AU8150198A

AU8150198A - Alpha 1a adrenergic receptor antagonists

Info

Publication number: AU8150198A
Application number: AU81501/98A
Authority: AU
Inventors: Mark G. Bock; Michael A. Patane
Original assignee: Merck and Co Inc
Current assignee: Merck and Co Inc
Priority date: 1997-06-18
Filing date: 1998-06-17
Publication date: 1999-01-04
Also published as: JP2002508764A; CA2294346A1; EP1019052A4; EP1019052A1; WO1998057640A1

Description

WO 98/57640 PCT/US98/12672 TITLE OF THE INVENTION ALPHA la ADRENERGIC RECEPTOR ANTAGONISTS This application claims the benefit of U.S. Provisional 5 Application No. 60/050,960, filed June 18, 1997. FIELD OF THE INVENTION: This invention relates to certain novel compounds and derivatives thereof, their synthesis, and their use as alpha la 10 adrenoceptor antagonists. More particularly, the compounds of the present invention are useful for treating benign prostatic hyperplasia (BPH). BACKGROUND OF THE INVENTION 15 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. 20 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 25 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 30 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 B2 subtypes. Functional differences between alpha 1 and alpha 2 receptors -1- WO 98/57640 PCT/US98/12672 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 5 Adrenoreceptors: Molecular Biology, Biochemistry and Pharmacology, (Progress in Basic and Clinical Pharmacologyv 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' 10 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 15 alpha 1 receptors into alpha ld (formerly known as alpha la or la/ld), alpha lb 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 20 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 id. The new nomenclature is used 25 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 30 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 prostatic hypertrophy or BPH, is an illness typically affecting men over fifty years of age, increasing in 35 severity with increasing age. The symptoms of the condition include, -2- WO 98/57640 PCT/US98/12672 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. 5 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 prostatic hyperplasia, the male hormone 5alpha 10 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 15 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 PROSCAR® (finasteride). 20 The effect of this compound is to inhibit the enzyme testosterone 5-a reductase, which converts testosterone into 5a-dihydrotesterone, resulting in a reduced rate of prostatic enlargement, and often reduction in prostatic mass. The development of such agents as PROSCAR® bodes well 25 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. 30 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 35 disease, would be good candidates for this activity. Thus, one such agent -3- WO 98/57640 PCT/US98/12672 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 alphal subtype was reported. In addition, in WO 92/161213, 5 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 10 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 ld and alpha lb receptors in the peripheral vasculature, e.g., hypotension 15 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 20 receptor. [PCT International Application Publication Nos. WO94/08040, 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 25 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 30 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 35 alpha la adrenergic receptor. It is another object of the invention to -4- WO 98/57640 PCT/US98/12672 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 5 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 10 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 15 The present invention provides compounds for the treatment of urinary obstruction caused by benign prostatic 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 ld and alpha lb 20 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 25 structure: 1M R1R 16

R

2 4 M R 26 R N C Q R1-N _ 3 J /n R3 q S G R 7

R

18 L wherein Q is selected from -5- WO 98/57640 PCT/US98/12672 (X)S ss ( s S( OV 8 RR 9'R9 N N S0 N R0 O Rio R o R9 H (X)s R22 ,N -(X)s N N 0 N R R1 NRO

R

5 NH (X)s (X)s N 0 O R 11 R12 N N 'N NV R7 W R 7 W O N R0 N H R 12 H 0 ' R1 3 4 R 1 3 0 Ns 1 4 R N -Is - N ( Z R O J N or O 5 E, G, L and M are each independently selected from hydrogen, C1-8 alkyl, C3-8 cycloalkyl, (CH2)0-40R 6 , (CH2)0-4N(R 1 9 )2, (CH2)0-4CN, (CH2)0-4CF3, (CH2)0-4CO2R 1 9 , (CH2)0-4CON(R 1 9 )2, (CH2)0-4SO2R 1 9 , or (CH2)0-4SO2N(R 1 9 )2; -6- WO 98/57640 PCT/US98/12672 J is selected from hydrogen, C1-8 alkyl, C3-8 cycloalkyl, (CH2)1-40R 6 , (CH2)1-4N(R 1 9 )2, (CH2)1-4CN, (CH2)0-4CF3, (CH2)0-4CO2R 19 , (CH2)0-4CON(R 1 9 )2, (CH2)0-4SO2R 1 9 , or (CH2)0-4SO2N(R 19 )2; 5

R

1 is selected from unsubstituted, mono- or poly-substituted phenyl wherein the substituents on the phenyl are independently selected from halogen, CF3, cyano, nitro, N(R 1 9 )2, NR 1 9

