FIELD OF THE INVENTION: This invention relates to certain novel compounds and derivatives thereof, their synthesis, and their use as alpha la adrenoceptor antagonists. More particularly, the compounds of the present invention are useful for treating benign pro static hyperplasia (BPH).

BACKGROUND OF THE INVENTION Human adrenergic receptors are integral membrane proteins which have been classified into two broad classes, the alpha and the beta adrenergic receptors. Both types mediate the action of the peripheral sympathetic nervous system upon binding of catecholamines, norepinephrine and epinephrine.

Norepinephrine is produced by adrenergic nerve endings, while epinephrine is produced by the adrenal medulla. The binding affinity of adrenergic receptors for these compounds forms one basis of the classification: alpha receptors bind norepinephrine more strongly than epinephrine and much more strongly than the synthetic compound isoproterenol. The binding affinity of these hormones is reversed for the beta receptors. In many tissues, the functional responses, such as smooth muscle contraction, induced by alpha receptor activation are opposed to responses induced by beta receptor binding.

Subsequently, the functional distinction between alpha and beta receptors was further highlighted and refined by the pharmacological characterization of these receptors from various animal and tissue sources. As a result, alpha and beta adrenergic receptors were further subdivided into alpha 1, alpha 2, 131, and 2 subtypes. Functional differences between alpha 1 and alpha 2 receptors

have been recognized, and compounds which exhibit selective binding between these two subtypes have been developed.

For a general background on the alpha adrenergic receptors, the reader's attention is directed to Robert R. Ruffolo, Jr., a- Adrenoreceutors: Molecular BioloPv. Biochemistrv and Pharmacologv, (progress in Basic and Clinical Pharmacologv series, Karger, 1991), wherein the basis of alpha 1/alpha 2 subclassification, the molecular biology, signal transduction (G-protein interaction and location of the significant site for this and ligand binding activity away from the 3'- terminus of alpha adrenergic receptors), agonist structure-activity relationships, receptor functions, and therapeutic applications for compounds exhibiting alpha-adrenergic receptor affinity was explored.

The cloning, sequencing and expression of alpha receptor subtypes from animal tissues has led to the subclassification of the alpha 1 receptors into alpha 1d (formerly known as alpha la or la/ld), alpha 1b and alpha la (formerly known as alpha 1c) subtypes. Each alpha 1 receptor subtype exhibits its own pharmacologic and tissue specificities. The designation "alpha la" is the appellation recently approved by the IUPHAR Nomenclature Committee for the previously designated "alpha 1c" cloned subtype as outlined in the 1995 Receptor and Ion Channel Nomenclature Supplement (Watson and Girdlestone, 1995). The designation alpha la is used throughout this application to refer to this subtype. At the same time, the receptor formerly designated alpha la was renamed alpha ld. The new nomenclature is used throughout this application. Stable cell lines expressing these alpha 1 receptor subtypes are referred to herein; however, these cell lines were deposited with the American Type Culture Collection (ATCC) under the old nomenclature. For a review of the classification of alpha 1 adrenoceptor subtypes, see, Martin C. Michel, et al., Naunyn- Schmiedeberg's Arch. Pharmacol. (1995) 352:1-10.

The differences in the alpha adrenergic receptor subtypes have relevance in pathophysiologic conditions. Benign prostatic hyperplasia, also known as benign pro static hypertrophy or BPH, is an illness typically affecting men over fifty years of age, increasing in severity with increasing age. The symptoms of the condition include,

but are not limited to, increased difficulty in urination and sexual dysfunction. These symptoms are induced by enlargement, or hyperplasia, of the prostate gland. As the prostate increases in size, it impinges on free-flow of fluids through the male urethra.

Concommitantly, the increased noradrenergic innervation of the enlarged prostate leads to an increased adrenergic tone of the bladder neck and urethra, further restricting the flow of urine through the urethra.

In benign pro static hyperplasia, the male hormone Salpha- dihydrotestosterone has been identified as the principal culprit. The continual production of 5a-dihydrotestosterone by the male testes induces incremental growth of the prostate gland throughout the life of the male. Beyond the age of about fifty years, in many men, this enlarged gland begins to obstruct the urethra with the pathologic symptoms noted above.

The elucidation of the mechanism summarized above has resulted in the recent development of effective agents to control, and in many cases reverse, the pernicious advance of BPH. In the forefront of these agents is Merck & Co., Inc.s' product PROSCARB (finasteride).

The effect of this compound is to inhibit the enzyme testosterone 5-a reductase, which converts testosterone into Sa-dihydrotesterone, resulting in a reduced rate of pro static enlargement, and often reduction in prostatic mass.

The development of such agents as PROSCARB bodes well for the long-term control of BPH. However, as may be appreciated from the lengthy development of the syndrome, its reversal also is not immediate. In the interim, those males suffering with BPH continue to suffer, and may in fact lose hope that the agents are working sufficiently rapidly.

In response to this problem, one solution is to identify pharmaceutically active compounds which complement slower-acting therapeutics by providing acute relief. Agents which induce relaxation of the lower urinary tract tissue, by binding to alpha 1 adrenergic receptors, thus reducing the increased adrenergic tone due to the disease, would be good candidates for this activity. Thus, one such agent

is alfuzosin, which is reported in EP 0 204597 to induce urination in cases of prostatic hyperplasia. Likewise, in WO 92/0073, the selective ability of the R(+) enantiomer of terazosin to bind to adrenergic receptors of the alpha1 subtype was reported. In addition, in WO 92/161213, combinations of 5a-reductase inhibitory compounds and alphal- adrenergic receptor blockers (terazosin, doxazosin, prazosin, bunazosin, indoramin, alfuzosin) were disclosed. However, no information as to the alpha ld, alpha lb, or alpha la subtype specificity of these compounds was provided as this data and its relevancy to the treatment of BPH was not known. Current therapy for BPH uses existing non-selective alpha 1 antagonists such as prazosin (Minipress, Pfizer), Terazosin (Hytrin, Abbott) or doxazosin mesylate (Cardura, Pfizer). These non-selective antagonists suffer from side effects related to antagonism of the alpha 1d and alpha 1b receptors in the peripheral vasculature, e.g., hypotension and syncope.

The recent cloning of the human alpha la adrenergic receptor (ATCC CRL 11140) and the use of a screening assay utilizing the cloned human alpha la receptor enables identification of compounds which specifically interact with the human alpha la adrenergic receptor. [PCT International Application Publication Nos. W094/08040, published 14 April 1994 and WO94/10989, published 26 May 1994] As disclosed in the instant patent disclosure, a cloned human alpha la adrenergic receptor and a method for identifying compounds which bind the human alpha la receptor has now made possible the identification of selective human alpha la adrenergic receptor antagonists useful for treating BPH. The instant patent disclosure discloses novel compounds which selectively bind to the human alpha la receptor. These compounds are further tested for binding to other human alpha 1 receptor subtypes, as well as counterscreened against other types of receptors (e.g., alpha 2), thus defining the specificity of the compounds of the present invention for the human alpha la adrenergic receptor.

It is an object of the present invention to identify compounds which bind to the alpha la adrenergic receptor. It is a further object of the invention to identify compounds which act as antagonists of the alpha la adrenergic receptor. It is another object of the invention to

identify alpha la adrenergic receptor antagonist compounds which are useful agents for treating BPH in animals, preferably mammals, especially humans. Still another object of the invention is to identify alpha la adrenergic receptor antagonists which are useful for relaxing lower urinary tract tissue in animals, preferably mammals, especially humans.

It has now been found that the compounds of the present invention are alpha la adrenergic receptor antagonists. Thus, the compounds of the present invention are useful for treating BPH in mammals. Additionally, it has been found that the alpha la adrenergic receptor antagonists of the present invention are also useful for relaxing lower urinary tract tissue in mammals.

SUMMARY OF THE INVENTION The present invention provides compounds for the treatment of urinary obstruction caused by benign pro static hyperplasia (BPH). The compounds antagonize the human alpha la adrenergic receptor at nanomolar and subnanomolar concentrations while exhibiting at least ten fold lower affinity for the alpha id and alpha ib human adrenergic receptors and many other G-protein coupled receptors. This invention has the advantage over non-selective alpha 1 adrenoceptor antagonists of reduced side effects related to peripheral adrenergic blockade. Such side effects include hypotension, syncope, lethargy, etc. The compounds of the present invention have the structure: wherein Q is selected from

E, G, L and M are each independently selected from hydrogen, C1-8 alkyl, C3-8 cycloalkyl, (CH2)0-4OR6, (CH2)0-4N(R19)2, (CH2)0-4CN, (CH2)0-4CF3, (CH2)0-4CO2R19, (CH2)0-4CON(R19)2, (CH2)0-4SO2R19, or (CH2)o-4SO2N(R19)2;

J is selected from hydrogen, C1-8 alkyl, C3-8 cycloalkyl, (CH2)1-4OR6, (CH2)1-4N(R19)2, (CH2 ) 1-4CN, (CH2)0-4CF3, (CH2)0-4CO2R19, (CH2)0-4CON(R19)2, (CH2)0-4SO2R19, or (CH2)0-4SO2N(R19)2; R1 is selected from unsubstituted, mono- or poly-substituted phenyl wherein the substituents on the phenyl are independently selected from halogen, CF3, cyano, nitro, N(R19)2, NR19COR20, NR19CON(R20)2, NR19SO2R20, NR19SO2N(R20)2, OR6, (CH2)0-4CO2R19, oxadiazolyl-, C1- 4 alkyl oxadiazolyl-, (CH2)0-4CON(R19)2, (CH2)0-4SO2N(R19)2, (CH2)0- 4SO2R6 or C1-4 alkyl; or unsubstituted, mono- or poly-substituted pyridyl, pyrazinyl, thienyl, thiazolyl, furanyl, quinazolinyl or naphthyl wherein the substituents on the pyridyl, pyrazinyl, thienyl, thiazolyl, furanyl, quinazolinyl or naphthyl are independently selected from CF3, cyano, nitro, (CH2)0-4CO2R19, (CH2)04CON(R19)2, (CH2)0-4SO2N(R19)2, (CH2)0-4SO2R6, phenyl, OR6, halogen, C1-4 alkyl or C3-8 cycloalkyl; R2, R3, R8, R10, R15, R16, R17 and R18 are each independently selected from hydrogen, C1-8 alkyl, C3-8 cycloalkyl, (CH2)2 40R6 or (CH2)o-4CF3; R4 is selected from hydrogen, (CH2)0-4COR6, (CH2)0-4CN, (CH2)0-4CF3, (CH2)0-4CO2R19, (CH2)0-4CON(R19)2, (CH2)0-4SO2R6 or (CH2)o-4SO2N(R19)2; R5 is selected from hydrogen, C1-8 alkyl, C3-8 cycloalkyl, (CH2)1 40R6 or (CH2)0-4CF3; R6 is selected from hydrogen, C1-8 alkyl, C3-8 cycloalkyl or (CH2)0-4CF3; R7 is selected from hydrogen, C1-8 alkyl, C4-8 cycloalkyl, (CH2)0-4CO2R19, (CH2)0-4CON(R19)2, (CH2)0-4COR19, (CH2)2-4OR6, (CH2)1-4CF3, (CH2)0-4SO2R6, (CH2)0-4SO2N(R19)2 or (CH2)1-4CN;

R9 is selected from hydrogen, C1-8 alkyl, C3-8 cycloalkyl, CO2R6, CON(R6)2, (CH2)1 4OR6 or (CH2)0-4 CF3; R11 and R12 are each independently selected from hydrogen, C1-8 alkyl or C3-8 cycloalkyl; R13 and R14 are each independently selected from hydrogen, C1-8 alkyl, C3-8 cycloalkyl, (CH2)1-4OR6, (CH2)0-4CF3, unsubstituted, mono- or poly-substituted phenyl wherein the substituents on the phenyl are independently selected from halogen, CF3, cyano, nitro, amino, OR6, (CH2)04CoN(Rl9)2 (CH2)0-4CO2R19 or C14 alkyl; or unsubstituted, mono- or poly-substituted: pyridyl, thienyl, furanyl or naphthyl wherein the substituents on the pyridyl, thienyl, furanyl or naphthyl are independently selected from CF3, phenyl, OR6, halogen, C1-4 alkyl or C3-8 cycloalkyl; R19 and R20 are each independently selected from hydrogen, C1-8 alkyl, C3-8 cycloalkyl or (CH2)l-4CF3; R22 is selected from hydrogen, C1-8 alkyl, C3-8 cycloalkyl, (CH2)o 40R6 or (CH2)0-4CF3; R24 and R26 are each independently selected from hydrogen or OR28; R28 is selected from hydrogen, C1-8 alkyl, C3-8 cycloalkyl, or (CH2)0-4CF3; W is O or NR11; each X is independently selected from halogen, cyano, nitro, C1-8 alkyl, C3-8 cycloalkyl, (CH2)0-4OR6 or (CH2)o-4CF3; Y is C-R19 or N;

Z is hydrogen, oxygen or sulphur; m, p and q are each independently an integer from zero to two, provided that when q is zero, R26 is hydrogen; n, o, and s are each independently an integer from zero to four; and v is an integer from zero to one; and the pharmaceutically acceptable salts thereof.

In a first embodiment of the invention is the compound having the structure wherein R1 is selected from unsubstituted, mono- or poly-substituted phenyl wherein the substituents on the phenyl are independently selected from halogen, CF3, cyano, nitro, N(R19)2, NR19COR20, NR19CON(R20)2, NR19SO2R20, NR19SO2N(R20)2, OR6, (CH2)0.

4CO2R19, (CH2)0-4CON(R19)2, (CH2)0-4SO2N(R19)2, (CH2)0-4SO2R6 or C1-4 alkyl; or unsubstituted, mono- or poly-substituted pyridyl, pyrazinyl, thienyl, thiazolyl, furanyl, quinazolinyl or naphthyl wherein the substituents on the pyridyl, pyrazinyl, thienyl, thiazolyl, furanyl, quinazolinyl or naphthyl are independently selected from CF3, cyano, nitro, (CH2)0-4CO2R19, (CH2)0-4CON(R19)2, (CH2)0-4SO2N(R19)2, (CH2)0-4SO2R6, phenyl, OR6, halogen, C1-4 alkyl or C3-8 cycloalkyl; R4 is selected from (CH2)0 4COR6, (CH2)0-4CN, (CH2)0-4CF3, (CH2)0-4CO2R19, (CH2)0-4CON(R19)2, (CH2)0-4So2R6 or (CH2)o-4SO2N(R19)2; R5 is selected from hydrogen, C1-8 alkyl, C3-8 cycloalkyl, (CH2)2 40R6 or (CH2)0-4CF3;

R9 is selected from hydrogen, C1-8 alkyl, C3-8 cycloalkyl, (CH2)2-4OR6 or (CH2)0-4CF3; and all other variables are as defined above; and the pharmaceutically acceptable salts thereof.

In a second embodiment of the invention is the compound of the formula wherein E, G, L, M and J are each independently selected from hydrogen, C1-8 alkyl, C3-8 cycloalkyl, or (CH2)o-4CF3; R1 is selected from unsubstituted, mono-, di- or tri-substituted phenyl wherein the substituents on the phenyl are independently selected from halogen, CF3, cyano, nitro, N(R19)2 NR19COR20, NR19CON(R20)2, NR19SO2R20, NR19SO2N(R20)2, OR6, (CH2)0-4CO2R19, oxadiazolyl-, C 1-4 alkyloxadiazolyl, (CH2)0-4CON(R19)2, (CH2)0-4SO2N(R19)2, (CH2)0- 4SO2R6 or C1-4 alkyl; or unsubstituted, mono-, di- or tri-substituted pyridyl, pyrazinyl, thienyl, thiazolyl, furanyl, quinazolinyl or naphthyl wherein the substituents on the pyridyl, pyrazinyl, thienyl, thiazolyl, furanyl, quinazolinyl or naphthyl are independently selected from CF3, cyano, nitro, (CH2)0-4CO2R19, (CH2)0-4CON(R19)2, (CH2)0-4SO2N(R19)2, (CH2)0-4SO2R6, phenyl, OR6, halogen, C1-4 alkyl or C3-8 cycloalkyl; R7 is selected from hydrogen, C1-8 alkyl, C4-8 cycloalkyl or (CH2)1-4CF3;

R13 and R14 are each independently selected from hydrogen, C1-8 alkyl, C3-8 cycloalkyl, (CH2)1-40R6, (CH2)0-4CF3, unsubstituted, mono-, di- or tri-substituted phenyl wherein the substituents on the phenyl are independently selected from halogen, CF3, cyano, nitro, amino, OR6, (CH2)0-4 CON(R19)2, (CH2)0-4CO2R19 or C1-4 alkyl; or unsubstituted, mono-, di- or tri--substituted: pyridyl, thienyl, furanyl or naphthyl wherein the substituents on the pyridyl, thienyl, furanyl or naphthyl are independently selected from CF3, phenyl, OR6, halogen, C1-4 alkyl or C3-8 cycloalkyl; and n is an integer from zero to two; and all other variables are as originally defined above; and the pharmaceutically acceptable salts thereof.

In a third embodiment of the invention is the compound of the formula wherein E, G, L, M and J are each independently selected from hydrogen, C1-8 alkyl, C3-8 cycloalkyl, or (CH2)0-4CF3; R1 is selected from unsubstituted, mono-, di- or tri-substituted phenyl wherein the substituents on the phenyl are independently selected from halogen, CF3, cyano, nitro, N(R19)2, NR19COR20, NR19CON(R20)2, NR19SO2R20, NR19S02N(R20)2, OR6, (CH2)0-4CO2R19, (CH2)0-4CON(R19)2, (CH2)0-4SO2N(R19)2, (CH2)0 4SO2R6 or C1-4 alkyl; or unsubstituted, mono-, di- or tri-substituted pyridyl, pyrazinyl, thienyl, thiazolyl, furanyl, quinazolinyl or naphthyl wherein the substituents on the pyridyl, pyrazinyl, thienyl, thiazolyl, furanyl, quinazolinyl or naphthyl are independently selected from CF3, cyano,

nitro, (CH2)0-4CO2R19, (CH2)0-4CON(R19)2, (CH2)0-4SO2N(R19)2, (CH2)0-4SO2R6, phenyl, OR6, halogen, C1-4 alkyl or C3-8 cycloalkyl; R7 is selected from hydrogen, C1-8 alkyl, C4-8 cycloalkyl or (CH2)1 4CF3; R13 and R14 are each independently selected from hydrogen, C1-8 alkyl, C3-8 cycloalkyl, (CH2)1-40R6, (CH2)0-4CF3, unsubstituted, mono-, di- or tri-substituted phenyl wherein the substituents on the phenyl are independently selected from halogen, CF3, cyano, nitro, amino, OR6, (CH2)0-4CON(R19)2, (CH2)0-4CO2R19 or C1-4 alkyl; or unsubstituted, mono-, di- or tri--substituted: pyridyl, thienyl, furanyl or naphthyl wherein the substituents on the pyridyl, thienyl, furanyl or naphthyl are independently selected from CF3, phenyl, OR6, halogen, C1-4 alkyl or C3-8 cycloalkyl; n is an integer from zero to two; and all other variables are as defined in the first embodiment; and the pharmaceutically acceptable salts thereof.

