％ by weight of the compound of the invention, or salt thereof. Methods for isolating compounds and their salts are routine in the art.

Although the disclosed compounds are suitable, other functional groups can be incorporated into the compound with an expectation of similar results. In particular, thioamides and thioesters are anticipated to have very similar properties. The distance between aromatic rings can impact the geometrical pattern of the compound and this distance can be altered by incorporating aliphatic chains of varying length, which can be optionally substituted or can comprise an amino acid, a dicarboxylic acid or a diamine. The distance between and the relative orientation of monomers within the compounds can also be altered by replacing the amide bond with a surrogate having additional atoms. Thus, replacing a carbonyl group with a dicarbonyl alters the distance between the monomers and the propensity of dicarbonyl unit to adopt an anti arrangement of the two carbonyl moiety and alter the periodicity of the compound. Pyromellitic anhydride represents still another alternative to simple amide linkages which can alter the conformation and physical properties of the compound. Modern methods of solid phase organic chemistry (E. Atherton and R. C. Sheppard, Solid Phase Peptide Synthesis A Practical Approach IRL Press Oxford 1989) now allow the synthesis of homodisperse compounds with molecular weights approaching 5,000 Daltons. Other substitution patterns are equally effective.

The compounds also include derivatives referred to as prodrugs.

Compounds containing an amine function can also form N-oxides. A reference herein to a compound that contains an amine function also includes the N-oxide. Where a compound contains several amine functions, one or more than one nitrogen atom can be oxidized to form an N-oxide. Examples of N-oxides include N-oxides of a tertiary amine or a nitrogen atom of a nitrogen-containing heterocycle. N-Oxides can be formed by treatment of the corresponding amine with an oxidizing agent such as hydrogen peroxide or a per-acid (e. g. , aperoxycarboxylic acid) (see, Advanced Organic Chemistry, by Jerry March, 4th Edition, Wiley Interscience) .

Embodiments of various compounds and salts thereof are provided. Where a variable is not specifically recited, the variable can be any option described herein, except as otherwise noted or dictated by context.

The presently described compounds have the surprising effect of being specific for C. difficile. Thus, the presently described compounds can target the pathogenic C. difficile while leaving “good” bacteria intact. Accordingly, the compounds described herein can be used to treat or prevent a C. difficile infection because the compounds specifically target C. difficile over other bacteria.

In some embodiments, a compound, or a pharmaceutically acceptable salt thereof, of Formula I is provided:

wherein:

Z is haloalkyl, or optionally substituted C₁-C₆ alkyl；

In some embodiments, X is S. In some embodiments, X is O. In some embodiments, X is OCH₂, SCH₂, CH₂O, CH₂S. In some embodiments, X is C (＝C) , OCH (CH₂) or CH (CH₂) . In some embodiments, X is NR₅, wherein R₅ is C₁-C₆ alkyl. In some embodiments, X is a bond. In some embodiments, X is a C (CH₃) ₂.

In some embodiments of a compound, or a pharmaceutically acceptable salt thereof, of Formula I, Z is CHR₄, C (R₄) ₂, or CH₂CHR₄ wherein each R₄ is independently methyl, ethyl, phenyl, OH, NH₂, or halo. In some embodiments, Z is CH₂ or CHR₄, wherein R₄ is OH. In some embodiments, Z is CF₂, or optionally substituted C₁-C₄ alkyl with, for example, the various substitutions described. In some embodiments, wherein Z is an alkyl it is obtionally substituted with with halo, amino, hydroxyl, or mono-alkyl.

In some embodiments of a compound, or a pharmaceutically acceptable salt thereof, of Formula I, R₂ and R₃ are each independently H, halo or haloalkyl. In some embodiments, haloalkyl is CF₃.In some embodiments, R₂ is H.

In some embodiments of a compound, or a pharmaceutically acceptable salt thereof, of Formula I, R₁ and R₉ are each independently H, halo or haloalkyl. In some embodiments, R₁ is halo or haloalkyl and R₉ is H. In some embodiments, R₁ is CF₃. In some embodiments, R₉ is CF₃ or F. In some embodiments, R₁ and R₉ are each CF₃. In some emboiments, R₁ is fluoro.

In some embodiments of a compound, or a pharmaceutically acceptable salt thereof, of Formula I, R₃, R₇, and R₈ are H. In some embodiments, R₃, R₇, and R₈ are each halo. In some embodiments, R₃, R₇, and R₈ are flouro. In some embodiments, R₃ and R₇ are halo or haloalkyl and R₈ is H. In some embodiments, R₃ and R₇ are CF₃. In some embodiments, R₃ and R₇ are flouro. In some embodiments, R₃ is C₁-C₆ alkyl, halo, or haloalkyl and R₇ and R₈ are H. In some embodiments, R₃ is methyl. In some embodiments, R₃ is flouro or chloro. In some embodiments, R₃ is CF₃.

In some embodiments, the compounds described herein are a compound, or a pharmaceutically acceptable salt thereof, wherein the compound has a formula of Formulas II-VI:

In some embodiments of a compound, or a pharmaceutically acceptable salt thereof, of Formulas (II) , (III) , (IV) , (V) , or (VI) , R₂ is H.

In some embodiments of a compound, or a pharmaceutically acceptable salt thereof, of Formulas (II) , (III) , (IV) , (V) , or (VI) , R₁ is H, halo or haloalkyl. In some embodiments, R₁ is H, F, or CF₃.

In some embodiments of a compound, or a pharmaceutically acceptable salt thereof, of Formulas (II) , (III) , (IV) , (V) , or (VI) , R₉ is H, CF₃ or F.

In some embodiments of a compound, or a pharmaceutically acceptable salt thereof, of Formulas (II) , (III) , (IV) , (V) , or (VI) , Zis CH₂ or CHR₄, wherein R₄ is OH.

In some embodiments of a compound, or a pharmaceutically acceptable salt thereof, of Formulas (II) , (III) , (IV) , (V) , or (VI) , R₁ and R₉ are CF₃. In some embodiments, R₁ and R₉ are H. In some embodiments, R₁ is F and R₉ is H. In some embodiments, R₁ is H and R₉ is CF3 or F.

In some embodiments of a compound, or a pharmaceutically acceptable salt thereof, of Formulas (II) , (III) , (IV) , (V) , or (VI) , R₃, R₇, and R₈ are H. In some embodiments, R₃, R₇, and R₈ are each halo. In some embodiments, R₃, R₇, and R₈ are flouro. In some embodiments, R₃ and R₇ are halo or haloalkyl and R₈ is H. In some embodiments, R₃ and R₇ are CF₃. In some embodiments, R₃ and R₇ are flouro.

In some embodiments of a compound, or a pharmaceutically acceptable salt thereof, of Formulas (II) , (III) , (IV) , (V) , or (VI) , R₃ is C₁-C₆ alkyl, halo, or haloalkyl and R₇ and R₈ are H. In some embodiments, R₃ is methyl. In some embodiments, R₃ is flouro or chloro. In some embodiments, R₃ is CF₃.

In some embodiments, the compounds described herein are a compound, or a pharmaceutically acceptable salt thereof, wherein the compound has a formula of Formula (VII) :

wherein X, Z, R₁, R₂, R₃, and R₉ are defined as indicated for a compound of Formula (I) . In some embodiments, R₂ is H. In some embodiments, R₃ is halo, haloalkyl, H, or methyl. In some embodiments, R₁ and R₉ are each independently H, halo or haloalkyl. In some embodiments, R₁ is halo or haloalkyl and R₉ is H. In some embodiments, R₉ is CF₃ or F. In some embodiments, R₁ and R₉ are each CF₃. In some embodiments, R₁ is fluoro. In some embodiments, R₁ is CF₃.

In some embodiments, the compounds described herein are a compound, or a pharmaceutically acceptable salt thereof, wherein the compound has a formula of Formula (VIII) :

wherein X, Z, R₁, R₂, R₃, R₇and R₉ are defined as indicated for a compound of Formula (I) . In some embodiments, R₂ is H. In some embodiments, R₃ is halo, haloalkyl, H, or methyl. In some embodiments, R₃ is halo, haloalkyl, H, or methyl. In some embodiments, R₁ and R₉ are each independently H, halo or haloalkyl. In some embodiments, R₁ is halo or haloalkyl and R₉ is H. In some embodiments, R₉ is CF₃ or F. In some embodiments, R₁ and R₉ are each CF₃. In some embodiments, R₁ is fluoro. In some embodiments, R₁ is CF₃.

In some embodiments, the compound is a compound of Formula (II) , or a pharmaceutically acceptable salt thereof

as the variables are defined herein. In some embodiments, R₁ and R₉ are the same. In some emboddiments, R₁ and R₂ are different. In some embodiments, R₁ and R₉ are each independently H, CF₃ or F. In some embodiments, R₂ is H. In some embodiments, X is O. In some embodiments, R₃ is H. In some embodiments, R₇ and R₈are in the ortho or meta position. In some embodiments, R₇ and R₈ are each independently H, CF₃ or F. In some embodiments, R₇ and R₈ are the same. In some embodiments, R₇ and R₈ are different. In some embodiments, one of R₁ and R₉ is CF₃ or F and the other is H. In some embodiments, one of R₇ and R₈ is CF₃ or F and the other is H. In some embodiments, two of R₁, R₇, R₈, and R₉ are independnently CF₃ or F and the remaining two of R₁, R₇, R₈, and R₉ are H. In some embodiments, three of R₁, R₇, R₈, and R₉ are independnently CF₃ or F and the remaining one of R₁, R₇, R₈, and R₉ is H.

In some embodiments, a compound of Formula (II) , or a pharmaceutically acceptable salt thereof, is selected from the group consisting of:

The compounds listed in the foregoing and throughout the present specification can also be recited or claimed separately or in combination with any other compound described herein.

In some embodiments, or pharmaceutically acceptable salt thereof, the compound is a compound selected from the group shown in Figure 1. In some embodiments, or pharmaceutically acceptable salt thereof, the compound is a compound selected from the group shown in Figure 2. In some embodiments, or pharmaceutically acceptable salt thereof, the compound is a compound selected from the group shown in Figure 3. In some embodiments, or pharmaceutically acceptable salt thereof, the compound is a compound selected from the group shown in Figure 4. In some embodiments, or pharmaceutically acceptable salt thereof, the compound is a compound selected from the group shown in Figure 5. In some embodiments, or pharmaceutically acceptable salt thereof, the compound is a compound selected from the group shown in Figure 6. In some embodiments, or pharmaceutically acceptable salt thereof, the compound is a compound selected from the group shown in Figure 7. In some embodiments, or pharmaceutically acceptable salt thereof, the compound is a compound selected from the group shown in Figure 8.

In some embodiments, the compound is selected from the following:

Also provided herein are compounds used in the preparation of compounds of Formula I. Accordingly, in some embodiments, a compound, or a pharmaceutically acceptable salt thereof, of Formula IX is provided:

wherein

Z is haloalkyl, or optionally substituted C₁-C₆ alkyl；

In some embodiments of a compound, or a pharmaceutically acceptable salt thereof, of Formula (IX) , Zis CHR₄, C (R₄) ₂, or CH₂CHR₄ wherein each R₄ is independently H, methyl, ethyl, phenyl, OH, NH₂, or halo. In some embodiments, Z is CH₂ or CHR₄, wherein R₄ is OH. In some embodiments, Z is CF₂ or optionally substituted C₁-C₄ alkyl. In some embodiments, wherein Z is an alkyl it is obtionally substituted with with halo, amino, hydroxyl, or mono-alkyl.

In some embodiments of a compound, or a pharmaceutically acceptable salt thereof, of Formula (IX) , R₁ and R₉ are each independently H, halo or haloalkyl. In some embodiments, R₁ is halo or haloalkyl and R₉ is H. In some embodiments, R₁ is CF₃. In some embodiments, R₉ is CF₃ or F. In some embodiments, R₁ and R₉ are each CF₃. In some embodiments, R₁ is fluoro.

In some embodiments, a compound, or a pharmaceutically acceptable salt thereof, of Formula (XI) is provided:

wherein R₂ R₃, R₇, and R₈ are each independently H, optionally substituted C₁-C₆ alkyl, optionally substituted C₁-C₆ alkoxy, halo, hydroxy, cyano, or haloalkyl； and

X is a bond, C (R₅) ₂, O, NR₅, S, [C (R₅) ₂] 2, OC (R₅) ₂, SC (R₅) ₂, NR₅C (R₆) ₂, C (R₅) ₂O, C (R₅) ₂S, C (R₅) ₂NR₆, wherein each R₅ and R₆ are each independently H, optionally substituted C₁-C₆ alkyl.

In some embodiments of a compound, or a pharmaceutically acceptable salt thereof, of Formula (XI) X is S. In some embodiments, X is O. In some embodiments, X is OCH₂, SCH₂, CH₂O, CH₂S. In some embodiments, X is C (＝C) , OCH (CH₂) or CH (CH₂) . In some embodiments, X is NR₅, wherein R₅ is C₁-C₆ alkyl. In some embodiments, X is a bond. In some embodiments, X is a C (CH₃) ₂.

In some embodiments of a compound, or a pharmaceutically acceptable salt thereof, of Formula (XI) R₂ and R₃ are each independently H, halo or haloalkyl. In some embodiments, haloalkyl is CF₃. In some embodiments, R₂ is H.

In some embodiments of a compound, or a pharmaceutically acceptable salt thereof, of Formula (XI) R₃, R₇, and R₈ are H. In some embodiments, R₃, R₇, and R₈ are each halo. In some embodiments, R₃, R₇, and R₈ are flouro. In some embodiments, R₃ and R₇ are halo or haloalkyl and R₈ is H. In some embodiments, R₃ and R₇ are CF₃. In some embodiments, R₃ and R₇ are flouro. In some embodiments, R₃ is C₁-C₆ alkyl, halo, or haloalkyl and R₇ and R₈ are H. In osme embodiments, R₃ is methyl. In some embodiments, R₃ is flouro or chloro. In some embodiments, R₃ is CF₃.

As described herein, in some embodiments, the compounds described herein can be used to treat a Clostridium difficile infection. In some embodiments, the compounds described herein can be used to inhibit Clostridium difficile replication. In some embodiments, the compounds described herein can be used to inhibit Clostridium difficile growth or division. Embodiments disclosed herein provided methods of treating Clostridium difficile replication, aClostridium difficile infection, or Clostridium difficile growth. In some embodiments, the method comprises contacting Clostridium difficile with a compound, or pharmaceutically acceptable salt thereof, described herein. In some embodiments, the method comprises administering a compound, or pharmaceutically acceptable salt thereof, described herein to a subject that is infected or suspected of being infected with Clostridium difficile. In some embodiments, the compound, or a pharmaceutically acceptable salt thereof is provided prophylactically, that is to prevent an infection or to prevent an infection from taking hold.

In some embodiments, the compounds described herein can be used to specifically treat a Clostridium difficile infection. As used herein “specifically treat a Clostridium difficile infection” refers to an effective dose that will preferentially inhibit the growth or replication of Clostridium difficile over other types of bacteria. In some embodiments, the compounds are at least 10％ , 20％ , 30％ , 40％ , 50％ , 60％ , 70％ , 80％ 90％ , or more specific for Clostridium difficile as compared to other types or strains of bacteria. In some embodiments, the compound described herein are 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 fold more selective for Clostridium difficile as compared to other types or strains of bacteria. In some embodiments, the compound described herein are 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 fold more potent against a Clostridium difficile as compared to another type of bacterial infection. The ability to selectively treat a Clostridium difficile is unexpected. This surprising result enables the compounds to also be used prophylactically without the risk of affecting the normal flora present in a subject.

In some embodiments, the compound is at least twice more potent against Clostridium difficile than another bacteria. In some embodiments, the compound is at least four times as potent for Clostridium difficile than another bacteria. As used herein, “potency ” when comparing a compound directed towards Clostridium difficile as compared to another bacteria refers to the compound’ sminimum inhibitory concentration (MIC) . For example, if a compound has a MIC of 0.125 ug/ml against C. diff and a MIC of greater than 64.0ug/ml against another bacteria, such as Staphylococcus aureus, the compound is said to be at leasdt 512 times more potent against C. diff than against another bacteria. In some embodiments, the other bacteria is Staphylococcus aureus. In some embodiments, the potency of the compound is compared between C. diff ATCC 700057 and Staphylococcus aureus. In some embodiments, the potency of the compound is compared between C. diff ATCC BAA-1870 and Staphylococcus aureus. In some embodiments, the potency of the compound is compared between C. diff ATCC BAA-1382 and Staphylococcus aureus. In some embodiments, the potency of the compound is compared between C. diff ATCC 43255and Staphylococcus aureus. In some embodiments, the strain of Staphylococcus aureus is ATCC 29213. In some embodiments, the strain of Staphylococcus aureus is ATCC 43300.

Accordingly, in some embodiments, methods of treating a Clostridium difficileinfection in a subject comprising administering to the subject a compound described herein or a pharmaceutical composition described herein is provided.

In some embodiments, a method of inhibiting Clostridium difficilereplication or growth comprising contacting a Clostridium difficile bacterium with a compound described herein or a pharmaceutical composition described herein is provided.

In some embodiments, a symptom ofa Clostridium difficileinfection is treated. In some embodiments, the symptom is diarrhea.

Additionally, the subject treated with a compound or pharmaceutical composition described herein may be a subject suspected of having a Clostridium difficileinfection. In some embodiments, a method of treating a subject suspected of having a Clostridium difficileinfection is provided, wherein the method comprises determining whether the subject has a Clostridium difficileinfection and administering to a subject determined to have a Clostridium difficileinfection a compound or a pharmaceutical composition described herein.

In some embodiments, a compound or pharmaceutical composition described herein can be used to prevent recurrence of a Clostridium difficileinfection after a patient has been previously treated with a different compound or antibiotic. For example, a patient infected with Clostridium difficilecan be initially treated with fidaxomicin, vancomycin and/or metronidazole, and then be administered a compound or pharmaceutical composition described herein in order to prevent a recurrence of the Clostridium difficileinfection. In some embodiments, a compound or pharmaceutical composition described herein is administered with another antibiotic, such as, but not limited to, with fidaxomicin, vancomycin and/or metronidazole. Accordingly, the present embodiments provide combination therapies that include at least one compound described herein.

The compounds described herein can be administered in any conventional manner by any route where they are active. Administration can be systemic, rectal, topical, or oral. For example, administration can be, but is not limited to, parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, transdermal, oral, buccal, sublingual, or ocular routes, or intravaginally, by inhalation, by depot injections, or by implants. In some embodiments, the mode of administration is one of oral, rectal or intravenous. The mode of administration can depend on the conditions or disease to be targeted or treated. The selection of the specific route of administration can be selected or adjusted by the clinician according to methods known to the clinician to obtain the desired clinical response.

In some embodiments, it may be desirable to administer one or more compounds, or a pharmaceutically acceptable salt thereof, locally to an area in need of treatment. This may be achieved, for example, and not by way of limitation, by local infusion during surgery, topical application, e. g. , in conjunction with a wound dressing after surgery, by injection, by means of a catheter, by means of a suppository, or by means of an implant, wherein the implant is of a porous, non-porous, or gelatinous material, including membranes, such as sialastic membranes, or fibers.

The compounds described herein can be administered either alone or in combination (concurrently or serially) with other pharmaceuticals. For example, the compounds can be administered in combination with other antibiotics or anti-diarrheal pharmaceuticals. Examples of other pharmaceuticals or medicaments are known to one of skill in the art and include, but are not limited to those described herein.

The means and methods for administration are known in the art and an artisan can refer to various pharmacologic references for guidance (see, for example, Modern Pharmaceutics, Banker & Rhodes, Marcel Dekker, Inc. (1979) ； and Goodman & Gilman’ sThe Pharmaceutical Basis of Therapeutics, 6th Edition, MacMillan Publishing Co. , New York (1980) ) .

The amount of compound to be administered is that amount which is therapeutically effective. The dosage to be administered will depend on the characteristics of the subject being treated, e. g. , the particular animal treated, age, weight, health, types of concurrent treatment, if any, and frequency of treatments, and can be easily determined by one of skill in the art (e. g. , by the clinician) . The standard dosing for protamine can be used and adjusted (i. e. , increased or decreased) depending upon the factors described above. The selection of the specific dose regimen can be selected or adjusted or titrated by the clinician according to methods known to the clinician to obtain the desired clinical response.

The amount of a compound described herein that will be effective in the treatment and/or prevention of a particular disease, condition, or disorder will depend on the nature and extent of the disease, condition, or disorder, and can be determined by standard clinical techniques. In addition, in vitro or in vivo assays may optionally be employed to help identify optimal dosage ranges. The precise dose to be employed in the compositions will also depend on the route of administration, and the seriousness of the disorder, and should be decided according to the judgment of the practitioner and each patient’ scircumstances. However, a suitable dosage range for oral administration is, generally, from about 0.001 milligram to about 200 milligrams per kilogram body weight, from about 0.01 milligram to about 100 milligrams per kilogram body weight, from about 0.01 milligram to about 70 milligrams per kilogram body weight, from about 0.1 milligram to about 50 milligrams per kilogram body weight, from 0.5 milligram to about 20 milligrams per kilogram body weight, or from about 1 milligram to about 10 milligrams per kilogram body weight. In some embodiments, the oral dose is about 5 milligrams per kilogram body weight.

In some embodiments, suitable dosage ranges for intravenous (i. v. ) administration are from about 0.01 mg to about 500 mg per kg body weight, from about 0.1mg to about 100 mg per kg body weight, from about 1 mg to about 50 mg per kg body weight, or from about 10 mg to about 35 mg per kg body weight. Suitable dosage ranges for other modes of administration can be calculated based on the forgoing dosages as known by those skilled in the art. For example, recommended dosages for rectal, intranasal, transmucosal, intradermal, intramuscular, intraperitoneal, subcutaneous, epidural, sublingual, intracerebral, intravaginal, transdermal administration or administration by inhalation are in the range of from about 0.001 mg to about 200 mg per kg of body weight, from about 0.01 mg to about 100 mg per kg of body weight, from about 0.1 mg to about 50 mg per kg of body weight, or from about 1 mg to about 20 mg per kg of body weight. Effective doses may be extrapolated from dose-response curves derived from in vitro or animal model test systems. Such animal models and systems are well known in the art.

The compounds described herein can be formulated for parenteral administration by injection, such as by bolus injection or continuous infusion. The compounds can be administered by continuous infusion subcutaneously over a period of about 15 minutes to about 24 hours. Formulations for injection can be presented in unit dosage form, such as in ampoules or in multi-dose containers, with an optionally added preservative. The compositions can take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and can contain formulatory agents such as suspending, stabilizing and/or dispersing agents. In some embodiments, the injectable is in the form of short-acting, depot, or implant and pellet forms injected subcutaneously or intramuscularly. In some embodiments, the parenteral dosage form is the form of a solution, suspension, emulsion, or dry powder.

For oral administration, the compounds described herein can be formulated by combining the compounds with pharmaceutically acceptable carriers well known in the art. Such carriers enable the compounds to be formulated as tablets, pills, dragees, capsules, emulsions, liquids, gels, syrups, caches, pellets, powders, granules, slurries, lozenges, aqueous or oily suspensions, and the like, for oral ingestion by a patient to be treated. Pharmaceutical preparations for oral use can be obtained by, for example, adding a solid excipient, optionally grinding the resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores. Suitable excipients include, but are not limited to, fillers such as sugars, including, but not limited to, lactose, sucrose, mannitol, and sorbitol； cellulose preparations such as, but not limited to, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, and polyvinylpyrrolidone (PVP) . If desired, disintegrating agents can be added, such as, but not limited to, the cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.

Orally administered compositions can contain one or more optional agents, for example, sweetening agents such as fructose, aspartame or saccharin； flavoring agents such as peppermint, oil of wintergreen, or cherry； coloring agents； and preserving agents, to provide a pharmaceutically palatable preparation. Moreover, where in tablet or pill form, the compositions may be coated to delay disintegration and absorption in the gastrointestinal tract thereby providing a sustained action over an extended period of time. Selectively permeable membranes surrounding an osmotically active driving compound are also suitable for orally administered compounds. Oral compositions can include standard vehicles such as mannitol, lactose, starch, magnesium stearate, sodium saccharine, cellulose, magnesium carbonate, etc. Such vehicles are suitably of pharmaceutical grade.

Dragee cores can be provided with suitable coatings. For this purpose, concentrated sugar solutions can be used, which can optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyestuffs or pigments can be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses.

Pharmaceutical preparations which can be used orally include, but are not limited to, push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. The push-fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active compounds can be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In addition, stabilizers can be added.

For buccal administration, the compositions can take the form of, such as, tablets or lozenges formulated in a conventional manner.

For administration by inhalation, the compounds described herein can be delivered in the form of an aerosol spray presentation from pressurized packs or a nebulizer, with the use of a suitable propellant, such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol the dosage unit can be determined by providing a valve to deliver a metered amount. Capsules and cartridges of, such as gelatin for use in an inhaler or insufflator can be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch.

The compounds described herein can also be formulated in rectal compositions such as suppositories or retention enemas, such as containing conventional suppository bases such as cocoa butter or other glycerides. The compounds described herein can also be formulated in vaginal compositions such as vaginal creams, suppositories, pessaries, vaginal rings, and intrauterine devices.

In transdermal administration, the compounds can be applied to a plaster, or can be applied by transdermal, therapeutic systems that are consequently supplied to the organism. In some embodiments, the compounds are present in creams, solutions, powders, fluid emulsions, fluid suspensions, semi-solids, ointments, pastes, gels, jellies, and foams, or in patches containing any of the same.

The compounds described herein can also be formulated as a depot preparation. Such long acting formulations can be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection. Depot injections can be administered at about 1 to about 6 months or longer intervals. Thus, for example, the compounds can be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.

In some embodiments, the compounds can be delivered in a controlled release system. In one embodiment, a pump may be used (see Langer, supra； Sefton, CRC Crit. Ref. Biomed. Eng. , 1987, 14, 201； Buchwald et al. , Surgery, 1980, 88, 507 Saudek et al. , N. Engl. J. Med. , 1989, 321, 574) . In some embodiments, polymeric materials can be used (see Medical Applications of Controlled Release, Langer and Wise (eds. ) , CRC Pres. , Boca Raton, Fla. (1974) ； Controlled Drug Bioavailability, Drug Product Design and Performance, Smolen and Ball (eds. ) , Wiley, New York (1984) ； Ranger et al. , J. Macromol. Sci. Rev. Macromol. Chem. , 1983, 23, 61； see, also Levy et al. , Science, 1985, 228, 190； During et al. , Ann. Neurol. , 1989, 25, 351； Howard et al. , J. Neurosurg. , 1989, 71, 105) . In yet another embodiment, a controlled-release system can be placed in proximity of the target of the compounds described herein, such as the liver, thus requiring only a fraction of the systemic dose (see, e. g. , Goodson, in Medical Applications of Controlled Release, supra, vol. 2, pp. 115-138 (1984) ) . Other controlled-release systems discussed in the review by Langer, Science, 1990, 249, 1527-1533) may be used.

It is also known in the art that the compounds can be contained in such formulations with pharmaceutically acceptable diluents, fillers, disintegrants, binders, lubricants, surfactants, hydrophobic vehicles, water soluble vehicles, emulsifiers, buffers, humectants, moisturizers, solubilizers, preservatives and the like. The pharmaceutical compositions can also comprise suitable solid or gel phase carriers or excipients. Examples of such carriers or excipients include, but are not limited to, calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin, and polymers such as polyethylene glycols. In some embodiments, the compounds described herein can be used with agents including, but not limited to, topical analgesics (e. g. , lidocaine) , barrier devices (e. g. , GelClair) , or rinses (e. g. , Caphosol) .

In some embodiments, the compounds described herein can be delivered in a vesicle, in particular a liposome (see, Langer, Science, 1990, 249, 1527-1533； Treat et al. , in Liposomes in the Therapy of Infectious Disease and Cancer, Lopez-Berestein and Fidler (eds. ) , Liss, New York, pp. 353-365 (1989) ； Lopez-Berestein, ibid. , pp. 317-327； see generally ibid. ) .

Suitable compositions include, but are not limited to, oral non-absorbed compositions. Suitable compositions also include, but are not limited to saline, water, cyclodextrin solutions, and buffered solutions of pH 3-9.

The compounds described herein, or pharmaceutically acceptable salts thereof, can be formulated with numerous excipients including, but not limited to, purified water, propylene glycol, PEG 400, glycerin, DMA, ethanol, benzyl alcohol, citric acid/sodium citrate (pH3) , citric acid/sodium citrate (pH5) , tris (hydroxymethyl) amino methane HCl (pH7.0) , 0.9％ saline, and 1.2％ saline, and any combination thereof. In some embodiments, excipient is chosen from propylene glycol, purified water, and glycerin.

In some embodiments, the formulation can be lyophilized to a solid and reconstituted with, for example, water prior to use.

When administered to a mammal (e. g. , to an animal for veterinary use or to a human for clinical use) the compounds can be administered in isolated form.

When administered to a human, the compounds can be sterile. Water can be used as a suitable carrier when the compounds described herein are administered intravenously. Saline solutions and aqueous dextrose and glycerol solutions can also be employed as liquid carriers, particularly for injectable solutions. Suitable pharmaceutical carriers also include excipients such as starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol and the like. The present compositions, if desired, can also contain minor amounts of wetting or emulsifying agents, or pH buffering agents.

The compositions described herein can take the form of a solution, suspension, emulsion, tablet, pill, pellet, capsule, capsule containing a liquid, powder, sustained-release formulation, suppository, aerosol, spray, or any other form suitable for use. Examples of suitable pharmaceutical carriers are described in Remington’ sPharmaceutical Sciences, A. R. Gennaro (Editor) Mack Publishing Co.

In some embodiments, the compounds are formulated in accordance with routine procedures as a pharmaceutical composition adapted for administration to humans. Typically, compounds are solutions in sterile isotonic aqueous buffer. Where necessary, the compositions can also include a solubilizing agent. Compositions for intravenous administration may optionally include a local anesthetic such as lidocaine to ease pain at the site of the injection. Generally, the ingredients are supplied either separately or mixed together in unit dosage form, for example, as a dry lyophilized powder or water free concentrate in a hermetically sealed container such as an ampoule or sachette indicating the quantity of active agent. Where the compound is to be administered by infusion, it can be dispensed, for example, with an infusion bottle containing sterile pharmaceutical grade water or saline. Where the compound is administered by injection, an ampoule of sterile water for injection or saline can be provided so that the ingredients may be mixed prior to administration.

The pharmaceutical compositions can be in unit dosage form. In such form, the composition can be divided into unit doses containing appropriate quantities of the active component. The unit dosage form can be a packaged preparation, the package containing discrete quantities of the preparations, for example, packeted tablets, capsules, and powders in vials or ampules. The unit dosage form can also be a capsule, cachet, or tablet itself, or it can be the appropriate number of any of these packaged forms.

In some embodiments, a composition of the present invention is in the form of a liquid wherein the active agent (i. e. , one of the facially amphiphilic polymers or oligomers disclosed herein) is present in solution, in suspension, as an emulsion, or as a solution/suspension. In some embodiments, the liquid composition is in the form of a gel. In other embodiments, the liquid composition is aqueous. In other embodiments, the composition is in the form of an ointment.

In some embodiments, the composition is in the form of a solid article. For example, in some embodiments, the ophthalmic composition is a solid article that can be inserted in a suitable location in the eye, such as between the eye and eyelid or in the conjunctival sac, where it releases the active agent as described, for example, U. S. Pat. No. 3, 863, 633； U. S. Pat. No. 3, 867, 519； U. S. Pat. No. 3, 868, 445； U. S. Pat. No. 3, 960, 150； U. S. Pat. No. 3, 963, 025； U. S. Pat. No. 4, 186, 184； U. S. Pat. No. 4, 303, 637； U. S. Pat. No. 5, 443, 505； and U. S. Pat. No. 5, 869, 079. Release from such an article is usually to the cornea, either via the lacrimal fluid that bathes the surface of the cornea, or directly to the cornea itself, with which the solid article is generally in intimate contact. Solid articles suitable for implantation in the eye in such fashion are generally composed primarily of polymers and can be bioerodible or non-bioerodible. Bioerodible polymers that can be used in the preparation of ocular implants carrying one or more of the anti-microbial, facially amphiphilic polymer or oligomer active agents in accordance with the present invention include, but are not limited to, aliphatic polyesters such as polymers and copolymers of poly (glycolide) , poly (lactide) , poly (epsilon-caprolactone) , poly- (hydroxybutyrate) and poly (hydroxyvalerate) , polyamino acids, polyorthoesters, polyanhydrides, aliphatic polycarbonates and polyether lactones. Suitable non-bioerodible polymers include silicone elastomers.

The compositions described herein can contain preservatives. Suitable preservatives include, but are not limited to, mercury-containing substances such as phenylmercuric salts (e. g. , phenylmercuric acetate, borate and nitrate) and thimerosal； stabilized chlorine dioxide； quaternary ammonium compounds such as benzalkonium chloride, cetyltrimethylammonium bromide and cetylpyridinium chloride； imidazolidinyl urea； parabens such as methylparaben, ethylparaben, propylparaben and butylparaben, and salts thereof； phenoxyethanol； chlorophenoxyethanol； phenoxypropanol； chlorobutanol； chlorocresol； phenylethyl alcohol； disodium EDTA； and sorbic acid and salts thereof.

Optionally one or more stabilizers can be included in the compositions to enhance chemical stability where required. Suitable stabilizers include, but are not limited to, chelating agents or complexing agents, such as, for example, the calcium complexing agent ethylene diamine tetraacetic acid (EDTA) . For example, an appropriate amount of EDTA or a salt thereof, e. g. , the disodium salt, can be included in the composition to complex excess calcium ions and prevent gel formation during storage. EDTA or a salt thereof can suitably be included in an amount of about 0.01％ to about 0.5％ . In those embodiments containing a preservative other than EDTA, the EDTA or a salt thereof, more particularly disodium EDTA, can be present in an amount of about 0.025％ to about 0.1％ by weight.

One or more antioxidants can also be included in the compositions. Suitable antioxidants include, but are not limited to, ascorbic acid, sodium metabisulfite, sodium bisulfite, acetylcysteine, polyquaternium-1, benzalkonium chloride, thimerosal, chlorobutanol, methyl paraben, propyl paraben, phenylethyl alcohol, edetate disodium, sorbic acid, or other agents know to those of skill in the art. Such preservatives are typically employed at a level of from about 0.001％ to about 1.0％ by weight.

One or more acceptable pH adjusting agents and/or buffering agents can be included in the compositions, including acids such as acetic, boric, citric, lactic, phosphoric and hydrochloric acids； bases such as sodium hydroxide, sodium phosphate, sodium borate, sodium citrate, sodium acetate, sodium lactate and tris-hydroxymethylaminomethane； and buffers such as citrate/dextrose, sodium bicarbonate and ammonium chloride. Such acids, bases and buffers are included in an amount required to maintain pH of the composition in an acceptable range.

One or more acceptable salts can be included in the compositions of the invention in an amount required to bring osmolality of the composition into an acceptable range. Such salts include, but are not limited to, those having sodium, potassium or ammonium cations and chloride, citrate, ascorbate, borate, phosphate, bicarbonate, sulfate, thiosulfate or bisulfite anions. In some embodiments, salts include sodium chloride, potassium chloride, sodium thiosulfate, sodium bisulfite and ammonium sulfate. In some embodiments, the salt is sodium chloride.

Optionally one or more acceptable surfactants, preferably nonionic surfactants, or co-solvents can be included in the compositions to enhance solubility of the components of the compositions or to impart physical stability, or for other purposes. Suitable nonionic surfactants include, but are not limited to, polyoxyethylene fatty acid glycerides and vegetable oils, e. g. , polyoxyethylene (60) hydrogenated castor oil； and polyoxyethylene alkylethers and alkylphenyl ethers, e. g. , octoxynol 10, octoxynol 40； polysorbate 20, 60 and 80； polyoxyethylene/polyoxypropylene surfactants (e. g. , F-68, F84 and P-103) ； cyclodextrin； or other agents known to those of skill in the art. Typically, such co-solvents or surfactants are employed in the compositions at a level of from about 0.01％ to about 2％ by weight.

The present invention also provides pharmaceutical packs or kits comprising one or more containers filled with one or more compounds described herein. Optionally associated with such container (s) can be a notice in the form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceuticals or biological products, which notice reflects approval by the agency of manufacture, use or sale for human administration for treating a condition, disease, or disorder described herein. In some embodiments, the kit contains more than one compound described herein. In some embodiments, the kit comprises a compound described herein in a single injectable dosage form, such as a single dose within an injectable device such as a syringe with a needle.

The present invention also provides methods of treating Clostridium difficilein a subject comprising administering to the subject one or more compounds described herein or a salt thereof, or a pharmaceutical composition of the same. In some embodiments, the subject is a subject in need of such treatment. In some embodiments, the compound is administered as a prodrug.

The present invention also provides one or more compounds described above, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising one or more compounds described above, for the treatment of Clostridium difficilein a subject. In some embodiments, the compounds are for the treatment of Clostridium difficilein a mammal in need thereof.

The present invention also provides one or more compounds described above, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising one or more compounds described above, for use in the manufacture of a medicament for the treatment of Clostridium difficile.

Any other known medicament, compound, or composition use for the treatment of Clostridium difficilecan be used in co-therapy, co-administration or co-formulation with a composition or compound as described herein.

Frequency of administration is typically such that the dosing interval, for example, the period of time between one dose and the next, during waking hours is from about 2 to about 12 hours, from about 3 to about 8 hours, or from about 4 to about 6 hours. It will be understood by those of skill in the art that an appropriate dosing interval is dependent to some degree on the length of time for which the selected composition is capable of maintaining a concentration of the compound (s) in the subject and/or in the target tissue (e. g. , above the EC50 (the minimum concentration of the compound which reduces bacterial growth (or density) by 50％ ) . In some embodiments, the concentration remains above the EC50 for at least 100％ of the dosing interval. Where this is not achievable it is desired that the concentration should remain above the EC50 for at least about 60％ of the dosing interval, or should remain above the EC50 for at least about 40％ of the dosing interval.

Embodiments of making the compounds disclosed herein are also provided. In some embodiments, the compounds are made according to the following scheme and in the examples provided herein. For example, general methods of synthesizing compounds of Formulas I are described in the scheme and general procedures set forth below. A synthetic protocol for the synthesis of macrocyclic compounds is described in Marcaurelle L. A. et al. ,

J. Am. Chem. Soc. 132, 16962-16976, 2010, which is hereby incorporated by reference in its entirety.

This scheme can be modified to produce the compounds described herein based upon the present examples and the knowledge of the skilled artisan without undue experimentation. For example, in some embodiments, the reaction of S8 to S9 in the scheme above could be modified and represented by the generic scheme of:

wherein

R₁ and R₉ are each independently H, optionally substituted C₁-C₆ alkyl, optionally substituted C₁-C₆ alkoxy, halo, haloalkyl, hydroxy, or cyano； and Z is optionally substituted C₁-C₆ alkyl. In some embodiments, wherein Z is an alkyl it is obtionally substituted with with halo, amino, hydroxyl, or mono-alkyl.