COR

2 0 , NR 1 9

CON(R

2 0 )2,

NR

1 9 SO2R 2 0 , NR 1 9 SO2N(R 2 0 )2, OR 6 , (CH2)0-4CO2R 1 9 , oxadiazolyl-, Cj 10 4 alkyl oxadiazolyl-, (CH2)0-4CON(R 1 9 )2, (CH2)0-4SO2N(R 1 9 )2, (CH2)0 4SO2R 6 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, 15 cyano, nitro, (CH2)0-4CO2R 1 9 , (CH2)0-4CON(R 1 9 )2, (CH2)0-4SO2N(R 1 9 )2, (CH2)0-4SO2R 6 , phenyl, OR 6 , halogen, C1-4 alkyl or C3-8 cycloalkyl;

R

2 , R 3 , R 8 , R 1 0 , R 1 5 , R 1 6 , R 1 7 and R 1 8 are each independently selected from hydrogen, C1-8 alkyl, C3-8 cycloalkyl, (CH2)2-4OR 6 or (CH2)0-4CF3; 20

R

4 is selected from hydrogen, (CH2)0-4COR 6 , (CH2)0-4CN, (CH2)0-4CF3, (CH2)0-4CO2R 1 9 , (CH2)0-4CON(R 1 9 )2, (CH2)0-4SO2R 6 or (CH2)0-4SO2N(R 1 9 )2; 25 R 5 is selected from hydrogen, C1-8 alkyl, C3-8 cycloalkyl, (CH2)1-40R 6 or (CH2)0-4CF3;

R

6 is selected from hydrogen, 01-8 alkyl, C3-8 cycloalkyl or (CH2)0-4CF3; 30

R

7 is selected from hydrogen, C1-8 alkyl, C4-8 cycloalkyl, (CH2)0-4CO2R 1 9 , (CH2)0-4CON(R 1 9 )2, (CH2)0-4COR 1 9 , (CH2)2-40R 6 , (CH2)1-4CF3, (CH2)0-4SO2R 6 , (CH2)0-4SO2N(R 1 9 )2 or (CH2)1-4CN; -7- WO 98/57640 PCT/US98/12672

R

9 is selected from hydrogen, C1-8 alkyl, C3-8 cycloalkyl, CO2R 6 ,

CON(R

6 )2, (CH2)1-40R 6 or (CH2)0-4 CF3;

R

11 and R 12 are each independently selected from hydrogen, 5 C1-8 alkyl or C3-8 cycloalkyl;

R

13 and R 14 are each independently selected from hydrogen, C1-8 alkyl, C3-8 cycloalkyl, (CH2)1-40R 6 , (CH2)0-4CF3, unsubstituted, mono- or poly-substituted phenyl wherein the substituents on the phenyl are 10 independently selected from halogen, CF3, cyano, nitro, amino, OR 6 , (CH2)0-4CON(R 19 )2, (CH2)0-4CO2R 19 or C1-4 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, OR 6 , halogen, C1-4 alkyl or 15 C3-8 cycloalkyl;

R

19 and R 2 0 are each independently selected from hydrogen, C1-8 alkyl, C3-8 cycloalkyl or (CH2)1-4CF3; 20 R 2 2 is selected from hydrogen, C1-8 alkyl, C3-8 cycloalkyl, (CH2)0-40R 6 or (CH2)0-4CF3;

R

24 and R 2 6 are each independently selected from hydrogen or OR 2 8 ; 25 R 2 8 is selected from hydrogen, C1-8 alkyl, C3-8 cycloalkyl, or (CH2)0-4CF3; W is O or NR 11 ; 30 each X is independently selected from halogen, cyano, nitro, C1-8 alkyl, C3-8 cycloalkyl, (CH2)0-40R 6 or (CH2)0-4CF3; Y is C-R 19 or N; -8- WO 98/57640 PCT/US98/12672 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, R 2 6 is hydrogen; 5 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 10 having the structure M R15R 1 6 2 (n E )mR

R

1 -N N C 0 J

}

p R 3 q o G R 17

R

1 8 L wherein R 1 is selected from unsubstituted, mono- or poly-substituted phenyl wherein the substituents on the phenyl are independently selected from halogen, CF3, cyano, nitro, N(R 1 9 )2, NR 1 9

COR

2 0 , 15 NR 1 9

CON(R

2 0 )2, NR 1 9 SO2R 2 0 , NR 1 9 SO2N(R 2 0 )2, OR 6 , (CH2)0 4CO2R 1 9 , (CH2)0-4CON(R 1 9 )2, (CH2)0-4SO2N(R 1 9 )2, (CH2)0-4SO2R 6 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, 20 quinazolinyl or naphthyl are independently selected from CF3, cyano, nitro, (CH2)0-4CO2R 1 9 , (CH2)0-4CON(R 1 9 )2, (CH2)0-4SO2N(R 1 9 )2, (CH2)0-4SO2R 6 , phenyl, OR 6 , halogen, C1-4 alkyl or C3-8 cycloalkyl;

R

4 is selected from (CH2)0-4COR 6 , (CH2)0-4CN, (CH2)0-4CF3, 25 (CH2)0-4CO2R 1 9 , (CH2)0-4CON(R 1 9 )2, (CH2)0-4SO2R 6 or (CH2)0-4SO2N(R 1 9 )2;

