RU2775783C2 - Methods for treatment of post-traumatic stress disorder - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention relates to a method for the treatment of a patient with a periodic explosive disorder, including the administration to the specified patient of a compound of the formula

or pharmaceutically acceptable salt of any of the specified compounds.

EFFECT: compounds are proposed for the effective treatment of a periodic explosive disorder.

5 cl, 2 dwg, 238 ex

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority under 35 U.S.C. § 119(e) with respect to Provisional Application US 61/360686, filed July 1, 2010, the entire contents of which are hereby incorporated by reference.

FIELD OF TECHNOLOGY

The invention described herein relates to compounds, compositions, drugs and methods for the treatment of post-traumatic stress disorder using vasopressin antagonists.

BACKGROUND AND BRIEF DESCRIPTION OF THE INVENTION

Post-traumatic stress disorder (PTSD) is recognized by the Department of Defense, the Department of Veterans Affairs and the National Institute of Mental Health as a major medical concern for both deployed and returning US troops. In particular, recent studies show that the incidence of PTSD among veterans of Iraq and Afghanistan is 20% and can reach 35%, which is 4-7 times higher than among the rest of the population. PTSD is a disease that affects more than just military personnel; According to the National Institute of Mental Health (NIMH), almost eight million Americans have the disorder, and it is among the most common mental disorders in the country. PTSD is characterized by decreased emotionality, disturbed relationships with family and friends, decreased interest in pleasurable activities, irritability, increased aggression, and sometimes violent behavior. Often, PTSD co-occurs with additional disorders, including depression, substance abuse, other anxiety disorders, anger and impulsivity disorders, and the like. Like other mental disorders, the effects of PTSD extend not only to the patient but also to their families. There are not only increased costs for long-term care, but also reduced work capacity and adverse effects on quality of life. Together, these circumstances create a cycle of increasing need for federal government assistance, lost wages, and rising permanent social and economic costs. Improved treatments for PTSD and depression, especially during the first two years after deployment, could reduce the cost of medical treatment for US military personnel (estimated at between $4.0 billion and $6.2 billion) by 25%-40%.

Current drug therapies for PTSD are based on existing mutated antidepressants and anxiolytics, which have not been shown to be effective, include unwanted side effects, and have also been recognized to be limited due to patient compliance issues; see, for example, Keane, et al. Posttraumatic stress disorder: etiology, epidemiology, and treatment outcome. Annu Rev Clin Psychol, 2: 61-97 (2006); Lader, Effectiveness of benzodiazepines: do they work or not? Expert Rev Neurother, 8(8): 1189-91 (2008); Marks, et al., Paroxetine: safety and tolerability issues. Expert Opin Drug Saf, 7(6):783-94 (2008). The publications cited above and each additional publication referenced herein are incorporated herein by reference. Whether due to the complexity of PTSD or the differences in the underlying neurobiology of the disorder, available drugs provide limited relief. A new approach to pharmacotherapy is needed to significantly improve clinical outcomes.

According to the present invention, PTSD and related diseases and disorders have been found to be treatable with selective V1a vasopressin antagonists of the formula

and their pharmaceutically acceptable salts; where:

A is a carboxylic acid, ester or amide;

B is a carboxylic acid, ester or amide; or B is an alcohol or a thiol, or a derivative thereof;

R ¹ represents hydrogen or C ₁ -C ₆ alkyl;

R ² is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, halogen, haloalkyl, cyano, formyl, alkylcarbonyl or a substituent selected from the group consisting of -CO ₂ R ⁸ , -CONR ⁸ R ⁸ ' and -NR ⁸ (COR ⁹ ); where R ⁸ and R ⁸ ' each independently selected from hydrogen, alkyl, cycloalkyl, optionally substituted aryl or optionally substituted arylalkyl; or R ⁸ and R ⁸ ' together with the attached nitrogen atom form a heterocyclyl group; and where R ⁹ is selected from hydrogen, alkyl, cycloalkyl, alkoxyalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, and R ⁸ R ⁸ 'N-(C ₁ -C ₄ alkyl);

R ³ is an amino, amido, acylamido or optionally substituted ureido group; or R ³ is a nitrogen-containing heterocyclyl group attached at the nitrogen atom; and

R ⁴ is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, alkylcarbonyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted aryl haloalkyl, optionally substituted arylalkoxyalkyl, optionally substituted arylalkenyl, optionally substituted aryl haloalkenyl, or optionally substituted arylalkynyl.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows 3D images of the Papez circuit, where black areas represent mean significant BOLD activation in eight animals for (A) ferret-only unconditional activation; (B) unconditional activation patterns in a ferret after pre-treatment with AVN576 (5 mg/kg bw); (C) conditional activation schemes where animals are re-exposed to sucrose alone in a magnet after two weeks; (D) Conditional activation schemes where animals are pre-treated with AVN576 (5 mg/kg bw) and re-exposed to sucrose alone in the magnet two weeks later.

FIG. 2 shows the average (A) time spent in the light; (B) time spent in the dark; and (C) the number of light-dark state transitions.

DETAILED DESCRIPTION

This document describes the use of arginine vasopressin (AVP) antagonists as a therapeutic approach for the treatment of PTSD. The compounds described herein may have effects that significantly improve the lives of active-duty military personnel, returning veterans, their families, and the general public by addressing an unmet medical need and reducing the overall economic burden of one of the most common and growing mental disorders in the United States. .

In one exemplary embodiment of the methods described herein, one or more compounds of the formula are administered to a PTSD patient:

and their pharmaceutically acceptable salts; where

A is a carboxylic acid, ester or amide;

B is a carboxylic acid, ester or amide; or B is an alcohol or a thiol, or a derivative thereof;

R ¹ represents hydrogen or C ₁ -C ₆ alkyl;

R ² is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, halogen, haloalkyl, cyano, formyl, alkylcarbonyl or a substituent selected from the group consisting of -CO ₂ R ⁸ , -CONR ⁸ R ⁸ ' and -NR ⁸ (COR ⁹ ); where R ⁸ and R ⁸ ' each independently selected from hydrogen, alkyl, cycloalkyl, optionally substituted aryl or optionally substituted arylalkyl; or R ⁸ and R ⁸ ' together with the attached nitrogen atom form a heterocyclyl group; and where R ⁹ is selected from hydrogen, alkyl, cycloalkyl, alkoxyalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, and R ⁸ R ⁸ 'N-(C ₁ -C ₄ alkyl);

R ³ is an amino, amido, acylamido or optionally substituted ureido group; or R ³ is a nitrogen-containing heterocyclyl group attached at the nitrogen atom; and

R ⁴ is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, alkylcarbonyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted aryl haloalkyl, optionally substituted arylalkoxyalkyl, optionally substituted arylalkenyl, optionally substituted aryl haloalkenyl, or optionally substituted arylalkynyl.

In another illustrative embodiment, the patient is administered one or more compounds of formula (I):

and their pharmaceutically acceptable salts; where

A and A' are each independently selected from -CO ₂ H or an ester or amide derivative thereof;

n is an integer selected from 0 to about 3;

R ¹ represents hydrogen or C ₁ -C ₆ alkyl;

R ² is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, halogen, haloalkyl, cyano, formyl, alkylcarbonyl or a substituent selected from the group consisting of -CO ₂ R ⁸ , -CONR ⁸ R ⁸ ' and -NR ⁸ (COR ⁹ ); where R ⁸ and R ⁸ ' each independently selected from hydrogen, alkyl, cycloalkyl, optionally substituted aryl or optionally substituted arylalkyl; or R ⁸ and R ⁸ ' together with the attached nitrogen atom form a heterocycle; and where R ⁹ is selected from hydrogen, alkyl, cycloalkyl, alkoxyalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted heteroaryl alkyl, and R ⁸ R ⁸ 'N-(C ₁ -C ₄ alkyl);

R ³ is an amino, amido, acylamido or optionally substituted ureido group; or R ³ is a nitrogen-containing heterocyclyl group attached at the nitrogen atom; and

R ⁴ is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, alkylcarbonyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted aryl haloalkyl, optionally substituted arylalkoxyalkyl, optionally substituted arylalkenyl, optionally substituted aryl haloalkenyl, or optionally substituted arylalkynyl.

In another illustrative embodiment, the patient is administered one or more compounds of formula (II):

and their pharmaceutically acceptable salts; where

A represents CO ₂ H or its ester or amide derivative;

Q is oxygen; or Q is sulfur or disulfide, or an oxidized derivative thereof;

n is an integer from 0 to 3;

R ¹ , R ² , R ³ and R ⁴ are as defined in formula (I); and

R ⁵ is selected from hydrogen, alkyl, cycloalkyl, alkoxyalkyl, optionally substituted arylalkyl, optionally substituted heterocyclyl or optionally substituted heterocyclylalkyl, and optionally substituted aminoalkyl.

In one embodiment of the compounds of formulas (I) or (II) And represents -CO ₂ R ⁵ ; where R ⁵ is selected from hydrogen, alkyl, cycloalkyl, alkoxyalkyl, optionally substituted arylalkyl, heterocyclyl, heterocyclyl(C ₁ -C ₄ alkyl) and R ⁶ R ⁷ N-(C ₂ -C ₄ alkyl). In another embodiment of the compounds of formulas (I) or (II), A is a monosubstituted amido, a disubstituted amido, or an optionally substituted nitrogen-containing heterocyclylamido.

It should be understood that in each instance of the various embodiments described herein, heterocyclyl is independently selected in each instance. In one exemplary embodiment, heterocyclyl is independently selected from tetrahydrofuryl, morpholinyl, pyrrolidinyl, piperidinyl, piperazinyl, homopiperazinyl, or quinuclidinyl; wherein said morpholinyl, pyrrolidinyl, piperidinyl, piperazinyl, homopiperazinyl or quinuclidinyl is optionally N-substituted with C ₁ -C ₄ alkyl or optionally substituted aryl(C ₁ -C ₄ alkyl).

It should also be understood that in each instance of the various embodiments described herein, R ⁶ and R ⁷ are each independently selected in each instance. According to another illustrative aspect, R ⁶ is independently selected from hydrogen or alkyl; and R ⁷ is independently selected at each occurrence from alkyl, cycloalkyl, optionally substituted aryl, or optionally substituted arylalkyl. According to another illustrative aspect, R ⁶ and R ⁷ together with the attached nitrogen atom form an optionally substituted heterocycle such as pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl and homopiperazinyl; wherein said piperazinyl or homopiperazinyl is also optionally N-substituted with R ¹³ ; where R ¹³ is independently selected at each occurrence from hydrogen, alkyl, cycloalkyl, alkoxycarbonyl, optionally substituted aryloxycarbonyl, optionally substituted arylalkyl, and optionally substituted aryloyl.

In another embodiment, compounds of formula (I) are described wherein A and/or A' is an amide. In another embodiment, A and A' are amides. In another embodiment, A and/or A' is a secondary amine amide, also referred to herein as a secondary amide. In another embodiment, A and A' are both secondary amides. Secondary amides should be understood to include cyclic amine amides attached at the nitrogen.

In another embodiment, compounds of formula (II) are described wherein A is an amide. In another embodiment, A is a secondary amine amide, also referred to herein as a secondary amide.

In another embodiment, compounds of formula (I) are described that are diesters, acid esters, or diacids, including pharmaceutically acceptable salts thereof, wherein A and A' are each independently selected. In another embodiment, compounds of formula (I) are described which are ester-amides wherein one of A and A' is an ester and the other is an amide. In another embodiment, compounds of formula (I) are described which are diamides, wherein A and A' are each independently selected from monosubstituted amido, disubstituted amido, and optionally substituted nitrogen-containing heterocyclylamido.

In one embodiment of compounds of formula (I), A and/or A' is an independently selected monosubstituted amido of formula C(O)NHX-, where X is selected from alkyl, cycloalkyl, alkoxyalkyl, optionally substituted aryl, optionally substituted arylalkyl, heterocyclyl, heterocyclyl -(C ₁ -C ₄ alkyl), R ⁶ R ⁷ N- and R ⁶ R ⁷ N-(C ₂ -C ₄ alkyl), where each heterocyclyl is independently selected.

In another embodiment, A and/or A' is an independently selected disubstituted amido of the formula C(O)NR ¹⁴ X-, where R ¹⁴ is selected from hydroxy, alkyl, alkoxycarbonyl and benzyl; and X is selected from alkyl, cycloalkyl, alkoxyalkyl, optionally substituted aryl, optionally substituted arylalkyl, heterocyclyl, heterocyclyl-(C ₁ -C ₄ alkyl), R ⁶ R ⁷ N- and R ⁶ R ⁷ N-(C ₂ -C ₄ alkyl), where each heterocyclyl is independently selected.

In another embodiment, A and/or A' is an amide of an independently selected, optionally substituted nitrogen-containing heterocycle attached at the nitrogen. Illustrative nitrogen-containing heterocycles include, but are not limited to, pyrrolidinyl, piperidinyl, piperazinyl, homopiperazinyl, triazolidinyl, triazinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, 1,2-oxazinyl, 1,3-oxazinyl, morpholinyl, oxadiazolidinyl, and thiadiazolidinyl; each of which optionally contains substituents. These possible substituents include the R ¹⁰ , R ¹² , R ⁶ R ⁷ N- and R ⁶ R ⁷ N-(C ₁ -C ₄ alkyl) groups defined herein. In one embodiment, A and/or A' is independently selected from pyrrolidinonyl, piperidinonyl, 2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl, or 1,2,3,4-tetrahydroisoquinolin-2-yl, each of which optionally substituted and attached at the nitrogen.

In another embodiment, A and/or A' is an independently selected amide of an optionally substituted piperidinyl attached at the nitrogen. Illustrative possible substituents include hydroxy, alkyl, cycloalkyl, alkoxy, alkoxycarbonyl, hydroxyalkyloxyalkyl, including (hydroxy(C ₂ -C ₄ alkyloxy))-(C ₂ -C ₄ alkyl), R ⁶ R ⁷ N-, R ⁶ R ⁷ N -alkyl, including R ⁶ R ⁷ N-(C ₁ -C ₄ -alkyl), diphenylmethyl, optionally substituted aryl, optionally substituted aryl(C ₁ -C ₄ alkyl) and piperidin-1-yl(C ₁ -C ₄ alkyl ). In one embodiment, A and/or A' is an independently selected piperidinyl substituted at the 4-position and attached at the nitrogen.

In another embodiment, A and/or A' is an independently selected amide of an optionally substituted piperazinyl attached at the nitrogen. Illustrative possible substituents include hydroxy, alkyl, cycloalkyl, alkoxy, alkoxycarbonyl, hydroxyalkyloxyalkyl, including (hydroxy(C ₂ -C ₄ alkyloxy))-(C ₂ -C ₄ alkyl), R ⁶ R ⁷ N-, R ⁶ R ⁷ N -alkyl, including R ⁶ R ⁷ N-(C ₁ -C ₄ -alkyl), diphenylmethyl, optionally substituted aryl, optionally substituted aryl(C ₁ -C ₄ alkyl) and piperidin-1-yl(C ₁ -C ₄ alkyl ). In one embodiment, A and/or A' is an independently selected piperazinyl substituted at the 4-position and attached at the nitrogen.

In another embodiment, A and/or A' is an independently selected amide of an optionally substituted homopiperazinyl attached at the nitrogen. Illustrative possible substituents include hydroxy, alkyl, cycloalkyl, alkoxy, alkoxycarbonyl, hydroxyalkyloxyalkyl, including (hydroxy(C ₂ -C ₄ alkyloxy))-(C ₂ -C ₄ alkyl), R ⁶ R ⁷ N-, R ⁶ R ⁷ N -alkyl, including R ⁶ R ⁷ N-(C ₁ -C ₄ alkyl), diphenylmethyl, optionally substituted aryl, optionally substituted aryl(C ₁ -C ₄ alkyl) and piperidin-1-yl(C ₁ -C ₄ alkyl) . In one embodiment, A and/or A' is an independently selected homopiperazinyl substituted at the 4-position and attached at the nitrogen. In another embodiment, A and/or A' is an independently selected homopiperazinyl substituted with alkyl, aryl, aryl(C ₁ -C ₄ alkyl) at the 4-position and attached at the nitrogen.

In another embodiment of the compounds of formula (I), A' is a monosubstituted amido, a disubstituted amido, or an optionally substituted nitrogen-containing heterocyclylamido. In another embodiment of the compounds of formula (I) A' represents -CO ₂ R ⁵ '; where R ⁵ ' is selected from hydrogen, alkyl, cycloalkyl, alkoxyalkyl, optionally substituted arylalkyl, heterocyclyl, heterocyclyl(C ₁ -C ₄ alkyl) and R ⁶ R ⁷ N-(C ₂ -C ₄ alkyl); where the heterocyclyl is at each occurrence independently selected from tetrahydrofuryl, morpholinyl, pyrrolidinyl, piperidinyl, piperazinyl, homopiperazinyl, or quinuclidinyl; wherein said morpholinyl, pyrrolidinyl, piperidinyl, piperazinyl, homopiperazinyl or quinuclidinyl may be N-substituted with C ₁ -C ₄ alkyl or optionally substituted aryl(C ₁ -C ₄ alkyl). In one embodiment, R ⁵ ' is an optionally substituted heterocyclylalkyl or an optionally substituted aminoalkyl, including R ⁶ R ⁷ N-(C ₂ -C ₄ alkyl).

In another embodiment of the compounds of formulas (I) or (II), A has the formula

where ^RN is hydrogen or optionally substituted alkyl, or an amide group forming a prodrug; R ^a is hydrogen or optionally substituted alkyl; and R ^Ar is hydrogen or one or more aryl substituents such as, but not limited to, halogen, hydroxy, optionally substituted alkyl, optionally substituted alkoxy, nitro, and the like. In another embodiment, at least one of R ^N , R ^a and R ^Ar is not hydrogen. In another embodiment, at least one of ^RN and R ^a is not hydrogen. In another embodiment, A has the formula

where R ^N , R ^a and R ^Ar are as defined in the present description.

In another embodiment, compounds of formula (II) are described wherein A is selected from monosubstituted amido, disubstituted amido, and optionally substituted nitrogen-containing heterocyclylamido. In another embodiment, A is an optionally substituted 1-tetrahydronaphthylamine amide.

In one embodiment, A and/or A' is a monosubstituted amido of the formula C(O)NHX, where X is selected from alkyl, cycloalkyl, alkoxyalkyl, optionally substituted aryl, optionally substituted arylalkyl, heterocyclyl, heterocyclyl-(C ₁ -C ₄ alkyl ), R ⁶ R ⁷ N- and R ⁶ R ⁷ N-(C ₂ -C ₄ alkyl), where each heterocyclyl is independently selected.

In another embodiment, A and/or A' is a disubstituted amido of the formula C(O)NR ¹⁴ X, where R ¹⁴ is selected from hydroxy, alkyl, alkoxycarbonyl and benzyl; and X is selected from alkyl, cycloalkyl, alkoxyalkyl, optionally substituted aryl, optionally substituted arylalkyl, heterocyclyl, heterocyclyl-(C ₁ -C ₄ alkyl), R ⁶ R ⁷ N- and R ⁶ R ⁷ N-(C ₂ -C ₄ alkyl), where each heterocyclyl is independently selected.

In another embodiment, A and/or A' is an amide of an optionally substituted nitrogen-containing heterocycle attached at the nitrogen. Illustrative nitrogen-containing heterocycles include, but are not limited to, pyrrolidinyl, piperidinyl, piperazinyl, homopiperazinyl, triazolidinyl, triazinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, 1,2-oxazinyl, 1,3-oxazinyl, morpholinyl, oxadiazolidinyl, and thiadiazolidinyl; each of which optionally contains substituents. These possible substituents include the R ¹⁰ , R ¹² , R ⁶ R ⁷ N- and R ⁶ R ⁷ N-(C ₁ -C ₄ alkyl) groups defined herein. In one embodiment, A is pyrrolidinonyl, piperidinonyl, 2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl, or 1,2,3,4-tetrahydroisoquinolin-2-yl, each of which is optionally substituted and is attached at nitrogen.

In another embodiment, A and/or A' is an amide of an optionally substituted piperidinyl attached at the nitrogen. Illustrative possible substituents include hydroxy, alkyl, cycloalkyl, alkoxy, alkoxycarbonyl, hydroxyalkyloxyalkyl, including (hydroxy(C ₂ -C ₄ alkyloxy))-(C ₂ -C ₄ alkyl), R ⁶ R ⁷ N-, R ⁶ R ⁷ N -alkyl, including R ⁶ R ⁷ N-(C ₁ -C ₄ -alkyl), diphenylmethyl, optionally substituted aryl, optionally substituted aryl(C ₁ -C ₄ alkyl) and piperidin-1-yl(C ₁ -C ₄ alkyl ). In one embodiment, A and/or A' is piperidinyl substituted at the 4-position and attached at the nitrogen.

In another embodiment, A and/or A' is an amide of an optionally substituted piperazinyl attached at the nitrogen. Illustrative possible substituents include hydroxy, alkyl, cycloalkyl, alkoxy, alkoxycarbonyl, hydroxyalkyloxyalkyl, including (hydroxy(C ₂ -C ₄ alkyloxy))-(C ₂ -C ₄ alkyl), R ⁶ R ⁷ N-, R ⁶ R ⁷ N -alkyl, including R ⁶ R ⁷ N-(C ₁ -C ₄ -alkyl), diphenylmethyl, optionally substituted aryl, optionally substituted aryl(C ₁ -C ₄ alkyl) and piperidin-1-yl(C ₁ -C ₄ alkyl). In one embodiment, A and/or A' is piperazinyl substituted at the 4-position and attached at the nitrogen.

In another embodiment, A and/or A' is an amide of an optionally substituted homopiperazinyl attached at the nitrogen. Illustrative possible substituents include hydroxy, alkyl, cycloalkyl, alkoxy, alkoxycarbonyl, hydroxyalkyloxyalkyl, including (hydroxy(C ₂ -C ₄ alkyloxy))-(C ₂ -C ₄ alkyl), R ⁶ R ⁷ N-, R ⁶ R ⁷ N -alkyl, including R ⁶ R ⁷ N-(C ₁ -C ₄ -alkyl), diphenylmethyl, optionally substituted aryl, optionally substituted aryl(C ₁ -C ₄ alkyl) and piperidin-1-yl(C ₁ -C ₄ alkyl). In one embodiment, A and/or A' is homopiperazinyl substituted at the 4-position and attached at the nitrogen. In another embodiment, A and/or A' is homopiperazinyl substituted with alkyl, aryl, aryl(C ₁ -C ₄ alkyl) at the 4-position and attached at the nitrogen.

In another embodiment, A and/or A' is a nitrogen attached heterocycle amide, said heterocycle being substituted with heterocyclyl, heterocyclyl alkyl, cycloalkyl, cycloalkylalkyl, aryl and arylalkyl.

In another embodiment, A and/or A' in formula (I) or (II) is an amide of an optionally substituted benzyl, optionally substituted 1-naphthylmethyl, or optionally substituted 2-naphthylmethyl amine. Possible substituents include, but are not limited to, 2,3-dichloro, 2,5-dichloro, 2,5-dimethoxy, 2-trifluoromethyl, 2-fluoro-3-trifluoromethyl, 2-fluoro-5-trifluoromethyl, 2-methyl , 2-methoxy, 3,4-dichloro, 3,5-ditrifluoromethyl, 3,5-dichloro, 3,5-dimethyl, 3,5-difluoro, 3,5-dimethoxy, 3-bromo, 3-trifluoromethyl, 3 -chloro-4-fluoro, 3-chloro, 3-fluoro-5-trifluoromethyl, 3-fluoro, 3-methyl, 3-nitro, 3-trifluoromethoxy, 3-methoxy, 3-phenyl, 4-trifluoromethyl, 4-chloro -3-trifluoromethyl, 4-fluoro-3-trifluoromethyl, 4-methyl, and the like.

In another embodiment, A and/or A' in formula (I) or (II) is an optionally substituted benzyl-N-methylamine amide. In another embodiment, A in formula (I) or (II) is an optionally substituted benzyl-N-butylamine amide, including n-butyl and t-butyl. In another embodiment, A in formula (I) or (II) is an optionally substituted benzyl-N-benzylamine amide. Possible substituents include, but are not limited to, 2,3-dichloro, 3,5-dichloro, 3-bromo, 3-trifluoromethyl, 3-chloro, 3-methyl, and the like.

In another embodiment, A and/or A' in formula (I) or (II) is an amide of optionally substituted 1-phenylethyl-, 2-phenylethyl-, 2-phenylpropyl-, or 1-phenylbenzylamine. In another embodiment, A and/or A' in formula (I) or (II) is an amide of optionally substituted 1-phenylethyl-, 2-phenylethyl-, 2-phenylpropyl-, 1-phenylbenzylamino-N-methylamine. In another embodiment, A and/or A' in formula (I) or (II) is an amide of optionally substituted 2-phenyl-β-alanine or a derivative thereof, 1-phenylpropanolamine, and the like. Possible substituents include, but are not limited to, 3-trifluoromethoxy, 3-methoxy, 3,5-dimethoxy, 2-methyl, and the like.

In another embodiment, A and/or A' in formula (I) or (II) is an amide of optionally substituted 1-phenylcyclopropyl-, 1-phenylcyclopentyl-, or 1-phenylcyclohexylamine. Possible substituents include, but are not limited to, 3-fluoro, 4-methoxy, 4-methyl, 4-chloro, 2-fluoro, and the like.

In another embodiment, A and/or A' in formula (I) or (II) is an amide of an optionally substituted heteroarylmethylamine, including, but not limited to, 2-furyl, 2-thienyl, 2-pyridyl, 3-pyridyl, 4 -pyridyl, and the like. Possible substituents include, but are not limited to, 5-methyl, 3-chloro, 2-methyl, and the like.

In another embodiment, A and/or A' in formula (I) or (II) is a partially saturated bicyclic aryl amide, including, but not limited to, 1-, 2-, 4-, and 5-indanylamine, 1st 2-tetrahydronaphthylamine, indolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like, each of which optionally contains substituents.

In another embodiment, A and/or A' in formula (I) or (II) is a substituted piperidine or piperazine amide. Substituents on piperidine or piperazine include heterocyclyl, heterocyclylalkyl, optionally substituted aryl, and optionally substituted arylalkyl. Illustrative piperidines and piperazines include the formulas:

In another embodiment, A' in formula (I) is a substituted heterocycle amide attached at the nitrogen. Substituents include alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl and arylalkyl. In one embodiment, A' in formula (I) is a nitrogen attached heterocycle amide substituted with alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, or heterocyclylalkyl.

In another embodiment, A' in formula (I) is an amide of an optionally substituted arylheterocyclylamine, arylalkyl heterocyclylamine, heterocyclylalkylamine, or heteroarylalkylamine. In another embodiment, A' is piperidin-1-yl-piperidine or piperidin-1-ylalkyl-piperidine amide. In another embodiment, alkyl is C ₁ -C ₂ alkyl.

Obviously, in the above illustrative examples A and/or A' containing a chiral center, any of the optically pure enantiomers can be included in the compounds described herein; alternatively, the racemic form can be used. For example, any or both of the following enantiomers may be included in the compounds described herein, (R)-1-(3-methoxyphenyl)ethylamine, (S)-1-(3-trifluoromethylphenyl)ethylamine, (R)-1 ,2,3,4-tetrahydro-1-naphthylamine, (R)-1-indanylamine, (R)-α,N-dimethylbenzylamine, (R)-α-methyl benzylamine, (S)-1-(3- methoxyphenyl)ethylamine, (S)-1-(3-trifluoromethylphenyl)ethylamine, (S)-1,2,3,4-tetrahydro-1-naphthylamine, (S)-1-indanylamine and (S)-α-methylbenzylamine , etc.