In some embodiments, a compound of Formula I can be prepared according to the scheme of:

wherein

Z is optionally substituted C₁-C₆ alkyl； and

X is a bond, C (R₅) ₂, O, NR₅, S, [C (R₅) ₂] ₂, OC (R₅) ₂, SC (R₅) ₂, NR₅C (R₆) ₂, C (R₅) ₂O, C (R₅) ₂S, C (R₅) ₂NR₆, wherein each R₅ and R₆ are each independently H, optionally substituted C₁-C₆ alkyl. In some embodiments, wherein Z is an alkyl it is obtionally substituted with with halo, amino, hydroxyl, or mono-alkyl.

The disclosures of each and every patent, patent application, publication, and accession number cited herein are hereby incorporated herein by reference in their entirety.

In order that the embodiments disclosed herein may be more efficiently understood, examples are provided below. It should be understood that these examples are for illustrative purposes only and are not to be construed as limiting in any manner.

Examples

Example 1: Methods of Making Compounds. All oxygen and/or moisture sensitive reactions were carried out under N₂ atmosphere in glassware that had flame-dried under vacuum (0.5 mmHg) and purged with N₂ prior to use. All reagents and solvents were purchased from commercial vendors and used as received, or synthesized according to the footnoted references. NMR spectra were recorded on a Bruker 400 (400 MHz ¹H, 75 MHz ¹³C) or Varian (400 MHz ¹H, 75 MHz ¹³C) spectrometer. Proton and carbon chemical shifts are reported in ppm (δ) referenced to the NMR solvent. Data are reported as follows: chemical shifts, multiplicity (br＝broad, s＝singlet, t＝triplet, q＝quartet, m＝multiplet； coupling constant (s) in Hz) . Unless otherwise indicated NMR data were collected at 25 ℃. Flash chromatography was performed using 100-200 mesh Silica Gel. Liquid Chromotography /Mass Spectrometry (LCMS) was performed on Agilent1200HPLC and 6110MS. Analytical thin layer chromatography (TLC) was performed on 0.2 mm silica gel plates. Visualization was accomplished with UV light and aqueous potassium permanganate (KMnO₄) stain followed by heating.

(2S, 3S) -4- ( (tert-butoxycarbonyl) (methyl) amino) -3-hydroxy-2-methylbutanoic acid, S2. A jacketed 5-L, 3-neck round bottom flask was fitted with a magnetic stirrer and internal temperature probe. Under a positive flow of N₂, the reactor was charged with (4S) -4-benzyl-3-propanoyl-oxazolidin-2-one (78.00 g, 334.39 mmol) followed by CH₂Cl₂ (835 mL) . The colorless solution was cooled to an internal temperature of -10 ℃ and sparged with N₂ for 30 min. Dibutylboron triflate (402 mL, 401.26 mmol, 1 M in toluene) was added by dropwise addition, maintaining an internal temperature below -0.5 ℃. To the resulting yellow-green colored solution was added TEA (50.75 g, 501.58 mmol) dropwise while maintaining the internal temperature below -0.5 ℃ and the resulting bright yellow enolate solution was stirred at -5 ℃ for 90 min. Tert-butyl N-methyl-N- (2-oxoethyl) carbamate (75.29 g, 434.70 mmol) was added dropwise, keeping the internal temperature below -0.5 ℃. Upon complete addition, the light yellow solution was stirred at -5 ℃ for 90 min. The solution was cooled to -10 ℃ and quenched by the slow addition of MeOH (420 mL) followed by a solution of THF: H₂O₂ (1.2L, 2: 1) that changed the yellow homogenous solution to a biphasic milky-white suspension. The initial rapid exotherm induced by the peroxide addition can be minimized by slow addition until no further exotherm is observed. The reaction was stirred at -10 ℃ for 90 min at which time both layers became homogeneous. LiOH (70.2 g, 1.67 mol) was added to the biphasic mixture and the mixture was allowed to warm to r. t. and stirred for 12 h.

Excess peroxides were reduced by the careful addition of solid Na₂SO₃, organic solvents were removed in vacuo, and the slurry was dissolved in CH₂Cl₂. The organic layer was washed with aq. NaOH (1.0 M, 1 L) and brine (100 mL) . The aqueous layer was back extracted with CH₂Cl₂ (2x100 mL) to remove the oxazolidinone. The combined aqueous layers were cooled to 0 ℃, agitated with a magnetic stir bar and then carefully acidified with concentrated HCl (12 M) until pH＝4 as indicated by pH strip. The aqueous layer was extracted with ethyl acetate (3x600 mL) . The combined organics were dried over MgSO₄ and concentrated to provide (2S, 3S) -4- [tert-butoxycarbonyl (methyl) amino] -3-hydroxy-2-methyl-butanoic acid S2 (80.00 g, 323.51 mmol, 97％ yield) as a yellow oil. TLC: R_f＝0.3 (10％ MeOH in DCM) . ¹H NMR (400 MHz, CDCl₃) δ3.70-3.66 (m, 1H) , 2.64-2.58 (m, 1H) , 3.22-3.18 (m, 1H) , 2.93 (s, 3H) , 2.64-2.58 (m, 1H) , 1, 47 (s, 9H) , 1.27 (d, J＝10 Hz, 3H) . MS (ESI) [M+1] ⁺＝270.1312.

(2S, 3S) -4- ( (tert-butoxycarbonyl) (methyl) amino) -3- ( (tert-butyldimethylsilyl) oxy) -2-methylbutanoic acid, S3. A oven dried, 10-L 3-neck round bottom flask equipped with magnetic stirrer and internal temperature probe was charged with (2S, 3S) -4- [tert-butoxycarbonyl (methyl) amino] -3-hydroxy-2-methyl-butanoic acid (117.00 g, 473.13 mmol) , CH₂Cl₂ (4 L) and 2, 6-lutidine (270.13 g, 2.37 mol) under a positive flow of N₂. The reaction mixture was cooled to -78 ℃ and tert-butyldimethylsilyl trifluoromethanesulfonate (TBSOTf) (325.17 g, 1.23 mol) was added dropwise over 20 min. The reaction mixture was stirred at -78 ℃ for 1 h, quenched with aqueous sat. NaHCO₃, the layers were separated, and the aqueous layer was extracted with CH₂Cl₂. The combined organic extracts were washed with sat. NH₄Cl and brine, dried (Na₂SO₄) , filtered and the solvent evaporated. The residue was dissolved in MeOH (800 mL) and THF (800 mL) and cooled to 0 ℃. An aqueous solution of K₂CO₃ (98.09 g, 709.70 mmol, 210 mL) was added and the mixture was stirred at 0 ℃ for 1 h. The reaction mixture was concentrated to remove volatiles and the remaining aqueous layer was extracted with EtOAc. The organic layer was washed with 1 N HCl, then dried over Na₂SO₄, filtered and concentrated in vacuo to yield the crude product as a clear oil which was coevaporated with toluene to remove excess TBSOH and dried to provide (2S, 3S) -4- [tert- butoxycarbonyl (methyl) amino] -3- [tert-butyl (dimethyl) silyl] oxy-2-methyl-butanoic acid S3 (132.00 g, 365.09 mmol, 77％ yield) as clear oil.

tert-butyl-N- [(2S, 3S) -2- [tert-butyl (dimethyl) silyl] oxy-4- [ [ (1S) -2- [ (4-methoxyphenyl) methoxy] -1-methyl-ethyl] amino] -3-methyl-4-oxo-butyl] -N-methyl-carbamate, S4. An oven-dried, 3-L, 3-neck round bottom flask was equipped with a magnetic stirrer, addition funnel and a temperature probe. Under a positive flow of N₂, the vessel was charged with (2S, 3S) -4- [tert-butoxycarbonyl (methyl) amino] -3- [tert-butyl (dimethyl) silyl] oxy-2-methyl-butanoic acid (110.00 g, 304.25 mmol, 1.00 equiv) dissolved in CH₂Cl₂ (1.5L) , followed by PyBOP (158.33 g, 304.25 mmol, 1.00 equiv) , and diisopropyl ethylamine (DIPEA) (117.96 g, 912.74 mmol, 3.0equiv) . The resulting mixture was cooled in an ice bath before (2S) -1- [ (4-methoxyphenyl) methoxy] propan-2-amine (71.29 g, 365.10 mmol, 1.20 equiv) was added as a solution in CH₂Cl₂ (0.5L) by addition funnel. The rate of addition was controlled so as to maintain an internal temperature between 3-5 ℃. When addition was complete, the mixture was warmed to ambient temperature and allowed to stir for 15 h. The reaction was quenched with water, and extracted with CH₂Cl₂. The combined organic extracts were dried over MgSO₄, filtered and concentrated. The yellow oil was taken up in Et₂O and the phosphoramide byproducts were removed via filtration. The solvent was removed in vacuo and the crude product was isolated. Flash chromatography on silica gel (Petroleum ether/EtOAc＝4: 1 to 7: 3) gave tert-butyl N- [ (2S, 3S) -2- [tert-butyl (dimethyl) silyl] oxy-4- [ [ (1S) -2- [ (4-methoxyphenyl) methoxy] -1-methyl-ethyl] amino] -3-methyl-4-oxo-butyl] -N-methyl-carbamate S4 (73.00 g, 135.49 mmol, 45％ yield) as colorless oil. ¹H NMR (400 MHz, CDCl₃) δ 7.17 (d, J＝8.0 Hz, 2H) , 6.80 (d, J＝8.0 Hz, 2H) , 6.57 (br s, 1H, NH) , 4.46 (d, J＝12.0, 1H) , 4.42 (d, J＝12.0, 1H) , 4.21-4.15 (m, 1H) , 4.02-3.97 (m, 1H) , 3.75 (s, 3H) , 3.47-3.34 (m, 3H) , 2.84-2.82 (m, 1H) , 2.75 (s, 3H) , 2.38-2.42 (m, 1H) , 1.41 (s, 9H) , 1.13-1.06 (m, 6H) , 0.86 (s, 9H) , 0.04 (s, 3H) , 0.01 (s, 3H) .

tert-butyl-N- [ (2S， 3R) -2- [tert-butyl (dimethyl) silyl] oxy-4- [ [ (1S) -2- [ (4-methoxyphenyl) methoxy] -1-methyl-ethyl] amino] -3-methyl-butyl] -N-methyl-carbamate, S5. An oven-dried, 2-L, 1-necked round bottom flask was equipped with a magnetic stirrer. Under a positive flow of N₂, the flask was charged with tert-butyl N- [ (2S, 3S) -2- [tert-butyl (dimethyl) silyl] oxy-4- [ [ (1S) -2- [ (4-methoxyphenyl) methoxy] -1-methyl-ethyl] amino] -3-methyl-4-oxo-butyl] -N-methyl-carbamate (72.00 g, 133.63 mmol, 1.00 Eq) and anhydrous THF (1.5L) . Borane-tetrahydrofuran (1 M, 700.00 mL, 5.24 Eq) ) was added dropwise via syringe. Afterwards the reaction mixture was heated at 65 ℃ for 5 h. After cooling to ambient temperature, excess hydride was quenched by the careful addition of MeOH. The mixture was concentrated under reduced pressure to afford a colorless oil, which was then co-evaporated with MeOH three times to remove excess B (OMe) ₃. The oil was then re-dissolved in MeOH and 10％ aqueous potassium sodium tartrate (113.14 g, 400.89 mmol, 3.00 Eq) . The resulting slurry was heated at reflux for 12 h. The volatiles were removed under reduced pressure and aqueous layer was extracted three times with ethyl acetate. The combined organic layers were washed once with brine, dried over magnesium sulfate, filtered and concentrated to providetert-butyl N- [ (2S, 3R) -2- [tert-butyl (dimethyl) silyl] oxy-4-[ [ (1S) -2- [ (4-methoxyphenyl) methoxy] -1-methyl-ethyl] amino] -3-methyl-butyl] -N-methyl-carbamate S5 (56.50 g, 107.66 mmol, 81％ yield) as colorless oil.

tert-butyl N- [ (2S, 3R) -2- [tert-butyl (dimethyl) silyl] oxy-4- [ (2-fluoro-3-nitro-benzoyl) - [ (1S) -2- [ (4-methoxyphenyl) methoxy] -1-methyl-ethyl] amino] -3-methyl-butyl] -N-methyl-carbamate, S6. Triethylamine (25.07 g, 247.71 mmol, 5.00 Eq) was added to a solution of tert-butyl N- [ (2S, 3R) -2- [tert-butyl (dimethyl) silyl] oxy-4- [ [ (1S) -2- [ (4-methoxyphenyl) methoxy] -1-methyl-ethyl] amino] -3-methyl-butyl] -N-methyl-carbamate (26.00 g, 49.54 mmol, 1.00 Eq) and 2-fluoro-3-nitro-benzoyl chloride (25.21 g, 123.86 mmol, 2.50 Eq) in CH₂Cl₂ (60 mL) at 0 ℃ under dry nitrogen atmosphere. The reaction was warmed to room temperature and stirred until complete consumption of starting amine was observed (1h) . The reaction was quenched with water and the resulting mixture was extracted with CH₂Cl₂. The combined organic extracts were dried over MgSO₄, filtered and concentrated. Flash chromatography on silica gel (gradient: 10％ to 30％ EtOAc in petroleum ether) provided tert-butyl N- [ (2S, 3R) -2- [tert-butyl (dimethyl) silyl] oxy-4- [ (2-fluoro-3-nitro-benzoyl) - [ (1S) -2- [ (4-methoxyphenyl) methoxy] -1-methyl-ethyl] amino] -3-methyl-butyl] -N-methyl-carbamate S6 (6.50 g, 9.39 mmol, 19％ yield) as colourless oil.

tert-butyl N- [ [ (2S, 3R) -5- [ (1S) -2- [ (4-methoxyphenyl) methoxy] -1-methyl-ethyl] -3-methyl-10-nitro-6-oxo-3, 4-dihydro-2H-1, 5-benzoxazocin-2-yl] methyl] -N-methyl-carbamate, S7. Cesium fluoride (7.13 g, 46.95 mmol, 5.00 Eq) was added to a solution of tert-butyl N- [ (2S, 3R) -2- [tert-butyl (dimethyl) silyl] oxy-4- [ (2-fluoro-3-nitro-benzoyl) - [ (1S) -2- [ (4-methoxyphenyl) methoxy] -1-methyl-ethyl] amino] -3-methyl-butyl] -N-methyl-carbamate (6.50 g, 9.39 mmol, 1.00 Eq) in DMF (200 mL) at room temperature under N₂. The reaction was heated to 100 ℃ and stirred until complete consumption of starting material was observed (2h) . The reaction was cooled and concentrated. The resulting oil was taken up in EtOAc, washed with water and brine, dried over sodium sulfate, filtered and concentrated again to give tert-butyl N- [ [ (2S, 3R) -5- [ (1S) -2- [ (4-methoxyphenyl) methoxy] -1-methyl-ethyl] -3-methyl-10-nitro-6-oxo-3, 4-dihydro-2H-1, 5-benzoxazocin-2-yl] methyl] -N-methyl-carbamate S7 (5.20 g, 9.33 mmol, 99％ yield) was obtained as a brown solid. The material was used without further purification.

tert-butyl N- [ [ (2S, 3R) -10-amino-5- [ (1S) -2- [ (4-methoxyphenyl) methoxy] -1-methyl-ethyl] -3-methyl-6-oxo-3, 4-dihydro-2H-1, 5-benzoxazocin-2-yl] methyl] -N-methyl-carbamate, S8. tert-butyl N- [ [ (2S, 3R) -5- [ (1S) -2- [ (4-methoxyphenyl) methoxy] -1-methyl-ethyl] -3-methyl-10-nitro-6-oxo-3, 4-dihydro-2H-1, 5-benzoxazocin-2-yl] methyl] -N-methyl-carbamate (5.20 g, 9.33 mmol, 1.00 Eq) and palladium (10％ on activated carbon, 3.0 g) were stirred in EtOH (90 mL) at 35 ℃ under a hydrogen atmosphere. The reaction was monitored by LC-MS for complete consumption of starting material (0.5h) . After the reaction was complete, the mixture was cooled, filtered through Celite and concentrated to give tert-butyl N- [ [ (2S, 3R) -10-amino-5- [ (1S) -2- [ (4-methoxyphenyl) methoxy] -1-methyl-ethyl] -3-methyl-6-oxo-3, 4-dihydro-2H-1, 5-benzoxazocin-2-yl] methyl] -N-methyl-carbamate S8 (4.50 g, 8.53 mmol, 91％ yield) as a white solid.

tert-butyl N- [ [ (2S, 3R) -5- [ (1S) -2- [ (4-methoxyphenyl) methoxy] -1-methyl-ethyl] -3-methyl-6-oxo-10- [ [2- [4- (trifluoromethyl) phenyl] acetyl] amino] -3, 4-dihydro-2H-1, 5-benzoxazocin-2-yl] methyl] -N-methyl-carbamate, S9. To a solution of tert-butyl N- [ [ (2S, 3R) -10-amino-5- [ (1S) -2- [ (4-methoxyphenyl) methoxy] -1-methyl-ethyl] -3-methyl-6-oxo-3, 4-dihydro-2H-1, 5-benzoxazocin-2-yl] methyl] -N-methyl-carbamate (4.00 g, 7.58 mmol, 1.00 Eq) and 2- [4-(trifluoromethyl) phenyl] acetyl chloride (3.37 g, 15.16 mmol, 2.00 Eq) inCH₂Cl₂ (80 mL) was added a solution oftriethylamine (3.84 g, 37.90 mmol, 5.00 Eq) drop-wise at 0 ℃ over a period of20 min under N₂. After 10 min, TLC (Petroleum ether: EtOAc＝1: 1) showed the starting material was consumed completely. The reaction was quenched by ice slowly and then extracted with CH₂Cl₂ (10 mL*3) . The combined organic phase was washed with saturated brine (50 mL) , dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo. The residue was purified bycolumn chromatography (Petroleum ether: EtOAc＝3: 1) to give tert-butyl N- [ [ (2S, 3R) -5- [ (1S) -2- [ (4-methoxyphenyl) methoxy] -1-methyl-ethyl] -3-methyl-6-oxo-10- [ [2- [4-(trifluoromethyl) phenyl] acetyl] amino] -3, 4-dihydro-2H-1, 5-benzoxazocin-2-yl] methyl] -N-methyl-carbamate S9 (4.50 g, 6.30 mmol, 83％ yield) as a yellow solid.

N- [ (2S, 3R) -5- [ (1S) -2-hydroxy-1-methyl-ethyl] -3-methyl-2- (methylaminomethyl) -6-oxo-3, 4-dihydro-2H-1, 5-benzoxazocin-10-yl] -2- [4- (trifluoromethyl) phenyl] acetamide, S10. To a solution oftert-butyl N- [ [ (2S, 3R) -5- [ (1S) -2- [ (4-methoxyphenyl) methoxy] -1-methyl-ethyl] -3-methyl-6-oxo-10- [ [2- [4- (trifluoromethyl) phenyl] acetyl] amino] -3, 4-dihydro-2H-1, 5-benzoxazocin-2-yl] methyl] -N-methyl-carbamate (4.00 g, 5.60 mmol, 1.00 Eq) intrifluoroacetic acid (10 mL) and CH₂Cl₂ (40 mL) . The reaction mixture was stirred at room temperature for 30 min. The reaction was quenched by ice slowly, adjusted to pH＝9 with sat. Na₂CO₃ solution and then extracted with CH₂Cl₂ (10 mL*3) . The combined organic phase was washed with saturated brine (20 mL*2) , dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo to give N- [ (2S, 3R) -5- [ (1S) -2-hydroxy-1-methyl-ethyl] -3-methyl-2- (methylaminomethyl) -6-oxo-3, 4-dihydro-2H-1, 5-benzoxazocin-10-yl] -2- [4- (trifluoromethyl) phenyl] acetamide S10 (3.00 g, 4.86 mmol, 87％ yield, 80％ purity) as a yellow solid.

General Procedure A–Reductive amination:

N- ( (2S, 3R) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-2- ( (methyl (4- (3-(trifluoromethyl) benzyl) benzyl) amino) methyl) -6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) -2- (4- (trifluoromethyl) phenyl) acetamide, 60. To a mixture of N- [ (2S, 3R) -5- [ (1S) -2-hydroxy-1-methyl-ethyl] -3-methyl-2- (methylaminomethyl) -6-oxo-3, 4-dihydro-2H-1, 5-benzoxazocin-10-yl] -2- [4- (trifluoromethyl) phenyl] acetamide (64.00 mg, 139.58 umol, 1.00 Eq) and 4- (3- (trifluoromethyl) benzyl) benzaldehyde (36.71 mg, 139.58 umol, 1.00 Eq) in MeOH/DCE (1mL/0.5mL) was addedAcOH (1drop) . After 2hr, NaBH₃CN (17.54 mg, 279.16 umol, 2.00 Eq) was added in one portion at r. t. , then heated to45 ℃ for 16 hr. TLC showed the reaction was completed. The mixture was concentrated in reduced pressure, and the residue was purified by Prep-HPLC to afford N- ( (2S, 3R)-5- ( (S)-1-hydroxypropan-2-yl)-3-methyl-2-( (methyl (4- (3- (trifluoromethyl) benzyl) benzyl) amino) methyl)-6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl)-2- (4- (trifluoromethyl) phenyl) acetamide 60 (21.35 mg, 28.35 umol, 20％ yield) as a whitesolid. ¹H NMR (400MHz, DMSO-d₆) δ 8.67 (s, 1H) , 7.90 (d, J＝7.9 Hz, 1H) , 7.63 (d, J＝7.9 Hz, 2H) , 7.58-7.40 (m, 6H) , 7.25-7.05 (m, 5H) , 6.93-6.75 (m, 1H) , 4.83 (br. s. , 1H) , 4.61 (br. s. , 1H) , 4.48-4.31 (m, 1H) , 3.99 (s, 2H) , 3.85-3.73 (m, 2H) , 3.64-3.50 (m, 1H) , 3.45-3.34 (m, 3H) , 3.25-3.13 (m, 1H) , 2.87 (t, J＝13.9 Hz, 1H) , 2.13-1.92 (m, 4H) , 1.08 (d, J＝7.1 Hz, 3H) , 0.64 (d, J＝6.2 Hz, 3H) . ESI [M+H] ＝742.2

General Procedure B–Synthesis of benzylbenzaldehydes:

4- (3- (trifluoromethyl) benzyl) benzaldehyde. To a mixture of (4-formylphenyl) boronic acid (333.00 mg, 2.22 mmol, 1.00 Eq) , 1- (bromomethyl) -3- (trifluoromethyl) benzene (260.72 mg, 1.1 mmol) , K₂CO₃ (613.65 mg, 4.44 mmol, 2.0Eq) andPd (PPh₃) ₄ (256.53 mg, 222.00 umol, 0.10 Eq) in THF/H₂O (5mL/1mL) was heated to reflux for 16hr under N₂. TLC showed the starting material was consumed completely. After cooled to r. t, the solution wasconcentrated and purified by column chromatography (Petroleum ether: EtOAc＝10: 1) to give 4- (3-(trifluoromethyl) benzyl) benzaldehyde (412.2mg, 1.56 mmol, 70％ yield) as a yellow solid.

General Procedure C–Synthesis of arylbenzaldehydes:

2', 4'-dimethyl- [1, 1'-biphenyl] -4-carbaldehyde. A mixture of 4-bromobenzaldehyde (3.5 g, 0.019 mol) , 2, 4-dimethylphenyl) boronic acid (3.5 g, 0.023 mol) , Na₂CO₃ (2.8 g, 0.026 mol) , Pd (dppf) Cl₂ (1g, 0.0019 mol) in MeCN: H₂O＝1: 1 (50mL) was stirred at 80 ℃ under N₂ for 18hrs. The solvent was removed in vacuum and the residue was partitioned between H₂O and EtOAc. The organic layer was dried over Na₂SO₄, filtered, concentrated and purified by column chromatography (Petroleum ether: EtOAc＝10: 1) to give 2', 4'-dimethyl- [1, 1'-biphenyl] -4-carbaldehyde (5.5 g, yield 92％ ) as a yellow solid.

General Procedure D–Synthesis of benzaldehyde-ethers:

4- (2-fluorophenoxy) benzaldehyde. To the solution of 4-fluorobenzaldehyde (2.48 g, 20 mmol) and2-fluorophenol (2.46 g, 22 mmol) in DMF (50 mL) was added potassium carbonate (5.52 g, 40 mmol) . The mixture was stirred at 110 ℃ for 16 hrs. After reaction, it was poured in water and extracted with ethyl acetate (80 mL*3) . The combined organic layer was washed with water (100 mL *3) and saturated brine, dried over anhydrous Na₂SO₄ and concentrated. The residue was purified by silica gel chromatography (Petroleum ether: EtOAc＝10: 1) to get 4- (2-fluorophenoxy) benzaldehyde (3.25 g, yield 75％ ) .

General Procedure E–Synthesis of anilinebenzaldehydes:

4- (phenylamino) benzaldehyde. Aniline (130 mg, 1.40 mmol) and4-bromobenzaldehyde (291 mg, 1.68 mmol) was added into a solution of PhMe (10mL) with Pd (OAc) ₂ (15.7mg, 0.07 mmol) , BINAP (60.96 mg, 0.10 mmol) , Cs₂CO₃ (910 mg, 2.8mmol) . Then the mixture was heated at reflux under N₂. After 16hrs, the solvent was partitioned between H₂O and EtOAc. The organic layer was concentrated and purified by column chromatography (Petroleum ether: EtOAc ＝5: 1) to give 4- (phenylamino) benzaldehyde (236.6 mg, yield 69％ ) .

General Procedure F–Synthesis of benzenethiolbenzaldehydes:

4- (phenylthio) benzaldehyde. A mixture of 4-fluorobenzaldehyde (500 mg, 4 mmol) , benzenethiol (440mg, 4 mmol) and K₂CO₃ (1.1g, 2 mmol) in DMF (20 mL) was stirred at 100 ℃ for 16hrs. After cooling to room temperature (25 ℃) , the mixture was poured into water and extracted with EtOAc (30 mL*3) . The combined organic layer was washed with brine, dried over Na₂SO₄ and concentrated in vacuo. The residue was purified by column chromatography (Petroleum ether: EtOAc ＝10: 1) to give 4- (phenylthio) benzaldehyde (800 mg, yield 57％ ) as yellow oil.

General Procedure G–Synthesis of otheraldehydes:

4- (benzyloxy) benzaldehyde. To a solution of 4-hydroxybenzaldehyde (250 mg, 2.05 mmol) in DMF (5mL) was added (bromomethyl) benzene (418 mg, 2.46 mmol) and K₂CO₃ (566 mg, 4.10 mmol) . The mixture was stirred at 80 ℃. After 16hrs, the solvent was partitioned between H₂O and EtOAc. The organic layer was concentrated and purified by column chromatography (Petroleum ether: EtOAc ＝5: 1) to give 4- (benzyloxy) benzaldehyde (305 mg, yield 66％ ) .

4- (2-phenylpropan-2-yl) benzaldehyde. A mixture of 4, 4'- (propane-2, 2-diyl) diphenol (5g, 0.022 mol) , TEA (6.6g, 0.066 mol) in DCM (50mL) was cooled to 0 ℃. Then MsCl (5.25 g, 0.046 mol) was added. The mixture was stirred at 13 ℃ for 0.5hr. Water was added to the reaction and the mixture was extracted with DCM (20mL*3) . The combined organic phase was concentrated to get crude product purified by column chromatography (Petroleum ether: EtOAc ＝10: 1) to give propane-2, 2-diylbis (4, 1-phenylene) dimethanesulfonate (3 g, yield 37％ ) .

A mixture of propane-2, 2-diylbis (4, 1-phenylene) dimethanesulfonate (2.84 g, 7.4mmol) , Pd/C (2.4 g) and TEA (1.5 g, 14.8mmol) in EtOAc (30 mL) was stirred at 80 ℃ under H₂ (45 Psi) for 48 hrs. The mixture was filtrated, the filtrate was concentrated purified column chromatography (Petroleum ether: EtOAc ＝10: 1) to give propane-2, 2-diyldibenzene (1.2 yield 85％ ) .

A mixture of propane-2, 2-diyldibenzene (196 mg, 1 mmol) and 1, 3, 5, 7-tetraazaadamantane (140 mg, 1 mmol) in TFA (35 mL) was heated at 100 ℃ for 16hrs. The mixture was allowed to cooled to RT, poured into cold water and made alkaline (pH＝9) with solid K₂CO₃. The aqueous solution was extracted with EtOAc (10 mL*3) . The combine organic phase was purified Prep-TLC (Petroleum ether: EtOAc ＝10: 1) to give 4- (2-phenylpropan-2-yl) benzaldehyde (0.15 g yield 6％ ) .

4- (1-phenylvinyl) benzaldehyde. Synthesized using General Procedure C, replacing 2, 4-dimethylphenyl) boronic acid with (1-phenylvinyl) boronic acid.

4- (1-phenylethyl) benzaldehyde. A mixture of 4- (1-phenylvinyl) benzaldehyde (104 mg, 0.5 mmol) , and Pd/C (60 mg) in EtOAc (10 mL) was stirred at 0 ℃ under H₂ (20 Psi) . After 10min, the mixture was filtrated and the filtrate was concentrated to give 4- (1-phenylethyl) benzaldehyde (56 mg, yield 54％ ) .

4- (3-fluorobenzyl) benzaldehyde. Synthesized using General Procedure B, replacing 1-(bromomethyl) -3- (trifluoromethyl) benzene with 1- (bromomethyl) -3-fluorobenzene.

4- (2, 5-difluorobenzyl) benzaldehyde. Synthesized using General Procedure B, replacing 1-(bromomethyl) -3- (trifluoromethyl) benzene with 1- (bromomethyl) -2, 5-difluorobenzene.

4- (2, 3-difluorobenzyl) benzaldehyde. Synthesized using General Procedure B, replacing 1-(bromomethyl) -3- (trifluoromethyl) benzene with 1- (bromomethyl) -2, 3-difluorobenzene.

4- (5-fluoro-2-methoxybenzyl) benzaldehyde. Synthesized using General Procedure B, replacing 1- (bromomethyl) -3- (trifluoromethyl) benzene with 1- (bromomethyl) -5-fluoro-2-methoxybenzene.

4- (difluoro (phenyl) methyl) benzaldehyde. A mixture of 4-benzoylbenzoic acid (5 g, 22 mmol) and SOCl₂ (7.8g, 66 mmol) in MeOH (30mL) was stirred at 70 ℃ for 4hrs. The solvent was removed in vacuum to give methyl 4-benzoylbenzoate (3.7 g, yield 70％ ) .

A mixture of methyl 4-benzoylbenzoate (2.4 g, 10 mmol) , BF₃ (HOAc) ₂ (4.6g, 25 mmol) and ethane-1, 2-dithiol (1.88 g, 20 mmol) in DCM (30mL) was stirred at 13 ℃ for 18hrs. Water was added and the mixture was extracted with DCM (20mL*3) . The combine organic phase was concentrated to get crude methyl 4- (2-phenyl-1, 3-dithiolan-2-yl) benzoate (3.6 g, crude) .

A mixture of Selectfluor (3.56 g, 10 mmol) , HF-pyridine reagent (15.8mL) and 4- (2-phenyl-1, 3-dithiolan-2-yl) benzoate (3.2 g, 10 mmol) in DCM (30 mL) was stirred at 13 ℃ for 0.5hr. Water was added and the mixture was extracted with DCM (20mL*3) . The combine organic phase was concentrated to get methyl 4- (difluoro (phenyl) methyl) benzoate (1.8 g, crude) .

A solution of methyl 4- (difluoro (phenyl) methyl) benzoate (216 mg, 0.8mmol) in THF (5mL)was cooled to 0 ℃. Then LiAlH₄ (46 mg, 1.23 mmol) was added. The mixture was stirred at 0 ℃ for 1hr. Sat. MgSO₄ was added to the reaction. The mixture was filtered, and the filtrate was concentrated to give (4- (difluoro (phenyl) methyl) phenyl) methanol (186 mg, crude)

A mixture of (4- (difluoro (phenyl) methyl) phenyl) methanol (186 mg, 0.8mmol) , MnO₂ (700 mg) in DCM (5mL) was stirred at 18 ℃ for 72hrs. The mixture was filtrated and the filtrate was concentrated to give 4- (difluoro (phenyl) methyl) benzaldehyde (100 mg, yield 54％ ) .

4- (3-methylbenzyl) benzaldehyde. Synthesized using General Procedure B, replacing 1-(bromomethyl) -3- (trifluoromethyl) benzene with 1- (bromomethyl) -3-methylbenzene.

4- (3, 5-dimethylbenzyl) benzaldehyde. Synthesized using General Procedure B, replacing 1-(bromomethyl) -3- (trifluoromethyl) benzene with 1- (bromomethyl) -3, 5-dimethylbenzene.

4- (3, 4-difluorobenzyl) benzaldehyde. Synthesized using General Procedure B, replacing 1-(bromomethyl) -3- (trifluoromethyl) benzene with 4- (bromomethyl) -1, 2-difluorobenzene.

4- (3, 4, 5-trifluorobenzyl) benzaldehyde. Synthesized using General Procedure B, replacing 1-(bromomethyl) -3- (trifluoromethyl) benzene with 5- (bromomethyl) -1, 2, 3-trifluorobenzene.

4- ( (perfluorophenyl) methyl) benzaldehyde. Synthesized using General Procedure B, replacing 1- (bromomethyl) -3- (trifluoromethyl) benzene with 1- (bromomethyl) -2, 3, 4, 5, 6-pentafluorobenzene.

4- (4-fluoro-3- (trifluoromethyl) benzyl) benzaldehyde. Synthesized using General Procedure B, replacing 1- (bromomethyl) -3- (trifluoromethyl) benzene with 4- (bromomethyl) -1-fluoro-2-(trifluoromethyl) benzene.

4- (2-chloro-5- (trifluoromethyl) benzyl) benzaldehyde. Synthesized using General Procedure B, replacing 1- (bromomethyl) -3- (trifluoromethyl) benzene with 2- (bromomethyl) -1-chloro-4-(trifluoromethyl) benzene.

2', 4'-dimethoxy- [1, 1'-biphenyl] -4-carbaldehyde. Synthesized using General Procedure C, replacing (2, 4-dimethylphenyl) boronic acid with (2, 4-dimethoxyphenyl) boronic acid.

2', 4'-bis (trifluoromethyl) - [1, 1'-biphenyl] -4-carbaldehyde. Synthesized using General Procedure C, replacing (2, 4-dimethylphenyl) boronic acid with (2, 4-bis (trifluoromethyl) phenyl) boronic acid.

4'-fluoro-2'-methyl- [1, 1'-biphenyl] -4-carbaldehyde. Synthesized using General Procedure C, replacing (2, 4-dimethylphenyl) boronic acid with (4-fluoro-2-methylphenyl) boronic acid.

2'-fluoro-4'-methyl- [1, 1'-biphenyl] -4-carbaldehyde. Synthesized using General Procedure C, replacing (2, 4-dimethylphenyl) boronic acid with (2-fluoro-4-methylphenyl) boronic acid.

2'-fluoro-4'-methoxy- [1, 1'-biphenyl] -4-carbaldehyde. Synthesized using General Procedure C, replacing (2, 4-dimethylphenyl) boronic acid with (2-fluoro-4-methoxyphenyl) boronic acid.

2'-fluoro-4'- (trifluoromethyl) - [1, 1'-biphenyl] -4-carbaldehyde. Synthesized using General Procedure C, replacing (2, 4-dimethylphenyl) boronic acid with (2-fluoro-4-(trifluoromethyl) phenyl) boronic acid.

4'-methoxy-2'-methyl- [1, 1'-biphenyl] -4-carbaldehyde. Synthesized using General Procedure C, replacing (2, 4-dimethylphenyl) boronic acid with (4-methoxy-2-methylphenyl) boronic acid.

2', 4'-difluoro- [1, 1'-biphenyl] -4-carbaldehyde. Synthesized using General Procedure C, replacing (2, 4-dimethylphenyl) boronic acid with (2, 4-difluorophenyl) boronic acid.

2', 4', 6'-trimethyl- [1, 1'-biphenyl] -4-carbaldehyde. Synthesized using General Procedure C, replacing (2, 4-dimethylphenyl) boronic acid with mesitylboronic acid.

3', 5'-bis (trifluoromethyl) - [1, 1'-biphenyl] -4-carbaldehyde. Synthesized using General Procedure C, replacing (2, 4-dimethylphenyl) boronic acid with (3, 5-bis (trifluoromethyl) phenyl) boronic acid.

5'-fluoro-2'- (trifluoromethyl) - [1, 1'-biphenyl] -4-carbaldehyde. Synthesized using General Procedure C, replacing (2, 4-dimethylphenyl) boronic acid with (5-fluoro-2-(trifluoromethyl) phenyl) boronic acid.

3'-fluoro-5'-methoxy- [1, 1'-biphenyl] -4-carbaldehyde. Synthesized using General Procedure C, replacing (2, 4-dimethylphenyl) boronic acid with (3-fluoro-5-methoxyphenyl) boronic acid.

3', 4', 5'-trifluoro- [1, 1'-biphenyl] -4-carbaldehyde. Synthesized using General Procedure C, replacing (2, 4-dimethylphenyl) boronic acid with (3, 4, 5-trifluorophenyl) boronic acid.

3', 4'-difluoro- [1, 1'-biphenyl] -4-carbaldehyde. Synthesized using General Procedure C, replacing (2, 4-dimethylphenyl) boronic acid with (3, 4-difluorophenyl) boronic acid.

3'-chloro-5'-fluoro- [1, 1'-biphenyl] -4-carbaldehyde. Synthesized using General Procedure C, replacing (2, 4-dimethylphenyl) boronic acid with (3-chloro-5-fluorophenyl) boronic acid.

3', 5'-difluoro- [1, 1'-biphenyl] -4-carbaldehyde. Synthesized using General Procedure C, replacing (2, 4-dimethylphenyl) boronic acid with (3, 5-difluorophenyl) boronic acid.

2'-fluoro-5'-methyl- [1, 1'-biphenyl] -4-carbaldehyde. Synthesized using General Procedure C, replacing (2, 4-dimethylphenyl) boronic acid with (2-fluoro-5-methylphenyl) boronic acid.

3'-fluoro-5'-methyl- [1, 1'-biphenyl] -4-carbaldehyde. Synthesized using General Procedure C, replacing (2, 4-dimethylphenyl) boronic acid with (3-fluoro-5-methylphenyl) boronic acid.