R

5 is selected from hydrogen, C1-8 alkyl, C3-8 cycloalkyl, (CH2)2-40R 6 or (CH2)0-4CF3; -9- WO 98/57640 PCT/US98/12672

R

9 is selected from hydrogen, C1-8 alkyl, C3-8 cycloalkyl, (CH2)2-40R 6 or (CH2)0-4CF3; and 5 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 R15R 16

R

2 4 M RR m R ( n E 26 R (N C

R

1 -N ) Q G R 17 R18 L 10 wherein E, G, L, M and J are each independently selected from hydrogen, C1-8 alkyl, C3-8 cycloalkyl, or (CH2)0-4CF3; 15 R 1 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(R 1 9 )2, NR 1 9

COR

2 0 , NR 1 9

CON(R

2 0 )2,

NR

1 9 SO2R 2 0 , NR 1 9 SO2N(R 2 0 )2, OR 6 , (CH2)0-4CO2R 19 , oxadiazolyl-, C1-4 alkyloxadiazolyl, (CH2)0-4CON(R 1 9 )2, (CH2)0-4SO2N(R 1 9 )2, (CH2)0 20 4SO2R 6 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)0-4CO2R 1 9 , (CH2)0-4CON(R 1 9 )2, (CH2)0-4SO2N(R 1 9 )2, 25 (CH2)0-4SO2R 6 , phenyl, OR 6 , halogen, 01-4 alkyl or C3-8 cycloalkyl;

R

7 is selected from hydrogen, C1-8 alkyl, C4-8 cycloalkyl or (CH2)1-4CF3; - 10- WO 98/57640 PCT/US98/12672

R

1 3 and R 1 4 are each independently selected from hydrogen, C1-8 alkyl, C3-8 cycloalkyl, (CH2)1-40R 6 , (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, OR 6 , 5 (CH2)0-4 CON(R 1 9 )2, (CH2)0-4CO2R 1 9 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, OR 6 , halogen, C1-4 alkyl or C3-8 cycloalkyl; and 10 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 15 the formula M R15R 16 n E N C

R

1 -N N J P \Rq G R 17

R

18 L wherein E, G, L, M and J are each independently selected from hydrogen, C1-8 alkyl, C3-8 cycloalkyl, or (CH2)0-4CF3; 20 R 1 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(R 1 9 )2, NR 1 9

COR

2 0 , NR 1 9

CON(R

2 0 )2,

NR

1 9 SO2R 2 0 , NR 1 9 SO2N(R 2 0 )2, OR 6 , (CH2)0-4CO2R 1 9 , (CH2)0-4CON(R 1 9 )2, (CH2)0-4SO2N(R 1 9 )2, (CH2)0-4SO2R 6 or 25 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, -11- WO 98/57640 PCT/US98/12672 nitro, (CH2)0-4CO2R 1 9 , (CH2)0-4CON(R 1 9 )2, (CH2)0-4SO2N(R 1 9 )2, (CH2)0-4SO2R 6 , phenyl, OR 6 , halogen, C1-4 alkyl or C3-8 cycloalkyl;

R

7 is selected from hydrogen, C1-8 alkyl, C4-8 cycloalkyl or 5 (CH2)1-4CF3;

R

1 3 and R 1 4 are each independently selected from hydrogen, C1-8 alkyl, C3-8 cycloalkyl, (CH2)1-40R 6 , (CH2)0-4CF3, unsubstituted, mono-, di- or tri-substituted phenyl wherein the substituents on the phenyl are 10 independently selected from halogen, CF3, cyano, nitro, amino, OR 6 , (CH2)0-4CON(R 1 9 )2, (CH2)0-4CO2R 1 9 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, OR 6 , halogen, C1-4 alkyl or 15 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. 20 In a first class of the invention is the compound selected from

R

1 -N N R 26

R

26 (CH2)qQ R 1 -N N (CH 2 )-Q R24

R

1 - N 26 r R26 ( H 2 )_Q o R1 N /Z(CH2)_Q wherein Q is selected from - 12 - WO 98/57640 PCT/US98/12672 (X) s ( s 00 0 N N R4 N R9 R R 9 7 R 7 , O N R5 R7 0R1, Oj R9 H R1R1 7 R 22 R1 3 or - (X)s

R

1 is selected from unsubstituted, mono-, di- or tri-substituted phenyl wherein the substituents on the phenyl are independently selected from halogen, CF3, cyano, nitro, OR 6 , (CH2)0-2CO2R 1 9 , (CH2)0-2CON(R 1 9)2, 5 (CH2)0-2SO2N(R 1 9)2, (CH2)0-2SO2R 6 , C1-4 alkyl oxadiazolyl- or C1-4 alkyl; or unsubstituted, mono-, or di-substituted pyridyl wherein the substituents on the pyridyl are independently selected from halogen, CF3, cyano, nitro, OR 6 , (CH2)0-2CO2R 1 9 , (CH2)0-2CON(R 1 9 )2, (CH2)0-2SO2N(R 1 9 )2, (CH2)0-2SO2R 6 or C1-4 alkyl; 10