In another embodiment of compounds of formula (II), Q is oxygen or sulphur. In another embodiment of compounds of formula (II), R'' is an optionally substituted arylalkyl. In another embodiment of the compounds of formula (II), A is a substituted piperidine or piperazine amide.

In another embodiment of compounds of formula (I), n is 1 or 2. In another embodiment of compounds of formula (I), n is 1. In another embodiment of compounds of formula (II), n is 1 or 2. In another embodiment of compounds of formula (II), n is one.

In another embodiment of the compounds of formulas (I) or (II), R ² is hydrogen, alkyl, alkoxy, alkylthio, cyano, formyl, alkylcarbonyl, or a substituent selected from the group consisting of -CO ₂ R ⁸ and -CONR ⁸ R ⁸ ' where R ⁸ and R ⁸ ' each independently selected from hydrogen and alkyl. In another embodiment of the compounds of formulas (I) or (II) R ² represents hydrogen or alkyl. In another embodiment of the compounds of formulas (I) or (II) R ² represents hydrogen.

In another embodiment of the compounds of formulas (I) or (II) R ¹ represents hydrogen. In another embodiment of compounds of formulas (I) or (II), R ¹ is methyl. In another embodiment of the compounds of formulas (I) or (II), both R ¹ and R ² are hydrogen.

In another embodiment of the compounds of formulas (I) or (II) R ³ has the formula:

where R ¹⁰ and R ¹¹ are each independently selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, alkoxycarbonyl, alkylcarbonyloxy, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted arylalkyloxy, optionally substituted arylalkylcarbonyloxy, diphenylmethoxy, triphenylmethoxy, and the like; and R ¹² is selected from hydrogen, alkyl, cycloalkyl, alkoxycarbonyl, optionally substituted aryloxycarbonyl, optionally substituted arylalkyl, optionally substituted aryloyl, and the like.

In another embodiment of the compounds of formulas (I) or (II) R ³ has the formula:

where R ¹⁰ , R ¹¹ and R ¹² are as defined herein. In another embodiment of the compounds of formulas (I) or (II) R ³ has the formula:

where R ¹⁰ , R ¹¹ and R ¹² are as defined herein. In another embodiment of the compounds of formulas (I) or (II), R ³ has the formula:

where R ¹⁰ and R ¹¹ are as defined herein.

In another embodiment of the compounds of formulas (I) or (II) R ⁴ has the formula:

where Y is an electron withdrawing group such as halogen and Y ¹ is hydrogen or one or more aryl substituents, for example, but not limited to, halogen, hydroxy, amino, nitro, optionally substituted alkyl, optionally substituted alkoxy, etc. . It should be understood that the double bonds in these formulas may be all or essentially all (E), all or essentially all (Z), or a mixture thereof. In another embodiment, the double bonds in the formulas are all or substantially all (E). In another embodiment of the compounds of formulas (I) or (II), R ⁴ has the formula:

where Y ¹ is as defined in the present description. In another embodiment, is not hydrogen.

Obviously, the compounds of formulas (I) and (II) are chiral at the α-carbon, except when A=A' and n=0. In one embodiment of the compounds of formula (I), when n is 1, the stereochemistry of the α-carbon is (S) or (R), or an epimeric mixture. In another embodiment of the compounds of formula (I), when n is 1, the stereochemistry of the α-carbon is (R). In another embodiment of the compounds of formula (I), when n is 2, the stereochemistry of the α-carbon is (S). In one embodiment of compounds of formula (II), when n is 1 and Q is oxygen, the α-carbon stereochemistry is (R). In another embodiment of the compounds of formula (II), when n is 1 and Q is sulfur, the stereochemistry of the α-carbon is (S).

In another embodiment, compounds of formula (II) are described wherein R ^5'' is an optionally substituted aryl(C ₂ -C ₄ alkyl). In another embodiment, R ^5'' is an optionally substituted aryl(C ₁ -C ₂ -alkyl). In another embodiment, R ^5'' is an optionally substituted benzyl. In another embodiment, R ^5'' is an optionally substituted alkyl.

It should be understood that each of the above variants of formula (I), various types, subtypes and types of each of A, A', Y, Y ¹ , n, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , etc. P. may be combined without limitation, and therefore each such further embodiment of the present invention is thus described by said combination. It should also be understood that each of the above variants of formula (II), various types, subtypes and types of each of A, Q, Y, Y ¹ , n, R ¹ , R ² , R ³ ; R ⁴ , R ⁵ R ⁵ '' and the like can be combined without limitation, and therefore each such further embodiment of the present invention is thus described by said combination. For example, in another embodiment, compounds of formula (I) are described, wherein:

(a) A has the formula

where R ^N , R ^a and R ^At are as defined in the present description; and n is 1;

(b) n is 1 and R ¹ is hydrogen;

(c) A has the formula

where R ^N , R ^a and R ^Ar are as defined in the present description; n is 1; and R ¹ is hydrogen;

(d) R ¹ and R ³ are both hydrogen;

(e) R ¹ and R ² are both hydrogen; and R ³ has the formula

where R ¹⁰ , R ¹¹ and R ¹² are as defined in the present description;

(f) A has the formula

where R ^N , R ^a and R ^Ar are as defined in the present description; n is 1; R ¹ and R ² are both hydrogen; and R ³ has the formula

where R ¹⁰ and R ¹¹ are as defined in the present description;

(g) A has the formula

where R ^N , R ^a and R ^Ar are as defined in the present description; n is 1; R ¹ and R ² are both hydrogen; and A' has the formula

или

or

etc.

In the present description, the term "alkyl" includes a chain of carbon atoms, which is not necessarily branched. As used herein, the terms "alkenyl" and "alkynyl" include a chain of carbon atoms that is optionally branched and contains at least one double bond or triple bond, respectively. It should be understood that alkynyl may also contain one or more double bonds. It should also be understood that in some embodiments, the alkyl preferably has a limited length, including C ₁ -C ₂₄ , C ₁ -C ₁₂ , C ₁ -C ₈ , C ₁ -C ₆ and C ₁ -C ₄ . It should also be understood that in some embodiments, the alkenyl and/or alkynyl may each preferably have a limited length, including C ₂ -C ₂₄ , C ₂ -C ₁₂ , C ₂ -C ₈ , C ₂ -C ₆ and C ₂ -C ₄ . In the present description, it is obvious that shorter alkyl, alkenyl and/or alkynyl groups can confer less lipophilicity to the compound and, accordingly, will have a different pharmacokinetic behavior. Illustrative alkyl groups are, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, pentyl, 2-pentyl, 3-pentyl, neopentyl, hexyl, heptyl , octyl, etc.

In the present description, the term "cycloalkyl" includes a chain of carbon atoms, which is not necessarily branched, while at least part of the specified chain is cyclic. It should be understood that cycloalkyl alkyl is a subgroup of cycloalkyl. It should be understood that cycloalkyl may be polycyclic. Illustrative cycloalkyl includes, but is not limited to, cyclopropyl, cyclopentyl, cyclohexyl, 2-methylcyclopropyl, cyclopentyleth-2-yl, adamantyl, and the like. In the present description, the term "cycloalkenyl" includes a chain of carbon atoms, which is optionally branched and contains at least one double bond, while at least part of the specified chain is cyclic. It should be understood that one or more double bonds may be in the cyclic portion of the cycloalkenyl and/or the non-cyclic portion of the cycloalkenyl. It should be understood that cycloalkenylalkyl and cycloalkylalkenyl are each a subgroup of cycloalkenyl. It should be understood that cycloalkyl may be polycyclic. Illustrative cycloalkenyl includes, but is not limited to, cyclopentenyl, cyclohexylethen-2-yl, cycloheptenylpropenyl, and the like. It should also be understood that the chain forming cycloalkyl and/or cycloalkenyl is preferably of limited length, including C ₃ -C ₂₄ , C ₃ -C ₁₂ , C ₃ -C ₈ , C ₃ -C ₆ and C ₅ -C ₆ . In the present description, it is obvious that shorter alkyl and/or alkenyl chains, forming cycloalkyl and/or cycloalkenyl, respectively, can impart less lipophilicity to the compound and, accordingly, will have a different pharmacokinetic behavior.

In the present description, the term "heteroalkyl" includes a chain of atoms that contains both carbon and at least one heteroatom and, optionally, is branched. Illustrative heteroatoms include nitrogen, oxygen, and sulfur. In some embodiments, illustrative heteroatoms also include phosphorus and selenium. In the present description, the term "cycloheteroalkyl", including heterocyclyl and heterocycle, includes a chain of atoms that contains both carbon and at least one heteroatom, for example, heteroalkyl, and is optionally branched, while at least part of the specified chain is cyclic. Illustrative heteroatoms include nitrogen, oxygen, and sulfur. In some embodiments, illustrative heteroatoms also include phosphorus and selenium. Illustrative cycloheteroalkyl includes, but is not limited to, tetrahydrofuryl, pyrrolidinyl, tetrahydropyranyl, piperidinyl, morpholinyl, piperazinyl, homopiperazinyl, quinuclidinyl, and the like.

In the present description, the term "aryl" includes monocyclic and polycyclic aromatic carbocyclic groups, each of which may contain substituents. Illustrative aromatic carbocyclic groups described herein include, but are not limited to, phenyl, naphthyl, and the like. In the present description, the term "heteroaryl" includes aromatic heterocyclic groups, each of which may contain substituents. Illustrative aromatic heterocyclic groups include, but are not limited to, pyridinyl, pyrimidinyl, pyrazinyl, triazinyl, tetrazinyl, quinolinyl, quinazolinyl, quinoxalinyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, benzimidazolyl , benzothiazolyl, benzisoxazolyl, benzisothiazolyl, and the like.

As used herein, the term "amino" includes the NH ₂ group, alkylamino, and dialkylamino, and the two alkyl groups in the dialkylamino may be the same or different, i. alkylalkylamino. By way of illustration, amino includes methylamino, ethylamino, dimethylamino, methylethylamino, and the like. In addition, it should be understood that when amino is modified or modified by another term such as aminoalkyl or acylamino, the term "amino" includes the above options. By way of illustration, aminoalkyl includes Shi-alkyl, methylaminoalkyl, ethylaminoalkyl, dimethylaminoalkyl, methylethylaminoalkyl, and the like. By way of illustration, acylamino includes acyl methyl amino, acylethylamino, and the like.

As used herein, the term "amino and its derivatives" includes the amino group described herein and alkylamino, alkenylamino, alkynylamino, heteroalkylamino, heteroalkenylamino, heteroalkynylamino, cycloalkylamino, cycloalkenylamino, cycloheteroalkylamino, cycloheteroalkenylamino, arylamino, arylalkylamino, arylalkenylamino, heteroarylkynylamino, , heteroarylalkenylamino, heteroarylalkynylamino, acylamino, and the like, each of which optionally contains substituents. The term "amine derivative" also includes urea, carbamate, and the like.

As used herein, the term "hydroxy and its derivatives" includes OH and alkyloxy, alkenyloxy, alkynyloxy, heteroalkyloxy, heteroalkenyloxy, heteroalkynyloxy, cycloalkyloxy, cycloalkenyloxy, cycloheteroalkyloxy, cycloheteroalkenyloxy, aryloxy, arylalkyloxy, arylalkenyloxy, arylalkynyloxy, heteroaryloxy, heteroarylalkyloxy, heteroarylalkynyloxy, heteroarylalkynyloxy, and the like, each of which optionally contains substituents. The term "hydroxy derivative" also includes carbamate and the like.

In the present description, the term "thio and its derivatives" includes SH and alkylthio, alkenylthio, alkynylthio, heteroalkylthio, heteroalkenylthio, heteroalkynylthio, cycloalkylthio, cycloalkenylthio, cycloheteroalkylthio, cycloheteroalkenylthio, arylthio, arylalkylthio, arylalkenylthio, aryl alkynylthio, heteroarylthioarylthio, heteroalkylthioarylthio, heteroarylalkynylthio, acylthio, and the like, each of which optionally contains substituents. The term "thio derivative" also includes thiocarbamate and the like.

В настоящем описании термин «ацил» включает формил и алкил кар бонил, алкенилкарбонил, алкинилкарбонил, гетероалкилкарбонил, гетероалкенилкарбонил, гетер оалкинилкар бонил, циклоалкилкарбонил, циклоалкенилкар бонил, циклогетероалкилкарбонил, циклогетероалкенилкарбонил, арилкарбонил, арилалкилкарбонил, арилалкенилкарбонил, арил алкинилкарбонил, гетероарилкарбонил, гетероарилалкилкарбонил, гетероарилалкенилкарбонил, heteroarylalkynylcarbonyl, acylcarbonyl, and the like, each of which optionally contains substituents.

As used herein, the term "carboxylate and its derivatives" includes the CO2H group and its salts, and its esters and amides, and CN.

As used herein, the term "optionally substituted" includes the substitution of hydrogen atoms with other functional groups in a substituent that optionally contains substituents. These other functional groups, by way of illustration, include, but are not limited to, amino, hydroxyl, halogen, thiol, alkyl, haloalkyl, heteroalkyl, aryl, arylalkyl, arylheteroalkyl, heteroaryl, heteroarylalkyl, heteroarylheteroalkyl, nitro, sulfonic acids and their derivatives, carboxylic acids and their derivatives, etc. By way of illustration, any group of: amino, hydroxyl, thiol, alkyl, haloalkyl a, heteroalkyl, aryl, arylalkyl, arylheteroalkyl, heteroaryl, heteroarylalkyl, heteroarylheteroalkyl and/or sulfonic acid optionally contains substituents.

As used herein, the terms "optionally substituted aryl" and "optionally substituted heteroaryl" include the substitution of hydrogen atoms with other functional groups in an aryl or heteroaryl that optionally contains substituents. These other functional groups, by way of illustration, include, but are not limited to, amino, hydroxy, halogen, thio, alkyl, haloalkyl, heteroalkyl, aryl, arylalkyl, arylheteroalkyl, heteroaryl, heteroarylalkyl, heteroarylheteroalkyl, nitro, sulfonic acids and their derivatives, carboxylic acids and their derivatives, etc. By way of illustration, any group of: amino, hydroxy, thio, alkyl, haloalkyl, heteroalkyl, aryl, arylalkyl, arylheteroalkyl, heteroaryl, heteroarylalkyl, heteroarylheteroalkyl, and/or sulfonic acid is optionally substituted.

Illustrative substituents include, but are not limited to, the -(CH ₂ ) _x Z ^X substituent, where x is an integer from 0 to 6, and Z ^X is selected from halogen, hydroxy, alkanoyloxy, including C ₁ -C ₆ alkanoyloxy, optionally substituted aroyloxy, alkyl, including C ₁ -C ₆ alkyl, alkoxy, including C ₁ -C ₆ alkoxy, cycloalkyl, including C ₃ -C ₈ cycloalkyl, cycloalkoxy, including C ₃ -C ₈ cycloalkoxy, alkenyl, including C ₂ -C ₆ alkenyl, alkynyl, including C ₂ -C ₆ alkynyl, haloalkyl, including C ₁ -C ₆ haloalkyl, haloalkoxy, including C ₁ -C ₆ haloalkoxy, halocycloalkyl, including C ₃ -C ₈ halocycloalkyl, halocycloalkoxy, including C ₃ -C ₈ halocycloalkoxy, amino, C ₁ -C ₆ alkylamino, (C ₁ -C ₆ alkyl) (C ₁ -C ₆ alkyl) amino, alkylcarbonylamino, N-(C ₁ -C ₆ alkyl) alkylcarbonylamino, aminoalkyl, C ₁ -C ₆ alkylaminoalkyl, (C ₁ -C ₆ alkyl)(C ₁ -C ₆ alkyl)aminoalkyl, alkylcarbonylaminoalkyl, N-(C ₁ -C ₆ alkyl)alkylcarbonylaminoalkyl, cyano and nitro; or Z ^X is selected from -CO ₂ R ⁴ and -CONR ⁵ R ⁶ where R ⁴ , R ⁵ and R ⁶ are each independently selected at each occurrence from hydrogen, C ₁ -C ₆ alkyl, aryl-C ₁ -C ₆ - alkyl and heteroaryl-C ₁ -C ₆ -alkyl.

The term "protected amino group" refers to an amine protected by a protective group that can be used to protect the nitrogen, eg the nitrogen in the β-lactam ring, during preparation or subsequent reactions. Examples of such groups are benzyl, 4-methoxybenzyl, 4-methoxyphenyl, trialkylsilyl, eg trimethylsilyl, and the like.

The term "protected carboxy group" refers to a carboxy group protected or blocked by a conventional protecting group commonly used to temporarily block an acidic carboxy group. Examples of such groups include lower alkyl, such as tert-butyl, lower alkyl substituted with halogen, such as 2-iodoethyl and 2,2,2-trichloroethyl, benzyl and substituted benzyl, such as 4-methoxybenzyl and 4-nitrobenzyl , diphenylmethyl, alkenyl, eg allyl, trialkylsilyl, eg trimethylsilyl and t-butyldiethylsilyl, and like carboxy protecting groups.

It should be understood that in the embodiments described herein, an exemplary alkyl variant is C ₁ -C ₆ alkyl such as methyl, ethyl, propyl, prop-2-yl, and the like; exemplary alkenyl is C ₂ -C ₆ alkenyl such as vinyl, allyl, and the like; exemplary alkynyl is C ₂ -C ₆ alkynyl such as ethynyl, propynyl, and the like; exemplary alkoxy is C ₁ -C ₄ alkoxy such as methoxy, pent-3-oxy, and the like; exemplary alkylthio is C ₁ -C ₄ alkylthio such as ethylthio, 3-methylbut-2-ylthio, and the like; exemplary alkylcarbonyl is C ₁ -C ₃ alkylcarbonyl such as acetyl, propanoyl, and the like; an exemplary variant of cycloalkyl is C ₃ -C ₈ cycloalkyl; an exemplary variant of cycloalkenyl is C ₃ -C ₉ cycloalkenyl such as limonenyl, pinenyl, and the like; exemplary optionally substituted arylalkyl is optionally substituted aryl(C ₁ -C ₄ alkyl); an exemplary variant of an optionally substituted arylalkenyl is an optionally substituted aryl(C ₂ -C ₄ alkenyl); exemplary optionally substituted arylalkynyl is optionally substituted aryl(C ₂ -C ₄ alkynyl); an exemplary alkoxyalkyl variant is (C ₁ -C ₄ alkoxy)-(C ₁ -C ₄ alkyl); exemplary optionally substituted heteroarylalkyl is optionally substituted heteroaryl(C ₁ -C ₄ alkyl); and an exemplary alkoxycarbonyl variant is C ₁ -C ₄ alkoxycarbonyl.

As used herein, the term "prodrug" generally refers to any compound that, when introduced into a biological system, produces a biologically active compound through one or more spontaneous chemical reactions, enzyme-catalyzed chemical reactions, and/or metabolic chemical reactions, or combinations thereof. In vivo, the prodrug is typically subjected to the action of an enzyme (eg, esterases, amidases, phosphatases, etc.), simple biological chemistry, or another in vivo process to release or regenerate the more pharmacologically active drug. This activation may result from the action of an endogenous host enzyme or a non-endogenous enzyme that is administered to the host before, after, or during administration of the prodrug. Additional details regarding the use of prodrugs are described in US Patent No. 5627165; and Pathalk et al., Enzymic protecting group techniques in organic synthesis, Stereosel. Biocatal. 775-797 (2000). Obviously, the prodrug is preferably converted to the parent drug as soon as the goal is achieved, for example, targeted delivery, safety, stability, etc., followed by rapid elimination of the released residues of the prodrug-forming group.

Prodrugs can be prepared from the compounds described herein by attaching groups that are ultimately cleavable in vivo to one or more functional groups present on the compound, such as -OH-, -SH, -CO ₂ H, - NR ₂ . Illustrative prodrugs include, but are not limited to, carboxylate esters wherein said group is alkyl, aryl, arylalkyl, heteroaryl, heteroaryl alkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl, and hydroxyl, thiol, and amine esters wherein the attached group is an acyl group, an alkoxycarbonyl, an aminocarbonyl, a phosphate or a sulfate. Exemplary esters, also referred to as active esters, include, but are not limited to, 1-indanyl, N-hydroxysuccinimide; acyloxyalkyl groups such as acetoxymethyl, pivaloyloxymethyl, β-acetoxyethyl, β-pivaloyloxyethyl, 1-(cyclohexylcarbonyloxy)prop-1-yl, (1-aminoethyl)carbonyloxymethyl and the like; alkoxycarbonyloxyalkyl groups such as ethoxycarbonyloxymethyl, α-ethoxycarbonyloxyethyl, β-ethoxycarbonyloxyethyl and the like; dialkylaminoalkyl groups including di(lower)alkylaminoalkyl groups such as dimethylaminomethyl, dimethylaminoethyl, diethylaminomethyl, diethylaminoethyl and the like; 2-(alkoxycarbonyl)-2-alkenyl groups such as 2-(isobutoxycarbonyl)pent-2-enyl, 2-(ethoxycarbonyl)but-2-enyl and the like; and lactone groups such as phthalidyl, dimethoxyphthalidyl and the like.

Additional illustrative prodrugs contain a chemical group, such as an amide or phosphorus group, functioning to increase the solubility and/or stability of the compounds described herein. Additional exemplary amino prodrugs include, but are not limited to, (C ₃ -C ₂₀ )alkanoyl; halo-(C ₃ -C ₂₀ )alkanoyl; (C ₃ -C ₂₀ ) alkenoyl; (C ₄ -C ₇ )cycloalkanoyl; (C ₃ -C ₆ )-cycloalkyl(C ₂ -C ₁₆ )alkanoyl; optionally substituted aroyl such as unsubstituted aroyl or aroyl containing 1 to 3 substituents selected from the group consisting of halogen, cyano, trifluoromethanesulfonyloxy, (C ₁ -C ₃ )alkyl and (C ₁ -C ₃ )alkoxy, each of which optionally additionally contains as substituents one or more of 1-3 halogen atoms; optionally substituted aryl(C ₂ -C ₁₆ )alkanoyl and optionally substituted heteroaryl(C ₂ -C ₁₆ )alkanoyl, such as an aryl or heteroaryl substituent, unsubstituted or containing from 1 to 3 substituents selected from the group consisting of halogen, (C ₁ -C ₃ )alkyl and (C ₁ -C ₃ )alkoxy, each of which optionally additionally contains from 1 to 3 halogen atoms as substituents; and optionally substituted heteroarylalkanoyl having one to three heteroatoms selected from O, S and N in the heteroaryl group and 2 to 10 carbon atoms in the alkanoyl group, such as a heteroaryl substituent, unsubstituted or having 1 to 3 substituents, selected from the group consisting of halogen, cyano, trifluoromethanesulfonyloxy, (C ₁ -C ₃ )alkyl and (C ₁ -C ₃ )alkoxy, each of which optionally additionally contains from 1 to 3 halogen atoms as substituents. The illustrated groups are typical, their list is not exhaustive, and they can be obtained by conventional methods.

Obviously, prodrugs may not have significant biological activity on their own, but instead undergo one or more spontaneous chemical reactions, enzyme-catalyzed chemical reactions, and/or metabolic chemical reactions, or a combination thereof, after administration in vivo to form the compound described herein, which is biologically active or which is a precursor of a biologically active compound. However, it is clear that in some cases the prodrug is biologically active. It is also apparent that prodrugs can often serve to improve drug efficacy or safety through improved oral bioavailability, pharmacodynamic half-life, and the like. Prodrugs also refer to derivatives of the compounds described herein containing groups that simply mask undesirable drug properties or improve drug delivery. For example, one or more of the compounds described herein may exhibit an undesirable property that is preferably blocked or minimized and may become a pharmacological, pharmaceutical, or pharmacokinetic barrier to clinical drug use, such as poor oral absorption of the drug, lack of specificity, chemical instability. , toxicity and poor patient acceptance (unpleasant taste, smell, pain at the injection site, etc.), and others. In the present description, it is clear that a prodrug or other strategy using reversible derivatives can be useful in optimizing the clinical use of the drug.

As used herein, the term "antagonist" refers to a complete or partial antagonist. Whereas a partial antagonist with any intrinsic activity may be suitable, partial antagonists illustratively exhibit at least about 50% antagonistic effect or at least about 80% antagonistic effect. The term also includes compounds that are full antagonists of one or more vasopressin receptors. Clearly, the exemplary methods described herein require therapeutically effective amounts of vasopressin receptor antagonists; therefore, compounds exhibiting partial antagonism at one or more vasopressin receptors may be administered at higher doses to exhibit sufficient antagonistic activity to inhibit the effects of the vasopressin or vasopressin agonist.

As used herein, the term “therapeutically effective amount” refers to that amount of an active compound or pharmaceutical agent that elicits a biological or medical response in a tissue system, animal, or human that is sought by a researcher, veterinarian, physician, or other clinician, including alleviation of the symptoms of a disease or the disorder being treated. In one aspect, a therapeutically effective amount is one that can treat or alleviate a disease or symptoms of a disease at a reasonable benefit/risk ratio applicable to any therapeutic treatment. However, it should be understood that the total daily intake of the compounds and compositions described herein may be determined by the attending physician as part of a thorough medical examination.

The specific level of therapeutically effective dose for any particular patient will depend on a variety of factors, including the disorder being treated and the severity of said disorder; the activity of the particular compound used; the particular composition used; age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the particular compound used; duration of treatment; drugs used in combination or simultaneously with the specific compound used; and like factors well known to the researcher, veterinarian, physician or other average clinician.

As used herein, the term "composition" generally refers to any product containing the specified ingredients in the specified amounts, as well as any product obtained directly or indirectly from combinations of the specified ingredients in the specified amounts. It should be understood that the compositions described herein may be prepared from the isolated compounds described herein, or from salts, solutions, hydrates, solvates, and other forms of the compounds described herein. It should also be understood that compositions can be prepared from various amorphous, non-amorphous, partially crystalline, crystalline and/or other morphological forms of the compounds described herein. It should also be understood that compositions may be prepared from various hydrates and/or solvates of the compounds described herein. Accordingly, such pharmaceutical compositions that contain the compounds described herein are to be understood to contain each or any combination of the various morphological forms and/or solvate or hydrate forms of the compounds described herein. By way of illustration, the compositions may contain one or more carriers, diluents and/or excipients. The compounds described herein, or compositions containing them, can be obtained in a therapeutically effective amount in any conventional dosage forms suitable for the methods described herein. The compounds described herein, or compositions containing them, including such formulations, may be administered in a wide variety of conventional routes for the methods described herein and in a wide variety of dosage formats using known techniques (in general, see Remington: The Science and Practice of Pharmacy, (21 ^st ed, 2005)).

As used herein, the term "administration" includes all methods of administering to a patient the compounds and compositions described herein, including, but not limited to, oral (PO), intravenous (IV), intramuscular (IM), subcutaneous (SC), transdermal, inhalation, buccal, ophthalmic, sublingual, vaginal, rectal, etc. The compounds and compositions described herein may be administered in dosage forms and/or formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and excipients.

Exemplary routes of oral administration include tablets, capsules, elixirs, syrups, and the like. Exemplary parenteral routes include intravenous, intraarterial, intraperitoneal, epidural, intraurethral, intrasternal, intramuscular, and subcutaneous administration, as well as any other parenteral route accepted in the art.

It should be understood that in the methods described herein, the individual components of the co-administration or combination can be administered by any suitable means, simultaneously, together, sequentially, separately, or in the same pharmaceutical composition. When the co-administered compounds or compositions are administered in separate dosage forms, the number of doses administered per day for each compound may be the same or different. The compounds or compositions may be administered via the same or different routes of administration. The compounds or compositions may be administered according to simultaneous or alternating regimens, at the same or different times during the course of therapy, simultaneously in divided or single form.