3', 5'-dimethyl- [1, 1'-biphenyl] -4-carbaldehyde. Synthesized using General Procedure C, replacing (2, 4-dimethylphenyl) boronic acid with (3, 5-dimethylphenyl) boronic acid.

3'-chloro- [1, 1'-biphenyl] -4-carbaldehyde. Synthesized using General Procedure C, replacing (2, 4-dimethylphenyl) boronic acid with (3-chlorophenyl) boronic acid.

2'-chloro-5'- (trifluoromethyl) - [1, 1'-biphenyl] -4-carbaldehyde. Synthesized using General Procedure C, replacing (2, 4-dimethylphenyl) boronic acid with (2-chloro-5-(trifluoromethyl) phenyl) boronic acid.

2'-fluoro-5'- (trifluoromethyl) - [1, 1'-biphenyl] -4-carbaldehyde. Synthesized using General Procedure C, replacing (2, 4-dimethylphenyl) boronic acid with (2-fluoro-5-(trifluoromethyl) phenyl) boronic acid.

4- (4-fluorophenoxy) benzaldehyde. Synthesized using General Procedure D, replacing 2-fluorophenol with 4-fluorophenol.

4- (p-tolyloxy) benzaldehyde. Synthesized using General Procedure D, replacing 2-fluorophenol with p-cresol.

4- (o-tolyloxy) benzaldehyde. Synthesized using General Procedure D, replacing 2-fluorophenol with o-cresol.

4- (2, 4-difluorophenoxy) benzaldehyde. Synthesized using General Procedure D, replacing 2-fluorophenol with 2, 4-difluorophenol.

4- (2, 6-dimethylphenoxy) benzaldehyde. Synthesized using General Procedure D, replacing 2-fluorophenol with 2, 6-dimethylphenol.

4- (2, 4, 6-trimethylphenoxy) benzaldehyde. Synthesized using General Procedure D, replacing 2-fluorophenol with 2, 4, 6-trimethylphenol.

4- (2, 4-dimethylphenoxy) benzaldehyde. Synthesized using General Procedure D, replacing 2-fluorophenol with 2, 4-dimethylphenol.

4- (2, 6-dimethoxyphenoxy) benzaldehyde. Synthesized using General Procedure D, replacing 2-fluorophenol with 2, 6-dimethoxyphenol.

4- (2, 4-dimethoxyphenoxy) benzaldehyde. Synthesized using General Procedure D, replacing 2-fluorophenol with 2, 4-dimethoxyphenol.

4- (4-fluoro-2-methylphenoxy) benzaldehyde. Synthesized using General Procedure D, replacing 2-fluorophenol with 4-fluoro-2-methylphenol

4- (2-methoxy-4-methylphenoxy) benzaldehyde. Synthesized using General Procedure D, replacing 2-fluorophenol with2-methoxy-4-methylphenol

4- (4-fluoro-2- (trifluoromethyl) phenoxy) benzaldehyde. Synthesized using General Procedure D, replacing 2-fluorophenol with4-fluoro-2- (trifluoromethyl) phenol.

4- (2-fluoro-4-methylphenoxy) benzaldehyde. Synthesized using General Procedure D, replacing 2-fluorophenol with2-fluoro-4-methylphenol.

4- (3-chlorophenoxy) benzaldehyde. Synthesized using General Procedure D, replacing 2-fluorophenol with3-chlorophenol

4- (3, 5-dimethylphenoxy) benzaldehyde. Synthesized using General Procedure D, replacing 2-fluorophenol with 3, 5-dimethylphenol.

4- (3, 5-difluorophenoxy) benzaldehyde. Synthesized using General Procedure D, replacing 2-fluorophenol with 3, 5-difluorophenol.

4- (3, 4, 5-trifluorophenoxy) benzaldehyde. Synthesized using General Procedure D, replacing 2-fluorophenol with 3, 4, 5-trifluorophenol.

4- (3, 4, 5-trimethylphenoxy) benzaldehyde. Synthesized using General Procedure D, replacing 2-fluorophenol with3, 4, 5-trimethylphenol.

4- (4-chloro-3- (trifluoromethyl) phenoxy) benzaldehyde. Synthesized using General Procedure D, replacing 2-fluorophenol with 4-chloro-3- (trifluoromethyl) phenol.

[1] 4- (3-fluoro-5-methylphenoxy) benzaldehyde. Synthesized using General Procedure D, replacing 2-fluorophenol with3-fluoro-5-methylphenol.

[2] 4- (3, 5-bis (trifluoromethyl) phenoxy) benzaldehyde. Synthesized using General Procedure D, replacing 2-fluorophenol with3, 5-bis (trifluoromethyl) phenol.

[3] 4- (methyl (phenyl) amino) benzaldehyde. Synthesized using General Procedure E, replacinganilinewithN-methylaniline

4- (methyl (o-tolyl) amino) benzaldehyde. Synthesized using General Procedure E, replacinganilinewith 2-methyl-N-methylaniline

4- (ethyl (phenyl) amino) benzaldehyde. Synthesized using General Procedure E, replacinganilinewith 2-methyl-N-ethylaniline

4- (phenyl (propyl) amino) benzaldehyde. Synthesized using General Procedure E, replacinganilinewith 2-methyl-N-propylaniline

4- ( (4-formylphenyl) (methyl) amino) benzonitrile. Synthesized using General Procedure E, replacinganilinewith4- (methylamino) benzonitrile.

4- (methyl (4- (trifluoromethyl) phenyl) amino) benzaldehyde. Synthesized using General Procedure E, replacinganilinewithN-methyl-4- (trifluoromethyl) aniline.

4- ( (4-methoxyphenyl) (methyl) amino) benzaldehyde. Synthesized using General Procedure E, replacinganilinewith4-methoxy-N-methylaniline

4- (methyl (2- (trifluoromethyl) phenyl) amino) benzaldehyde. Synthesized using General Procedure E, replacinganilinewithN-methyl-2- (trifluoromethyl) aniline.

4- ( (2-methoxyethyl) (phenyl) amino) benzaldehyde. Synthesized using General Procedure E, replacinganilinewithN- (2-methoxyethyl) aniline.

4- (methyl (p-tolyl) amino) benzaldehyde. Synthesized using General Procedure E, replacinganilinewithN-methyl-4-methylaniline.

4- (methyl (p-tolyl) amino) benzaldehyde. Synthesized using General Procedure E, replacing aniline with N-methyl-3-methylaniline.

4- ( (3-fluorophenyl) (methyl) amino) benzaldehyde. Synthesized using General Procedure E, replacing aniline with 3-fluoro-N-methylaniline.

4- ( (2, 5-dimethylphenyl) (methyl) amino) benzaldehyde. Synthesized using General Procedure E, replacing aniline with N-methyl-2, 5-dimethylaniline.

4- (butyl (phenyl) amino) benzaldehyde. Synthesized using General Procedure E, replacing aniline with N-butylaniline.

4- ( (2, 3-dimethylphenyl) (methyl) amino) benzaldehyde. Synthesized using General Procedure E, replacing aniline with N-methyl-2, 3-dimethylaniline.

4- (isopropyl (phenyl) amino) benzaldehyde. Synthesized using General Procedure E, replacing aniline with N-isopropylaniline.

4- ( (3, 5-difluorophenyl) (methyl) amino) benzaldehyde. Synthesized using General Procedure E, replacing aniline with3, 5-difluoro-N-methylaniline.

4- ( (3-fluoro-4- (trifluoromethyl) phenyl) (methyl) amino) benzaldehyde. Synthesized using General Procedure E, replacing aniline with3-fluoro-N-methyl-4- (trifluoromethyl) aniline.

4- (methyl (2, 4, 5-trifluorophenyl) amino) benzaldehyde. Synthesized using General Procedure E, replacing aniline with2, 4, 5-trifluoro-N-methylaniline.

[4]

4- ( (2-fluorophenyl) (methyl) amino) benzaldehyde. Synthesized using General Procedure E, replacing aniline with2-fluoro-N-methylaniline.

4- ( (3, 4-difluorophenyl) (methyl) amino) benzaldehyde. Synthesized using General Procedure E, replacing aniline with3, 4-difluoro-N-methylaniline.

4- (phenylsulfonyl) benzaldehyde. The mixture of 4-chlorobenzaldehyde (1.4g, 10 mmol) and sodium benzenesulfinate (1.7 g, 10 mmol) and CuI (190 mg, 1 mmol) and K₂CO₃ (138 mg, 1 mmol) in NMP (10 mL) was stirred at 150 ℃ for 1 hr with the microwave. The mixture was quenched with H₂O and extracted with EtOAc. The combined organic layer was washed with brine, dried over MgSO₄ and concentrated in vacuo. The residue was purified by column chromatography (Petroleum ether: EtOAc ＝10: 1) to give 4- (phenylsulfonyl) benzaldehyde (300 mg, yield 12％ ) .

4- (m-tolylthio) benzaldehyde. Synthesized using General Procedure F, replacing benzenethiol with3-methylbenzenethiol.

4- (o-tolylthio) benzaldehyde. Synthesized using General Procedure F, replacing benzenethiol with 2-methylbenzenethiol.

4- ( (3-methoxyphenyl) thio) benzaldehyde. Synthesized using General Procedure F, replacing benzenethiol with3-methoxybenzenethiol.

4- (p-tolylthio) benzaldehyde. Synthesized using General Procedure F, replacing benzenethiol with4-methylbenzenethiol.

4- ( (3, 5-bis (trifluoromethyl) phenyl) thio) benzaldehyde. Synthesized using General Procedure F, replacing benzenethiol with3, 5-bis (trifluoromethyl) benzenethiol.

4- ( (3-chlorophenyl) thio) benzaldehyde. Synthesized using General Procedure F, replacing benzenethiol with3-chlorobenzenethiol.

4- ( (3, 5-dimethylphenyl) thio) benzaldehyde. Synthesized using General Procedure F, replacing benzenethiol with3, 5-dimethylbenzenethiol.

4- ( (3, 4-difluorophenyl) thio) benzaldehyde. Synthesized using General Procedure F, replacing benzenethiol with3, 4-difluorobenzenethiol.

4- (phenoxymethyl) benzaldehyde. Synthesized using General Procedure G, replacing 4-hydroxybenzaldehydewithphenol and (bromomethyl) benzenewith 4- (bromomethyl) benzaldehyde.

4-styrylbenzaldehyde. Synthesized using General Procedure C, replacing 2, 4-dimethylphenyl) boronic acid with styrylboronic acid.

4-phenethylbenzaldehyde. A mixture of 4-styrylbenzaldehyde (100 mg, 0.48 mmol) , and Pd/C (30 mg) in EtOAc (10 mL) was stirred at 0 ℃ under H₂ (20 Psi) . After 15 min, the mixture was filtrated and the filtrate was concentrated to give 4-phenethylbenzaldehyde (70 mg, yield 69％ ) .

4-phenethoxybenzaldehyde. Synthesized using General Procedure G, replacing (bromomethyl) benzene with (2-bromoethyl) benzene.

4- ( (3-methylbenzyl) oxy) benzaldehyde. Synthesized using General Procedure G, replacing (bromomethyl) benzene with1- (bromomethyl) -3-methylbenzene.

4- ( (3-fluorobenzyl) oxy) benzaldehyde. Synthesized using General Procedure G, replacing (bromomethyl) benzene with1- (bromomethyl) -3-fluorobenzene.

4- (benzylthio) benzaldehyde. The mixture of 4-bromobenzaldehyde (200 mg, 1.08 mmol) , phenylmethanethiol (134 mg, 1.08 mmol) , DIPEA (418 mg, 3.24 mmol) , Xantphos (62 mg, 0.107 mmol) and Pd₂ (dba) ₃ (99 mg, 0.107 mmol) in toluene (5mL) was stirred at 80 ℃ for 16 hrs. The solution was concentrated and purified by column chromatography (Petroleum ether: EtOAc ＝10: 1) to give 4- (benzylthio) benzaldehyde (220 mg, yield 89％ ) .

4- ( (m-tolylthio) methyl) benzaldehyde. Synthesized using General Procedure G, replacing 4-hydroxybenzaldehydewith3-methylbenzenethiol and (bromomethyl) benzenewith 4-(bromomethyl) benzaldehyde.

4- ( (3, 5-dimethylbenzyl) oxy) benzaldehyde. Synthesized using General Procedure G, replacing (bromomethyl) benzene with1- (bromomethyl) -3, 5-dimethylbenzene.

4- ( (3, 4-difluorobenzyl) oxy) benzaldehyde. Synthesized using General Procedure G, replacing (bromomethyl) benzene with4- (bromomethyl) -1, 2-difluorobenzene.

4- ( (2, 5-difluorobenzyl) oxy) benzaldehyde. Synthesized using General Procedure G, replacing (bromomethyl) benzene with2- (bromomethyl) -1, 4-difluorobenzene.

[5]

4- ( (4-fluoro-3- (trifluoromethyl) benzyl) oxy) benzaldehyde. Synthesized using General Procedure G, replacing (bromomethyl) benzene with4- (bromomethyl) -1-fluoro-2-(trifluoromethyl) benzene.

4- ( (3, 5-bis (trifluoromethyl) benzyl) oxy) benzaldehyde. Synthesized using General Procedure G, replacing (bromomethyl) benzene with1- (bromomethyl) -3, 5-bis (trifluoromethyl) benzene.

4- ( (4-bromo-2-fluorophenoxy) methyl) benzaldehyde. Synthesized using General Procedure G, replacing 4-hydroxybenzaldehydewith4-bromo-2-fluorophenol and (bromomethyl) benzenewith 4- (bromomethyl) benzaldehyde.

4- ( ( (3-chloro-4-fluorophenyl) thio) methyl) benzaldehyde. Synthesized using General Procedure G, replacing 4-hydroxybenzaldehydewith3-chloro-4-fluorobenzenethiol and (bromomethyl) benzenewith 4- (bromomethyl) benzaldehyde.

4- ( (methyl (phenyl) amino) methyl) benzaldehyde. Synthesized using General Procedure G, replacing 4-hydroxybenzaldehydewithN-methylaniline and (bromomethyl) benzenewith 4-(bromomethyl) benzaldehyde.

4- ( (3- (trifluoromethyl) benzyl) oxy) benzaldehyde. Synthesized using General Procedure G, replacing (bromomethyl) benzene with1- (bromomethyl) -3- (trifluoromethyl) benzene.

4- ( (2-chloro-5- (trifluoromethyl) benzyl) oxy) benzaldehyde. Synthesized using General Procedure G, replacing (bromomethyl) benzene with2- (bromomethyl) -1-chloro-4-(trifluoromethyl) benzene.

4- ( ( (2, 4-dimethylphenyl) thio) methyl) benzaldehyde. Synthesized using General Procedure G, replacing 4-hydroxybenzaldehydewith2, 4-dimethylbenzenethiol and (bromomethyl) benzenewith 4- (bromomethyl) benzaldehyde.

4- (1-phenylethoxy) benzaldehyde. Synthesized using General Procedure G, replacing (bromomethyl) benzene with (1-bromoethyl) benzene.

4- ( ( (3-fluorophenyl) (methyl) amino) methyl) benzaldehyde. Synthesized using General Procedure G, replacing 4-hydroxybenzaldehydewith3-fluoro-N-methylaniline and (bromomethyl) benzenewith 4- (bromomethyl) benzaldehyde.

N- ( (2S, 3R) -2- ( ( ( [1, 1'-biphenyl] -4-ylmethyl) (methyl) amino) methyl) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) -2- (p-tolyl) acetamid, 1 Synthesized using General Procedure A, replacing 2- (4- (trifluoromethyl) phenyl) acetyl chloride and 4- (3- (trifluoromethyl) benzyl) benzaldehyde with 2- (p-tolyl) acetyl chloride and [1, 1'-biphenyl] -4-carbaldehyde. 1H NMR (400MHz, DMSO-d6) δ 8.34 (s, 1H) , 8.10 (d, J＝7.5 Hz, 1H) , 7.60 (dd, J＝7.7, 17.9 Hz, 4H) , 7.49-7.38 (m, 2H) , 7.36-7.26 (m, 3H) , 7.22-7.15 (m, 2H) , 7.13-7.01 (m, 3H) , 6.86 (t, J＝7.9 Hz, 1H) , 4.84 (t, J＝5.1 Hz, 1H) , 4.64 (br. s. , 1H) , 4.52-4.35 (m, 1H) , 3.65 (s, 2H) , 3.59-3.51 (m, 1H) , 3.46-3.41 (m, 3H) , 3.24 (dd, J＝5.5, 15.2 Hz, 1H) , 2.98-2.80 (m, 1H) , 2.44-2.38 (m, 2H) , 2.25 (s, 3H) , 2.13-1.89 (m, 4H) , 1.09 (d, J＝7.1 Hz, 3H) , 0.65 (d, J＝6.6Hz, 3H) . ESI [M+H] ＝606.3.

N- ( (2S, 3R) -2- ( ( ( [1, 1'-biphenyl] -4-ylmethyl) (methyl) amino) methyl) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) -2- (4-(trifluoromethyl) phenyl) acetamide, 2 Synthesized using General Procedure A, replacing 4- (3-(trifluoromethyl) benzyl) benzaldehyde with [1, 1'-biphenyl] -4-carbaldehyde. ESI [M+H] ＝660.2.

N- ( (2S, 3R) -2- ( ( ( [1, 1'-biphenyl] -4-ylmethyl) (methyl) amino) methyl) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) -2- (4-cyanophenyl) acetamide, 3 Synthesized using General Procedure A, replacing 2- (4-(trifluoromethyl) phenyl) acetyl chloride and 4- (3- (trifluoromethyl) benzyl) benzaldehyde with 2-(4-cyanophenyl) acetyl chloride and [1, 1'-biphenyl] -4-carbaldehyde. ESI [M+H] ＝617.3.

N- ( (2S, 3R) -2- ( ( ( [1, 1'-biphenyl] -4-ylmethyl) (methyl) amino) methyl) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) -2- (3-(trifluoromethyl) phenyl) acetamide, 4 Synthesized using General Procedure A, replacing 2- (4-(trifluoromethyl) phenyl) acetyl chloride and 4- (3- (trifluoromethyl) benzyl) benzaldehyde with 2-(3- (trifluoromethyl) phenyl) acetyl chloride and [1, 1'-biphenyl] -4-carbaldehyde. 1H NMR (400MHz, DMSO-d6) δ 8.76 (br. s. , 1H) , 7.88 (d, J＝7.1 Hz, 1H) , 7.68 (br. s. , 1H) , 7.64-7.48 (m, 7H) , 7.42 (t, J＝7.3 Hz, 2H) , 7.37-7.26 (m, 3H) , 7.11 (d, J＝7.5 Hz, 1H) , 6.86 (t, J＝7.7 Hz, 1H) , 4.84 (br. s. , 1H) , 4.64 (br. s. , 1H) , 4.46 (br. s. , 1H) , 3.95-3.70 (m, 2H) , 3.64-3.39 (m, 5H) , 2.90 (t, J＝13.7 Hz, 1H) , 2.04 (br. s. , 4H) , 1.10 (d, J＝6.2 Hz, 3H) , 0.69 (br. s. , 3H) . ESI [M+H] ＝660.2.

N- ( (2S, 3R) -2- ( ( ( [1, 1'-biphenyl] -4-ylmethyl) (methyl) amino) methyl) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) -2- (3-methoxyphenyl) acetamide, 5 Synthesized using General Procedure A, replacing 2- (4-(trifluoromethyl) phenyl) acetyl chloride and 4- (3- (trifluoromethyl) benzyl) benzaldehyde with 2-(3-methoxyphenyl) acetyl chloride and [1, 1'-biphenyl] -4-carbaldehyde. ESI [M+H] ＝622.2.

N- ( (2S, 3R) -2- ( ( ( (2', 4'-dimethyl- [1, 1'-biphenyl] -4-yl) methyl) (methyl) amino) methyl) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) -2- (4-(trifluoromethyl) phenyl) acetamide, 6 Synthesized using General Procedure A, replacing 4- (3-(trifluoromethyl) benzyl) benzaldehyde with 2', 4'-dimethyl- [1, 1'-biphenyl] -4-carbaldehyde. ESI [M+H] ＝688.2.

N- ( (2S, 3R) -2- ( ( ( (2', 4'-dimethoxy- [1, 1'-biphenyl] -4-yl) methyl) (methyl) amino) methyl) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) -2- (4-(trifluoromethyl) phenyl) acetamide, 7 Synthesized using General Procedure A, replacing 4- (3-(trifluoromethyl) benzyl) benzaldehyde with 2', 4'-dimethoxy- [1, 1'-biphenyl] -4-carbaldehyde. 1H NMR (400MHz, DMSO-d6) δ 8.69 (br. s. , 1H) , 7.91 (d, J＝7.5 Hz, 1H) , 7.65 (d, J＝7.5 Hz, 2H) , 7.51 (d, J＝7.1 Hz, 2H) , 7.33 (d, J＝7.5 Hz, 2H) , 7.23-6.99 (m, 4H) , 6.86 (t, J＝7.7 Hz, 1H) , 6.69-6.32 (m, 2H) , 4.83 (br. s. , 1H) , 4.64 (br. s. , 1H) , 4.45 (d, J＝6.6 Hz, 1H) , 3.85-3.74 (m, 5H) , 3.70 (s, 3H) , 3.54 (br. s. , 1H) , 3.42 (br. s. , 3H) , 2.98-2.78 (m, 1H) , 2.21-1.95 (m, 4H) , 1.09 (d, J＝6.2 Hz, 3H) , 0.68 (d, J＝5.7 Hz, 3H) . ESI [M+H] ＝720.2.

N- ( (2S, 3R) -2- ( ( ( (2', 4'-bis (trifluoromethyl) - [1, 1'-biphenyl] -4-yl) methyl) (methyl) amino) methyl) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) -2- (4- (trifluoromethyl) phenyl) acetamide, 8 Synthesized using General Procedure A, replacing 4- (3- (trifluoromethyl) benzyl) benzaldehyde with 2', 4'-bis (trifluoromethyl) - [1, 1'-biphenyl] -4-carbaldehyde. ESI [M+H] ＝796.2.

N- ( (2S, 3R) -2- ( ( ( (4'-fluoro-2'-methyl- [1, 1'-biphenyl] -4-yl) methyl) (methyl) amino) methyl) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) -2-(4- (trifluoromethyl) phenyl) acetamide, 10 Synthesized using General Procedure A, replacing 4-(3- (trifluoromethyl) benzyl) benzaldehyde with 4'-fluoro-2'-methyl- [1, 1'-biphenyl] -4-carbaldehyde. 1H NMR (400MHz, DMSO-d6) δ 8.74 (s, 1H) , 8.00-7.80 (m, 1H) , 7.70-7.58 (m, 2H) , 7.54 (d, J＝7.9 Hz, 2H) , 7.29-7.07 (m, 7H) , 7.06-6.98 (m, 1H) , 6.86 (t, J＝7.9 Hz, 1H) , 4.84 (t, J＝5.1 Hz, 1H) , 4.64 (br. s. , 1H) , 4.50-4.35 (m, 1H) , 3.94-3.74 (m, 2H) , 3.62-3.51 (m, 1H) , 3.48-3.38 (m, 3H) , 2.89 (t, J＝13.9 Hz, 1H) , 2.18 (s, 3H) , 2.13-1.84 (m, 4H) , 1.09 (d,J＝6.6 Hz, 3H) , 0.68 (d, J＝6.6 Hz, 3H) . ESI [M+H] ＝692.2.

N- ( (2S, 3R) -2- ( ( ( (2'-fluoro-4'-methyl- [1, 1'-biphenyl] -4-yl) methyl) (methyl) amino) methyl) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) -2-(4- (trifluoromethyl) phenyl) acetamide, 11 Synthesized using General Procedure A, replacing 4-(3- (trifluoromethyl) benzyl) benzaldehyde with 2'-fluoro-4'-methyl- [1, 1'-biphenyl] -4-carbaldehyde. ESI [M+H] ＝692.2.

N- ( (2S, 3R) -2- ( ( ( (2'-fluoro-4'-methoxy- [1, 1'-biphenyl] -4-yl) methyl) (methyl) amino) methyl) -5-( (S) -1-hydroxypropan-2-yl) -3-methyl-6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) -2- (4- (trifluoromethyl) phenyl) acetamide, 12 Synthesized using General Procedure A, replacing 4- (3- (trifluoromethyl) benzyl) benzaldehyde with 2'-fluoro-4'-methoxy- [1, 1'-biphenyl] -4-carbaldehyde. 1H NMR (400MHz, DMSO-d6) δ 8.72 (s, 1H) , 7.90 (d, J＝7.5 Hz, 1H) , 7.63 (d, J＝7.5 Hz, 2H) , 7.51 (d, J＝7.5 Hz, 2H) , 7.43-7.35 (m, 3H) , 7.27 (d, J＝7.9 Hz, 2H) , 7.10 (d, J＝7.5 Hz, 1H) , 6.96-6.75 (m, 3H) , 4.84 (t, J＝5.1 Hz, 1H) , 4.64 (br. s. , 1H) , 4.52-4.30 (m, 1H) , 3.95-3.72 (m, 5H) , 3.63-3.51 (m, 1H) , 3.44 (s, 3H) , 3.25-3.13 (m, 1H) , 2.96-2.79 (m, 1H) , 2.02 (s, 4H) , 1.08 (d, J＝7.1 Hz, 3H) , 0.68 (d, J＝6.6 Hz, 3H) . ESI [M+H] ＝708.2.

N- ( (2S, 3R) -2- ( ( ( (2'-fluoro-4'- (trifluoromethyl) - [1, 1'-biphenyl] -4-yl) methyl) (methyl) amino) methyl) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) -2- (4- (trifluoromethyl) phenyl) acetamide, 13 Synthesized using General Procedure A, replacing 4- (3- (trifluoromethyl) benzyl) benzaldehyde with 2'-fluoro-4'- (trifluoromethyl) - [1, 1'-biphenyl] -4-carbaldehyde. ESI [M+H] ＝746.2.

N- ( (2S, 3R) -5- ( (S) -1-hydroxypropan-2-yl) -2- ( ( ( (4'-methoxy-2'-methyl- [1, 1'-biphenyl] -4-yl) methyl) (methyl) amino) methyl) -3-methyl-6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) -2- (4- (trifluoromethyl) phenyl) acetamide, 14 Synthesized using General Procedure A, replacing 4- (3- (trifluoromethyl) benzyl) benzaldehyde with 4'-methoxy-2'-methyl- [1, 1'-biphenyl] -4-carbaldehyde. 1H NMR (400MHz, DMSO-d6) δ 8.72 (s, 1H) , 7.90 (d, J＝7.5 Hz, 1H) , 7.65 (d, J＝7.5 Hz, 2H) , 7.53 (d, J＝7.5 Hz, 2H) , 7.31-7.14 (m, 4H) , 7.13-6.99 (m, 2H) , 6.94-6.69 (m, 3H) , 4.89-4.78 (m, 1H) , 4.64 (br. s. , 1H) , 4.45 (d, J＝6.2 Hz, 1H) , 3.97-3.77 (m, 2H) , 3.74 (s, 3H) , 3.62-3.50 (m, 1H) , 3.44 (br. s. , 3H) , 3.27-3.20 (m, 1H) , 2.89 (t, J＝13.9 Hz, 1H) , 2.17 (s, 3H) , 2.04 (s, 4H) , 1.09 (d, J＝6.6 Hz, 3H) , 0.68 (d, J＝6.6 Hz, 3H) . ESI [M+H] ＝704.2.

N- ( (2S, 3R) -2- ( ( ( (2', 4'-difluoro- [1, 1'-biphenyl] -4-yl) methyl) (methyl) amino) methyl) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) -2- (4-(trifluoromethyl) phenyl) acetamide, 15 Synthesized using General Procedure A, replacing 4- (3- (trifluoromethyl) benzyl) benzaldehyde with 2', 4'-difluoro- [1, 1'-biphenyl] -4-carbaldehyde. ESI [M+H] ＝696.2.

N- ( (2S, 3R) -2- ( ( ( [1, 1'-biphenyl] -4-ylmethyl) (methyl) amino) methyl) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) -2-hydroxy-2-phenylacetamide, 16 Synthesized using General Procedure A, replacing 2- (4-(trifluoromethyl) phenyl) acetyl chloride and 4- (3- (trifluoromethyl) benzyl) benzaldehyde with 2-chloro-2-oxo-1-phenylethyl acetate and [1, 1'-biphenyl] -4-carbaldehyde, then removal of the acetyl group was accomplished by stirring in a solution of NaOH in H₂O and MeOH. ESI [M+H]＝608.2.

N- ( (2S, 3R) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-2- ( (methyl ( (2', 4', 6'-trimethyl- [1, 1'-biphenyl] -4-yl) methyl) amino) methyl) -6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) -2- (4- (trifluoromethyl) phenyl) acetamide, 17 Synthesized using General Procedure A, replacing 4- (3- (trifluoromethyl) benzyl) benzaldehyde with 2', 4', 6'-trimethyl- [1, 1'-biphenyl] -4-carbaldehyde. ESI [M+H] ＝702.3.

N- ( (2S, 3R) -2- ( ( ( [1, 1'-biphenyl] -4-ylmethyl) (methyl) amino) methyl) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) -2- (3-fluoro-4-(trifluoromethyl) phenyl) acetamide, 18 Synthesized using General Procedure A, replacing 2- (4-(trifluoromethyl) phenyl) acetyl chloride and 4- (3- (trifluoromethyl) benzyl) benzaldehyde with 2-(3-fluoro-4- (trifluoromethyl) phenyl) acetyl chloride and [1, 1'-biphenyl] -4-carbaldehyde. ESI [M+H] ＝678.2.

N- ( (2S, 3R) -2- ( ( ( [1, 1'-biphenyl] -4-ylmethyl) (methyl) amino) methyl) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) -2- (3, 5-bis (trifluoromethyl) phenyl) acetamide, 19 Synthesized using General Procedure A, replacing 2- (4- (trifluoromethyl) phenyl) acetyl chloride and 4- (3- (trifluoromethyl) benzyl) benzaldehyde with 2- (3, 5-bis (trifluoromethyl) phenyl) acetyl chloride and [1, 1'-biphenyl] -4-carbaldehyde. ESI [M+H] ＝728.2.

N- ( (2S, 3R) -2- ( ( ( [1, 1'-biphenyl] -4-ylmethyl) (methyl) amino) methyl) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) -2- (2, 5-bis (trifluoromethyl) phenyl) acetamide, 20 Synthesized using General Procedure A, replacing 2-(4- (trifluoromethyl) phenyl) acetyl chloride and 4- (3- (trifluoromethyl) benzyl) benzaldehyde with 2- (2, 5-bis (trifluoromethyl) phenyl) acetyl chloride and [1, 1'-biphenyl] -4-carbaldehyde. ESI [M+H] ＝728.2.

N- ( (2S, 3R) -2- ( ( ( (2', 4'-bis (trifluoromethyl) - [1, 1'-biphenyl] -4-yl) methyl) (methyl) amino) methyl) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10- yl) -2- (2, 5-bis (trifluoromethyl) phenyl) acetamide, 21 Synthesized using General Procedure A, replacing 2- (4- (trifluoromethyl) phenyl) acetyl chloride and 4- (3-(trifluoromethyl) benzyl) benzaldehyde with 2- (2, 5-bis (trifluoromethyl) phenyl) acetyl chloride and2', 4'-bis (trifluoromethyl)- [1, 1'-biphenyl]-4-carbaldehyde. 1H NMR (400MHz, DMSO-d6) δ 8.86 (s, 1H) , 8.17-8.03 (m, 2H) , 7.95 (d, J＝4.4 Hz, 2H) , 7.91-7.78 (m, 2H) , 7.62 (d, J＝7.9 Hz, 1H) , 7.41-7.19 (m, 4H) , 7.11 (d, J＝7.5 Hz, 1H) , 6.86 (t, J＝7.7 Hz, 1H) , 4.85 (t, J＝5.3 Hz, 1H) , 4.69 (br. s. , 1H) , 4.54-4.40 (m, 1H) , 4.16-3.97 (m, 2H) , 3.68-3.39 (m, 5H) , 3.02-2.87 (m, 1H) , 2.74-2.55 (m, 3H) , 2.12 (s, 4H) , 1.12 (d, J＝7.1 Hz, 3H) , 0.75 (d, J＝6.6 Hz, 3H) . ESI [M+H] ＝864.2.

N- ( (2S, 3R) -2- ( ( ( (3', 5'-bis (trifluoromethyl) - [1, 1'-biphenyl] -4-yl) methyl) (methyl) amino) methyl) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) -2- (4- (trifluoromethyl) phenyl) acetamide, 22 Synthesized using General Procedure A, replacing 4- (3- (trifluoromethyl) benzyl) benzaldehyde with 3', 5'-bis (trifluoromethyl) - [1, 1'-biphenyl] -4-carbaldehyde. ESI [M+H] ＝796.3.

N- ( (2S, 3R) -2- ( ( ( (5'-fluoro-2'- (trifluoromethyl) - [1, 1'-biphenyl] -4-yl) methyl) (methyl) amino) methyl) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) -2- (4- (trifluoromethyl) phenyl) acetamide, 23 Synthesized using General Procedure A, replacing 4- (3- (trifluoromethyl) benzyl) benzaldehyde with 5'-fluoro-2'- (trifluoromethyl) - [1, 1'-biphenyl] -4-carbaldehyde. ESI [M+H] ＝746.3.

N- ( (2S, 3R) -2- ( ( ( (3'-fluoro-5'-methoxy- [1, 1'-biphenyl] -4-yl) methyl) (methyl) amino) methyl) -5-( (S) -1-hydroxypropan-2-yl) -3-methyl-6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) -2- (4- (trifluoromethyl) phenyl) acetamide, 24 Synthesized using General Procedure A, replacing 4- (3- (trifluoromethyl) benzyl) benzaldehyde with 3'-fluoro-5'-methoxy- [1, 1'-biphenyl] -4-carbaldehyde. ESI [M+H] ＝708.2.

N- ( (2S, 3R) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-2- ( (methyl ( (3', 4', 5'-trifluoro- [1, 1'-biphenyl] -4-yl) methyl) amino) methyl) -6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) -2- (4-(trifluoromethyl) phenyl) acetamide, 25 Synthesized using General Procedure A, replacing 4- (3-(trifluoromethyl) benzyl) benzaldehyde with 3', 4', 5'-trifluoro- [1, 1'-biphenyl] -4-carbaldehyde. ESI [M+H] ＝714.2.

N- ( (2S, 3R) -2- ( ( ( (3', 4'-difluoro- [1, 1'-biphenyl] -4-yl) methyl) (methyl) amino) methyl) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) -2- (4-(trifluoromethyl) phenyl) acetamide, 26 Synthesized using General Procedure A, replacing 4- (3-(trifluoromethyl) benzyl) benzaldehyde with 3', 4'-difluoro- [1, 1'-biphenyl] -4-carbaldehyde. ESI [M+H] ＝696.2.

N- ( (2S, 3R) -2- ( ( ( (3'-chloro-5'-fluoro- [1, 1'-biphenyl] -4-yl) methyl) (methyl) amino) methyl) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) -2-(4- (trifluoromethyl) phenyl) acetamide, 27 Synthesized using General Procedure A, replacing 4-(3- (trifluoromethyl) benzyl) benzaldehyde with 3'-chloro-5'-fluoro- [1, 1'-biphenyl] -4-carbaldehyde. ESI [M+H] ＝712.2.

N- ( (2S, 3R) -2- ( ( ( (3', 5'-difluoro- [1, 1'-biphenyl] -4-yl) methyl) (methyl) amino) methyl) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) -2- (4-(trifluoromethyl) phenyl) acetamide, 28 Synthesized using General Procedure A, replacing 4- (3-(trifluoromethyl) benzyl) benzaldehyde with 3', 5'-difluoro- [1, 1'-biphenyl] -4-carbaldehyde. ESI [M+H] ＝696.2.

N- ( (2S, 3R) -2- ( ( ( (2'-fluoro-5'-methyl- [1, 1'-biphenyl] -4-yl) methyl) (methyl) amino) methyl) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) -2-(4- (trifluoromethyl) phenyl) acetamide, 29 Synthesized using General Procedure A, replacing 4-(3- (trifluoromethyl) benzyl) benzaldehyde with 2'-fluoro-5'-methyl- [1, 1'-biphenyl] -4-carbaldehyde. ESI [M+H] ＝692.2.

N- ( (2S, 3R) -2- ( ( ( (3'-fluoro-5'-methyl- [1, 1'-biphenyl] -4-yl) methyl) (methyl) amino) methyl) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) -2-(4- (trifluoromethyl) phenyl) acetamide, 30 Synthesized using General Procedure A, replacing 4-(3- (trifluoromethyl) benzyl) benzaldehyde with 3'-fluoro-5'-methyl- [1, 1'-biphenyl] -4-carbaldehyde. ESI [M+H] ＝692.2.

N- ( (2S, 3R) -2- ( ( ( (3', 5'-dimethyl- [1, 1'-biphenyl] -4-yl) methyl) (methyl) amino) methyl) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) -2- (4-(trifluoromethyl) phenyl) acetamide, 31 Synthesized using General Procedure A, replacing 4- (3-(trifluoromethyl) benzyl) benzaldehyde with 3', 5'-dimethyl- [1, 1'-biphenyl] -4-carbaldehyde. ESI [M+H] ＝688.3.

N- ( (2S, 3R) -2- ( ( ( [1, 1'-biphenyl] -4-ylmethyl) (methyl) amino) methyl) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) -2- (2-fluoro-4-(trifluoromethyl) phenyl) acetamide, 32 Synthesized using General Procedure A, replacing 2- (4-(trifluoromethyl) phenyl) acetyl chloride and 4- (3- (trifluoromethyl) benzyl) benzaldehyde with 2-(2-fluoro-4- (trifluoromethyl) phenyl) acetyl chloride and [1, 1'-biphenyl]-4-carbaldehyde. 1H NMR (400MHz, DMSO-d6) δ 8.85 (s, 1H) , 7.88 (d, J＝7.5 Hz, 1H) , 7.68-7.48 (m, 6H) , 7.42 (t, J＝7.5 Hz, 2H) , 7.35-7.25 (m, 3H) , 7.12 (d, J＝7.5 Hz, 1H) , 6.87 (t, J＝7.9 Hz, 1H) , 4.85 (t, J＝5.3 Hz, 1H) , 4.69 (br. s. , 1H) , 4.54-4.37 (m, 1H) , 3.99-3.74 (m, 2H) , 3.64-3.40 (m, 3H) , 2.92 (t, J＝13.9 Hz, 1H) , 2.08 (s, 4H) , 1.10 (d, J＝7.1 Hz, 3H) , 0.74 (d, J＝6.6 Hz, 3H) . ESI [M+H] ＝678.2.