R

4 is selected from hydrogen, COR 6 , CO2R 1 9 , SO2R 6 or CON(R 1 9 )2;

R

5 is selected from hydrogen, C1-6 alkyl, C3-6 cycloalkyl, (CH2)1-30R 6 or (CH2)0-3CF3; 15

R

6 is selected from hydrogen, C1-6 alkyl, C3-6 cycloalkyl or (CH2)0-3CF3;

R

8 and R 1 0 are each independently selected from hydrogen, 20 C1-6 alkyl, C3-6 cycloalkyl, (CH2)2-40R 6 or (CH2)0-3CF3;

R

9 is selected from hydrogen, C1-6 alkyl, C3-6 cycloalkyl, CO2R 6 ,

CON(R

6 )2, (CH2)1-40R 6 or (CH2)0-3CF3; - 13 - WO 98/57640 PCT/US98/12672

R

1 3 is selected from hydrogen, C1-6 alkyl, C3-6 cycloalkyl, (CH2)2-40R 6 , (CH2)0-2CF3 or unsubstituted, mono- or di-substituted phenyl wherein the substituents on the phenyl are independently 5 selected from halogen, CF3, cyano, nitro, amino, OR 6 , CO2R 1 9 or C1-4 alkyl;

R

1 9 is selected from hydrogen, C1-6 alkyl, C3-6 cycloalkyl or (CH2)1-3CF3; 10

R

2 2 is selected from hydrogen, C1-6 alkyl, C3-6 cycloalkyl, (CH2)0-40R 6 or (CH2)0-3CF3;

R

2 8 is selected from hydrogen, C1-6 alkyl, C3-6 cycloalkyl, or 15 (CH2)0-3CF3; 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 20 embodiment; and the pharmaceutically acceptable salts thereof. In a second class of the invention is the compound selected from R'-N N (C H2 q- Q R'-N _-Na (CH2)qQ R'-NO-- N (CH 2 )-Q R-NN (CH Sor R N 7 NJ G 2 ~ 25 wherein Q is selected from - 14- WO 98/57640 PCT/US98/12672 N NN R o7 N Rs O O Ri 5 OR R

R

22

R

13 H 0 0 0R or ,-N (X)s

R

1 is selected from unsubstituted, mono-, di- or tri-substituted phenyl wherein the substituents on the phenyl are independently selected from 5 halogen, CF3, cyano, nitro, OR 6 , (CH2)0-2CO2R 1 9 , (CH2)0-2CON(R 1 9)2, (CH2)0-2SO2N(R 1 9 )2, (CH2)0-2SO2R 6 or C1-4 alkyl; or unsubstituted, mono-, or di-substituted pyridyl wherein the substituents on the pyridyl are independently selected from halogen, CF3, cyano, nitro, OR 6 , (CH2)0-2CO2R 1 9 , (CH2)0-2CON(R 1 9 )2, (CH2)0-2SO2N(R 1 9 )2, 10 (CH2)0-2SO2R 6 or C1-4 alkyl;

R

4 is selected from COR 6 , CO2R 1 9 , SO2R 6 or CON(R 1 9 )2;

R

5 is selected from hydrogen, C1-6 alkyl, C3-6 cycloalkyl, (CH2)1-30R 6 or 15 (CH2)0-3CF3;

R

6 is selected from hydrogen, C1-6 alkyl, C3-6 cycloalkyl or (CH2)0-3CF3; 20 R 8 , R 9 and R 1 0 are each independently selected from hydrogen, C1-6 alkyl, C3-6 cycloalkyl, (CH2)2-.40R 6 or (CH2)0-3CF3;

R

13 is selected from hydrogen, C1-6 alkyl, C3-6 cycloalkyl, - 15- WO 98/57640 PCT/US98/12672 (CH2)2-4OR 6 , (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, OR 6 , CO2R 1 9 or C1-4 alkyl; 5

R

1 9 is selected from hydrogen, C1-6 alkyl, C3-6 cycloalkyl or (CH2)1-3CF3;

R

2 2 is selected from hydrogen, C1-6 alkyl, C3-6 cycloalkyl, (CH2)0-40R 6 10 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 15 embodiment; and the pharmaceutically acceptable salts thereof. In a first subclass of the invention is the compound wherein Q is selected from (X)s

N

s -/ O(X) s R4 0 Ns O / N NJ R H) R\ HO N or H H 20 R 1 3 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, OR 6 , C02R 1 9 or C1-4 alkyl; 25 each X is a halogen; - 16- WO 98/57640 PCT/US98/12672 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 5 0 (X)s / O (X)s N J N R4N R9 O / H H N ,O N - RsH O 5 or H R H