In a first class of the invention is the compound selected from wherein Q is selected from

R1 is selected from unsubstituted, mono-, di- or tri-substituted phenyl wherein the substituents on the phenyl are independently selected from halogen, CF3, cyano, nitro, OR6, (CH2)0-2CO2R19, (CH2)0-2CON(R19)2, (CH2)0-2SO2N(R19)2, (CH2)0-2SO2R6, C 1-4 alkyl oxadiazolyl- or C 1-4 alkyl; or unsubstituted, mono-, or di-substituted pyridyl wherein the substituents on the pyridyl are independently selected from halogen, CF3, cyano, nitro, OR6, (CH2)0-2CO2R19, (CH2)02CON(R19)2, (CH2)0-2SO2N(R19)2, (CH2)0-2SO2R6 or C 1-4 alkyl; R4 is selected from hydrogen, COR6, CO2R19, SO2R6 or CON(R19)2; R5 is selected from hydrogen, C1-6 alkyl, C3-6 cycloalkyl, (CH2)1-30R6 or (CH2)o-3CF3; R6 is selected from hydrogen, C1-6 alkyl, C3-6 cycloalkyl or (CH2)0-3CF3; R8 and R10 are each independently selected from hydrogen, C1-6 alkyl, C3-6 cycloalkyl, (CH2)2-40R6 or (CH2)o-3CF3; R9 is selected from hydrogen, C1-6 alkyl, C3-6 cycloalkyl, CO2R6, CON(R6)2, (CH2)1-40R6 or (CH2)0-3CF3;

R13 is selected from hydrogen, C1-6 alkyl, C3-6 cycloalkyl, (CH2)2 40R6, (CH2)0-2CF3 or unsubstituted, mono- or di-substituted phenyl wherein the substituents on the phenyl are independently selected from halogen, CF3, cyano, nitro, amino, OR6, CO2R19 or C1-4 alkyl; R19 is selected from hydrogen, C1-6 alkyl, C3-6 cycloalkyl or (CH2)1 3CF3; R22 is selected from hydrogen, C1-6 alkyl, C36 cycloalkyl, (CH2)0-40RG or (CH2)o-3CF3; R28 is selected from hydrogen, C1-6 alkyl, C3-6 cycloalkyl, or (CH2)o-3CF3; q is an integer from zero to two; and s is an integer from zero to three; and all other variables are as defined previously in the second embodiment; and the pharmaceutically acceptable salts thereof.

In a second class of the invention is the compound selected from wherein Q is selected from

R1 is selected from unsubstituted, mono-, di- or tri-substituted phenyl wherein the substituents on the phenyl are independently selected from halogen, CF3, cyano, nitro, OR6, (CH2)0-2CO2R19, (CH2)0 2CON(R19)2, (CH2)0 -2SO2N(R19)2, (CH2)0-2SO2R6 or C 1-4 alkyl; or unsub stituted, mono-, or di-substituted pyridyl wherein the substituents on the pyridyl are independently selected from halogen, CF3, cyano, nitro, OR6, (CH2)0-2CO2R19, (CH2)0-2CON(R19)2, (CH2)0-2SO2N(R19)2, (CH2)0-2SO2R6 or C1-4 alkyl; R4 is selected from COR6, C02R19, S02R6 or CON(R19)2;

R5 is selected from hydrogen, C1-6 alkyl, C3-6 cycloalkyl, (CH2)1 30R6 or (CH2)0-3CF3; R6 is selected from hydrogen, C1-6 alkyl, C3-6 cycloalkyl or (CH2)0-3CF3; R8, R9 and R10 are each independently selected from hydrogen, C1-6 alkyl, C3-6 cycloalkyl, (CH2)2-4OR6 or (CH2)0-3CF3; R13 is selected from hydrogen, C 1-6 alkyl, C3-6 cycloalkyl,

(CH2)2 40R6, (CH2)0-2CF3 or unsubstituted, mono- or di-substituted phenyl wherein the substituents on the phenyl are independently selected from halogen, CF3, cyano, nitro, amino, OR6, CO2R19 or C1-4 alkyl; R19 is selected from hydrogen, C1-6 alkyl, C3-6 cycloalkyl or (CH2)l-3CF3; R22 is selected from hydrogen, C1-6 alkyl, C3-6 cycloalkyl, (CH2)0-40R6 or (CH2)0-3CF3; q is an integer from zero to two; s is an integer from zero to three; and all other variables are as defined previously in the third embodiment; and the pharmaceutically acceptable salts thereof.

In a first subclass of the invention is the compound wherein Q is selected from R13 is selected from hydrogen, C1-4 alkyl or unsubstituted, mono- or di- substituted phenyl wherein the substituents on the phenyl are independently selected from halogen, CF3, cyano, nitro, amino, OR6, C02R19 or C1-4 alkyl; each X is a halogen;

and all other variables are as defined previously in the first class; and the pharmaceutically acceptable salts thereof.

In a second subclass of the invention is the compound wherein Q is selected from R13 is selected from hydrogen, C1-4 alkyl or unsubstituted, mono- or di- substituted phenyl wherein the substituents on the phenyl are independently selected from halogen, CF3, cyano, nitro, amino, OR6, CO2R19 or C1-4 alkyl; each X is a halogen; and all other variables are as defined previously in the second class; and the pharmaceutically acceptable salts thereof.

In a first illustration of the invention is the compound selected from

wherein A is C-R21 or N; each R21 is independently selected from hydrogen, halogen, cyano, OC1-4 alkyl, OCF3, OCH2CF3, CO2CH3, CONH2, SO2NH2 or SO2C1-4 alkyl; R24 and R26 are each independently selected from hydrogen or OR28, wherein R28 is hydrogen or C1-4 alkyl; each X is fluorine; r is an integer from zero to two; and q is an integer from zero to one; and all other variables are as defined previously in the first subclass; and the pharmaceutically acceptable salts thereof.

In a second illustration of the invention is the compound selected from

wherein A is C-R21 or N; each R21 is independently selected from hydrogen, halogen, cyano, OC 4 alkyl, OCF3, OCH2CF3, C02CH3, CONH2, SO2NH2 or SO2C1-4 alkyl; each X is fluorine; r is an integer from zero to two; q is an integer from zero to one; and all other variables are as defined previously in the second subclass; and the pharmaceutically acceptable salts thereof.

In a first exemplification of the invention is the compound wherein Q is selected from R4 is CO2R19; R5 is (CH2)1 30R6;

and all other variables are as defined previously in the first illustration; and the pharmaceutically acceptable salts thereof.

In a second exemplification of the invention is the compound wherein Q is selected from R4 is CO2R19; R5 is (CH2)1 30R6; and all other variables are as defined previously in the second illustration; and the pharmaceutically acceptable salts thereof.

An illustration of the invention is a pharmaceutical composition comprising a therapeutically effective amount of any of the compounds described above and a pharmaceutically acceptable carrier.

An example of the invention is a pharmaceutical composition made by combining any of the compounds described above and a pharmaceutically acceptable carrier. Another illustration of the invention is a process for making a pharmaceutical composition comprising combining any of the compounds described above and a pharmaceutically acceptable carrier.

Another example of the invention is the composition further comprising a therapeutically effective amount of a testosterone 5-alpha reductase inhibitor. Preferably, the testosterone 5-alpha reductase inhibitor is a type 1, a type 2, both a type 1 and a type 2 (i.e., a three component combination comprising any of the compounds described above combined with both a type 1 testosterone 5-alpha reductase

inhibitor and a type 2 testosterone 5-alpha reductase inhibitor) or a dual type 1 and type 2 testosterone 5-alpha reductase inhibitor. More preferably, the testosterone 5-alpha reductase inhibitor is a type 2 testosterone 5-alpha reductase inhibitor. Most preferably, the testosterone 5-alpha reductase inhibitor is finasteride.

More specifically illustrating the invention is a method of treating benign prostatic hyperplasia in a subject in need thereof which comprises administering to the subject a therapeutically effective amount of any of the compounds (or any of the compositions) described above.

Further exemplifying the invention is the method of treating BPH wherein the compound (or composition) additionally does not cause a fall in blood pressure at dosages effective to alleviate BPH.

Another illustration of the invention is the method of treating benign prostatic hyperplasia wherein the compound is administered in combination with a testosterone 5-alpha reductase inhibitor. Preferably, the testosterone 5-alpha reductase inhibitor is finasteride.

Further illustrating the invention is a method of inhibiting contraction of prostate tissue or relaxing lower urinary tract tissue in a subject in need thereof which comprises administering to the subject a therapeutically effective amount of any of the compounds (or any of the compositions) described above.

More specifically exemplifying the invention is the method of inhibiting contraction of prostate tissue or relaxing lower urinary tract tissue wherein the compound (or composition) additionally does not cause a fall in blood pressures at dosages effective to inhibit contraction of prostate tissue.

More particularly illustrating the invention is the method of inhibiting contraction of prostate tissue or relaxing lower urinary tract tissue wherein the compound (or composition) is administered in combination with a testosterone 5-alpha reductase inhibitor; preferably, the testosterone 5-alpha reductase inhibitor is finasteride.

More particularly exemplifying the invention is a method of treating a disease which is susceptible to treatment by antagonism of the

alpha la receptor which comprises administering to a subject in need thereof an amount of any of the compounds described above effective to treat the disease. Diseases which are susceptible to treatment by antagonism of the alpha la receptor include, but are not limited to, BPH, high intraocular pressure, high cholesterol, impotency, sympathetically mediated pain, migraine (see, K.A. Vatz, Headache 1997:37: 107-108) and cardiac arrhythmia.

An additional illustration of the invention is the use of any of the compounds described above in the preparation of a medicament for: a) the treatment of benign prostatic hyperplasia; b) relaxing lower urinary tract tissue; or c) inhibiting contraction of prostate tissue; in a subject in need thereof.

DETAILED DESCRIPTION OF THE INVENTION Representative compounds of the present invention exhibit selectivity for the human alpha la adrenergic receptor. One implication of this selectivity is that these compounds display selectivity for lowering intraurethral pressure without substantially affecting diastolic blood pressure.

Representative compounds of this invention display submicromolar affinity for the human alpha la adrenergic receptor subtype while displaying at least ten-fold lower affinity for the human alpha 1d and alpha 1b adrenergic receptor subtypes, and many other G- protein coupled human receptors. Particular representative compounds of this invention exhibit nanomolar and subnanomolar affinity for the human alpha la adrenergic receptor subtype while displaying at least 30 fold lower affinity for the human alpha id and alpha ib adrenergic receptor subtypes, and many other G-protein coupled human receptors (e.g., serotonin, dopamine, alpha 2 adrenergic, beta adrenergic or muscarinic receptors).

These compounds are administered in dosages effective to antagonize the alpha la receptor where such treatment is needed, as in BPH. For use in medicine, the salts of the compounds of this invention refer to non-toxic "pharmaceutically acceptable salts." Other salts may, however, be useful in the preparation of the compounds according to the

invention or of their pharmaceutically acceptable salts. Suitable pharmaceutically acceptable salts of the compounds of this invention include acid addition salts which may, for example, be formed by mixing a solution of the compound according to the invention with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, sulphuric acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid.

Furthermore, where the compounds of the invention carry an acidic moiety, suitable pharmaceutically acceptable salts thereof may include alkali metal salts, e.g. sodium or potassium salts; alkaline earth metal salts, e.g. calcium or magnesium salts; and salts formed with suitable organic ligands, e.g. quaternary ammonium salts. Thus, representative pharmaceutically acceptable salts include the following: Acetate, Benzenesulfonate, Benzoate, Bicarbonate, Bisulfate, Bitartrate, Borate, Bromide, Calcium, Camsylate, Carbonate, Chloride, Clavulanate, Citrate, Dihydrochloride, Edetate, Edisylate, Estolate, Esylate, Fumarate, Gluceptate, Gluconate, Glutamate, Glycollylarsanilate, Hexylresorcinate, Hydrabamine, Hydrobromide, Hydrochloride, Hydroxynaphthoate, Iodide, Isothionate, Lactate, Lactobionate, Laurate, Malate, Maleate, Mandelate, Mesylate, Methylbromide, Methylnitrate, Methylsulfate, Mucate, Napsylate, Nitrate, N-methylglucamine ammonium salt, Oleate, Pamoate (Embonate), Palmitate, Pantothenate, Phosphate/diphosphate, Polygalacturonate, Salicylate, Stearate, Sulfate, Subacetate, Succinate, Tannate, Tartrate, Teoclate, Tosylate, Triethiodide and Valerate.

Compounds of this invention are used to reduce the acute symptoms of BPH. Thus, compounds of this invention may be used alone or in conjunction with a more long-term anti-BPH therapeutics, such as testosterone 5-a reductase inhibitors, including PROSCARB (finasteride). Aside from their utility as anti-BPH agents, these compounds may be used to induce highly tissue-specific, localized alpha la adrenergic receptor blockade whenever this is desired. Effects of this blockade include reduction of intra-ocular pressure, control of cardiac arrhythmias, and possibly a host of alpha la receptor mediated central nervous system events.

The present invention includes within its scope prodrugs of the compounds of this invention. In general, such prodrugs will be functional derivatives of the compounds of this invention which are readily convertible in vivo into the required compound. Thus, in the methods of treatment of the present invention, the term "administering" shall encompass the treatment of the various conditions described with the compound specifically disclosed or with a compound which may not be specifically disclosed, but which converts to the specified compound in vivo after administration to the patient. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in "Design of Prodrugs," ed. H. Bundgaard, Elsevier, 1985.

Metabolites of these compounds include active species produced upon introduction of compounds of this invention into the biological milieu.

Where the compounds according to the invention have at least one chiral center, they may accordingly exist as enantiomers.

Where the compounds according to the invention possess two or more chiral centers, they may additionally exist as diastereoisomers. It is to be understood that all such isomers and mixtures thereof are encompassed within the scope of the present invention. Furthermore, some of the crystalline forms for compounds of the present invention may exist as polymorphs and as such are intended to be included in the present invention. In addition, some of the compounds of the present invention may form solvates with water (i.e., hydrates) or common organic solvents. Such solvates are also encompassed within the scope of this invention.

The term "alkyl" shall mean straight or branched chain alkanes of one to ten total carbon atoms, or any number within this range (i.e., methyl, ethyl, 1-propyl, 2-propyl, n-butyl, s-butyl, t-butyl, etc.).

The term "alkenyl" shall mean straight or branched chain alkenes of two to ten total carbon atoms, or any number within this range.

The term "aryl" as used herein, except where otherwise specifically defined, refers to unsubstituted, mono- or poly-substituted aromatic groups such as phenyl or naphthyl.

The term "cycloalkyl" shall mean cyclic rings of alkanes of three to eight total carbon atoms (i.e., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl).

Whenever the term "alkyl" or "aryl" or either of their prefix roots appear in a name of a substituent (e.g., aralkoxyaryloxy) it shall be interpreted as including those limitations given above for "alkyl" and "aryl." Designated numbers of carbon atoms (e.g., Cl- 10) shall refer independently to the number of carbon atoms in an alkyl or cyclic alkyl moiety or to the alkyl portion of a larger substituent in which alkyl appears as its prefix root.

The term "halogen" shall include iodine, bromine, chlorine and fluorine.

The term "substituted" shall be deemed to include multiple degrees of substitution by a named substituent. The term "poly- substituted" as used herein shall include di-, tri-, tetra- and penta- substitution by a named substituent. Preferably, a poly-substituted moiety (e.g., phenyl) is di-, tri- or tetra-substituted by the named substituents, most preferably, di- or tri-substituted.

It is intended that the definition of any substituent or variable (e.g., X, R19, R20) at a particular location in a molecule be independent of its definitions elsewhere in that molecule. Thus, - N(R19)2 represents -NH2, -NHCH3, -NHC2H5, -N(CH3)C2H5, etc. and represents for m=2 It is understood that substituents and substitution patterns on the compounds of the instant invention can be selected by one of ordinary skill in the art to provide compounds that are chemically stable and that can be readily synthesized by techniques known in the art as well as those methods set forth below. Where multiple substituent moieties are disclosed or claimed, the substituted compound can be independently substituted by one or more of the disclosed or claimed substituent moieties, singly or plurally.

The term "Z is hydrogen," when refering to the "Q" group refers to the moiety The term heterocycle or heterocyclic ring, as used herein, represents an unsubstituted or substituted stable 5- to 7-membered monocyclic ring system which may be saturated or unsaturated, and which consists of carbon atoms and from one to three heteroatoms selected from N, O or S, and wherein the nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized. The heterocyclic ring may be attached at any heteroatom or carbon atom which results in the creation of a stable structure. Examples of such heterocyclic groups include, but is not limited to, piperidinyl, piperazinyl, oxopiperazinyl, oxopiperidinyl, oxopyrrolidinyl, oxoazepinyl, azepinyl, pyrrolyl, pyrrolidinyl, furanyl, thienyl, pyrazolyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolidinyl, isooxazolyl, isoxazolidinyl, morpholinyl, thiazolyl, thiazolidinyl, is othiaz olyl, thiadiazolyl, tetrahydropyranyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, and oxadiazolyl. Morpholino is the same as morpholinyl.

The term "thienyl," as used herein, refers to the group The terms "(+)-DHP" and "DHP" as used herein, refer to a dihydropyrimidinone group of the formula for example: The term "activated (+)-DHP," as used herein, refers to a N- 3-(activated)carbamate of the desired dihydropyrimidinone where the activating group is, for example, a p-nitrophenyloxy group. A specific example of an activated (+)-DHP is 4-(3,4-difluorophenyl)-5- methoxycarbonyl-6-methoxymethyl-2-oxo- 1,2,3 ,4-tetrahydropyrimidine- 3-carboxylic acid (4-nitrophenyl ester), also referred to as the compound 8.

The term "(S)-oxa" as used herein, refers to an oxazolidinone group of the formula

for example, The term "activated (S)-oxa" as used herein, refers to an N- (activated)carbamate of the desired oxazolidinone where the activating group is, for example, a p-nitrophenyloxy group. A specific example of an activated (S)-oxa group is 4-(3 ,4-difluorophenyl)-2-oxo-oxazolidine-3- carboxylic acid 4-nitrophenyl ester (i.e., compound 19).

The term "selective alpha la adrenergic receptor antagonist," as used herein, refers to an alpha la antagonist compound which is at least ten fold selective for the human alpha la adrenergic receptor as compared to the human alpha lb, alpha ld, alpha 2a, alpha 2b and alpha 2c adrenergic receptors.

The term "lower urinary tract tissue," as used herein, refers to and includes, but is not limited to, pro static smooth muscle, the pro static capsule, the urethra and the bladder neck.

The term "subject," as used herein refers to an animal, preferably a mammal, most preferably a human, who has been the object of treatment, observation or experiment.

The term "therapeutically effective amount" as used herein means that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, which includes alleviation of the symptoms of the disease being treated.