The dosage of each compound of the claimed combinations depends on several factors including: the route of administration, the condition being treated, the severity of the condition, the need for treatment or the need to prevent the condition, and the age, weight, and health of the person being treated. In addition, the pharmacogenomic (influence of the genotype on the pharmacokinetic, pharmacodynamic or efficacy characteristics of the drug) information about a particular patient can influence the dosage used.

Without being bound by any particular theory, according to the present invention, it is believed that AVP and related peptides are a family of chemical signals in vertebrates and have an important function in the control of social behavior and emotions. AVP is synthesized in neurons in the hypothalamus of all mammals. It is released from nerve endings in the median eminence and transported to the pituitary gland, where it increases adrenocorticotropic hormone (ACTH) release and ultimately circulatory stress hormone levels by acting on pituitary AVP receptors. From the nerve endings in the pituitary gland, AVP also enters the general circulation, where it acts on the heart and blood vessels, affecting the functioning of the heart and kidneys with a decrease in urine volume. AVP neurons and nerve fibers are also found throughout the limbic system of the brain. AVP exerts physiological and behavioral effects by binding to specific G protein coupled receptors (GPCRs) in the central nervous system and some peripheral tissues/sites. Three different AVP receptor subtypes have been identified - V1a, V1b and V2. V1a is the predominant AVP receptor found in the limbic system and cerebral cortex, the V1b receptor is found in the limbic system and pituitary gland, although it is less abundant than V1a. The V2 receptor is localized in the kidney, where it mediates the antidiuretic effects of vasopressin. In general, V2 is not thought to be expressed in the nervous system of adult animals or humans. These discoveries have led to widespread interest in the V1a and V1b receptors as potential targets for drugs that act on the CNS.

According to the present invention, it has been found that major in PTSD and PTSD comorbidities is a disruption of the hypothalamic-pituitary-adrenal (HPA) axis and altered vasopressin signaling, for example, through and between the limbic system, the cerebral cortex, the anterior pituitary gland and the adrenal cortex, and/or delayed signaling of certain neurotransmitters (CRH, AVP, etc.) by feedback, rate-sensitive feedback of some neurotransmitters and other signaling molecules (plasma ACTH, plasma corticosterone, etc.) and their dysfunctions.

Without being bound by any particular theory, it is believed by the present invention that the low efficacy of existing therapies and the lack of new options may each be due to the complexity of PTSD and the differences in the neurobiology underlying the disorder. For example, while not bound by the scope of any particular theory, PTSD is considered to be a collection of disorders according to the present invention. Illustrative comorbid disorders include, but are not limited to, major depression, anxiety disorders, impulsivity and anger disorders, periodic explosive disorder, substance abuse, and the like.

According to another implementation variant, the present document describes compounds, compositions, drugs and methods for treating a patient in need of relief from PTSD (Diagnostic and Statistical Manual of Mental Disorders, IV edition (DSM-IV): 309.81). In another embodiment, provided herein are compounds, compositions, medicaments, and methods for treating a patient in need of alleviation of PTSD with common comorbid disorders, such as other anxiety disorders, including one or more of general anxiety disorder or related anxiety disorders, and the like. .P. In another embodiment, the present document describes compounds, compositions, medicaments, and methods for treating a patient in need of relief from PTSD with comorbid periodic explosive disorder such as DSM-IV: 312.34 and the like. In another embodiment, the present document describes compounds, compositions, medicaments, and methods for treating a patient in need of alleviation of PTSD with comorbid one or more depressive disorders, including major depression and treatment-resistant depression, such as DSM-IV: 296.33, etc. In another embodiment, the present document describes compounds, compositions, medicaments, and methods for treating a patient in need of alleviation of PTSD with co-existing one or more impulse control disorders/anger-related disorders, such as DSM-IV: 301.7, 301.83, 312.82 etc. In another embodiment, compounds, compositions, medicaments, and methods for treating a patient in need of alleviating combinations of such comorbid disorders are described herein.

Periodic explosive disorder and PTSD and other anxiety disorders are recognized by the Department of Defense and the National Institute of Mental Health as a major medical problem. These conditions have been observed with high frequency in active duty soldiers and returning veterans. In addition, it is clear that the emotional, social and medical consequences extend not only to soldiers suffering from these disorders, but also to their families. Existing treatment options include mutated antidepressants and anxiolytics, but these regimens have not been shown to be effective, may have unwanted and side effects, and are reported to provide limited relief. In particular, there is evidence that drugs currently in use that are not specific for periodic explosive disorder are minimally effective and may have unwanted side effects, including sexual dysfunction, sleep disturbances, and in some cases suicidal ideation. .

Improved treatments are needed that are more effective and also have fewer side effects. Accordingly, there is a need for methods of treating periodic explosive disorder and other stress-related mental illnesses. According to another embodiment, the present document describes methods, uses, compositions and compounds for the treatment of PTSD, including PTSD with comorbidities and disorders that do not cause sexual dysfunction or do not cause significant sexual dysfunction.

The compounds described herein, which target vasopressin receptors in the brain, represent a new therapeutic approach for the treatment of periodic explosive disorder and other stress-related mental illnesses. The potential benefit of vasopressin antagonists (AVPs) is based on preclinical and clinical observations. Without being bound by any particular theory, it is believed by the present invention that elevated levels of AVP are a clinical indicator of individuals exhibiting inappropriate aggression and anger and may be combined with impaired stress response.

In another embodiment, the compounds described herein are active at the V1a AVP receptor. In another embodiment, the compounds described herein are selectively active for the V1a AVP receptor and less active, substantially less active and/or inactive for another AVP receptor, such as the V1b and/or V2 subtypes of AVP receptors. In another embodiment, the compounds described herein have a 10-fold selectivity for the V1a receptor over the V1b and/or V2 receptor. In another embodiment, the compounds described herein have 100-fold selectivity for the V1a receptor over the V1b and/or V2 receptor. In another embodiment, the compounds described herein have a 1000-fold selectivity for the V1a receptor over the V1b and/or V2 receptor. In another embodiment, the compounds described herein have a 10,000-fold selectivity for the V1a receptor over the V1b and/or V2 receptor.

In another embodiment, the compounds described herein cross the blood-brain barrier (BBB) and exhibit high CNS permeability. In another embodiment, the compounds described herein demonstrate effective brain dose levels for the treatment of PTSD. In another embodiment, the compounds described herein exhibit effective brain dose levels for the treatment of periodic explosive disorder. In another embodiment, the compounds described herein demonstrate effective brain dose levels for the treatment of PTSD with comorbid periodic explosive disorders. In another embodiment, the compounds described herein exhibit plasma levels equal to or greater than those required for clinical efficacy in the treatment of PTSD and PTSD with co-occurring other disorders, including, but not limited to, one or more of: disorder, major depressive disorder, anxiety and/or other stress-related mood disorders. In another embodiment, the compounds described herein exhibit pharmacokinetics consistent with twice daily (b.i.d.) dosing. In another embodiment, the compounds described herein exhibit pharmacokinetics consistent with once daily (q.d.) dosing. In the present description, it is clear that the introduction of doses both twice a day and once a day can be an important element in improving patient compliance with the regimen and treatment regimen, leading to an overall increased clinical efficacy. In another embodiment, the compounds described herein are metabolically stable in the stomach and blood. In another embodiment, the compounds described herein exhibit both in vivo and in vitro cardiovascular safety characteristics consistent with the treatment of PTSD and PTSD with other comorbid disorders, including, but not limited to, one or more of : periodic explosive disorder, major depressive disorder, anxiety disorders, impulse control disorders and anger-related disorders, and/or other stress-related mood disorders. In another embodiment, the compounds described herein demonstrate respiratory safety in vivo.

In another embodiment, the compounds described herein, as well as pharmaceutical compositions and drugs containing them, exhibit high plasma levels and high brain levels, including when administered orally. According to another embodiment, the compounds described herein, as well as pharmaceutical compositions and drugs containing them, are able to pass through the blood-brain barrier (BBB), including when administered orally. In another embodiment, the compounds described herein, and pharmaceutical compositions and drugs containing them, exhibit high CNS bioavailability and high affinity without significant or competitive binding to other predefined GPCRs or other predefined receptors, including but not limited to , neurotransmitter-related receptors, steroid receptors, ion channels, second messenger receptors, prostaglandin receptors, growth factor and hormone receptors, other peptide receptors in the brain and gastrointestinal tract, other enzymes, etc. In accordance with one aspect , the compounds described herein, as well as pharmaceutical compositions and drugs containing them, are inactive or essentially inactive at 100 nM against a standard panel of 64 receptors, including 35 GPCRs (Novascreen panel), including neurotransmitter-associated receptors , steroid receptors, ion channels, second messenger receptors, prostaglandin receptors, growth factor receptors, hormone receptors, brain/gut peptides (not including vasopressin 1), and enzymes.

According to another embodiment, the compounds described herein, as well as pharmaceutical compositions and drugs containing them, have a specific effect on behavior that depends on the situation (see, for example, Ferris & Potegal (1988)). For example, according to another embodiment, the compounds described herein, as well as pharmaceutical compositions and drugs containing them, block aggression, but have little or no effect on sexual behavior. In another embodiment, the compounds described herein and pharmaceutical compositions and drugs containing them block fear recall but have little or no effect on fear recognition under appropriate circumstances.

EXAMPLES

EXAMPLES OF METHODS

EXAMPLE. Human vasopressin V _1a receptor binding assay. A cell line expressing the human V _1a receptor in CHO cells (hereinafter referred to as the hV _1a cell line) was obtained from Dr. Michael Brownstein, NIMH, Batesda, MD, USA. The cDNA sequence of hV _1a is described by Thibonnier et al., Journal of Biological Chemistry, 269, 3304-3310 (1994), and the expression method was the same as described by Morel et al. (1992). The hV _1a cell line was grown in alpha-MEM with 10% fetal bovine serum and 250 μg/ml G418 (Gibco, Grand Island, NY, USA). For competition binding assay, hV1a cells were seeded in a 6-well culture plate at a 1:10 dilution from a confluent flask and kept in culture for at least two days. Then the culture medium was removed, the cells were washed with 2 ml of binding buffer (25 mm Hepes, 0.25% BSA, 1x DMEM, pH=7.0). 990 µl of binding buffer containing 1 nM 3H-AVP was added to each well, followed by 10 µl of serially diluted compounds from Examples dissolved in DMSO. All incubations were performed in triplicate, the inhibition-dose curves consisted of points corresponding to total binding (DMSO) and 5 concentrations (0.1, 1.0, 10, 100 and 1000 nM) of test agents, including IC ₅₀ . 100 nM cold AVP (Sigma) was used to assess non-specific binding. Cells were incubated for 45 minutes at 37° C., the assay mixture was removed and each well was washed three times with phosphate buffered saline (PBS) (pH=7.4). 1 ml of 2% sodium dodecyl sulfate (SDS) was added per well and the plates were allowed to stand for 30 minutes. The entire contents of the well were transferred to a scintillation vial. Each well was washed with 0.5 ml PBS, which was then added to the appropriate vial. Scintillation fluid (Ecoscint, National Diagnostics, Atlanta, GA) was then added at 3 ml per vial. Samples were counted on a liquid scintillation counter (Beckman LS3801). IC ₅₀ values were calculated using Prism Curve point-to-point curve fitting software.

This assay tested all of the alkandi-esters and amides presented in the above examples dissolved in DMSO. Binding curves were generated according to the methods described by Thibonnier et al. (1994). [ ³ H]-AVP was added to hV1a cell cultures followed by 10-fold dilutions of each test compound. All active compounds exhibited a dose-dependent competitive binding curve with IC ₅₀ and K _i values indicative of high binding affinity for V _1a receptors in CHO cells expressing the human V _1a receptor (hV1a cell line). For example, Example 225 showed a dose dependent competitive binding curve with IC ₅₀ values (1.86-2.13 nM) and K _i (1.14-1.30 nM).

Binding affinities (IC ₅₀ ) and inhibition constants (K _i ) of exemplary compounds are shown in the following Table.

EXAMPLE. Cells expressing human vasopressin V _1b receptors. human vasopressin receptor 1b (hV1b) cDNA (see, Lolait et al., "Extrapituitary expression of the rat V1b vasopressin receptor gene" Proc. Natl. Acad. Sci. USA. 92:6783-7 (1995); de Keyzer et al., "Cloning and characterization of the human V3(V1b) pituitary vasopressin receptor" FEBS Lett. 356:215-20 (1994); Sugimoto et al., "Molecular cloning and functional expression of a cDNA encoding the human V1b vasopressin receptor "J. Biol. Chem. 269:27088-92 (1994)) was inserted into the expression vector of mammalian cells PCI-neo (Promega) in the EcoR1 region. A recombinant plasmid carrying the hV1b cDNA was isolated from transformed E. coli clones and used to transfect Chinese Hamster Ovary (CHO-K1, ATCC) cells. Two micrograms of hV1b receptor DNA was introduced into 10 ⁵ CHO cells that were cultured in a 6-well plate using Fugene-6 mediated transfection technology (Boehringer Mannheim). Twenty-four hours after transfection, cells were cultured under G-418 selection conditions (0.25 mg/ml) added to the culture medium. Three days later, a limited dilution was performed to obtain single cell clones in 96-well plates. After a 2 week growth period, the monoclones were divided into two groups of 12-well plates. Upon reaching confluency, one set of wells was analyzed for the ability to bind tritiated arginine vasopressin (NEN). Nine positive clones were initially identified out of 60 clones screened, and the clones showing the highest AVP binding were retained as permanent cell lines for hV1b affinity screening.

EXAMPLE. Human or rat cell-based vasopressin V1b receptor binding assay. V1b cell lines (cells expressing either human or rat V1b receptor) were grown in alpha-MEM supplemented with 10% fetal bovine serum and 250 μg/ml G418 (Gibco, Grand Island, NY) in a 75 cm ³ flask . For competition binding assays, hV1b cells were dissociated with an enzyme-free PBS-based cell dissociation solution (Speciality Media, Phillipsburg, NJ) according to the manufacturer's protocol. Cells were seeded in 12-well culture plates in the amount of one flask per 18 plates (the amount should be adjusted depending on the degree of confluence) and kept in culture for 2-3 days. Then the culture medium was removed, the cells were washed once with 2 ml of binding buffer (25 mm Hepes, 0.25% BSA, 1xDMEM, pH=7.0) at room temperature. 990 μl of binding buffer containing 1 nM ³ H-AVP was added to each well, followed by the addition of 10 μl of serially diluted test compounds or cold AVP, all dissolved in DMSO. All incubations were performed in triplicate and the dose-inhibition curves consisted of points corresponding to total binding (DMSO only) and 5 concentrations (0.1, 1.0, 10, 100 and 1000 nM) of test agent or cold AVP, including IC ₅₀ . Cells were incubated for 30 minutes at 37°C in a humidified incubator. The assay mixture was then removed and each well was washed three times with PBS (pH=7.4). After washing, 1 ml of 2% SDS per well was added and the plates were left to stand for 15 minutes at room temperature. The plate was gently tapped to ensure that lysed cells separated. The entire contents of the well were transferred to a scintillation vial. Each well was then washed with 0.5 ml PBS and added to the appropriate vial. Scintillation fluid (Ecoscint, National Diagnostics, Atlanta, GA) was then added at 3 ml per vial. Samples were counted on a liquid scintillation counter (Beckman LS3801). IC ₅₀ and Ki values were calculated using the Prism Curve point-to-point curve fitting software. Exemplary compounds shown in the previous table show a binding constant greater than 100 nM or greater than 1000 nM. Illustrative inhibition data (Ki, nM) are shown in the following table for selected compounds from the Examples.

EXAMPLE. Inhibition of the metabolism of phosphatidylinositol (V _1a ). The physiological effects of vasopressin are mediated by specific G-protein coupled receptors. The V _1a vasopressin receptor is coupled to the G _q /G ₁₁ G protein family and mediates the metabolism of phosphatidylinositol. The agonistic or antagonistic nature of the compounds of the present invention can be determined by their ability to inhibit vasopressin-mediated metabolism of phosphatidylinositol using the methodology described in the following paragraphs. The exemplary compounds, Examples 35, 44, 88, 110 and 133, were tested in this assay and found to be V _1a vasopressin antagonists.

EXAMPLE. Inhibition of phosphatidylinositis metabolism mediated by V _1b vasopressin, functional analysis of antagonist activity. The physiological effects of vasopressin are mediated by specific G-protein coupled receptors. The V _1b vasopressin receptor is coupled to a G protein that is coupled to cAMP. The agonistic or antagonistic nature of the compounds described herein can be determined by their ability to inhibit vasopressin-mediated metabolism of phosphatidylinositol using conventional methods, including the methodology described in the following paragraphs.

Cell culture and cell labeling. Three days before the assay, cultures of hV1a or hV1b cells close to confluency were dissociated and plated in 6-well tissue culture plates, with approximately 100 wells seeded from each 75 cm ³ flask (equivalent to a dilution index of 12:1). Each well contained 1 ml of culture medium with 2 μCi of [ ³ H]myoinositol (American Radiolabeled Chemicals, St. Louis, MO, USA).

Cells expressing human or rat V _1b receptors were grown in alpha-modified minimal nutrient medium containing 10% fetal bovine serum and 0.25 mg/ml G418. Three days prior to assay, cultures close to confluent were dissociated and plated in 6-well tissue culture plates, with approximately 100 wells inoculated from each 75 ^cc flask (equivalent to a dilution index of 12:1). Each well contained 1 ml of culture medium with 2 μCi of [ ³ H]myoinositol (American Radiolabeled Chemicals, St. Louis, MO, USA).

Incubations (V _1a and V _1b ). All assays were performed in triplicate except for baseline and 10 nM AVP (both n=6). AVP ((arginine vasopressin) Peninsula Labs, Belmont, CA, USA (#8103)) was dissolved in 0.1N. acetic acid. The test agents were dissolved in DMSO and diluted with DMSO up to 200 times the final test concentration. Test agents and AVP (or appropriate volumes of DMSO) were separately added as 5 µl in DMSO to 12×75 mm glass tubes containing 1 ml assay buffer (Tyrode's balanced salt solution containing 50 mM glucose, 10 mM LiCl, 15 mM HEPES, pH 7.4, 10 μM phosphoramidon and 100 μM bacitracin). Incubation was carried out in random order. Incubation was initiated by removing the media containing the label, washing the monolayer with 1 ml of 0.9% NaCl once, and transferring the contents of the assay tubes to the appropriate wells. The plates were incubated for 1 hour at 37°C. The incubation was terminated by removing the incubation medium and adding 500 μl of ice-cold 5% (w/v) trifluoroacetic acid, and leaving the wells to stand for 15 minutes.

Measurement of [ ³ H]inositol phosphates (V _1a and V _1b ). Poly-Prep Econo-Columns BioRad columns were filled with 0.3 ml of formate resin AG 1 X-8 100-200. The resin was mixed with water 1:1 and 0.6 ml was added to each column. The columns were then washed with 10 ml of water. Scintillation vials (20 ml) were placed under each column. The contents of each well were transferred to a mini-column, after which the well was washed with 0.5 ml of distilled water, which was also added to the indicated mini-column. The columns were then washed twice with 5 ml of 5 mM myo-inositol to elute free inositol. Aliquots (1 ml) were transferred to 20 ml scintillation vials and 10 ml Beckman Ready Protein Plus was added. After washing with myoinositol, empty scintillation vials were placed under the columns and [ ³ H]inositol phosphates were eluted with three additions of 1 ml of 0.5 M ammonium formate containing 0.1 N ammonium formate. formic acid. Elution conditions were optimized to recover inositol mono-, bis- and trisphosphates without eluting the more metabolically inert tetrakis-, pentakis- and hexakisphosphates. To each sample was added 10 ml of high salt capacity scintillation fluid such as Tru-Count High Salt Capacity or Packard Hionic-Fluor. The content of inositol-containing lipids was measured by adding 1 ml of 2% sodium dodecyl sulfate (SDS) to each well, after which the wells were left to stand for at least 30 minutes, and transferring the solution to 20 ml scintillation vials, to which then 10 ml of Beckman scintillation fluid was added. Ready Protein Plus. Samples were measured on a Beckman LS 3801 liquid scintillation counter for 10 minutes. Total inositol incorporation for each well was calculated as the sum of free inositol, inositol phosphates, and inositol containing lipids.

Data analysis (V _1a and V _1b ): concentration-inhibition experiments. Concentration-response curves for AVP and concentration-inhibition curves for test agents with respect to 10 nM AVP were analyzed by non-linear least squares, correlating the curves with a 4-parameter logistic function. The parameters of the main and maximum levels of inositol phosphates, EC ₅₀ or IC ₅₀ , and the Hill coefficient were varied to achieve the best fit. The curve fitting was evaluated under the assumption that the standard deviation is proportional to the number of radioactive decays per minute (dpm). In each experiment built full curves concentration-effect for AVP. IC ₅₀ values were converted to Ki _values reflecting AVP antagonistic activity in the formation of the IP3 signaling molecule by using the Cheng-Prusoff equation based on EC ₅₀ for AVP in the same experiment. Inositol phosphate content was expressed as disintegrations per minute (dpm) per 10 ⁶ disintegrations per minute (dpm) of total inositol incorporation.

Data Analysis (V _1a and V _1b ): Competitiveness Experiments. Competitiveness experiments with respect to V _1a of test agents consisted of constructing concentration-response curves for AVP in the absence and in the presence of two or more concentrations of the test agent. Competition experiments for V _1b test agents consisted of plotting concentration-response curves for AVP in the absence and presence of at least five concentrations of the test agent. Data were selected in accordance with the logistic equation describing competitive binding:

where Y is the dpm of inositol phosphates, B is the concentration of the original inositol phosphates, M is the maximum increase in the concentration of inositol phosphates, A is the concentration of the agonist (AVP), E is the EC ₅₀ for the agonist, D is the concentration of the antagonist (test agent), K is K _i for an antagonist, and Q is cooperativity (Hill's coefficient).

The compound of Example 225 causes dose-dependent suppression of the action of AVP with IC ₅₀ (2.68 nM) and K _i (0.05 nM). These values are consistent with the high binding affinity of Example 225 and inhibition of the synthesis of inositol-containing lipids via the human V _1a receptor.

EXAMPLE. The usefulness of the compounds and compositions described herein for the treatment of PTSD and stress-related affective disorder is established using a predator fear conditioning model. This model uses fMRI data from rats seeing a ferret, a natural predator, as the unconditioned stimulus, while sucrose taste, which is highly reinforcing, is used as the conditioned stimulus. The taste of sucrose becomes associated with the traumatic memory of the ferret. Rats show a pattern of over-activation (hyperarousal) of the brain in the limbic cortex and hippocampus in response to the mere taste of sucrose several weeks later. This pattern of excessive brain activation in response to a traumatic memory stimulus is characteristic of PTSD. The data show that the brain activity associated with fear memory induced by sucrose exposure is higher than the initial predator exposure. Thus, the memory of fear is stronger than the fear itself. Treatment with the compounds and compositions described herein blocks the over-activation seen in sucrose-associated traumatic memory in untreated animals. The compounds described herein are efficacious in this new preclinical rat model of PTSD using fear of a predator as the conditioned stimulus and sucrose taste as the conditioned stimulus. Pretreatment with the V1a receptor antagonist AVN576 blocked the excessive brain activation circuitry induced by the taste of sucrose several weeks after predator exposure. The compounds described herein are also effective in established models of depression (social interaction test), anxiety (elevated plus maze, LightDark Shuttle Box), and aggression (outsider:resident test).

The development of a conditioned reflex of fear of a predator connects an aversive unconditioned stimulus (the threat of extermination by a predator) with the taste of sucrose as a conditioned stimulus. During the imaging session, awake rats were shown a live black ferret placed in a magnet hole. This predator display was performed with or without sucrose placed on the tongue of the rat. Memory retrieval after a few weeks using only sucrose (as a conditioned stimulus) in the absence of a ferret caused a strong increase in brain activity, which significantly exceeded the increase in the initial display of a predator. This pattern of brain overactivation focuses on the limbic cortex, hippocampus, and amygdala—neural circuits involved in emotional experience, learning, and memory, and which are implicated in PTSD and other neuropsychiatric disorders, including disorders often associated with PTSD, see e.g. (Ferris et al., Imaging the Neural Circuitry and Chemical Control of Aggressive Motivation. BMC Neurosci, 9(1): 111 (2008); Shin & Liberzon, The neurocircuitry of fear, stress, and anxiety disorders. Neuropsychopharmacology. 35(1 ): 169-91 (2010); Price and Drevets, 2009; Rodriguez et al., 2009). This model is unique for several reasons, but most importantly, it links fear of predators to a highly reinforcing hedonic stimulus, sucrose. Without being bound by any particular theory, the present invention believes that this model parallels an emotional dilemma that may well reflect the complex associations that reinforce PTSD in soldiers returning from combat areas.

Protocol for functional MRI. Experiments were carried out in a 7.0 T/20-cm USR Bruker Biospec horizontal magnet (Bruker, Billerica, MA, USA) and a 20-G/cm magnetic field gradient insert (ID=12 cm) allowing a rise time of 120 µs (Bruker ). RF signals are sent and received using a two-coil electronic device built into the animal restraint box (Ludwig et al., 2004). At the start of each imaging session, a high-resolution anatomical data set is obtained using a RARE pulse train (slice 14; 1.2 mm; FOV 3.0 cm, 256 X 256; TR 2.1 sec; TE 12.4 ms; NEX 6 ; study time 6.5 min). Functional images are acquired using a multi-slice fast spin echo sequence. In one scan session, fourteen slices are obtained every 6 seconds (TR=2108 ms, TEeff=53.2 ms, RARE factor=16, NEX 1), repeated 100 times during a 10 minute scan. After 5 minutes of initial functional imaging, place the ferret/inject sucrose or only inject sucrose and acquire functional images for another 5 minutes.

Scan session. During the imaging session, male Long Evans rats were shown an adult male black ferret kept in a vivarium or an empty vivarium placed in a magnet hole. The PE 10 tube was passed through the opening in the front of the restraint system and positioned in the rat's mouth. The mouth of the rats was kept slightly open with a bite plate built into the head holder. When a ferret or an empty vivarium was placed, 0.1 ml of a 10% sucrose solution or water was injected through a tube. Changes in heart rate, respiration and temperature were non-invasively monitored throughout the entire 10 minutes of the scanning session. After the imaging session, the rats were returned to their home cage and left undisturbed until the next imaging session 14 days later. Animals were placed one at a time in a 12:12 light-dark cycle and provided with food and water ad libitum.

Received three-dimensional images of the Papez neural circuit (limbic cortex involved in emotional experience) along with the amygdala and the hippocampus of the rat. Papetz's cortical neural circuit regions included the prelimbic cortex, second motor cortex, anterior cingulate cortex, primary somatosensory cortex, entorhinal cortex, anterior thalamus, mammillary bodies, retrosplenal cortex, insular cortex, and supraorbital cortex. The regions of the amygdala included the striate terminal nucleus, the anterior nucleus, the nucleus basalis, the posterior nucleus, the nucleus medialis, the nucleus cortex, the lateral nucleus, and the nucleus centrale. Hippocampal regions included the dentate nucleus, supporting structure, CA1 and CA3. With reference to FIG. 1, black areas represent the mean significant BOLD activation of eight animals for each condition.