N- ( (2S, 3R) -2- ( ( ( (3'-chloro- [1, 1'-biphenyl] -4-yl) methyl) (methyl) amino) methyl) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) -2- (4-(trifluoromethyl) phenyl) acetamide, 33 Synthesized using General Procedure A, replacing 4- (3-(trifluoromethyl) benzyl) benzaldehyde with 3'-chloro- [1, 1'-biphenyl] -4-carbaldehyde. ESI [M+H] ＝694.2.

N- ( (2S, 3R) -2- ( ( ( (2'-chloro-5'- (trifluoromethyl) - [1, 1'-biphenyl] -4-yl) methyl) (methyl) amino) methyl) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) -2- (4- (trifluoromethyl) phenyl) acetamide, 34 Synthesized using General Procedure A, replacing 4- (3- (trifluoromethyl) benzyl) benzaldehyde with 2'-chloro-5'- (trifluoromethyl) - [1, 1'-biphenyl] -4-carbaldehyde. ESI [M+H] ＝762.2.

N- ( (2S, 3R) -2- ( ( ( [1, 1'-biphenyl] -4-ylmethyl) (methyl) amino) methyl) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) -2, 2-difluoro-2-phenylacetamide, 35 Synthesized using General Procedure A, replacing 2- (4-(trifluoromethyl) phenyl) acetyl chloride and 4- (3- (trifluoromethyl) benzyl) benzaldehyde with 2, 2-difluoro-2-phenylacetyl chloride and [1, 1'-biphenyl] -4-carbaldehyde. ESI [M+H] ＝628.2.

N- ( (2S, 3R) -2- ( ( ( [1, 1'-biphenyl] -4-ylmethyl) (methyl) amino) methyl) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) -2, 2-diphenylacetamide, 36 Synthesized using General Procedure A, replacing 2- (4- (trifluoromethyl) phenyl) acetyl chloride and 4- (3- (trifluoromethyl) benzyl) benzaldehyde with 2, 2-diphenylacetyl chloride and [1, 1'-biphenyl] -4-carbaldehyde. ESI [M+H] ＝668.3.

N- ( (2S, 3R) -2- ( ( ( [1, 1'-biphenyl] -4-ylmethyl) (methyl) amino) methyl) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) -2- (2, 4-bis (trifluoromethyl) phenyl) acetamide, 37 Synthesized using General Procedure A, replacing 2-(4- (trifluoromethyl) phenyl) acetyl chloride and 4- (3- (trifluoromethyl) benzyl) benzaldehyde with 2- (2, 4-bis (trifluoromethyl) phenyl) acetyl chloride and [1, 1'-biphenyl] -4-carbaldehyde. ESI [M+H] ＝728.2.

N- ( (2S, 3R) -2- ( ( ( (2', 4'-bis (trifluoromethyl) - [1, 1'-biphenyl] -4-yl) methyl) (methyl) amino) methyl) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) -2- (3, 5-bis (trifluoromethyl) phenyl) acetamide, 38 Synthesized using General Procedure A, replacing 2- (4- (trifluoromethyl) phenyl) acetyl chloride and 4- (3-(trifluoromethyl) benzyl) benzaldehyde with2- (3, 5-bis (trifluoromethyl) phenyl) acetyl chloride and 2', 4'-bis (trifluoromethyl) - [1, 1'-biphenyl] -4-carbaldehyde. ESI [M+H] ＝864.2.

N- ( (2S, 3R) -2- ( ( ( (2'-fluoro-5'- (trifluoromethyl) - [1, 1'-biphenyl] -4-yl) methyl) (methyl) amino) methyl) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) -2- (4- (trifluoromethyl) phenyl) acetamide, 39 Synthesized using General Procedure A, replacing 4- (3- (trifluoromethyl) benzyl) benzaldehyde with 2'-fluoro-5'- (trifluoromethyl) - [1, 1'-biphenyl] -4-carbaldehyde. ESI [M+H] ＝746.2.

N- ( (2S, 3R) -2- ( ( ( [1, 1'-biphenyl] -4-ylmethyl) (methyl) amino) methyl) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) -2- (4-fluorophenyl) -2-hydroxyacetamide, 40 Synthesized using General Procedure A, replacing 2- (4-(trifluoromethyl) phenyl) acetyl chloride and 4- (3- (trifluoromethyl) benzyl) benzaldehyde with 2-chloro-1- (4-fluorophenyl) -2-oxoethyl acetate and [1, 1'-biphenyl] -4-carbaldehyde, then removal of the acetyl group was accomplished by stirring in a solution of NaOH in H₂O and MeOH. . ESI [M+H] ＝626.2.

N- ( (2S, 3R) -2- ( ( ( [1, 1'-biphenyl] -4-ylmethyl) (methyl) amino) methyl) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) -2-hydroxy-2- (4-(trifluoromethyl) phenyl) acetamide, 41 Synthesized using General Procedure A, replacing 2- (4-(trifluoromethyl) phenyl) acetyl chloride and 4- (3- (trifluoromethyl) benzyl) benzaldehyde with 2-chloro-2-oxo-1- (4- (trifluoromethyl) phenyl) ethyl acetate and [1, 1'-biphenyl] -4-carbaldehyde, then removal of the acetyl group was accomplished by stirring in a solution of NaOH in H₂O and MeOH. 1H NMR (400MHz, DMSO-d6) δ 9.89-9.54 (m, 1H) , 8.31-8.09 (m, 1H) , 7.81-7.21 (m, 13H) , 7.19-6.99 (m, 2H) , 6.88 (t, J＝7.9 Hz, 1H) , 5.23 (d, J＝4.0 Hz, 1H) , 5.03-4.74 (m, 2H) , 4.63-4.43 (m, 1H) , 3.70-3.40 (m, 4H) , 3.10-2.76 (m, 2H) , 2.74-2.61 (m, 1H) , 2.14 (d,J＝11.0 Hz, 4H) , 1.15-1.01 (m, 3H) , 0.91-0.70 (m, 3H) . ESI [M+H] ＝676.2.

N- ( (2S, 3R) -2- ( ( ( [1, 1'-biphenyl] -4-ylmethyl) (methyl) amino) methyl) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) -2, 2-difluoro-2- (4-(trifluoromethyl) phenyl) acetamide, 42 Synthesized using General Procedure A, replacing 2- (4-(trifluoromethyl) phenyl) acetyl chloride and 4- (3- (trifluoromethyl) benzyl) benzaldehyde with2, 2- difluoro-2- (4- (trifluoromethyl) phenyl) acetyl chloride and [1, 1'-biphenyl]-4-carbaldehyde. 1H NMR (400MHz, DMSO-d6) δ 10.23 (s, 1H) , 7.97-7.79 (m, 4H) , 7.67-7.49 (m, 4H) , 7.47-7.37 (m, 3H) , 7.35-7.27 (m, 2H) , 7.24 (d, J＝7.9 Hz, 2H) , 6.92 (t, J＝7.7 Hz, 1H) , 4.85 (t, J＝5.1 Hz, 1H) , 4.57 (br. s. , 1H) , 4.48-4.33 (m, 1H) , 3.65-3.46 (m, 1H) , 3.45-3.36 (m, 2H) , 3.28-3.15 (m, 2H) , 3.00-2.81 (m, 1H) , 2.34-2.09 (m, 2H) , 2.06-1.82 (m, 4H) , 1.08 (d, J＝6.6 Hz, 3H) , 0.62 (d, J＝6.2 Hz, 3H) . ESI [M+H] ＝696.2.

N- ( (2S, 3R) -2- ( ( ( (2', 4'-bis (trifluoromethyl) - [1, 1'-biphenyl] -4-yl) methyl) (methyl) amino) methyl) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) -2- (2, 4-bis (trifluoromethyl) phenyl) acetamide, 43 Synthesized using General Procedure A, replacing 2- (4- (trifluoromethyl) phenyl) acetyl chloride and 4- (3-(trifluoromethyl) benzyl) benzaldehyde with2- (2, 4-bis (trifluoromethyl) phenyl) acetyl chloride and 2', 4'-bis (trifluoromethyl) - [1, 1'-biphenyl] -4-carbaldehyde. ESI [M+H] ＝864.2.

(R) -N- ( (2S, 3R) -2- ( ( ( [1, 1'-biphenyl] -4-ylmethyl) (methyl) amino) methyl) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) -2-hydroxy-2-phenylacetamide, 44 Synthesized using General Procedure A, replacing 2- (4-(trifluoromethyl) phenyl) acetyl chloride and 4- (3- (trifluoromethyl) benzyl) benzaldehyde with (R) -2-chloro-2-oxo-1-phenylethyl acetate and [1, 1'-biphenyl] -4-carbaldehyde, then removal of the acetyl group was accomplished by stirring in a solution of NaOH in H₂O and MeOH. ESI [M+H] ＝608.2.

N- ( (2S, 3R) -2- ( ( (4-benzylbenzyl) (methyl) amino) methyl) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) -2- (4-(trifluoromethyl) phenyl) acetamide, 45. Synthesized using General Procedure A, replacing 4- (3-(trifluoromethyl) benzyl) benzaldehyde with 4-benzylbenzaldehyde. 1H NMR (400MHz, DMSO-d6) δ 8.71 (s, 1H) , 7.98-7.80 (m, 1H) , 7.70-7.57 (m, 2H) , 7.52 (d, J＝7.5 Hz, 2H) , 7.29-7.07 (m, 10H) , 6.86 (t, J＝7.9 Hz, 1H) , 4.83 (t, J＝5.1 Hz, 1H) , 4.61 (br. s. , 1H) , 4.50-4.28 (m, 1H) , 3.87 (s, 2H) , 3.85-3.74 (m, 2H) , 3.59-3.50 (m, 1H) , 3.46-3.35 (m, 4H) , 3.27-3.19 (m, 1H) , 2.87 (t, J＝13.9 Hz, 1H) , 2.17-1.87 (m, 4H) , 1.08 (d, J＝6.6 Hz, 3H) , 0.65 (d, J＝6.6 Hz, 3H) . ESI [M+H] ＝674.2.

N- ( (2S, 3R) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-2- ( (methyl (4- (2-phenylpropan-2-yl) benzyl) amino) methyl) -6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) -2- (4-(trifluoromethyl) phenyl) acetamide, 46. Synthesized using General Procedure A, replacing 4- (3-(trifluoromethyl) benzyl) benzaldehyde with 4- (2-phenylpropan-2-yl) benzaldehyde. ESI [M+H] ＝702.3.

N- ( (2S, 3R) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-2- ( (methyl (4- (1-phenylethyl) benzyl) amino) methyl) -6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) -2- (4- (trifluoromethyl) phenyl) acetamide, 47. Synthesized using General Procedure A, replacing 4- (3- (trifluoromethyl) benzyl) benzaldehyde with 4- (1-phenylethyl) benzaldehyde. ESI [M+H] ＝688.3.

N- ( (2S, 3R) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-2- ( (methyl (4- (1-phenylvinyl) benzyl) amino) methyl) -6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) -2- (4- (trifluoromethyl) phenyl) acetamide, 48. Synthesized using General Procedure A, replacing 4- (3- (trifluoromethyl) benzyl) benzaldehyde with 4- (1-phenylvinyl) benzaldehyde. ESI [M+H] ＝686.2.

N- ( (2S, 3R) -2- ( ( (4- (3-fluorobenzyl) benzyl) (methyl) amino) methyl) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) -2- (4- (trifluoro methyl) phenyl) acetamide, 49. Synthesized using General Procedure A, replacing 4- (3-(trifluoromethyl) benzyl) benzaldehyde with 4- (3-fluorobenzyl) benzaldehyde. ESI [M+H] ＝692.2.

N- ( (2S, 3R) -2- ( ( (4- (2, 5-difluorobenzyl) benzyl) (methyl) amino) methyl) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) -2- (4-(trifluoromethyl) phenyl) acetamide, 50. Synthesized using General Procedure A, replacing 4- (3-(trifluoromethyl) benzyl) benzaldehyde with 4- (2, 5-difluorobenzyl) benzaldehyde. ESI [M+H] ＝710.2.

N- ( (2S, 3R) -2- ( ( (4- (2, 3-difluorobenzyl) benzyl) (methyl) amino) methyl) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) -2- (4-(trifluoromethyl) phenyl) acetamide, 51. Synthesized using General Procedure A, replacing 4- (3-(trifluoromethyl) benzyl) benzaldehyde with 4- (2, 3-difluorobenzyl) benzaldehyde. ESI [M+H] ＝710.2.

N- ( (2S, 3R) -2- ( ( (4- (5-fluoro-2-methoxybenzyl) benzyl) (methyl) amino) methyl) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) -2- (4-(trifluoromethyl) phenyl) acetamide, 52. Synthesized using General Procedure A, replacing 4- (3-(trifluoromethyl) benzyl) benzaldehyde with 4- (5-fluoro-2-methoxybenzyl) benzaldehyde. ESI [M+H] ＝722.3.

N- ( (2S, 3R) -2- ( ( (4- (difluoro (phenyl) methyl) benzyl) (methyl) amino) methyl) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) -2- (4-(trifluoromethyl) phenyl) acetamide, 53. Synthesized using General Procedure A, replacing 4- (3-(trifluoromethyl) benzyl) benzaldehyde with 4- (difluoro (phenyl) methyl) benzaldehyde. ESI [M+H] ＝710.3.

N- ( (2S, 3R) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-2- ( (methyl (4- (3-methylbenzyl) benzyl) amino) methyl) -6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) -2- (4- (trifluoromethyl) phenyl) acetamide, 54. Synthesized using General Procedure A, replacing 4- (3- (trifluoromethyl) benzyl) benzaldehyde with 4- (3-methylbenzyl) benzaldehyde. ESI [M+H] ＝688.2.

N- ( (2S, 3R) -2- ( ( (4- (3, 5-dimethylbenzyl) benzyl) (methyl) amino) methyl) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) -2- (4-(trifluoromethyl) phenyl) acetamide, 55. Synthesized using General Procedure A, replacing 4- (3-(trifluoromethyl) benzyl) benzaldehyde with 4- (3, 5-dimethylbenzyl) benzaldehyde. 1H NMR (400MHz, DMSO-d6) δ 8.68 (s, 1H) , 7.90 (d, J＝7.5 Hz, 1H) , 7.63 (d, J＝7.9 Hz, 2H) , 7.50 (d, J＝7.9 Hz, 2H) , 7.26-7.01 (m, 5H) , 6.86 (t, J＝7.9 Hz, 1H) , 6.81-6.67 (m, 3H) , 4.83 (br. s. , 1H) , 4.61 (br. s. , 1H) , 4.50-4.35 (m, 1H) , 3.92-3.69 (m, 4H) , 3.22 (dd, J＝5.1, 15.2 Hz, 1H) , 2.87 (t, J＝13.7 Hz, 1H) , 2.26-2.13 (m, 6H) , 2.08-1.88 (m, 4H) , 1.08 (d, J＝7.1 Hz, 3H) , 0.64 (d, J＝6.2 Hz, 3H) . ESI [M+H] ＝702.3.

N- ( (2S, 3R) -2- ( ( (4- (3, 4-difluorobenzyl) benzyl) (methyl) amino) methyl) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) -2- (4-(trifluoromethyl) phenyl) acetamide, 56. Synthesized using General Procedure A, replacing 4- (3-(trifluoromethyl) benzyl) benzaldehyde with 4- (3, 4-difluorobenzyl) benzaldehyde. ESI [M+H] ＝710.3.

N- ( (2S, 3R) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-2- ( (methyl (4- (3, 4, 5-trifluorobenzyl) benzyl) amino) methyl) -6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) -2- (4- (trifluoromethyl) phenyl) acetamide, 57. Synthesized using General Procedure A, replacing 4- (3- (trifluoromethyl) benzyl) benzaldehyde with 4- (3, 4, 5-trifluorobenzyl) benzaldehyde. 1H NMR (400MHz, DMSO-d6) δ 8.68 (s, 1H) , 7.90 (d, J＝7.5 Hz, 1H) , 7.71-7.56 (m, 2H) , 7.49 (d, J＝7.9 Hz, 2H) , 7.21-7.06 (m, 7H) , 6.86 (t, J＝7.9 Hz, 1H) , 4.84 (br. s. , 1H) , 4.61 (br. s. , 1H) ,4.45-4.33 (m, 1H) , 3.87 (s, 2H) , 3.79 (br. s. , 2H) , 3.59-3.49 (m, 1H) , 3.47-3.35 (m, 3H) , 3.23 (dd, J＝5.1, 15.2 Hz, 1H) , 2.87 (t, J＝13.9 Hz, 1H) , 2.10-1.91 (m, 4H) , 1.15-0.99 (m, 3H) , 0.64 (d, J＝6.6 Hz, 3H) . ESI [M+H] ＝728.3.

N- ( (2S, 3R) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-2- ( (methyl (4- ( (perfluorophenyl)methyl) benzyl) amino) methyl) -6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) -2- (4-(trifluoromethyl) phenyl) acetamide, 58. Synthesized using General Procedure A, replacing 4- (3-(trifluoromethyl) benzyl) benzaldehyde with 4- ( (perfluorophenyl) methyl) benzaldehyde. ESI [M+H] ＝764.2.

N- ( (2S, 3R) -2- ( ( (4- (4-fluoro-3- (trifluoromethyl) benzyl) benzyl) (methyl) amino) methyl) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) -2- (4-(trifluoromethyl) phenyl) acetamide, 59. Synthesized using General Procedure A, replacing 4- (3-(trifluoromethyl) benzyl) benzaldehyde with 4- (4-fluoro-3- (trifluoromethyl) benzyl) benzaldehyde. ESI [M+H] ＝760.3.

N- ( (2S, 3R) -2- ( ( (4- (2-chloro-5- (trifluoromethyl) benzyl) benzyl) (methyl) amino) methyl) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) -2- (4-(trifluoromethyl) phenyl) acetamide, 61. Synthesized using General Procedure A, replacing 4- (3-(trifluoromethyl) benzyl) benzaldehyde with 4- (2-chloro-5- (trifluoromethyl) benzyl) benzaldehyde. 1H NMR (400MHz, DMSO-d6) δ 8.68 (s, 1H) , 7.89 (d, J＝7.5 Hz, 1H) , 7.73-7.55 (m, 6H) , 7.51 (d, J＝7.5 Hz, 2H) , 7.40-7.21 (m, 1H) , 7.17-7.05 (m, 5H) , 6.86 (t, J＝7.9 Hz, 1H) , 4.81 (br. s. , 1H) , 4.61 (br. s. , 1H) , 4.42 (d, J＝6.2 Hz, 1H) , 4.16-4.04 (m, 2H) , 3.86-3.74 (m, 2H) , 3.61-3.41 (m, 2H) , 2.93-2.81 (m, 1H) , 2.10-1.85 (m, 4H) , 1.08 (d, J＝6.6 Hz, 3H) , 0.64 (d, J＝6.2 Hz, 3H) . ESI [M+H] ＝776.2.

N- ( (2S, 3R) -2- ( ( (4- (2-fluorophenoxy) benzyl) (methyl) amino) methyl) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) -2, 2-diphenylacetamide, 62 Synthesized using General Procedure A, replacing 2- (4- (trifluoromethyl) phenyl) acetyl chloride and 4- (3- (trifluoromethyl) benzyl) benzaldehyde with2, 2-diphenylacetyl chloride and 4-(2-fluorophenoxy) benzaldehyde. ESI [M+H] ＝702.3.

2- (4-fluorophenyl) -N- ( (2S, 3R) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-2- ( (methyl (4-phenoxybenzyl) amino) methyl) -6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) acetamide, 63 Synthesized using General Procedure A, replacing 2- (4-(trifluoromethyl) phenyl) acetyl chloride and 4- (3- (trifluoromethyl) benzyl) benzaldehyde with2- (4-fluorophenyl) acetyl chloride and 4-phenoxybenzaldehyde. ESI [M+H] ＝626.3.

N- ( (2S, 3R) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-2- ( (methyl (4-phenoxybenzyl) amino) methyl) -6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) -2- (p-tolyl) acetamide, 64 Synthesized using General Procedure A, replacing 2- (4-(trifluoromethyl) phenyl) acetyl chloride and 4- (3- (trifluoromethyl) benzyl) benzaldehyde with2- (p-tolyl) acetyl chloride and 4-phenoxybenzaldehyde. ESI [M+H] ＝622.3.

N- ( (2S, 3R) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-2- ( (methyl (4-phenoxybenzyl) amino) methyl) -6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) -2- (4-(trifluoromethyl) phenyl) acetamide, 65. Synthesized using General Procedure A, replacing 4- (3-(trifluoromethyl) benzyl) benzaldehyde with 4-phenoxybenzaldehyde. 1H NMR (400MHz, DMSO-d6) δ 8.72 (s, 1H) , 7.89 (d, J＝7.5 Hz, 1H) , 7.66 (d, J＝8.4 Hz, 2H) , 7.55 (d, J＝7.9 Hz, 2H) , 7.35 (t, J＝7.9 Hz, 2H) , 7.20 (d, J＝8.4 Hz, 2H) , 7.14-7.03 (m, 2H) , 7.00-6.76 (m, 5H) , 4.82 (t, J＝5.3 Hz, 1H) , 4.62 (t, J＝5.1 Hz, 1H) , 4.51-4.40 (m, 1H) , 3.89-3.73 (m, 2H) , 3.65-3.49 (m, 1H) , 3.46-3.36 (m, 3H) , 3.25-3.18 (m, 1H) , 2.89 (t, J＝13.9 Hz, 1H) , 2.12-1.88 (m, 4H) , 1.09 (d, J＝6.6 Hz, 3H) , 0.68 (d, J＝6.6 Hz, 3H) . ESI [M+H] ＝676.2.

2- (4-cyanophenyl) -N- ( (2S, 3R) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-2- ( (methyl (4-phenoxybenzyl) amino) methyl) -6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) acetamide, 66 Synthesized using General Procedure A, replacing 2- (4-(trifluoromethyl) phenyl) acetyl chloride and 4- (3- (trifluoromethyl) benzyl) benzaldehyde with2- (4-cyanophenyl) acetyl chloride and 4-phenoxybenzaldehyde. 1H NMR (400MHz, CHLOROFORM-d) δ 8.21 (d, J＝7.5 Hz, 1H) , 7.54 (d, J＝7.5 Hz, 2H) , 7.37 (d, J＝7.5 Hz, 2H) , 7.30-7.15 (m, 4H) , 7.13-6.99 (m, 2H) , 6.97 -6.78 (m, 5H) , 4.86 (br. s. , 1H) , 4.63 (br. s. , 1H) , 3.86-3.66 (m, 3H) , 3.63-3.42 (m, 3H) , 3.18-2.94 (m, 2H) , 2.64-2.34 (m, 2H) , 2.27-2.08 (m, 3H) , 2.07-1.88 (m, 1H) , 1.25-1.01 (m, 3H) , 0.58 (d, J＝6.2 Hz, 3H) . ESI [M+H] ＝633.2.

N- ( (2S, 3R) -2- ( ( (4- (2-fluorophenoxy) benzyl) (methyl) amino) methyl) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) -2- (4-fluorophenyl) acetamide, 67 Synthesized using General Procedure A, replacing 2- (4-(trifluoromethyl) phenyl) acetyl chloride and 4- (3- (trifluoromethyl) benzyl) benzaldehyde with2- (4-fluorophenyl) acetyl chloride and 4- (2-fluorophenoxy) benzaldehyde. 1H NMR (400MHz, CHLOROFORM-d) δ 8.35 (d, J＝7.9 Hz, 1H) , 7.80 (br. s. , 1H) , 7.28-7.14 (m, 4H) , 7.13-6.94 (m, 6H) , 6.90-6.81 (m, 3H) , 4.65 (t, J＝5.3 Hz, 1H) , 4.55-4.30 (m, 1H) , 3.73 (dd, J＝3.5, 11.9 Hz, 1H) , 3.67 (s, 2H) , 3.58-3.43 (m, 2H) , 3.32 (d, J＝12.8 Hz, 1H) , 3.07-3.00 (m, 2H) , 2.35 (dd, J＝6.2, 12.8 Hz, 1H) , 2.23-2.06 (m, 4H) , 2.03-1.89 (m, 1H) , 1.21-1.10 (m, 3H) , 0.48 (d, J＝6.6 Hz, 3H) . ESI [M+H] ＝644.2.

N- ( (2S, 3R) -2- ( ( (4- (4-fluorophenoxy) benzyl) (methyl) amino) methyl) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) -2- (4-fluorophenyl) acetamide, 68 Synthesized using General Procedure A, replacing 2- (4-(trifluoromethyl) phenyl) acetyl chloride and 4- (3- (trifluoromethyl) benzyl) benzaldehyde with2- (4-fluorophenyl) acetyl chloride and 4- (4-fluorophenoxy) benzaldehyde. ESI [M+H] ＝644.2.

N- ( (2S, 3R) -2- ( ( (4- (2-fluorophenoxy) benzyl) (methyl) amino) methyl) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) -2- (4-methoxyphenyl) acetamide, 69 Synthesized using General Procedure A, replacing 2- (4-(trifluoromethyl) phenyl) acetyl chloride and 4- (3- (trifluoromethyl) benzyl) benzaldehyde with2- (4-methoxyphenyl) acetyl chloride and 4- (2-fluorophenoxy) benzaldehyde. ESI [M+H] ＝656.2.

N- ( (2S, 3R) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-2- ( (methyl (4- (p-tolyloxy) benzyl) amino) methyl) -6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) -2- (4-methoxyphenyl) acetamide, 70 Synthesized using General Procedure A, replacing 2- (4-(trifluoromethyl) phenyl) acetyl chloride and 4- (3- (trifluoromethyl) benzyl) benzaldehyde with2- (4-methoxyphenyl) acetyl chloride and 4- (p-tolyloxy) benzaldehyde. ESI [M+H] ＝652.2.

N- ( (2S, 3R) -2- ( ( (4- (4-fluorophenoxy) benzyl) (methyl) amino) methyl) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) -2- (4-methoxyphenyl) acetamide, 71 Synthesized using General Procedure A, replacing 2- (4-(trifluoromethyl) phenyl) acetyl chloride and 4- (3- (trifluoromethyl) benzyl) benzaldehyde with2- (4-methoxyphenyl) acetyl chloride and 4- (4-fluorophenoxy) benzaldehyde. 1H NMR (400MHz, DMSO-d6) δ 8.32 (s, 1H) , 8.10 (d, J＝7.9 Hz, 1H) , 7.31-7.11 (m, 6H) , 7.07-6.95 (m, 3H) , 6.92 -6.75 (m, 5H) , 4.83 (t, J＝5.1 Hz, 1H) , 4.59 (br. s. , 1H) , 4.50-4.38 (m, 1H) , 3.71 (s, 3H) , 3.64 (s, 2H) , 3.58-3.47 (m, 1H) , 3.41 (dd, J＝5.3, 11.0 Hz, 1H) , 2.84 (t, J＝13.9 Hz, 1H) , 2.43-2.26 (m, 2H) , 2.18-1.87 (m, 4H) , 1.07 (d, J＝7.1 Hz, 3H) , 0.66 (d, J＝6.6 Hz, 3H) . ESI [M+H] ＝656.2.

2- (4-fluorophenyl) -N- ( (2S, 3R) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-2- ( (methyl (4- (o-tolyloxy) benzyl) amino) methyl) -6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) acetamide, 72 Synthesized using General Procedure A, replacing 2- (4-(trifluoromethyl) phenyl) acetyl chloride and 4- (3- (trifluoromethyl) benzyl) benzaldehyde with2- (4-fluorophenyl) acetyl chloride and 4- (o-tolyloxy) benzaldehyde. ESI [M+H] ＝640.2.

2- (4-fluorophenyl) -N- ( (2S, 3R) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-2- ( (methyl (4- (p-tolyloxy) benzyl) amino) methyl) -6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) acetamide, 74 Synthesized using General Procedure A, replacing 2- (4-(trifluoromethyl) phenyl) acetyl chloride and 4- (3- (trifluoromethyl) benzyl) benzaldehyde with2- (4-fluorophenyl) acetyl chloride and 4- (p-tolyloxy) benzaldehyde. 1H NMR (400MHz, CHLOROFORM-d) δ 8.35 (d, J＝7.9 Hz, 1H) , 7.81 (br. s. , 1H) , 7.28-7.13 (m, 4H) , 7.12-7.04 (m, 3H) , 6.98 (t, J＝8.4 Hz, 2H) , 6.91-6.78 (m, 4H) , 4.66 (t, J＝5.3 Hz, 1H) , 4.50 (br. s. , 1H) , 3.74 (dd, J＝3.1, 11.9 Hz, 1H) , 3.69-3.61 (m, 2H) , 3.57-3.41 (m, 2H) , 3.37-3.27 (m, 1H) , 3.08 -2.99 (m, 2H) , 2.35 (dd, J＝6.2, 12.8 Hz, 1H) , 2.26 (s, 3H) , 2.19-2.08 (m, 4H) , 2.02-1.89 (m, 1H) , 1.21-1.06 (m, 3H) , 0.49 (d, J＝6.6 Hz, 3H) . ESI [M+H] ＝640.2.

N- ( (2S, 3R) -2- ( ( (4- (2-fluorophenoxy) benzyl) (methyl) amino) methyl) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) -2- (p-tolyl) acetamide, 75 Synthesized using General Procedure A, replacing 2- (4- (trifluoromethyl) phenyl) acetyl chloride and 4- (3- (trifluoromethyl) benzyl) benzaldehyde with2- (p-tolyl) acetyl chloride and 4- (2-fluorophenoxy) benzaldehyde. ESI [M+H] ＝640.2.

N- ( (2S, 3R) -2- ( ( (4- (4-fluorophenoxy) benzyl) (methyl) amino) methyl) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) -2- (p-tolyl) acetamide, 76 Synthesized using General Procedure A, replacing 2- (4- (trifluoromethyl) phenyl) acetyl chloride and 4- (3- (trifluoromethyl) benzyl) benzaldehyde with2- (p-tolyl) acetyl chloride and 4- (4-fluorophenoxy) benzaldehyde. 1H NMR (400MHz, DMSO-d6) δ 8.35 (s, 1H) , 8.08 (d, J＝7.5 Hz, 1H) , 7.27-7.15 (m, 6H) , 7.15-7.10 (m, 2H) , 7.09-6.96 (m, 3H) , 6.93-6.78 (m, 3H) , 4.83 (t, J＝5.3 Hz, 1H) , 4.60 (br. s. , 1H) , 4.52-4.29 (m, 1H) , 3.78-3.61 (m, 2H) , 3.58-3.34 (m, 4H) ,3.23 (dd, J＝5.1, 15.2 Hz, 1H) , 3.00-2.76 (m, 1H) , 2.46-2.36 (m, 2H) , 2.32-2.21 (m, 3H) , 2.10 -1.91 (m, 4H) , 1.12-1.03 (m, 3H) , 0.65 (d, J＝6.6 Hz, 3H) . ESI [M+H] ＝640.2.

N- ( (2S, 3R) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-2- ( (methyl (4- (o-tolyloxy) benzyl) amino) methyl) -6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) -2- (p-tolyl) acetamide, 77 Synthesized using General Procedure A, replacing 2- (4-(trifluoromethyl) phenyl) acetyl chloride and 4- (3- (trifluoromethyl) benzyl) benzaldehyde with2- (p-tolyl) acetyl chloride and 4- (o-tolyloxy) benzaldehyde. 1H NMR (400MHz, DMSO-d6) δ 8.34 (s, 1H) , 8.08 (d, J＝7.9 Hz, 1H) , 7.37-7.24 (m, 1H) , 7.23-6.95 (m, 9H) , 6.88-6.68 (m, 4H) , 4.83 (t, J＝5.3 Hz, 1H) , 4.60 (br. s. , 1H) , 4.50-4.32 (m, 1H) , 3.74-3.62 (m, 2H) , 3.58-3.34 (m, 4H) , 3.27-3.15 (m, 1H) , 2.95-2.76 (m, 1H) , 2.45-2.36 (m, 2H) , 2.32-2.22 (m, 3H) , 2.14 (s, 3H) , 2.08-1.85 (m, 4H) , 1.08 (d, J＝7.1 Hz, 3H) , 0.64 (d, J＝6.6 Hz, 3H) . ESI [M+H] ＝636.3.

N- ( (2S, 3R) -2- ( ( (4- (2-fluorophenoxy) benzyl) (methyl) amino) methyl) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) -2- (4-(trifluoromethyl) phenyl) acetamide, 78. Synthesized using General Procedure A, replacing 4- (3- (trifluoromethyl) benzyl) benzaldehyde with 4- (2-fluorophenoxy) benzaldehyde. ESI [M+H] ＝694.2.

N- ( (2S, 3R) -2- ( ( (4- (4-fluorophenoxy) benzyl) (methyl) amino) methyl) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) -2- (4-(trifluoromethyl) phenyl) acetamide, 79. Synthesized using General Procedure A, replacing 4- (3-(trifluoromethyl) benzyl) benzaldehyde with 4- (4-fluorophenoxy) benzaldehyde. 1H NMR (400MHz, DMSO-d6) δ 8.73 (s, 1H) , 7.89 (d, J＝7.5 Hz, 1H) , 7.66 (d, J＝7.9 Hz, 2H) , 7.54 (d, J＝7.9 Hz, 2H) , 7.28-7.14 (m, 4H) , 7.10 (d, J＝7.5 Hz, 1H) , 7.00 (dd, J＝4.6, 9.0 Hz, 2H) , 6.91-6.75 (m, 3H) , 4.83 (t, J＝5.3 Hz, 1H) , 4.61 (br. s. , 1H) , 4.51-4.35 (m, 1H) , 4.00-3.76 (m, 2H) , 3.67-3.44 (m, 3H) , 3.29-3.17 (m, 2H) , 2.96-2.79 (m, 1H) , 2.14-1.87 (m, 4H) , 1.08 (d, J＝6.6 Hz, 3H) , 0.67 (d, J＝6.2 Hz, 3H) . ESI [M+H] ＝694.2.

N- ( (2S, 3R) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-2- ( (methyl (4- (o-tolyloxy) benzyl) amino) methyl) -6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) -2- (4-(trifluoromethyl) phenyl) acetamide, 80. Synthesized using General Procedure A, replacing 4- (3-(trifluoromethyl) benzyl) benzaldehyde with 4- (o-tolyloxy) benzaldehyde. 1H NMR (400MHz, DMSO-d6) δ 8.73 (s, 1H) , 7.88 (d, J＝7.5 Hz, 1H) , 7.65 (d, J＝7.9 Hz, 2H) , 7.53 (d, J＝7.5 Hz, 2H) , 7.28 (d, J＝7.5 Hz, 1H) , 7.16 (d, J＝8.4 Hz, 3H) , 7.12-7.01 (m, 2H) , 6.93-6.70 (m, 4H) , 4.83 (t, J＝5.3 Hz, 1H) , 4.61 (br. s. , 1H) , 4.48-4.28 (m, 1H) , 4.04-3.71 (m, 2H) , 3.62-3.50 (m, 1H) , 3.46-3.40 (m, 2H) , 3.24-3.11 (m, 1H) , 2.88 (t, J＝13.9 Hz, 1H) , 2.23-2.11 (m, 3H) , 2.08-1.93 (m, 4H) , 1.08 (d, J＝7.1 Hz, 3H) , 0.66 (d, J＝6.6 Hz, 3H) . ESI [M+H] ＝690.2.

N- ( (2S, 3R) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-2- ( (methyl (4- (p-tolyloxy) benzyl) amino) methyl) -6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) -2- (4-(trifluoromethyl) phenyl) acetamide, 81. Synthesized using General Procedure A, replacing 4- (3-(trifluoromethyl) benzyl) benzaldehyde with 4- (p-tolyloxy) benzaldehyde. ESI [M+H] ＝690.2.

N- ( (2S, 3R) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-2- ( (methyl (4-phenoxybenzyl) amino) methyl) -6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) -2- (3- (trifluoromethyl) phenyl) acetamide, 82 Synthesized using General Procedure A, replacing 2- (4-(trifluoromethyl) phenyl) acetyl chloride and 4- (3- (trifluoromethyl) benzyl) benzaldehyde with2- (3-(trifluoromethyl) phenyl) acetyl chloride and 4-phenoxybenzaldehyde. ESI [M+H] ＝676.2.

N- ( (2S, 3R) -2- ( ( (4- (2-fluorophenoxy) benzyl) (methyl) amino) methyl) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) -2- (3-(trifluoromethyl) phenyl) acetamide, 83 Synthesized using General Procedure A, replacing 2- (4-(trifluoromethyl) phenyl) acetyl chloride and 4- (3- (trifluoromethyl) benzyl) benzaldehyde with2- (3-(trifluoromethyl) phenyl) acetyl chloride and 4- (2-fluorophenoxy) benzaldehyde. ESI [M+H] ＝694.2.

N- ( (2S, 3R) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-2- ( (methyl (4- (o-tolyloxy) benzyl) amino) methyl) -6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) -2- (3-(trifluoromethyl) phenyl) acetamide, 84 Synthesized using General Procedure A, replacing 2- (4-(trifluoromethyl) phenyl) acetyl chloride and 4- (3- (trifluoromethyl) benzyl) benzaldehyde with2- (3-(trifluoromethyl) phenyl) acetyl chloride and 4- (o-tolyloxy) benzaldehyde. 1H NMR (400MHz, DMSO-d6) δ 8.77 (s, 1H) , 7.86 (d, J＝7.5 Hz, 1H) , 7.69 (br. s. , 1H) , 7.64-7.57 (m, 2H) , 7.56-7.46 (m, 1H) , 7.28 (d, J＝7.1 Hz, 1H) , 7.22-7.02 (m, 5H) , 6.92-6.71 (m, 4H) , 4.83 (t, J＝5.3 Hz, 1H) , 4.60 (br. s. , 1H) , 4.48-4.32 (m, 1H) , 3.93-3.72 (m, 2H) , 3.65-3.40 (m, 4H) , 2.89 (t, J＝13.9 Hz, 1H) , 2.13 (s, 3H) , 2.09-1.94 (m, 4H) , 1.09 (d, J＝6.6 Hz, 3H) , 0.66 (d, J＝6.6 Hz, 3H) . ESI [M+H] ＝690.2.