The present invention also provides pharmaceutical compositions comprising one or more compounds of this invention in association with a pharmaceutically acceptable carrier. Preferably these compositions are in unit dosage forms such as tablets, pills, capsules, powders, granules, sterile parenteral solutions or suspensions, metered aerosol or liquid sprays, drops, ampoules, auto- injector devices or suppositories; for oral, parenteral, intranasal, sublingual or rectal administration, or for administration by inhalation or insufflation. Alternatively, the compositions may be presented in a form suitable for once-weekly or once-monthly administration; for example, an insoluble salt of the active compound, such as the decanoate salt, may be adapted to provide a depot preparation for intramuscular injection. For preparing solid compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical carrier, e.g. conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, e.g. water, to form a solid preformulation composition containing a homogeneous mixture of a compound of the present invention, or a pharmaceutically acceptable salt thereof. When referring to these preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules. This solid preformulation composition is then subdivided into unit dosage forms of the type described above containing from 0.1 to about 500 mg of the active ingredient of the present invention. The tablets or pills of the novel composition can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action. For example, the tablet or pill can comprise an inner

dosage and an outer dosage component, the latter being in the form of an envelope over the former. The two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permits the inner component to pass intact into the duodenum or to be delayed in release. A variety of materials can be used for such enteric layers or coatings, such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol and cellulose acetate.

As used herein, the term "composition" is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.

The liquid forms in which the novel compositions of the present invention may be incorporated for administration orally br by injection include aqueous solutions, suitably flavoured syrups, aqueous or oil suspensions, and flavoured emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil or peanut oil, as well as elixirs and similar pharmaceutical vehicles. Suitable dispersing or suspending agents for aqueous suspensions include synthetic and natural gums such as tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinyl-pyrrolidone or gelatin.

Where the processes for the preparation of the compounds according to the invention give rise to mixtures of stereoisomers, these isomers may be separated by conventional techniques such as preparative chromatography. The compounds may be prepared in racemic form, or individual enantiomers may be prepared either by enantiospecific synthesis or by resolution. The compounds may, for example, be resolved into their component enantiomers by standard techniques, such as the formation of diastereomericpairs by salt formation with an optically active acid, such as (-)-di-p-toluoyl-d-tartaric acid and/or (+)-di-p-toluoyl-l-tartaric acid followed by fractional crystallization and regeneration of the free base. The compounds may also be resolved by formation of diastereomeric esters or amides,

followed by chromatographic separation and removal of the chiral auxiliary. Alternatively, the compounds may be resolved using a chiral HPLC column.

During any of the processes for preparation of the compounds of the present invention, it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups, such as those described in Protective Groups in Organic Chemistrv, ed. J.F.W. McOmie, Plenum Press, 1973; and T.W. Greene & P.G.M. Wuts, Protective Grounds in Organic Svnthesis, John Wiley & Sons, 1991. The protecting groups may be removed at a convenient subsequent stage using methods known from the art.

The specificity of binding of compounds showing affinity for the alpha la receptor is shown by comparing affinity to membranes obtained from tranfected cell lines that express the alpha la receptor and membranes from cell lines or tissues known to express other types of alpha (e.g., alpha id, alpha lb) or beta adrenergic receptors. Expression of the cloned human alpha id, alpha ib, and alpha la receptors and comparison of their binding properties with known selective antagonists provides a rational way for selection of compounds and discovery of new compounds with predictable pharmacological activities. Antagonism by these compounds of the human alpha la adrenergic receptor subtype may be functionally demonstrated in anesthetized animals. These compounds may be used to increase urine flow without exhibiting hypotensive effects.

The ability of compounds of the present invention to specifically bind to the alpha la receptor makes them useful for the treatment of BPH. The specificity of binding of compounds showing affinity for the alpha la receptor is compared against the binding affinities to other types of alpha or beta adrenergic receptors. The human alpha adrenergic receptor of the la subtype was recently identified, cloned and expressed as described in PCT International Application Publication Nos. W094/08040, published 14 April 1994 and WO 94/21660, published 29 September 1994. The cloned human alpha la receptor, when expressed in mammalian cell lines, is used to discover

ligands that bind to the receptor and alter its function. Expression of the cloned human alpha id, alpha ib, and alpha la receptors and comparison of their binding properties with known selective antagonists provides a rational way for selection of compounds and discovery of new compounds with predictable pharmacological activities.

Compounds of this invention exhibiting human alpha la adrenergic receptor antagonism may further be defined by counterscreening. This is accomplished according to methods known in the art using other receptors responsible for mediating diverse biological functions. FSee e.ff., PCT International Application Publication No.

WO94/10989, published 26 May 1994; U.S. Patent No. 5,403,847, issued April 4, 1995]. Compounds which are both selective amongst the various human alphal adrenergic receptor subtypes and which have low affinity for other receptors, such as the alpha2 adrenergic receptors, the - adrenergic receptors, the muscarinic receptors, the serotonin receptors, and others are particularly preferred. The absence of these non-specific activities may be confirmed by using cloned and expressed receptors in an analogous fashion to the method disclosed herein for identifying compounds which have high affinity for the various human alphal adrenergic receptors. Furthermore, functional biological tests are used to confirm the effects of identified compounds as alpha la adrenergic receptor antagonists.

The present invention also has the objective of providing suitable topical, oral, systemic and parenteral pharmaceutical formulations for use in the novel methods of treatment of the present invention. The compositions containing compounds of this invention as the active ingredient for use in the specific antagonism of human alpha la adrenergic receptors can be administered in a wide variety of therapeutic dosage forms in conventional vehicles for systemic administration. For example, the compounds can be administered in such oral dosage forms as tablets, capsules (each including timed release and sustained release formulations), pills, powders, granules, elixirs, tinctures, solutions, suspensions, syrups and emulsions, or by injection. Likewise, they may also be administered in intravenous (both bolus and infusion), intraperitoneal,

subcutaneous, topical with or without occlusion, or intramuscular form, all using forms well known to those of ordinary skill in the pharmaceutical arts. An effective but non-toxic amount of the compound desired can be employed as an alpha la antagonistic agent.

Advantageously, compounds of the present invention may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three or four times daily. Furthermore, compounds for the present invention can be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal routes, using those forms of transdermal skin patches well known to those of ordinary skill in that art. To be administered in the form of a transdermal delivery system, the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen.

The dosage regimen utilizing the compounds of the present invention is selected in accordance with a variety of factors including type, species, age, weight, sex and medical condition of the patient; the severity of the condition to be treated; the route of administration; the renal and hepatic function of the patient; and the particular compound thereof employed. A physician or veterinarian of ordinary skill can readily determine and prescribe the effective amount of the drug required to prevent, counter or arrest the progress of the condition. Optimal precision in achieving concentration of drug within the range that yields efficacy without toxicity requires a regimen based on the kinetics of the drug's availability to target sites. This involves a consideration of the distribution, equilibrium, and elimination of a drug.

In the methods of the present invention, the compounds herein described in detail can form the active ingredient, and are typically administered in admixture with suitable pharmaceutical diluents, excipients or carriers (collectively referred to herein as "carrier" materials) suitably selected with respect to the intended form of administration, that is, oral tablets, capsules, elixirs, syrups

and the like, and consistent with conventional pharmaceutical practices.

For instance, for oral administration in the form of a tablet or capsule, the active drug component can be combined with an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like. Moreover, when desired or necessary, suitable binders, lubricants, disintegrating agents and coloring agents can also be incorporated into the mixture. Suitable binders include, without limitation, starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes and the like.

Lubricants used in these dosage forms include, without limitation, sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like.

Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum and the like.

The liquid forms in suitably flavored suspending or dispersing agents such as the synthetic and natural gums, for example, tragacanth, acacia, methyl-cellulose and the like. Other dispersing agents which may be employed include glycerin and the like. For parenteral administration, sterile suspensions and solutions are desired. Isotonic preparations which generally contain suitable preservatives are employed when intravenous administration is desired.

The compounds of the present invention can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multil amellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines.

Compounds of the present invention may also be delivered by the use of monoclonal antibodies as individual carriers to which the compound molecules are coupled. The compounds of the present invention may also be coupled with soluble polymers as targetable drug carriers. Such polymers can include polyvinyl- pyrrolidone, pyran copolymer, polyhydroxypropylmethacryl-

amidephenol, polyhydroxy-ethylaspartamidephenol, or polyethyl- eneoxidepolylysine substituted with palmitoyl residues.

Furthermore, the compounds of the present invention may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydro-pyrans, polycyanoacrylates and cross-linked or amphipathic block copolymers of hydrogels.

Compounds of this invention may be administered in any of the foregoing compositions and according to dosage regimens established in the art whenever specific blockade of the human alpha la adrenergic receptor is required.

The daily dosage of the products may be varied over a wide range from 0.01 to 1,000 mg per adult human per day. For oral administration, the compositions are preferably provided in the form of tablets containing 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0 and 100 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated. A medicament typically contains from about 0.01 mg to about 500 mg of the active ingredient, preferably, from about 1 mg to about 100 mg of active ingredient. An effective amount of the drug is ordinarily supplied at a dosage level of from about 0.0002 mg/kg to about 20 mg/kg of body weight per day.

Preferably, the range is from about 0.001 to 10 mg/kg of body weight per day, and especially from about 0.001 mg/kg to 7 mg/kg of body weight per day. The compounds may be administered on a regimen of 1 to 4 times per day.

Compounds of this patent disclosure may be used alone at appropriate dosages defined by routine testing in order to obtain optimal antagonism of the human alpha la adrenergic receptor while minimizing any potential toxicity. In addition, co-administration or sequential administration of other agents which alleviate the effects of BPH is desirable. Thus, in one embodiment, this includes administration of compounds of this invention and a human testosterone 5-a reductase inhibitor. Included with this embodiment are inhibitors of 5-alpha reductase isoenzyme 2. Many such compounds are

now well known in the art and include such compounds as PROSCARB, (also known as finasteride, a 4-Aza-steroid; see US Patents 4,377,584 and 4,760,071, for example). In addition to PROSCARB, which is principally active in prostatic tissue due to its selectivity for human 5-a reductase isozyme 2, combinations of compounds which are specifically active in inhibiting testosterone 5-alpha reductase isozyme 1 and compounds which act as dual inhibitors of both isozymes 1 and 2, are useful in combination with compounds of this invention. Compounds that are active as 5a-reductase inhibitors have been described in W093/23420, EP 0572166; WO 93/23050; W093/23038,; W093/23048; WO93/23041; W093/23040; W093/23039; W093/23376; WO93/23419, EP 0572165; WO93/23051.

The dosages of the alpha la adrenergic receptor and testosterone 5-alpha reductase inhibitors are adjusted when combined to achieve desired effects. As those skilled in the art will appreciate, dosages of the 5-alpha reductase inhibitor and the alpha la adrenergic receptor antagonist may be independently optimized and combined to achieve a synergistic result wherein the pathology is reduced more than it would be if either agent were used alone. In accordance with the method of the present invention, the individual components of the combination can be administered separately at different times during the course of therapy or concurrently in divided or single combination forms. The instant invention is therefore to be understood as embracing all such regimes of simultaneous or alternating treatment and the term "administering" is to be interpreted accordingly.

Thus, in one preferred embodiment of the present invention, a method of treating BPH is provided which comprises administering to a subject in need of treatment any of the compounds of the present invention in combination with finasteride effective to treat BPH. The dosage of finasteride administered to the subject is about 0.01 mg per subject per day to about 50 mg per subject per day in combination with an alpha la antagonist. Preferably, the dosage of finasteride in the combination is about 0.2 mg per subject per day to about 10 mg per subject per day, more preferably, about 1 to about 7

mg per subject to day, most preferably, about 5 mg per subject per day.

For the treatment of benign pro static hyperplasia, compounds of this invention exhibiting alpha la adrenergic receptor blockade can be combined with a therapeutically effective amount of a Sa-reductase 2 inhibitor, such as finasteride, in addition to a 5a- reductase 1 inhibitor, such as 4,713-dimethyl-4-aza-5a-cholestan-3- one, in a single oral, systemic, or parenteral pharmaceutical dosage formulation. Alternatively, a combined therapy can be employed wherein the alpha la adrenergic receptor antagonist and the 5a- reductase 1 or 2 inhibitor are administered in separate oral, systemic, or parenteral dosage formulations. See, e.g., U.S. Patent No.'s 4,377,584 and 4,760,071 which describe dosages and formulations for 5 a-reductase inhibitors.

Abbreviations used in the instant specification, particularly the Schemes and Examples, are as follows: AcOH or HOAc = acetic acid BCE = bromochloroethane Boc or BOC = t-butyloxycarbonyl BOC2O = di-tert-butyl dicarbonate BOPCl = bis(2-oxo-3-oxazolidinyl)phosphinic chloride BuOH = butanol Cbz-Cl = benzyloxycarbonyl chloride DAST = diethylaminosulfurtrifluoride DEAD = diethylazodicarboxylate DMF = N,N-dimethylformamide DMSO = dimethylsulfoxide DPPA = diphenylphosphoryl azide ED CI = 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride Et = ethyl Et3N = triethylamine EtOAc = ethyl acetate EtOH = ethanol

FABLRMS = fast atom bombardment low resolution mass spectroscopy FABMS = fast atom bombardment mass spectroscopy HMPA = hexamethylphosporamide HPLC = high performance liquid chromatography HOBt = 1-hydroxy benzotriazole hydrate i-Pr or iPr = isopropyl i-PrOH = 2-propanol i-Pr2NEt = diisopropylethylamine LAH = lithium aluminum hydride mCPBA = meta-chloroperbenzoic acid Me = methyl MeOH = methanol n-BuLi = n-butyl lithium NMR = nuclear magnetic resonance PCTLC = preparative centrifugal thin layer chromatography PEI = polyethylenimine Ph = phenyl RT = retention time TEBAC = benzyltriethylammonium chloride TFA = trifluoroacetic acid THF = tetrahydrofuran TLC = thin layer chromatography TMS = trimethylsilyl Tos2O or TO SO = p-toluenesulfonic anhydride The compounds of the present invention can be prepared readily according to the following reaction schemes and examples, or modifications thereof, using readily available starting materials, reagents and conventional synthesis procedures. In these reactions, it is also possible to make use of variants which are themselves known to those of ordinary skill in this art, but are not mentioned in greater detail.

Unless otherwise indicated, all variables are as defined above.

The preparation of some desired compounds are described in Schemes 1-11. 3-(tert-Butyloxycarbonyl)amino piperidine was prepared from nipecotic acid in three steps, Scheme 1. Subsequent reductive amination with a piperidone derivative, followed by Boc deprotection provided the desired acylation/alkylation precursor which after treatment with activated (+)-DHP, (S)-oxa, or difluorophenyl acetic acid derivatives produced the alpha la antagonists. When desired, the ketone starting materials can be further elaborated, for instance, via enolate alkylation to provide the alpha substituted ketones.

The 3-aminomethyl piperidinyl derivatives were assembled as outlined in Scheme 2 starting with reductive amination of 3-hydroxy methyl piperidine and a piperidone derivative. The hydroxy group was converted to a tosylate, displaced with azide and reduced to the amino compound. Acylation or alkylation under standard conditions produced the targeted analogs.

The 3-aminopyrrolidinyl analogs were constructed by reductive amination of 3-(tert-butoxycarbonyl)amino pyrrolidine and a piperidone derivative, Scheme 3. Acidic deprotection of the carbamate produced the 3-amino pyrrolidinyl intermediate which was acylated under standard conditions.

In Scheme 4, the 3-aminomethyl pyrrolidinyl analogs were assembled in an analogous manner to the 3-aminomethyl piperidinyl analogs illustrated in Scheme 2.

Similarly, Scheme 5 describes the preparation of the 3- aminoazetidinyl analogs.

Examples of the preparation of some desired compounds are outlined in Scheme 6. Selective Boc protection of 4-aminomethyl piperidine (1) on the piperidine nitrogen provided (2) and CBZ protection of the primary amine resulted in (3). TFA treatment of (3) produced (4) which after reductive amination with ketone (5) yielded (6).

Hydrogenolysis of (6) left the primary amine (7) which clearly acylated with (8) which produced the DHP derivative (9). Amine (7) was also acylated with the oxazolidinone (19) producing (28).

Other derivatives were prepared via the route outlined in Schemes 7 to 8. N-protected 3-hydroxy azetidine (10) was tosylated

providing (11). Azide displacement produced (12) followed by reduction with PPh3/H2O resulted in N-protected 3-amino azetidine (13). Boc protection provided (14) which after hydrogenation produced (15).

Reductive amination with (5) yielding (16), followed by TFA treatment set up the requisite amine (17). Acylation with activated DHP (8), oxa (19) and acids (29) and (31) produced (18), (20), (30) and (32), respectively.

The synthesis of some 3-substituted piperidinyl analogs was accomplished starting with reductive amination of 3-hydroxymethyl piperidine (21) and (5) providing (22) as shown in Scheme 8. Tosylation, azide displacement and subsequent reduction provided the 3- aminomethyl piperidinyl intermediate (25). Acylation with activated DHP (8) and oxa (19) produced (26) and (27). These diastereomeric mixtures were separated using a Chiracel AD column providing the pairs (26a) & (26b) and (27a) & (27b).

Antagonists with cycloalkyl linking chains can be assembled by reductive amination of the prerequisite amino alcohol and a ketone, for example, N-(2-cyanophenyl)piperidin-4-one, Scheme 9.

Conversion of the hydroxy to a tosylate with tosyl anhydride, followed by displacement by the sodium or lithium salt of the desired Q group completes the synthesis of the targeted antagonists.

The 3-aminomethyl azetidine analogs were assembled starting from the N-protected 3-cyanoazetidine (33) by LAH (lithium aluminum hydride) reduction (34), amine protection with BOC2O (35) and azetidine deprotection (36) under catalytic hydrogenation conditions, Scheme 10. Reductive amination with (5) produced (37), which after Boc deprotection with TFA liberated the required amine (38) for coupling with activated species (8) and (19) providing (39) and (40), respectively.

Selective acylation of the primary amines was accomplished by treatment of the amines with nearly equimolar quantities of the activated termini species (i.e., the "Q" groups). The activated termini species comprising the "Q" groups are readily prepared by one of ordinary skill in the art. For example, unsubstituted, alkyl- and cycloalkyl-substituted oxazolidinones are prepared and activated in general by published and well developed chemistry, in particular, of Evans. [Evans, D.A.; Nelson, J.V.; Taber, T.R. Top. Stereochem. 13 1

(1982)] The starting materials, in general, are natural and unnatural amino acids. For instance, some of the preferred compounds are prepared from substituted phenyl glycine derivatives, which after reduction of the carboxylate and a phosgene equivalent mediated cyclization provides the substituted oxazolidinone ring system.

Deprotonation with n-butyl lithium and addition to a THF solution of p- nitrophenylchloroformate produces the stable, isolable "activated"oxazolidinone (oxa).

Oxazolidinones substituted with carboxylate, carboxamide, and hydroxymethyl are prepared by hydroxyamination of olefins to provide protected aminoalcohols, using procedures as described in Sharpless et al., Angew. Chem. Int. Ed. Engl., 35, 2813 (1996).