All animals were fully conscious during the 10 minute imaging session (5 controls and 5 with stimulus). (A) shows the pattern of unconditional activation in the ferret-only case. (B) shows the pattern of unconditional activation in a ferret alone after pre-treatment with AVN576 (5 mg/kg bw). (C) shows a pattern of conditioned activation when animals are re-exposed to sucrose alone in a magnet after two weeks. (D) shows a conditioned activation pattern when animals are pre-treated with AVN576 (5 mg/kg bw) and re-exposed to sucrose alone in the magnet two weeks later. Also received data for the scheme of unconditional activation in the case of only ferret + sucrose (not shown). All areas of the Papez, amygdala, and hippocampus cortical neural circuitry showed increased activation when animals were re-exposed to sucrose alone (C) compared to ferret (A) or ferret and sucrose (not shown). All increases were significant (p<0.05) except for the entorhinal cortex, anterior cingulate cortex, cortical nucleus, and central nucleus. The data in (D) show that pretreatment of rats with the compounds described herein significantly reduces brain activation in neural circuits associated with emotional experience, learning, and memory when animals are re-exposed to sucrose alone after conditioned reflexes have been conditioned. The data in (C) show that the response to fear of a predator in the test animal with an undeveloped conditioned reflex is preserved.

AVN576 (Example 266) effectively blocked the return of memory for fear of a predator. Without being bound by any particular theory, it is believed by the present invention that vasopressin is involved in fear memory and not in the fear response itself. The compounds described herein attenuate the excessive brain activation circuitry associated with the return of aversive memory. There is evidence of a pattern of over-activation in fear circuits in patients with PTSD (see, for example, Shin et al., Regional cerebral blood flow in the amygdala and medial prefrontal cortex during traumatic imagery in male and female Vietnam veterans with PTSD. Arch Gen Psychiatry. Feb;61(2): 168-76 (2004); Shin and Liberzon, 2010).

EXAMPLE. A resident alien model of stress and aggression in rats. Neuroimaging is used to assess stress/arousal blockade by a test compound compared to a control. The effect of AVN251-HC1 on the functional circuit was investigated using the imaging method for awake rats. Additional details of the analysis are described in Ferris et al. (2008). This study provided insight into the action of AVN251-HCl on the CNS and the differentiated neurobiological changes produced by AVN251-HCl compared to fluoxetine (AVN251-HCl left sexual motivation intact, while fluoxetine markedly reduced activation of this circuit).

Male rats in the same cage as a female will experience piloerection in the presence of an intruder male. This piloerection is a sign of stress and aggressive intent, and is associated with the activation of stress/arousal circuits in the brain. Treatment with AVN251-HCl (5 mg/kg) blocks the activation of this stress chain. It is important to note that this effect appears to be specific, as the function of the mesocorticolimbic dopamine reward system in response to a sexual motivating stimulus (estrogen-progesterone primed female) remained intact in the presence of AVN251-HCl. Male resident rats from six pairs of male hamsters were visualized while they were in a fully awake state. During one data imaging session, males were given vehicle or AVN251-HCl (5 mg/kg).

The total volume of brain activation for resident males encountered only mate, mate and stranger, and mate and stranger in the presence of AVN251-HCl can be estimated in 3D models. While there appears to be an overall decrease in BOLD signal in major areas with AVN251-HCl treatment, V1a receptor blockade did not affect sexual motivation as assessed by presenting a new receptive female. The visualization shows strong activation of different areas of the brain when a new female is presented as a stimulus. Moreover, resident males treated with AVN251-HCl exhibit normal sexual behavior towards receptive females (new oophorectomy females receiving estrogen/progesterone treatment) in a home cage setting.

Activation of the stress circuit in response to an intruder male is assessed by obtaining brain scans, viewed from a caudal/dorsal position, in the form of translucent shells. The localization of activated voxels is displayed as three-dimensional activation volumes, each of which consists of 10 objects. After full registration and segmentation, the statistical responses for each object are averaged on a voxel-by-voxel basis (voxel-by-voxel). Data averaged voxels exceeding the 2.0% threshold are presented in the corresponding spatial arrangement. Functional images are obtained from awake rats at 4.7T.

Oral administration of each of the compounds from Example 225 (AVN251) or Example 224 (AVN246) blocked stress and aggressive motivation compared to controls. The test compounds attenuate the activity of the stress/arousal circuit normally elicited in response to an intruder stimulus.

Sexual motivation also activates the reward circuitry in the presence of AVN251. AVN251-HCl selectively blocks aggressive motivation (friend/outsider) but not sexual motivation (new female) as seen in 3D models of activity in the primary olfactory system and reinforcer (mesocorticolimbic dopaminergic system) pathways. Three-dimensional activation volumes consist of the results obtained from 10 objects in each state. Significant reduction on a voxel-by-voxel basis was observed in both systems in the friend/outsider scenario in the treatment group. However, in the scenario with new females, both systems showed preserved activity. Specific olfactory systems measured included the anterior olfactory nucleus, olfactory tubercle, piriform cortex, lateral olfactory tract, and entorhinal cortex. Specific dopaminergic systems measured included the prelimbic cortex, contiguous regions, ventral pallidum, medial dorsal thalamus, and ventral tegmentum.

EXAMPLE. Neuroimaging demonstrates stress blockade in important areas of the brain. Awake rats were visualized when they were presented with their "comrade" + stranger, a highly stressful stimulus. Pre-treatment with AVN251 (5 mg/kg) 90 minutes prior to the testing session blocked the response to stress/arousal. Sexual motivation and behavior remained intact. Separate areas of the brain were assessed, including the amygdala, cortex, hippocampus, and thalamus, each of which showed similar results.

EXAMPLE. Hamster alien-resident model. Placing an unfamiliar male hamster in the home cage of another male hamster elicits a well-defined sequence of agonistic behaviors in the resident, including offensive aggression.

Male Syrian golden hamsters (Mesocricetus auratus) (140-150 g) obtained from Harlan Sprague-Dawley Laboratories (Indianapolis, Ind.) were individually housed in plexiglass cages (24 cm x 24 cm x 20 cm), housed in reverse cycle mode light:dark (14S:10T; lights on at 19:00) and food and water provided ad libitum. Animals were habituated to a reverse light:dark cycle for at least two weeks prior to testing. All behavioral tests were performed during the dark phase of the circadian cycle.

Measurement and analysis of behavior. Hamsters are nocturnal and therefore behavioral tests are performed during the first four hours of the dark phase under low red light. The resident is assessed for stress, such as delay before biting an intruder, total contact time with an intruder, total number of bites and flank marking, over a 10-minute testing period (Ferris, C.F., Potegal, M. Physiology and Behavior, 44, 235-239 (1988)). Lateral body tagging is a form of olfactory communication in which the hamster arches its back and rubs its pheromone-producing lateral glands against objects in its environment (Johnston, R.E. Communication, In: THE HAMSTER REPRODUCTION AND BEHAVIOR. Ed Siegel, H.I. Plenum Press, New York, pp 121-154 (1985)). The frequency of lateral body tagging is significantly increased during aggressive encounters and is especially high in dominant, fight initiating and winning animals (Ferris, C.F., et al., Physiology and Behavior, 40, 661-664 (1987)).

The compounds described herein are tested using five groups of five animals each in a dose range (100 ng/kg, 10 μg/kg, 1 mg/kg, 10 mg/kg and saline vehicle as control). Ninety minutes after drug administration via oral probe, the alien is placed in a home cage and the resident is assessed for offensive aggression. After testing for aggression, the animals are screened for open field locomotor activity and sexual motivation.

Parametric data, i.e. delays and contact times are analyzed by one-way analysis of variance (ANOVA) followed by Newman-Keuls post hoc tests. Non-parametric data, i.e. the number of bites and flank marks are analyzed using the Kruskal-Wallis test followed by the Mann-Whitney U-test to determine differences between groups.

The pre-bite delay is increased and the number of bites is reduced with the administration of the compounds described herein, indicating lower levels of stress in treated animals. The contact time can also be increased.

EXAMPLE. Chronic subordinate model of depression in mice. Social stress is one factor in the etiology of several psychopathologies, with individuals differing in susceptibility. Adult male mice are subjected to a model of chronic psychosocial stress in which resident/outsider pairs constantly live in sensory contact and interact physically on a daily basis. Alien animals chronically subdued by this technique exhibit behaviors characteristic of depression and depression-related disorders.

EXAMPLE. Antidepressant effect in the social interaction test. Continuous social submission is a standard way of producing animals that exhibit depression-like physiological and behavioral characteristics. The fast compliance paradigm in mice results in reduced social interaction behavior, with the dependent measures being distance traveled and time spent in the interaction zone. A 28-day regimen of fluoxetine, the standard antidepressant, reversed the deficiency caused by chronic compliance, while the same regimen using chlordiazepoxide (CDP), the standard anxiolytic, had no effect. These observations are consistent with the subordination/social interaction model as a rapid behavioral screening for potential antidepressants. Additional details are described in Berton et al. (2006).

Briefly, C57B1/6J males were defeated daily for 10 days by resident, highly aggressive CF-1 males. After 5 minutes of direct exposure, a perforated plastic septum was placed in the cage, allowing olfactory and visual contact without physical damage for the remaining 23 hours and 55 minutes each day. C57 males were shown a different resident male in a different cage each day with increasing stress from the technique (all CF-1 males were observed to attack the intruder each day). At the end of the 10 day lesion protocol, C57 males were tested in an open field apparatus during the dark phase. The dominant male was placed in a cage in an area of the open field apparatus called the "zone of social interaction". Recorded the time and distance traveled in this zone. C57 males were then randomly assigned to the following treatment groups: AVN246-HCl (2 mg/kg), vehicle saline (0.45%) or chlordiazepoxide (10 mg/kg). The treatment was carried out daily (ip) for 28 days and the animals were retested. Changes in behavior were determined by calculating the difference scores (Post-Pretest) and analyzed these scores.

As shown in Table 1, AVN246-HCl treatment significantly increased both distance traveled and time in the interaction zone, indicating that the compounds described herein reverse the deficits in social interaction behavior after social submission.

A statistically significant difference (p<0.05) was observed between the test compound and both the untreated control (saline) and the negative control (CDP). Fluoxetine, an antidepressant, produced comparable improvements; chlordiazepoxide (CDP), a standard anxiolytic, had no effect. These results confirm that the deficit in social interaction induced by chronic obedience is susceptible to antidepressants, but not to anxiolytics. AVN246 is observed to give similar results.

EXAMPLE. Anxiolytic effect in the Dark-Light chamber. The dark-light chamber assay is a standard and well-studied assay for evaluating the anxiolytic effects of a test compound. Rats naturally avoid the light side of the camera because it causes stress. The increased time on the light side of the treatment group compared to controls reflects an anxiolytic effect (Bourin and Hascoet, 2003). Adult male Long Evans rats were injected with AVN251 (0.1-2 mg/kg) via oral gavage 90 minutes prior to testing in a dark-light chamber. A dose-dependent reduction in anxiety was observed in response to AVN251 compared to vehicle. Depending on the dose, test animals spent significantly more time in the light (FIG. 2A), less time in the dark (FIG. 2B) and more light-dark entries (FIG. 2C) after treatment with 1 or 2 mg/kg AVN251.

EXAMPLE. General synthesis routes. Proximal amide approach providing variation in synthesis at the distal amide site; the proximal amide is prepared first, followed by the distal amide variety via parallel synthesis.

A distal amide approach providing variation in proximal synthesis; the distal amide is prepared first, followed by the proximal amide variety via parallel synthesis.

Synthesis of AVN251 is presented below. All other compounds are obtained in a similar way with an appropriate choice of starting materials.

Additional details and alternative syntheses for the preparation of the compounds described herein are described in U.S. Patent No. 7119083, the full content of which is incorporated into the present description by reference. The compounds described herein may be formulated and administered according to the methods described in US Patent No. 7,119,083. Additional details are described in Guillon, CD., et al., Azetidinones as vasopressin V1a antagonists. Bioorg Med Chem, 15(5):2054-80 (2007).

CONNECTION EXAMPLES

Example 1 (4(S)-Phenyloxazolidin-2-on-3-yl)acetyl chloride. A solution of 1.0 equivalents of (4(S)-phenyloxazolidin-2-one-3-yl)acetic acid (Evans, US Pat. No. 4,665,171) and 1.3 equivalents of oxalyl chloride in 200 ml of dichloromethane was treated with a catalytic amount of anhydrous dimethylformamide (85 μl /milliequivalent of an acetic acid derivative), which led to intense gas evolution. After 45 minutes, gas evolution had completely ceased and the reaction mixture was concentrated under reduced pressure to give the title compound as an off-white solid after drying for 2 hours under vacuum.

Example 1A. (4(R-Phenyloxazolidin-2-on-3-yl)acetyl chloride. The compound of Example 1A was prepared according to the procedure of Example 1, except that (4(R)-phenyloxazolidin-2-on-3-yl )acetic acid was used instead of (4(S)-phenyloxazolidin-2-one-3-yl)acetic acid (see Evans & Sjogren, Tetrahedron Lett. 26:3783 (1985)).

Example 1B. Methyl (4(S)-phenyloxazolidin-2-on-3-yl)acetate. A solution of (4(S)-phenyloxazolidin-2-one-3-yl)-acetic acid (1 g, 4.52 mmol) (prepared according to Evans in US Pat. No. 4,665,171) in 20 ml of anhydrous methanol was treated every hour with 5 equivalents of acetyl chloride, for a total of 20 equivalents. The resulting solution was stirred overnight. The residue obtained after MeOH evaporation was redissolved in 30 ml of CH ₂ Cl ₂ and treated with 50 ml of saturated aqueous Na ₂ CO ₃ . The organic phase was evaporated and dried (MgSO ₄ ) to give the title compound as a colorless oil (1.001 g, 94%); ¹ H NMR (CDCl ₃ ) δ 3.37 (d, J=18.0 Hz, 1H), 3.69 (s, 3H), 4.13 (t, J=8.3 Hz, 1H), 4 .28 (d, J=18.0 Hz, 1H), 4.69 (t, J=8.8 Hz, 1H), 5.04 (t, J=8.4 Hz, 1H), 7.26 -7.29 (m, 2H), 7.36-7.42 (m, 3H).

Example 1C. Methyl 2-(4(S)-phenyloxazolidin-2-on-3-yl)propanoate. A solution of methyl (4(S)-phenyloxazolidin-2-one-3-yl)acetate (1 g, 4.25 mmol) in 10 ml anhydrous THF at -78° C. was treated with 4.68 ml (4.68 mmol) 1 M solution of lithium bis(trimethylsilyl)amide in THF. The reaction mixture was stirred for 1 hour at about -70°C before adding MeI (1.59 ml, 25.51 mmol). After complete conversion of the azetidinone, the reaction was quenched with saturated aqueous NH ₄ Cl and partitioned into EtOAc and water. The organic phase was washed successively with saturated aqueous sodium bisulfite and saturated aqueous NaCl. The resulting organic phase was dried (MgSO ₄ ) and evaporated to give the title compound (mixture of diastereomers) as a white solid (1.06 g, 93%); ¹ H NMR (CDCl ₃ ) δ 1.07/1.53 (d/d, J=7.5 Hz, 3H), 3.59/3.74 (s/s, 3H), 3.85/4 .48 (q/q, J=7.5 Hz, 1H), 4.10-4.14 (m, 1H), 4.60-4.64/4.65-4.69 (m/m, 1H), 4.88-4.92/4.98-5.02 (m/m, 1H), 7.24-7.40 (m, 5H).

Example 1D. 2-(4(S)-Phenyloxazolidin-2-on-3-yl)propanoic acid. To a solution of methyl 2-(4(S)-phenyloxazolidin-2-on-3-yl)propanoate (1 g, 4.01 mmol) in 35 ml MeOH was added at 0 ) 0.84 M solution of LiOH in water. The reaction mixture was then stirred for 3 hours at ambient temperature. After complete hydrolysis of the azetidinone, the MeOH was removed by evaporation, the crude residue was dissolved in CH ₂ Cl ₂ and treated with saturated aqueous NaCl. The resulting organic phase was dried (MgSO ₄ ) and evaporated to give the title compound (racemic mixture) as a white solid (0.906 g, 96%); ¹ H NMR (CDCl ₃ ) δ 1.13/1.57 (d/d, J=7.5 Hz, 3H), 3.75/4.50 (q/q, J=7.5 Hz, 1H ), 4.10-4.16(m, 1H), 4.62-4.72(m, 1H), 4.92-5.03(m, 1H), 7.32-7.43(m , 5H).

Example 1E. 2-(4(S)-Phenyloxazolidin-2-on-3-yl)propanoyl chloride. A solution of 1 equivalent of the compound from Example 1D and 1.3 equivalents of oxalyl chloride in 200 ml of CH ₂ Cl ₂ (150 ml/g of propanoic acid derivative) was treated with a catalytic amount of anhydrous dimethylformamide (DMF) (85 μl/mmol of propanoic acid derivative) resulting in intensive outgassing. After 45 minutes, gas evolution had completely ceased and the reaction mixture was concentrated under reduced pressure to give the title compound as an off-white solid after drying for 2 hours under vacuum.

Example 2 General procedure for preparing an amide from an activated ester derivative. N-Benzyloxycarbonyl-L-aspartic acid β-tert-butyl ester α-(3-trifluoromethyl)benzylamide. A solution of N-benzyloxycarbonyl-L-aspartic acid β-tert-butyl ester α-N-hydroxysuccinimide ester (1.95 g, 4.64 mmol, Advanced ChemTech) in 20 ml dry tetrahydrofuran was treated with 0.68 ml (4.74 mmol ) 3-(trifluoromethyl)benzylamine. After completion (TLC, hexanes/ethyl acetate 60:40), the mixture was evaporated and the resulting oil was partitioned between dichloromethane and saturated aqueous sodium bicarbonate. The organic phase was evaporated to give 2.23 g (quantitative) of the title compound as a white solid; ¹ H NMR (CDCl ₃ ) δ 1.39 (s, 9H), 2.61 (dd, J=6.5 Hz, J=17.2 Hz, 1H), 2.98 (dd, J=3, 7 Hz, J=17.0 Hz, 1H), 4.41 (dd, J=5.9 Hz, J=15.3 Hz, 1H), 4.50-4.57 (m, 2H), 5 .15 (s, 2H), 5.96-5.99 (m, 1H), 6.95 (s, 1H), 7.29-7.34 (m, 5H), 7.39-7.43 (m, 2H), 7.48-7.52 (m, 2H).

The compounds of Examples 2A-2C and 3-5 were prepared according to the procedure of Example 2 except that the N-benzyloxycarbonyl-L-aspartic acid β-tert-butyl ester α-N-hydroxysuccinimide ester was replaced by the corresponding amino acid derivative, and 3-(trifluoromethyl)benzylamine was replaced by the corresponding amine.

Example 2A. N-Benzyloxycarbonyl-L-aspartic acid β-tert-butyl ester α-[4-(2-phenylethyl)]piperazinamide. From N-benzyloxycarbonyl-L-aspartic acid β-tert-butyl ester α-N-hydroxysuccinimide ester (5.0 g, 12 mmol, Advanced ChemTech) and 4-(phenylethyl)piperazine 2.27 mL (11.9 mmol) obtained 5.89 g (quantitative yield) of the title compound as an off-white oil; ¹ H NMR (CDCl ₃ ) δ 1.40 (s, 9H), 2.45-2.80 (m, 10H), 3.50-3.80 (m, 4H), 4.87-4.91 (m, 1H), 5.08 (s, 2H), 5.62-5.66 (m, 1H), 7.17-7.33 (m, 10H).

Example 2B. N-benzyloxycarbonyl-L-glutamic acid γ-tert-butyl ester α-(3-trifluoromethyl)benzylamide. From N-benzyloxycarbonyl-L-glutamic acid β-tert-butyl ester α-N-hydroxysuccinimide ester (4.83 g, 11.1 mmol, Advanced ChemTech) and 3-(trifluoromethyl)benzylamine 1.63 ml (11.4 mmol) gave 5.41 g (98%) of the title compound as an off-white solid; ¹ H NMR (CDCl ₃ ) δ 1.40 (s, 9H), 1.88-1.99 (m, 1H), 2.03-2.13 (m, 1H), 2.23-2.33 (m, 1H), 2.38-2.47 (m, 1H), 4.19-4.25 (s, 1H), 4.46-4.48 (m, 2H), 5.05-5 .08 (m, 2H), 5.67-5.72 (m, 1H), 7.27-7.34 (m, 5H), 7.39-7.43 (m, 2H), 7.48 -7.52 (m, 2H).

Example 2C. N-benzyloxycarbonyl-L-glutamic acid γ-tert-butyl ester α-[4-(2-phenylethyl)]piperazinamide. From N-benzyloxycarbonyl-L-glutamic acid γ-tert-butyl ester α-N-hydroxysuccinimide ester (5.0 g, 12 mmol, Advanced ChemTech) and 4-(phenylethyl)piperazine 2.19 mL (11.5 mmol) obtained 5.87 g (quantitative yield) of the title compound as an off-white oil; ¹ H NMR (CDCl ₃ ) δ 1.43 (s, 9H); 1.64-1.73 (m, 1H); 1.93-2.01 (m, 1H); 2.23-2.40 (m, 2H); 2.42-2.68 (m, 6H); 2.75-2.85 (m, 2H); 3.61-3.74 (m, 4H); 4.66-4.73 (m, 1H); 5.03-5.12 (m, 2H); 5.69-5.72 (m, 1H); 7.16-7.34 (m, 10H).

Example 3 N-benzyloxycarbonyl-L-aspartic acid β-tert-butyl ester α-[4-(2-phenylethyl)]piperazinamide. From N-benzyloxycarbonyl-L-aspartic acid β-tert-butyl ester α-N-hydroxysuccinimide ester (5.0 g, 12 mmol, Advanced ChemTech) and 4-(phenylethyl)piperazine 2.27 mL (11.9 mmol) obtained 5.89 g (quantitative yield) of the title compound as an off-white oil; ¹ H NMR (CDCl ₃ ) δ 1.40 (s, 9H), 2.45-2.80 (m, 10H), 3.50-3.80 (m, 4H), 4.87-4.91 (m, 1H), 5.08 (s, 2H), 5.62-5.66 (m, 1H), 7.17-7.33 (m, 10H).

Example 4 N-benzyloxycarbonyl-L-glutamic acid γ-tert-butyl ester α-(3-trifluoromethyl)benzylamide. From N-benzyloxycarbonyl-L-glutamic acid β-tert-butyl ester α-N-hydroxysuccinimide ester (4.83 g, 11.1 mmol, Advanced ChemTech) and 3-(trifluoromethyl)benzylamine 1.63 ml (11.4 mmol) gave 5.41 g (98%) of the title compound as an off-white solid; ¹ H NMR (CDCl ₃ ) δ 1.40 (s, 9H), 1.88-1.99 (m, 1H), 2.03-2.13 (m, 1H), 2.23-2.33 (m, 1H), 2.38-2.47 (m, 1H), 4.19-4.25 (s, 1H), 4.46-4.48 (m, 2H), 5.05-5 .08 (m, 2H), 5.67-5.72 (m, 1H), 7.27-7.34 (m, 5H), 7.39-7.43 (m, 2H), 7.48 -7.52 (m, 2H).

Example 5 N-benzyloxycarbonyl-L-glutamic acid γ-tert-butyl ester α-[4-(2-phenylethyl)]piperazinamide. From N-benzyloxycarbonyl-G-glutamic acid γ-tert-butyl ester α-N-hydroxysuccinimide ester (5.0 g, 12 mmol, Advanced ChemTech) and 4-(phenylethyl)piperazine 2.19 mL (11.5 mmol) obtained 5.87 g (quantitative yield) of the title compound as an off-white oil; ¹ H NMR (CDCl ₃ ) δ 1.43 (s, 9H); 1.64-1.73 (m, 1H); 1.93-2.01 (m, 1H); 2.23-2.40 (m, 2H); 2.42-2.68 (m, 6H); 2.75-2.85 (m, 2H); 3.61-3.74 (m, 4H); 4.66-4.73 (m, 1H); 5.03-5.12 (m, 2H); 5.69-5.72 (m, 1H); 7.16-7.34 (m, 10H).

Example 5A. N-[(9H-fluoren-9-yl)methoxycarbonyl]-O-(benzyl)-D-serine tert-butyl ether. N-[(9H-fluoren-9-yl)methoxycarbonyl]-O-(benzyl)-D-serine (0.710 g, 1.70 mmol) in dichloromethane (8 ml) was treated with tert-butyl acetate (3 ml) and concentrated sulfuric acid (40 µl) in a sealed flask at 0°C. After completion (TLC), the reaction was quenched with dichloromethane (10 ml) and saturated aqueous potassium bicarbonate (15 ml). The organic phase was washed with distilled water and evaporated. The resulting residue was purified by flash column chromatography (dichloromethane/methanol 98:2) to give the title compound as a colorless oil (0.292 g, 77%); ¹ H NMR (CDCl ₃ ) δ 1.44 (s, 9H); 3.68 (dd, J=2.9 Hz, J=9.3 Hz, 1H); 3.87 (dd, H=2.9 Hz, J=9.3 Hz, 1H); 4.22 (t, J=7.1 Hz, 1H); 4.30-4.60 (m, 5H); 5.64-5.67 (m, 1H); 7.25-7.39 (m, 9H); 7.58-7.61 (m, 2H); 7.73-7.76 (m, 2H).

Example 5B. O-(benzyl)-D-serine tert-butyl ether. The compound from Example 5A (0.620 g, 1.31 mmol) in dichloromethane (5 ml) was treated with tris(2-aminoethyl)amine (2.75 ml) for 5 hours. The resulting mixture was washed twice with phosphate buffer (pH=5.5), once with saturated aqueous potassium bicarbonate and evaporated to give 0.329 g (quantitative) of the title compound as an off-white solid; ¹ H NMR (CD ₃ OD) δ 1.44 (s, 9H); 3.48 (dd, J=J'=4.2 Hz, 1H); 3.61 (dd, J=4.0 Hz, J=9.2 Hz, 1H); 3.72 (dd, J=4.6 Hz, J=9.2 Hz, 1H); 4.47 (d, J=12.0 Hz, 1H); 4.55 (d, Γ=12.0 Hz, 1H); 7.26-7.33 (m, 5H).

Example 6 General procedure for preparing an amide from a carboxylic acid. N-Benzyloxycarbonyl-D-aspartic acid β-tert-butyl ester α-(3-trifluoromethyl)benzylamide. A solution of 1 g (2.93 mmol) of N-benzyloxycarbonyl-D-aspartic acid β-tert-butyl ester monohydrate (Novabiochem) in 3-4 ml of dichloromethane was treated by successively adding 0.46 ml (3.21 mmol) of 3-( trifluoromethyl)benzylamine, 0.44 g (3.23 mmol) 1-hydroxy-7-benzotriazole and 0.62 g (3.23 mmol) 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride. After at least 12 hours at ambient temperature or until completion as determined by thin layer chromatography (eluent dichloromethane/methanol 95:5), the reaction mixture was washed successively with saturated aqueous sodium bicarbonate and distilled water. The organic phase was evaporated to give 1.41 g (quantitative) of the title compound as an off-white solid; ¹ H NMR (CDCl ₃ ) δ 1.39 (s, 9H); 2.61 (dd, J=6.5 Hz, J=17.2 Hz, 1H); 2.98 (dd, J=4.2 Hz, J=17.2 Hz, 1H); 4.41 (dd, J=5.9 Hz, J=15.3 Hz, 1H); 4.50-4.57 (m, 2H); 5.10 (s, 2H); 5.96-6.01 (m, 1H); 6.91-7.00 (m, 1H); 7.30-7.36 (m, 5H); 7.39-7.43 (m, 2H); 7.48-7.52 (m, 2H).