N- ( (2S, 3R) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-2- ( (methyl (4- (p-tolyloxy) benzyl) amino) methyl) -6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) -2- (p-tolyl) acetamide, 85 Synthesized using General Procedure A, replacing 2- (4-(trifluoromethyl) phenyl) acetyl chloride and 4- (3- (trifluoromethyl) benzyl) benzaldehyde with2- (p-tolyl) acetyl chloride and 4- (p-tolyloxy) benzaldehyde. 1H NMR (400MHz, DMSO-d6) δ 8.34 (s, 1H) , 8.07 (d, J＝7.5 Hz, 1H) , 7.26-6.97 (m, 9H) , 6.90-6.78 (m, 5H) , 4.83 (t, J＝5.1 Hz, 1H) , 4.59 (br. s. , 1H) , 4.49-4.29 (m, 1H) , 3.74-3.60 (m, 2H) , 3.56-3.39 (m, 2H) , 2.84 (t, J＝13.7 Hz, 1H) , 2.43-2.35 (m, 2H) , 2.26 (s, 6H) , 2.08-1.77 (m, 4H) , 1.08 (s, 3H) , 0.64 (d, J＝6.6 Hz, 3H) . ESI [M+H] ＝636.3.

N- ( (2S, 3R) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-2- ( (methyl (4- (o-tolyloxy) benzyl) amino) methyl) -6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) -2- (pyridin-4-yl) acetamide, 86 Synthesized using General Procedure A, replacing 2- (4-(trifluoromethyl) phenyl) acetyl chloride and 4- (3- (trifluoromethyl) benzyl) benzaldehyde with2-(pyridin-4-yl) acetyl chloride and 4- (o-tolyloxy) benzaldehyde. ESI [M+H] ＝623.2.

N- ( (2S, 3R) -2- ( ( (4- (2-fluorophenoxy) benzyl) (methyl) amino) methyl) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) -2- (2-(trifluoromethyl) phenyl) acetamide, 87 Synthesized using General Procedure A, replacing 2- (4-(trifluoromethyl) phenyl) acetyl chloride and 4- (3- (trifluoromethyl) benzyl) benzaldehyde with2- (2-(trifluoromethyl) phenyl) acetyl chloride and 4- (2-fluorophenoxy) benzaldehyde. ESI [M+H] ＝694.2.

N- ( (2S, 3R) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-2- ( (methyl (4- (o-tolyloxy) benzyl) amino) methyl) -6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) -2- (2-(trifluoromethyl) phenyl) acetamide, 88 Synthesized using General Procedure A, replacing 2- (4-(trifluoromethyl) phenyl) acetyl chloride and 4- (3- (trifluoromethyl) benzyl) benzaldehyde with2- (2-(trifluoromethyl) phenyl) acetyl chloride and 4- (o-tolyloxy) benzaldehyde. 1H NMR (400MHz, DMSO-d6) δ 8.43 (s, 1H) , 8.00 (d, J＝7.9 Hz, 1H) , 7.73 (d, J＝7.9 Hz, 1H) , 7.68-7.60 (m, 1H) , 7.59-7.47 (m, 2H) , 7.30 (d, J＝7.1 Hz, 1H) , 7.24-7.13 (m, 3H) , 7.11-7.01 (m, 2H) , 6.92-6.75 (m, 4H) , 4.83 (t, J＝5.3 Hz, 1H) , 4.63 (br. s. , 1H) , 4.50-4.39 (m, 1H) , 4.05-3.81 (m, 2H) , 3.65-3.51 (m, 1H) , 3.43 (d, J＝13.7 Hz, 3H) , 3.25-3.11 (m, 1H) , 2.87 (t, J＝13.9 Hz, 1H) , 2.14 (s, 3H) , 2.08-1.93 (m, 4H) , 1.15-1.00 (m, 3H) , 0.66 (d, J＝6.6 Hz, 3H) . ESI [M+H] ＝690.3.

N- ( (2S, 3R) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-2- ( (methyl (4- (o-tolyloxy) benzyl) amino) methyl) -6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) -2- (2-methoxyphenyl) acetamide, 89 Synthesized using General Procedure A, replacing 2- (4-(trifluoromethyl) phenyl) acetyl chloride and 4- (3- (trifluoromethyl) benzyl) benzaldehyde with2- (2-methoxyphenyl) acetyl chloride and 4- (o-tolyloxy) benzaldehyde. ESI [M+H] ＝652.2.

N- ( (2S, 3R) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-2- ( (methyl (4-phenoxybenzyl) amino) methyl) -6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) -2- (4-(trifluoromethoxy) phenyl) acetamide, 90 Synthesized using General Procedure A, replacing 2-(4- (trifluoromethyl) phenyl) acetyl chloride and 4- (3- (trifluoromethyl) benzyl) benzaldehyde with2-(4- (trifluoromethoxy) phenyl) acetyl chloride and 4-phenoxybenzaldehyde. ESI [M+H] ＝692.2.

N- ( (2S, 3R) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-2- ( (methyl (4- (o-tolyloxy) benzyl) amino) methyl) -6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) -2- (4-(trifluoromethoxy) phenyl) acetamide, 91 Synthesized using General Procedure A, replacing 2-(4- (trifluoromethyl) phenyl) acetyl chloride and 4- (3- (trifluoromethyl) benzyl) benzaldehyde with2-(4- (trifluoromethoxy) phenyl) acetyl chloride and 4- (o-tolyloxy) benzaldehyde. ESI [M+H] ＝706.2.

N- ( (2S, 3R) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-2- ( (methyl (4-phenoxybenzyl) amino) methyl) -6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) -2- (3-methoxyphenyl) acetamide, 92 Synthesized using General Procedure A, replacing 2- (4-(trifluoromethyl) phenyl) acetyl chloride and 4- (3- (trifluoromethyl) benzyl) benzaldehyde with2- (3-methoxyphenyl) acetyl chloride and 4-phenoxybenzaldehyde. ESI [M+H] ＝638.3.

N- ( (2S, 3R) -2- ( ( (4- (2-fluorophenoxy) benzyl) (methyl) amino) methyl) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) -2- (3-methoxyphenyl) acetamide, 93 Synthesized using General Procedure A, replacing 2- (4-(trifluoromethyl) phenyl) acetyl chloride and 4- (3- (trifluoromethyl) benzyl) benzaldehyde with2- (3-methoxyphenyl) acetyl chloride and 4- (2-fluorophenoxy) benzaldehyde. ESI [M+H] ＝656.2.

N- ( (2S, 3R) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-2- ( (methyl (4- (o-tolyloxy) benzyl) amino) methyl) -6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) -2- (3-methoxyphenyl) acetamide, 94 Synthesized using General Procedure A, replacing 2- (4-(trifluoromethyl) phenyl) acetyl chloride and 4- (3- (trifluoromethyl) benzyl) benzaldehyde with2- (3-methoxyphenyl) acetyl chloride and 4- (o-tolyloxy) benzaldehyde. 1H NMR (400MHz, DMSO-d6) δ 8.38 (s, 1H) , 8.07 (d, J＝7.5 Hz, 1H) , 7.33-7.12 (m, 5H) , 7.11-7.02 (m, 2H) , 6.96-6.73 (m, 7H) , 4.82 (t, J＝5.1 Hz, 1H) , 4.58 (br. s. , 1H) , 4.48-4.34 (m, 1H) , 3.75-3.62 (m, 5H) , 3.59-3.47 (m, 1H) , 3.45-3.35 (m, 4H) , 3.25-3.16 (m, 2H) , 2.84 (t, J＝13.9 Hz, 1H) , 2.13 (s, 3H) , 2.08 -1.85 (m, 4H) , 1.07 (d, J＝7.1 Hz, 3H) , 0.63 (d, J＝6.6 Hz, 3H) . ESI [M+H] ＝652.3.

N- ( (2S, 3R) -2- ( ( (4- (2-fluorophenoxy) benzyl) (methyl) amino) methyl) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) -2-phenylpropanamide, 95 Synthesized using General Procedure A, replacing 2- (4- (trifluoromethyl) phenyl) acetyl chloride and 4- (3- (trifluoromethyl) benzyl) benzaldehyde with2-phenylpropanoyl chloride and 4-(2-fluorophenoxy) benzaldehyde. ESI [M+H] ＝640.2.

N- ( (2S, 3R) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-2- ( (methyl (4- (o-tolyloxy) benzyl) amino) methyl) -6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) -2-phenylpropanamide, 96 Synthesized using General Procedure A, replacing 2- (4-(trifluoromethyl) phenyl) acetyl chloride and 4- (3- (trifluoromethyl) benzyl) benzaldehyde with2-phenylpropanoyl chloride and 4- (o-tolyloxy) benzaldehyde. 1H NMR (400MHz, DMSO-d6) δ 8.60-8.29 (m, 1H) , 7.96 (dd, J＝7.5, 19.0 Hz, 1H) , 7.52-7.11 (m, 10H) , 7.06 (q, J＝7.8 Hz, 2H) , 6.92-6.57 (m, 4H) , 4.84 (br. s. , 1H) , 4.58 (d, J＝5.7 Hz, 1H) , 4.44 (br. s. , 1H) , 4.10-3.79 (m, 1H) , 3.63-3.48 (m, 1H) , 3.46-3.35 (m, 2H) , 3.26-3.14 (m, 1H) , 2.99-2.73 (m, 1H) , 2.14 (s, 3H) , 2.09-1.87 (m, 4H) , 1.41 (dd, J＝7.1, 11.5 Hz, 3H) , 1.15-0.97 (m, 3H) , 0.75-0.35 (m, 3H) . ESI [M+H] ＝636.3.

N- ( (2S, 3R) -2- ( ( (4- (2, 4-difluorophenoxy) benzyl) (methyl) amino) methyl) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) -2- (4-(trifluoromethyl) phenyl) acetamide, 97. Synthesized using General Procedure A, replacing 4- (3-(trifluoromethyl) benzyl) benzaldehyde with 4- (2, 4-difluorophenoxy) benzaldehyde. 1H NMR (400MHz, DMSO-d6) δ 8.72 (br. s. , 1H) , 7.89 (d, J＝7.5 Hz, 1H) , 7.65 (d, J＝7.5 Hz, 2H) , 7.54 (d, J＝7.5 Hz, 2H) , 7.48-7.37 (m, 1H) , 7.29-7.14 (m, 3H) , 7.13-7.01 (m, 2H) , 6.96-6.75 (m, 3H) , 4.83 (br. s. , 1H) , 4.61 (br. s. , 1H) , 4.51-4.32 (m, 1H) , 4.02-3.74 (m, 2H) , 3.66-3.49 (m, 1H) , 3.47-3.37 (m, 2H) , 3.27-3.18 (m, 1H) , 2.96-2.76 (m, 1H) , 2.14-1.89 (m, 4H) , 1.08 (d, J＝6.6 Hz, 3H) , 0.75-0.60 (m, 3H) . ESI [M+H] ＝712.2.

N- ( (2S, 3R) -2- ( ( (4- (2, 6-dimethylphenoxy) benzyl) (methyl) amino) methyl) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) -2- (4-(trifluoromethyl) phenyl) acetamide, 98. Synthesized using General Procedure A, replacing 4- (3-(trifluoromethyl) benzyl) benzaldehyde with 4- (2, 6-dimethylphenoxy) benzaldehyde. ESI [M+H] ＝704.2.

N- ( (2S, 3R) -5- ( (S) -1-hydroxypropan-2-yl) -2- ( ( (4- (mesityloxy) benzyl) (methyl) amino) methyl) -3-methyl-6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) -2- (4-(trifluoromethyl) phenyl) acetamide, 99. Synthesized using General Procedure A, replacing 4- (3-(trifluoromethyl) benzyl) benzaldehyde with 4- (mesityloxy) benzaldehyde. 1H NMR (400MHz, DMSO-d6) δ 8.73 (s, 1H) , 7.88 (d, J＝7.5 Hz, 1H) , 7.65 (d, J＝7.5 Hz, 2H) , 7.53 (d, J＝7.5 Hz, 2H) , 7.10 (d, J＝7.9 Hz, 3H) , 6.92 (s, 2H) , 6.85 (t, J＝7.9 Hz, 1H) , 6.61 (d, J＝8.4 Hz, 2H) , 4.82 (br. s. , 1H) , 4.60 (br. s. , 1H) , 4.42 (d, J＝6.2 Hz, 1H) , 3.93-3.76 (m, 2H) , 3.62-3.50 (m, 1H) , 3.45-3.38 (m, 1H) , 3.23 (dd, J＝4.9, 15.0 Hz, 1H) , 2.87 (t, J＝13.9 Hz, 1H) , 2.23 (s, 3H) , 2.10-1.84 (m, 11H) , 1.08 (d, J＝7.1 Hz, 3H) , 0.64 (d, J＝6.2 Hz, 3H) . ESI [M+H] ＝718.3.

N- ( (2S, 3R) -2- ( ( (4- (2, 4-dimethylphenoxy) benzyl) (methyl) amino) methyl) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) -2- (4-(trifluoromethyl) phenyl) acetamide, 100. Synthesized using General Procedure A, replacing 4-(3- (trifluoromethyl) benzyl) benzaldehyde with 4- (2, 4-dimethylphenoxy) benzaldehyde. ESI [M+H] ＝704.2.

N- ( (2S, 3R) -2- ( ( (4- (2, 6-dimethoxyphenoxy) benzyl) (methyl) amino) methyl) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) -2- (4-(trifluoromethyl) phenyl) acetamide, 101. Synthesized using General Procedure A, replacing 4-(3- (trifluoromethyl) benzyl) benzaldehyde with 4- (2, 6-dimethoxyphenoxy) benzaldehyde. 1H NMR (400MHz, DMSO-d6) δ 8.67 (br. s. , 1H) , 7.90 (d, J＝7.1 Hz, 1H) , 7.67 (d, J＝7.9 Hz, 2H) , 7.53 (d, J＝7.5 Hz, 2H) , 7.17 (t, J＝8.4 Hz, 1H) , 7.12-6.99 (m, 3H) , 6.86 (t, J＝7.9 Hz, 1H) , 6.76 (d, J＝8.8 Hz, 2H) , 6.63 (d, J＝8.4 Hz, 2H) , 4.82 (br. s. , 1H) , 4.61 (br. s. , 1H) , 4.44 (d, J＝6.2 Hz, 1H) , 3.92-3.76 (m, 2H) , 3.65 (s, 7H) , 3.53 (br. s. , 1H) , 3.49-3.39 (m, 1H) , 3.22 (br. s. , 1H) , 2.94-2.75 (m, 1H) , 2.15-1.88 (m, 4H) , 1.08 (d, J＝6.6 Hz, 3H) , 0.65 (d, J＝6.2 Hz, 3H) . ESI [M+H] ＝736.2.

N- ( (2S, 3R) -2- ( ( (4- (2, 4-dimethoxyphenoxy) benzyl) (methyl) amino) methyl) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) -2- (4-(trifluoromethyl) phenyl) acetamide, 102. Synthesized using General Procedure A, replacing 4-(3- (trifluoromethyl) benzyl) benzaldehyde with 4- (2, 4-dimethoxyphenoxy) benzaldehyde. ESI [M+H] ＝736.2.

N- ( (2S, 3R) -2- ( ( (4- (4-fluoro-2-methylphenoxy) benzyl) (methyl) amino) methyl) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) -2- (4-(trifluoromethyl) phenyl) acetamide, 103. Synthesized using General Procedure A, replacing 4-(3- (trifluoromethyl) benzyl) benzaldehyde with 4- (4-fluoro-2-methylphenoxy) benzaldehyde. ESI [M+H] ＝708.2.

N- ( (2S, 3R) -5- ( (S) -1-hydroxypropan-2-yl) -2- ( ( (4- (2-methoxy-4-methylphenoxy) benzyl) (methyl) amino) methyl) -3-methyl-6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) -2- (4- (trifluoromethyl) phenyl) acetamide, 104. Synthesized using General Procedure A, replacing 4- (3- (trifluoromethyl) benzyl) benzaldehyde with 4- (2-methoxy-4-methylphenoxy) benzaldehyde. ESI [M+H] ＝720.2.

N- ( (2S, 3R) -2- ( ( (4- (4-fluoro-2- (trifluoromethyl) phenoxy) benzyl) (methyl) amino) methyl) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) -2-(4- (trifluoromethyl) phenyl) acetamide, 105. Synthesized using General Procedure A, replacing 4- (3- (trifluoromethyl) benzyl) benzaldehyde with 4- (4-fluoro-2-(trifluoromethyl) phenoxy) benzaldehyde. ESI [M+H] ＝762.2.

N- ( (2S, 3R) -2- ( ( (4- (2-fluoro-4-methylphenoxy) benzyl) (methyl) amino) methyl) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) -2- (4-(trifluoromethyl) phenyl) acetamide, 106. Synthesized using General Procedure A, replacing 4-(3- (trifluoromethyl) benzyl) benzaldehyde with 4- (2-fluoro-4-methylphenoxy) benzaldehyde. ESI [M+H] ＝708.2.

N- ( (2S, 3R) -2- ( ( (4- (2-fluorophenoxy) benzyl) (methyl) amino) methyl) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) -2-methyl-2- (4-(trifluoromethyl) phenyl) propanamide, 107 Synthesized using General Procedure A, replacing 2-(4- (trifluoromethyl) phenyl) acetyl chloride and 4- (3- (trifluoromethyl) benzyl) benzaldehyde with2-methyl-2- (4- (trifluoromethyl) phenyl) propanoyl chloride and 4- (2-fluorophenoxy) benzaldehyde. ESI [M+H] ＝722.3.

2- (4-fluorophenyl) -N- ( (2S, 3R) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-2- ( (methyl (4-phenoxybenzyl) amino) methyl) -6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) propanamide, 108 Synthesized using General Procedure A, replacing 2- (4-(trifluoromethyl) phenyl) acetyl chloride and 4- (3- (trifluoromethyl) benzyl) benzaldehyde with2- (4-fluorophenyl) propanoyl chloride and 4-phenoxybenzaldehyde. ESI [M+H] ＝640.2.

N- ( (2S, 3R) -2- ( ( (4- (2-fluorophenoxy) benzyl) (methyl) amino) methyl) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) -2- (4-fluorophenyl) propanamide, 109 Synthesized using General Procedure A, replacing 2- (4-(trifluoromethyl) phenyl) acetyl chloride and 4- (3- (trifluoromethyl) benzyl) benzaldehyde with2- (4-fluorophenyl) propanoyl chloride and 4- (2-fluorophenoxy) benzaldehyde. ESI [M+H] ＝658.2.

2- (4-fluorophenyl) -N- ( (2S, 3R) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-2- ( (methyl (4- (o-tolyloxy) benzyl) amino) methyl) -6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) propanamide, 110 Synthesized using General Procedure A, replacing 2- (4-(trifluoromethyl) phenyl) acetyl chloride and 4- (3- (trifluoromethyl) benzyl) benzaldehyde with2- (4-fluorophenyl) propanoyl chloride and 4- (o-tolyloxy) benzaldehyde. 1H NMR (400MHz, DMSO-d6) δ 8.61-8.38 (m, 1H) , 8.00-7.79 (m, 1H) , 7.37 (d, J＝6.2 Hz, 2H) , 7.28 (d, J＝7.1 Hz, 1H) , 7.22-6.96 (m, 7H) , 6.91-6.69 (m, 4H) , 4.82 (br. s. , 1H) , 4.67-4.29 (m, 2H) , 4.06-3.83 (m, 1H) , 3.64-3.47 (m, 1H) , 2.98-2.75 (m, 1H) , 2.20-2.09 (m, 3H) , 2.05-1.88 (m, 4H) , 1.38 (dd, J＝7.1, 10.1 Hz, 3H) , 1.07 (t, J＝6.8 Hz, 3H) , 0.76-0.42 (m, 3H) . ESI [M+H] ＝654.3.

N- ( (2S, 3R) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-2- ( (methyl (4- (o-tolyloxy) benzyl) amino) methyl) -6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) -2- (4-(2-methoxyethoxy) phenyl) acetamide, 111 Synthesized using General Procedure A, replacing 2-(4- (trifluoromethyl) phenyl) acetyl chloride and 4- (3- (trifluoromethyl) benzyl) benzaldehyde with2-(4- (2-methoxyethoxy) phenyl) acetyl chloride and 4- (o-tolyloxy) benzaldehyde. ESI [M+H] ＝696.3.

2-hydroxy-N- ( (2S, 3R) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-2- ( (methyl (4-phenoxybenzyl) amino) methyl) -6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) -2-phenylacetamide, 112 Synthesized using General Procedure A, replacing 2- (4-(trifluoromethyl) phenyl) acetyl chloride and 4- (3- (trifluoromethyl) benzyl) benzaldehyde with2-chloro-2-oxo-1-phenylethyl acetate and 4-phenoxybenzaldehyde, then removal of the acetyl group was accomplished by stirring in a solution of NaOH in H₂O and MeOH. . 1H NMR (400MHz, DMSO-d6) δ 9.79-9.51 (m, 1H) , 8.33-8.05 (m, 1H) , 7.49-7.15 (m, 9H) , 7.14-7.00 (m, 2H) , 7.00-6.76 (m, 6H) , 5.08 (br. s. , 1H) , 4.95-4.72 (m, 2H) , 4.55 (br. s. , 1H) , 3.65-3.42 (m, 4H) , 3.06-2.75 (m, 1H) , 2.68 (d, J＝15.4 Hz, 1H) , 2.21-1.98 (m, 4H) , 1.09 (br. s. , 3H) , 0.92 -0.68 (m, 3H) . ESI [M+H] ＝624.2.

N- ( (2S, 3R) -2- ( ( (4- (2-fluorophenoxy) benzyl) (methyl) amino) methyl) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) -2-hydroxy-2-phenylacetamide, 113 Synthesized using General Procedure A, replacing 2- (4-(trifluoromethyl) phenyl) acetyl chloride and 4- (3- (trifluoromethyl) benzyl) benzaldehyde with2-chloro-2-oxo-1-phenylethyl acetate and 4- (2-fluorophenoxy) benzaldehyde, then removal of the acetyl group was accomplished by stirring in a solution of NaOH in H₂O and MeOH. . ESI [M+H] ＝642.2.

2-hydroxy-N- ( (2S, 3R) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-2- ( (methyl (4- (o-tolyloxy) benzyl) amino) methyl) -6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) -2-phenylacetamide, 114 Synthesized using General Procedure A, replacing 2- (4-(trifluoromethyl) phenyl) acetyl chloride and 4- (3- (trifluoromethyl) benzyl) benzaldehyde with2-chloro-2-oxo-1-phenylethyl acetate and 4- (o-tolyloxy) benzaldehyde, then removal of the acetyl group was accomplished by stirring in a solution of NaOH in H₂O and MeOH. ESI [M+H] ＝638.3.

N- ( (2S, 3R) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-2- ( (methyl (4-phenoxybenzyl) amino) methyl) -6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) -2- (4-(trifluoromethyl) phenyl) propanamide, 115 Synthesized using General Procedure A, replacing 2-(4- (trifluoromethyl) phenyl) acetyl chloride and 4- (3- (trifluoromethyl) benzyl) benzaldehyde with2-(4- (trifluoromethyl) phenyl) propanoyl chloride and 4-phenoxybenzaldehyde. ESI [M+H] ＝690.2.

N- ( (2S, 3R) -2- ( ( (4- (2-fluorophenoxy) benzyl) (methyl) amino) methyl) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) -2- (4-(trifluoromethyl) phenyl) propanamide, 116 Synthesized using General Procedure A, replacing 2-(4- (trifluoromethyl) phenyl) acetyl chloride and 4- (3- (trifluoromethyl) benzyl) benzaldehyde with2-(4- (trifluoromethyl) phenyl) propanoyl chloride and 4- (2-fluorophenoxy) benzaldehyde. ESI [M+H] ＝708.2.

N- ( (2S, 3R) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-2- ( (methyl (4- (o-tolyloxy) benzyl) amino) methyl) -6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) -2- (4-(trifluoromethyl) phenyl) propanamide, 117 Synthesized using General Procedure A, replacing 2-(4- (trifluoromethyl) phenyl) acetyl chloride and 4- (3- (trifluoromethyl) benzyl) benzaldehyde with2-(4- (trifluoromethyl) phenyl) propanoyl chloride and 4- (o-tolyloxy) benzaldehyde. ESI [M+H] ＝704.3.

2- (4-fluorophenyl) -N- ( (2S, 3R) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-2- ( (methyl (4-phenoxybenzyl) amino) methyl) -6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) butanamide, 118 Synthesized using General Procedure A, replacing 2- (4-(trifluoromethyl) phenyl) acetyl chloride and 4- (3- (trifluoromethyl) benzyl) benzaldehyde with2- (4-fluorophenyl) butanoyl chloride and 4-phenoxybenzaldehyde. 1H NMR (400MHz, DMSO-d6) δ 8.81-8.58 (m, 1H) , 7.87-7.68 (m, 1H) , 7.48-7.27 (m, 4H) , 7.25-7.01 (m, 6H) , 6.98-6.76 (m, 5H) , 4.96-4.75 (m, 1H) , 4.58 (br. s. , 1H) , 4.50-4.27 (m, 1H) , 3.75 (t, J＝7.5 Hz, 1H) , 3.60-3.48 (m, 1H) , 3.46-3.37 (m, 4H) , 3.27-3.14 (m, 1H) , 3.00-2.72 (m, 1H) , 2.15-1.88 (m, 5H) , 1.66 (qd, J＝7.0, 13.8 Hz, 1H) , 1.16-1.01 (m, 3H) , 0.90-0.67 (m, 5H) , 0.56 (d, J＝6.2 Hz, 1H) . ESI [M+H] ＝654.3.

N- ( (2S, 3R) -2- ( ( (4- (2-fluorophenoxy) benzyl) (methyl) amino) methyl) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) -2- (4-fluorophenyl) butanamide, 119 Synthesized using General Procedure A, replacing 2- (4-(trifluoromethyl) phenyl) acetyl chloride and 4- (3- (trifluoromethyl) benzyl) benzaldehyde with2- (4-fluorophenyl) butanoyl chloride and 4- (2-fluorophenoxy) benzaldehyde. ESI [M+H] ＝672.2.

2- (4-fluorophenyl) -N- ( (2S, 3R) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-2- ( (methyl (4- (o-tolyloxy) benzyl) amino) methyl) -6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) butanamide, 120 Synthesized using General Procedure A, replacing 2- (4-(trifluoromethyl) phenyl) acetyl chloride and 4- (3- (trifluoromethyl) benzyl) benzaldehyde with2- (4-fluorophenyl) butanoyl chloride and 4- (o-tolyloxy) benzaldehyde. ESI [M+H] ＝668.3.

2- (3-fluoro-4- (trifluoromethyl) phenyl) -N- ( (2S, 3R) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-2-( (methyl (4-phenoxybenzyl) amino) methyl) -6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) acetamide, 121 Synthesized using General Procedure A, replacing 2- (4-(trifluoromethyl) phenyl) acetyl chloride and 4- (3- (trifluoromethyl) benzyl) benzaldehyde with2- (3-fluoro-4- (trifluoromethyl) phenyl) acetyl chloride and 4-phenoxybenzaldehyde. 1H NMR (400MHz, DMSO-d6) δ 8.95 (s, 1H) , 7.90 (d, J＝7.5 Hz, 1H) , 7.80 (t, J＝7.9 Hz, 1H) , 7.56 (d, J＝11.9 Hz, 1H) , 7.43 (t, J＝7.9 Hz, 3H) , 7.27 (d, J＝7.9 Hz, 2H) , 7.19 (q, J＝7.4 Hz, 2H) , 7.06-6.86 (m, 5H) , 4.91 (t, J＝5.1 Hz, 1H) , 4.71 (br. s. , 1H) , 4.60-4.42 (m, 1H) , 4.04-3.83 (m, 2H) , 3.72-3.58 (m, 1H) , 3.57-3.43 (m, 3H) , 3.32 (d, J＝3.5 Hz, 2H) , 2.98 (t, J＝14.1 Hz, 1H) , 2.22-1.99 (m, 4H) , 1.18 (d, J＝7.1 Hz, 3H) , 0.79 (d, J＝6.6 Hz, 3H) . ESI [M+H] ＝694.2.

2- (3-fluoro-4- (trifluoromethyl) phenyl) -N- ( (2S, 3R) -2- ( ( (4- (2-fluorophenoxy) benzyl) (methyl) amino) methyl) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) acetamide, 122 Synthesized using General Procedure A, replacing 2- (4- (trifluoromethyl) phenyl) acetyl chloride and 4- (3-(trifluoromethyl) benzyl) benzaldehyde with2- (3-fluoro-4- (trifluoromethyl) phenyl) acetyl chloride and 4- (2-fluorophenoxy) benzaldehyde. ESI [M+H] ＝712.2.

2- (3-fluoro-4- (trifluoromethyl) phenyl) -N- ( (2S, 3R) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-2-( (methyl (4- (o-tolyloxy) benzyl) amino) methyl) -6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) acetamide, 123 Synthesized using General Procedure A, replacing 2- (4- (trifluoromethyl) phenyl) acetyl chloride and 4- (3- (trifluoromethyl) benzyl) benzaldehyde with2- (3-fluoro-4- (trifluoromethyl) phenyl) acetyl chloride and 4- (o-tolyloxy) benzaldehyde. ESI [M+H] ＝708.2.

2- (3, 5-bis (trifluoromethyl) phenyl) -N- ( (2S, 3R) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-2-( (methyl (4-phenoxybenzyl) amino) methyl) -6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) acetamide, 124 Synthesized using General Procedure A, replacing 2- (4-(trifluoromethyl) phenyl) acetyl chloride and 4- (3- (trifluoromethyl) benzyl) benzaldehyde with2-(3, 5-bis (trifluoromethyl) phenyl) acetyl chloride and 4-phenoxybenzaldehyde. 1H NMR (400MHz, DMSO-d6) δ 9.05 (s, 1H) , 8.01 (s, 3H) , 7.73 (d, J＝7.5 Hz, 1H) , 7.39-7.27 (m, 2H) , 7.21-7.03 (m, 4H) , 6.96-6.75 (m, 5H) , 4.83 (t, J＝5.1 Hz, 1H) , 4.60 (br. s. , 1H) , 4.43 (d, J＝5.7 Hz, 1H) , 4.08-3.83 (m, 2H) , 3.68-3.49 (m, 1H) , 3.47-3.34 (m, 3H) , 2.91 (t, J＝13.7 Hz, 1H) , 2.14-1.88 (m, 4H) , 1.09 (d, J＝6.6 Hz, 3H) , 0.70 (d, J＝6.6 Hz, 3H) . ESI [M+H] ＝744.2.

2- (3, 5-bis (trifluoromethyl) phenyl) -N- ( (2S, 3R) -2- ( ( (4- (2-fluorophenoxy) benzyl) (methyl) amino) methyl) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) acetamide, 125 Synthesized using General Procedure A, replacing 2- (4- (trifluoromethyl) phenyl) acetyl chloride and 4- (3-(trifluoromethyl) benzyl) benzaldehyde with2- (3, 5-bis (trifluoromethyl) phenyl) acetyl chloride and 4- (2-fluorophenoxy) benzaldehyde. ESI [M+H] ＝762.3.

2- (3, 5-bis (trifluoromethyl) phenyl) -N- ( (2S, 3R) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-2-( (methyl (4- (o-tolyloxy) benzyl) amino) methyl) -6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) acetamide, 126 Synthesized using General Procedure A, replacing 2- (4- (trifluoromethyl) phenyl) acetyl chloride and 4- (3- (trifluoromethyl) benzyl) benzaldehyde with2- (3, 5-bis (trifluoromethyl) phenyl) acetyl chloride and 4- (o-tolyloxy) benzaldehyde. ESI [M+H] ＝758.2.

N- ( (2S, 3R) -2- ( ( (4- (3-chlorophenoxy) benzyl) (methyl) amino) methyl) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) -2- (4- (trifluoromethyl) phenyl) acetamide, 127. Synthesized using General Procedure A, replacing 4-(3- (trifluoromethyl) benzyl) benzaldehyde with 4- (3-chlorophenoxy) benzaldehyde. ESI [M+H] ＝710.2.

N- ( (2S, 3R) -2- ( ( (4- (3, 5-dimethylphenoxy) benzyl) (methyl) amino) methyl) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) -2- (4-(trifluoromethyl) phenyl) acetamide, 128. Synthesized using General Procedure A, replacing 4-(3- (trifluoromethyl) benzyl) benzaldehyde with 4- (3, 5-dimethylphenoxy) benzaldehyde. ESI [M+H] ＝704.3.

N- ( (2S, 3R) -2- ( ( (4- (3, 5-difluorophenoxy) benzyl) (methyl) amino) methyl) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) -2- (4-(trifluoromethyl) phenyl) acetamide, 129. Synthesized using General Procedure A, replacing 4-(3- (trifluoromethyl) benzyl) benzaldehyde with 4- (3, 5-difluorophenoxy) benzaldehyde. 1H NMR (400MHz, DMSO-d6) δ 8.72 (s, 1H) , 7.89 (d, J＝7.5 Hz, 1H) , 7.66 (d, J＝7.9 Hz, 2H) , 7.54 (d, J＝7.9 Hz, 2H) , 7.26 (d, J＝7.9 Hz, 2H) , 7.10 (d, J＝7.9 Hz, 1H) , 7.02 (d, J＝8.4 Hz, 2H) , 6.95 (t, J＝9.3 Hz, 1H) , 6.85 (t, J＝7.9 Hz, 1H) , 6.68-6.58 (m, 2H) , 4.81 (t, J＝5.3 Hz, 1H) , 4.68-4.57 (m, 1H) , 4.51-4.36 (m, 1H) , 3.91-3.74 (m, 2H) , 3.65-3.49 (m, 1H) , 3.48-3.36 (m, 3H) , 2.88 (t, J＝13.9 Hz, 1H) , 2.14-1.93 (m, 4H) , 1.08 (d, J＝6.6 Hz, 3H) , 0.67 (d, J＝6.2 Hz, 3H) . ESI [M+H] ＝712.2.

N- ( (2S, 3R) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-2- ( (methyl (4- (3, 4, 5-trifluorophenoxy) benzyl) amino) methyl) -6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) -2- (4- (trifluoromethyl) phenyl) acetamide, 130. Synthesized using General Procedure A, replacing 4- (3- (trifluoromethyl) benzyl) benzaldehyde with 4- (3, 4, 5-trifluorophenoxy) benzaldehyde. ESI [M+H] ＝730.2.

2- (4-fluorophenyl) -N- ( (2S, 3R) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-2- ( (methyl (4- (o-tolyloxy) benzyl) amino) methyl) -6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10- yl) pentanamide, 131 Synthesized using General Procedure A, replacing 2- (4-(trifluoromethyl) phenyl) acetyl chloride and 4- (3- (trifluoromethyl) benzyl) benzaldehyde with2- (4-fluorophenyl) pentanoyl chloride and 4- (o-tolyloxy) benzaldehyde. ESI [M+H] ＝682.3.

2- (2, 5-bis (trifluoromethyl) phenyl) -N- ( (2S, 3R) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-2-( (methyl (4-phenoxybenzyl) amino) methyl) -6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) acetamide, 132 Synthesized using General Procedure A, replacing 2- (4-(trifluoromethyl) phenyl) acetyl chloride and 4- (3- (trifluoromethyl) benzyl) benzaldehyde with2-(2, 5-bis (trifluoromethyl) phenyl) acetyl chloride and 4-phenoxybenzaldehyde. ESI [M+H] ＝744.2.

2- (2, 5-bis (trifluoromethyl) phenyl) -N- ( (2S, 3R) -2- ( ( (4- (2-fluorophenoxy) benzyl) (methyl) amino) methyl) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) acetamide, 133 Synthesized using General Procedure A, replacing 2- (4- (trifluoromethyl) phenyl) acetyl chloride and 4- (3-(trifluoromethyl) benzyl) benzaldehyde with2- (2, 5-bis (trifluoromethyl) phenyl) acetyl chloride and 4- (2-fluorophenoxy) benzaldehyde. ESI [M+H] ＝762.2.

2- (2, 5-bis (trifluoromethyl) phenyl) -N- ( (2S, 3R) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-2-( (methyl (4- (o-tolyloxy) benzyl) amino) methyl) -6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) acetamide, 134 Synthesized using General Procedure A, replacing 2- (4- (trifluoromethyl) phenyl) acetyl chloride and 4- (3- (trifluoromethyl) benzyl) benzaldehyde with2- (2, 5-bis (trifluoromethyl) phenyl) acetyl chloride and 4- (o-tolyloxy) benzaldehyde. ESI [M+H] ＝758.2.

N- ( (2S, 3R) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-2- ( (methyl (4- (3, 4, 5-trimethylphenoxy) benzyl) amino) methyl) -6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) -2- (4- (trifluoromethyl) phenyl) acetamide, 135. Synthesized using General Procedure A, replacing 4- (3- (trifluoromethyl) benzyl) benzaldehyde with 4- (3, 4, 5-trimethylphenoxy) benzaldehyde. 1H NMR (400MHz, DMSO-d6) δ 8.69 (s, 1H) , 7.87 (d, J＝7.5 Hz, 1H) , 7.63 (d, J＝7.9 Hz, 2H) , 7.51 (d, J＝7.9 Hz, 2H) , 7.20-7.03 (m, 3H) , 6.91-6.75 (m, 3H) , 6.60 (s, 2H) , 4.80 (t, J＝5.1 Hz, 1H) , 4.60 (br. s. , 1H) , 4.48-4.33 (m, 1H) , 3.93-3.69 (m, 2H) , 3.62-3.33 (m, 4H) , 3.22 (dd, J＝5.1, 15.2 Hz, 1H) , 2.86 (t, J＝13.7 Hz, 1H) , 2.15 (s, 6H) , 2.09-1.92 (m, 7H) , 1.07 (d, J＝7.1 Hz, 3H) , 0.65 (d, J＝6.2 Hz, 3H) . ESI [M+H] ＝718.3.

N- ( (2S, 3R) -2- ( ( (4- (4-chloro-3- (trifluoromethyl) phenoxy) benzyl) (methyl) amino) methyl) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) -2-(4- (trifluoromethyl) phenyl) acetamide, 136. Synthesized using General Procedure A, replacing 4- (3- (trifluoromethyl) benzyl) benzaldehyde with 4- (4-chloro-3-(trifluoromethyl) phenoxy) benzaldehyde. ESI [M+H] ＝778.2.

2- (2-fluoro-4- (trifluoromethyl) phenyl) -N- ( (2S, 3R) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-2-( (methyl (4-phenoxybenzyl) amino) methyl) -6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) acetamide, 137 Synthesized using General Procedure A, replacing 2- (4-(trifluoromethyl) phenyl) acetyl chloride and 4- (3- (trifluoromethyl) benzyl) benzaldehyde with2- (2-fluoro-4- (trifluoromethyl) phenyl) acetyl chloride and 4-phenoxybenzaldehyde. 1H NMR (400MHz, DMSO-d6) δ 8.85 (s, 1H) , 7.86 (d, J＝7.5 Hz, 1H) , 7.71-7.58 (m, 2H) , 7.56-7.51 (m, 1H) , 7.34 (t, J＝7.9 Hz, 2H) , 7.22 (d, J＝8.4 Hz, 2H) , 7.14-7.04 (m, 2H) , 6.98-6.79 (m, 5H) , 4.83 (t, J＝5.1 Hz, 1H) , 4.66 (br. s. , 1H) , 4.51-4.40 (m, 1H) , 4.02-3.73 (m, 2H) , 3.66-3.50 (m, 1H) , 3.49-3.40 (m, 3H) , 2.91 (t, J＝13.9 Hz, 1H) , 2.05 (s, 4H) , 1.10 (d, J＝6.6 Hz, 3H) , 0.73 (d, J＝6.6 Hz, 3H) . ESI [M+H] ＝694.2.