R

1 3 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, OR 6 , 10 CO2R 1 9 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. 15 In a first illustration of the invention is the compound selected from (R 2 1 )r N N / - R 24 R 2 6

(CH

2 )q Q

(R

2 1 )r

R

24 N

R

26 / - N N

(CH

2 )-Q - 17- WO 98/57640 PCT/US98/12672

(R

21 )r

IR

2 4 S N N R26 (CH2)q-Q

(R

2 1 )r N 26 (-1A -N -,> (H wherein A is C-R 2 1 or N; each R 2 1 is independently selected from hydrogen, halogen, cyano, 5 OC1-4 alkyl, OCF3, OCH2CF3, CO2CH3, CONH2, SO2NH2 or S02C1-4 alkyl;

R

24 and R 2 6 are each independently selected from hydrogen or OR 2 8 , wherein R 2 8 is hydrogen or C1-4 alkyl; 10 each X is fluorine; r is an integer from zero to two; and q is an integer from zero to one; 15 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

(R

2 1 r

(CH

2 -Q N Nc? -A

(R

21 )r /1 \NZ-N

-(CH

2 qQ - 18 - WO 98/57640 PCT/US98/12672

(R

2 1 )r

N

N - (C H 2 O-Q -A o r

(R

21 )r -N N(CH 2 ;-Q wherein A is C-R 2 1 or N; each R 2 1 is independently selected from hydrogen, halogen, cyano, OC1 5 4 alkyl, OCF3, OCH2CF3, CO2CH3, CONH2, SO2NH2 or SO2C1-4 alkyl; each X is fluorine; r is an integer from zero to two; 10 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 15 Q is selected from F F F F |0 1 F N N R4H o F H ~ N HO O or H R 13 H

R

4 is C02R 19 ;

R

5 is (CH2)1-30R 6 ; - 19- WO 98/57640 PCT/US98/12672 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 5 Q is selected from F F F \N F o F 0N 1N 00 Jt, R4 N R13N N N H HO0 N Rs O O or N R13 H

R

4 is CO2R 19 ;

R

5 is (CH2)1-30R 6 ; 10 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 15 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 20 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 25 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 -20 - WO 98/57640 PCT/US98/12672 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 5 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 10 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 15 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 20 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 25 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 30 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 35 treating a disease which is susceptible to treatment by antagonism of the -21- WO 98/57640 PCT/US98/12672 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, 5 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 10 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 15 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. 20 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 ld and alpha lb adrenergic receptor subtypes, and many other G protein coupled human receptors. Particular representative compounds 25 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 ld and alpha lb adrenergic receptor subtypes, and many other G-protein coupled human receptors (e.g., serotonin, dopamine, alpha 2 adrenergic, beta adrenergic or 30 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, 35 however, be useful in the preparation of the compounds according to the -22- WO 98/57640 PCT/US98/12672 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 5 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 10 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, 15 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, 20 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, 25 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 PROSCAR® 30 (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 35 nervous system events. -23 - WO 98/57640 PCT/US98/12672 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 5 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 10 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 15 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, 20 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 25 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.). 30 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 35 aromatic groups such as phenyl or naphthyl. -24- WO 98/57640 PCT/US98/12672 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 5 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., C1-10) 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 10 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 15 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 20 variable (e.g., X, R 1 9 , R 2 0 ) at a particular location in a molecule be independent of its definitions elsewhere in that molecule. Thus, N(R 19 )2 represents -NH2, -NHCH3, -NHC2H5, -N(CH3)C2H5, etc. and R24 2 represents for m=2 OH OH OH OH ,e4,etc. It is understood that substituents and substitution patterns on the 25 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 -25 - WO 98/57640 PCT/US98/12672 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. 5 The term "Z is hydrogen," when refering to the "Q" group R13

R

8 , refers to the moiety

R

13 14 N

R

8 The term heterocycle or heterocyclic ring, as used herein, 10 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 15 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, 20 thienyl, pyrazolyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolidinyl, isooxazolyl, isoxazolidinyl, morpholinyl, thiazolyl, thiazolidinyl, isothiazolyl, thiadiazolyl, tetrahydropyranyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, 25 and oxadiazolyl. Morpholino is the same as morpholinyl. -26- WO 98/57640 PCT/US98/12672 The term "thienyl," as used herein, refers to the group S The terms "(+)-DHP" and "DHP" as used herein, refer to a dihydropyrimidinone group of the formula (X)q 0