The compounds of Examples 7-7H were prepared according to the procedure of Example 6 except that N-benzyloxycarbonyl-D-aspartic acid β-tert-butyl ester monohydrate was replaced with the corresponding amino acid derivative and 3-(trifluoromethyl)benzylamine was replaced with the corresponding amine.

Example 7 N-benzyloxycarbonyl-D-glutamic acid γ-tert-butyl ester α-(3-trifluoromethyl)benzylamide. From N-benzyloxycarbonyl-D-glutamic acid γ-tert-butyl ester (1.14 g, 3.37 mmol) and 0.53 ml (3.70 mmol, Novabiochem) 3-(trifluoromethyl)benzylamine 1.67 g (quantitative yield) of the compound from Example 7 as an off-white solid. The compound from Example 7 showed a ¹ H NMR spectrum consistent with the established structure.

Example 7A. N-Benzyloxycarbonyl-L-glutamic acid α-tert-butyl ester γ-(4-cyclohexyl)piperazinamide. From N-benzyloxycarbonyl-L-glutamic acid α-tert-butyl ester (1.36 g, 4.03 mmol) and 0.746 g (4.43 mmol) 1-cyclohexylpiperazine, 1.93 g (98%) of the compound from Example 7A as an off-white solid; ¹ H NMR (CDCl ₃ ) δ 1.02-1.12 (m, 5H); 1.43 (s, 9H), 1.60-1.64 (m, 1H); 1.80-1.93 (m, 5H); 2.18-2.52 (m, 8H); 3.38-3.60 (m, 4H); 4.20-4.24 (m, 1H); 5.03-5.13 (m, 2H); 5.53-5.57 (m, 1H); 7.28-7.34 (m, 5H).

Example 7B. N-Benzyloxycarbonyl-D-aspartic acid β-tert-butyl ester α-(2-fluoro-3-trifluoromethyl)benzylamide. 0.365 g (quantitative yield) compounds from Example 7B as an off-white solid; ¹ H NMR (CDCl ₃ ) δ 1.38 (s, 9H); 2.59 (dd, J=6.5 Hz, J=17.0 Hz, 1H); 2.95 (dd, J=4.3 Hz, J=17.0 Hz, 1H); 4.46-4.56 (m, 3H); 5.11 (s, 2H); 5.94-5.96 (m, 1H); 7.15 (t, J=8.0 Hz, 1H); 7.30-7.36 (m, 5H); 7.47-7.52 (m, 2H).

Example 7C. N-Benzyloxycarbonyl-D-aspartic acid β-tert-butyl ester α-[(S)-α-methylbenzyl]amide. From N-Benzyloxycarbonyl-D-aspartic acid β-tert-butyl ester monohydrate (Novabiochem) (0.25 g, 0.73 mmol) and 0.094 ml of (S)-α-methylbenzylamine, 0.281 g (90%) of the compound from Example 7C as an off-white solid; ¹ H NMR (CDCl ₃ ) δ 1.41 (s, 9H); 1.44 (d, J=7.0 Hz, 3H); 2.61 (dd, J=7.0 Hz, J=17.0 Hz, 1H); 2.93 (dd, J=4.0 Hz, J=17.5 Hz, 1H); 4.50-4.54 (m, 1H); 5.04-5.14 (m, 3H); 5.94-5.96 (m, 1H); 6.76-6.80 (m, 1H); 7.21-7.37 (m, 10H).

Example 7D. N-Benzyloxycarbonyl-D-aspartic acid β-tert-butyl ester α-[(R)-α-methylbenzyl]amide. From N-Benzyloxycarbonyl-D-aspartic acid β-tert-butyl ester monohydrate (Novabiochem) (0.25 g, 0.73 mmol) and 0.094 ml of (R)-α-methylbenzylamine, 0.281 g (90%) of the compound from Example 7D as an off-white solid; ¹ H NMR (CDCl ₃ ) δ 1.38 (s, 9H); 1.43 (d, J=6.9 Hz, 3H); 2.54 (dd, J=7.3 Hz, J=17.2 Hz, 1H); 2.87 (dd, J=4.1 Hz, J=17.3 Hz, 1H); 4.46-4.50 (m, 1H); 4.99-5.15 (m, 3H); 5.92-5.96 (m, 1H); 6.78-6.82 (m, 1H); 7.21-7.33 (m, 10H).

Example 7E. N-Benzyloxycarbonyl-D-aspartic acid γ-tert-butyl ester α-[N-methyl-N-(3-trifluoromethylbenzyl)]amide. From N-Benzyloxycarbonyl-D-aspartic acid γ-tert-butyl ester (0.303 g, 0.89 mmol, Novabiochem) and 0.168 g (0.89 mmol) N-methyl-N-(3-trifluoromethylbenzyl)amine gave 0.287 g (65%) of the compound from Example 7E as an off-white solid; ¹ H NMR (CDCl ₃ ) δ 1.40 (s, 9H); 2.55 (dd, J=5.8 Hz, J=15.8 Hz, 1H); 2.81 (dd, J=7.8 Hz, J=15.8 Hz, 1H); 3.10 (s, 3H); 4.25 (d, J=15.0 Hz, 1H); 4.80 (d, J=15.5 Hz, 1H); 5.01-5.13 (m, 3H); 5.52-5.55 (m, 1H); 7.25-7.52 (m, 10H).

Example 7F. N-Benzyloxycarbonyl-D-aspartic acid β-tert-butyl ester α-[(δ)-1-(3-trifluoromethylphenyl)ethyl]amide. From N-Benzyloxycarbonyl-D-aspartic acid β-tert-butyl ester monohydrate (Novabiochem) (84 mg, 0.25 mmol) and 47 mg of (S)-1-(3-trifluoromethylphenyl)ethylamine 122 g (quantitative yield) compounds from Example 7F as an off-white solid. The compound from Example 7F showed a ¹ H NMR spectrum consistent with the established structure.

Example 7G. N-Benzyloxycarbonyl-D-aspartic acid β-tert-butyl ester a-[(R)-1-(3-trifluoromethylphenyl)ethyl]amide. From N-Benzyloxycarbonyl-D-aspartic acid β-tert-butyl ester monohydrate (Novabiochem) (150 mg, 0.44 mmol) and 83 mg of (R)-1-(3-trifluoromethylphenyl)ethylamine 217 g (quantitative yield) compounds from Example 7G as an off-white solid. The compound from Example 7G showed a ¹ H NMR spectrum consistent with the established structure.

Example 7H. N-Benzyloxycarbonyl-D-glutamic acid α-methyl ester γ-(3-trifluoromethyl)benzylamide. From N-benzyloxycarbonyl-D-glutamic acid α-methyl ester (508 mg, 1.72 mmol) and 317 mg (1.81 mmol) 3-(trifluoromethyl)benzylamine, 662 mg (85%) of the compound from Example 7H was obtained as off-white solid. The compound from Example 7H showed a ¹ H NMR spectrum consistent with the established structure.

Example 8 General procedure for the hydrogenation of benzyloxycarbonylamine. L-aspartic acid β-tert-butyl ester α-(3-trifluoromethyl)benzylamide. Suspension of 2.23 g (4.64 mmol) of N-benzyloxycarbonyl-L-aspartic acid of β-tert-butyl ester of α-(3-trifluoromethyl)benzylamide and palladium (5 wt.% on activated carbon, 0.642 g) in 30 ml methanol was kept in a hydrogen atmosphere until complete conversion, determined by thin layer chromatography (eluent dichloromethane/methanol 95:5). The reaction mixture was filtered to remove the palladium-carbon and the filtrate was evaporated to give 1.52 g (96%) of the title compound as an oil; ¹ H NMR (CDCl ₃ ) δ 1.42 (s, 9H); 2.26 (brs, 2H); 2.63-2.71 (m, 1H); 2.82-2.87 (m, 1H); 3.75-3.77 (m, 1H); 4.47-4.50 (m, 2H); 7.41-7.52 (m, 4H); 7.90 (brs, 1H).

The compounds of Examples 9-13P were prepared according to the procedure of Example 8, except that the N-benzyloxycarbonyl-L-aspartic acid β-tert-butyl ester α-(3-trifluoromethyl)benzylamide was replaced by the corresponding amino acid derivative.

Example 9 L-Aspartic acid β-tert-butyl ester α-[4-(2-phenylethyl)]piperazinamide. 4.24 g (98%) of the compound from Example 9 as off-white oil; ¹ H NMR (CDCl ₃ ): δ 1.42 (s, 9H); 2.61-2.95 (m, 10H); 3.60-3.90 (m, 4H); 4.35-4.45 (m, 1H); 7.17-7.29 (m, 5H).

Example 10 D-Aspartic acid β-tert-butyl ester α-(3-trifluoromethyl)benzylamide. From N-benzyloxycarbonyl-D-aspartic acid β-tert-butyl ester of α-(3-trifluoromethyl)benzylamide (1.41 g, 2.93 mmol) was obtained 0.973 g (96%) of the compound from Example 10 as an off-white oils; ¹ H NMR (CDCl ₃ ): δ 1.42 (s, 9H); 2.21 (brs, 2H); 2.67 (dd, J=7.1 Hz, J=16.8 Hz, 1H); 2.84 (dd, 3=3.6Hz, J=16.7Hz, 1H); 3.73-3.77 (m, 1H); 4.47-4.50 (m, 2H); 7.41-7.52 (m, 4H); 7.83-7.87 (m, 1H).

Example 11 L-Glutamic acid γ-tert-butyl ester α-(3-trifluoromethyl)benzylamide. From N-benzyloxycarbonyl-L-glutamic acid γ-tert-butyl ester of α-(3-trifluoromethyl)benzylamide (5.41 g, 10.9 mmol) was obtained 3.94 g (quantitative yield) of the compound from Example 11 as a dirty - white oil; ¹ H NMR (CDCl ₃ ): δ 1.41 (s, 9H); 1.73-1.89 (m, 3H); 2.05-2.16 (m, 1H); 2.32-2.38 (m, 2H); 3.47 (dd, J=5.0 Hz, J=7.5 Hz, 1H); 4.47-4.49 (m, 2H); 7.36-7.54 (m, 4H); 7.69-7.77 (m, 1H).

Example 12 L-Glutamic acid γ-tert-butyl ester α-[4-(2-phenylethyl)]piperazinamide. From N-benzyloxycarbonyl-L-glutamic acid γ-tert-butyl ester of α-[4-(2-phenylethyl)]piperazinamide (5.86 g, 11.50 mmol) was obtained 4.28 g (99%) of the compound from Example 12 as off-white oil; ¹ H NMR (CDCl ₃ ) δ 1.39 (s, 9H); 2.00-2.08 (m, 1H); 2.38-2.46 (m, 1H); 2.55-2.90 (m, 9H); 3.61-3.82 (m, 4H); 4.48-4.56 (m, 1H); 7.17-7.26 (m, 5H).

Example 13 D-Glutamic acid γ-tert-butyl ester α-(3-trifluoromethyl)benzylamide. From N-benzyloxycarbonyl-D-glutamic acid γ-tert-butyl ester of α-(3-trifluoromethyl)benzylamide (1.667 g, 3.37 mmol) was obtained 1.15 g (94%) of the compound from Example 13 as an off-white oils; ¹ H NMR (CDCl ₃ ) δ 1.41 (s, 9H); 1.80-2.20 (m, 4H); 2.31-2.40 (m, 2H); 3.51-3.59 (m, 1H); 4.47-4.49 (m, 2H); 7.39-7.52 (m, 4H); 7.71-7.79 (m, 1H).

Example 13A. L-Glutamic acid α-tert-butyl ester γ-(4-cyclohexyl)piperazinamide. From N-benzyloxycarbonyl-L-glutamic acid α-tert-butyl ester of γ-(4-cyclohexyl)piperazinamide (1.93 g, 3.96 mmol) was obtained 1.30 g (93%) of the compound from Example 13A as a dirty - white oil; ¹ H NMR (CDCl ₃ ) δ 1.02-1.25 (m, 5H); 1.41 (s, 9H); 1.45-1.50 (m, 1H); 1.56-1.60 (m, 1H); 1.69-1.80 (m, 6H); 3.30 (dd, J=4.8 Hz, J=8.5 Hz, 1H); 3.44 (t, J=9.9 Hz, 2H); 3.56 (t, J=9.9 Hz, 2H).

Example 13B. D-Aspartic acid β-tert-butyl ester α-(2-fluoro-3-trifluoromethyl)benzylamide. From N-benzyloxycarbonyl-D-aspartic acid β-tert-butyl ester of α-(2-fluoro-3-trifluoromethyl)benzylamide (0.36 g, 0.72 mmol) was obtained 0.256 g (92%) of the compound from Example 13 B as off-white oil; ¹ H NMR (CDCl ₃ ) δ 1.39 (s, 9H); 2.50 (brs, 2H); 2.74 (dd, J=7.0 Hz, J=16.5 Hz, 1H); 2.86 (dd, J=4.8 Hz, J=16.8 Hz, 1H); 3.89 (brs, 2H); 4.47-4.57 (m, 2H); 7.16 (t, J=7.8 Hz, 1H); 7.48 (t, J=7.3 Hz, 1H); 7.56 (t, J=7.3 Hz, 1H); 7.97-8.02 (m, 1H).

Example 13C. D-Aspartic acid β-tert-butyl ester α-[(S)-α-methyl]benzylamide. From N-benzyloxycarbonyl-D-aspartic acid β-tert-butyl ester of α-[(S)-α-methylbenzyl]amide (0.275 g, 0.65 mmol) was obtained 0.17 g (90%) of the compound from Example 13C in the form of dirty white oil; ¹ H NMR (CDCl ₃ ) δ 1.40 (s, 9H); 1.47 (d, J=6.9 Hz, 3H); 1.98 (brs, 2H); 2.49 (dd, J=7.9 Hz, J=17.7 Hz, 1H); 2.83 (dd, J=3.6Hz, J=16.7Hz, 1H); 3.69 (brs, 1H); 4.99-5.10 (m, 1H); 7.19-7.33 (m, 5H); 7.65-7.68 (m, 1H).

Example 13D. D-Aspartic acid β-tert-butyl ester α-[(R)-α-methylbenzyl]amide. From N-benzyloxycarbonyl-D-aspartic acid β-tert-butyl ester α-[(R)-α-methylbenzyl]amide (0.273 g, 0.64 mmol) 0.187 g (quantitative yield) of the compound from Example 13D was obtained as a dirty - white oil; ¹ H NMR (CDCl ₃ ) δ 1.38 (s, 9H); 1.46 (d, Γ=6.9 Hz, 3H); 1.79 (brs, 2H); 2.51 (dd, J=7.8 Hz, H=17.5 Hz, 1H); 2.87 (dd, J=3.6Hz, 3=16.9Hz, 1H); 4.19 (brs, 1H); 4.99-5.11 (m, 1H); 7.18-7.34 (m, 5H); 7.86-7.90 (m, 1H).

Example 13E. D-Aspartic acid β-tert-butyl ester α-[N-methyl-N-(3-trifluoromethylbenzyl)]amide. 0.195 g (95%) of the compound from Example 13E as off-white oil. The compound from Example 13E showed a ¹ H NMR spectrum consistent with the established structure.

Example 13F. L-Aspartic acid β-tert-butyl ester α-[4-(2-phenylethyl)]piperazinamide. 4.24 g (98%) of the compound from Example 13F as off-white oil; ¹ H NMR (CDCl ₃ ): δ 1.42 (s, 9H); 2.61-2.95 (m, 10H); 3.60-3.90 (m, 4H); 4.35-4.45 (m, 1H); 7.17-7.29 (m, 5H).

Example 13G. D-Aspartic acid β-tert-butyl ester α-(3-trifluoromethyl)benzylamide. From N-benzyloxycarbonyl-D-aspartic acid β-tert-butyl ester of α-(3-trifluoromethyl)benzylamide (1.41 g, 2.93 mmol) was obtained 0.973 g (96%) of the compound from Example 13G as an off-white oils; ¹ H NMR (CDCl ₃ ): δ 1.42 (s, 9H); 2.21 (brs, 2H); 2.67 (dd, J=7.1 Hz, J=16.8 Hz, 1H); 2.84 (dd, J=3.6Hz, J=16.7Hz, 1H); 3.73-3.77 (m, 1H); 4.47-4.50 (m, 2H); 7.41-7.52 (m, 4H); 7.83-7.87 (m, 1H).

Example 13H. L-Glutamic acid γ-tert-butyl ester α-(3-trifluoromethyl)benzylamide. From N-benzyloxycarbonyl-L-glutamic acid γ-tert-butyl ester of α-(3-trifluoromethyl)benzylamide (5.41 g, 10.9 mmol) was obtained 3.94 g (quantitative yield) of the compound from Example 13H as a dirty - white oil; ¹ H NMR (CDCl ₃ ): δ 1.41 (s, 9H); 1.73-1.89 (m, 3H); 2.05-2.16 (m, 1H); 2.32-2.38 (m, 2H); 3.47 (dd, J=5.0 Hz, J=7.5 Hz, 1H); 4.47-4.49 (m, 2H); 7.36-7.54 (m, 4H); 7.69-7.77 (m, 1H).

Example 131 L-Glutamic acid γ-tert-butyl ester α-[4-(2-phenylethyl)]piperazinamide 4.28 g (99%) of the compound from Example 131 as off-white oil; ¹ H NMR (CDCl ₃ ) δ 1.39 (s, 9H); 2.00-2.08 (m, 1H); 2.38-2.46 (m, 1H); 2.55-2.90 (m, 9H); 3.61-3.82 (m, 4H); 4.48-4.56 (m, 1H); 7.17-7.26 (m, 5H).

Example 13J. D-Glutamic acid γ-tert-butyl ester α-(3-trifluoromethyl)benzylamide. From N-benzyloxycarbonyl-D-glutamic acid γ-tert-butyl ester of α-(3-trifluoromethyl)benzylamide (1.667 g, 3.37 mmol) was obtained 1.15 g (94%) of the compound from Example 13J as an off-white oils; ¹ H NMR (CDCl ₃ ) δ 1.41 (s, 9H); 1.80-2.20 (m, 4H); 2.31-2.40 (m, 2H); 3.51-3.59 (m, 1H); 4.47-4.49 (m, 2H); 7.39-7.52 (m, 4H); 7.71-7.79 (m, 1H).

Example 13K. L-Glutamic acid α-tert-butyl ester γ-(4-cyclohexyl)piperazinamide. From N-benzyloxycarbonyl-L-glutamic acid α-tert-butyl ester of γ-(4-cyclohexyl)piperazinamide (1.93 g, 3.96 mmol) was obtained 1.30 g (93%) of the compound from Example 13K as a dirty - white oil; ¹ H NMR (CDCl ₃ ) δ 1.02-1.25 (m, 5H); 1.41 (s, 9H); 1.45-1.50 (m, 1H); 1.56-1.60 (m, 1H); 1.69-1.80 (m, 6H); 3.30 (dd, J=4.8 Hz, J=8.5 Hz, 1H); 3.44 (t, J=9.9 Hz, 2H); 3.56 (t, H=9.9 Hz, 2H).

Example 13L. D-Aspartic acid β-tert-butyl ester α-(2-fluoro-3-trifluoromethyl)benzylamide. From N-benzyloxycarbonyl-D-aspartic acid β-tert-butyl ester of α-(2-fluoro-3-trifluoromethyl)benzylamide (0.36 g, 0.72 mmol) was obtained 0.256 g (92%) of the compound from Example 13L in the form of dirty white oil; ¹ H NMR (CDCl ₃ ) δ 1.39 (s, 9H); 2.50 (brs, 2H); 2.74 (dd, J=7.0 Hz, J=16.5 Hz, 1H); 2.86 (dd, J=4.8 Hz, J=16.8 Hz, 1H); 3.89 (brs, 2H); 4.47-4.57 (m, 2H); 7.16 (t, J=7.8 Hz, 1H); 7.48 (t, J=7.3 Hz, 1H); 7.56 (t, J=7.3 Hz, 1H); 7.97-8.02 (m, 1H).

Example 13M. D-Aspartic acid β-tert-butyl ester α-[(S)-1-(3-trifluoromethylphenyl)ethyl]amide. 91 mg (91%) of the compound from Example 13M was an off-white oil and showed a ¹ H NMR spectrum consistent with the established structure.

Example 13N. D-Aspartic acid β-tert-butyl ester α-[(R)-1-(3-trifluoromethylphenyl)ethyl]amide. From N-benzyloxycarbonyl-D-aspartic acid β-tert-butyl ester α-[(R)-1-(3-trifluoromethylphenyl)ethyl]amide (217 g, 0.44 mmol) gave 158 mg (quantitative yield) of the compound from Example 13N as an off-white oil and showed a ¹ H NMR spectrum consistent with the established structure.

Example 13O. D-Aspartic acid β-tert-butyl ester α-[N-methyl-N-(3-trifluoromethylbenzyl)]amide. 0.195 g (95%) of the compound from Example 13O as an off-white oil and showed a ¹ H NMR spectrum consistent with the established structure.

Example 13P. D-Glutamic acid a-methyl ester γ-(3-trifluoromethyl)benzylamide. From N-benzyloxycarbonyl-D-glutamic acid α-methyl ester of γ-(3-trifluoromethyl)benzylamide (764 mg, 1.69 mmol) g (516 mg, 96%) of Example 13P was obtained as an off-white oil, and it showed a ¹ H NMR spectrum consistent with the established structure.

Example 14 General procedure for the preparation of 2-azetidinone from imine and acetyl chloride.

Step 1: General procedure for preparing an imine from an amino acid derivative. A solution of 1 equivalent of the α-amino acid ester or amide in dichloromethane was treated successively with 1 equivalent of the appropriate aldehyde and a drying agent such as magnesium sulfate or silica gel in an amount of about 2 grams of drying agent per gram of starting α-amino acid ester or amide. The reaction mixture was stirred at ambient temperature until complete consumption of all reagents, measured by thin layer chromatography. Reactions were typically completed within an hour. The reaction mixture was then filtered, the filter residue was washed with dichloromethane, and the filtrate was concentrated under reduced pressure to give the title imine, which was used as in the next step.

Step 2: General procedure for 2+2 cycloaddition of imine and acetyl chloride. A solution of imine in dichloromethane (10 ml of dichloromethane/1 gram of imine) was cooled to 0°C. To this cooled solution was added 1.5 equivalents of the appropriate amine, typically triethylamine, followed by dropwise addition of a solution of 1.1 equivalents of the appropriate acetyl chloride in dichloromethane, such as described for example in Example 1 (10 ml dichloromethane/1 g appropriate acetyl chloride) . The reaction mixture was allowed to warm to ambient temperature over 1 hour, and then the reaction was quenched by adding a saturated aqueous ammonium chloride solution. The resulting mixture was partitioned between water and dichloromethane. The phases were separated, and the organic phase was washed successively with 1N. hydrochloric acid, saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride. The organic phase was dried over magnesium sulfate and concentrated under reduced pressure. The residue can be used directly for subsequent reactions or purified by chromatography or by crystallization from an appropriate solvent system, if necessary. In each case, after a 2+2 reaction, the stereochemistry of the β-lactam can be confirmed by circular dichroism/optical rotational dispersion (CD/ORD). By way of illustration, examples of (αR,3S,4R) and (αS,3S,4R) stereochemical configurations of the β-lactam backbone from previous syntheses can be used as CD/ORD standards.

Example 15 tert-Butyl[3(S)-(4(S)-phenyloxazolidin-2-on-3-yl)-4(R)-(2-styryl)azetidin-2-on-1-yl]acetate . Using the procedure of Example 14, an imine prepared from 4.53 g (34.5 mmol) of glycine tert-butyl ester and cinnamaldehyde was mixed with 2-(4(S)-phenyloxazolidin-2-one-3-yl)acetyl chloride (Example 1) to obtain 5.5 g (30%) of the compound from Example 15 as colorless crystals (recrystallized, n-chlorobutane); So pl. 194-195°C.

Example 16 General procedure for the acylation of azetidin-2-on-1-ylacetate. A solution of (azetidin-2-on-1-yl)acetate in tetrahydrofuran (0.22M in azetidinone) was cooled to -78°C and mixed with lithium bis(trimethylsilyl)amide (2.2 equivalents). The resulting anion was treated with the appropriate acyl halide (1.1 equivalents). After complete conversion of the azetidinone, the reaction was quenched with saturated aqueous ammonium chloride and partitioned between ethyl acetate and water. The organic phase was washed successively with 1N. hydrochloric acid, saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride. The resulting organic phase was dried (magnesium sulfate) and evaporated. The residue was purified by silica gel chromatography with an appropriate eluent such as hexane/ethyl acetate 3:2.

Example 17 2,2,2-Trichloroethyl-2(RS)-(tert-butoxycarbonyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-on-3-yl)-4(R )-(2-styryl)azetidin-2-one-1-yl]acetate.

Using the procedure of Example 16, 9.0 g (20 mmol) of the compound of Example 15 was acylated with 4.2 g (20 mmol) of trichloroethyl chloroformate to give 7.0 g (56%) of the compound of Example 17; So pl. 176-178°C.

Example 18 2(RS)-(T-butoxycarbonyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-one-3-yl)-4(R)-(2-styryl)azetidium -2-on-1-yl]acetic acid N-(3-trifluoromethylbenzyl)amide. A solution of 0.20 g (0.32 mmol) of the compound from Example 17 and 52 μl (0.36 mmol) of (3-trifluoromethylbenzyl)amine in THF was heated under reflux. After complete conversion (TLC), the solvent was evaporated and the residue was recrystallized (chloroform/hexane) to give 0.17 g (82%) of the compound from Example 18 as a white solid; So pl. 182-184°C.

Example 18A. 2(RS)-(T-butoxycarbonyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-one-3-yl)-4(R)-(2-styryl)azetidine-2- on-1-yl]acetic acid N-(2-fluoro-3-trifluoromethylbenzyl)amide. The compound from Example 18A was prepared according to the procedure of Example 18 using 2-fluoro-3-(trifluoromethyl)benzylamine instead of (3-trifluoromethylbenzyl)amine. The compound from Example 18A was obtained as a white solid (140 mg, 41%) and showed a ¹ H NMR spectrum consistent with the established structure.

The compound of Examples 19-25AF was prepared according to the procedure of Example 14, with the corresponding amino acid derivative and aldehyde used in Step 1 and the corresponding acetyl chloride used in Step 2.

Example 19 2(S)-(T-butoxycarbonylmethyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-one-3-yl)-4(R)-(2-styryl)azetidine -2-on-1-yl]acetic acid N-(3-trifluoromethylbenzyl)amide. An imine prepared from 1.52 g (4.39 mmol) of L-aspartic acid β-tert-butyl ester of α-(3-trifluoromethyl)benzylamide and cinnamic aldehyde was mixed with 2-(4(S)-phenyloxazolidin-2- on-3-yl)acetyl chloride (Example 1) to give 2.94 g of an orange-brown oil, from which, after purification by flash column chromatography (hexanes/ethyl acetate 70:30) 2.06 g (70%), compounds from Example 19 as a white solid; ¹ H NMR (CDCl ₃ ) δ 1.39 (s, 9H); 2.46 (dd, J=11.1 Hz, J=16.3 Hz, 1H); 3.18 (dd, J=3.8 Hz, J=16.4 Hz, 1H); 4.12-4.17 (m, 1H); 4.26 (d, J=5.0 Hz, 1H); 4.45 (dd, J=6.0 Hz, J=14.9 Hz, 1H); 4.54 (dd, J=5.3 Hz, J=9.8 Hz, 1H); 4.58-4.66 (m, 3H); 4.69-4.75 (m, 1H); 4.81 (dd, J=3.8 Hz, J=ll, l Hz, 1H); 6.25 (dd, J=9.6 Hz, J=15.8 Hz, 1H); 6.70 (d, J=15.8 Hz, 1H); 7.14-7.17 (m, 2H); 7.28-7.46 (m, 11H); 7.62 (s, 1H); 8.27-8.32 (m, 1H).