2- (2-fluoro-4- (trifluoromethyl) phenyl) -N- ( (2S, 3R) -2- ( ( (4- (2-fluorophenoxy) benzyl) (methyl) amino) methyl) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) acetamide, 138 Synthesized using General Procedure A, replacing 2- (4- (trifluoromethyl) phenyl) acetyl chloride and 4- (3- (trifluoromethyl) benzyl) benzaldehyde with2- (2-fluoro-4- (trifluoromethyl) phenyl) acetyl chloride and 4- (2-fluorophenoxy) benzaldehyde. ESI [M+H] ＝712.2.

2- (2-fluoro-4- (trifluoromethyl) phenyl) -N- ( (2S, 3R) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-2-( (methyl (4- (o-tolyloxy) benzyl) amino) methyl) -6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) acetamide, 139 Synthesized using General Procedure A, replacing 2- (4- (trifluoromethyl) phenyl) acetyl chloride and 4- (3- (trifluoromethyl) benzyl) benzaldehyde with2- (2-fluoro-4- (trifluoromethyl) phenyl) acetyl chloride and 4- (o-tolyloxy) benzaldehyde. ESI [M+H] ＝708.2.

2- (2, 4-bis (trifluoromethyl) phenyl) -N- ( (2S, 3R) -2- ( ( (4- (2-fluorophenoxy) benzyl) (methyl) amino) methyl) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) acetamide, 140 Synthesized using General Procedure A, replacing 2- (4- (trifluoromethyl) phenyl) acetyl chloride and 4- (3-(trifluoromethyl) benzyl) benzaldehyde with2- (2, 4-bis (trifluoromethyl) phenyl) acetyl chloride and 4- (2-fluorophenoxy) benzaldehyde. 1H NMR (400MHz, DMSO-d6) δ 8.84 (s, 1H) , 8.09-7.94 (m, 2H) , 7.86-7.71 (m, 2H) , 7.40-7.27 (m, 1H) , 7.25-7.01 (m, 6H) , 6.93-6.77 (m, 3H) , 4.83 (t, J＝5.1 Hz, 1H) , 4.64 (br. s. , 1H) , 4.50-4.32 (m, 1H) , 4.16-3.95 (m, 2H) , 3.63-3.53 (m, 1H) , 3.48-3.37 (m, 4H) , 3.02-2.81 (m, 1H) , 2.04 (s, 4H) , 1.13-1.03 (m, 3H) , 0.72 (d, J＝6.6 Hz, 3H) . ESI [M+H] ＝762.2.

2, 2-difluoro-N- ( (2S, 3R) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-2- ( (methyl (4-phenoxybenzyl) amino) methyl) -6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) -2-phenylacetamide, 141 Synthesized using General Procedure A, replacing 2- (4-(trifluoromethyl) phenyl) acetyl chloride and 4- (3- (trifluoromethyl) benzyl) benzaldehyde with2, 2-difluoro-2-phenylacetyl chloride and 4-phenoxybenzaldehyde. ESI [M+H] ＝644.2.

2, 2-difluoro-N- ( (2S, 3R) -2- ( ( (4- (2-fluorophenoxy) benzyl) (methyl) amino) methyl) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) -2-phenylacetamide, 142 Synthesized using General Procedure A, replacing 2- (4-(trifluoromethyl) phenyl) acetyl chloride and 4- (3- (trifluoromethyl) benzyl) benzaldehyde with2, 2-difluoro-2-phenylacetyl chloride and 4- (2-fluorophenoxy) benzaldehyde. ESI [M+H] ＝662.2.

2, 2-difluoro-N- ( (2S, 3R) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-2- ( (methyl (4- (o-tolyloxy) benzyl) amino) methyl) -6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) -2-phenylacetamide, 143 Synthesized using General Procedure A, replacing 2- (4-(trifluoromethyl) phenyl) acetyl chloride and 4- (3- (trifluoromethyl) benzyl) benzaldehyde with2, 2-difluoro-2-phenylacetyl chloride and 4- (o-tolyloxy) benzaldehyde. ESI [M+H] ＝658.2.

2- (2, 4-bis (trifluoromethyl) phenyl) -N- ( (2S, 3R) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-2-( (methyl (4-phenoxybenzyl) amino) methyl) -6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) acetamide, 144 Synthesized using General Procedure A, replacing 2- (4-(trifluoromethyl) phenyl) acetyl chloride and 4- (3- (trifluoromethyl) benzyl) benzaldehyde with2-(2, 4-bis (trifluoromethyl) phenyl) acetyl chloride and 4-phenoxybenzaldehyde. ESI [M+H] ＝744.2.

N- ( (2S, 3R) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-2- ( (methyl (4- (o-tolyloxy) benzyl) amino) methyl) -6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) -2, 2-diphenylacetamide, 145 Synthesized using General Procedure A, replacing 2- (4-(trifluoromethyl) phenyl) acetyl chloride and 4- (3- (trifluoromethyl) benzyl) benzaldehyde with2, 2-diphenylacetyl chloride and 4- (o-tolyloxy) benzaldehyde. ESI [M+H] ＝698.3.

N- ( (2S, 3R) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-2- ( (methyl (4-phenoxybenzyl) amino) methyl) -6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) -2, 2-diphenylacetamide, 146 Synthesized using General Procedure A, replacing 2- (4-(trifluoromethyl) phenyl) acetyl chloride and 4- (3- (trifluoromethyl) benzyl) benzaldehyde with2, 2-diphenylacetyl chloride and 4-phenoxybenzaldehyde. 1H NMR (400MHz, DMSO-d6) δ 8.81 (s, 1H) , 8.09-7.96 (m, 1H) , 7.48-7.20 (m, 14H) , 7.18-7.08 (m, 2H) , 7.05-6.86 (m, 5H) , 5.38 (s, 1H) , 4.88 (t, J＝5.3 Hz, 1H) , 4.64 (t, J＝5.1 Hz, 1H) , 4.54-4.34 (m, 1H) , 3.65-3.52 (m, 1H) , 3.51 -3.41 (m, 2H) , 2.99-2.87 (m, 1H) , 2.46-2.33 (m, 2H) , 2.23-1.91 (m, 4H) , 1.13 (d, J＝7.1 Hz, 3H) , 0.67 (d, J＝6.6 Hz, 3H) . ESI [M+H] ＝684.3.

N- ( (2S, 3R) -2- ( ( (4- (3-fluoro-5-methylphenoxy) benzyl) (methyl) amino) methyl) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) -2- (4-(trifluoromethyl) phenyl) acetamide, 147. Synthesized using General Procedure A, replacing 4-(3- (trifluoromethyl) benzyl) benzaldehyde with 4- (3-fluoro-5-methylphenoxy) benzaldehyde. ESI [M+H] ＝708.3.

2- (4-fluorophenyl) -2-hydroxy-N- ( (2S, 3R) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-2- ( (methyl (4-phenoxybenzyl) amino) methyl) -6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) acetamide, 148 Synthesized using General Procedure A, replacing 2- (4-(trifluoromethyl) phenyl) acetyl chloride and 4- (3- (trifluoromethyl) benzyl) benzaldehyde with2-chloro-1- (4-fluorophenyl) -2-oxoethyl acetate and 4-phenoxybenzaldehyde, then removal of the acetyl group was accomplished by stirring in a solution of NaOH in H₂O and MeOH. ESI [M+H] ＝642.2.

N- ( (2S, 3R) -2- ( ( (4- (2-fluorophenoxy) benzyl) (methyl) amino) methyl) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) -2- (4-fluorophenyl) -2-hydroxyacetamide, 149 Synthesized using General Procedure A, replacing 2- (4-(trifluoromethyl) phenyl) acetyl chloride and 4- (3- (trifluoromethyl) benzyl) benzaldehyde with2-chloro-1- (4-fluorophenyl) -2-oxoethyl acetate and 4- (2-fluorophenoxy) benzaldehyde, then removal of the acetyl group was accomplished by stirring in a solution of NaOH in H₂O and MeOH. ESI [M+H] ＝660.2.

2-hydroxy-N- ( (2S, 3R) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-2- ( (methyl (4-phenoxybenzyl) amino) methyl) -6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) -2- (4-(trifluoromethyl) phenyl) acetamide, 150 Synthesized using General Procedure A, replacing 2- (4-(trifluoromethyl) phenyl) acetyl chloride and 4- (3- (trifluoromethyl) benzyl) benzaldehyde with2-hydroxy-2- (4- (trifluoromethyl) phenyl) acetyl chloride and 4-phenoxybenzaldehyde, then removal of the acetyl group was accomplished by stirring in a solution of NaOH in H₂O and MeOH. ESI [M+H] ＝692.2.

N- ( (2S, 3R) -2- ( ( (4- (2-fluorophenoxy) benzyl) (methyl) amino) methyl) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) -2-hydroxy-2- (4-(trifluoromethyl) phenyl) acetamide, 151 Synthesized using General Procedure A, replacing 2- (4-(trifluoromethyl) phenyl) acetyl chloride and 4- (3- (trifluoromethyl) benzyl) benzaldehyde with2-hydroxy-2- (4- (trifluoromethyl) phenyl) acetyl chloride and 4- (2-fluorophenoxy) benzaldehyde, then removal of the acetyl group was accomplished by stirring in a solution of NaOH in H₂O and MeOH. ESI [M+H] ＝710.2.

2-hydroxy-N- ( (2S, 3R) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-2- ( (methyl (4- (o-tolyloxy) benzyl) amino) methyl) -6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) -2- (4-(trifluoromethyl) phenyl) acetamide, 152 Synthesized using General Procedure A, replacing 2- (4-(trifluoromethyl) phenyl) acetyl chloride and 4- (3- (trifluoromethyl) benzyl) benzaldehyde with2-hydroxy-2- (4- (trifluoromethyl) phenyl) acetyl chloride and 4- (o-tolyloxy) benzaldehyde, then removal of the acetyl group was accomplished by stirring in a solution of NaOH in H₂O and MeOH. ESI [M+H] ＝706.2.

2-amino-N- ( (2S, 3R) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-2- ( (methyl (4-phenoxybenzyl) amino) methyl) -6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) -2-phenylacetamide, 153 Synthesized using General Procedure A, replacing 2- (4- (trifluoromethyl) phenyl) acetyl chloride and 4- (3- (trifluoromethyl) benzyl) benzaldehyde with (9H-fluoren-9-yl) methyl (2-chloro-2-oxo-1-phenylethyl) carbamate and 4-phenoxybenzaldehyde, then removal of the FMOC group was accomplished by stirring in a solution of piperdine in MeOH. 1H NMR (400MHz, DMSO-d6) δ 10.52-10.14 (m, 1H) , 8.28-8.13 (m, 1H) , 7.56-6.73 (m, 16H) , 4.97-4.75 (m, 2H) , 4.62-4.40 (m, 2H) , 3.69-3.39 (m, 4H) , 3.04-2.78 (m, 2H) , 2.75 -2.56 (m, 4H) , 2.14 (d, J＝3.5 Hz, 4H) , 1.27-1.02 (m, 3H) , 0.88-0.73 (m, 3H) . ESI [M+H] ＝623.3.

2, 2-difluoro-N- ( (2S, 3R) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-2- ( (methyl (4-phenoxybenzyl) amino) methyl) -6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) -2- (4-(trifluoromethyl) phenyl) acetamide, 154 Synthesized using General Procedure A, replacing 2- (4-(trifluoromethyl) phenyl) acetyl chloride and 4- (3- (trifluoromethyl) benzyl) benzaldehyde with2, 2-difluoro-2- (4- (trifluoromethyl) phenyl) acetyl chloride and 4-phenoxybenzaldehyde. ESI [M+H] ＝712.2.

2, 2-difluoro-N- ( (2S, 3R) -2- ( ( (4- (2-fluorophenoxy) benzyl) (methyl) amino) methyl) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) -2- (4-(trifluoromethyl) phenyl) acetamide, 155 Synthesized using General Procedure A, replacing 2- (4-(trifluoromethyl) phenyl) acetyl chloride and 4- (3- (trifluoromethyl) benzyl) benzaldehyde with2, 2-difluoro-2- (4- (trifluoromethyl) phenyl) acetyl chloride and 4- (2-fluorophenoxy) benzaldehyde. ESI [M+H] ＝730.2.

2, 2-difluoro-N- ( (2S, 3R) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-2- ( (methyl (4- (o-tolyloxy) benzyl) amino) methyl) -6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) -2- (4-(trifluoromethyl) phenyl) acetamide, 156 Synthesized using General Procedure A, replacing 2- (4-(trifluoromethyl) phenyl) acetyl chloride and 4- (3- (trifluoromethyl) benzyl) benzaldehyde with2, 2-difluoro-2- (4- (trifluoromethyl) phenyl) acetyl chloride and 4- (o-tolyloxy) benzaldehyde. ESI [M+H] ＝726.2.

2-amino-N- ( (2S, 3R) -2- ( ( (4- (2-fluorophenoxy) benzyl) (methyl) amino) methyl) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) -2-phenylacetamide, 157 Synthesized using General Procedure A, replacing 2- (4-(trifluoromethyl) phenyl) acetyl chloride and 4- (3- (trifluoromethyl) benzyl) benzaldehyde with (9H-fluoren-9-yl) methyl (2-chloro-2-oxo-1-phenylethyl) carbamate and 4- (2-fluorophenoxy) benzaldehyde, then removal of the FMOC group was accomplished by stirring in a solution of piperdine in MeOH. 1H NMR (400MHz, DMSO-d6) δ 10.63-10.23 (m, 1H) , 8.49 -8.25 (m, 1H) , 7.68-7.22 (m, 11H) , 7.20-7.11 (m, 1H) , 7.01 (q, J＝9.0 Hz, 3H) , 5.10-4.94 (m, 2H) , 4.75-4.58 (m, 2H) , 3.80-3.54 (m, 4H) , 3.27-2.93 (m, 2H) , 2.90-2.70 (m, 3H) , 2.33-2.22 (m, 4H) , 1.30-1.19 (m, 3H) , 1.02-0.90 (m, 3H) . ESI [M+H] ＝641.5.

2-amino-N- ( (2S, 3R) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-2- ( (methyl (4- (o-tolyloxy) benzyl) amino) methyl) -6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) -2-phenylacetamide, 158 Synthesized using General Procedure A, replacing 2- (4-(trifluoromethyl) phenyl) acetyl chloride and 4- (3- (trifluoromethyl) benzyl) benzaldehyde with (9H-fluoren-9-yl) methyl (2-chloro-2-oxo-1-phenylethyl) carbamate and 4- (o-tolyloxy) benzaldehyde, then removal of the FMOC group was accomplished by stirring in a solution of piperdine in MeOH. 1H NMR (400MHz, DMSO-d6) δ 10.44-10.11 (m, 1H) , 8.33-8.08 (m, 1H) , 7.48-7.12 (m, 9H) , 7.11-6.95 (m, 2H) , 6.89-6.73 (m, 4H) , 5.01-4.78 (m, 2H) , 4.64-4.43 (m, 2H) , 3.65-3.40 (m, 4H) , 3.05-2.79 (m, 2H) , 2.73-2.55 (m, 3H) , 2.25-2.07 (m, 7H) , 1.09 (dd, J＝2.9, 6.8 Hz, 3H) , 0.88-0.71 (m, 3H) . ESI [M+H] ＝637.5.

N- ( (2S, 3R) -2- ( ( (4- (3, 5-bis (trifluoromethyl) phenoxy) benzyl) (methyl) amino) methyl) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) -2- (4-(trifluoromethyl) phenyl) acetamide, 159. Synthesized using General Procedure A, replacing 4-(3- (trifluoromethyl) benzyl) benzaldehyde with 4- (3, 5-bis (trifluoromethyl) phenoxy) benzaldehyde. ESI [M+H] ＝812.2.

(R) -2-hydroxy-N- ( (2S, 3R) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-2- ( (methyl (4-phenoxybenzyl) amino) methyl) -6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) -2-phenylacetamide, 160 Synthesized using General Procedure A, replacing 2- (4-(trifluoromethyl) phenyl) acetyl chloride and 4- (3- (trifluoromethyl) benzyl) benzaldehyde with (R) -2-chloro-2-oxo-1-phenylethyl acetate and 4-phenoxybenzaldehyde, then removal of the acetyl group was accomplished by stirring in a solution of NaOH in H₂O and MeOH. 1H NMR (400MHz, DMSO-d6) δ 9.72 (s, 1H) , 8.25 (d, J＝7.5 Hz, 1H) , 7.41-7.31 (m, 4H) , 7.27 -7.15 (m, 5H) , 7.14-7.02 (m, 2H) , 6.96 (d, J＝7.9 Hz, 2H) , 6.92-6.83 (m, 4H) , 5.08 (d, J＝3.5 Hz, 1H) , 4.94-4.76 (m, 2H) , 4.55 (d, J＝6.2 Hz, 1H) , 3.63-3.44 (m, 5H) , 2.99 (t, J＝13.9 Hz, 1H) , 2.86 (dd, J＝7.9, 13.2 Hz, 1H) , 2.69 (d, J＝13.2 Hz, 1H) , 2.24-1.99 (m, 4H) , 1.10 (d, J＝6.6 Hz, 3H) , 0.84 (d, J＝6.6 Hz, 3H) . ESI [M+H] ＝624.2.

(R) -N- ( (2S, 3R) -2- ( ( (4- (2-fluorophenoxy) benzyl) (methyl) amino) methyl) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) -2-hydroxy-2-phenylacetamide, 161 Synthesized using General Procedure A, replacing 2- (4-(trifluoromethyl) phenyl) acetyl chloride and 4- (3- (trifluoromethyl) benzyl) benzaldehyde with (R) -2-chloro-2-oxo-1-phenylethyl acetate and 4- (2-fluorophenoxy) benzaldehyde, then removal of the acetyl group was accomplished by stirring in a solution of NaOH in H₂O and MeOH. ESI [M+H] ＝642.2.

(R) -2-hydroxy-N- ( (2S, 3R) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-2- ( (methyl (4- (o-tolyloxy) benzyl) amino) methyl) -6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) -2-phenylacetamide, 162 Synthesized using General Procedure A, replacing 2- (4-(trifluoromethyl) phenyl) acetyl chloride and 4- (3- (trifluoromethyl) benzyl) benzaldehyde with (R) -2-chloro-2-oxo-1-phenylethyl acetate and 4- (o-tolyloxy) benzaldehyde, then removal of the acetyl group was accomplished by stirring in a solution of NaOH in H₂O and MeOH. ESI [M+H] ＝638.2.

N- ( (2S, 3R) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-2- ( (methyl (4-(phenylamino) benzyl) amino) methyl) -6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) -2- (4- (trifluoromethyl) phenyl) acetamide, 163. Synthesized using General Procedure A, replacing 4- (3- (trifluoromethyl) benzyl) benzaldehyde with 4- (phenylamino) benzaldehyde. 1H NMR (400MHz, DMSO-d6) δ 8.70 (br. s. , 1H) , 8.08 (br. s. , 1H) , 7.89 (d, J＝7.5 Hz, 1H) , 7.71-7.57 (m, 2H) , 7.55-7.39 (m, 2H) , 7.22-7.13 (m, 2H) , 7.12-6.91 (m, 8H) , 6.86 (t, J＝7.9 Hz, 1H) , 6.76 (t, J＝7.1 Hz, 1H) , 4.84 (br. s. , 1H) , 4.61 (br. s. , 1H) , 4.43 (d, J＝5.7 Hz, 1H) , 3.93 -3.72 (m, 2H) , 3.55 (d, J＝4.4 Hz, 1H) , 3.46-3.40 (m, 2H) , 3.22 (br. s. , 1H) , 2.88 (t, J＝13.7 Hz, 1H) , 2.13-1.91 (m, 4H) , 1.09 (d, J＝6.6 Hz, 3H) , 0.66 (d, J＝6.2 Hz, 3H) . ESI [M+H] ＝675.2.

N- ( (2S, 3R) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-2- ( (methyl (4-(methyl (phenyl) amino) benzyl) amino) methyl) -6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) -2- (4- (trifluoromethyl) phenyl) acetamide, 164. Synthesized using General Procedure A, replacing 4- (3- (trifluoromethyl) benzyl) benzaldehyde with 4-(methyl (phenyl) amino) benzaldehyde. ESI [M+H] ＝689.3.

2- (4-fluorophenyl) -N- ( (2S, 3R) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-2- ( (methyl (4-(methyl (phenyl) amino) benzyl) amino) methyl) -6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) acetamide, 165 Synthesized using General Procedure A, replacing 2- (4- (trifluoromethyl) phenyl) acetyl chloride and 4- (3- (trifluoromethyl) benzyl) benzaldehyde with2- (4-fluorophenyl) acetyl chloride and 4- (methyl (phenyl) amino) benzaldehyde. ESI [M+H] ＝639.3.

N- ( (2S, 3R) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-2- ( (methyl (4-(methyl (phenyl) amino) benzyl) amino) methyl) -6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) -2- (p-tolyl) acetamide, 166 Synthesized using General Procedure A, replacing 2- (4- (trifluoromethyl) phenyl) acetyl chloride and 4- (3-(trifluoromethyl) benzyl) benzaldehyde with2- (p-tolyl) acetyl chloride and 4-(methyl (phenyl) amino) benzaldehyde. ESI [M+H] ＝635.3.

N- ( (2S, 3R) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-2- ( (methyl (4-(methyl (phenyl) amino) benzyl) amino) methyl) -6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) -2- (4-methoxyphenyl) acetamide, 167 Synthesized using General Procedure A, replacing 2- (4- (trifluoromethyl) phenyl) acetyl chloride and 4- (3-(trifluoromethyl) benzyl) benzaldehyde with2- (4-methoxyphenyl) acetyl chloride and 4-(methyl (phenyl) amino) benzaldehyde. 1H NMR (400MHz, DMSO-d6) δ 8.32 (br. s. , 1H) , 8.10 (d, J＝7.5 Hz, 1H) , 7.27-7.16 (m, 4H) , 7.14-7.00 (m, 3H) , 6.97-6.76 (m, 8H) , 4.83 (br. s. , 1H) , 4.59 (br. s. , 1H) , 4.44 (d, J＝6.6 Hz, 1H) , 3.71 (s, 3H) , 3.64 (s, 2H) , 3.59-3.48 (m, 1H) , 3.47 - 3.38 (m, 1H) , 3.26-3.16 (m, 4H) , 2.94-2.77 (m, 1H) , 2.42-2.31 (m, 1H) , 2.16-1.88 (m, 4H) , 1.08 (d, J＝6.6 Hz, 3H) , 0.65 (d, J＝6.6 Hz, 3H) . ESI [M+H] ＝651.3.

2- (4-cyanophenyl) -N- ( (2S, 3R) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-2- ( (methyl (4-(methyl (phenyl) amino) benzyl) amino) methyl) -6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) acetamide, 168 Synthesized using General Procedure A, replacing 2- (4- (trifluoromethyl) phenyl) acetyl chloride and 4- (3- (trifluoromethyl) benzyl) benzaldehyde with2- (4-cyanophenyl) acetyl chloride and 4- (methyl (phenyl) amino) benzaldehyde. ESI [M+H] ＝646.3.

N- ( (2S, 3R) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-2- ( (methyl (4- (methyl (o-tolyl) amino) benzyl) amino) methyl) -6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) -2- (4- (trifluoromethyl) phenyl) acetamide, 169. Synthesized using General Procedure A, replacing 4- (3- (trifluoromethyl) benzyl) benzaldehyde with 4- (methyl (o-tolyl) amino) benzaldehyde. 1H NMR (400MHz, DMSO-d6) δ 8.68 (br. s. , 1H) , 7.89 (d, J＝7.5 Hz, 1H) , 7.64 (d, J＝7.9 Hz, 2H) , 7.52 (d, J＝7.5 Hz, 2H) , 7.32-7.13 (m, 3H) , 7.12-7.02 (m, 2H) , 6.96 (d, J＝7.9 Hz, 2H) , 6.85 (t, J＝7.9 Hz, 1H) , 6.38 (d, J＝8.4 Hz, 2H) , 4.81 (br. s. , 1H) , 4.59 (br. s. , 1H) , 4.41 (d, J＝6.6 Hz, 1H) , 3.93-3.73 (m, 2H) , 3.54 (d, J＝4.9 Hz, 1H) , 3.45-3.36 (m, 2H) , 3.11 (s, 3H) , 2.87 (t, J＝13.7 Hz, 1H) , 1.99 (d, J＝16.8 Hz, 7H) , 1.09 (d, J＝6.6 Hz, 3H) , 0.64 (d, J＝6.2 Hz, 3H) . ESI [M+H] ＝703.3.

N- ( (2S, 3R) -2- ( ( (4- (ethyl (phenyl) amino) benzyl) (methyl) amino) methyl) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) -2- (4-(trifluoromethyl) phenyl) acetamide, 170. Synthesized using General Procedure A, replacing 4-(3- (trifluoromethyl) benzyl) benzaldehyde with 4- (ethyl (phenyl) amino) benzaldehyde. ESI [M+H] ＝703.3.

N- ( (2S, 3R) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-2- ( (methyl (4-(phenyl (propyl) amino) benzyl) amino) methyl) -6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) -2- (4- (trifluoromethyl) phenyl) acetamide, 171. Synthesized using General Procedure A, replacing 4- (3- (trifluoromethyl) benzyl) benzaldehyde with 4-(phenyl (propyl) amino) benzaldehyde. 1H NMR (400MHz, DMSO-d6) δ 8.73 (br. s. , 1H) , 7.88 (d, J＝7.5 Hz, 1H) , 7.70-7.60 (m, 2H) , 7.53 (d, J＝7.9 Hz, 2H) , 7.29-7.14 (m, 2H) , 7.08 (d, J＝7.9 Hz, 3H) , 6.95-6.76 (m, 6H) , 4.83 (br. s. , 1H) , 4.61 (br. s. , 1H) , 4.43 (d, J＝6.2 Hz, 1H) , 3.94-3.75 (m, 2H) , 3.62-3.51 (m, 3H) , 3.47-3.36 (m, 1H) , 3.23-3.15 (m, 1H) , 2.96-2.78 (m, 1H) , 2.11-1.92 (m, 4H) , 1.59-1.42 (m, 2H) , 1.09 (d, J＝7.1 Hz, 3H) , 0.83 (t, J＝7.5 Hz, 3H) , 0.66 (d, J＝6.6 Hz, 3H) . ESI [M+H] ＝717.3.

N- ( (2S, 3R) -2- ( ( (4- ( (4-cyanophenyl) (methyl) amino) benzyl) (methyl) amino) methyl) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) -2- (4-(trifluoromethyl) phenyl) acetamide, 172. Synthesized using General Procedure A, replacing 4-(3- (trifluoromethyl) benzyl) benzaldehyde with 4- ( (4-formylphenyl) (methyl) amino) benzonitrile. ESI [M+H] ＝714.2.

N- ( (2S, 3R) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-2- ( (methyl (4- (methyl (4-(trifluoromethyl) phenyl) amino) benzyl) amino) methyl) -6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) -2- (4- (trifluoromethyl) phenyl) acetamide, 173. Synthesized using General Procedure A, replacing 4- (3- (trifluoromethyl) benzyl) benzaldehyde with 4- (methyl (4-(trifluoromethyl) phenyl) amino) benzaldehyde. ESI [M+H] ＝757.2.

N- ( (2S, 3R) -5- ( (S) -1-hydroxypropan-2-yl) -2- ( ( (4- ( (4-methoxyphenyl) (methyl) amino) benzyl) (methyl) amino) methyl) -3-methyl-6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) -2- (4- (trifluoromethyl) phenyl) acetamide, 174. Synthesized using General Procedure A, replacing 4- (3- (trifluoromethyl) benzyl) benzaldehyde with 4- ( (4-methoxyphenyl) (methyl) amino) benzaldehyde. 1H NMR (400MHz, DMSO-d6) δ 8.70 (s, 1H) , 7.89 (d, J＝7.5 Hz, 1H) , 7.64 (d, J＝7.9 Hz, 2H) , 7.52 (d, J＝7.9 Hz, 2H) , 7.09 (d, J＝7.9 Hz, 1H) , 7.03-6.93 (m, 4H) , 6.91-6.75 (m, 3H) , 6.64 (d, J＝8.4 Hz, 2H) , 4.96-4.75 (m, 1H) , 4.59 (br. s. , 1H) , 4.47-4.33 (m, 1H) , 3.92-3.74 (m, 2H) , 3.74-3.66 (m, 3H) , 3.61-3.49 (m, 1H) , 3.47-3.38 (m, 1H) , 3.22 (dd, J＝4.9, 15.0 Hz, 1H) , 3.13 (s, 3H) , 2.87 (t, J＝14.1 Hz, 1H) , 2.15-1.92 (m, 4H) , 1.08 (d, J＝6.6 Hz, 3H) , 0.65 (d, J＝6.6 Hz, 3H) . ESI [M+H] ＝719.3.

N- ( (2S, 3R) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-2- ( (methyl (4-(methyl (phenyl) amino) benzyl) amino) methyl) -6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) -2- (4- (trifluoromethyl) phenyl) propanamide, 175 Synthesized using General Procedure A, replacing 2- (4- (trifluoromethyl) phenyl) acetyl chloride and 4- (3-(trifluoromethyl) benzyl) benzaldehyde with2- (4- (trifluoromethyl) phenyl) propanoyl chloride and 4- (methyl (phenyl) amino) benzaldehyde. ESI [M+H] ＝703.3.

N- ( (2S, 3R) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-2- ( (methyl (4- (methyl (2-(trifluoromethyl) phenyl) amino) benzyl) amino) methyl) -6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) -2- (4- (trifluoromethyl) phenyl) acetamide, 176. Synthesized using General Procedure A, replacing 4- (3- (trifluoromethyl) benzyl) benzaldehyde with 4- (methyl (2-(trifluoromethyl) phenyl) amino) benzaldehyde. ESI [M+H] ＝757.2.

2- (2, 5-bis (trifluoromethyl) phenyl) -N- ( (2S, 3R) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-2-( (methyl (4- (methyl (phenyl) amino) benzyl) amino) methyl) -6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) acetamide, 177 Synthesized using General Procedure A, replacing 2- (4- (trifluoromethyl) phenyl) acetyl chloride and 4- (3- (trifluoromethyl) benzyl) benzaldehyde with2- (2, 5-bis (trifluoromethyl) phenyl) acetyl chloride and 4-(methyl (phenyl) amino) benzaldehyde. ESI [M+H] ＝757.2.

N- ( (2S, 3R) -5- ( (S) -1-hydroxypropan-2-yl) -2- ( ( (4- ( (2-methoxyethyl) (phenyl) amino) benzyl) (methyl) amino) methyl) -3-methyl-6-oxo-3, 4, 5, 6-tetrahydro- 2H-benzo [b] [1, 5] oxazocin-10-yl) -2- (4- (trifluoromethyl) phenyl) acetamide, 178. Synthesized using General Procedure A, replacing 4- (3- (trifluoromethyl) benzyl) benzaldehyde with 4- ( (2-methoxyethyl) (phenyl) amino) benzaldehyde. ESI [M+H] ＝733.3.

N- ( (2S, 3R) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-2- ( (methyl (4- (methyl (p-tolyl) amino) benzyl) amino) methyl) -6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) -2- (4- (trifluoromethyl) phenyl) acetamide, 179. Synthesized using General Procedure A, replacing 4- (3- (trifluoromethyl) benzyl) benzaldehyde with 4- (methyl (p-tolyl) amino) benzaldehyde. ESI [M+H] ＝703.3.

N- ( (2S, 3R) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-2- ( (methyl (4- (methyl (m-tolyl) amino) benzyl) amino) methyl) -6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) -2- (4- (trifluoromethyl) phenyl) acetamide, 180. Synthesized using General Procedure A, replacing 4- (3- (trifluoromethyl) benzyl) benzaldehyde with 4- (methyl (m-tolyl) amino) benzaldehyde. ESI [M+H] ＝703.3.

N- ( (2S, 3R) -2- ( ( (4- ( (3-fluorophenyl) (methyl) amino) benzyl) (methyl) amino) methyl) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) -2- (4-(trifluoromethyl) phenyl) acetamide, 181. Synthesized using General Procedure A, replacing 4-(3- (trifluoromethyl) benzyl) benzaldehyde with 4- ( (3-fluorophenyl) (methyl) amino) benzaldehyde. ESI [M+H] ＝707.3.

N- ( (2S, 3R) -2- ( ( (4- ( (2, 5-dimethylphenyl) (methyl) amino) benzyl) (methyl) amino) methyl) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) -2- (4-(trifluoromethyl) phenyl) acetamide, 182. Synthesized using General Procedure A, replacing 4-(3- (trifluoromethyl) benzyl) benzaldehyde with 4- ( (2, 5-dimethylphenyl) (methyl) amino) benzaldehyde. ESI [M+H] ＝717.3.

N- ( (2S, 3R) -2- ( ( (4- (butyl (phenyl) amino) benzyl) (methyl) amino) methyl) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) -2- (4-(trifluoromethyl) phenyl) acetamide, 183. Synthesized using General Procedure A, replacing 4-(3- (trifluoromethyl) benzyl) benzaldehyde with 4- (butyl (phenyl) amino) benzaldehyde. ESI [M+H] ＝731.3.

N- ( (2S, 3R) -2- ( ( (4- ( (2, 3-dimethylphenyl) (methyl) amino) benzyl) (methyl) amino) methyl) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) -2- (4-(trifluoromethyl) phenyl) acetamide, 184. Synthesized using General Procedure A, replacing 4-(3- (trifluoromethyl) benzyl) benzaldehyde with 4- ( (2, 3-dimethylphenyl) (methyl) amino) benzaldehyde. 1H NMR (400MHz, DMSO-d6) δ 8.69 (s, 1H) , 7.88 (d, J＝7.5 Hz, 1H) , 7.63 (d, J＝7.9 Hz, 2H) , 7.51 (d, J＝7.5 Hz, 2H) , 7.22-7.01 (m, 3H) , 6.96 -6.67 (m, 4H) , 6.35 (d, J＝8.4 Hz, 2H) , 4.82 (t, J＝5.3 Hz, 1H) , 4.58 (br. s. , 1H) , 4.47-4.33 (m, 1H) , 3.92-3.71 (m, 2H) , 3.61-3.49 (m, 1H) , 3.45-3.34 (m, 1H) , 3.24-3.16 (m, 1H) , 3.08 (s, 3H) , 2.86 (t, J＝13.9 Hz, 1H) , 2.33-2.16 (m, 3H) , 2.08-1.81 (m, 7H) , 1.13-0.96 (m, 3H) , 0.63 (d, J＝6.2 Hz, 3H) . ESI [M+H] ＝717.3.

N- ( (2S, 3R) -5- ( (S) -1-hydroxypropan-2-yl) -2- ( ( (4-(isopropyl (phenyl) amino) benzyl) (methyl) amino) methyl) -3-methyl-6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) -2- (4- (trifluoromethyl) phenyl) acetamide, 185. Synthesized using General Procedure A, replacing 4- (3- (trifluoromethyl) benzyl) benzaldehyde with 4-(isopropyl (phenyl) amino) benzaldehyde. 1H NMR (400MHz, DMSO-d6) δ 8.73 (s, 1H) , 7.89 (d, J＝7.5 Hz, 1H) , 7.73-7.61 (m, 2H) , 7.58-7.49 (m, 2H) , 7.21 (t, J＝7.5 Hz, 2H) , 7.11 (d, J＝7.9 Hz, 3H) , 6.94-6.81 (m, 2H) , 6.72 (d, J＝7.1 Hz, 4H) , 4.83 (t, J＝5.1 Hz, 1H) , 4.62 (br. s. , 1H) , 4.43 (d, J＝6.2 Hz, 1H) , 4.26 (td, J＝6.5, 13.1 Hz, 1H) , 3.97-3.75 (m, 2H) , 3.64-3.50 (m, 1H) , 3.48-3.35 (m, 4H) , 3.27-3.17 (m, 1H) , 2.93-2.83 (m, 1H) , 2.14-1.92 (m, 4H) , 1.09 (d, J＝6.6 Hz, 3H) , 1.03 (d, J＝5.3 Hz, 6H) , 0.67 (d, J＝6.6 Hz, 3H) . ESI [M+H] ＝717.6.

N- ( (2S, 3R) -2- ( ( (4- ( (3, 5-difluorophenyl) (methyl) amino) benzyl) (methyl) amino) methyl) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) -2- (4-(trifluoromethyl) phenyl) acetamide, 186. Synthesized using General Procedure A, replacing 4-(3- (trifluoromethyl) benzyl) benzaldehyde with 4- ( (3, 5-difluorophenyl) (methyl) amino) benzaldehyde ESI [M+H] ＝725.2.

N- ( (2S, 3R) -2- ( ( (4- ( (3-fluoro-4-(trifluoromethyl) phenyl) (methyl) amino) benzyl) (methyl) amino) methyl) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) -2- (4-(trifluoromethyl) phenyl) acetamide, 187. Synthesized using General Procedure A, replacing 4-(3- (trifluoromethyl) benzyl) benzaldehyde with 4- ( (3-fluoro-4-(trifluoromethyl) phenyl) (methyl) amino) benzaldehyde ESI [M+H] ＝775.3.

N- ( (2S, 3R) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-2- ( (methyl (4- (methyl (2, 4, 5-trifluorophenyl) amino) benzyl) amino) methyl) -6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) -2- (4- (trifluoromethyl) phenyl) acetamide, 188. Synthesized using General Procedure A, replacing 4- (3- (trifluoromethyl) benzyl) benzaldehyde with 4-(methyl (2, 4, 5-trifluorophenyl) amino) benzaldehyde ESI [M+H] ＝743.3.

N- ( (2S, 3R) -2- ( ( (4- ( (2-fluorophenyl) (methyl) amino) benzyl) (methyl) amino) methyl) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) -2- (4-(trifluoromethyl) phenyl) acetamide, 189. Synthesized using General Procedure A, replacing 4-(3- (trifluoromethyl) benzyl) benzaldehyde with 4- ( (2-fluorophenyl) (methyl) amino) benzaldehyde ESI [M+H] ＝707.2.

N- ( (2S, 3R) -2- ( ( (4- ( (3, 4-difluorophenyl) (methyl) amino) benzyl) (methyl) amino) methyl) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) -2- (4-(trifluoromethyl) phenyl) acetamide, 190. Synthesized using General Procedure A, replacing 4-(3- (trifluoromethyl) benzyl) benzaldehyde with 4- ( (3, 4-difluorophenyl) (methyl) amino) benzaldehyde ESI [M+H] ＝725.2.