-

N R 4 0 N R 5 H for example: F F O O oo N j 0 H The term "activated (+)-DHP," as used herein, refers to a N 3-(activated)carbamate of the desired dihydropyrimidinone where the 10 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. 15 The term "(S)-oxa" as used herein, refers to an oxazolidinone group of the formula -27 - WO 98/57640 PCT/US98/12672 (X)q O R' R N Rio 0O for example, F F O A N 0 The term "activated (S)-oxa" as used herein, refers to an N 5 (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 10 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, 15 refers to and includes, but is not limited to, prostatic smooth muscle, the prostatic 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. -28 - WO 98/57640 PCT/US98/12672 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, 5 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 10 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 15 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 20 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 25 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 30 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 35 prolonged action. For example, the tablet or pill can comprise an inner -29- WO 98/57640 PCT/US98/12672 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 5 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 10 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 15 present invention may be incorporated for administration orally or 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 20 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 25 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 30 example, be resolved into their component enantiomers by standard techniques, such as the formation of diastereomeric pairs 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 35 also be resolved by formation of diastereomeric esters or amides, -30 - WO 98/57640 PCT/US98/12672 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 5 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 Chemistry, ed. J.F.W. McOmie, Plenum Press, 1973; and T.W. Greene & 10 P.G.M. Wuts, Protective Groups in Organic Synthesis, 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 15 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 ld, alpha lb) or beta adrenergic receptors. Expression of the cloned human alpha ld, alpha lb, and alpha la receptors and comparison of their binding properties with known selective antagonists 20 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 25 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 30 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 35 receptor, when expressed in mammalian cell lines, is used to discover -31- WO 98/57640 PCT/US98/12672 ligands that bind to the receptor and alter its function. Expression of the cloned human alpha id, alpha lb, 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 5 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 10 functions. [See e.g., PCT International Application Publication No. W094/10989, 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 B 15 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 20 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 25 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 30 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 35 in intravenous (both bolus and infusion), intraperitoneal, -32 - WO 98/57640 PCT/US98/12672 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 5 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 10 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 15 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 20 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 25 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 30 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 -33 - WO 98/57640 PCT/US98/12672 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 5 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 10 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 15 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, 20 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. 25 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 multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines. 30 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 35 pyrrolidone, pyran copolymer, polyhydroxypropylmethacryl -34- WO 98/57640 PCT/US98/12672 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 5 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 10 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 15 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, 20 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 25 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 30 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 35 inhibitors of 5-alpha reductase isoenzyme 2. Many such compounds are -35- WO 98/57640 PCT/US98/12672 now well known in the art and include such compounds as PROSCAR®, (also known as finasteride, a 4-Aza-steroid; see US Patents 4,377,584 and 4,760,071, for example). In addition to PROSCAR®, which is principally active in prostatic tissue due to its selectivity for human 5-a reductase 5 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 WO93/23420, EP 10 0572166; WO 93/23050; WO93/23038,; W093/23048; W093/23041; WO93/23040; W093/23039; WO93/23376; WO93/23419, EP 0572165; WO93/23051. The dosages of the alpha la adrenergic receptor and testosterone 5-alpha reductase inhibitors are adjusted when 15 combined to achieve desired effects. As those skilled in the art vill 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 20 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 25 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 30 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 35 about 10 mg per subject per day, more preferably, about 1 to about 7 -36- WO 98/57640 PCT/US98/12672 mg per subject to day, most preferably, about 5 mg per subject per day. For the treatment of benign prostatic hyperplasia, compounds of this invention exhibiting alpha la adrenergic receptor 5 blockade can be combined with a therapeutically effective amount of a 5a-reductase 2 inhibitor, such as finasteride, in addition to a 5a reductase 1 inhibitor, such as 4,71-dimethyl-4-aza-5a-cholestan-3 one, in a single oral, systemic, or parenteral pharmaceutical dosage formulation. Alternatively, a combined therapy can be employed 10 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 5a-reductase inhibitors. 15 Abbreviations used in the instant specification, particularly the Schemes and Examples, are as follows: AcOH or HOAc = acetic acid BCE = bromochloroethane 20 Boc or BOC = t-butyloxycarbonyl BOC20 = di-tert-butyl dicarbonate BOPC1 = bis(2-oxo-3-oxazolidinyl)phosphinic chloride BuOH = butanol Cbz-C1 = benzyloxycarbonyl chloride 25 DAST = diethylaminosulfurtrifluoride DEAD = diethylazodicarboxylate DMF = N,N-dimethylformamide DMSO = dimethylsulfoxide DPPA = diphenylphosphoryl azide 30 EDCI = 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride Et = ethyl Et3N = triethylamine EtOAc = ethyl acetate 35 EtOH = ethanol -37 - WO 98/57640 PCT/US98/12672 FABLRMS = fast atom bombardment low resolution mass spectroscopy FABMS = fast atom bombardment mass spectroscopy HMPA = hexamethylphosporamide 5 HPLC = high performance liquid chromatography HOBt = 1-hydroxy benzotriazole hydrate i-Pr or iPr = isopropyl i-PrOH = 2-propanol i-Pr2NEt = diisopropylethylamine 10 LAH = lithium aluminum hydride mCPBA = meta-chloroperbenzoic acid Me = methyl MeOH = methanol n-BuLi = n-butyl lithium 15 NMR = nuclear magnetic resonance PCTLC = preparative centrifugal thin layer chromatography PEI = polyethylenimine Ph = phenyl 20 RT = retention time TEBAC = benzyltriethylammonium chloride TFA = trifluoroacetic acid THF = tetrahydrofuran TLC = thin layer chromatography 25 TMS = trimethylsilyl Tos20 or TOS20 = p-toluenesulfonic anhydride The compounds of the present invention can be prepared readily according to the following reaction schemes and examples, or 30 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. -38 - WO 98/57640 PCT/US98/12672 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 5 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. 10 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 15 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 20 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 25 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) 30 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 35 Schemes 7 to 8. N-protected 3-hydroxy azetidine (10) was tosylated -39- WO 98/57640 PCT/US98/12672 providing (11). Azide displacement produced (12) followed by reduction with PPh3/H20 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 5 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, 10 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). 15 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 20 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 BOC20 (35) and azetidine deprotection (36) under catalytic hydrogenation conditions, 25 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 30 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 35 Evans. [Evans, D.A.; Nelson, J.V.; Taber, T.R. Top. Stereochem. 13 1 -40 - WO 98/57640 PCT/US98/12672 (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 5 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, 10 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 15 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 20 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. 25 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 30 according to known methods, e.g., page 40 and Examples 21 and 22 of PCT International Application Publication No. WO96/25934, published August 29, 1996. The dihydropyrimidinones and the unsubstituted, alkyl and cycloalkyl-substituted oxazolidinones were synthesized 35 independently in racemic form, and then separated utilizing preparative -41- WO 98/57640 PCT/US98/12672 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 5 (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 oxazolidinones substituted with carboxylate, carboxamide, and hydroxymethyl were prepared in enantiomer 10 enriched form and the assignments of (4S,5R) were made in accordance with Sharpless et al., Angew. Chem. Int. Ed. Engl., 35, 2813 (1996) -42- WO 98/57640 PCT/US98/12672 SCHEME 1 AcOH or Ti(OiPr) 4 NaCNBH 3 Na MeOH CN NHBOC CN ,... O HN NHBOC IQ HCI, 0 EtOAc NH 1) CBZCI 2) DPPA