Deprotection under standard conditions followed by a phosgene equivalent to mediate cyclization provides the substituted oxazolidinone ring system. Deprotonation with a strong base, for example, lithium bis(trimethylsilyl)amide, and addition to a THF solution of p- nitrophenylchloroformate produces the stable, isolatable "activated" oxazolidinone.

Dihydropyrimidinones are prepared by condensation reaction of the aldehyde, urea and a 1,3-acetoacetate type derivative catalyzed by a Lewis Acid, a copper (I) species and acetic acid.

Activation was accomplished by treatment with a strong base, for instance, LiN(TMS)2, followed by addition to a THF solution of p- nitrophenylchloroformate .

Hydantoins and cycloimide were prepared in two chemical steps from ketones as outlined in the literature. More specifically, hydantoins were prepared according to known methodology, e.g., J.J.

Edmunds et al., J. Med. Chem. 1995, 38, pp. 3759-3771; J.H. Poupart et al., J. Chem. Res. 1979, pp. 174-175. Saccharins were prepared according to known methods, e.g., page 40 and Examples 21 and 22 of PCT International Application Publication No. W096/25934, published August 29, 1996.

The dihydropyrimidinones and the unsubstituted, alkyl- and cycloalkyl-substituted oxazolidinones were synthesized independently in racemic form, and then separated utilizing preparative

chiral HPLC. Their optical rotations were recorded. Then they were activated and reacted with prerequisite amines. From the receptor binding studies, a preferred isomer was identified, the (+) rotational isomer in each case. The absolute configurations were determined to be (S) for both the dihydropyrimidinones and oxazolidinones by correlating their optical rotations with x-ray crystal structures obtained of fragments involved in the production of the antagonists.

The oxazolidinone s substituted with carboxylate, carboxamide, and hydroxymethyl were prepared in enantiomer- enriched form and the assignments of (4S,5R) were made in accordance with Sharpless et al., Angew. Chem. Int. Ed. Engl., 35, (1996) SCHEME 1 SCHEME 1 (CONT"D) SCHEME 2 SCHEME 2 (Cont'd) SCHEME 3 SCHEME 4 SCHEME 4 (Cont'd) SCHEME 5 SCHEME 5 (Cont'd) SCHEME 6 SCHEME 6 (cont'd) SCHEME 7 SCHEME 7 (cont'd) SCHEME 8 26a Diastereomer A 26b Diastereomer B SCHEME 8 (cont'd) 31a Diastereomer A 31b Diastereomer B SCHEME 9 SCHEME 9 (cont'd) SCHEME 10 SCHEME 10 (Cont'd)

SCHEME 11 u o o FOH¼¼W F3!?n#OMe{{;{1{N}A{: ¼#UN;HoMe 5H NH2 Pd/C Me F~ r I a triphosgene ~W&02Me », 'PrzNEt Hh p-N02PhOCOCI F\ R 21 F R21 F F O2Me 02Me 02M e 02N N H2 R21 F F RZ F~S\ R21 .,,,e Fs < CHCI3 NH3 <5

Scheme 11 (cont'd) The following examples are provided to further define the invention without, however, limiting the invention to the particulars of these examples.

EXAMPLE 1 4-Aminomethvl-piperidine-1-carboxvlic acid tert-butvl ester (2) A solution of C-piperidin-4-yl-methylamine (1) (5.0 g, 44 mmol) and triethylamine (12 ml 88 mmol) in 150 ml of chloroform was cooled to 00 C. To this solution was added dropwise ditertbutyldicarbonate (8.6 g, 40 mmol) in 100 ml of chloroform. After stirring at room temperature for 24 hours the solution was washed with water, dried over MgSO4, filtered and the solvents removed in vacuo to give the title compound

1H NMR (CDCl3, 400 MHz) 4.20-4.00 (br m, 2H), 2.75-2.62 (br t, 2H), 2.60 (d, 2H), 1.75-1.65 (br m, 2H), 1.50-1.30 (m, 3H), 1.63 (s, 9H), 1.20-1.00 (m, 2H).

EXAMPLE 2 4-(Benzyloxycarbonylamino-methyl)-piperidine- 1-carboxylic acid tert- butvl ester (3) To a solution of 2 (2.4 g, 11.8 mmol) in 60 ml of ethyl acetate was added 60 ml of saturated K2CO3. To this biphasic solution was added benzyl chloroformate (2.03 ml, 14.23 mmol) dropwise. After stirring at room temperature for 3 hours the layers were separated and the organic layer dried over MgSO4, filtered, and the solvents removed in vacuo. The crude product was purified by chromatography on silica gel (3:1 hexane:ethyl acetate) to give the title compound.

1H NMR (CDCl3, 400 MHz) 7.39-7.30 (m, 5H), 5.09 (s, 1H), 4.90-4.80 (m, 1H), 4.15-4.05 (m, 2H), 3.09 (br t, 2H J=5.62 Hz), 2.66 (m, 2H), 1.70-1.62 (m, 3H), 1.45 (s, 9H), 1.20-1.00 (m, 2H).

EXAMPLE 3 Piperidin-4-vlmethvl-carbamic acid benzvl ester (4) To a solution of 3 (4.4 g, 13 mmol) in 90 ml of methylene chloride was added 45 ml of TFA. After stirring at room temperature for 24 hours, the solvents were removed in vacuo and the residue partitioned between chloroform and 10% Na2CO3. The organics were dried over MgSO4, filtered, and the solvent removed in vacuo to give the title compound.

1H NMR (CDC13, 400 MHz) 7.35 (s, 5H), 5.09 (s, 2H), 4.97 (br s, 1H), 3.36 (br s, 1H), 3.20-3.00 (m, 3H), 2.60 (t, 2H, J=11.96 Hz), 1.75-1.50 (m, 3H), 1.25-1.05 (m, 3H).

EXAMPLE 4

[1'-(2-Cyano-phenyl)-[1,4']bipiperidinyl-4-ylmethyl]-carbami c acid benzyl ester (6) To a solution of 2-(4-oxo-piperidin- 1-yl)-benzonitrile (AS (653 mg, 3.26 mmol) and 4 (890 mg, 3.58 mmol) in 40 ml of methanol was added 4 g of powdered 4A molecular sieves. The resulting suspension was stirred at room temperature for 24 hours. The suspension was subsequently acidified to pH 5 with acetic acid and a 1M solution of NaCNBH3 in THF (6.0 ml 5.6 mmol) was added slowly with a syringe pump over 24 hours. When the addition was complete, the solvent was removed in vacuo and the residue taken up in chloroform and filtered.

The solution was then washed with 10% Na2CO3, dried over MgSO4, and the solvent removed in vacuo to give the crude amine. The crude product was purified by chromatography on silica gel (5% MeOH/CHCl3) to give the title compound.

1H NMR (CDCl3, 400 MHz) 7.54 (dd 1H, J=7.5Hz, J=1.46Hz), 7.45 (m, 1H), 7.40-7.30 (m, 5H), 7.0-6.95 (m, 2H), 5.09 (s, 2H), 4.89 (m, 1H), 3.65 (d, 2H, J=11.9 Hz), 3.10 (t, 2H, J=6.4Hz) 2.99 (d, 2H, J=10.62Hz)2.80 (t, 2H, J=10.8Hz), 2.52 (br t, 1H, J=11.16Hz), 2.27 (t, 2H, J=10.81Hz), 1.98-1.70 (m, 6H), 1.60-1.45 (m, 1H), 1.40-1.25 (m, 2H).

EXAMPLE 5 2-(4-Aminomethvl-F 1 *4'lbipiperidinvl- 1'-vl)-benzonitrile (7) A suspension of 6 (100 mg, 0.232 mmol) and 10% Pd/C (30 mg) in 50 ml of ethyl acetate was hydrogenated at atmospheric pressure for 6 days. The suspension was subsequently filtered through celite and the solvent removed in vacuo to give the title compound.

1H NMR (CDCl3, 400 MHz) 7.53 (dd, 1H, J=7.69Hz, J=1.4Hz) 7.45, (m, 1H), 7.05-6.90 (m, 2H), 3.66 (d, 2H, J=11.71Hz), 2.98 (d, 2H, J=11.36 Hz), 2.80 (t, 2H, J=11.9Hz), 2.59 (d, 2H, J=5.86Hz), 2.50-2.40 (m, 1H), 2.30-2.15 (m, 2H), 2.00-1.75 (m, 6H), 1.35-1.10 (m, 4H).

EXAMPLE 6

3-{[1'-(2-Cyano-phenyl)-f 1,4']bipiperidinyl-4-ylmethyl]-carbamoyl}-4-(3,4- <BR> <BR> <BR> <BR> <BR> difluoro-phenyl )-6-methoxymethyl-2-oxo- 1,2,3 ,4-tetrahydro-nvrimidine-5- carboxvlic acid methvl ester trifluoroacetic acid salt (9) To a solution of 7 in 30 ml of chloroform was added dropwise 8 (100 mg, 0.232 mmol) in 10 ml of chloroform. The resulting solution was stirred for 20 minutes and the crude material purified by chromatography on silica gel (5% MeOH/CHCl3).

1H NMR (CD30D, 400 MHz) 9.15 (br s, 1H), 7.70-7.55 (m, 2H), 7.30-7.10 (m, 5H), 6.63 (s, 1H), 4.66 (AB q, 2H, J=39Hz, J=15.02), 3.72 (s, 3H), 3.80-3.60 (m, 3H), 3.50-3.30 (m, 3H), 3.44 (s, 3H), 3.07 (t, 2H, J=10.8Hz), 2.90 (t, 2H, J=11.54Hz), 2.23 (d, 2H, J=9.89 Hz), 2.10-2.80 (m, 6H), 1.60-1.42 (m, 2H). MS (FAB) 637 (M+1) Analysis calculated for C33 H38 N6 O5 F2 0.80 H2O, 1.40 TFA: C, 53.03; H, 5.10; N, 10.37 Found: C 53.03 H 5.12 N 10.37.

EXAMPLE 7 Toluene-4-sulfonic acid 1-benzhvdrvl-azetidin-3-vl ester (11) To a cooled (OOC) solution of 10 (7 g, 29 mmol) in 100 ml of chloroform was added paratoluene sulfonic anhydride (11.5 g, 35.2mmol), and triethylamine (12 ml, 88mmol). The resulting solution was stirred at room temperature for 24 hours. The solution was subsequently washed with water, dried over MgSO4, filtered, and the solvent removed in vacuo. The crude material was purified by chromatography on silica gel to give the desired product as an oil.

1H NMR (CDCl3, 400 MHz) 7.75 (d, 2H, J=8.3Hz), 7.35-7.15 (m, 12H), 4.95-4.82 (m, 1H), 4.32 (s, 1H), 3.50-3.40 (m, 2H), 3.10-3.00 (m, 2H), 2.43 (s, 3H).

EXAMPLE 8 3-Azido- 1-benzhvdrvl-azetidine (12) A solution of 11 (11.5 g, 31.8 mmol) and sodium azide (4.12 g, 64 mmol) in 250 ml of DMF was heated to 700C for 24 hours. After cooling to room temperature the solvent was removed in vacuo and the

residue partitioned between chloroform and water. The organics were dried over MgSO4, filtered and the solvent removed in vacuo. The crude product was purified by chromatography on silica gel (8:1 hexane: ethyl acetate) to give the title compound.

1H NMR (CDCl3, 400 MHz) 7.41-7.15 (m, 10H), 4.33 (s, 1H), 4.02-3.95 (m, 1H) 3.50-3.41 (m, 2H), 3.07-3.00 (m, 2H).

EXAMPLE 9 1-Benzhvdrvl-azetidin-3-vlamine (13) A solution of 12 (5.7 g, 21.6 mmol), triphenylphosphine (11.3 g, 43 mmol) and water (5 ml) was heated to reflux for 24 hours. After cooling to room temperature the solvent was removed in vacuo and the residue purified by chromatography on silica gel (90:9:1 CHCl3: MeOH:NH40H).

1H NMR (CDC13, 400 MHz) 7.41-7.15 (m, 10H), 4.27 (s, 1H), 3.65-3.55 (m, 1H), 3.55-3.50 (m, 2H), 2.65-2.60 (m, 2H) 1.44 (br s, 2H).

EXAMPLE 10 (1-Benzhvdrvl-azetidin-3-vl)- carbamic acid tert-butvl ester (14) A solution of 13 (3.5 g, 14.7 mmol) di-tert-butyl dicarbonate (3.8 g, 17.6 mmol) and triethyl amine (4.0 ml, 29 mmol) in 100 ml of chloroform was stirred at room temperature for 24 hours. The solution was subsequently washed with water, dried over MgSO4, filtered and the solvent removed in vacuo. The crude product was purified by chromatography on silica gel (3:1 hexane:ethyl acetate) to give the title compound.

1H NMR (CDCl3, 400 MHz) 7.38-7.15 (m, 10H), 4.81-4.90 (br s, 1H), 4.28 (s, 1H), 3.52 (t, 2H, J=6.96Hz) 2.81 (m, 2H), 1.42 (s, 9H).

EXAMPLE 11 Azetidin-3-vl-carbamic acid tert-butvl ester acetic acid salt (15) A suspension of 14 (4.6 g, 13.6 mmol) and 10% Pd/C (2.0 g) in 200 ml of 10:2:1 ethanol:water:acetic acid was hydrogenated at 50 psi for 24 hours. The suspension was subsequently filtered through celite and the solvents removed in vacuo to give the title compound.

1H NMR (CD3OD, 400 MHz) 4.55-4.45 (m, 1H), 4.20-4.10 (m, 2H), 4.10-4.00 (m, 2H), 1.91 (s, 3H), 1.44 (s, 9H).

EXAMPLE 12 1-[ 1-(2-Cyano-phenyl)-piperidin-4-yl]-azetidin-3-yl}-carbamic acid tert- butvl ester (16) The title compound was prepared from 15 (1.0 g, 4.9 mmol) and 3 (1.0 g, 4.3 mmol) using the procedure described for the preparation of 6 to give the title compound.

1H NMR (CDC13, 400 MHz) 7.54-7.51 (m, 1H,), 7.46-7.40 (m, 1H), 7.00-6.92 (m, 2H), 5.00-4.85 (br s, 1H), 4.35-4.21 (br s, 1H), 3.64 (t, 2H, J=6.83Hz), 3.55-3.42 (m, 2H), 2.95-2.80 (m, 4H), 2.25-2.10 (m, 1H), 1.90-1.75 (m, 2H), 1.62-1.50 (m, 2H), 1.45 (s, 9H).

EXAMPLE 13 2-r4-(3-Amino-azetidin-1-vl)-piperidin-1-vll-benzonitrile (17) The title compound was prepared from 16 (1.5 g) using the procedure described for the preparation of 4.

1H NMR (CDCl3, 400 MHz) 7.53 (dd, 1H, J=7.57Hz, 1.46Hz), 7.50-7.37 (m, 1H), 7.05-6.90 (m, 2H), 3.70-3.55 (m, 3H), 3.55-3.45 (m, 2H), 2.95-2.85 (m, 2H), 2.70-2.60 (m, 2H), 2.20-2.10 (m, 1H), 1.90-1.77 (m, 2H), 1.70-1.30 (m, 4H).

EXAMPLE 14 3-{1-[1-(2-Cyano-phenyl)-piperidin-4-yl]-azetidin-3-ylcarbam oyl}-4-(3,4- difluoro-phenyl)-6-methoxymethyl-2-oxo- 1,2,3 ,4-tetrahydro-pyrimidine-5- carboxvlic acid methvl ester (18) The title compound was prepared from 17 (1.0 g, 3.9 mmol) and 8 (520 mg, 1.1 mmol) using the procedure described for 9.

1H NMR (CDCl3, 400 MHz) 9.04 (d, 1H, J=6.6Hz), 7.72 (s, 1H), 7.55-7.50 (m, 1H), 7.40-7.50 (m, 1H), 7.21-6.90 (m, 5H), 6.65 (s, 1H), 4.68 (s, 2H), 4.55-4.50 (m, 1H), 3.75-3.65 (m, 2H), 3.71 (s, 3H), 3.55-3.42 (m, 2H), 3.50 (s, 3H), 2.95-2.82 (m, 4H), 2.30-2.15 (m, 1H), 2.87-2.75 (m, 2H), 1.63-1.45 (m, 2H).

MS (FAB) 595 (M+1).

Analysis calculated for C30 H22 N6 O5 F2 1.00 H2O: C, 58.81; H, 5.59, N, 13.72. Found: C, 58.58; H, 5.20; N, 13.59.

EXAMPLE 15 4-(3,4-Difluoro-phenyl)-2-oxo-oxazolidine-3-carboxylic acid { 1-[ 1-(2-cyano- phenyl)-piperidin-4-yl]-azetidin-3-yl}-amide triflouroacetic acid salt (20) The title compound was prepared from 17 (100 mg, 0.4 mmol) and 19 (171 mg, 0.48 mmol) using the procedure described for 9.

1H NMR (CD30D, 400 MHz) 7.65-7.55 (m, 2H), 7.35-7.25 (m, 2H) 7.15-7.20 (m, 3H), 5.45-5.50 (m, 1H), 4.85-4.78 (m, 1H), 4.75-4.62 (br s, 1H), 4.50-4.35 (m, 4H), 4.32-4.22 (m, 1H), 3.63 (d, 2H, J=12.27Hz), 3.50-3.40 (m, 1H), 2.88 (t, 2H, J=12.27), 2.16 (d, 2H, J=10.99Hz), 1.75-1.60 (m, 2H).

MS (FAB) 482 (M+1).

Analysis calculated for C25 H25 Ng O3 F2 1.05 H2O, 1.35 TFA: C, 50.84; H, 4.38; N, 10.70. Found: C, 50.83; H, 4.29; N, 11.09.

EXAMPLE 16 2-(3-Hvdroxvmethvl-F 1.4'lbipiperidinvl- 1'-vl)-benzonitrile (22) The title compound was prepared from 21 (1.13 g, 5.6 mmol) and 5 (750 mg, 3.75 mmol) using the procedure described in 16 to give the title compound.

1H NMR (CDCl3, 400 MHz) 7.37-7.35 (m, 1H), 7.50-7.41 (m, 1H), 7.20-6.93 (m, 2H), 3.77-3.55 (m, 4H), 2.98-2.90 (m, 1H), 2.90-2.67 (m, 3H), 2.57-2.23 (m, 4H), 1.98-1.50 (m, 8H), 1.27-1.08 (m, 1H).

EXAMPLE 17 p-Tolyl-methanesulfonic acid 1'-(2-cyano-phenyl)-[ 1 ,4']bipiperidinyl-3- vlmethvl ester (23) The title compound was prepared from 22 (1.1 g, 5.0mmol) and para-toluene sulfonic anhydride (2.48 g, 7.58 mmol) using the procedure described in 11.

1H NMR (CDCl3, 400 MHz) 7.80 (d, 2H, J=8.24Hz), 7.55-7.53 (m, 1H), 7.45 (m, 1H), 7.40-7.32 (m, 2H), 7.02-6.95 (m, 2H), 3.95-3.85 (m, 2H), 3.63 (d, 2H, J=11.71Hz), 2.82-2.70 (m, 3H), 2.45 (s, 3H), 2.45-2.35 (m,

1H), 2.27-2.18 (m, 1H), 2.07-1.90 (m, 2H), 1.85-1.57 (m, 7H), 1.57-1.45 (m, 1H), 1.10-0.97 (m, 1H).