N- ( (2S, 3R) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-2- ( (methyl (4-(phenylthio) benzyl) amino) methyl) -6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) -2, 2-diphenylacetamide, 191 Synthesized using General Procedure A, replacing 2- (4-(trifluoromethyl) phenyl) acetyl chloride and 4- (3- (trifluoromethyl) benzyl) benzaldehyde with2, 2-diphenylacetyl chloride and 4- (phenylthio) benzaldehyde. ESI [M+H] ＝700.2.

N- ( (2S, 3R) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-2- ( (methyl (4-(phenylthio) benzyl) amino) methyl) -6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) -2-(p-tolyl) acetamide, 192 Synthesized using General Procedure A, replacing 2- (4-(trifluoromethyl) phenyl) acetyl chloride and 4- (3- (trifluoromethyl) benzyl) benzaldehyde with2- (p-tolyl) acetyl chloride and 4- (phenylthio) benzaldehyde. 1H NMR (400MHz, DMSO-d6) δ 8.34 (s, 1H) , 8.08 (d, J＝7.5 Hz, 1H) , 7.36-7.30 (m, 2H) , 7.29-7.16 (m, 9H) , 7.11 (d, J＝7.9 Hz, 2H) , 7.05 (d, J＝6.6 Hz, 1H) , 6.85 (t, J＝7.9 Hz, 1H) , 4.83 (t, J＝5.3 Hz, 1H) , 4.61 (br. s. , 1H) , 4.50-4.27 (m, 1H) , 3.74-3.61 (m, 2H) , 3.58-3.48 (m, 1H) , 3.46-3.36 (m, 3H) , 3.25-3.13 (m, 1H) , 2.88-2.78 (m, 1H) , 2.43-2.35 (m, 2H) , 2.31-2.17 (m, 3H) , 2.12-1.90 (m, 4H) , 1.07 (d, J＝6.6 Hz, 3H) , 0.64 (d, J＝6.6 Hz, 3H) . ESI [M+H] ＝638.3.

N- ( (2S, 3R) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-2- ( (methyl (4-(phenylthio) benzyl) amino) methyl) -6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) -2-(4- (trifluoromethyl) phenyl) acetamide, 193. Synthesized using General Procedure A, replacing 4- (3- (trifluoromethyl) benzyl) benzaldehyde with 4- (phenylthio) benzaldehyde. 1H NMR (400MHz, DMSO-d6) δ 8.74 (s, 1H) , 7.87 (d, J＝7.5 Hz, 1H) , 7.64 (d, J＝7.9 Hz, 2H) , 7.52 (d, J＝7.5 Hz, 2H) , 7.37 -7.29 (m, 2H) , 7.28 -7.16 (m, 6H) , 7.09 (d, J＝7.5 Hz, 1H) , 6.85 (t, J＝7.7 Hz, 1H) , 4.83 (t, J＝4.9 Hz, 1H) , 4.61 (br. s. , 1H) , 4.51-4.33 (m, 1H) , 3.94-3.73 (m, 2H) , 3.62-3.49 (m, 1H) , 3.46-3.39 (m, 3H) , 3.23 (dd, J＝5.1, 15.2 Hz, 1H) , 2.96-2.79 (m, 1H) , 2.12-1.93 (m, 4H) , 1.07 (d, J＝6.6 Hz, 3H) , 0.74-0.57 (m, 3H) . ESI [M+H] ＝692.2.

N- ( (2S, 3R) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-2- ( (methyl (4-(phenylthio) benzyl) amino) methyl) -6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) -2-(3- (trifluoromethyl) phenyl) acetamide, 195 Synthesized using General Procedure A, replacing 2-(4- (trifluoromethyl) phenyl) acetyl chloride and 4- (3- (trifluoromethyl) benzyl) benzaldehyde with2-(3- (trifluoromethyl) phenyl) acetyl chloride and 4- (phenylthio) benzaldehyde. ESI [M+H] ＝692.2.

N- ( (2S, 3R) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-2- ( (methyl (4-(phenylthio) benzyl) amino) methyl) -6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) -2-(pyridin-4-yl) acetamide, 197 Synthesized using General Procedure A, replacing 2- (4-(trifluoromethyl) phenyl) acetyl chloride and 4- (3- (trifluoromethyl) benzyl) benzaldehyde with2-(pyridin-4-yl) acetyl chlorideand 4- (phenylthio) benzaldehyde. 1H NMR (400MHz, DMSO-d6) δ 8.84 (s, 1H) , 8.47 (d, J＝5.7 Hz, 2H) , 7.84 (d, J＝7.1 Hz, 1H) , 7.40-7.19 (m, 11H) , 7.12 (d, J＝7.5 Hz, 1H) , 6.87 (t, J＝7.9 Hz, 1H) , 4.64 (br. s. , 1H) , 4.52-4.37 (m, 1H) , 3.85-3.68 (m, 2H) , 3.61-3.52 (m, 1H) , 3.50-3.41 (m, 5H) , 3.22-3.12 (m, 2H) , 3.01-2.84 (m, 1H) , 2.70-2.55 (m, 1H) , 2.13-2.01 (m, 4H) , 1.09 (d, J＝6.6 Hz, 3H) , 0.71 (d, J＝6.6 Hz, 3H) . ESI [M+H] ＝625.2.

N- ( (2S, 3R) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-2- ( (methyl (4-(phenylthio) benzyl) amino) methyl) -6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) -2-(2- (trifluoromethyl) phenyl) acetamide, 198 Synthesized using General Procedure A, replacing 2-(4- (trifluoromethyl) phenyl) acetyl chloride and 4- (3- (trifluoromethyl) benzyl) benzaldehyde with2-(2- (trifluoromethyl) phenyl) acetyl chloride and 4- (phenylthio) benzaldehyde. 1H NMR (400MHz, DMSO-d6) δ 8.44 (s, 1H) , 8.00 (d, J＝7.5 Hz, 1H) , 7.73 (d, J＝7.5 Hz, 1H) , 7.67-7.59 (m, 1H) , 7.59-7.46 (m, 2H) , 7.41-7.20 (m, 9H) , 7.08 (d, J＝7.5 Hz, 1H) , 6.87 (t, J＝7.9 Hz, 1H) , 4.84 (t, J＝5.1 Hz, 1H) , 4.64 (br. s. , 1H) , 4.52-4.38 (m, 1H) , 4.04-3.83 (m, 2H) , 3.62-3.50 (m, 1H) , 3.49-3.38 (m, 4H) , 3.27-3.22 (m, 2H) , 2.87 (t, J＝13.9 Hz, 1H) , 2.15-1.97 (m, 4H) , 1.15-1.01 (m, 3H) , 0.66 (d, J＝6.6 Hz, 3H) . ESI [M+H] ＝692.2.

N- ( (2S, 3R) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-2- ( (methyl (4-(phenylthio) benzyl) amino) methyl) -6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) -2-(2-methoxyphenyl) acetamide, 199 Synthesized using General Procedure A, replacing 2- (4-(trifluoromethyl) phenyl) acetyl chloride and 4- (3- (trifluoromethyl) benzyl) benzaldehyde with2- (2-methoxyphenyl) acetyl chloride and 4- (phenylthio) benzaldehyde. ESI [M+H] ＝654.2.

N- ( (2S, 3R) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-2- ( (methyl (4-(phenylsulfonyl) benzyl) amino) methyl) -6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) -2- (4- (trifluoromethyl) phenyl) acetamide, 200 Synthesized using General Procedure A, replacing 4- (3- (trifluoromethyl) benzyl) benzaldehyde with 4- (phenylsulfonyl) benzaldehyde. ESI [M+H] ＝724.2.

N- ( (2S, 3R) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-2- ( (methyl (4-(phenylthio) benzyl) amino) methyl) -6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) -2-(4- (trifluoromethoxy) phenyl) acetamide, 201 Synthesized using General Procedure A, replacing 2- (4- (trifluoromethyl) phenyl) acetyl chloride and 4- (3- (trifluoromethyl) benzyl) benzaldehyde with2- (4- (trifluoromethoxy) phenyl) acetyl chloride and 4- (phenylthio) benzaldehyde. 1H NMR (400MHz, DMSO-d6) δ 8.69 (s, 1H) , 7.89 (d, J＝7.5 Hz, 1H) , 7.42 (d, J＝7.9 Hz, 2H) , 7.36-7.18 (m, 11H) , 7.09 (d, J＝7.5 Hz, 1H) , 6.92-6.79 (m, 1H) , 4.82 (t, J＝4.9 Hz, 1H) , 4.63 (br. s. , 1H) , 4.44 (d, J＝6.2 Hz, 1H) , 3.83-3.64 (m, 2H) , 3.60-3.39 (m, 6H) , 2.87 (t, J＝13.9 Hz, 1H) , 2.18-1.91 (m, 4H) , 1.07 (d, J＝7.1 Hz, 3H) , 0.67 (d, J＝6.6 Hz, 3H) . ESI [M+H] ＝708.2.

N- ( (2S, 3R) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-2- ( (methyl (4-(phenylthio) benzyl) amino) methyl) -6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) -2-(3-methoxyphenyl) acetamide, 202 Synthesized using General Procedure A, replacing 2- (4-(trifluoromethyl) phenyl) acetyl chloride and 4- (3- (trifluoromethyl) benzyl) benzaldehyde with2- (3-methoxyphenyl) acetyl chloride and 4- (phenylthio) benzaldehyde. 1H NMR (400MHz, DMSO-d6) δ 8.38 (s, 1H) , 8.07 (d, J＝7.5 Hz, 1H) , 7.38-7.29 (m, 2H) , 7.29-7.14 (m, 8H) , 7.05 (d, J＝7.9 Hz, 1H) , 6.94-6.78 (m, 4H) , 4.82 (t, J＝5.1 Hz, 1H) , 4.59 (br. s. , 1H) , 4.44 (d, J＝6.2 Hz, 1H) , 3.77-3.60 (m, 5H) , 3.57-3.47 (m, 1H) , 3.45-3.35 (m, 3H) , 3.21 (d, J＝4.9 Hz, 2H) , 2.84 (t, J＝13.9 Hz, 1H) , 2.11-1.88 (m, 4H) , 1.06 (d, J＝6.6 Hz, 3H) , 0.63 (d, J＝6.2 Hz, 3H) . ESI [M+H] ＝654.2.

1- (4-fluorophenyl) -N- ( (2S, 3R) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-2- ( (methyl (4-(phenylthio) benzyl) amino) methyl) -6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) cyclopropanecarboxamide, 203 Synthesized using General Procedure A, replacing 2- (4-(trifluoromethyl) phenyl) acetyl chloride and 4- (3- (trifluoromethyl) benzyl) benzaldehyde with1- (4-fluorophenyl) cyclopropanecarbonyl chloride and 4- (phenylthio) benzaldehyde. ESI [M+H] ＝668.2.

N- ( (2S, 3R) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-2- ( (methyl (4-(phenylthio) benzyl) amino) methyl) -6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) -2- phenylpropanamide, 204 Synthesized using General Procedure A, replacing 2- (4-(trifluoromethyl) phenyl) acetyl chloride and 4- (3- (trifluoromethyl) benzyl) benzaldehyde with2-phenylpropanoyl chloride and 4- (phenylthio) benzaldehyde. ESI [M+H] ＝638.2.

N- ( (2S, 3R) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-2- ( (methyl (4- (m-tolylthio) benzyl) amino) methyl) -6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) -2- (4-(trifluoromethyl) phenyl) acetamide, 205. Synthesized using General Procedure A, replacing 4-(3- (trifluoromethyl) benzyl) benzaldehyde with 4- (m-tolylthio) benzaldehyde. ESI [M+H] ＝706.2.

N- ( (2S, 3R) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-2- ( (methyl (4- (o-tolylthio) benzyl) amino) methyl) -6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) -2- (4- (trifluoromethyl) phenyl) acetamide, 206. Synthesized using General Procedure A, replacing 4-(3- (trifluoromethyl) benzyl) benzaldehyde with 4- (o-tolylthio) benzaldehyde. ESI [M+H] ＝706.2.

N- ( (2S, 3R) -5- ( (S) -1-hydroxypropan-2-yl) -2- ( ( (4- ( (3-methoxyphenyl) thio) benzyl) (methyl) amino) methyl) -3-methyl-6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) -2- (4- (trifluoromethyl) phenyl) acetamide, 207. Synthesized using General Procedure A, replacing 4- (3- (trifluoromethyl) benzyl) benzaldehyde with 4- ( (3-methoxyphenyl) thio) benzaldehyde. ESI [M+H] ＝722.2.

2- (4-fluorophenyl) -N- ( (2S, 3R) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-2- ( (methyl (4-(phenylthio) benzyl) amino) methyl) -6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) propanamide, 208 Synthesized using General Procedure A, replacing 2- (4-(trifluoromethyl) phenyl) acetyl chloride and 4- (3- (trifluoromethyl) benzyl) benzaldehyde with2- (4- fluorophenyl) propanoyl chloride and 4- (phenylthio) benzaldehyde. 1H NMR (400MHz, DMSO-d6) δ 8.82-8.54 (m, 1H) , 8.16-7.90 (m, 1H) , 7.60-7.45 (m, 4H) , 7.44-7.16 (m, 10H) , 6.99 (t, J＝7.9 Hz, 1H) , 4.99 (br. s. , 1H) , 4.81-4.48 (m, 2H) , 4.24-3.97 (m, 1H) , 3.82-3.51 (m, 3H) , 3.11-2.89 (m, 1H) , 2.55 (d, J＝5.7 Hz, 1H) , 2.26-2.05 (m, 4H) , 1.65-1.44 (m, 3H) , 1.31-1.14 (m, 3H) , 0.92-0.58 (m, 3H) . ESI [M+H] ＝656.2.

N- ( (2S, 3R) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-2- ( (methyl (4- (p-tolylthio) benzyl) amino) methyl) -6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) -2- (4-(trifluoromethyl) phenyl) acetamide, 209. Synthesized using General Procedure A, replacing 4-(3- (trifluoromethyl) benzyl) benzaldehyde with 4- (p-tolylthio) benzaldehyde. 1H NMR (400MHz, DMSO-d6) δ 8.70 (br. s. , 1H) , 7.88 (d, J＝7.1 Hz, 1H) , 7.72-7.59 (m, 2H) , 7.52 (d, J＝7.5 Hz, 2H) , 7.33-7.13 (m, 8H) , 7.10 (d, J＝7.5 Hz, 1H) , 6.86 (t, J＝7.9 Hz, 1H) , 4.82 (br. s. , 1H) , 4.62 (br. s. , 1H) , 4.45 (d, J＝5.7 Hz, 1H) , 3.96-3.70 (m, 2H) , 3.53 (d, J＝5.3 Hz, 1H) , 3.46-3.35 (m, 3H) , 3.22 (br. s. , 1H) , 2.87 (t, J＝13.7 Hz, 1H) , 2.35-2.22 (m, 3H) , 2.12-1.85 (m, 4H) , 1.14-1.00 (m, 3H) , 0.66 (d, J＝6.2 Hz, 3H) . ESI [M+H] ＝706.2.

N- ( (2S, 3R) -5- ( (S) -1-aminopropan-2-yl) -3-methyl-2- ( (methyl (4-(phenylthio) benzyl) amino) methyl) -6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) -2-(4- (trifluoromethyl) phenyl) acetamide, 210. To a solution of N- ( (2S, 3R) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-2- ( (methyl (4- (phenylthio) benzyl) amino) methyl) -6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) -2- (4- (trifluoromethyl) phenyl) acetamide (120 mg, 0.17 mmol) and DBU (129 mg, 0.85 mmol) in toluene (4mL) and dichloromethane (2mL) was added dropwise DPPA (234 mg, 0.85 mmol) with stirring at an ice-water bath. The mixture was stirred at 15 ℃ for 16 hrs. After reaction, it was evaporated and purified by prep-TLC (Petroleum ether: EtOAc＝3: 1) to get N- ( (2S, 3R) -5- ( (S) -1-azidopropan-2-yl) -3-methyl-2-( (methyl (4- (phenylthio) benzyl) amino) methyl) -6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) -2- (4- (trifluoromethyl) phenyl) acetamide (110 mg, yield 90％ ) .

To a solution of N- ( (2S, 3R) -5- ( (S) -1-azidopropan-2-yl) -3-methyl-2- ( (methyl (4-(phenylthio) benzyl) amino) methyl) -6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) -2-(4- (trifluoromethyl) phenyl) acetamide (110 mg, 0.15 mmol) in THF (10 mL) and H₂O (1mL) was added PPh₃ (79 mg, 0.3mmol) . The mixture was stirred at 15 ℃ for 16 hrs. After reaction, it was evaporated. The residue was diluted with ethyl acetate (20 mL) , washed with H₂O and brine, the organic layer was dried over s Na₂SO₄ and concentrated. The crude was purified by Prep-HPLC to get the final product (10 mg, yield 10 ％ ) . 1H NMR (400MHz, DMSO-d6) δ 8.87 (s, 1H) , 7.84 (d, J＝7.5 Hz, 1H) , 7.66 (d, J＝7.9 Hz, 2H) , 7.54 (d, J＝7.5 Hz, 2H) , 7.42-7.29 (m, 2H) , 7.28-7.08 (m, 8H) , 6.88 (t, J＝7.9 Hz, 1H) , 4.44 (br. s. , 1H) , 4.02-3.71 (m, 3H) , 3.03 (t, J＝13.9 Hz, 1H) , 2.82 (dd, J＝5.5, 12.6 Hz, 1H) , 2.01 (s, 4H) , 1.30 (d, J＝6.6 Hz, 3H) , 0.83-0.60 (m, 3H) . ESI [M+H] ＝691.5.

2-hydroxy-N- ( (2S, 3R) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-2- ( (methyl (4-(phenylthio) benzyl) amino) methyl) -6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) -2-phenylacetamide, 211 Synthesized using General Procedure A, replacing 2- (4-(trifluoromethyl) phenyl) acetyl chloride and 4- (3- (trifluoromethyl) benzyl) benzaldehyde with2-chloro-2-oxo-1-phenylethyl acetate and 4- (phenylthio) benzaldehyde, then removal of the acetyl group was accomplished by stirring in a solution of NaOH in H₂O and MeOH. 1H NMR (400MHz, DMSO-d6) δ 9.80-9.51 (m, 1H) , 8.35-8.11 (m, 1H) , 7.43 (d, J＝7.1 Hz, 1H) , 7.37-7.12 (m, 13H) , 7.05 (t, J＝7.7 Hz, 1H) , 6.93-6.81 (m, 2H) , 5.07 (br. s. , 1H) , 4.94-4.72 (m, 2H) , 4.63-4.29 (m, 1H) , 3.70-3.41 (m, 5H) , 3.09-2.75 (m, 2H) , 2.68 (d, J＝17.2 Hz, 1H) , 2.20-2.05 (m, 4H) , 1.08 (t, J＝5.7 Hz, 3H) , 0.91-0.69 (m, 3H) . ESI [M+H] ＝640.2.

N- ( (2S, 3R) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-2- ( (methyl (4-(phenylthio) benzyl) amino) methyl) -6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) -2-(4- (trifluoromethyl) phenyl) propanamide, 212 Synthesized using General Procedure A, replacing 2- (4- (trifluoromethyl) phenyl) acetyl chloride and 4- (3- (trifluoromethyl) benzyl) benzaldehyde with2- (4- (trifluoromethyl) phenyl) propanoyl chloride and 4- (phenylthio) benzaldehyde. ESI [M+H] ＝706.2.

2- (4-fluorophenyl) -N- ( (2S, 3R) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-2- ( (methyl (4-(phenylthio) benzyl) amino) methyl) -6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) butanamide, 213 Synthesized using General Procedure A, replacing 2- (4-(trifluoromethyl) phenyl) acetyl chloride and 4- (3- (trifluoromethyl) benzyl) benzaldehyde with2- (4-fluorophenyl) butanoyl chloride and 4- (phenylthio) benzaldehyde. ESI [M+H] ＝670.2.

2- (3-fluoro-4- (trifluoromethyl) phenyl) -N- ( (2S, 3R) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-2-( (methyl (4- (phenylthio) benzyl) amino) methyl) -6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) acetamide, 214 Synthesized using General Procedure A, replacing 2- (4- (trifluoromethyl) phenyl) acetyl chloride and 4- (3- (trifluoromethyl) benzyl) benzaldehyde with2- (3-fluoro-4- (trifluoromethyl) phenyl) acetyl chloride and 4- (phenylthio) benzaldehyde. 1H NMR (400MHz, DMSO-d6) δ 8.87 (s, 1H) , 7.81 (d, J＝7.5 Hz, 1H) , 7.70 (t, J＝7.7 Hz, 1H) , 7.46 (d, J＝11.9 Hz, 1H) , 7.38-7.29 (m, 3H) , 7.28-7.17 (m, 7H) , 7.12 (d, J＝7.1 Hz, 1H) , 6.86 (t, J＝7.9 Hz, 1H) , 4.84 (t, J＝5.3 Hz, 1H) , 4.62 (br. s. , 1H) , 4.51-4.37 (m, 1H) , 3.93-3.75 (m, 2H) , 3.62-3.49 (m, 1H) , 3.47-3.36 (m, 4H) , 3.25 (dd, J＝5.3, 15.0 Hz, 2H) , 2.89 (t, J＝13.7 Hz, 1H) , 2.15-1.88 (m, 4H) , 1.08 (d, J＝6.6 Hz, 3H) , 0.69 (d, J＝6.6 Hz, 3H) . ESI [M+H] ＝710.2.

2- (3, 5-bis (trifluoromethyl) phenyl) -N- ( (2S, 3R) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-2-( (methyl (4- (phenylthio) benzyl) amino) methyl) -6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) acetamide, 215 Synthesized using General Procedure A, replacing 2- (4- (trifluoromethyl) phenyl) acetyl chloride and 4- (3- (trifluoromethyl) benzyl) benzaldehyde with2- (3, 5-bis (trifluoromethyl) phenyl) acetyl chloride and 4- (phenylthio) benzaldehyde. 1H NMR (400MHz, DMSO-d6) δ 9.06 (s, 1H) , 8.00 (s, 3H) , 7.72 (d, J＝7.9 Hz, 1H) , 7.44-7.08 (m, 10H) , 6.85 (t, J＝7.7 Hz, 1H) , 4.83 (t, J＝5.1 Hz, 1H) , 4.60 (br. s. , 1H) , 4.43 (d, J＝6.2 Hz, 1H) , 4.06-3.80 (m, 2H) , 3.54 (d, J＝6.2 Hz, 1H) , 3.47-3.35 (m, 3H) , 2.90 (t, J＝13.9 Hz, 1H) , 2.15-1.87 (m, 4H) , 1.08 (d, J＝6.6 Hz, 3H) , 0.70 (d, J＝6.6 Hz, 3H) . ESI [M+H] ＝760.2.

N- ( (2S, 3R) -2- ( ( (4- ( (3, 5-bis (trifluoromethyl) phenyl) thio) benzyl) (methyl) amino) methyl) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) -2- (4-(trifluoromethyl) phenyl) acetamide, 216. Synthesized using General Procedure A, replacing 4-(3- (trifluoromethyl) benzyl) benzaldehyde with 4-( (3, 5-bis (trifluoromethyl) phenyl) thio) benzaldehyde. ¹H NMR (400MHz, DMSO-d6) δ 8.73 (s, 1 H) , 7.89 (br. s. , 2 H) , 7.69 (s, 2 H) , 7.63 (d, J＝7.94 Hz, 2 H) , 7.46-7.56 (m, 4 H) , 7.36 (d, J＝7.94 Hz, 2 H) , 7.11 (d, J＝7.94 Hz, 1 H) , 6.87 (t, J＝7.94 Hz, 1 H) , 4.82 (t, J＝5.07 Hz, 1 H) , 4.65 (br. s. , 1 H) , 4.45 (d, J＝6.62 Hz, 1 H) , 3.82 (s, 2 H) , 3.39-3.61 (m, 5 H) , 2.80-2.96 (m, 1 H) , 1.95-2.15 (m, 4 H) , 1.08 (d, J＝7.06 Hz, 3 H) , 0.68 (d, J＝6.62 Hz, 3 H) . ESI [M+H] ＝828.2.

2- (4-fluorophenyl) -N- ( (2S, 3R) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-2- ( (methyl (4-(phenylthio) benzyl) amino) methyl) -6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) pentanamide, 217 Synthesized using General Procedure A, replacing 2- (4-(trifluoromethyl) phenyl) acetyl chloride and 4- (3- (trifluoromethyl) benzyl) benzaldehyde with2- (4-fluorophenyl) pentanoyl chloride and 4- (phenylthio) benzaldehyde. ESI [M+H] ＝684.2.

2- (2, 5-bis (trifluoromethyl) phenyl) -N- ( (2S, 3R) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-2-( (methyl (4- (phenylthio) benzyl) amino) methyl) -6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) acetamide, 218 Synthesized using General Procedure A, replacing 2- (4- (trifluoromethyl) phenyl) acetyl chloride and 4- (3- (trifluoromethyl) benzyl) benzaldehyde with2- (2, 5-bis (trifluoromethyl) phenyl) acetyl chloride and 4- (phenylthio) benzaldehyde. ESI [M+H] ＝760.2.

N- ( (2S, 3R) -2- ( ( (4- ( (3-chlorophenyl) thio) benzyl) (methyl) amino) methyl) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) -2- (4-(trifluoromethyl) phenyl) acetamide, 219. Synthesized using General Procedure A, replacing 4-(3- (trifluoromethyl) benzyl) benzaldehyde with 4- ( (3-chlorophenyl) thio) benzaldehyde. 1H NMR (400MHz, DMSO-d6) δ 8.72 (s, 1H) , 7.90 (d, J＝7.1 Hz, 1H) , 7.65 (d, J＝7.9 Hz, 2H) , 7.59-7.47 (m, 2H) , 7.41-7.22 (m, 6H) , 7.21-7.05 (m, 3H) , 6.87 (t, J＝7.9 Hz, 1H) , 4.83 (t, J＝5.1 Hz, 1H) , 4.64 (br. s. , 1H) , 4.53-4.40 (m, 1H) , 3.91-3.75 (m, 2H) , 3.62-3.50 (m, 1H) , 3.48-3.37 (m, 3H) , 3.24 (dd, J＝4.9, 15.0 Hz, 1H) , 2.89 (t, J＝13.9 Hz, 1H) , 2.16-1.93 (m, 4H) , 1.17-1.00 (m, 3H) , 0.68 (d, J＝6.6 Hz, 3H) . ESI [M+H] ＝726.3.

N- ( (2S, 3R) -2- ( ( (4- ( (3, 5-dimethylphenyl) thio) benzyl) (methyl) amino) methyl) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) -2- (4-(trifluoromethyl) phenyl) acetamide, 220. Synthesized using General Procedure A, replacing 4- (3- (trifluoromethyl) benzyl) benzaldehyde with 4- ( (3, 5-dimethylphenyl) thio) benzaldehyde. 1H NMR (400MHz, DMSO-d6) δ 8.70 (s, 1H) , 7.90 (d, J＝7.5 Hz, 1H) , 7.65 (d, J＝7.9 Hz, 2H) , 7.52 (d, J＝7.9 Hz, 2H) , 7.28-7.15 (m, 4H) , 7.11 (d, J＝6.6 Hz, 1H) , 6.95-6.80 (m, 4H) , 4.82 (t, J＝5.3 Hz, 1H) , 4.63 (t, J＝4.9 Hz, 1H) , 4.52-4.38 (m, 1H) , 3.88-3.75 (m, 2H) , 3.61-3.50 (m, 1H) , 3.48-3.35 (m, 3H) , 3.24 (dd, J＝5.3, 15.4 Hz, 1H) , 2.93-2.82 (m, 1H) , 2.28-2.14 (m, 6H) , 2.11 -1.91 (m, 4H) , 1.08 (d, J＝7.1 Hz, 3H) , 0.66 (d, J＝6.6 Hz, 3H) . ESI [M+H] ＝720.2.

2- (2-fluoro-4- (trifluoromethyl) phenyl) -N- ( (2S, 3R) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-2-( (methyl (4- (phenylthio) benzyl) amino) methyl) -6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) acetamide, 221 Synthesized using General Procedure A, replacing 2- (4- (trifluoromethyl) phenyl) acetyl chloride and 4- (3- (trifluoromethyl) benzyl) benzaldehyde with2- (2-fluoro-4- (trifluoromethyl) phenyl) acetyl chloride and 4- (phenylthio) benzaldehyde. ESI [M+H] ＝710.2.

2, 2-difluoro-N- ( (2S, 3R) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-2- ( (methyl (4-(phenylthio) benzyl) amino) methyl) -6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) -2-phenylacetamide, 222 Synthesized using General Procedure A, replacing 2- (4-(trifluoromethyl) phenyl) acetyl chloride and 4- (3- (trifluoromethyl) benzyl) benzaldehyde with2, 2-difluoro-2-phenylacetyl chloride and 4- (phenylthio) benzaldehyde. 1H NMR (400MHz, DMSO-d6) δ 9.92 (s, 1H) , 7.62 (d, J＝7.5 Hz, 2H) , 7.57-7.42 (m, 4H) , 7.37-7.17 (m, 9H) , 6.91 (t, J＝7.7 Hz, 1H) , 4.84 (br. s. , 1H) , 4.59 (br. s. , 1H) , 4.49-4.32 (m, 1H) , 3.65-3.49 (m, 1H) , 3.46-3.37 (m, 2H) , 2.92 (t, J＝13.9 Hz, 1H) , 2.40-2.22 (m, 2H) , 2.11-1.88 (m, 4H) , 1.09 (d, J＝6.6 Hz, 3H) , 0.64 (d, J＝6.2 Hz, 3H) . ESI [M+H] ＝660.2.

2- (2, 4-bis (trifluoromethyl) phenyl) -N- ( (2S, 3R) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-2-( (methyl (4- (phenylthio) benzyl) amino) methyl) -6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) acetamide, 223 Synthesized using General Procedure A, replacing 2- (4- (trifluoromethyl) phenyl) acetyl chloride and 4- (3- (trifluoromethyl) benzyl) benzaldehyde with2- (2, 4-bis (trifluoromethyl) phenyl) acetyl chloride and 4- (phenylthio) benzaldehyde. ESI [M+H] ＝760.2.

2- (4-fluorophenyl) -2-hydroxy-N- ( (2S, 3R) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-2- ( (methyl (4-(phenylthio) benzyl) amino) methyl) -6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) acetamide, 224 Synthesized using General Procedure A, replacing 2- (4-(trifluoromethyl) phenyl) acetyl chloride and 4- (3- (trifluoromethyl) benzyl) benzaldehyde with2-chloro-1- (4-fluorophenyl) -2-oxoethyl acetate and 4- (phenylthio) benzaldehyde, then removal of the acetyl group was accomplished by stirring in a solution of NaOH in H₂O and MeOH. 1H NMR (400MHz, DMSO-d6) δ 9.89-9.40 (m, 1H) , 8.35-7.97 (m, 1H) , 7.54-6.79 (m, 15H) , 5.10 (br. s. , 1H) , 4.85 (d, J＝15.9 Hz, 2H) , 3.64-3.41 (m, 3H) , 2.76-2.62 (m, 1H) , 2.12 (d, J＝9.7 Hz, 3H) , 1.14-1.03 (m, 3H) , 0.91-0.73 (m, 3H) . ESI [M+H] ＝658.2.

2-hydroxy-N- ( (2S, 3R) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-2- ( (methyl (4-(phenylthio) benzyl) amino) methyl) -6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) -2-(4- (trifluoromethyl) phenyl) acetamide, 225 Synthesized using General Procedure A, replacing 2-(4- (trifluoromethyl) phenyl) acetyl chloride and 4- (3- (trifluoromethyl) benzyl) benzaldehyde with2-chloro-2-oxo-1- (4- (trifluoromethyl) phenyl) ethyl acetate and 4- (phenylthio) benzaldehyde, then removal of the acetyl group was accomplished by stirring in a solution of NaOH in H₂O and MeOH. 1H NMR (400MHz, DMSO-d6) δ 9.81-9.49 (m, 1H) , 8.32-8.03 (m, 1H) , 7.74-7.62 (m, 2H) , 7.56 (s, 2H) , 7.41-7.01 (m, 11H) , 6.87 (t, J＝7.9 Hz, 1H) , 5.23 (br. s. , 1H) , 4.99-4.73 (m, 2H) , 4.63-4.43 (m, 1H) , 3.66-3.42 (m, 4H) , 3.08-2.73 (m, 2H) , 2.66 (d, J＝12.8 Hz, 1H) , 2.10 (d, J＝11.5 Hz, 4H) , 1.15-1.01 (m, 3H) , 0.94-0.65 (m, 3H) . ESI [M+H] ＝708.2.

2, 2-difluoro-N- ( (2S, 3R) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-2- ( (methyl (4-(phenylthio) benzyl) amino) methyl) -6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) -2-(4- (trifluoromethyl) phenyl) acetamide, 226 Synthesized using General Procedure A, replacing 2-(4- (trifluoromethyl) phenyl) acetyl chloride and 4- (3- (trifluoromethyl) benzyl) benzaldehyde with2, 2-difluoro-2- (4- (trifluoromethyl) phenyl) acetyl chloride and 4- (phenylthio) benzaldehyde. 1H NMR (400MHz, DMSO-d6) δ 10.22 (s, 1H) , 8.01-7.80 (m, 4H) , 7.46-7.12 (m, 11H) , 6.91 (t, J＝7.9 Hz, 1H) , 4.82 (s, 1H) , 4.54 (br. s. , 1H) , 4.42 (d, J＝6.6 Hz, 1H) , 3.58-3.36 (m, 2H) , 3.24 -3.15 (m, 3H) , 3.03-2.80 (m, 1H) , 2.35-2.08 (m, 2H) , 1.98 (br. s. , 1H) , 1.89 (s, 3H) , 1.06 (d, J＝6.6 Hz, 3H) , 0.60 (d, J＝6.2 Hz, 3H) . ESI [M+H] ＝728.2.

N- ( (2S, 3R) -2- ( ( (4- ( (3, 4-difluorophenyl) thio) benzyl) (methyl) amino) methyl) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) -2- (4-(trifluoromethyl) phenyl) acetamide, 227. Synthesized using General Procedure A, replacing 4-(3- (trifluoromethyl) benzyl) benzaldehyde with 4- ( (3, 4-difluorophenyl) thio) benzaldehyde. 1H NMR (400MHz, DMSO-d6) δ 8.72 (s, 1H) , 7.88 (d, J＝7.5 Hz, 1H) , 7.65 (d, J＝7.9 Hz, 2H) , 7.53 (d, J＝7.9 Hz, 2H) , 7.45-7.19 (m, 6H) , 7.15-7.02 (m, 2H) , 6.86 (t, J＝7.9 Hz, 1H) , 4.81 (t, J＝5.3 Hz, 1H) , 4.62 (br. s. , 1H) , 4.51-4.36 (m, 1H) , 3.92-3.74 (m, 2H) , 3.64-3.48 (m, 1H) , 3.47-3.36 (m, 3H) , 2.96-2.81 (m, 1H) , 2.10-1.89 (m, 4H) , 1.08 (d, J＝7.1 Hz, 3H) , 0.67 (d, J＝6.6 Hz, 3H) . ESI [M+H] ＝728.2.

2-amino-N- ( (2S, 3R) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-2- ( (methyl (4-(phenylthio) benzyl) amino) methyl) -6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) -2-phenylacetamide, 228 Synthesized using General Procedure A, replacing 2- (4-(trifluoromethyl) phenyl) acetyl chloride and 4- (3- (trifluoromethyl) benzyl) benzaldehyde with (9H-fluoren-9-yl) methyl (2-chloro-2-oxo-1-phenylethyl) carbamate and 4- (phenylthio) benzaldehyde, then removal of the FMOC group was accomplished by stirring in a solution of piperdine in MeOH. 1H NMR (400MHz, DMSO-d6) δ 10.45-10.15 (m, 1H) , 8.33-8.13 (m, 1H) , 7.46 -7.21 (m, 12H) , 7.21-7.11 (m, 2H) , 7.07-6.96 (m, 1H) , 6.85 (t, J＝7.9 Hz, 1H) , 4.96-4.76 (m, 2H) , 4.65-4.44 (m, 2H) , 3.66-3.40 (m, 4H) , 3.04-2.78 (m, 2H) , 2.74-2.56 (m, 3H) , 2.25-2.03 (m, 4H) , 1.16-1.00 (m, 3H) , 0.90-0.75 (m, 3H) . ESI [M+H] ＝639.5.

(R) -2-hydroxy-N- ( (2S, 3R) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-2- ( (methyl (4-(phenylthio) benzyl) amino) methyl) -6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) -2-phenylacetamide, 229 Synthesized using General Procedure A, replacing 2- (4-(trifluoromethyl) phenyl) acetyl chloride and 4- (3- (trifluoromethyl) benzyl) benzaldehyde with (R) -2-chloro-2-oxo-1-phenylethyl acetate and 4- (phenylthio) benzaldehyde, then removal of the acetyl group was accomplished by stirring in a solution of NaOH in H₂O and MeOH. ESI [M+H] ＝640.2.

N- ( (2S, 3R) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-2- ( (methyl (4-(phenylthio) benzyl) amino) methyl) -6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) -2-(methylsulfonamido) -2-phenylacetamide, 230 Synthesized using General Procedure A, replacing 2- (4- (trifluoromethyl) phenyl) acetyl chloride and 4- (3-(trifluoromethyl) benzyl) benzaldehyde with2- (methylsulfonamido) -2-phenylacetyl chloride and 4- (phenylthio) benzaldehyde. ESI [M+H] ＝717.2.

N- ( (2S, 3R) -2- ( ( (4- (benzyloxy) benzyl) (methyl) amino) methyl) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) -2- (4-(trifluoromethyl) phenyl) acetamide, 231. Synthesized using General Procedure A, replacing 4-(3- (trifluoromethyl) benzyl) benzaldehyde with 4- (benzyloxy) benzaldehyde. ESI [M+H] ＝690.3.