CO

2 H Et 3 N/tBuOH 3) H 2 /Pd-C NC N HOBt O F -43 F NCN - 43 - WO 98/57640 PCT/US98/12672 SCHEME 1 (CONT"D) F |F NC N 0 2 N N O C0 2 Me O N N 8 O N H O

NH

2 F

CO

2 Me F N F H CN N NNH F \/N 00 0 0 0 2 N 19 F F\ H O CN N N 0 N 0 0 -44- WO 98/57640 PCT/US98/12672 SCHEME 2 AcOH NaCNBH 3 MeOH N CN N HN OH CN N N OH 1) Tos20 2) NaN 3 N 3) Ph 3

P/H

2 0 N NH 2 8 F F NJ C N C02M e 0 19 ONN NOkN OM H F F CN0 N N N N 0 -45 - WO 98/57640 PCT/US98/12672 SCHEME 2 (Cont'd) Na CN N NH 2 EDCI/HOBt HO F 0 0 F ON N N N FF H -46- WO 98/57640 PCT/US98/12672 SCHEME 3 AcOH NaCNBH 3 N MeOH NC NHBOC N ~NHBOC HBO NC H EtOAc F 19 F ON NH ON NEDN NO 8 F CO2 0 N F O CN N N N NH 00 EDCI/HOBt HO F 0F No H F -47 - WO 98/57640 PCT/US98/12672 SCHEME 4 AcOH NaCNBH 3 N N N MeOH OH ON C O HN OH CN N OH 1) Tos 2 0 2) NaN 3 ON 3) Ph 3

P/H

2 0 N N NH 2 8 F F 19 0

OCNCO

2 Me H F F Na 0 ON CNN N O 0/ _ -48 - WO 98/57640 PCT/US98/12672 SCHEME 4 (Cont'd) Na CN N N H 2 EDCI/HOBt HO F o F ON N N FF H -49 - WO 98/57640 PCT/US98/12672 SCHEME 5 AcOH NaCNBH 3 MeOH / N N CN N NHBOC [IN O O HN,,, NHBOC 1) Tos 2 0 HCI 2) NaN 3 EtOAc Ph 3) Ph 3 P N OH 4)BOC 2 0 N Ph 5) H 2 /Pd-C N C N N

NH

2 8 F

CO

2 Me 19 N F H O CN N kLNH N ~Fo F C N Na N N N O 0 0 -50 - WO 98/57640 PCT/US98/12672 SCHEME 5 (Cont'd) N ONa

NH

2 EDCI/HOBt R22 R 22 = H, i-Pr HO F O NC F CN N R22 F O

F

WO 98/57640 PCT/US98/12672 SCHEME 6 N BOC 2 0 O H Cbz-CI

HNH

2 0

NH

2 1 2 00 TFA O N N- HN N H4 4H 0 3 CN NaCNBH 3 ( CO CN 5 aO CN H NN

NH

2 7 N- NH2 6 - 52 - WO 98/57640 PCT/US98/12672 SCHEME 6 (cont'd) CN "N H N' H 0 [ 0 N N'0"" N 0 0 9 F F C N N N CN N N y19 N 0