EXAMPLE 18 2-(3-Azidomethyl-[1,4']bipiperidinyl-1'-yl)-benzonitrile (24) The title compound was prepared from 23 (1.37 g, 3.0 mmol) and sodium azide (0.4 g, 6.0 mmol) according to the procedure described in 12 to give the title compound.

1H NMR (CDCl3, 400 MHz) 7.55-7.52 (m, 1H), 7.50-7.42 (m, 1H), 7.02-6.94 (m, 2H), 3.66 (d, 2H, J=11.97Hz), 3.30-3.15 (m, 2H), 2.95-2.75 (m, 5H), 2.55-2.40 (m, 1H), 2.30-2.20 (m, 1H), 2.06 (t, 1H, J=10.01Hz), 1.95- 1.65 (m, 6H), 1.65-1.50 (m, 1H), 1.10-0.95 (m, 1H).

EXAMPLE 19 2-(3-Aminomethvl-F 1 .4'lbinioeridinvl- 1 '-vl)-benzonitrile (25) The title compound was prepared from 24 (560 mg, 1.73 mmol) and triphenylphosphine (900 mg, 3.4mmol) using the procedure described for 13.

1H NMR (CDCl3, 400 MHz) 7.55-7.53 (m, 1H), 7.47-7.43 (m, 1H), 7.00-6.95 (m, 2H), 3.66 (d, 2H, J=11.72Hz), 3.02 (d, 1H, J=10.25Hz), 2.91 (d, 1H, J=10.98Hz), 2.81 (t, 2H, J=11.9Hz), 2.62 (br s, 2H), 2.60-2.45 (m, 1H), 2.30-2.20 (m, 1H), 2.05-1.52 (m, 11H), 1.00-0.87 (m, 1H).

EXAMPLE 20 3-{[1'-(2-Cyano-phenyl)-[1,4']bipiperidinyl-3-ylmethyl]-carb amoyl}-4-(3,4- difluoro-phenyl)-6-methoxymethyl-2-oxo-1,2,3,4-tetrahydro-py rimidine-5- carboxvlic acid methvl ester trifluoroacetic acid salt (26) The title compound was prepared from 25 (175 mg, 0.58 mmol) and 8 (140 mg, 0.29 mmol) using the procedure described for 9.

1H NMR (CD30D, 400 MHz) 9.20-9.10 (m, 1H), 7.67-7.55 (m, 2H), 7.25-7.10 (m, 5H), 6.61-6.59 (m, 1H), 4.66 (AB q, 2H, J=39.37Hz, J=15.2Hz), 3.72 (s, 3H), 3.70-3.20 (m, 4H), 3.00-2.73 (m, 5H), 2.25-1.70 (m, 10H), 1.35-1.20 (m, 1H).

MS (FAB) 637 (M+1).

Analysis calculated for C33 H38 N6 O5 F2 0.35 H2O, 1.65 TFA: C, 52.45; H, 4.89; N, 10.11. Found: C, 52.45; H, 4.88; N, 10.13.

EXAMPLE 21 4-(3 ,4-Difluoro-phenyl)-2-oxo-oxazolidine-3-carboxylic acid [1'-(2-cyano- phenyl)-[1,4']bipiperidinyl-3-ylmethyl]-amide trifluoroacetic acid salt (27) The title compound was prepared from 25 (175 g, 0.58 mmol) and 19 (105 mg, 0.28 mmol) using the procedure described for 9.

1H NMR (DMSO-d6, 400 MHz) 8.10-8.00 (m, 1H), 7.78-7.70 (m, 1H), 7.65-7.57 (m, 1H), 7.50-7.37 (m, 2H), 7.21-7.08 (m, 3H), 5.47-5.39 (m, 1H), 4.76 (t, 1H, J=8.79Hz), 4.23-4.13 (m, 1H), 3.70-2.60 (m, 12H), 2.25- 1.57 (m, 8H), 1.23-1.03 (m, 1H).

MS (FAB) 524 (M+1).

Analysis calculated for C28 H31 N5 O3 F2 1.30 TFA: C, 54.70; H, 4.85; N, 10.43. Found: C, 54.72; H, 4.77; N, 10.11.

EXAMPLE 22 4-(3 ,4-Difluoro-phenyl)-2-oxo-oxazolidine-3-carboxylic acid [1 '-(2-cyano- Dhenvl)-T1 .4'lbiDiDeridinvl-4-vlmethvll-amide triflouroacetic acid salt (28) The title compound was prepared from 7(140 mg, 0.47 mmol) and 19 (170 mg, 0.47 mmol) using the procedure described for 9.

1H NMR (CD30D, 400 MHz) 7.65-7.52 (m, 2H), 7.35-7.25 (m, 2H), 7.20-7.15 (m, 3H), 5.27-5.20 (m, 1H), 4.77 (t, 1H, J=8.97Hz), 4.27-4.20 (m, 1H), 3.74-3.58 (m, 4H), 3.40-3.30 (m, 1H), 3.25-3.15 (m, 2H), 3.10-3.00 (m, 2H), 2.95-2.82 (t, 2H, J=11.71Hz), 2.24 (d, 2H, J=11.54), 2.10-1.80 (m, 5H), 1.58-1.42 (m, 2H).

MS (FAB) 524 (M+1).

Analysis calculated for C28 H31 Ng O3 F2 0.30 H2O, 1.85 TFA: C, 51.45; H, 4.56; N, 9.47. Found: C, 51.47; H, 4.58; N, 9.36.

EXAMPLE 23 3-Aminomethvl N-diphenvlmethvl azetidine. (34) To a cooled solution of aluminum chloride (0.33 g, 2.41 mmol) in ether (50 mL) at -780 C was added lithium aluminum hydride (2.41 ml, 2.41 mmol). After stirring 15 minutes at -78° C the slurry was added a solution of 33 (0.50 g, 2.01 mmol) in ether (10 mL) dropwise. The resulting mixture was stirred at room temperature for 2 hours. The solution was cooled to 0°C and quenched with water (10 mL) dropwise followed by 25% NaOH solution (10 mL). The aqueous layer was extracted with EtOAc. The organics were dried over Na2SO4, filtered, and removed in vacuo. The crude product was not purified.

1H NMR (CD Cl3, 300 MHz) 7.41-7.13 (m, 10 H), 4.32 (s, 1 H), 3.28 (t, 2 H), 2.88-2.79 (m, 4 H), 2.52-2.42(m, 1 H), 1.28 (s, 1 H).

EXAMPLE 24 3-N-(1,1-dimethylethoxyearbonyl)aminomethyl N-diphenylmethyl azetidine. (35) The title compound was prepared from 34 using the procedure described for the preparation of 14.

1H NMR (CDCl3, 300 MHz) 7.40-7.14 (m, 10 H), 4.84 (s, 1 H), 4.31 (s, 1 H), 3.50-3.21 (m, 4 H), 2.85 (t, 2 H), 2.59-2.48 (m, 1 H), 1.44 (s, 9 H).

EXAMPLE 25 3-N-[(1,1-dimethylethoxycarbonyl)methyl]aminomethyl azetidine, (36) The title compound was prepared from 35 using the procedure described for the preparation of 15.

1H NMR (CD30D, 300 MHz) 4.92-4.85 (m, 4 H), 4.05 (br m, 2 H), 3.88-3.86 (br m, 2 H), 1.94-1.90 (m, 1 H), 1.46 (s, 9 H) EXAMPLE 26

2-[4-(3-N-(1,1-Dimethylethoxycarbonyl)aminomethyl-azetidin- 1-yl)- piperidin-1-vll-benzonitrile (37) The title compound was prepared from 36 using the procedure described for the preparation of 16.

1H NMR (CDCl3, 300 MHz) 7.57-7.40 (m, 2 H), 7.05-6.92 (m, 2 H), 4.89 (s, 1 H), 3.53-3.46 (m, 3 H), 3.39-3.27 (m, 4 H), 2.95-2.85 (m, 4 H), 2.64-2.58 (m, 1 H), 2.25-2.19 (m, 1 H), 1.85-1.79 (m, 2 H), 1.60-1.44 (m, 10 H).

EXAMPLE 27 2-F4-(3-Aminomethvl-azetidin- 1-vl)-piperidin- 1-vll-benzonitrile. (38) The title compound was prepared from 37 using the procedure desrcibed for the preparation of 17.

1H NMR (CDCl3, 300 MHz) 7.54-7.40 (m, 2 H), 7.00-6.91 (m, 2 H), 3.55-3.46 (m, 2 H), 3.44-3.38 (m, 2 H), 2.93-2.83 (m, 6 H), 2.58-2.46 (m, 1 H), 2.23-2.14 (m, 1 H), 1.85-1.80 (m, 2 H), 1.60-1.48 (m, 2 H), 1.01-0.95 (br s, 2 H).

EXAMPLE 28

Compound (39) The title compound 39 was prepared from 38 using the procedure described for the preparation of 18.

1H NMR (CDCl3, 400 MHz) 8.98-8.95 (t, 1 H), 7.72 (s, 1 H), 7.54-7.52 (dd, 1 H), 7.46-7.42 (m, 1 H), 7.09-7.06 (m, 2 H), 6.99-6.93 (m, 2 H), 6.66 (s, 1 H), 4.68 (s, 2 H), 3.71 (s, 3 H), 3.55-3.39 (m, 10 H), 3.02-2.98 (t, 2 H), 2.88-2.73 (m, 3 H), 2.28-2.26 (m, 1 H), 1.83-1.80 (m, 2 H), 1.61-.1.56(m, 2 H).

MS (FAB) 609 (M+1) EXAMPLE 29 Compound (40) The title compound 40 was prepared from 38 using the procedure described for the preparation of 20.

1H NMR (CDCl3, 400 MHz) 8.01-7.98 (s, 1 H), 7.53-7.51 (d, 1 H), 7.45-7.41 (t, 1 H), 7.22-7.12 (m, 1 H), 7.07-7.00 (m, 1 H), 6.98-6.92 (m, 2 H), 5.41-5.40 (m, 1 H), 4.74-4.70 (t, 1 H), 4.27-4.23 (m, 1 H), 3.52-3.44 (m, 3 H), 3.40-3.31 (m, 3 H), 2.91-2.86 (m, 4 H), 2.67-2.64 (m, 1 H), 2.21 (br s, 1 H), 1.81-1.78 (m, 2 H), 1.58-1.53(m, 2 H).

Anal. Calcd for C26H27N5O3F2 0.25 CHCl3 + 0.20 H2O: C = 61.94, H = 5.48, N = 13.87. Found: C = 61.97, H = 5.55, N = 13.50.

MS (FAB) 496 (M+1) Utilizing the methodology described in detail herein, the following additional compounds shown in Tables 1 and 2 were made. In Tables 1 and 2, (+)DHP is TABLE 1 A FABLRMS HPLC elemental RT. cV)EP = 2»»" z min. u, H 285.2lg/mole 5.60 min. Caic. for ç ~ n o mol. wt.=515.98g/mofr CaIc:C=54.86%H=7.37%N=13.47% Wa Z UmUO Uv, UO UVIU .~ diast.(A) 623.396g/mole 8.98 min. Caic. for 0.40CHCI;070EtOAc Solvate mol. E E E ;F F o æ N p, , \o o\ ts 3:p( od v; 1.36% ev L cm mol. E E e: 1.58% t e ~ ~ (s es e ç o 00 x c v c < ao 0 0 Y Y O SC TABLE 1 (cont.) Obs:C=55.55%H=5.76%N=11.51%<BR> 439.24g/mole 8.62 min. Calc. for 1.0HCl;0.80H2O;0.20EtOAc<BR> Solvate mol.wt.=474.99g/mole<BR> Calc:C=61.12%H=6.40%N=11.05%<BR> Obs:C=61.08%H=6.32%N=11.06% TABLE 2 a PeP N f A FABLRMS HPLC Elemental R.T. os Z z $ Z z ; $ Z z W~ \o 7.231 min. Caic. for 0.2SCHCl3;O.20H2O Solvate mol. zero U 0 0 H 271.14/mole 4.87 min. Caic. for ° O.70C11C13 Solvate mol. 000 V 00 U CTVO d E E ~ É U E E; G t (A:B) 6O9.17g/mole 9.43lmin. Caic. for 0.05CHCl;0.55EtOAc Solvate o; wt.=736.00g/mole o, 1.42% Ct clo 2 É E on ; on t ~ < F F o v es ç m ot° TABLE 2 (cont.) 425.00g/mole 7.43 min. Calc. for 1.0HCl;0.80CHCl3;0.55EtOAc<BR> Solvate mol.wt.=509.99g/mole<BR> Calc:C=58.64%H=5.63%N=10.99%<BR> Obs:C=58.79%H=5.98%N=10.99%

EXAMPLE 30 (4S, 5R)-4-(3 ,4-Difluorophenyl-3-( 1-f 1-[4-fluoro-2-(3-methyl- <BR> <BR> [1,2, 4]oxadiazol-5-yl)phenyl]piperidin-4-yl}- (3R)-pyrrolidin-3- ylcarbamoyl)-2-oxo-oxazolidine-5-carboxylic acid methyl ester Step A: trans-3,4-Difluorocinnamic acid methyl ester To a solution of trans-3,4-difluorocinnamic acid (10 g, 54 mmol) in 300 mL methanol was added concentrated sulfuric acid (2 mL). The solution was stirred 48 h at ambient temperature and then concentrated in vacuo. The residue was taken up in ethyl acetate (500 mL) and washed with saturated sodium bicarbonate (2 x 100 mL), brine (1 x 100 mL), dried with magnesium sulfate, and concentrated in vacuo to provide trans-3,4-difluorocinnamic acid methyl ester (10.7 g, 54 mmol, 100%) as a white solid.

1H NMR dH (400 MHz, CDC13) 7.59 (d, 1H, J = 15.9), 7.34 (m, 1H), 7.24 (m, 1H) 7.18 (dd, 1H, J = 9.9, 2.0), 6.35 (d, 1H, J = 16.1), 3.81 (s, 3H).

Step B: (2R, 3S)-N-Benzyloxycarbonyl-3-amino-3-(3 ,4- difluorophenyl)-2-hydroxypropionic acid methyl ester A solution of NaOH (4.1 g, 103 mmol) was prepared in 175 mL water. Potassium osmate dihydrate (491 mg, 1.3 mmol) was dissolved in 35 mL of this NaOH solution, resulting in a dark pink homogeneous mixture. To a 1000 mL round bottom flask is added the remaining NaOH solution prepared above, 135 mL n-propanol and benzyl cabamate

(9.8 g, 110 mmol). The suspension was stirred at ambient temperature for 30 min wherein the mixture was nearly homogeneous. The reaction flask was placed in a room temperature water bath and the surrounding lights were turned off. Freshly prepared t-butylhypochlorite (11.2 mL, 103 mmol) was added dropwise with vigorous stirring, and the reaction stirred an additional 15 min. In a separate 250 mL round bottom flask was suspended trans-3,4-difluorocinnamic acid methyl ester (6.6 g, 33.3 mmol) and (DHQ)2PHAL (1.3 g, 1.7 mmol) in 100 mL n-propanol. The suspension was added to the above reaction mixture and the residue rinsed into the reaction flask (2 x 10 mL). To the reaction was added the above prepared solution of potassium osmate dihydrate. The resulting green solution became amber/brown over 1 h. Sodium metabisulfite (66 g, 347 mmol) was added and the resulting suspension stirred 3 h when it was poured into a separatory funnel containing ethyl acetate (200 mL) and the layers separated. The aqueous layer was extracted with ethyl acetate (150 mL) and the combined organics washed with brine (100 mL), dried with magnesium sulfate, and concentrated in vacuo to provide a pale yellow solid. The crude material was passed through silica (25% ethyl acetate/hexane) to give (2R, 3S)-N-benzyloxycarbonyl-3-amino-3- (3,4-difluorophenyl)-2-hydroxypropionic acid methyl ester contaminated with benzyl carbamate.

Step C: (2R, 3S)-3-Amino-3-(3,4-difluorophenyl)-2-hydroxypropionic acid methyl ester (2R, 3S)-N-Benzyloxycarbonyl-3-amino-3-(3 ,4-difluorophenyl)-2- hydroxypropionic acid methyl ester (>12.2 g, 33.3 mmol maximum) was dissolved in 750 mL ethanol. The flask was purged and filled with argon three times. Palladium on carbon (2 g, 10% wt) was added under argon and the suspension was again purged and filled with argon three times.

The suspension was then purged, filled with hydrogen, and stirred 16 h.

The suspension was purged, filled with argon three times, filtered through celite and concentrated in vacuo to give (2R, 3S)-3-amino-3-(3,4- difluorophenyl)-2-hydroxypropionic acid methyl ester (5.8 g, 25 mmol, 75% from trans-3,4-difluorocinnamic acid methyl ester).

'H NMR dH (400 MHz, CDCl3) 7.26 (m, 1H), 7.15-7.08 (m, 2H), 4.28 (s, 2H), 3.82 (s, 3H), 2.48 (bs, 2H).

Step D: (4S, 5R)-4-(3 ,4-Difluorophenyl)-2-oxo-oxazolidine-5- carboxylic acid methyl ester To a solution of (2R, 3S)-3-amino-3-(3,4-difluorophenyl)-2- hydroxypropionic acid methyl ester (5.8 g, 25 mmol) in 250 mL tetrahydrofuran at 0°C was added N,N-diisopropylethylamine (8.75 mL, 50 mmol) and triphosgene (2.48 g, 8.4 mmol). The reaction was stirred at 0°C for 30 min when it was poured over ethyl acetate (200 mL) and saturated sodium carbonate solution (100 mL). The layers were separated, the organic layer washed with saturated sodium carbonate solution (1 x 100 mL), dried with magnesium sulfate, and concentrated in vacuo to provide a pale yellow oil. The material was triturated with 25% ethyl acetate/hexane from dichloromethane to provide (4S, 5R)-4- (3 ,4-difluorophenyl)-2-oxo-oxazolidine-5carboxylic acid methyl ester.

The recovered mother liqour was passed through silica (50% ethyl acetate/hexane) to give an additional 1.1 g (4.8 g total, 18 mmol, 75%) 'H NMR dH (400 MHz, CDCl3) 7.25-7.20 (m, 2H), 7.15 (m, 1H), 6.33 (bs, 1H), 4.98 (d, 1H, J = 5.1), 4.72 (d, 1H, J = 5.3), 3.89 (s, 3H).

FABMS M+H = 258 Step E: (4S, 5R)-4-(3 ,4-Difluorophenyl)-2-oxo-oxazolidine-3 ,5- dicarboxylic acid methyl ester 3-(4-nitrophenyl) ester To a solution of (4S, 5R)-4-(3 ,4-difluorophenyl)-2-oxo-oxazolidine-5- carboxylic acid methyl ester (910 mg, 3.5 mmol) in anhydrous tetrahydrofuran (50 mL), cooled to -78°C under argon, was added a 1 M solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (3.5 mL, 3.5 mmol) dropwise. The reaction mixture was warmed to 0°C in an ice bath, stirred 30 minutes, then returned to -780C. In a separate flask, p- nitrophenylchloroformate (714 mg, 3.54 mmol) was dissolved in anhydrous tetrahydrofuran (40 mL) under argon and cooled to -780C.