N- ( (2S, 3R) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-2- ( (methyl (4-(phenoxymethyl) benzyl) amino) methyl) -6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10- yl) -2- (4- (trifluoromethyl) phenyl) acetamide, 232. Synthesized using General Procedure A, replacing 4- (3- (trifluoromethyl) benzyl) benzaldehyde with 4- (phenoxymethyl) benzaldehyde. 1H NMR (400MHz, DMSO-d6) δ 8.70 (s, 1H) , 7.91 (d, J＝7.5 Hz, 1H) , 7.65 (d, J＝7.9 Hz, 2H) , 7.52 (d, J＝7.5 Hz, 2H) , 7.35 (d, J＝7.9 Hz, 2H) , 7.29-7.17 (m, 4H) , 7.11 (d, J＝7.9 Hz, 1H) , 7.00-6.70 (m, 4H) , 5.03 (s, 2H) , 4.83 (t, J＝5.1 Hz, 1H) , 4.63 (br. s. , 1H) , 4.52-4.41 (m, 1H) , 3.94 -3.75 (m, 2H) , 3.60-3.52 (m, 1H) , 3.46-3.39 (m, 3H) , 3.22 (d, J＝4.9 Hz, 1H) , 2.88 (t, J＝13.9 Hz, 1H) , 2.11-1.88 (m, 4H) , 1.09 (d, J＝6.6 Hz, 3H) , 0.67 (d, J＝6.6 Hz, 3H) . ESI [M+H] ＝690.2.

N- ( (2S, 3R) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-2- ( (methyl (4-phenethylbenzyl) amino) methyl) -6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) -2-(4- (trifluoromethyl) phenyl) acetamide, 233. Synthesized using General Procedure A, replacing 4- (3- (trifluoromethyl) benzyl) benzaldehyde with 4-phenethylbenzaldehyde. ESI [M+H] ＝688.2.

N- ( (2S, 3R) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-2- ( (methyl (4- ( (E) -styryl) benzyl) amino) methyl) -6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) -2- (4-(trifluoromethyl) phenyl) acetamide, 234. Synthesized using General Procedure A, replacing 4-(3- (trifluoromethyl) benzyl) benzaldehyde with (E) -4-styrylbenzaldehyde. 1H NMR (400MHz, DMSO-d6) δ 8.69 (s, 1H) , 7.92 (d, J＝7.5 Hz, 1H) , 7.64 (d, J＝7.9 Hz, 2H) , 7.54 (dd, J＝7.7, 19.2 Hz, 6H) , 7.35 (t, J＝7.5Hz, 2H) , 7.28-7.17 (m, 5H) , 7.11 (d, J＝7.1 Hz, 1H) , 6.97-6.82 (m, 1H) , 4.84 (br. s. , 1H) , 4.64 (t, J＝4.9 Hz, 1H) , 4.52-4.41 (m, 1H) , 3.95-3.74 (m, 2H) , 3.55 (br. s. , 1H) , 3.48-3.39 (m, 3H) , 3.27-3.18 (m, 1H) , 2.89 (t, J＝13.9 Hz, 1H) , 2.15-1.95 (m, 4H) , 1.09 (d, J＝7.1 Hz, 3H) , 0.67 (d, J＝6.6 Hz, 3H) . ESI [M+H] ＝686.2.

N- ( (2S, 3R) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-2- ( (methyl (4-phenethoxybenzyl) amino) methyl) -6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) -2-(4- (trifluoromethyl) phenyl) acetamide, 235. Synthesized using General Procedure A, replacing 4- (3- (trifluoromethyl) benzyl) benzaldehyde with 4-phenethoxybenzaldehyde. ESI [M+H] ＝704.3.

N- ( (2S, 3R) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-2- ( (methyl (4- ( (3-methylbenzyl) oxy) benzyl) amino) methyl) -6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) -2- (4- (trifluoromethyl) phenyl) acetamide, 236. Synthesized using General Procedure A, replacing 4- (3- (trifluoromethyl) benzyl) benzaldehyde with 4- ( (3-methylbenzyl) oxy) benzaldehyde. ESI [M+H] ＝704.3.

N- ( (2S, 3R) -2- ( ( (4- ( (3-fluorobenzyl) oxy) benzyl) (methyl) amino) methyl) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) -2- (4-(trifluoromethyl) phenyl) acetamide, 237. Synthesized using General Procedure A, replacing 4-(3- (trifluoromethyl) benzyl) benzaldehyde with 4- ( (3-fluorobenzyl) oxy) benzaldehyde. 1H NMR (400MHz, DMSO-d6) δ 8.68 (s, 1H) , 7.97-7.85 (m, 1H) , 7.64 (d, J＝7.9 Hz, 2H) , 7.53 (d, J＝7.9 Hz, 2H) , 7.45-7.33 (m, 1H) , 7.29-7.19 (m, 2H) , 7.16-7.07 (m, 3H) , 6.99-6.78 (m, 3H) , 5.06 (s, 2H) , 4.82 (t, J＝5.3 Hz, 1H) , 4.61 (br. s. , 1H) , 4.49-4.36 (m, 1H) , 3.93-3.73 (m, 2H) , 3.62-3.51 (m, 1H) , 3.47-3.33 (m, 3H) , 3.26-3.13 (m, 1H) , 2.88 (t, J＝13.9 Hz, 1H) , 2.17-1.92 (m, 4H) , 1.15-1.02 (m, 3H) , 0.65 (d, J＝6.6 Hz, 3H) . ESI [M+H] ＝708.2.

N- ( (2S, 3R) -2- ( ( (4- (benzylthio) benzyl) (methyl) amino) methyl) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) -2- (4-(trifluoromethyl) phenyl) acetamide, 238. Synthesized using General Procedure A, replacing 4-(3- (trifluoromethyl) benzyl) benzaldehyde with 4- (benzylthio) benzaldehyde. 1H NMR (400MHz, DMSO-d6) δ 8.68 (s, 1H) , 7.90 (d, J＝7.9 Hz, 1H) , 7.75-7.60 (m, 2H) , 7.56-7.45 (m, 2H) , 7.38 -7.16 (m, 7H) , 7.15-7.02 (m, 3H) , 6.93-6.73 (m, 1H) , 4.82 (t, J＝5.3 Hz, 1H) , 4.61 (br. s. , 1H) , 4.49-4.41 (m, 1H) , 4.25-4.11 (m, 2H) , 3.90-3.76 (m, 2H) , 3.59-3.50 (m, 1H) , 3.46-3.35 (m, 3H) , 3.28-3.18 (m, 1H) , 2.88 (t, J＝13.9 Hz, 1H) , 2.09-1.91 (m, 4H) , 1.08 (d, J＝6.6 Hz, 3H) , 0.66 (d, J＝6.2 Hz, 3H) . ESI [M+H] ＝706.2.

N- ( (2S, 3R) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-2- ( (methyl (4- ( (m-tolylthio) methyl) benzyl) amino) methyl) -6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) -2- (4- (trifluoromethyl) phenyl) acetamide, 239. Synthesized using General Procedure A, replacing 4- (3- (trifluoromethyl) benzyl) benzaldehyde with 4- ( (m-tolylthio) methyl) benzaldehyde. ESI [M+H] ＝720.3.

N- ( (2S, 3R) -2- ( ( (4- ( (3, 5-dimethylbenzyl) oxy) benzyl) (methyl) amino) methyl) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) -2- (4-(trifluoromethyl) phenyl) acetamide, 240. Synthesized using General Procedure A, replacing 4-(3- (trifluoromethyl) benzyl) benzaldehyde with 4- ( (3, 5-dimethylbenzyl) oxy) benzaldehyde. 1H NMR (400MHz, DMSO-d6) δ 8.67 (s, 1H) , 7.90 (d, J＝7.9 Hz, 1H) , 7.64 (d, J＝7.9 Hz, 2H) , 7.52 (d, J＝7.9 Hz, 2H) , 7.11 (d, J＝8.4 Hz, 3H) , 6.99 (s, 2H) , 6.95-6.77 (m, 4H) , 4.94 (s, 2H) , 4.82 (t, J＝5.3 Hz, 1H) , 4.61 (br. s. , 1H) , 4.51-4.33 (m, 1H) , 3.93-3.75 (m, 2H) , 3.62-3.50 (m, 1H) , 3.47-3.33 (m, 3H) , 3.23 (dd, J＝5.5, 15.2 Hz, 1H) , 2.97-2.80 (m, 1H) , 2.24 (s, 6H) , 2.14-1.86 (m, 4H) , 1.09 (d, J＝6.6 Hz, 3H) , 0.65 (d, J＝6.2 Hz, 3H) . ESI [M+H] ＝718.3.

N- ( (2S, 3R) -2- ( ( (4- ( (3, 4-difluorobenzyl) oxy) benzyl) (methyl) amino) methyl) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) -2- (4-(trifluoromethyl) phenyl) acetamide, 241. Synthesized using General Procedure A, replacing 4-(3- (trifluoromethyl) benzyl) benzaldehyde with 4- ( (3, 4-difluorobenzyl) oxy) benzaldehyde. ESI [M+H] ＝726.2.

N- ( (2S, 3R) -2- ( ( (4- ( (2, 5-difluorobenzyl) oxy) benzyl) (methyl) amino) methyl) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) -2- (4-(trifluoromethyl) phenyl) acetamide, 242. Synthesized using General Procedure A, replacing 4-(3- (trifluoromethyl) benzyl) benzaldehyde with 4- ( (2, 5-difluorobenzyl) oxy) benzaldehyde. ESI [M+H] ＝726.2.

N- ( (2S, 3R) -2- ( ( (4- ( (4-fluoro-3- (trifluoromethyl) benzyl) oxy) benzyl) (methyl) amino) methyl) -5-( (S) -1-hydroxypropan-2-yl) -3-methyl-6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10- yl) -2- (4- (trifluoromethyl) phenyl) acetamide, 243. Synthesized using General Procedure A, replacing 4- (3- (trifluoromethyl) benzyl) benzaldehyde with 4- ( (4-fluoro-3-(trifluoromethyl) benzyl) oxy) benzaldehyde. ESI [M+H] ＝776.2.

N- ( (2S, 3R) -2- ( ( (4- ( (3, 5-bis (trifluoromethyl) benzyl) oxy) benzyl) (methyl) amino) methyl) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) -2- (4-(trifluoromethyl) phenyl) acetamide, 244. Synthesized using General Procedure A, replacing 4-(3- (trifluoromethyl) benzyl) benzaldehyde with 4- ( (3, 5-bis (trifluoromethyl) benzyl) oxy) benzaldehyde. ESI [M+H] ＝826.2.

N- ( (2S, 3R) -2- ( ( (4- ( (4-bromo-2-fluorophenoxy) methyl) benzyl) (methyl) amino) methyl) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) -2- (4-(trifluoromethyl) phenyl) acetamide, 245. Synthesized using General Procedure A, replacing 4- (3- (trifluoromethyl) benzyl) benzaldehyde with 4- ( (4-bromo-2-fluorophenoxy) methyl) benzaldehyde. ESI [M+H] ＝786.2.

N- ( (2S, 3R) -2- ( ( (4- ( ( (3-chloro-4-fluorophenyl) thio) methyl) benzyl) (methyl) amino) methyl) -5-( (S) -1-hydroxypropan-2-yl) -3-methyl-6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) -2- (4- (trifluoromethyl) phenyl) acetamide, 246. Synthesized using General Procedure A, replacing 4- (3- (trifluoromethyl) benzyl) benzaldehyde with 4- ( ( (3-chloro-4-fluorophenyl) thio) methyl) benzaldehyde. ESI [M+H] ＝758.2.

N- ( (2S, 3R) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-2- ( (methyl (4-( (methyl (phenyl) amino) methyl) benzyl) amino) methyl) -6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) -2- (4- (trifluoromethyl) phenyl) acetamide, 247. Synthesized using General Procedure A, replacing 4- (3- (trifluoromethyl) benzyl) benzaldehyde with 4-( (methyl (phenyl) amino) methyl) benzaldehyde. 1H NMR (400MHz, DMSO-d6) δ 8.70 (s, 1H) , 7.89 (d, J＝7.5 Hz, 1H) , 7.64 (d, J＝7.9 Hz, 2H) , 7.52 (d, J＝7.9 Hz, 2H) , 7.22-6.97 (m, 7H) , 6.85 (t, J＝7.7 Hz, 1H) , 6.67 (d, J＝8.4 Hz, 2H) , 6.57 (t, J＝7.1 Hz, 1H) , 4.82 (t, J＝5.1 Hz, 1H) , 4.60 (br. s. , 1H) , 4.48 (s, 2H) , 4.43 (d, J＝6.2 Hz, 1H) , 3.92-3.73 (m, 2H) , 3.63-3.49 (m, 1H) , 3.45-3.36 (m, 4H) , 3.24-3.16 (m, 1H) , 2.94 (s, 3H) , 2.92-2.80 (m, 1H) , 2.11-1.92 (m, 4H) , 1.08 (d, J＝7.1 Hz, 3H) , 0.65 (d, J＝6.6 Hz, 3H) . ESI [M+H] ＝703.3.

N- ( (2S, 3R) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-2- ( (methyl (4- ( (3-(trifluoromethyl) benzyl) oxy) benzyl) amino) methyl) -6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) -2- (4- (trifluoromethyl) phenyl) acetamide, 248. Synthesized using General Procedure A, replacing 4- (3- (trifluoromethyl) benzyl) benzaldehyde with 4- ( (3-(trifluoromethyl) benzyl) oxy) benzaldehyde. ESI [M+H] ＝758.2.

N- ( (2S, 3R) -2- ( ( (4- ( (2-chloro-5- (trifluoromethyl) benzyl) oxy) benzyl) (methyl) amino) methyl) -5-( (S) -1-hydroxypropan-2-yl) -3-methyl-6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) -2- (4- (trifluoromethyl) phenyl) acetamide, 249. Synthesized using General Procedure A, replacing 4- (3- (trifluoromethyl) benzyl) benzaldehyde with 4- ( (2-chloro-5-(trifluoromethyl) benzyl) oxy) benzaldehyde. ESI [M+H] ＝792.2.

N- ( (2S, 3R) -2- ( ( (4- ( ( (2, 4-dimethylphenyl) thio) methyl) benzyl) (methyl) amino) methyl) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) -2- (4-(trifluoromethyl) phenyl) acetamide, 250. Synthesized using General Procedure A, replacing 4-(3- (trifluoromethyl) benzyl) benzaldehyde with 4- ( ( (2, 4-dimethylphenyl) thio) methyl) benzaldehyde. 1H NMR (400MHz, DMSO-d6) δ 8.69 (s, 1H) , 7.90 (d, J＝7.1 Hz, 1H) , 7.65 (d, J＝7.5 Hz, 2H) , 7.52 (d, J＝7.9 Hz, 2H) , 7.42-7.15 (m, 5H) , 7.11 (d, J＝7.9 Hz, 3H) , 7.02-6.79 (m, 5H) , 4.61 (br. s. , 1H) , 4.43 (br. s. , 1H) , 4.06 (s, 2H) , 3.90-3.74 (m, 2H) , 3.61-3.50 (m, 1H) , 2.88 (t, J＝13.9 Hz, 1H) , 2.18 (d, J＝11.5 Hz, 9H) , 2.08-1.89 (m, 4H) , 1.16-1.02 (m, 3H) , 0.66 (d, J＝6.6 Hz, 3H) . ESI [M+H] ＝734.3.

N- ( (2S, 3R) -5- ( (S) -1-hydroxypropan-2-yl) -3-methyl-2- ( (methyl (4- (1-phenylethoxy) benzyl) amino) methyl) -6-oxo-3, 4, 5, 6-tetrahydro-2H-benzo [b] [1, 5] oxazocin-10-yl) -2- (4- (trifluoromethyl) phenyl) acetamide, 251. Synthesized using General Procedure A, replacing 4- (3- (trifluoromethyl) benzyl) benzaldehyde with 4- (1-phenylethoxy) benzaldehyde. ESI [M+H] ＝704.3.

The following compounds were prepared according to the methods described herein:

[6]

Example 2: Compounds inhibit Clostridium difficile.

Vancomycin was purchased from Sigma (Sigma 94747-5G) . Bacteria tested were Clostridium difficile ATCC 700057, ATCC BAA-1870, ATCC BAA-1382 and ATCC 43255. All bacterial strains were purchased from American Type Culture Collection (ATCC) . The bacteria were cultured according to the manual from ATCC and frozen in 25％ (final concentration) glycerol at -80 ℃.

Broth Microdilution based Minimum Inhibition Concentration (MIC) determination: On the day of testing, the compounds were dissolved in pure DMSO (Sigma 276855-2L) to 3.2mg/ml as stock. In a v-bottom 96-well plate (Axygen-wipp02280) , 30 μl DMSO was added into well 1 to well 12 by manual pipetting. Into well 1, 30 μl of compound DMSO stock (3.2 mg/ml) was added and mixed by pipetting. Two fold serial dilutions were performed by transferring and mixing 30 μl of solution from well 1 to well 2, then well 2 to well 3 and so forth until well 11. The well 12 was loaded with 30 μl DMSO without compounds. This was drug ‘mother plate’ . From well 1 to well 12, the drug concentrations in the mother plate were 1.6, 0.8, 0.4, 0.2, 0.1, 0.05, 0.025, 0.0125, 0.00625, 0.003125, 0.0015625 and 0 mg/ml in DMSO. A multi-pipette was used to perform the serial dilutions.

For preparing u-bottom 96-well ‘daughter plates’ (Costar 3788) , 98 μl of Brain Heart Infusion (BHI) (BD 237500) broth was added into each well of a daughter plate. An aliquot of 2 μl solution from mother plate was then replicating transferred into the daughter plate using a multi-pipette. The daughter plate was then transferred into an YQX-II anaerobic workstation (Shanghai Yuejin Medical instruments Co. , Ltd. ) to equilibrate in anaerobic atmosphere for 3 hours before adding the bacterial suspension.

The preparation of bacterial inoculum was done in YQX-II anaerobic workstation. Two days prior to the day of MIC test, bacterial strains were streaked out from-80 ℃ glycerol stock onto Brain Heart Infusion Agar (BHA) (BD-211065) plates and incubated at 37 ℃ for 48 h. The single colonies were picked by using an inoculation loop (Greiner-731175) and suspended into 5 ml sterile saline. The turbidity of the suspension was adjusted to 0.12 (Siemens MicroScan turbidity meter) , equal to ～4×107 cfu/ml. The bacterial suspension was then diluted 40× in BHI. This was used for inoculation of daughter plates.

An aliquot of 100 μl of the bacterial suspension was inoculated into each well of the daughter plates using a multi-pipette. Each well contains ～1.0×105 cfu bacteria, 1％ DMSO and serially diluted compounds at 16, 8, 4, 2, 1, 0.5, 0.25, 0.125, 0.0625, 0.03125, 0.015625 and 0 μg/ml from well 1 to well 12 respectively, in 200 μl BHI.

The plates were incubated at 37 ℃ in YQX-II anaerobic workstation for 48 hours.

The MIC values were determined by following the standards of CLSI methods M11-A7, broth microdilution method. Briefly, MIC is the lowest compound concentration that completely or markedly inhibits the growth of bacteria in the testing medium.

Figures 1-8 illustrate the results obtained for the various compounds against Clostridium difficile. The compounds were found to be specifically active against Clostridium difficile, which can be seen through the lack of significant activity against Staphylococcus aureus.

While the embodiments have been depicted and described by reference to exemplary embodiments, such a reference does not imply a limitation on the scope, and no such limitation is to be inferred. The embodiments are capable of considerable modification, alteration, and equivalents in form and function, as will occur to those ordinarily skilled in the pertinent arts having the benefit of this disclosure. All references cited herein are hereby incorporated by reference in their entirety.

Claims

A compound, or a pharmaceutically acceptable salt thereof, of Formula I:

wherein:

R₁and R₉ are each independently H, optionally substituted C₁-C₆alkyl, optionally substituted C₁-C₆alkoxy, halo, haloalkyl, hydroxy, or cyano；

R₂R₃, R₇, and R₈ are each independently H, optionally substituted C₁-C₆ alkyl, optionally substituted C₁-C₆alkoxy, halo, hydroxy, cyano, or haloalkyl；

Z is haloalkyl, or optionally substituted C₁-C₆ alkyl；

X is a bond, C (R₅) ₂, O, NR₅, S, [C (R₅) ₂] ₂, OC (R₅) ₂, SC (R₅) ₂, NR₅C (R₆) ₂, C (R₅) ₂O, C (R₅) ₂S, C (R₅) ₂NR₆, whereineach R₅and R₆ are each independently H, optionally substituted C₁-C₆ alkyl.
The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein X is S.
The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein X is O.
The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein X is OCH₂, SCH₂, CH₂O, CH₂S.
The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein X is C (＝C) , OCH (CH₂) or CH (CH₂) .
The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein X is NR₅, wherein R₅ is C₁-C₆ alkyl.
The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein X is a bond.
The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein X is a C (CH₃) ₂.
The compound of any of claims 1-8, or a pharmaceutically acceptable salt thereof, wherein Z is CHR₄, C (R₄) ₂, or CH₂CHR₄ wherein each R₄is independentlymethyl, ethyl, phenyl, OH, NH₂, or halo.
The compound of claims any of claims 1-9, or a pharmaceutically acceptable salt thereof, wherein Z is CH₂ or CHR₄, wherein R₄is OH.
The compound of claims any of claims 1-9, or a pharmaceutically acceptable salt thereof, wherein Z is CF₂ or optionally substituted C₁-C₄alkyl.
The compound of any of claims 1-11, or a pharmaceutically acceptable salt thereof, wherein R₂ and R₃ are each independently H, halo or haloalkyl.
The compound of any of claims 1-12, or a pharmaceutically acceptable salt thereof, wherein haloalkyl is CF₃.
The compound of any of claims 1-12, or a pharmaceutically acceptable salt thereof, wherein R₂is H.
The compound of any of claims1-14, or a pharmaceutically acceptable salt thereof, wherein R₁and R₉ are each independently H, halo or haloalkyl.
The compound of any of claims1-15, or a pharmaceutically acceptable salt thereof, wherein R₁ is halo or haloalkyl and R₉ is H.
The compound of any of claims 1-16, or a pharmaceutically acceptable salt thereof, wherein R₁ is CF₃.
The compound of any of claims 1-15, or a pharmaceutically acceptable salt thereof, wherein R₉ is CF₃ or F.
The compound of any of claims 1-15, or a pharmaceutically acceptable salt thereof, wherein R₁ and R₉ are each CF₃
The compound of any of claims 1-16 or 18, or a pharmaceutically acceptable salt thereof, wherein R₁ is fluoro.
The compound of any of claims 1-20, or a pharmaceutically acceptable salt thereof, wherein R₃, R₇, and R₈ are H.
The compound of any of claims 1-20, or a pharmaceutically acceptable salt thereof, wherein R₃, R₇, and R₈ are each halo.
The compound of any of claims 1-20, or a pharmaceutically acceptable salt thereof, wherein R₃, R₇, and R₈ are flouro.
The compound of any of claims 1-20, or a pharmaceutically acceptable salt thereof, wherein R₃ and R₇ are halo or haloalkyl and R₈ is H.
The compound of any of claims 24, wherein R₃ and R₇ are CF₃.
The compound of any of claims 24, wherein R₃ and R₇ are flouro.
The compound of any of claims 1-20, or a pharmaceutically acceptable salt thereof, wherein R₃ is C₁-C₆ alkyl, halo, or haloalkyl and R₇ and R₈ are H.
The compound of claim 27, wherein R₃ is methyl.
The compound of claim 27, wherein R₃ is flouro or chloro.
The compound of claim 27, wherein R₃ is CF₃.
[Rectified under Rule 91, 11.06.2015]
The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound has a formula of Formulas II-VI:
[Rectified under Rule 91, 11.06.2015]
The compound of claim 31, or a pharmaceutically acceptable salt thereof, wherein R₂ is H.
[Rectified under Rule 91, 11.06.2015]
The compound of claims 31 or 32, or a pharmaceutically acceptable salt thereof, wherein R₁ is H, halo or haloalkyl.
[Rectified under Rule 91, 11.06.2015]
The compound of any of claims 31-33, or a pharmaceutically acceptable salt thereof, wherein R₁ is H, F, or CF₃.
[Rectified under Rule 91, 11.06.2015]
The compound of any of claims 31-34, or a pharmaceutically acceptable salt thereof, wherein R₉ is H, CF₃ or F.
[Rectified under Rule 91, 11.06.2015]
The compound of any of claims 31-35, or a pharmaceutically acceptable salt thereof, wherein Z is CH₂ or CHR₄, wherein R₄is OH.
[Rectified under Rule 91, 11.06.2015]
The compound of any of claims 31-36, or a pharmaceutically acceptable salt thereof, wherein R₁ and R₉ are CF₃.
[Rectified under Rule 91, 11.06.2015]
The compound of any of claims 31-36, or a pharmaceutically acceptable salt thereof, wherein R₁ and R₉ are H.
[Rectified under Rule 91, 11.06.2015]
The compound of any of claims 31-36, or a pharmaceutically acceptable salt thereof, wherein R₁ is F and R₉ is H.
[Rectified under Rule 91, 11.06.2015]
The compound of any of claims 31-36, or a pharmaceutically acceptable salt thereof, wherein R₁ is H and R₉ is CF3 or F.
[Rectified under Rule 91, 11.06.2015]
The compound of any of claims 31-40, or a pharmaceutically acceptable salt thereof, wherein R₃, R₇, and R₈ are H.
[Rectified under Rule 91, 11.06.2015]
The compound of any of claims 31-40, or a pharmaceutically acceptable salt thereof, wherein R₃, R₇, and R₈ are each halo.
[Rectified under Rule 91, 11.06.2015]
The compound of any of claims 31-40, or a pharmaceutically acceptable salt thereof, wherein R₃, R₇, and R₈ are flouro.
[Rectified under Rule 91, 11.06.2015]
The compound of any of claims 31-40, or a pharmaceutically acceptable salt thereof, wherein R₃ and R₇ are halo or haloalkyl and R₈ is H.
[Rectified under Rule 91, 11.06.2015]
The compound of claim 44, wherein R₃ and R₇ are CF₃.
[Rectified under Rule 91, 11.06.2015]
The compound of claim 44, wherein R₃ and R₇ are flouro.
[Rectified under Rule 91, 11.06.2015]
The compound of any of claims 31-40, or a pharmaceutically acceptable salt thereof, wherein R₃ is C₁-C₆ alkyl, halo, or haloalkyl and R₇ and R₈ are H.
[Rectified under Rule 91, 11.06.2015]
The compound of claim 47, wherein R₃ is methyl.
[Rectified under Rule 91, 11.06.2015]
The compound of claim 47, wherein R₃ is flouro or chloro.
[Rectified under Rule 91, 11.06.2015]
The compound of claim 47, wherein R₃ is CF₃.
[Rectified under Rule 91, 11.06.2015]
The compound of claim 1, or a pharmaceutically acceptable salt thereof, having a formula of Formula VII
[Rectified under Rule 91, 11.06.2015]
The compound of claim 51, wherein R₂ is H.
[Rectified under Rule 91, 11.06.2015]
The compound of claims 51 or 52, wherein R₃ is halo, haloalkyl, H, or methyl.
[Rectified under Rule 91, 11.06.2015]
The compound of any of claims 51-53, wherein R₁ and R₉ are each independently H, halo or haloalkyl.
[Rectified under Rule 91, 11.06.2015]
The compound of any of claims 51-54, or a pharmaceutically acceptable salt thereof, wherein R₁ is halo or haloalkyl and R₉ is H.
[Rectified under Rule 91, 11.06.2015]
The compound of any of claims 51-54, or a pharmaceutically acceptable salt thereof, wherein R₉ is CF₃ or F.
[Rectified under Rule 91, 11.06.2015]
The compound of any of claims 51-54, or a pharmaceutically acceptable salt thereof, wherein R₁ and R₉ are each CF₃
[Rectified under Rule 91, 11.06.2015]
The compound of any of claims 51-55, or a pharmaceutically acceptable salt thereof, wherein R₁ is fluoro.
[Rectified under Rule 91, 11.06.2015]
The compound of any of claims 51-55, or a pharmaceutically acceptable salt thereof, wherein R₁ is CF₃.
[Rectified under Rule 91, 11.06.2015]
The compound of claim 1, or a pharmaceutically acceptable salt thereof, having a formula of Formula VIII
[Rectified under Rule 91, 11.06.2015]
The compound of claim 60, wherein R₂ is H.
[Rectified under Rule 91, 11.06.2015]
The compound of claims 60 or 61, wherein R₃ is halo, haloalkyl, H, or methyl.
[Rectified under Rule 91, 11.06.2015]
The compound of any of claims 60-62, wherein R₃ is halo, haloalkyl, H, or methyl.
[Rectified under Rule 91, 11.06.2015]
The compound of any of claims 60-63, wherein R₁ and R₉ are each independently H, halo or haloalkyl.
[Rectified under Rule 91, 11.06.2015]
The compound of any of claims 60-64, or a pharmaceutically acceptable salt thereof, wherein R₁ is halo or haloalkyl and R₉ is H.
[Rectified under Rule 91, 11.06.2015]
The compound of any of claims 60-64, or a pharmaceutically acceptable salt thereof, wherein R₉ is CF₃ or F.
[Rectified under Rule 91, 11.06.2015]
The compound of any of claims 60-64, or a pharmaceutically acceptable salt thereof, wherein R₁ and R₉ are each CF₃
[Rectified under Rule 91, 11.06.2015]
The compound of any of claims 60-64, or a pharmaceutically acceptable salt thereof, wherein R₁ is fluoro.
[Rectified under Rule 91, 11.06.2015]
The compound of any of claims 60-64, or a pharmaceutically acceptable salt thereof, wherein R₁ is CF₃.
[Rectified under Rule 91, 11.06.2015]
The compound of claim 1, or pharmaceutically acceptable salt thereof, wherein the compound is a selected from the group shown in Figure 1.
[Rectified under Rule 91, 11.06.2015]
The compound of claim 1, or pharmaceutically acceptable salt thereof, wherein the compound is selected from the group shown in Figure 2.
[Rectified under Rule 91, 11.06.2015]
The compound of claim 1, or pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of:
[Rectified under Rule 91, 11.06.2015]
A compound, or a pharmaceutically acceptable salt thereof, of Formula IX:

wherein

R₁ and R₉ are each indepednently H, optionally substituted C₁-C₆alkyl, optionally substituted C₁-C₆alkoxy, halo, haloalkyl, hydroxy, or cyano； and

Z is haloalkyl or optionally substituted C₁-C₆ alkyl；
[Rectified under Rule 91, 11.06.2015]
The compound of claim 73, or a pharmaceutically acceptable salt thereof, wherein Z is CHR₄, C (R₄) ₂, or CH₂CHR₄ wherein each R₄ is independently H, methyl, ethyl, phenyl, OH, NH₂, or halo.
[Rectified under Rule 91, 11.06.2015]
The compound of claims 73 or 74, or a pharmaceutically acceptable salt thereof, wherein Z is CH₂ or CHR₄, wherein R₄ is OH.
[Rectified under Rule 91, 11.06.2015]
The compound of claim 73, or a pharmaceutically acceptable salt thereof, wherein Z is CF₂ or optionally substituted C₁-C₄ alkyl.
[Rectified under Rule 91, 11.06.2015]
The compound of any of claims 73-76, or a pharmaceutically acceptable salt thereof, wherein R₁ and R₉ are each independently H, halo or haloalkyl.
[Rectified under Rule 91, 11.06.2015]
The compound of any of claims 73-76, or a pharmaceutically acceptable salt thereof, wherein R₁ is halo or haloalkyl and R₉ is H.
[Rectified under Rule 91, 11.06.2015]
The compound of any of claims 73-76, or a pharmaceutically acceptable salt thereof, wherein R₁ is CF₃.
[Rectified under Rule 91, 11.06.2015]
The compound of any of claims 73-76, or a pharmaceutically acceptable salt thereof, wherein R₉ is CF₃ or F.
[Rectified under Rule 91, 11.06.2015]
The compound of any of claims 73-76, or a pharmaceutically acceptable salt thereof, wherein R₁ and R₉ are each CF₃
[Rectified under Rule 91, 11.06.2015]
The compound of any of claims 73-76, or a pharmaceutically acceptable salt thereof, wherein R₁ is fluoro.
[Rectified under Rule 91, 11.06.2015]
A compound, or a pharmaceutically acceptable salt thereof, of Formula (XI) :

wherein

R₂ R₃, R₇, and R₈ are each independently H, optionally substituted C₁-C₆ alkyl, optionally substituted C₁-C₆ alkoxy, halo, hydroxy, cyano, or haloalkyl； and

X is a bond, C (R₅) ₂, O, NR₅, S, [C (R₅) ₂] ₂, OC (R₅) ₂, SC (R₅) ₂, NR₅C (R₆) ₂, C (R₅) ₂O, C (R₅) ₂S, C (R₅) ₂NR6_, whereineach R₅and R₆ are each independently H, optionally substituted C₁-C₆ alkyl.
[Rectified under Rule 91, 11.06.2015]
The compound of claim 83, or a pharmaceutically acceptable salt thereof, wherein X is S.
[Rectified under Rule 91, 11.06.2015]
The compound of claim 83, or a pharmaceutically acceptable salt thereof, wherein X is O.
[Rectified under Rule 91, 11.06.2015]
The compound of claim 83, or a pharmaceutically acceptable salt thereof, wherein X is OCH₂, SCH₂, CH₂O, CH₂S.
[Rectified under Rule 91, 11.06.2015]
The compound of claim 83, or a pharmaceutically acceptable salt thereof, wherein X is C (＝C) , OCH (CH₂) or CH (CH₂) .
[Rectified under Rule 91, 11.06.2015]
The compound of claim 83, or a pharmaceutically acceptable salt thereof, wherein X is NR₅, wherein R₅ is C₁-C₆ alkyl.
[Rectified under Rule 91, 11.06.2015]
The compound of claim 83, or a pharmaceutically acceptable salt thereof, wherein X is a bond.
[Rectified under Rule 91, 11.06.2015]
The compound of claim 83, or a pharmaceutically acceptable salt thereof, wherein X is a C (CH₃) ₂.
[Rectified under Rule 91, 11.06.2015]
The compound of any of claims 83-90, or a pharmaceutically acceptable salt thereof, wherein R₂ and R₃ are each independently H, halo or haloalkyl.
[Rectified under Rule 91, 11.06.2015]
The compound of claim 91, or a pharmaceutically acceptable salt thereof, wherein haloalkyl is CF₃.
[Rectified under Rule 91, 11.06.2015]
The compound of any of claims 83-92, or a pharmaceutically acceptable salt thereof, wherein R₂ is H.
[Rectified under Rule 91, 11.06.2015]
The compound of any of claims 83-93, or a pharmaceutically acceptable salt thereof, wherein R₃, R₇, and R₈ are H.
[Rectified under Rule 91, 11.06.2015]
The compound of any of claims 83-93, or a pharmaceutically acceptable salt thereof, wherein R₃, R₇, and R₈ are each halo.
[Rectified under Rule 91, 11.06.2015]
The compound of any of claims 83-93, or a pharmaceutically acceptable salt thereof, wherein R₃, R₇, and R₈ are flouro.
[Rectified under Rule 91, 11.06.2015]
The compound of any of claims 83-93, or a pharmaceutically acceptable salt thereof, wherein R₃ and R₇ are halo or haloalkyl and R₈ is H.
[Rectified under Rule 91, 11.06.2015]
The compound of any of claims 97, wherein R₃ and R₇ are CF₃.
[Rectified under Rule 91, 11.06.2015]
The compound of any of claims 97, wherein R₃ and R₇ are flouro.
[Rectified under Rule 91, 11.06.2015]
The compound of any of claims 83-106, or a pharmaceutically acceptable salt thereof, wherein R₃ is C₁-C₆ alkyl, halo, or haloalkyl and R₇ and R₈ are H.
[Rectified under Rule 91, 11.06.2015]
The compound of claim 100, wherein R₃ is methyl.
[Rectified under Rule 91, 11.06.2015]
The compound of claim 100, wherein R₃ is flouro or chloro.
[Rectified under Rule 91, 11.06.2015]
The compound of claim 100, wherein R₃ is CF₃.
[Rectified under Rule 91, 11.06.2015]
The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of:
[Rectified under Rule 91, 11.06.2015]
A pharmaceutical composition comprising a compound of any of claims 1-104 and a pharmaceutically acceptable carrier.
[Rectified under Rule 91, 11.06.2015]
A method of treating a Clostridium difficileinfection in a subject comprising administering to the subject a compound of any of claims 1-104 or a pharmaceutical composition of claim 105.
[Rectified under Rule 91, 11.06.2015]
A method of inhibiting Clostridium difficilereplication or growth comprising contacting a Clostridium difficile bacterium with a compound of any of claims 1-104 or a pharmaceutical composition of claim 105.
[Rectified under Rule 91, 11.06.2015]
A method of treating diarrhea in a subject suspected of having a Clostridium difficileinfection comprising administering to the subject a compound of any of claims 1-104 or a pharmaceutical composition of claim 105.
[Rectified under Rule 91, 11.06.2015]
A method of treating a subject suspected of having a Clostridium difficileinfection comprising determining whether the subject has a Clostridium difficileinfection and administering to a subject determined to have a Clostridium difficileinfection a compound of any 1-104 or a pharmaceutical composition of claim 105.
[Rectified under Rule 91, 11.06.2015]
A method of specifically inhibiting Clostridium difficilereplication or growth comprising contacting a Clostridium difficile bacterium with a compound of any of claims 1-104 or a pharmaceutical composition of claim 105.
[Rectified under Rule 91, 11.06.2015]
A method of selectively inhibiting Clostridium difficilereplication or growth in a subject subject comprising administering to the subject a compound of any of claims 1-104 or a pharmaceutical composition of claim 105.
[Rectified under Rule 91, 11.06.2015]
The method of claim 111 wherein the compound is at least twice as potent against Clostridium difficile than another bacteria.
[Rectified under Rule 91, 11.06.2015]
The method of claim 111, wherein the compound is at least four times as potent for Clostridium difficile than another bacteria.
[Rectified under Rule 91, 11.06.2015]
A method of preventing a recurrence of a Clostridium difficileinfection comprising administering to a subject previously treated with a different antibiotic for aClostridium difficileinfection a compound of any of claims 1-104 or a pharmaceutical composition of claim 105.
[Rectified under Rule 91, 11.06.2015]
A method of preparing a compound of any of claims 1-104, the method comprising preparing a compound according to a scheme of:

R₁ and R₉ are each indepednently H, optionally substituted C₁-C₆alkyl, optionally substituted C₁-C₆alkoxy, halo, haloalkyl, hydroxy, or cyano；

R₂R₃, R₇, and R₈ are each independently H, optionally substituted C₁-C₆ alkyl, optionally substituted C₁-C₆alkoxy, halo, hydroxy, cyano, or haloalkyl；

Z is haloalkyl or optionally substituted C₁-C₆ alkyl；

X is a bond, C (R₅) ₂, O, NR₅, S, [C (R₅) ₂] ₂, OC (R₅) ₂, SC (R₅) ₂, NR₅C (R₆) ₂, C (R₅) ₂O, C (R₅) ₂S, C (R₅) ₂NR₆, whereineach R₅and R₆ are each independently H, optionally substituted C₁-C₆ alkyl.