Example 19A. 2(S)-(T-butoxycarbonylmethyl)-2-[3(R)-(4(R)-phenyloxazolidin-2-one-3-yl)-4(S)-(2-styryl)azetidine-2- on-1-yl]acetic acid N-(3-trifluoromethylbenzyl)amide. The compound from Example 19A was obtained in accordance with the method of Example 19, except that 2-(4(R)-phenyloxazolidin-2-on-3-yl)acetyl chloride (Example 1A) was used instead of 2-(4(S)- phenyloxazolidin-2-on-3-yl)acetyl chloride. The compound from Example 19A was obtained as a white solid (41 mg, 13%); ¹ H NMR (CDCl ₃ ) δ 1.37 (s, 9H); 3.11 (dd, J=3.7 Hz, J=17.8 Hz, 1H); 3.20 (dd, H=10.6 Hz, J=17.8 Hz, 1H); 4.02 (dd, J=3.7 Hz, J=10.6 Hz, 1H); 4.10-4.17 (m, 1H); 4.24 (d, J=4.9 Hz, 1H); 4.4652-4.574 (dd, H=5.9 Hz, H=15.1 Hz, 1H); 4.58-4.76 (m, 4H); 6.27 (dd, J=9.6Hz, J=15.8Hz, 1H); 6.79 (d, J=15.8 Hz, 1H); 7.23-7.53 (m, 13H); 7.63(s, 1H); 8.51-8.55 (m, 1H).

Example 20 2(S)-(T-butoxycarbonylethyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-one-3-yl)-4(R)-(2-styryl)azetidine -2-on-1-yl]acetic acid N-(3-trifluoromethylbenzyl)amide. An imine prepared from 3.94 g (10.93 mmol) of L-glutamic acid γ-tert-butyl ester of α-(3-trifluoromethyl)benzylamide and cinnamic aldehyde was mixed with 2-(4(S)-phenyloxazolidin-2- on-3-yl)acetyl chloride (Example 1) to give 5.53 g (75%) of the compound from Example 20 after purification by flash column chromatography (hexanes/ethyl acetate 70:30); ¹ H NMR (CDCl ₃ ) δ 1.36 (s, 9H); 1.85-1.96 (m, 1H); 2.18-2.49 (m, 3H); 4.14-4.19 (m, 1H); 4.30 (d, Γ=4.9 Hz, 2H); 4.44 (dd, 3=6.1 Hz, J=14.9 Hz, 1H); 4.56-4.67 (m, 4H); 4.71-4.75 (m, 1H); 6.26 (dd, J=9.6 Hz, J=15.8 Hz, 1H); 6.71 (d, J=15.8 Hz, 1H); 7.16-7.18 (m, 2H); 7.27-7.49 (m, 11H); 7.60(s, 1H); 8.08-8.12 (m, 1H).

Example 21 2(S)-(T-butoxycarbonylmethyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-one-3-yl)-4(R)-(2-styryl)azetidine -2-on-1-yl]acetic acid N-[4-(2-phenylethyl)]piperazinamide. An imine prepared from 4.20 g (11.6 mmol) of L-aspartic acid β-tert-butyl ester of α-[4-(2-phenylethyl)]piperazinamide and cinnamaldehyde was mixed with 2-(4(S)- phenyloxazolidin-2-one-3-yl)acetyl chloride (Example 1) to give 4.37 g (55%) of the compound from Example 21 after purification by flash column chromatography (hexanes/ethyl acetate 50:50); ¹ H NMR (CDCl ₃ ) δ 1.34 (s, 9H); 2.26-2.32 (m, 1H); 2.46-2.63 (m, 4H); 2.75-2.89 (m, 4H); 3.24-3.32 (m, 1H); 3.49-3.76 (m, 3H); 4.07-4.13 (m, 1H); 4.30 (d, Γ=4.6 Hz, 1H); 4.22-4.48 (m, 1H); 4.55-4.61 (m, 1H); 4.69-4.75 (m, 1H); 5.04-5.09 (m, 1H); 6.15 (dd, H=9.3 Hz, H=15.9 Hz, 1H); 6.63 (d, Γ=15.8 Hz, 1H); 7.18-7.42 (m, 15H).

Example 22 2(S)-(T-butoxycarbonylethyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-one-3-yl)-4(R)-(2-styryl)azetidine -2-on-1-yl]acetic acid N-[4-(2-phenylethyl)]piperazinamide. An imine prepared from 2.54 g (6.75 mmol) of L-glutamic acid γ-tert-butyl ester α-[4-(2-phenylethyl)]piperazinamide and cinnamaldehyde was mixed with 2-(4(S)- phenyloxazolidin-2-one-3-yl)acetyl chloride (Example 1) to give 3.55 g (76%) of the compound from Example 22 after purification by flash column chromatography (hexanes/ethyl acetate 50:50); 1H NMR (CDCl ₃ ) δ 1.32 (s, 9H); 1.96-2.07 (m, 1H); 2.15-2.44 (m, 6H); 2.54-2.62 (m, 2H); 2.69-2.81 (m, 3H); 3.28-3.34 (m, 1H); 3.59-3.68 (m, 1H); 4.08-4.13 (m, 1H); 4.33-4.44 (m, 2H); 4.48-4.60 (m, 2H); 4.67-4.77 (m, 1H); 6.14 (dd, J=8.9 Hz, J=16.0 Hz, 1H); 6.62 (d, J=16.0 Hz, 1H); 7.16-7.42 (m, 15H).

Example 23 2(R)-(T-butoxycarbonylmethyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-one-3-yl)-4(R)-(2-styryl)azetidine -2-on-1-yl]acetic acid N-(3-trifluoromethylbenzyl)amide. An imine prepared from 0.973 g (2.81 mmol) of D-aspartic acid β-tert-butyl ester of α-(3-trifluoromethyl)benzylamide and cinnamic aldehyde was mixed with 2-(4(S)-phenyloxazolidin-2-one- 3-yl)acetyl chloride (Example 1) to give 1.53 g (82%) of the compound from Example 23 after purification by flash column chromatography (hexanes/ethyl acetate 70:30); ¹ H NMR (CDCl ₃ ) δ 1.37 (s, 9H); 3.10 (dd, J=3.7 Hz, J=17.8 Hz, 1H); 3.20 (dd, J=10.7 Hz, J=17.8 Hz, 1H); 4.02 (dd, H=3.6 Hz, J=10.6 Hz, 1H); 4.11-4.17 (m, 1H); 4.24 (d, J=4.9 Hz, 1H); 4.46 (dd, J=5.8 Hz, J=15.1 Hz, 1H); 4.58-4.67 (m, 3H); 4.70-4.76 (m, 1H); 6.27 (dd, J=9.5 Hz, J=15.8 Hz, 1H); 6.79 (d, J=15.8 Hz, 1H); 7.25-7.50 (m, 13H); 7.63 (s, 1H); 8.50-8.54 (m, 1H).

Example 23A. 2(R)-(T-butoxycarbonylmethyl)-2-[3(R)-(4(R)-phenyloxazolidin-2-one-3-yl)-4(S)-(2-styryl)azetidine-2- on-1-yl]acetic acid N-(3-trifluoromethylbenzyl)amide. The compound from Example 23A was prepared according to the method of Example 23 except that 2-(4(R)-phenyloxazolidin-2-one-3-yl)acetyl chloride (Example 1A) was used instead of 2-(4(S)-phenyloxazolidine -2-on-3-yl)acetyl chloride. The compound from Example 23A was obtained as a white solid (588 mg, 49%); ¹ H NMR (CDCl ₃ ) δ 1.39 (s, 9H); 2.47 (dd, J=11.2 Hz, J=16.3 Hz, 1H); 3.18 (dd, J=3.8 Hz, J=16.3 Hz, 1H); 4.15 (t, J=8.25, Hz 1H); 4.26 (d, Γ=5.0 Hz, 1H); 4.45 (dd, J=6.0 Hz, J=15.0 Hz, 1H); 4.52-4.57 (m, 3H); 4.63 (t, J=9 Hz, 1H); 4.70 (t, J=8 Hz, 1H); 4.81 (dd, J=3.8 Hz, J=10.8 Hz, 1H); 6.25 (dd, J=9.8 Hz, J=15.8 Hz, 1H); 6.70 (d, J=15.8 Hz, 1H); 7.15-7.17 (m, 2H); 7.27-7.51(m, 11H); 7.62 (s, 1H); 8.27-8.32 (m, 1H).

Example 24 2(R)-(T-butoxycarbonylethyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-one-3-yl)-4(R)-(2-styryl)azetidine -2-on-1-yl]acetic acid N-(3-trifluoromethylbenzyl)amide. An imine prepared from 1.15 g (3.20 mmol) of D-glutamic acid γ-tert-butyl ester of α-(3-trifluoromethyl)benzylamide and cinnamic aldehyde was mixed with 2-(4(S)-phenyloxazolidin-2- on-3-yl)acetyl chloride (Example 1) to give 1.84 g (85%) of the compound from Example 24 after purification by flash column chromatography (hexanes/ethyl acetate 70:30); ¹ H NMR (CDCl ₃ ) δ 1.37 (s, 9H); 2.23-2.39 (m, 4H); 3.71-3.75 (m, 1H); 4.13-4.18 (m, 1H); 4.31 (d, J=4.9 Hz, 1H); 4.44-4.51 (m, 2H); 4.56-4.68 (m, 2H); 4.71-4.76 (m, 1H); 6.26 (dd, J=9.5 Hz, J=15.8 Hz, 1H); 6.71 (d, J=15.8 Hz, 1H); 7.25-7.52 (m, 13H); 7.63(s, 1H); 8.25-8.30 (m, 1H).

Example 25 2(S)-(T-butoxycarbonylethyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-one-3-yl)-4(R)-(2-styryl)azetidine -2-on-1-yl]acetic acid N-(4-cyclohexyl)piperazinamide. An imine prepared from 2.58 g (5.94 mmol) of L-glutamic acid γ-tert-butyl ester of a-(4-cyclohexyl)piperazinamide and cinnamaldehyde was mixed with 2-(4(S)-phenyloxazolidin-2- on-3-yl)acetyl chloride (Example 1) to give 3.27 g (94%) of the compound from Example 25 after purification by flash column chromatography (dichloromethane/methanol 95:5); ¹ H NMR (CDCl ₃ ) δ 1.32 (s, 9H); 1.10-1.18 (m, 1H); 1.20-1.31 (m, 2H); 1.38-1.45 (m, 2H); 1.61-1.66 (m, 1H); 1.84-1.89 (m, 2H); 1.95-2.01 (m, 1H); 2.04-2.14 (m, 3H); 2.20-2.24 (m, 1H); 2.29-2.35 (m, 1H); 2.85-2.92 (m, 1H); 3.24-3.32 (m, 1H); 3.36-3.45 (m, 2H); 3.80-3.86 (m, 1H); 4.08 (t, J=8.3 Hz, 1H); 4.27 (d, J=5.0 Hz, 1H); 4.31-4.55 (m, 4H); 4.71 (t, J=8.3 Hz, 1H); 4.83-4.90 (m, 1H); 6.18 (dd, J=9.1 Hz, J=15.9 Hz, 1H); 6.67 (d, J=15.9 Hz, 1H); 7.25-7.44 (m, 10H); 8.22 (brs, 1H).

Example 25 A. tert-Butyl-2(S)-(2-(4-cyclohexylpiperazinylcarbonyl)ethyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-one-3-yl)-4 (R)-(2-styryl)azetidin-2-on-1-yl]acetate. An imine prepared from 1.282 g (3.63 mmol) of L-glutamic acid α-tert-butyl ester of γ-(4-cyclohexyl)piperazinamide and cinnamaldehyde was mixed with 2-(4(S)-phenyloxazolidin-2-one- 3-yl)acetyl chloride (Example 1) to give 1.946 g (80%) of the compound from Example 25A after purification by flash column chromatography (hexanes/ethyl acetate 50:50); ¹ H NMR (CDCl ₃ ) δ 1.15-1.26 (m, 6H); 1.39 (s, 9H); 1.55-1.64 (m, 2H); 1.77-1.83 (m, 3H); 2.22-2.35 (m, 2H); 2.40-2.50 (m, 6H); 2.75-2.79 (m, 1H); 3.43-3.48 (m, 1H); 3.56-3.60 (m, 2H); 3.75-3.79 (m, 1H); 4.10 (t, J=8.3 Hz, 1H); 4.31-4.35 (m, 2H); 4.58 (t, J=8.8 Hz, 1H); 4.73 (t, J=8.4 Hz, 1H); 6.17 (dd, J=8.6 Hz, J=16.0 Hz, 1H); 6.65 (d, J=16.0 Hz, 1H); 7.27-7.42 (m, 10H).

Example 25V. 2(R)-(T-butoxycarbonylmethyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-one-3-yl)-4(R)-(2-styryl)azetidine-2- on-1-yl]acetic acid N-(2-fluoro-3-trifluoromethylbenzyl)amide. An imine prepared from 0.256 g (0.70 mmol) of D-aspartic acid β-tert-butyl ester of α-(2-fluoro-3-trifluoromethyl)benzylamide and cinnamic aldehyde was mixed with 2-(4(S)-phenyloxazolidin- 2-on-3-yl)acetyl chloride (Example 1) to give 0.287 g (60%) of the compound from Example 25B after purification by flash column chromatography (hexanes/ethyl acetate 70:30); ¹ H NMR (CDCl ₃ ) δ 1.38 (s, 9H); 3.12 (dd, J=4.0 Hz, J=17.8 Hz, 1H); 3.20 (dd, J=10.4 Hz, J=17.8 Hz, 1H); 4.05 (dd, J=3.9 Hz, J=10.4 Hz, 1H); 4.14 (dd, J=J'=8.2 Hz, 1H); 4.25 (d, J=4.9 Hz, 1H); 4.59-4.67 (m, 4H); 4.74 (t, J=8.3 Hz, 1H); 6.36 (dd, J=9.6 Hz, J=15.8 Hz, 1H); 6.83 (d, J=15.8 Hz, 1H); 7.02-7.07 (m, 1H); 7.28-7.55 (m, 12H); 8.44-8.48 (m, 1H).

Example 25C. 2(R)-(T-butoxycarbonylmethyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-one-3-yl)-4(R)-(2-styryl)azetidine-2- on-1-yl]acetic acid N-[(S)-α-methylbenzyl]amide. An imine prepared from 0.167 g (0.57 mmol) of D-aspartic acid β-tert-butyl ester [(S)-α-methylbenzyl]amide and cinnamic aldehyde was mixed with 2-(4(S)-phenyloxazolidin-2- on-3-yl)acetyl chloride (Example 1) to give 0.219 g (63%) of the compound from Example 25C after purification by flash column chromatography (hexanes/ethyl acetate 70:30); ¹ H NMR (CDCl ₃ ) δ 1.35 (s, 9H); 1.56 (d, J=7.0 Hz, 3H); 2.97 (dd, J=3.5 Hz, J=18.0 Hz, 1H); 3.15 (dd, J=11.0 Hz, J=17.5 Hz, 1H); 4.01 (dd, J=3.0 Hz, J=11.0 Hz, 1H); 4.14 (t, J=8.5 Hz, 1H); 4.24 (d, J=5.0 Hz, 1H); 4.57 (dd, J=5.0 Hz, J=9.5 Hz, 1H); 4.64 (t, J=8.8 Hz, 1H); 5.07 (t, J=8.5 Hz, 1H); 5.03-5.09 (m, 1H); 6.43 (dd, J=9.5 Hz, J=16.0 Hz, 1H); 6.83 (d, J=16.0 Hz, 1H); 7.16-7.20 (m, 1H); 7.27-7.49 (m, 14H); 8.07-8.10 (m, 1H).

Example 25D. 2(R)-(T-butoxycarbonylmethyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-one-3-yl)-4(R)-(2-styryl)azetidine-2- on-1-yl]acetic acid N-[(R)-α-methylbenzyl]amide. An imine prepared from 0.187 g (0.46 mmol) of D-aspartic acid β-tert-butyl ester [(R)-α-methylbenzyl]amide and cinnamic aldehyde was mixed with 2-(4(S)-phenyloxazolidin-2- on-3-yl)acetyl chloride (Example 1) to give 0.25 g (64%) of the compound from Example 25D after purification by flash column chromatography (hexanes/ethyl acetate 70:30); ¹ H NMR (CDCl ₃ ) δ 1.36 (s, 9H); 1.59 (d, J=7.1 Hz, 3H); 3.10 (dd, J=3.5 Hz, J=17.8 Hz, 1H); 3.22 (dd, J=10.9 Hz, J=17.8 Hz, 1H); 3.93 (dd, J=3.5 Hz, J=10.8 Hz, 1H); 4.14 (t, J=8.1 Hz, 1H); 4.24 (d, J=5.0 Hz, 1H); 4.58 (dd, J=5.0 Hz, J=9.5 Hz, 1H); 4.65 (t, J=8.7 Hz, 1H); 4.74 (t, J=8.2 Hz, 1H); 5.06-5.14 (m, 1H); 6.32 (dd, J=9.5 Hz, J=15.8 Hz, 1H); 6.74 (d, J=15.8 Hz, 1H); 7.19-7.43 (m, 15H); 8.15-8.18 (m, 1H).

Example 25E. 2(R)-(T-butoxycarbonylmethyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-one-3-yl)-4(R)-(2-styryl)azetidine-2- on-1-yl]acetic acid N-methyl-N-(3-trifluoromethylbenzyl)amide. An imine prepared from 0.195 g (0.41 mmol) of D-aspartic acid β-tert-butyl ester of α-[N-methyl-N-(3-trifluoromethylbenzyl)]amide and cinnamaldehyde was mixed with 2-(4(S )-phenyloxazolidin-2-one-3-yl)acetyl chloride (Example 1) to give 0.253 g (69%) of the compound from Example 25E after purification by flash column chromatography (hexanes/ethyl acetate 70:30); ¹ H NMR (CDCl ₃ ) δ 1.36 (s, 9H); 2.53 (dd, J=4.0 Hz, J=17.0 Hz, 1H); 3.06 (dd, J=10.8 Hz, J=16.8 Hz, 1H); 3.13 (s, 3H); 4.12 (dd, J=8.0 Hz, J=9.0 Hz, 1H); 4.26 (d, J=5.0 Hz, 1H); 4.38 (d, J=15.0 Hz, 1H); 4.46 (dd, J=5.0 Hz, J=9.5 Hz, 1H); 4.56 (t, J=6.8 Hz, 1H); 4.70-4.79 (m, 2H); 5.27 (dd, J=4.0 Hz, J=11.0 Hz, 1H); 6.22 (dd, J=9.3 Hz, J=15.8 Hz, 1H); 6.73 (d, J=15.8 Hz, 1H); 7.33-7.45 (m, 14H).

Example 25F. 2(S)-(T-butoxycarbonylethyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-on-3-yl)-4(R)-(2-chlorostyr-2-yl) azetidin-2-on-1-yl]acetic acid N-(3-trifluoromethylbenzyl)amide. An imine prepared from 1.62 g (4.44 mmol) of L-glutamic acid γ-tert-butyl ester of α-(3-trifluoromethyl)benzylamide and α-chlorocinnamic aldehyde was mixed with 2-(4(S)-phenyloxazolidin- 2-on-3-yl)acetyl chloride (Example 1) to give 0.708 g (22%) of the compound from Example 25F after purification by flash column chromatography (hexanes/ethyl acetate 70:30); ¹ H NMR (CDCl ₃ ) δ 1.35 (s, 9H); 1.68 (brs, 1H); 2.19-2.35 (m, 2H); 2.40-2.61 (m, 2H); 4.13 (dd, J=7.5 Hz, J=9.0 Hz, 1H); 4.22 (t, J=7.0 Hz, 1H); 4.34 (d, J=4.5 Hz, 1H); 4.45 (dd, J=5.5 Hz, J=15.0 Hz, 1H); 4.51-4.60 (m, 3H); 4.89 (dd, H=7.5 Hz, H=8.5 Hz, 1H); 6.89 (s, 1H); 7.28-7.54 (m, 14H).

Example 25G. 2(R)-(T-butoxycarbonylmethyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-one-3-yl)-4(R)-(2'-methoxystyr-2-yl )azetidin-2-on-1-yl]acetic acid N-(3-trifluoromethylbenzyl)amide. An imine prepared from 0.34 g (0.98 mmol) of D-aspartic acid β-tert-butyl ester of α-(3-trifluoromethylbenzyl)amide and 2'-methoxycinnamic aldehyde was mixed with 2-(4(S)-phenyloxazolidine -2-on-3-yl)acetyl chloride (Example 1) to give 0.402 g (59%) of the compound from Example 25G after purification by flash column chromatography (hexanes/ethyl acetate 70:30); ¹ H NMR (CDCl ₃ ) δ 1.35 (s, 9H); 1.68 (brs, 1H); 2.19-2.35 (m, 2H); 2.40-2.61 (m, 2H); 4.13 (dd, J=7.5 Hz, J=9.0 Hz, 1H); 4.22 (t, J=7.0 Hz, 1H); 4.34 (d, J=4.5 Hz, 1H); 4.45 (dd, J=5.5 Hz, J=15.0 Hz, 1H); 4.51-4.60 (m, 3H); 4.89 (dd, H=7.5 Hz, H=8.5 Hz, 1H); 6.89 (s, 1H); 7.28-7.54 (m, 14H).

Example 25H. tert-Butyl-(2R)-(benzyloxymethyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-one-3-yl)-4(R)-(2-styryl)azetidine-2 -on-1-yl]acetate. An imine prepared from 0.329 g (1.31 mmol) of O-(benzyl)-D-serine tert-butyl ether (Example 5B) and cinnamaldehyde was mixed with 2-(4(S )-phenyloxazolidin-2-on-3-yl)acetyl chloride (Example 1) to give 0.543 g (73%) of the compound from Example 25H after purification by flash column chromatography (hexanes/ethyl acetate 90:10); ¹ H NMR (CDCl ₃ ) δ 1.39 (s, 9H); 3.56 (dd, J=2.7 Hz, J=9.5 Hz, 1H); 3.82 (dd, J=4.8 Hz, J=9.5 Hz, 1H); 4.11 (t, J=8.3 Hz, 1H); 4.21-4.29 (m, 2H); 4.50-4.58 (m, 3H); 4.71-4.78 (m, 2H); 6.19 (dd, J=9.1 Hz, J=16.0 Hz, 1H); 6.49 (d, J=16.0 Hz, 1H); 7.07-7.11 (m, 1H); 7.19-7.40 (m, 14H).

Example 251 tert-Butyl-2(S)-(2-(4-cyclohexylpiperazinylcarbonyl)methyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-one-3-yl)-4( R)-(2-styryl)azetidin-2-one-1-yl]acetate. An imine prepared from 0.3 g (0.88 mmol) of L-aspartic acid α-tert-butyl ester of γ-(4-cyclohexyl)piperazinamide and cinnamic aldehyde was mixed with 2-(4(S)-phenyloxazolidin-2- on-3-yl)acetyl chloride (Example 1) to give 464 mg (80%) of the compound from Example 251 as a white solid after purification by flash column chromatography (hexanes/ethyl acetate 50:50). The compound from Example 251 showed a ¹ H NMR spectrum consistent with the established structure.

Example 25J. Tert-butyl-3(R)-[3(S)-(4(S)-phenyloxazolidin-2-one-3-yl)-3-methyl-4(R)-(sty-2-yl)azetidine- 2-on-1-yl]-3-[(3-trifluoromethyl)phenylmethylaminocarbonyl]propanoate. Imine prepared from 0.307 g (0.89 mmol) D-aspartic acid β-tert-butyl ester α-(3-trifluoromethyl) benzylamide (Example 20) and cinnamaldehyde, mixed with 2-(4(S)-phenyloxazolidin-2-one-3-yl)propanoyl chloride (Example 1E) to give 120 mg (20%) after purification by flash column chromatography ( 70% hexanes/30% EtOAc); ¹ H NMR (CDCl ₃ ) δ 1.25 (s, 3H), 1.38 (s, 9H); 3.09 (dd, J=3.0 Hz, J=18.0 Hz, 1H); 3.33 (dd, J=12.5 Hz, J=18.0 Hz, 1H); 4.01 (dd, J=3.0 Hz, J=11.5 Hz, 1H); 4.04 (dd, J=3.5 Hz, J=8.8 Hz, 1H); 4.42 (d, Γ=9.0 Hz, 1H); 4.45-4.51 (m, 3H); 4.61-4.66 (m, 1H); 4.75 (dd, J=3.5 Hz, J=8.5 Hz, 1H); 6.23 (dd, J=9.0 Hz, J=15.5 Hz, 1H); 6.78 (d, J=15.5 Hz, 1H); 7.23-7.53 (m, 13H); 7.64(s, 1H).

Example 25K. 2(R)-(Tert-butoxycarbonylmethyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-on-3-yl)-4(R)-(prop-1-enyl)azetidine- 2-on-1-yl]acetic acid N-(3-trifluoromethylbenzyl)amide. An imine prepared from 0.289 g (0.83 mmol) of D-aspartic acid β-tert-butyl ester of α-(3-trifluoromethyl)benzylamide and crotonic aldehyde was mixed with 2-(4(S)-phenyloxazolidin-2-one- 3-yl)acetyl chloride (Example 1) to give 381 mg (76%) of the compound from Example 25K after purification by flash column chromatography (CH ₂ Cl ₂ /MeOH 99:1); ¹ H NMR (CDCl ₃ ) δ 1.36 (s, 9H), 1.69 (dd, 3=2 Hz, J=6.5 Hz, 3H); 3.08 (dd, J=3.3 Hz, J=17.8 Hz, 1H); 3.18 (dd, J=11 Hz, J=17.5 Hz, 1H); 3.94 (dd, J=3.5 Hz, J=11 Hz, 1H); 4.12 (d, Γ=5 Hz, 1H); 4.15 (dd, J=7 Hz, J=8 Hz, 1H); 4.35 (dd, J=4.8 Hz, D=9.8 Hz, 1H); 4.44 (dd, J=6Hz, J=15Hz, 1H); 4.61 (dd, J=6Hz, J=15Hz, 1H); 4.67-4.75 (m, 2H); 5.52-5.58 (m, 1H); 5.92-6.00 (m, 1H); 7.33-7.60 (m, 9H); 8.47-8.50 (m, 1H).

Example 25O. Methyl-2(S)-(tert-butoxycarbonylethyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-on-3-yl)-4(R)-(2-styryl)azetidine- 2-on-1-yl]acetate. Imine prepared from 433 mg (1.99 mmol) of D-glutamic acid γ-tert-butyl ester of α-methyl ester and cinnamaldehyde was mixed with 2-(4(S)-phenyloxazolidin-2-one-3-yl) acetyl chloride (Example 1) to give 682 mg (64%) of the compound from Example 250 after purification by flash column chromatography (hexanes/ethyl acetate 70:30); ¹ H NMR (CDCl ₃ ) δ 1.32 (s, 9H); 2.10-2.26 (m, 1H); 2.30-2.41 (m, 3H); 3.66 (s, 3H); 3.95-3.99 (m, 1H); 4.16 (dd, J=7.5 Hz, G=9 Hz, 1H); 4.38 (dd, J=5 Hz, J=9 Hz, 1H); 4.55 (d, J=5 Hz 1H); 4.61 (t, J=9 Hz, 1H); 4.86 (dd, J=7.5 Hz, J=9 Hz, 1H); 6.00 (dd, J=9Hz, J=16Hz, 1H); 6.60 (d, 3=16Hz, 1H); 7.26-7.43 (m, 10H).