The above prepared anion solution was added via cannula to the

chloroformate solution and the reaction mixture was stirred 1 h at - 78"C. The reaction mixture was treated with ethyl acetate (150 mL) and the resulting solution was washed with water (1 x 150 ml), brine (1 x 150 ml) and dried over magnesium sulfate and filtered. The volitiles were removed under reduced pressure and the resulting oil was triturated with diethyl ether. Ether was twice decanted from the resulting pale yellow solid to give (4S, 5R)-4-(3 ,4-difluorophenyl)-2-oxo-oxazolidine-3,5- dicarboxylic acid methyl ester 3-(4-nitrophenyl) ester (1.3 g, 3.1 mmol, 87%).

FAB MS: m/z=423 (M+H) Step F: (4S,5R)-4-(3,4-Difluorophenyl-3-(1-81-[4-fluoro-2-(3- methyl[1,2,4]oxadiazol-5-yl)phenyl]-piperidin-4-yl)-(3R)- pyrrolidin-3-ylcarbamoyl)-2-oxo-oxazolidine-5-carboxylic acid methyl ester To a solution of 1-(1-[4-fluoro-2-(3-methyl[1,2,4]oxadiazol-5- yl)phenyl]piperidin-4-yl}-(3R)-pyrrolidin-3-ylamine (105 mg, 0.23 mmol) in dry, degassed N,N-dimethylformamide (2 mL) was added N,N- diisopropylethylamine (120 RL, 0.69 mmol) followed by (4S, 5R)-4-(3,4- difluorophenyl)-2-oxo-oxazolidine-3 ,5-dicarboxylic acid methyl ester 3-(4- nitrophenyl) ester (98 mg, 0.23 mmol). The reaction mixture was stirred at ambient temperature for 1 h when the volatiles were removed under reduced pressure. The residue was dissolved in ethyl acetate (100 mL) and washed with 10% aqueous sodium carbonate solution (8 x 100 mL), brine (1 x 100 mL), dried over magnesium sulfate and filtered. The volatiles were removed under reduced pressure and the resulting oil was purified by pressurized silica gel chromatography (2% methanol in ethyl acetate) to give a foam. The hydrochloride salt was prepared according to standard procedures to afford (4S, 5R)trans-4-(3,4- <BR> <BR> <BR> difluorophenyl-3-( 1-( 1-[4-fluoro-2-(3-methyl-[ 1,2,4] oxadiazol-5-yl)phenyl]- <BR> <BR> <BR> <BR> <BR> piperidin-4-yl}-(3R)-pyrrolidin-3-ylcarbamoyl)-2-oXo-oxazoli dine-5- carboxylic acid methyl ester as a solid.

HPLC retention time = 8.59 min, purity= 94% FAB MS: m/z=629 (M+H)

Analysis: Calcd for C30H3 1N6O6F3 2HCl 0.2EtOAc C 51.44, H 4.85, N 11.69.

Found: C 51.83, H 5.11, N 11.68.

The compounds in Examples 31 and 32 were prepared by procedures substantially as described above for Example 30, Step F.

EXAMPLE 31 (4S, 5R)-4-(3,4-Difluorophenyl-3-{1-[1-(4-fluoro-2- methoxyphenyl)piperidin-4-yl] -(3R)-pyrrolidin-3-ylcarbamoyl) -2-oxo- oxazolidine-5-carboxylic acid methyl ester FAB MS: m/z=577 (M+H) Analysis: Calcd for C28H31N406F3X2F3CCO2H C 45.81, H 4.42, N 6.68.

Found: C 45.85, H 4.54, N 6.62.

EXAMPLE 32 (4S, 5R)3-t1-[1-(2-Cyanophenyl)piperidin-4-yl]-(3R)-pyrrolidin-3- ylcarbamoyl}-4-(3,4-difluorophenyl)-2-oxo-oxazolidine-5-carb oxylic acid methyl ester

FAB MS: m/z=554 (M+H) Analysis: Calcd for C28H29N505F2HC1 0.25H200.75dioxane C 56.36, H 5.57, N 10.60.

Found: C 56.33, H 5.39, N 10.61.

EXAMPLE 33 (4S, 5R)-4-(3,4-Difluorophenyl)-5-hydroxymethyl-2-oxo-oxazolidine -3- carboxylic acid {1-[1-(2-cyanophenyl)piperidin-4-yl]-(3R)-pyrrolidin-3- yllamide Step A: (4S, 5R) 4-(3,4-Difluorophenyl)-5-hydroxymethyl-oxazolidin- 2-one To a solution of (45, 5R)-4-(3,4-difluorophenyl)-2-oxo- oxazolidine-5-carboxylic acid methyl ester [(200 mg, 0.8 mmol) product of Example 30 Step D] in tetrahydrofuran (10 mL) at 0°C) was added a 2 M solution of lithium borohydride in tetrahydrofuran (0.4 mL, 0.8 mmol).

After stirring for 20 min at OOC, saturated sodium bicarbonate (20 mL) was added and the mixture stirred at ambient temperature for 20 min.

Ethyl acetate (50 mL) was added and the layers separated. The organic layer was washed with brine (1 x 10 mL), dried with magnesium sulfate, filtered and concentrated in vacuo to provide (4S, 5R) 4-(3,4- difluorophenyl)-5-hydroxymethyl-oxazolidin-2-one as a white solid (180 mg, 0.8 mmol, 100%) 'H NMR dH (400 MHz, CDCl3) 7.23-7.15 (m, 2H), 7.10-7.07 (m, 1H), 6.48 (bs, 1H), 4.89 (d, 1H, J = 6.8), 4.31 (dt, 1H, J = 6.6, 2.9), 3.96 (dd, 1H, J = 12.82, 2.75), 3.70 (bdd, 1H, J = 12.1, 2.2), 3.53 (bs, 1H).

Step B: (4S, 5R) 4-(3 ,4-Difluorophenyl)-5-(tetrahydropyran-2- yloxymethyl)-oxazolidin-2-one To a solution of (4S, 5R) 4-(3,4-difluorophenyl)-5-hydroxymethyl- oxazolidin-2-one (695 mg, 3.0 mmol) in dry dichloromethane (30 mL) was added 2,3-dihydropyran (0.3 mL, 3.6 mmol) and camphorsulfonic acid (70 mg, 0.3 mmol). The reaction mixture was stirred at ambient temperature for 3 h. The reaction mixture was diluted with dichloromethane (100 mL), washed with saturated sodium bicarbonate solution (2 x 100 ml), brine (1 x 100 ml), dried over magnesium sulfate and filtered. The volatiles were removed under reduced pressure and the resulting solid was purified by pressurized silica gel chromatography (1:1 then 2:1 ethyl acetate:hexane) to afford (4S, 5R)-4- <BR> <BR> (3 ,4-difluorophenyl)-5-(tetrahydropyran-2-yloxymethyi)-oxazoli din-2-one as a colorless oil (750 mg, 2.4 mmol, 80%).

FAB MS: m/z=314 (M+H) Step C: (4S, 5R)-4-(3 ,4-Difluorophenyl)-2-oxo-5-(tetrahydropyran-2- yloxymethyl)-oxazolidine-3-carboxylic acid 4-nitrophenyl ester To a solution of (45, 5R)-4-(3,4-difluorophenyl)-5-(tetrahydropyran- 2-yloxymethyl)-oxazolidin-2-one (910 mg, 2.9 mmol) in anhydrous tetrahydrofuran (60 mL) cooled to -780C under argon, was added a 1 M solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (2.9 mL, 2.9 mmol) dropwise. The reaction mixture was warmed to OOC in an ice bath, stirred 45 min, and then returned to -780C. Meanwhile, in a separate dried flask, the p-nitrophenylchloroformate (586 mg, 2.9 mmol) was dissolved in anhydrous tetrahydrofuran (50 mL) under argon and cooled to -78°C. The above prepared anion solution was added via cannula to the chloroformate solution and reaction mixture was stirred 1 h at -78°C. The reaction mixture was treated with ethyl acetate (150 mL). The resulting solution was washed with water (1 x 150 ml), brine (1 x 150 mL), dried over magnesium sulfate and filtered. The volatiles were removed under reduced pressure to give (4S, 5R)-4-(3,4-

difluorophenyl)-2-oxo-5-(tetrahydropyran-2-yloxymethyl )-oxazolidine-3- carboxylic acid 4-nitrophenyl ester as a yellow foam (1.3g, 2.8 mmol, 96%).

FAB MS: m/z=479 (M+H) Step D: (4S, 5R)-4-(3 ,4-Difluorophenyl)-2-oxo-5-(tetrahydropyran-2- yloxymethyl)oxazolidine-3-carboxylic acid (1-[1-(2- cyanophenyl)piperidin-4-yl]-(3R)-pyrrolidin-3-yllamide To a solution of 2-[4-(3-amino-(3R)-pyrrolidin- 1-yl)piperidin- 1- yl]benzonitrile (166 mg, 0.44 mmol) in dry, degassed N,N- dimethylformamide (4 mL) was added N,N-diisopropylethylamine (230 RL, 1.3 mmol) followed by (4S, 5R)-4-(3,4-difluorophenyl)-2-oxo-5- (tetrahydropyran-2-yloxymethyl)-oxazolidine-3-carboxylic acid 4- nitrophenyl ester (210 mg, 0.44 mmol). The reaction mixture Was stirred at room temperature for 4 h when the volatiles were removed under reduced pressure, the residue dissolved in ethyl acetate (100 mL), washed with 10% aqueous sodium carbonate solution (8 x 100 mL), brine (1 x 100 mL), dried over magnesium sulfate and filtered. The volatiles were removed under reduced pressure and the resulting oil was purified by pressurized silica gel chromatography (1:1 then 2:1 ethyl acetate:hexane) to afford (4S, 5R)-4-(3 ,4-difluorophenyl)-2-oxo-5- (tetrahydropyran-2-yloxymethyl)oxazolidine-3-carboxylic acid { 1-[1-(2- cyanophenyl)piperidin-4-yl] -(3R)-pyrrolidin-3-yl}amide as a white foam (156 mg, 0.26 mmol, 59%).

FAB MS: m/z=610 (M+H) Step E: (4S, 5R)-4-(3 ,4-Difluorophenyl)-5-hydroxymethyl-2-oxo- oxazolidine-3-carboxylic acid (1- [ 1-(2-cyanophenyl)piperidin- 4-yl]-(3R)-pyrrolidin-3-yllamide To a solution of (45, 5R)-4-(3,4-difluorophenyl)-2-oxo-5- (tetrahydropyran-2-yloxymethyl)oxazolidine3 -carboxylic acid (1-[1-(2- cyanophenyl)piperidin-4-yl]-(3R)-pyrrolidin-3-yl}amide (156 mg, 0.26 mmol) in methanol (5 mL) was added p-toluenesulfonic acid (50 mg, 0.26

mmol). The reaction mixture was stirred at room temperature for 17 h.

The volatiles were removed under reduced pressure, the residue taken up in ethyl acetate (100 mL), washed with saturated sodium carbonate solution (3 x 100 mL), brine (1 x 100 ml), dried over magnesium sulfate and filtered. The volatiles were removed under reduced pressure to afford (4S, 5R)-4-(3,4-difluorophenyl)-5-hydroxymethyl-2-oxo-oxazolidine - 3-carboxylic acid { 1-[ 1-(2-cyanophenyl)piperidin-4-yl]-(3R)-pyrrolidin-3- yl}amide. The hydrochloride salt was prepared according to standard procedures to provide a white solid (123 mg, 0.22 mmol, 84%) HPLC: retention time= 7.20 min, purity=95% FAB MS: m/z=526 (M+H) 'H NMR HCl salt dH (400 MHz, CD30D) 7.97 (d, J= 7.33 Hz, 1H), 7.53 (d, J= 7.69 Hz, 1 H), 7.45 (t, J= 8.61, 1H), 7.16 (m, 2H), 7.04 (m, 1H), 6.96 (m, 2H), 5.26 (d, J=4.58 Hz, 1H), 4.39 (d, J=4.21, 1H), 4.25 (m, 1H), 3.95 (dd, J=8.61, 3.11, 1H), 3.82 (dd, J=9.16, 3.48, 1H), 3.57 (m, 2H), 2.88 (m. 3H), 2.77 (m, 1H), 2.68 (m, 1H), 2.47 (m, 1H), 2.22 (m, 3H), 1.95 (m, 2H), 1.78 (bm, 2H), 1.68 (bm, 1H) Analysis: Calcd for C27 H29 N5 04 F2-0.35 H2O C 60.97, H 5.63, N 13.17.

Found: C 61.02, H 5.59, N 13.12.

The compounds of Examples 34 and 35 were prepared by procedures described in Example 30 Steps A-F, followed by pressurized silica gel chromatography using an elution system containing chloroform saturated with ammonia gas and methanol.

(4S, 5R)-3-{1-[1-(2-Cyanophenyl)piperidin-4-yl]-(3R)-pyrrolidin-3 - ylcarbamoyl}-4-(3,4-difluorophenyl)-2-oxo-oxazolidine-5-carb oxamide FAB MS: m/z=539 (M+H) Analysis: Calcd for C27H28N6O4F2#HCl#0.9H2O C 54.85, H 5.25, N 14.22.

Found: C 54.83, H 5.02, N 14.05.

EXAMPLE 35 (4S, 5R)-4-(3,4-Difluorophenyl-3-{1-[1-(4-fluoro-2- methoxyphenyl)piperidin-4-yl]-(3R)-pyrrolidin-3-ylcarbamoyl) -2-oxo- oxazolidine-5-carboxamide FAB MS: m/z=562 (M+H) Analysis: Calcd for C27H30N505F3*0.85H20 C 56.21, H 5.54, N 12.14.

Found: C 56.20, H 5.20, N 12.05.

EXAMPLE 36 Mixture of 4S-4-(3,4-difluorophenyl)-6-methoxymethyl-2-oxo-1,2,3,4- tetrahydropyrimidine and 4S-4 -(3,4- difluorophe nyl)- 6-methoxymethyl - 2 - oxo-2,3 ,4,5-tetrahydropyrimidine

To a solution of (+)-4-(3 ,4-difluorophenyl)-6-methoxymethyl- 2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid methyl ester (4.63 g, 14.7 mmol) in a methanol (100 ml) was added sodium hydroxide (2.94 g, 73.6 mmol). The resulting mixture was refluxed at 90 °C for 16 hours.

After cooling to room temperature the solvent was removed in vacuo.

The solid was dissolved in CH2C12 and H2O then neutralized with 10% aqueous HCl solution. The organic layer was dried over Na2SO4, concentrated, and purified by PCTLC (7% MeOH in CHCla with 2% NH4OH) to afford a 2.65 g mixture of the title compounds (71% yield).

The 1H NMR was consistent with the assigned structure.

MS (FAB) 255 (M+1) EXAMPLE 37 Mixture of 4S-4-(3,4-difluorophenyl)-6-methoxymethyl-2-oxo-1,2,3,4- tetrahydropyrimidine and 4S-4-(3 ,4-difluorophenyl)-6-methoxymethyl-2- oxo-2,3,4,5-tetrahydropyrimidine To a solution of (+)-4-(3 ,4-difluorophenyl)-6-methoxymethyl- 2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid methyl ester (5.36 g, 17.0 mmol) in a methanol (150 ml) was added 1N NaOH (10 ml). The

resulting mixture was refluxed at 90 °C for 16 hours. After cooling to room temperature the solvent was removed in vacuo. The solid was dissolved in CH2C12 and H2O then neutralized with 10% aqueous HCl solution. The organic layer was dried over Na2 504, concentrated, and purified by PCTLC (7% MeOH in CHCl3 with 2% NH4OH) to afford a 2.35 g mixture of the title compounds (54% yield). The 'H NMR was consistent with the assigned structure.

MS (FAB) 255 (M+1) EXAMPLE 38 4S-4-(3 ,4-Difluorophenyl)-6-methoxymethyl-3-(4-nitrophenoxycarbonyl )-2 oxo- 1,2,3 ,4-tetrahydropyrimidine-5-carboxylic acid methyl ester The title compound was prepared by treating the mixture obtained from Example 36 or Example 37 (1.93 g, 7.59 mmol) with lithium diisopropylamide (2.0M THF solution, 1.1 equivalents) in THF at -78 C for 20 minutes followed by the rapid addition of 4-nitrophenyl chloroformate (1.5 equivalents) in THF. 0.488 g of the title compound was obtained in a 15% yield. The 'H NMR was consistent with the assigned structure.

EXAMPLE 39 Mixture of 4R-4-(3 ,4-difluorophenyl)-6-methoxymethyl-2-oxo 1,2,3,4- tetrahydropyrimidine and 4R-4-(3 ,4-difluorophenyl)-6-methoxymethyl-2- oxo-2 ,3,4,5-tetrahydropyrimidine

The title compounds were prepared from 4R-4-(3,4- <BR> <BR> <BR> difluorophenyl)- 6-methoxymethyl-2-oxo- 1,2,3 ,4-tetrahydropyrimidine-5- carboxylic acid methyl ester (5.0 g, 17.7 mmol) using the procedure described in Example 36. A mixture of 2.0 g of the title compounds was obtained in 50% yield. The 'H NMR was consistent with the assigned structure.

MS (FAB) 255 (M+1) Compounds of the invention can be prepared by reacting the products obtained in Example 38 in accordance with procedures and schemes described above. The compound of Example 38 can, for example, be reacted with an aminopiperidine or aminoalkylpiperidine as set forth in Schemes 1 and 2 to obtain the desired compounds.

Compounds of the invention can also be prepared by preparing a nitrophenoxy derivative of the compound of Example 39 in accordance with the procedure set forth in Example 38 and then reacting the derivative with an aminopiperidine or aminoalkylpiperidine as set forth in Schemes 1 and 2 to obtain compounds of the invention.

The following compounds were prepared in accordance with procedures set forth in the foregoing Schemes and Examples.

EXAMPLE 40 N-( 1-( 1-(2-Cyanophenyl)piperidin-4-yl)azeh.din-3-yl)-2-(3,4- difluorophenyl)acetamide

1H NMR (CDCl3, 400 MHz) consistent with assigned structure.

FABLRMS m/e 411 g/mole (M++H, C23H24F2N4°1 =410.47 g/mole.) HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H2O [0.1% H3PO4] - CH3CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 ml/min flow rate) focus = 215 nm; >95% pure.

Anal. Calcd for C23H24F5N5O3 # 1.20 TFA: C = 55.74, H = 4.64, N = 10.24. Found: C = 55.75, H = 4.65, N = 10.34.

EXAMPLE 41 (2#)-N-(1-(1-(2-Cyanophenyl)piperidin-4-yl)azetidin-3-yl)-2- (3,4- difluorophenyl)-2-(2-propyl)acetamide 1H NMR (CDCl3, 400 MHz) consistent with assigned structure.

FABLRMS m/e 453 g/mole (M++H, C26H30F2N4O1: =452.23 g/mole.)

HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H2O [0.1% H3PO4] - CH3CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 ml/min flow rate) focus = 215 nm; >95% pure.

Anal. Calcd for C26H30F2N4O1 1.15 TFA e 0.15 H2O: C = 57.96, H = 5.41, N = 9.56. Found: C = 57.98, H = 5.19, N = 9.73.

EXAMPLE 42 (4S)-4-(3 ,4-Difluorophenyl)-2-oxo-oxazolidine-3-carboxylic acid (1-[ 1-(2- cyanophenyl)-piperidin-4-yl]azetidin-3-yl}-amide 1H NMR (CDCl3, 400 MHz) consistent with assigned structure.

FABLRMS m/e 482 g/mole (M++H, C25H25F2N5°3 =481.51 g/mole.) HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H2O [0.1% H3PO4] - CH3CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 ml/min flow rate) focus = 215 nm; >99% pure.

Anal. Calcd for C25H25F2N5O3 1.35 TFA and 1.05 H2O: C = 50.84, H = 4.38, N = 10.70. Found: C = 50.83, H = 4.29, N = 11.09.

EXAMPLE 43 (4S)-3-{1-[1-(2-Cyanophenyl)piperidin-4-yl]azetidin-3-ylcarb amoyl}-4-(3,4- difluorophenyl)-6-methoxymethyl-2-oxo-1,2,3,4-tetrahydropyri midine-5- carboxylic acid methyl ester

1H NMR (CDCl3, 400 MHz) consistent with assigned structure.

FABLRMS m/e 595 g/mole (M++H, C30H32F2N6°5 = 594.62 g/mole.) HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H2O [0.1% H3PO4] - CH3CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 mI/min flow rate) focus = 215 nm; >97% pure.

Anal. Calcd for C30H32F2N6O5 e 1.55 TFA and 1.30 H2O: C = 50.02, H = 4.58, N = 10.58. Found: C = 49.99, H = 4.55, N = 10.59.

EXAMPLE 44 N-(1-(1-(2-Cyanophenyl)piperidin-4-yl)azetidin-3-ylmethyl)-2 -(3,4- difluorophenyl)acetamide 1H NMR (CDCl3, 400 MHz) consistent with assigned structure.

FABLRMS m/e 425 g/mole (M++H, C24H26F2N4°1 =424.49 g/mole.) HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H2O [0.1% H3PO4] - CH3CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 ml/min flow rate) focus = 215 nm; 99% pure.

Anal. Calcd for C24H26F2N401 e 0.05 CH2Cl2: C = 67.37, H = 6.14, N = 13.07. Found: C = 67.53, H = 6.15, N = 13.40.

EXAMPLE 45 N-( 1-( 1-(2-Cyanophenyl)piperidin-4-yl)azetidin-3-ylmethyl)-2 ,2- spirocyclopropyl-2-(3,4-difluorophenyl)acetamide 1H NMR (CDCl3, 400 MHz) consistent with assigned structure.

FABLRMS nile 451 g/mole (M++H, C26H28F2N4°1 =450.53 g/mole.) HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H2O [0.1% H3PO4] - CH3CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 ml/min flow rate) focus = 215 nm; 98% pure.

Anal. Calcd for C26H28F2N401 1.9 HCl and 0.15 Hexane: C = 60.64, H = 6.05, N = 10.52. Found: C = 60.63, H = 6.45, N = 10.78.

EXAMPLE 46 (4S)-3-{1-[1-(2-Cyanophenyl)piperidin-4-yl]azetidin-3-ylmeth ylcarbamoyl}- 4-(3,4-difluorophenyl)-6-methoxymethyl-2-oxo-1,2,3,4- tetrahydropyrimidine-5-carboxylic acid methyl ester

1H NMR (CDC13, 400 MHz) consistent with assigned structure.

FABLRMS m/e 609.26 g/mole (M++H, C31H34F2N6°5 = 608.64 g/mole.) HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H2O [0.1% H3PO4] - CH3CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 ml/min flow rate) focus = 215 nm; 93.4% pure.

EXAMPLE 47 (4S)-4-(3 ,4-Difluorophenyl)-2-oxo-oxazolidine-3-carboxylic acid {1-[1-(2- cyanophenyl)-piperidin-4-yl]azetidin-3-ylmethyl}-amide 1H NMR (CDCl3, 400 MHz) consistent with assigned structure.

FABLRMS m/e 496.26 g/mole (M++H, C26H27F2N5O3 = 495.53 g/mole.) HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H2O [0.1% H3PO4] - CH3CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 mI/min flow rate) focus = 215 nm; 94.8% pure.

Anal. Calcd for C29H32F5N5O5 0.05 CHCl3 and 0.2 H2O: C = 61.94, H = 5.48, N = 13.87. Found: C = 61.97, H = 5.55, N = 13.50.

EXAMPLE 48 (4S)-4-(3,4-Difluorophenyl)-2-oxo-oxazolidine-3-carboxylic acid {1-[1-(2- cyanophenyl)-piperidin-4-yl]-3-hydroxy-azetidin-3 -ylmethyl}-amide 1H NMR (CD Cl3, 400 MHz) consistent with assigned structure.

FABLRMS m/e 512 g/mole (M++H, C26H27F2N5°4 = 511.52 g/mole.) HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H2O [0.1% H3PO4] - CH3CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 ml/min flow rate) focus = 215 nm; 95% pure.

EXAMPLE 49 (4S)-3-{1-[1-(2-Cyanophenyl)piperidin-4-yl]-3-hydroxy-azetid in-3- ylmethylcarbamoyl)-4-(3 ,4-difluorophenyl)-6-methoxymethyl-2-oxo- 1,2,3,4-tetrahydropyrimidine-5-carboxylic acid methyl ester

1H NMR (CD Cl3, 400 MHz) consistent with assigned structure.

FABLRMS m/e 625 g/mole (M++H, C31H34F2N6°6 = 624.64 g/mole.) HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H2O [0.1% H3PO4] - CH3CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 mI/min flow rate) focus = 215 nm; 98% pure.

Anal. Calcd for C31H34F2N6O6 # 1.65 HCl and 0.2 Et2O: C = 54.59, H = 5.42, N = 12.01. Found: C = 54.65, H = 5.25, N = 11.99.

EXAMPLE 50 (3R)-N-( 1-( 1-(2-Nitrophenyl)piperidin-4-yl)pyrrolidin-3-yl)-2-(3 ,4- difluorophenyl)acetamide 1H NMR (CDCl3, 400 MHz) consistent with assigned structure.

FABLRMS m/e 445 g/mole (M++H, C23H26F2N4°3 =444.485 g/mole.) HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H2O [0.1% H3PO4] - CH3CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 ml/min flow rate) focus = 215 nm; 98% pure.

Anal. Calcd for C23H26F2N403 o 1.75 HCl: C = 54.35, H = 5.50, N = 11.02. Found: C = 54.29, H = 5.51, N = 10.63.

EXAMPLE 51 (Dias A) (3R)-N-(1-(1-(2-Nitrophenyl)piperidin-4-yl)pyrrolidin-3-yl)- 2-(3,4- difluorophenyl)acetamide

1H NMR (CDCl3, 400 MHz) consistent with assigned structure.

FABLRMS m/e 487 g/mole (M++H, C26H32F2N4°3 =486.567 g/mole.) HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H2O [0.1% H3PO4] - CH3CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 ml/min flow rate) focus = 215 nm; 100% pure.

Anal. Calcd for C26H32F2N403 1.4 HCl: C = 58.08, H = 6.26, N = 10.42. Found: C = 58.34, H = 6.22, N = 10.55.

EXAMPLE 52 (Dias A) (3R)-N-(1-(1-(2-Cyanophenyl)piperidin-4-yl)pyrrolidin-3-yl)- 2- (3,4-difluorophenyl)acetamide 1H NMR (CDCl3, 400 MHz) consistent with assigned structure.

FABLRMS m/e 467 g/mole (M++H, C27H32F2N4°1 =466.577 g/mole.) HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H2O [0.1% H3PO4] - CH3CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 mI/min flow rate) focus = 215 nm; 95.4% pure.

(Diast B)(3R)-N-(1-(1-(2-Cyanophenyl)piperidin-4-yl)pyrrolidin-3-yl )-2- (3,4-difluorophenyl)acetamide 1H NMR (CD Cl3, 400 MHz) consistent with assigned structure.

FABLRMS m/e 467 g/mole (M++H, C27H32F2N4°1 =466.577 g/mole.) HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H2O [0.1% H3PO4] - CH3CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 ml/min flow rate) focus = 215 nm; 95.8% pure.

EXAMPLE 54 (3R,4S)-4-(3,4-Difluorophenyl)-2-oxo-oxazolidine-3-carboxyli c acid {1-[1-(2- nitrophenyl)-piperidin-4-yl]pyrrolidin-3-yl}-amide 1H NMR (CDCl3, 400 MHz) consistent with assigned structure.

FABLRMS m/e 516 g/mole (M++H, C25H27F2N5°5 = 515.522 g/mole.) HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H2O [0.1% H3PO4] - CH3CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 ml/min flow rate) focus = 215 nm; 100% pure.

Anal. Calcd for C25H27F2N5O5 1.35 HCl; C = 53.17, H = 5.06, N = 12.40. Found: C = 53.26, H = 5.09, N = 12.08.

EXAMPLE 55 (3R,4S)-4-(3,4-Difluorophenyl)-2-oxo-oxazolidine-3-carboxyli c acid {1-[1-(2- [N-1-(N-3-methylureyl)]phenyl)-piperidin-4-yl]pyrrolidin-3-y l}-amide 1H NMR (CD Cl3, 400 MHz) consistent with assigned structure.

FABLRMS m/e 543 g/mole (M++H, C27H32F2N6O4 = 542.591 g/mole.) HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H2O [0.1% H3PO4] - CH3CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 mI/min flow rate) focus = 215 nm; 95% pure.

Anal. Calcd for C27H32F2N604 2.15 HCl: C = 52.22, H = 5.54, N = 13.53. Found: C = 52.20, H = 5.50, N = 13.22.

EXAMPLE 56 (3R,4S)-4-(3,4-Difluorophenyl)-2-oxo-oxazolidine-3-carboxyli c acid {1-[1-(2- (N-3-dimethylsulfonamido)aminophenyl)-piperidin-4-yl]pyrroli din-3-yl}- amide 1H NMR (CDCl3, 400 MHz) consistent with assigned structure.

FABLRMS m/e 593 g/mole (M++H, C27H34F2N605S = 592.666 g/mole.) HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H2O [0.1% H3PO4] - CH3CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 ml/min flow rate) focus = 215 nm; 99.1% pure.

Anal. Calcd for C27H34F2N6O5S # 1.90 HCl: C = 48.99, H = 5.47, N = 12.70. Found: C = 49.06, H = 5.76, N = 12.69.

EXAMPLE 57 (3R,4S)-4-(3,4-Difluorophenyl)-2-oxo-oxazolidine-3-carboxyli c acid {1-[1-(2- (N- 1-methanesulfonyl)aminophenyl)-piperidin-4-yl]pyrrolidin- 3-yl}- amide 1H NMR (CDC13, 400 MHz) consistent with assigned structure.

FABLRMS m/e 564 g/mole (M++H, C26H31F2N5°5S = 563.624 g/mole.)

HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H2O [0.1% H3PO4] - CH3CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 ml/min flow rate) focus = 215 nm; 100% pure.

Anal. Calcd for C26H31F2N5O5S 2.0 HC1: C = 49.05, H = 5.23, N = 11.00. Found: C = 49.03, H = 5.18, N = 10.93.

EXAMPLE 58 (3R,4S)-4-(3,4-Difluorophenyl)-2-oxo-oxazolidine-3-carboxyli c acid {1-[1-(2- (N- 1-acetyl)aminophenyl )-piperidin-4-yl]pyrrolidin-3-yl) -amide 1H NMR (CDCl3, 400 MHz) consistent with assigned structure.

FABLRMS m/e 528 g/mole (M++H, C27H31F2N5°4 = 527.576 g/mole.) HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H2O [0.1% H3PO4] - CH3CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 mI/min flow rate) focus = 215 nm; 95.7% pure.

EXAMPLE 59 (4S)-3-{1-[1-(2-Nitrophenyl)piperidin-4-yl]-pyrrolidin-3-ylc arbamoyl]-4- (3,4-difluorophenyl)-6-methoxymethyl-2-oxo-1,2,3,4- tetrahydropyrimidine-5-carboxylic acid methyl ester 1H NMR (CDC13, 400 MHz) consistent with assigned structure.

FABLRMS m/e 629 g/mole (M++H, C30H34F2N6°7 = 628.64 g/mole.) HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H2O [0.1% H3PO4] - CH3CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 mI/min flow rate) focus = 215 nm; 100% pure.

EXAMPLE 60 (4S)-3-{1-[1-(2-[N-1-(N-3-methylureyl)]phenyl)piperidin-4-yl ]-pyrrolidin-3- ylcarbamoyl}-4-(3,4-difluorophenyl)-6-methoxymethyl-2-oxo-1, 2,3,4- tetrahydropyrimidine-5-carboxylic acid methyl ester 1H NMR (CDC13, 400 MHz) consistent with assigned structure.

FABLRMS m/e 656 g/mole (M++H, C32H39F2N7O6: =655.709 g/mole.)

HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H20 [0.1% H3PO4] - CH3CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 ml/min flow rate) focus = 215 nm; 96.8% pure.

EXAMPLE 61 <BR> <BR> <BR> (4S)-3-t 1-[1-(2-(N-3-dimethylsulfonamido)aminophenyl)piperidin-4-yl] - <BR> <BR> <BR> <BR> <BR> <BR> <BR> pyrrolidin-3-ylcarbamoyl-4-(3 ,4-difluorophenyl)-6-methoxymethyl-2-oxo- 1,2 ,3,4-tetrahydropyrimidine-5-carboxylic acid methyl ester 1H NMR (CDCl3, 400 MHz) consistent with assigned structure.

FABLRMS m/e 706 g/mole (M++H, C32H41F2N7O7S = 705.783 g/mole.) HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H2O [0.1% H3PO4] - CH3CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 mI/min flow rate) focus = 215 nm; 99.1% pure.

Anal. Calcd for C32H41F2N707 2.10 HCl: C = 49.12, H = 5.55, N = 12.53. Found: C = 49.12, H = 5.60, N = 12.44.

EXAMPLE 62 (4S)-3-( 1-[ 1-(2-(N- 1-acetyl)aminophenyl)piperidin-4-yl]-pyrrolidin-3- ylcarbamoyl}-4-(3,4-difluorophenyl)-6-methoxymethyl-2-oXo- 1,2,3,4- tetrahydropyrimidine-5-carboxylic acid methyl ester

1H NMR (CDCl3, 400 MHz) consistent with assigned structure.

FABLRMS m/e 641 g/mole (M++H, C32H38F2N6°6 =640.693 g/mole.) HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H2O [0.1% H3PO4] - CH3CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 mI/min flow rate) focus = 215 nm; 100% pure.

EXAMPLE 63 (4S)-3-{1-[1-(2-(N-1-methanesulfonyl)aminophenyl)piperidin-4 -yl]- pyrrolidin-3-ylcarbamoyl}-4-(3,4-difluorophenyl)-6-methoxyme thyl-2-oxo- 1,2,3,4-tetrahydropyrimidine-5-carboxylic acid methyl ester 1H NMR (CDC13, 400 MHz) consistent with assigned structure.

FABLRMS m/e 677 g/mole (M++H, C31H38F2N6O7S = 676.747 g/mole.)

HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H2O [0.1% H3PO4] @ CH3CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 ml/min flow rate) focus = 215 nm; 99.9% pure.

EXAMPLE 64 (Diast A) (4S)-4-(3 ,4-Difluorophenyl)-2-oxo-oxazolidine-3-carboxylic acid{1-[1-(2-cyanophenyl)piperidin-4-yl]-3-hydroxy-pyrrolidi n-4-yl}amide 1H NMR (CDCl3, 400 MHz) consistent with assigned structure.

FABLRMS m/e 512 g/mole (M++H, C26H27F2N5°4 = 511.52 g/mole.) HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H2O [0.1% H3PO4] - CH3CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 ml/min flow rate) focus = 215 nm; 96% pure.

EXAMPLE 65 (Diast B) (4S)-4-(3 ,4-Difluorophenyl)-2-oxo-oxazolidine-3-carboxylic acid{1-[1-(2-cyanophenyl)piperidin-4-yl]-3-hydroxy-pyrrolidi n-4-yl}amide

1H NMR (CDCl3, 400 MHz) consistent with assigned structure.

FABLRMS m/e 512 g/mole (M++H, C26H27F2N5°4 = 511.52 g/mole.) HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H2O [0.1% H3PO4] - CH3CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 ml/min flow rate) focus = 215 nm; 98% pure.

EXAMPLE 66 (Racemic @ pyrrolidine) (4S)-3-{1-[1-(2-Cyanophenyl)piperidin-4-yl]-3- hydroxy-pyrrolidin-4-ylcarbamoyl)-4-(3 ,4-difluorophenyl)-6- methoxymethyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxyli c acid methyl ester 1H NMR (CDCl3, 400 MHz) consistent with assigned structure.

FABLRMS m/e 625.4 g/mole (M++H, C31H34F2N6°6 = 624.64 g/mole.) HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H2O [0.1% H3PO4] - CH3CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 mI/min flow rate) focus = 215 nm; 100% pure.

EXAMPLE 67 (Dias A) (4S)-3-{1-[1-(2-Cyanophenyl)piperidin-4-yl]-3-hydroxy-pyrrol idin- 4-ylcarbamoyl)-4-(3 ,4-difluorophenyl)-6-methoxymethyl- 2-oxo- 1,2,3,4- tetrahydropyrimidine-5-carboxylic acid methyl ester

1H NMR (CDCl3, 400 MHz) consistent with assigned structure.

FABLRMS m/e 625.4 g/mole (M++H, C31H34F2N6O6 = 624.64 g/mole.) HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H2O [0.1% H3PO4] - CH3CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 mI/min flow rate) focus = 215 nm; 100% pure.

EXAMPLE 68 (Dias B) (4S)-3-{1-[1-(2-Cyanophenyl)piperidin-4-yl]-3-hydroxy-pyrrol idin- 4-ylcarbamoyl) -4-(3,4-difluorophenyl)-6-methoxymethyl-2-oxo- 1,2,3,4- tetrahydropyrimidine-5-carboxylic acid methyl ester 1H NMR (CDCl3, 400 MHz) consistent with assigned structure.

FABLRMS m/e 625.4 glmole (M++H, C31H34F2N6°6 = 624.64 g/mole.)

HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H2O [0.1% H3PO4] @ CH3CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 ml/min flow rate) focus = 215 nm; 100% pure.

EXAMPLE 69 (racemic) (4S)-4-(3,4-Difluorophenyl)-2-oxo-oxazolidine-3-carboxylic acid {1-[1-(2-cyanophenyl)-piperidin-4-yl]pyrrolidin-3-ylmethyl}- amide 1H NMR (CDC13, 400 MHz) consistent with assigned structure.