Example 25M. tert-Butyl-2(S)-(methoxycarbonylethyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-on-3-yl)-4(R)-(2-styryl)azetidine- 2-on-1-yl]acetate. Imine prepared from 428 mg (1.97 mmol) of L-glutamic acid γ-tert-butyl ester of α-methyl ester and cinnamaldehyde was mixed with 2-(4(S)-phenyloxazolidin-2-one-3-yl) acetyl chloride (Example 1) to give 864 mg (82%) of the compound from Example 25M after purification by flash column chromatography (hexanes/ethyl acetate 70:30); ¹ H NMR (CDCl ₃ ) δ 1.40 (s, 9H); 2.12-2.27 (m, 1H); 2.32-2.55 (m, 3H); 3.50 (s, 3H); 3.72 (dd, J=4.6 Hz, J=10.4 Hz, 1H); 4.12-4.17 (m, 1H); 4.34 (dd, J=5 Hz, J=9 Hz, 1H); 4.50 (d, J=5 Hz, 1H); 4.60 (t, J=8.9 Hz, 1H); 4.81-4.86 (m, 1H); 6.06 (dd, J=9Hz, J=16Hz, 1H); 6.59 (d, J=16 Hz, 1H); 7.25-7.42 (m, 10H).

Example 25p. Methyl-2(S)-(tert-butoxycarbonylmethyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-on-3-yl)-4(R)-(2-styryl)azetidine- 2-on-1-yl]acetate. Imine prepared from 424 mg (2.09 mmol) of L-aspartic acid γ-tert-butyl ester of α-methyl ester and cinnamaldehyde was mixed with 2-(4(S)-phenyloxazolidin-2-one-3-yl) acetyl chloride (Example 1) to give 923 mg (85%) of the compound from Example 25P after recrystallization from CH ₂ Cl ₂ /hexanes; ¹ H NMR (CDCl ₃ ) δ 1.41 (s, 9H); 2.77 (dd, J=7.5 Hz, J=16.5 Hz, 1H); 3.00 (dd, J=7 Hz, J=16.5 Hz, 1H); 4.16 (dd, J=7.5 Hz, J=9 Hz, 1H); 4.41-48(m, 2H); 4.55 (d, J=5 Hz, 1H); 4.60 (t, J=8.8 Hz, 1H); 4.86 (dd, J=7.5 Hz, J=9 Hz, 1H); 5.93 (dd, J=9.5 Hz, J=15.5 Hz, 1H); 6.61 (d, J=15.5 Hz, 1H); 7.25-7.43 (m, 10H).

Example 25L. 2(R)-(T-butoxycarbonylmethyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-one-3-yl)-4(R)-(2-styryl)azetidine-2- on-1-yl]acetic acid N-[(R)-1-(3-trifluoromethylphenyl)ethyl]amide. An imine prepared from 160 mg (0.44 mmol) of D-aspartic acid β-tert-butyl ester α-[(R)-1-(3-trifluoromethylphenyl)ethyl]amide and cinnamic aldehyde was mixed with 2-(4( S)-phenyloxazolidin-2-on-3-yl)acetyl chloride (Example 1) to give 166 mg (55%) of the compound from Example 25L after purification by flash column chromatography (hexanes/EtOAc 70:30). The compound from Example 25L showed a ¹ H NMR spectrum consistent with the established structure.

Example 25N. 2(R)-(T-butoxycarbonylmethyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-one-3-yl)-4(R)-(2-styryl)azetidine-2- on-1-yl]acetic acid N-[(S)-1-(3-trifluoromethylphenyl)ethyl]amide. An imine prepared from 120 mg (0.22 mmol) of D-aspartic acid β-tert-butyl ester α-[(S)-1-(3-trifluoromethylphenyl)ethyl]amide and cinnamic aldehyde was mixed with 2-(4( S)-phenyloxazolidin-2-on-3-yl)acetyl chloride (Example 1) to give 75 mg (50%) of the compound from Example 25N after purification by flash column chromatography (hexanes/EtOAc 70:30). The compound from Example 25N showed a ¹ H NMR spectrum consistent with the established structure.

Example 25Q. Methyl-2(R)-(2-(3-trifluoromethylbenzyl)aminocarbonyl)ethyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-on-3-yl)-4(R)- (2-styryl)azetidin-2-on-1-yl]acetate. An imine prepared from 517 mg (1.62 mmol) of D-glutamic acid α-methyl ester of γ-(3-trifluoromethyl)benzylamide and cinnamic aldehyde was mixed with 2-(4(S)-phenyloxazolidin-2-one-3- yl)acetyl chloride (Example 1) to give 527 mg (51%) of the compound from Example 25Q after purification by flash column chromatography (hexanes/EtOAc 50:50). The compound from Example 25Q showed a ¹ H NMR spectrum consistent with the established structure.

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

Example 25AF. tert-Butyl-2(S)-(2-(3-trifluoromethylbenzyl)aminocarbonyl)ethyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-on-3-yl)-4(R )-(2-styryl)azetidin-2-one-1-yl]acetate.

Example 26 General procedure for the hydrolysis of tert-butyl ether. A solution of the tert-butyl ester derivative in formic acid, typically 1 g in 10 ml, was stirred at ambient temperature until the ester was no longer detectable by thin layer chromatography (dichloromethane 95%/methanol 5%), the usual reaction time is approx. 3 hours. Formic acid was evaporated under reduced pressure; the resulting solid was partitioned between dichloromethane and saturated aqueous sodium bicarbonate. The organic phase is evaporated to give an off-white solid which can be used directly for subsequent reactions or recrystallized from an appropriate solvent system if necessary.

Compounds from examples 27-34AE were prepared from the corresponding tert-butyl ether according to the procedure used in Example 26.

Example 27 2(R,S)-(Carboxy)-2-[3(S)-(4(S)-phenyloxazolidin-2-on-3-yl)-4(R)-(2-styryl)azetidine -2-on-1-yl]acetic acid N-(3-trifluoromethylbenzyl)amide.

The compound from Example 18 (0.30 g, 0.46 mmol) was hydrolyzed to give 0.27 g (quantitative) of the compound from Example 27 as an off-white solid; ¹ H NMR (CDCl ₃ ) δ 4.17-5.28 (m, 9H); 6.21-6.29 (m, 1H), 6.68-6.82 (m, 1H); 7.05-7.75 (m, 13H); 9.12-9.18 (m, 1H).

Example 28 2(S)-(Carboxymethyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-one-3-yl)-4(R)-(2-styryl)azetidine-2 -on-1-yl]acetic acid N-(3-trifluoromethylbenzyl)amide. The compound from Example 19 (1.72 g, 2.59 mmol) was hydrolyzed to give 1.57 g (quantitative) of the compound from Example 28 as an off-white solid; ¹ H NMR (CDCl ₃ ) δ 2.61 (dd, J=9.3 Hz, J=16.6 Hz, 1H); 3.09-3.14 (m, 1H); 4.10-4.13 (m, 1H); 4.30 (d, J=4.5 Hz, 1H); 4.39-4.85 (m, 6H); 6.20 (dd, H=9.6 Hz, H=15.7 Hz, 1H); 6.69 (d, J=15.8 Hz, 1H); 7.12-7.15 (m, 2H); 7.26-7.50 (m, PN); 7.61 (s, 1H); 8.41-8.45 (m, 1H).

Example 28A. 2(S)-(Carboxymethyl)-2-[3(R)-(4(K)-phenyloxazolidin-2-on-3-yl)-4(S)-(2-styryl)azetidin-2-on- 1-yl]acetic acid N-(3-trifluoromethylbenzyl)amide. The compound from Example 19A (41 mg, 0.06 mmol) was hydrolyzed to give 38 mg (quantitative yield) of the compound from Example 28A as an off-white solid; ¹ H NMR (CDCl ₃ ) δ 2.26 (d, J=7 Hz, 1H); 4.03 (t, J=7 Hz, 1H); 4.16 (t, J=8 Hz, 1H); 4.26 (d, J=4.3 Hz, 1H); 4.46 (dd, J=5.7Hz, J=15,l, 1H); 4.53-4.75 (m, 5H); 6.25 (dd, J=9.5 Hz, D=15.7 Hz, 1H); 6.77 (d, J=15.7 Hz, 1H); 7.28-7.53 (m, 13H); 7.64(s, 1H); 8.65-8.69 (m, 1H).

Example 29 2(S)-(Carboxyethyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-one-3-yl)-4(R)-(2-styryl)azetidine-2 -on-1-yl]acetic acid N-(3-trifluoromethylbenzyl)amide. The compound from Example 20 (4.97 g, 7.34 mmol) was hydrolyzed to give 4.43 g (97%) of the compound from Example 29 as an off-white solid; ¹ H NMR (CDCl ₃ ) δ 1.92-2.03 (m, 1H); 2.37-2.51 (m, 3H); 4.13-4.19 (m, 1H); 3.32 (d, J=4.9 Hz, 1H); 4.35-4.39 (m, 1H); 4.44 (dd, J=5.9 Hz, J=14.9 Hz, 1H); 4.50-4.57 (m, 2H); 4.61-4.67 (m, 1H); 4.70-4.76 (m, 1H); 6.24 (dd, J=9.6Hz, J=15.8Hz, 1H); 6.70 (d, J=15.8 Hz, 1H); 7.18-7.47 (m, 14H).

Example 30 2(S)-(Carboxymethyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-one-3-yl)-4(R)-(2-styryl)azetidine-2 -on-1-yl]acetic acid N-[4-(2-phenylethyl)]piperazinamide. The compound from Example 21 (1.88 g, 2.78 mmol) was hydrolyzed to give 1.02 g (60%) of the compound from Example 30 as an off-white solid; ¹ H NMR (CDCl ₃ ) δ 2.63 (dd, J=6.0 Hz, J=16.5 Hz, 1H); 2.75-2.85 (m, 1H); 3.00 (dd, J=8.2 Hz, H=16.6 Hz, 1H); 3.13-3.26 (m, 4H); 3.37-3.56 (m, 4H); 3.86-4.00 (m, 1H); 4.05-4.11 (m, 1H); 4.24 (d, J=5.0 Hz, 1H); 4.46-4.66 (m, 1H); 4.65-4.70 (m, 1H); 5.10-5.15 (m, 1H); 6.14 (dd, J=9.3 Hz, J=15.9 Hz, 1H); 6.71 (d, J=15.9 Hz, 1H); 7.22-7.41 (m, 15H); 12.02 (s, 1H).

Example 31 2(S)-(Carboxyethyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-one-3-yl)-4(R)-(2-styryl)azetidine-2 -on-1-yl]acetic acid N-[4-(2-phenylethyl)]piperazinamide. The compound from Example 22 (0.383 g, 0.55 mmol) was hydrolyzed to give 0.352 g (quantitative) of the compound from Example 31 as an off-white solid; ¹ H NMR (CDCl ₃ ) δ 1.93-2.01 (m, 1H); 2.07-2.36 (m, 6H); 2.82-2.90 (m, 1H); 3.00-3.20 (m, 4H); 3.36-3.54 (m, 4H); 3.74-3.82 (m, 1H); 4.06-4.11 (m, 1H); 4.29 (d, J=4.9 Hz, 1H); 4.33-4.46 (m, 2H); 4.50-4.58 (m, 2H); 4.67-4.72 (m, 1H); 4.95-5.00 (m, 1H); 6.18 (dd, H=9.2 Hz, J=16.0 Hz, 1H); 6.67 (d, J=15.9 Hz, 1H); 7.19-7.42 (m, 15H); 8.80 (brs, 1H).

Example 32 2(R)-(Carboxymethyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-one-3-yl)-4(R)-(2-styryl)azetidine-2 -on-1-yl]acetic acid N-(3-trifluoromethylbenzyl)amide. The compound from Example 23 (1.51 g, 2.27 mmol) was hydrolyzed to give 1.38 g (quantitative) of the compound from Example 32 as an off-white solid.

Example 32A. 2(R)-(Carboxymethyl)-2-[3(R)-(4(R)-phenyloxazolidin-2-on-3-yl)-4(S)-(2-styryl)azetidin-2-on- 1-yl]acetic acid N-(3-trifluoromethylbenzyl)amide. The compound from Example 23A (550 mg, 0.83 mmol) was hydrolyzed to give 479 mg (95%) of the compound from Example 32A as an off-white solid. The compound from Example 32A showed a ¹ H NMR spectrum consistent with the established structure.

Example 33 2(R-(Carboxyethyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-one-3-yl)-4(R)-(2-styryl)azetidine-2- on-1-yl]acetic acid N-(3-trifluoromethylbenzyl)amide The compound from Example 24 (0.604 g, 0.89 mmol) was hydrolyzed to give 0.554 g (quantitative yield) of the compound from Example 33 as an off-white solid .

Example 34 2(S)-(Carboxyethyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-one-3-yl)-4(R)-(2-styryl)azetidine-2 -on-1-yl]acetic acid N-(4-cyclohexyl)piperazinamide. The compound from Example 25 (0.537 g, 0.80 mmol) was hydrolyzed to give 0.492 g (quantitative) of the compound from Example 34 as an off-white solid; ¹ H NMR (CDCl ₃ ) δ 1.09-1.17 (m, 1H); 1.22-1.33 (m, 2H); 1.40-1.47 (m, 2H); 1.63-1.67 (m, 1H); 1.85-1.90 (m, 2H); 1.95-2.00 (m, 1H); 2.05-2.15 (m, 3H); 2.20-2.24 (m, 1H); 2.30-2.36 (m, 1H); 2.85-2.93 (m, 1H); 3.25-3.33 (m, 1H); 3.36-3.46 (m, 2H); 3.81-3.87 (m, 1H); 4.08 (t, J=8.3 Hz, 1H); 4.28 (d, J=5.0 Hz, 1H); 4.33-4.56 (m, 4H); 4.70 (t, J=8.3 Hz, 1H); 4.83-4.91 (m, 1H); 6.17 (dd, J=9.1 Hz, J=15.9 Hz, 1H); 6.67 (d, J=15.9 Hz, 1H); 7.25-7.44 (m, 10H); 8.22 (brs, 1H).

Example 34A. 2(S)-(2-(4-Cyclohexylpiperazinylcarbonyl)ethyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-on-3-yl)-4(R)-(2-styryl )azetidin-2-on-1-yl]acetic acid.

The compound from Example 25A (0.787 g, 1.28 mmol) was hydrolyzed to give 0.665 g (92%) of the compound from Example 34A as an off-white solid; ¹ H NMR (CDCl ₃ ) δ 1.05-1.13 (m, 1H); 1.20-1.40 (m, 5H); 1.60-1.64 (m, 1H); 1.79-1.83 (m, 2H); 2.00-2.05 (m, 2H); 2.22-2.44 (m, 3H); 2.67-2.71 (m, 1H); 2.93-3.01 (m, 4H); 3.14-3.18 (m, 1H); 3.38-3.42 (m, 1H); 3.48-3.52 (m, 1H); 3.64-3.69 (m, 1H); 4.06-4.14 (m, 2H); 4.34-4.43 (m, 2H); 4.56 (t, J=8.8 Hz, 1H); 4.73 (t, J=8.4 Hz, 1H); 6.15 (dd, J=9.1 Hz, J=16.0 Hz, 1H); 6.65 (d, J=16.0 Hz, 1H); 7.25-7.42 (m, 10H).

Example 34B. 2(R)-(Carboxymethyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-on-3-yl)-4(R)-(2-styryl)azetidin-2-on- 1-yl]acetic acid N-(2-fluoro-3-trifluoromethylbenzyl)carboxamide. The compound from Example 25B (0.26 g, 0.38 mmol) was hydrolyzed to give 0.238 g (quantitative) of the compound from Example 34B as an off-white solid; ¹ H NMR (CDCl ₃ ) δ 3.27 (d, J=7.2 Hz, 1H); 4.06 (t, J=7.2 Hz, 1H); 4.15 (t, J=8.1 Hz, 1H); 4.27 (d, J=4.8 Hz, 1H); 4.56-4.76 (m, 5H); 6.34 (dd, J=9.5 Hz, J=15.7 Hz, 1H); 6.80 (d, J=15.7 Hz, 1H); 7.06 (t, J=7.7 Hz, 1H); 7.31-7.54 (m, 12H); 8.58 (t, J=5.9 Hz, 1H).

Example 34C. 2(R)-(Carboxymethyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-on-3-yl)-4(R)-(2-styryl)azetidin-2-on- 1-yl]acetic acid N-[(S)-α-methylbenzyl]amide. The compound from Example 25C (0.215 g, 0.35 mmol) was hydrolyzed to give 0.195 g (quantitative) of the compound from Example 34C as an off-white solid; ¹ H NMR (CDCl ₃ ) δ 1.56 (d, J=7.0 Hz, 1H); 3.10 (dd, J=4.5 Hz, J=17.9 Hz, 1H); 3.18 (dd, J=9.8 Hz, J=17.9 Hz, 1H); 4.00 (dd, J=4.5 Hz, J=9.7 Hz, 1H); 4.14 (t, J=8.2 Hz, 1H); 4.26 (d, J=4.7 Hz, 1H); 5.02-5.09 (m, 1H); 6.41 (dd, J=9.4Hz, J=15.8Hz, 1H); 6.78 (d, J=15.8 Hz, 1H); 7.18 (t, J=7.3 Hz, 1H); 7.26-7.43 (m, 12H); 8.29 (d, J=8.2 Hz, 1H).

Example 34D. 2(R)-(Carboxymethyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-on-3-yl)-4(R)-(2-styryl)azetidin-2-on- 1-yl]acetic acid N-[(R)-α-methylbenzyl]amide. The compound from Example 25D (0.22 g, 0.35 mmol) was hydrolyzed to give 0.20 g (quantitative) of the compound from Example 34D as an off-white solid; ¹ H NMR (CDCl ₃ ) δ 1.59 (d, J=7.0 Hz, 1H); 3.25 (d, J=7.0 Hz, 2H); 3.92 (t, J=7.3 Hz, 1H); 4.15 (t, J=8.3 Hz, 1H); 4.26 (d, J=5.0 Hz, 1H); 4.52 (dd, J=4.8 Hz, J=9.3 Hz, 1H); 4.65 (t, J=8.8 Hz, 1H); 4.72 (t, J=8.3 Hz, 1H); 5.07-5.28 (m, 1H); 6.29 (dd, J=9.5 Hz, J=15.6 Hz, 1H); 6.71 (d, J=16.0 Hz, 1H); 7.20-7.43 (m, 13H); 8.31 (d, J=8.0 Hz, 1H).

Example 34E. 2(R)-(Carboxymethyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-on-3-yl)-4(R)-(2-styryl)azetidin-2-on- 1-yl]acetic acid N-methyl-N-(3-trifluoromethylbenzyl)amide. The compound from Example 25E (0.253 g, 0.37 mmol) was hydrolyzed to give 0.232 g (quantitative) of the compound from Example 34E as an off-white solid; ¹ H NMR (CDCl ₃ ) δ 3.07-3.15 (m, 4H); 4.13 (t, J=8.2 Hz, 1H); 4.30 (d, J=4.9 Hz, 1H); 4.46-4.78 (m, 5H); 5.23 (dd, J=4.6Hz, J=9.7Hz, 1H); 6.20 (dd, J=9.4Hz, J=15.9Hz, 1H); 6.73 (d, J=15.9 Hz, 1H); 7.25-7.43 (m, 15H).

Example 34F. 2(S)-(Carboxyethyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-on-3-yl)-4(^-(2-chlorosty-2-yl)azetidin-2 -on-1-yl]acetic acid N-(3-trifluoromethylbenzyl)amide The compound from Example 25F (0.707 g, 0.99 mmol) was hydrolyzed to give 0.648 g (99%) of the compound from Example 34F as an off-white solid substance, ¹ H NMR (CDCl ₃ ) δ 2.22-2.28 (m, 2H), 2.49-2.64 (m, 2H), 4.09 (t, J=8.0 Hz, 1H ); 4.25-4.62 (m, 6H); 4.87 (t, J=8.0 Hz, 1H); 6.88 (s, 1H); 7.25-7.66 (m, 15H).

Example 34G. 2(R)-(Carboxymethyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-on-3-yl)-4(R)-(2'-methoxystyr-2-yl)azetidine -2-on-1-yl]acetic acid N-(3-trifluoromethylbenzyl)amide. The compound from Example 25G (0.268 g, 0.39 mmol) was hydrolyzed to give 0.242 g (98%) of the compound from Example 34G as an off-white solid; ¹ H NMR (CDCl ₃ ) δ 3.26 (d, J=7.1 Hz, 1H); 3.79 (s, 3H); 4.14 (t, J=8.2 Hz, 1H); 4.25 (d, J=4.5 Hz, 1H); 4.51 (dd, J=5.9 Hz, J=15.5 Hz, 1H); 4.53-4.66 (m, 4H); 6.36 (dd, J=9.4Hz, J=15.8Hz, 1H); 8.88 (t, J=8.2 Hz, 1H); 6.70 (d, J=15.8 Hz, 1H); 7.18 (d, J=6.5 Hz, 1H); 7.25-7.48 (m, 10H); 7.48(s, 1H); 8.66-8.69 (m, 1H).

Example 34H. 2(R)-(Benzyloxymethyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-on-3-yl)-4(R)-(2-styryl)azetidin-2-on- 1-yl]acetic acid. The compound from Example 25H (0.16 g, 0.28 mmol) was hydrolyzed to give 0.144 g (quantitative) of the compound from Example 34H as an off-white solid; ¹ H NMR (CDCl ₃ ) δ 3.65 (dd, J=4.0 Hz, 3=9.5 Hz, 1H); 3.82 (dd, J=5.5 Hz, 3=9.5 Hz, 1H); 4.11 (dd, J=7.8 Hz, J=8.8 Hz, 1H); 4.33 (s, 2H); 4.50 (d, J=5.0 Hz, 1H); 4.57 (t, 3=9.0 Hz, 1H); 4.67 (dd, J=4.0 Hz, J=5.0 Hz, 1H); 4.69 (dd, H=5.0 Hz, H=9.5 Hz, 1H); 4.75 (t, Γ=8.0 Hz, 1H); 6.17 (dd, H=9.3 Hz, H=15.8 Hz, 1H); 6.55 (d, Γ=16.0 Hz, 1H); 7.09-7.12 (m, 2H); 7.19-7.42 (m, 13H).

Example 341 2(S)-(2-(4-Cyclohexylpiperazinylcarbonyl)methyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-on-3-yl)-4(R)-( 2-styryl)azetidin-2-on-1-yl]acetic acid.

The compound from Example 251 (737 mg, 1.12 mmol) was hydrolyzed to give 640 mg (95%) of the compound from Example 341 as an off-white solid. The compound from Example 341 showed a ¹ H NMR spectrum consistent with the established structure.

Example 34J. 3(R)-[3(S)-(4(S)-Phenyloxazolidin-2-one-3-yl)-3-methyl-4(R)-(styr-2-yl)azetidin-2-one- 1-yl]-3-[(3-trifluoromethyl)phenylmethylaminocarbonyl]propanoic acid. Using the general method of Example 26, 120 mg (0.18 mmol) of the compound of Example 25J was hydrolyzed to give 108 mg (98%) of the compound of Example 34J as an off-white solid; ¹ H NMR (CDCl ₃ ) δ 1.22 (s, 3H); 3.25 (dd, J=3.5 Hz, J=18.0 Hz, 1H); 3.36 (dd, J=10.8 Hz, J=18.2 Hz, 1H); 4.01 (dd, J=4.0 Hz, J=10.5 Hz, 1H); 4.05 (dd, H=3.8 Hz, H=8.8 Hz, 1H); 4.33 (d, Γ=9.0 Hz, 1H); 4.44-4.51 (m, 3H); 4.61-4.66 (m, 1H); 4.73 (dd, H=3.8 Hz, H=8.8 Hz, 1H); 6.19 (dd, H=9.0 Hz, H=16.0 Hz, 1H); 6.74 (d, J=16.0 Hz, 1H); 7.22-7.54 (m, 13H); 7.65(s, 1H).

Example 34K. 2(R)-(Carboxymethyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-on-3-yl)-4(R)-(propen-1-yl)azetidin-2- on-1-yl]acetic acid N-(3-trifluoromethylbenzyl)amide. Using the general method of Example 26, 160 mg (0.27 mmol) of the compound of Example 25K was hydrolyzed to give 131 mg (90%) of the compound of Example 34K as an off-white solid. ¹ H NMR (CDCl ₃ ) δ 1.69 (dd, J=l Hz, J=6.5 Hz, 3H); 3.23 (d, J=7 Hz, 1H); 3.93 (t, J=7.3 Hz, 1H); 4.14-4.20 (m, 3H); 4.29 (dd, J=5 Hz, J=9.5 Hz, 1H); 4.43 (dd, J=6Hz, J=15Hz, 1H); 4.61 (dd, J=6.5 Hz, J=15 Hz, 1H); 4.66 -4.74 (m, 2H); 5.50-5.55 (m, 1H); 5.90-5.98 (m, 1H); 7.32-7.60 (m, 9H); 8.60-8.64 (m, 1H).

Example 34L. 2(R-(Carboxymethyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-on-3-yl)-4(R)-(2-styryl)azetidin-2-on-1 -yl]acetic acid N-[(R)-1-(3-trifluoromethylphenyl)ethyl]amide The compound from Example 25L (166 mg, 0.24 mmol) was hydrolyzed to give 152 mg (quantitative yield) of the compound from Example 34L in as an off-white solid and exhibited a ¹ H NMR spectrum consistent with the established structure.

Example 34M. 2(S)-(Methoxycarbonylethyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-one-3-yl)-4(R)-(2-styryl)azetidin-2-one- 1-yl]acetic acid. The compound from Example 25M (875 mg, 1.64 mmol) was hydrolyzed to give 757 mg (97%) of the compound from Example 34M as an off-white solid and showed a ¹ H NMR spectrum consistent with the established structure.

Example 34N. 2(R-(Carboxymethyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-on-3-yl)-4(R)-(2-styryl)azetidin-2-on-1 -yl]acetic acid N-[(S)-1-(3-trifluoromethylphenyl)ethyl]amide The compound from Example 25N (38.5 mg, 0.057 mmol) was hydrolyzed to give 35 mg (quantitative yield) of the compound from Example 34N in as an off-white solid and exhibited a ¹ H NMR spectrum consistent with the established structure.

Example 340 2(S)-(T-butoxycarbonylethyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-on-3-yl)-4(R)-(2-styryl)azetidine -2-on-1-yl]acetic acid. The compound from Example 250 (97 mg, 0.18 mmol) was dissolved in methanol/tetrahydrofuran (2.5 ml/2 ml) and reacted with lithium hydroxide (0.85 ml of a 0.85 M solution in water; 0.72 mmol) for 6 hours at room temperature. The reaction mixture was diluted with 15 ml of dichloromethane and an aqueous solution of hydrochloric acid (1M) was added until the pH of the aqueous phase was 5 (measured using standard indicator paper). The organic phase was then separated and evaporated to dryness to give 84 mg (89%) of the compound from Example 340 as an off-white solid and showed a ¹ H NMR spectrum consistent with the established structure.

Example 34P. 2(S)-(T-butoxycarbonylethyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-one-3-yl)-4(R)-(2-styryl)azetidine-2- on-1-yl]acetic acid. The compound from Example 25P (200 mg, 0.39 mmol) was hydrolyzed according to the method used for Example 340 to give 155 mg (88%) of the compound from Example 34P as an off-white solid; and it showed a ¹ H NMR spectrum consistent with the established structure.

Example 34O. 2(R)-(2-(3-Trifluoromethylbenzyl)amino-1-ylcarbonyl)ethyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-on-3-yl)-4(R )-(2-styryl)azetidin-2-on-1-yl]acetic acid. The compound from Example 25O (150 mg, 0.24 mmol) was hydrolyzed according to the method used for Example 340 to give 143 mg (97%) of the compound from Example 34O as an off-white solid and it showed a ¹ H NMR spectrum corresponding to the established structure.

Example 34R. 2(R)-(T-butoxycarbonylmethyl)-2-[3(RS)-2-thienylmethyl)-4(R)-(2-styryl)azetidin-2-on-1-yl]acetic acid N-(3 -trifluoromethylbenzyl)amide. An imine prepared from 290 mg (0.84 mmol) of D-aspartic acid β-tert-butyl ester of α-(3-trifluoromethyl)benzylamide and cinnamic aldehyde was mixed with 2-thiopheneacetyl chloride to give 42 mg (8%) of the compound from Example 34R after purification by flash column chromatography (hexanes/ethyl acetate 70:30) and showed a ¹ H NMR spectrum consistent with the established structure.

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

Compounds from Examples 36-42A shown in the following table were prepared using the procedure from Example 6 except that N-benzyloxycarbonyl-D-aspartic acid β-tert-butyl ester monohydrate was replaced with the compound from Example 27 and 3-( trifluoromethyl)benzylamine was replaced by the corresponding amine; all compounds from the listed Examples showed a ¹ H NMR spectrum consistent with the established structure.

The compounds from Examples 43-86A shown in the following table were prepared using the procedure from Example 6 except that N-benzyloxycarbonyl-D-aspartic acid β-tert-butyl ester monohydrate was replaced with the compound from Example 28 and 3-( trifluoromethyl)benzylamine was replaced by the corresponding amine; all compounds from the listed Examples showed a ¹ H NMR spectrum consistent with the established structure.

Example 86 B The compound from Example 63 (44 mg, 0.06 mmol) was dissolved in 4 ml dichloromethane and reacted with 3-chloroperoxybenzoic acid (12 mg, 0.07 mmol) until completion as judged by TLC (dichloromethane 94% /methanol 6%, UV detection). The reaction was quenched with aqueous sodium sulfite, the dichloromethane phase was washed with 5% aqueous sodium bicarbonate and distilled water. Evaporation of the dichloromethane phase gave the compound of Example 86B as an off-white solid (35 mg, 78%) and showed a ¹ H NMR spectrum consistent with the established structure.

The compounds of Examples 121-132 shown in the following table were prepared using the procedure of Example 6 except that N-benzyloxycarbonyl-D-aspartic acid β-tert-butyl ester monohydrate was replaced with the compound of Example 30 and 3-( trifluoromethyl)benzylamine was replaced by the corresponding amine; all compounds from the listed Examples showed a ¹ H NMR spectrum consistent with the established structure.

The compounds from Examples 132A-132B shown in the following table were prepared using the procedure from Example 6 except that N-benzyloxycarbonyl-D-aspartic acid β-tert-butyl ester monohydrate was replaced with the compound from Example 341 and 3-( trifluoromethyl)benzylamine was replaced by the corresponding amine; all compounds from the listed Examples showed a ¹ H NMR spectrum consistent with the established structure.

Example 132C. 2(S)-(T-butoxycarbonylmethyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-on-3-yl)-4(R)-(2-styryl)azetidine-2- on-1-yl]acetic acid N-(4-cyclohexyl)piperazinamide. The compound from Example 132C was prepared using the procedure from Example 6 except that N-benzyloxycarbonyl-D-aspartic acid β-tert-butyl ester monohydrate was replaced with the compound from Example 34P and 3-(trifluoromethyl)benzylamine was replaced with 1-cyclohexylpiperazine . The compound from Example 132C showed a ¹ H NMR spectrum consistent with the established structure.

The compounds presented in the following table were obtained in accordance with the methods described in this document.

The compounds from Examples 133-134G shown in the following table were prepared using the procedure from Example 6 except that N-benzyloxycarbonyl-D-aspartic acid β-tert-butyl ester monohydrate was replaced with the compound from Example 32 and 3-( trifluoromethyl)benzylamine was replaced by the corresponding amine; all compounds from the listed Examples showed a ¹ H NMR spectrum consistent with the established structure.

Example 134H. The compound from Example 134H was obtained using the procedure from Example 86B except that the compound from Example 133 was replaced with the compound from Example 110. The compound from Example 134H was obtained as an off-white solid (48 mg, 94%) and it exhibited ¹ H NMR spectrum corresponding to the established structure.

Example 1341 2(R)-[[4-(Piperidinyl)piperidinyl]carboxymethyl]-2-[3(S)-(4(R)-phenyloxazolidin-2-one-3-yl)-4(R)- (2-styryl)azetidin-2-on-1-yl]acetic acid N-(3-trifluoromethylbenzyl)amide. The compound from Example 1341 was prepared using the procedure from Example 6 except that N-benzyloxycarbonyl-D-aspartic acid β-tert-butyl ester monohydrate was replaced with the compound from Example 32A and 3-(trifluoromethyl)benzylamine was replaced with 4-( piperidinyl)piperidine, and it showed a ¹ H NMR spectrum consistent with the established structure.

The compounds presented in the following table were obtained in accordance with the methods described in this document.

Example 222 2(R)-[[4-(Piperidinyl)piperidinyl]carbonylmethyl]-2-[3(S)-(4(S)-phenyloxazolidin-2-on-3-yl)-4(R)- (2-styryl)azetidin-2-on-1-yl]acetic acid N-(2-fluoro-3-trifluoromethylbenzyl)carboxamide. The compound from Example 222 was prepared using the procedure from Example 6 except that N-benzyloxycarbonyl-D-aspartic acid β-tert-butyl ester monohydrate was replaced with the compound from Example 34B and 3-(trifluoromethyl)benzylamine was replaced with 4- (piperidinyl)piperidine; the compound from Example 222 showed a ¹ H NMR spectrum consistent with the established structure.

Example 223 2(R)-[[4-(Piperidinyl)piperidinyl]carbonylmethyl]-2-[3(S)-(4(S)-phenyloxazolidin-2-on-3-yl)-4(R)- (2-styryl)azetidin-2-on-1-yl]acetic acid N-[(S)-α-methylbenzyl]amide. The compound from Example 223 was prepared using the procedure from Example 6 except that N-benzyloxycarbonyl-D-aspartic acid β-tert-butyl ester monohydrate was replaced with the compound from Example 34C and 3-(trifluoromethyl)benzylamine was replaced with 4-( piperidinyl)piperidine; the compound from Example 223 showed a ¹ H NMR spectrum consistent with the established structure.

Example 224 2(R)-[[4-(Piperidinyl)piperidinyl]carbonylmethyl]-2-[3(S)-(4(S)-phenyloxazolidin-2-on-3-yl)-4(R)- (2-styryl)azetidin-2-on-1-yl]acetic acid N-[(R)-α-methylbenzyl]amide. The compound from Example 224 was prepared using the procedure from Example 6 except that N-benzyloxycarbonyl-D-aspartic acid β-tert-butyl ester monohydrate was replaced with the compound from Example 34D and 3-(trifluoromethyl)benzylamine was replaced with 4-( piperidinyl)piperidine; the compound from Example 224 showed a ¹ H NMR spectrum consistent with the established structure.

Example 225 2(R)-[[4-(Piperidinyl)piperidinyl]carbonylmethyl]-2-[3(S)-(4(S)-phenyloxazolidin-2-on-3-yl)-4(R)- (2-styryl)azetidin-2-on-1-yl]acetic acid N-methyl-N-(3-trifluoromethylbenzyl)amide. The compound from Example 225 was prepared using the procedure from Example 6, except that N-benzyloxycarbonyl-D-aspartic acid β-tert-butyl ester monohydrate was replaced with the compound from Example 34E, and 3-(trifluoromethyl)benzylamine was replaced with 4-( piperidinyl)piperidine; the compound from Example 225 showed a ¹ H NMR spectrum consistent with the established structure; Calcd for C ₄₃ H ₄₈ F ₃ N ₅ O ₅ : C, 66.91; H, 6.27; N, 9.07; found C, 66.68; H, 6.25; N, 9.01.

Example 225 Hydrochloride salt. The compound from Example 225 (212.5 mg) was dissolved in 30 ml of dry Et ₂ O. Dry HCL gas was bubbled through this solution, which led to the rapid formation of an off-white precipitate. The addition of HCL was stopped when no more precipitation was observed (approximately 5 minutes). The solid was isolated by suction filtration, washed twice with 15 ml dry Et ₂ O and dried to give 213.5 mg (96% yield) of an off-white solid; Calculated for C ₄₃ H ₄₉ ClF ₃ N ₅ O ₅ : C, 63.89; H, 6.11; N, 8.66; Cl, 4.39; found C, 63.41; H, 5.85; N, 8.60; Cl, 4.86.

Example 225A. 2(R)-[[4-[2-(Piperidinyl)ethyl]piperidinyl]carbonylmethyl]-2-[3(S)-(4(S)-phenyloxazolidin-2-on-3-yl)-4(R )-(2-styryl)azetidin-2-on-1-yl]acetic acid N-[(S)-α-methylbenzyl]amide. The compound from Example 225A was prepared using the procedure from Example 6 except that N-benzyloxycarbonyl-D-aspartic acid β-tert-butyl ester monohydrate was replaced with the compound from Example 34C and 3-(trifluoromethyl)benzylamine was replaced with 4-[ 2-(piperidinyl)ethyl]piperidine. The compound from Example 225A showed a ¹ H NMR spectrum consistent with the established structure.

Example 225 B. 2(R)-[[4-[2-(Piperidinyl)ethyl]piperidinyl]carbonylmethyl]-2-[3(S)-(4(S)-phenyloxazolidin-2-one-3-yl) -4(R)-(2-styryl)azetidin-2-on-1-yl]acetic acid N-[(R)-α-methylbenzyl]amide. The compound from Example 225B was prepared using the procedure from Example 6 except that N-benzyloxycarbonyl-D-aspartic acid β-tert-butyl ester monohydrate was replaced with the compound from Example 34D and 3-(trifluoromethyl)benzylamine was replaced with 4- [2-(piperidinyl)ethyl]piperidine. The compound from Example 225 B showed a ¹ H NMR spectrum consistent with the established structure.

Example 225C. 2(R)-[[4-(Piperidinyl)piperidinyl]carbonylmethyl]-2-[3(S)-(4(S)-phenyloxazolidin-2-on-3-yl)-4(R)-(2- styryl)azetidin-2-on-1-yl]acetic acid N-[(R)-1-(3-trifluoromethylphenyl)ethyl]amide. The compound from Example 225C was prepared using the procedure from Example 6 except that N-benzyloxycarbonyl-D-aspartic acid β-tert-butyl ester monohydrate was replaced with the compound from Example 34L and 3-(trifluoromethyl)benzylamine was replaced with 4-( piperidinyl)piperidine. The compound from Example 225C showed a ¹ H NMR spectrum consistent with the established structure.

Example 225D. 2(R)-[[4-(Piperidinyl)piperidinyl]carbonylmethyl]-2-[3(S)-(4(S)-phenyloxazolidin-2-on-3-yl)-4(R)-(2- styryl)azetidin-2-on-1-yl]acetic acid N-[(S)-1-(3-trifluoromethylphenyl)ethyl]amide. The compound from Example 225D was prepared using the procedure from Example 6 except that N-benzyloxycarbonyl-D-aspartic acid β-tert-butyl ester monohydrate was replaced with the compound from Example 34N and 3-(trifluoromethyl)benzylamine was replaced with 4-( piperidinyl)piperidine. The compound from Example 225D showed a ¹ H NMR spectrum consistent with the established structure.

Compounds from Examples 87-120E shown in the following table were prepared using the procedure from Example 6 except that N-benzyloxycarbonyl-D-aspartic acid β-tert-butyl ester monohydrate was replaced with the compound from Example 29 and 3-( trifluoromethyl)benzylamine was replaced by the corresponding amine; all compounds from the listed Examples showed a ¹ H NMR spectrum consistent with the established structure.

Example 120F. The compound from Example 120F was prepared using the procedure from Example 86B except that the compound from Example 63 was replaced with the compound from Example 110 to give an off-white solid (54.5 mg, 98%). The compound from Example 120F showed a ¹ H NMR spectrum consistent with the established structure.

Example 120G. 2(S)-(Methoxycarbonylethyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-one-3-yl)-4(R)-(2-styryl)azetidin-2-one- 1-yl]acetic acid N-(3-trifluoromethylbenzyl)amide. The compound from Example 120G was prepared using the procedure from Example 6, except that N-benzyloxycarbonyl-D-aspartic acid β-tert-butyl ester monohydrate was replaced with the compound from Example 34M, and it showed a ¹ H NMR spectrum consistent with the established structure.

Example 35 2(S)-[4-(2-phenylethyl)piperazinylcarbonylethyl]-2-[3(S)-(4(S)-phenyloxazolidin-2-one-3-yl)-4(R)-( 2-styryl)azetidin-2-on-1-yl]acetic acid N-(3-trifluoromethylbenzyl)amide. The title compound was prepared using the procedure of Example 6 except that N-benzyloxycarbonyl-D-aspartic acid β-tert-butyl ester monohydrate was replaced with the carboxylic acid from Example 29 and 3-(trifluoromethyl)benzylamine was replaced with 4-(2-phenylethyl)piperazine; ¹ H NMR (CDCl ₃ ) δ 2.21-2.23 (m, 1H); 2.25-2.45 (m, 6H); 2.52-2.63 (m, 3H); 2.72-2.82 (m, 2H); 3.42-3.48 (m, 2H); 3.52-3.58 (m, 1H); 4.13-4.18 (m, 1H); 4.26 (dd, J=5.1 Hz, J=8.3 Hz, 1H); 4.29 (d, J=5.0 Hz, 1H); 4.44 (dd, J=6.0 Hz, J=15.0 Hz, 1H); 4.54 (dd, J=6.2 Hz, J=14.9 Hz, 1H); 4.61-4.68 (m, 2H); 4.70-4.75 (m, 1H); 6.27 (dd, J=9.6Hz, J=15.8Hz, 1H); 6.73 (d, J=15.8 Hz, 1H); 7.16-7.60 (m, 19H); 8.07-8.12 (m, 1H); FAB ⁺ (M+H) ⁺ /z 794; Elemental analysis calculated for C ₄₅ H ₄₆ F ₃ N ₅ O ₅ : C, 68.08; H, 5.84; N, 8.82; found: C, 67.94; H, 5.90; N, 8.64.

The compounds of Examples 141-171 shown in the following table were prepared using the procedure of Example 6 except that N-benzyloxycarbonyl-D-aspartic acid β-tert-butyl ester monohydrate was replaced with the compound of Example 34 and 3-( trifluoromethyl)benzylamine was replaced by the corresponding amine; all compounds from the listed Examples showed a ¹ H NMR spectrum consistent with the established structure.

Compounds from Examples 172-221R shown in the following table were prepared using the procedure from Example 6 except that N-benzyloxycarbonyl-D-aspartic acid β-tert-butyl ester monohydrate was replaced with the compound from Example 34A and 3-( trifluoromethyl)benzylamine was replaced by the corresponding amine; all compounds from the listed Examples showed a ¹ H NMR spectrum consistent with the established structure.

The compounds presented in the following table were obtained in accordance with the methods described in this document.

The compounds of Examples 135-140 shown in the following table were prepared using the procedure of Example 6 except that N-benzyloxycarbonyl-D-aspartic acid β-tert-butyl ester monohydrate was replaced with the compound of Example 33 and 3-( trifluoromethyl)benzylamine was replaced by the corresponding amine; all compounds from the listed Examples showed a ¹ H NMR spectrum consistent with the established structure.

Example 140A. 2(R)-(2-(3-Trifluoromethylbenzyl)amino-1-ylcarbonyl)ethyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-on-3-yl)-4(R )-(2-styryl)azetidin-2-one-1-yl]acetic acid N-(4-cyclohexyl)piperazinamide. The compound from Example 140A was prepared using the procedure from Example 6 except that N-benzyloxycarbonyl-D-aspartic acid β-tert-butyl ester monohydrate was replaced with the compound from Example 34Q and 3-(trifluoromethyl)benzylamine was replaced with 1-cyclohexylpiperazine , and it showed a ¹ H NMR spectrum consistent with the established structure.

The compounds from Examples 226-230C shown in the following table were prepared using the procedure from Example 6 except that N-benzyloxycarbonyl-D-aspartic acid β-tert-butyl ester monohydrate was replaced with the compound from Example 34F and 3-( trifluoromethyl)benzylamine was replaced by the corresponding amine; all compounds from the listed Examples showed a ¹ H NMR spectrum consistent with the established structure.

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

Example 86C. 2(S)-[[4-(Piperidinyl)piperidinyl]carbonylmethyl]-2-[3(S)-(4(R)-phenyloxazolidin-2-on-3-yl)-4(R)-(2- styryl)azetidin-2-on-1-yl]acetic acid N-(3-trifluoromethylbenzyl)amide. The compound from Example 86C was prepared using the procedure from Example 6 except that N-benzyloxycarbonyl-D-aspartic acid β-tert-butyl ester monohydrate was replaced with the compound from Example 28A and 3-(trifluoromethyl)benzylamine was replaced with 4-( piperidinyl)piperidine, and it showed a ¹ H NMR spectrum consistent with the established structure.

Example 231 2(R)-[[4-(Piperidinyl)piperidinyl]carbonylmethyl]-2-[3(S)-(4(S)-phenyloxazolidin-2-on-3-yl)-4(R)- (2'-methoxystyr-2-yl)azetidin-2-on-1-yl]acetic acid N-(3-trifluoromethylbenzyl)amide. The compound from Example 231 was prepared using the procedure from Example 6 except that N-benzyloxycarbonyl-D-aspartic acid β-tert-butyl ester monohydrate was replaced with the compound from Example 34G and 3-(trifluoromethyl)benzylamine was replaced with 4-( piperidinyl)piperidine, and it showed a ¹ H NMR spectrum consistent with the established structure.

Compounds from Examples 232-233A shown in the following table were prepared using the procedure from Example 6 except that N-benzyloxycarbonyl-D-aspartic acid β-tert-butyl ester monohydrate was replaced with the compound from Example 34H and 3-( trifluoromethyl)benzylamine was replaced by the corresponding amine; all compounds from the listed Examples showed a ¹ H NMR spectrum consistent with the established structure.

Example 234 (2RS)-[4-(Piperidinyl)piperidinylcarbonyl]-2-methyl-2-[3(S)-(4(S)-phenyloxazolidin-2-one-3-yl)-4(R)- (2-styryl)azetidin-2-on-1-yl]acetic acid N-(3-trifluoromethylbenzyl)amide.

The compound from Example 37 (50 mg, 0.067 mmol) in tetrahydrofuran (4 ml) was treated sequentially with sodium hydride (4 mg, 0.168 mmol) and methyl iodide (6 μl, 0.094 mmol) at -78°C. The resulting mixture was slowly warmed to ambient temperature and evaporated. The residue obtained was partitioned into dichloromethane and water and the organic phase was evaporated. The resulting residue was purified by silica gel chromatography (chloroform/methanol 95:5) to give 28 mg (55%) of the title compound as an off-white solid; MS (ES ⁺ ): m/z=757 (M ⁺ ).

Example 234A. 4-(Piperidinyl)-piperidinyl-3(R)-[3(S)-(4(S)-phenyloxazolidin-2-one-3-yl)-3-methyl-4(R)-(styr-2- yl)azetidin-2-one-1-yl]-3-[(3-trifluoromethyl)phenylmethylaminocarbonyl]propanoic acid.

Using the procedure of Example 6, except that N-benzyloxycarbonyl-B-aspartic acid β-tert-butyl ester monohydrate was replaced with the carboxylic acid of Example 34J and 3-(trifluoromethyl)benzylamine was replaced with 4-(piperidinyl)piperidine, received the compound indicated in the title, with a quantitative yield; MS(m+H)+772.

The compounds presented in the following table were obtained in accordance with the methods described in this document.

Example 235 2(S)-[[(1-Benzylpiperidin-4-yl)amino]carbonylmethyl]-2-[3(S)-(4(S)-phenyloxazolidin-2-on-3-yl)-4 (R)-(2-phenylethyl-1-yl)azetidin-2-on-1-yl]acetic acid N-(3-trifluoromethylbenzyl)amide. The compound from Example 235 was prepared using the procedure from Example 8 except that N-benzyloxycarbonyl-L-aspartic acid β-tert-butyl ester α-(3-trifluoromethyl)benzylamide was replaced with the compound from Example 63 (50 mg, 0.064 mmol ) to give 40 mg (80%) of Example 235 as an off-white solid; the compound from Example 235 showed a ¹ H NMR spectrum consistent with the established structure.

Example 236 (2S)-[(4-Cyclohexylpiperazinyl)carbonylethyl]-2-[3(S)-(4(S)-phenyloxazolidin-2-one-3-yl)-4(R)-(2-phenyleth -1-yl)azetidin-2-on-1-yl]acetic acid N-(3-trifluoromethylbenzyl)amide. The compound from Example 236 was prepared using the procedure from Example 8 except that N-benzyloxycarbonyl-L-aspartic acid β-tert-butyl ester α-(3-trifluoromethyl)benzylamide was replaced with the compound from Example 110 (50 mg, 0.065 mmol ) to give 42 mg (84%) of Example 236 as an off-white solid; the compound from Example 236 showed a ¹ H NMR spectrum consistent with the established structure.

Example 236A. (2S)-[(4-Cyclohexylpiperazinyl)carbonylethyl]-2-[3(S)-(4(S)-phenyloxazolidin-2-on-3-yl)-4(R)-(2-phenyleth-1- yl)azetidin-2-on-1-yl]acetic acid N-[(R)-1,2,3,4-tetrahydronaphth-1-yl]amide. The compound from Example 236A was prepared using the procedure from Example 8 except that N-benzyloxycarbonyl-L-aspartic acid β-tert-butyl ester α-(3-trifluoromethyl)benzylamide was replaced with the compound from Example 215 (76 mg, 0. 10 mmol) to give 69 mg (90%) of Example 236A as an off-white solid. The compound from Example 236A showed a ¹ H NMR spectrum consistent with the established structure.

Example 237 (2R)-[[4-(Piperidinyl)piperidinyl]carbonylmethyl]-2-[3(S)-(4(S)-phenyloxazolidin-2-one-3-yl)-4(R)-( 2-propen-1-yl)azetidin-2-on-1-yl]acetic acid N-(3-trifluoromethylbenzyl)amide. The compound from Example 237 was prepared using the procedure from Example 6 except that K-benzyloxycarbonyl-D-aspartic acid β-tert-butyl ester monohydrate was replaced with the compound from Example 34K and 3-(trifluoromethyl)benzylamine was replaced with 4-( piperidinyl)piperidine. The compound from Example 237 showed a ¹ H NMR spectrum consistent with the established structure.

Example 238 (2S)-(Benzylthiomethyl)-2-[3(S)-(4(S)-phenyloxazolidin-2-one-3-yl)-4(R)-(2-styryl)azetidine-2- on-1-yl]acetic acid N-[4-[2-(piperid-1-yl)ethyl]piperidin-1-yl]amide. The compound of this Example was prepared using the procedure of Example 6 except that N-benzyloxycarbonyl-D-aspartic acid β-tert-butyl ester monohydrate was substituted for the corresponding benzyl-protected cysteine analogue and 3-(trifluoromethyl)benzylamine was substituted for 4 -[2-(piperid-1-yl)ethyl]piperidine.

Step 1 N-T-butyloxycarbonyl-(S)-(benzyl)-B-cysteine-[4-(2-(1-piperidyl)ethyl)]piperidinamide. From N-tert-butyloxycarbonyl-(S)-(benzyl)-N-(tert-butyloxycarbonyl)-B-cysteine (0.289 g, 0.93 mmol) and 4-[2-(1-piperidyl)ethyl]piperidine ( 0.192 g, 0.98 mmol) in dichloromethane (20 ml) gave 0.454 g (quantitative) of the compound from Example X as an off-white solid. ¹ H NMR (CDCl ₃ ) δ 0.89-1.15 (m, 2H); 1.39-1.44 (m, 16H); 1.54-1.61 (m, 4H); 1.62-1.71(m, 1H); 2.21-2.35 (m, 5H); 2.49-2.58 (m, 2H); 2.66-2.74 (m, 1H); 2.79-2.97 (m, 1H); 3.67-3.76 (m, 3H); 4.48-4.51 (m, 1H); 4.72-4.75 (m, 1H); 5.41-5.44 (m, 1H); 7.19-7.34 (m, 5H).

Step 2. (S)-(Benzyl)-D-cysteine-[4-(2-(1-piperidyl)ethyl)]piperidinamide, dihydrochloride. N-T-butyloxycarbonyl-(S)-(benzyl)-B-cysteine-[4-(2-(1-piperidyl)ethyl)]piperidinamide (0.453 g, 0.93 mmol) was reacted overnight with acetyl chloride ( 0.78 ml, 13.80 mmol) in anhydrous methanol (15 ml). The title compound was obtained as an off-white solid by evaporating the reaction mixture to dryness (0.417 g, 97%). ¹ H NMR (CD ₃ OD) δ 0.94-1.29 (m, 2H); 1.49-1.57 (m, 1H); 1.62-1.95 (m, 10H); 2.65-2.80 (m, 2H); 2.81-2.97 (m, 4H); 3.01-3.14 (m, 2H); 3.50-3.60 (m, 3H); 3.81-3.92 (m, 2H); 4.41-4.47 (m, 2H); 7.25-7.44 (m, 5H).

Step 3 Using the general procedures described herein, the imine prepared from (S)-(benzyl)-B-cysteine-[4-(2-(1-piperidyl)ethyl)]piperidinamide, dihydrochloride (0.417 g , 0.90 mmol) and cinnamaldehyde in the presence of triethylamine (0.26 ml, 1.87 mmol) were mixed with 2-(4(S)-phenyloxazolidin-2-on-3-yl)acetyl chloride (Example 1) with obtaining 0.484 g (76%) of the compound from Example 238 as an off-white solid after recrystallization from a mixture of dichloromethane/hexanes. ¹ H NMR (CDCl ₃ ) δ 0.89-1.06 (m, 2H); 1.40-1.44 (m, 5H); 1.57-1.67 (m, 6H); 2.25-2.43 (m, 6H); 2.45-2.59 (m, 2H); 2.71-2.88 (m, 2H); 3.55-3.70 (m, 3H); 4.11-4.17 (m, 1H); 4.37-4.47 (m, 2H); 4.54-4.61 (m, 1H); 4.64-4.69 (m, 1H); 4.76-4.84 (m, 2H); 6.05-6.19 (m, 1H); 6.66-6.71 (m, 1H); 7.12-7.40 (m, 15H).

The following compounds are described

The following compounds are described

The following compounds are described

The following compounds are described

The following compounds are described

The following compounds are described

The following table shows selected compounds further characterized by mass spectral analysis using FAB ⁺ to detect the corresponding parent ion (M+H) ⁺ .

Claims (13)

1. A method of treating a patient with periodic explosive disorder, comprising the step of administering to said patient a compound of the formula

,

or

or a pharmaceutically acceptable salt of any of these compounds. 2. The method according to p. 1, where the specified connection is a compound of the formula

or a pharmaceutically acceptable salt thereof. 3. The method according to p. 1, where the specified connection is a compound of the formula

or a pharmaceutically acceptable salt thereof. 4. The method according to p. 1, where the specified connection is a compound of the formula

or a pharmaceutically acceptable salt thereof. 5. The method according to any one of paragraphs. 1-4, wherein said salt is the hydrochloride salt.

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