FABLRMS m/e 510.34 g/mole (M++H, C27H29F2N503 = 509.55 g/mole.) HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H20 [0.1% H3PO4] @ CH3CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 mUmin flow rate) focus = 215 nm; 96% pure.

EXAMPLE 70 (racemic) (4S)-3-{1-[1-(2-Cyanophenyl)piperidin-4-yl]pyrrolidin-3- ylmethylcarbamoyl}-4-(3,4-difluorophenyl)-6-methoxymethyl-2- oxo- 1,2,3,4-tetrahydropyrimidine-5-carboxylic acid methyl ester

1H NMR (CDCl3, 400 MHz) consistent with assigned structure.

FABLRMS m/e 623.5 g/mole (M++H, C32H36F2N6O5 = 622.67 g/mole.) HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H2O [0.1% H3PO4] - CH3CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 mI/min flow rate) focus = 215 nm; 92% pure.

EXAMPLE 71 Diast A (4S)-3-t 1-[1-(2-Cyanophenyl)piperidin-4-yl]pyrrolidin-3- ylmethylcarbamoyl}-4-(3,4-difluorophenyl)-6-methoxymethyl-2- oxo- 1,2,3,4-tetrahydropyrimidine-5-carboxylic acid methyl ester 1H NMR (CDCl3, 400 MHz) consistent with assigned structure.

FABLRMS m/e 623.5 g/mole (M++H, C32H36F2N6°5 = 622.67 g/mole.) HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H2O [0.1% H3PO4] - CH3CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 mI/min flow rate) focus = 215 nm; 92% pure.

EXAMPLE 72 (Diast B) (4S)-3-(1-[1-(2-Cyanophenyl)piperidin-4-yl]pyrrolidin-3- ylmethylcarbamoyl}-4-(3,4-difluorophenyl)-6-methoxymethyl-2- oxo- 1,2,3,4-tetrahydropyrimidine-5-carboxylic acid methyl ester 1H NMR (CDC13, 400 MHz) consistent with assigned structure.

FABLRMS m/e 623.5 g/mole (M++H, C32H36F2N6O5 = 622.67 g/mole.) HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H2O [0.1% H3PO4] - CH3CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 mI/min flow rate) focus = 215 nm; 92% pure.

EXAMPLE 73 (Racemic) (4S)-4-(3,4-Difluorophenyl)-2-oxo-oxazolidine-3-carboxylic acid {1-[1-(2-cyanophenyl)-piperidin-4-yl]piperidin-3-ylmethyl}-a mide 1H NMR (CDC13, 400 MHz) consistent with assigned structure.

FABLRMS m/e 524 g/mole (M++H, C28H31F2N5O3 = 523.58 g/mole.) HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H2O [0.1% H3PO4] - CH3CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 ml/min flow rate) focus = 215 nm; >95% pure.

EXAMPLE 74 (Dias A) (4S)-4-(3 ,4-Difluorophenyl)-2-oxo-oxazolidine-3-carboxylic acid (1-[ 1-(2-cyanophenyl)-piperidin-4-yl]piperidin-3-ylmethyl}- amide 1H NMR (CDC13, 400 MHz) consistent with assigned structure.

FABLRMS m/e 524 g/mole (M++H, C28H31F2N5O3 = 523.58 g/mole.) HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H20 [0.1% H3PO4] - CH3CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 ml/min flow rate) focus = 215 nm; >95% pure.

EXAMPLE 75 (Dias B) (4S)-4-(3 ,4-Difluorophenyl)-2-oxo-oxazolidine-3-carboxylic acid (1- [1-(2-cyanophenyl)-piperidin-4-yl]piperidin-3-ylmethyl}-amid e 1H NMR (CDC13, 400 MHz) consistent with assigned structure.

FABLRMS m/e 524 g/mole (M++H, C28H31F2N5°3 = 523.58 g/mole.) HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H2O [0.1% H3PO4] - CH3CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 ml/min flow rate) focus = 215 nm; >95% pure.

EXAMPLE 76 (racemic) (4S)-3-{1-[1-(2-Cyanophenyl)piperidin-4-yl]piperidin-3- ylmethylcarbamoyl)-4-(3 ,4-difluorophenyl )-6-methoxymethyl-2-oxo- 1,2,3,4-tetrahydropyrimidine-5-carboxylic acid methyl ester 1H NMR (CDCl3, 400 MHz) consistent with assigned structure.

FABLRMS m/e 637 g/mole (M++H, C33H38F2N6°5 = 622.67 g/mole.) HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H2O [0.1% H3PO4] - CH3CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 mI/min flow rate) focus = 215 nm; >95% pure.

EXAMPLE 77 (Diast A) (4S)-3-{1-[1-(2-Cyanophenyl)piperidin-4-yl]piperidin-3- ylmethylcarbamoyl)-4-(3 ,4-difluorophenyl)-6-methoxymethyl-2-oxo- 1,2,3,4-tetrahydropyrimidine-5-carboxylic acid methyl ester

1H NMR (CDC13, 400 MHz) consistent with assigned structure.

FABLRMS m/e 637 g/mole (M++H, C33H38F2N6O5 = 622.67 g/mole.) HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H2O [0.1% H3PO4] - CH3CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 ml/min flow rate) focus = 215 nm; >95% pure.

EXAMPLE 78 (Diast B) (4S)-3-{1-[1-(2-Cyanophenyl)piperidin-4-yl]piperidin-3- ylmethylcarbamoyl)-4-(3 ,4-difluorophenyl)-6-methoxymethyl-2-oxo- 1,2,3,4-tetrahydropyrimidine-5-carboxylic acid methyl ester 1H NMR (CDC13, 400 MHz) consistent with assigned structure.

FABLRMS m/e 637 g/mole (M++H, C33H38F2N6°5 = 622.67 g/mole.)

HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H2O [0.1% H3PO4] - CH3CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 ml/min flow rate) focus = 215 nm; >95% pure.

EXAMPLE 79 (4S)-4-(3,4-Difluorophenyl)-2-oxo-oxazolidine-3-carboxylic acid {1-[1-(2- cyanophenyl)-piperidin-4-yl]piperidin-4-ylmethyl}-amide 1H NMR (CDCl3, 400 MHz) consistent with assigned structure.

FABLRMS m/e 524 g/mole (M++H, C28H31F2N5O3 = 523.5 g/mole.) HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H2O [0.1% H3PO4] - CH3CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 ml/min flow rate) focus = 215 nm; >95% pure.

EXAMPLE 80 (4S)-3-{1-[1-(2-Cyanophenyl)piperidin-4-yl]piperidin-4 ylmethylcarbamoyl}-4-(3,4-difluorophenyl)-6-methoxymethyl-2- oxo 1,2,3,4-tetrahydropyrimidine-5-carboxylic acid methyl ester 1H NMR (CDC13, 400 MHz) consistent with assigned structure.

FABLRMS m/e 637 g/mole (M++H, C33H38F2N6O5 = 622.67 g/mole.) HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H2O [0.1% H3PO4] - CH3CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 mi/min flow rate) focus = 215 nm; >99% pure.

EXAMPLE 81 (3R,4S,5S)-4-(3,4-Difluorophenyl)-5-methyl-2-oxo-oxazolidine -3-carboxylic acid (1- [ 1-(2-carboxymethylphenyl)-piperidin-4-yl]pyrrolid-3-yll-amid e 1H NMR (CDCl3, 400 MHz) consistent with assigned structure.

HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H2O [0.1% H3PO4] - CH3CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 mI/min flow rate) focus = 215 nm; 100% pure.

Anal. Calcd for C28H32F2N4O5 # 1.25 EtOAc and 1.85 H2O: C = 57.77, H = 6.71, N = 8.17. Found: C = 57.75, H = 6.95, N = 8.16.

EXAMPLE 82 (3R,4S,5R)-5-Carboxymethyl-4-(3,4-difluorophenyl)-2-oxo-oxaz olidine-3- carboxylic acid (1-[ 1-(2-carboxymethylphenyl)-piperidin-4-yl]pyrrolid-3- yl) -amide 1H NMR (CDCl3, 400 MHz) consistent with assigned structure.

HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H2O [0.1% H3PO4] - CH3CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 mI/min flow rate) focus = 215 nm; 96% pure.

Anal. Calcd for C29H32F2N407 2.1 HCl and 0.7 Et2O: C = 53.41, H = 5.79, N = 7.84. Found: C = 53.39, H = 5.56, N = 7.82.

EXAMPLE 83 As a specific embodiment of an oral composition, 100 mg of the compound of Example 6 (i.e., Compound S) is formulated with sufficient finely divided lactose to provide a total amount of 580 to 590 mg to fill a size 0 hard gel capsule.

EXAMPLE 84 Screening assav: Alpha la Adrenergic Receptor Binding Membranes prepared from the stably transfected human alpha la cell line (ATCC CRL 11140) were used to identify compounds

that bind to the human alpha la adrenergic receptor. These competition binding reactions (total volume = 200 Rl) contained 50 mM Tris-HCl pH.

7.4, 5 mM EDTA, 150 mM NaCl, 100 pM [125 I]-HEAT, membranes prepared from the alpha la cell line and increasing amounts of unlabeled ligand. Reactions were incubated at room temperature for one hour with shaking. Reactions were filtered onto Whatman GF/C glass fiber filters with a Inotec 96 well cell harvester. Filters were washed three times with ice cold buffer and bound radioactivity was determined (Ki). Representative compounds of the present invention were found to have Ki values <50 nM.

EXAMPLE 85 Selective Binding assavs Membranes prepared from stably transfected human alpha 1d and alpha 1b cell lines (ATCC CRL 11138 and CRL 11139, respectively) were used to identify compounds that selectively bind to the human alpha la adrenergic receptor. These competition binding reactions (total volume = 200 Ill) contained 50 mM Tris-HCl pH. 7.4, 5 mM EDTA, 150 mM NaCl, 100 pM [125 I]-HEAT, membranes prepared from cell lines transfected with the respective alpha 1 subtype expression plasmid and increasing amounts of unlabeled ligand. Reactions were incubated at room temperature for one hour with shaking. Reactions were filtered onto Whatman GF/C glass fiber filters with a Inotec 96 well cell harvester. Filters were washed three times with ice cold buffer and bound radioactivity was determined (Ki).

EXAMPLE 86 EXEMPLARY COUNTERSCREENS 1. Assav Title: Dopamine D2, D3, D4 in vitro screen Obiective of the Assav:

The objective of this assay is to eliminate agents which specifically affect binding of [3H] spiperone to cells expressing human dopamine receptors D2, D3 or D4.

Method: Modified from VanTol et al (1991); Nature (Vol 350) Pg 610- 613.

Frozen pellets containing specific dopamine receptor subtypes stably expressed in clonal cell lines are lysed in 2 ml lysing buffer (lOmM Tris-HCl/5mM Mg, pH 7.4). Pellets obtained after centrifuging these membranes (15' at 24,450 rpm) are resuspended in 50mM Tris-HCl pH 7.4 containing EDTA, MgCl[2], KCl, NaCl, CaCl[2] and ascorbate to give a 1 Mg/mL suspension. The assay is initiated by adding 50-75 ,ug membranes in a total volume of 500 tl containing 0.2 nM [3H]-spiperone. Non-specific binding is defined using 10 ,uM apomorphine. The assay is terminated after a 2 hour incubation at room temperature by rapid filtration over GF/B filters presoaked in 0.3% PEI, using 50mM Tris-HCl pH 7.4.

2. Assav Title: Serotonin 5HTla Obiective of the Assav The objective of this assay is to eliminate agents which specifically affect binding to cloned human 5HTla receptor Method: Modified from Schelegel and Peroutka Biochemical Pharmacology 35: 1943-1949 (1986).

Mammalian cells expressing cloned human 5HTla receptors are lysed in ice-cold 5 mM Tris-HCl, 2 mM EDTA (pH 7.4) and homogenized with a polytron homogenizer. The homogenate is centrifuged at 1000Xg for 30', and then the supernatant is centrifuged again at 38,000Xg for 30'. The binding assay contains 0.25 nM [3H]8-OH- DPAT (8-hydroxy-2-dipropylamino- 1,2,3,4-tetrahydronaphthalene) in 50 mM Tris-HCl, 4 mM CaCl2 and lmg/ml ascorbate. Non-specific binding

is defined using 10 I1M propranolol. The assay is terminated after a 1 hour incubation at room temperature by rapid filtration over GF/Cfilters EXAMPLE 87 EXEMPLARY FUNCTIONAL ASSAYS In order to confirm the specificity of compounds for the human alpha la adrenergic receptor and to define the biological activity of the compounds, the following functional tests may be performed: 1. In vitro Rat, Dog and Human Prostate and Dog Urethra Taconic Farms Sprague-Dawley male rats, weighing 250- 400 grams are sacrificed by cervical dislocation under anesthesia (methohexital; 50 mg/kg, i.p.). An incision is made into the lower abdomen to remove the ventral lobes of the prostate. Each prostate removed from a mongrel dog is cut into 6-8 pieces longitudinally along the urethra opening and stored in ice-cold oxygenated Krebs solution overnight before use if necessary. Dog urethra proximal to prostate is cut into approximately 5 mm rings, the rings are then cut open for contractile measurement of circular muscles. Human prostate chips from transurethral surgery of benign prostate hyperplasia are also stored overnight in ice-cold Krebs solution if needed.

The tissue is placed in a Petri dish containing oxygenated Krebs solution [NaCl, 118 mM; KCl, 4.7 mM; CaCl2, 2.5 mM; KH2PO4, 1.2 mM; MgSO4, 1.2 mM; NaHCO3, 2.0 mM; dextrose, 11 mM] warmed to 370C. Excess lipid material and connective tissue are carefully removed. Tissue segments are attached to glass tissue holders with 4-0 surgical silk and placed in a 5 ml jacketed tissue bath containing Krebs buffer at 37"C, bubbled with 5% C02/95% 02. The tissues are connected to a Statham-Gould force transducer; 1 gram (rat, human) or 1.5 gram (dog) of tension is applied and the tissues are allowed to equilibrate for one hour. Contractions are recorded on a Hewlett-Packard. 7700 series strip chart recorder.

After a single priming dose of 3 ,uM (for rat), 10 RM (for dog) and 20 ,uM (for human) of phenylephrine, a cumulative concentration response curve to an agonist is generated; the tissues are washed every 10 minutes for one hour. Vehicle or antagonist is added to the bath and allowed to incubate for one hour, then another cumulative concentration response curve to the agonist is generated.

ECso values are calculated for each group using GraphPad Inplot software. pA2 (-log Kb) values were obtained from Schild plot when three or more concentrations were tested. When less than three concentrations of antagonist are tested, Kb values are calculated according to the following formula Kb =S, x-l where x is the ratio of ECso of agonist in the presence and absence of antagonist and [B] is the antagonist concentration.

2. Measurement of Intra-Urethral Pressure in Anesthetized Dogs PURPOSE: Benign prostatic hyperplasia causes a decreased urine flow rate that may be produced by both passive physical obstruction of the prostatic urethra from increased prostate mass as well as active obstruction due to pro static contraction. Alpha adrenergic receptor antagonists such as prazosin and terazosin prevent active prostatic contraction, thus improve urine flow rate and provide symptomatic relief in man. However, these are non-selective alpha 1 receptor antagonists which also have pronounced vascular effects. Because we have identified the alpha la receptor subtype as the predominent subtype in the human prostate, it is now possible to specifically target this receptor to inhibit prostatic contraction without concomitant changes in the vasculature. The following model is used to measure adrenergically mediated changes in intra-urethral pressure and arterial pressure in anesthetized dogs in order to evaluate the efficacy and potency of selective alpha adrenergic receptor antagonists. The goals are to: 1) identify the alpha 1 receptor subtypes responsible for prostatic/urethral contraction and vascular responses, and 2) use this model to evaluate

novel selective alpha adrenergic antagonists. Novel and standard alpha adrenergic antagonists may be evaluated in this manner.

METHODS: Male mongrel dogs (7-12 kg) are used in this study. The dogs are anesthetized with pentobarbital sodium (35 mg/kg, i.v. plus 4 mg/kg/hr iv infusion). An endotracheal tube is inserted and the animal ventilated with room air using a Harvard instruments positive displacement large animal ventilator. Catheters (PE 240 or 260) are placed in the aorta via the femoral artery and vena cava via the femoral veins (2 catheters, one in each vein) for the measurement of arterial pressure and the administration of drugs, respectively. A supra-pubic incision -1/2 inch lateral to the penis is made to expose the urethers, bladder and urethra. The urethers are ligated and cannulated so that urine flows freely into beakers. The dome of the bladder is retracted to facilitate dissection of the proximal and distal urethra. Umbilical tape is passed beneath the urethra at the bladder neck and another piece of umbilical tape is placed under the distal urethra approximately 1-2 cm distal to the prostate. The bladder is incised and a Millar micro-tip pressure transducer is advanced into the urethra. The bladder incision is sutured with 2-0 or 3-0 silk (purse-string suture) to hold the transducer. The tip of the transducer is placed in the pro static urethra and the position of the Millar catheter is verified by gently squeezing the prostate and noting the large change in urethral pressure.

Phenylephrine, an alpha 1 adrenergic agonist, is administered (0.1-100 ug/kg, iv; 0.05 ml/kg volume) in order to construct dose response curves for changes in intra-urethral and arterial pressure. Following administration of increasing doses of an alpha adrenergic antagonist (or vehicle), the effects of phenylephrine on arterial pressure and intra-urethral pressure are re-evaluated. Four or five phenylephrine dose-response curves are generated in each animal (one control, three or four doses of antagonist or vehicle). The relative antagonist potency on phenylephrine induced changes in arterial and intra-urethral pressure are determined by Schild analysis. The family of averaged curves are fit simultaneously (using ALLFIT software package) with a four paramenter logistic equation constraining the

slope, minimum response, and maximum response to be constant among curves. The dose ratios for the antagonist doses (rightward shift in the dose-response curves from control) are calculated as the ratio of the EDso's for the respective curves. These dose-ratios are then used to construct a Schild plot and the Kb (expressed as ug/kg, iv) determined.

The Kb (dose of antagonist causing a 2-fold rightward shift of the phenylephrine dose-response curve) is used to compare the relative potency of the antagonists on inhibiting phenylephrine responses for intra-urethral and arterial pressure. The relative selectivity is calculated as the ratio of arterial pressure and intra-urethral pressure Kb's. Effects of the alpha 1 antagonists on baseline arterial pressure are also monitored. Comparison of the relative antagonist potency on changes in arterial pressure and intra-urethral pressure provide insight as to whether the alpha receptor subtype responsible for increasing intra-urethral pressure is also present in the systemic vasculature. According to this method, one is able to confirm the selectivity of alpha la adrenergic receptor antagonists that prevent the increase in intra-urethral pressure to phenylephrine without any activity at the vasculature.

While the foregoing specification teaches the principles of the present invention, with examples provided for the purpose of illustration, it will be understood that the practice of the invention encompasses all of the usual variations, adaptations and/or modifications as come within the scope of the following claims and their equivalents.