NH

2 H 7N N 7 0 28 ( F F -53 - WO 98/57640 PCT/US98/12672 SCHEME7

TOS

2 0 N NaN 3 HO - 11 10 0 Ph 3 P BOC20 N \ H20 N N H 2 N CN oN N OO N 5O O H 14 NaCNBH 3 15 CN CN TFA N O 17 NH 2 16 H -54- WO 98/57640 PCT/US98/12672 SCHEME 7 (cont'd) oc ON N 18 O O Na 19 aC N 17 NH 2 N F N F o0 N H --O N 20 O F 29 F HO F HO F F 31 Oc N N N F FF CN Na N 0F N N FFH 30 a Na30 32 N" F H -55 - WO 98/57640 PCT/US98/12672 SCHEME 8 CN N 5 N OH TOS 2 0 HN NaNBH 3 22 ~NaCNBHz 21 CN CN N O- NaN N 3 0 '~/ NaN.

3 IN -N 23 24 CN Ph3P N NH 2 ON N H 8 a NH N 25 N NN NO 0 0 26 F hiracel AD F 26a Diastereomer A 26b Diastereomer B -56- WO 98/57640 PCT/US98/12672 SCHEME 8 (cont'd) CN H N NH 2 Na H219 a NN ,/ N cr0 25 31 F Chiracel AD F 31a Diastereomer A 31b Diastereomer B -57 - WO 98/57640 PCT/US98/12672 SCHEME 9 AcOH or Ti(OiPr) 4 NaCNBH 3 N MeOH 1-2 N 1-2 N (CH 2

)

0

-

2 0H SHN (CH 2

)

0

-

2 0H ) 0-2 )0-2 o2 Tos 2 0 F nBuLi N

(CH

2

)

0

-

2 0Tos 0 I F ) 0-2 N o F N 1-2 CN N 0-2 N O 0-2 0 - 58 - WO 98/57640 PCT/US98/12672 SCHEME 9 (cont'd)

R

13 R14 O C NR NN 1-2 R 3 O R R13 N H CN N 1- 2 N R S (X)s0-2 HN, 0 ~ Na 0 N *0 2 OOY N 1-2 (Xg- Rs C N 0- 2 N HS a X) ) 0 -2 ,S 0-2 - 59- WO 98/57640 PCT/US98/12672 SCHEME 10 LAH N BOC 2 0 N AIC1 3

H

2 N NC 33 34 CN N -10% Pd-C 5 BOCHN 35 BOCHN NaCNBH 3 36 N TFAN N C N N NHBOC N NH 2 37 38 -60 - WO 98/57640 PCT/US98/1267 2 WO 98/57640 SCHEME 10 (Cont'd) CN N H N H 0 N 0 N Y 39 0 0 F 19 CN F N H N I N 40 9F

F

WO 98/57640 PCT/US98/1 2672 SCHEME 11 0 0 ~~BnOCONH 2 O' H0 HMe OH ~ Me tBuOC, NaOH -e o M

FH-

2 S 04 F ~o (DHQ) 2 PHAL - F8

K

2

OSO

2 (01H) 2 F

NH

2 O0 H 2 , Pd/C Me triphosgene ,C2eLiHMDS P F OH ------ H I p-NO 2 PhOCOCI F 'Pr 2 NEt 0 F 1 F 0 2 N ~1 i i g eN H2 R2 FQ ~ ~ 2 F R2 F R1F ~~J.~NcXN21% 3/H 3 6QN$h N N ,P 2esiica gel 19N '- NH 2 H 4 N4 5 00 10 15 -62 - WO 98/57640 PCT/US98/12672 Scheme 11 (cont'd) F F F F LiBH 4 2,3 dihydropyran LiBH4 .0 %0 CO2Me - -OH CSA, CH2Cl H N H N THF H NO F

R

m LiHMDS 02N FO 6 DNa NH2 p-NO2PhOCOCI O N Pr2NEt F F F 21 FF N N -0P pTsOH N F N -OH OMeOH O o & 5 The following examples are provided to further define the invention without, however, limiting the invention to the particulars of these examples. 10 EXAMPLE 1 4-Aminomethvl-piperidine- 1-carboxv1ic acid tert-butv1 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 15 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 MgSO 4 , filtered and the solvents removed in vacuo to give the title compound -63 - WO 98/57640 PCT/US98/12672 1H NMR (CDC13, 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). 5 EXAMPLE 2 4-(Benzyloxycarbonylamino-methyl)-piperidine-1-carboxylic acid tert butyl ester (3) 10 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 15 vacuo. The crude product was purified by chromatography on silica gel (3:1 hexane:ethyl acetate) to give the title compound. 1 H NMR (CDC13, 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). 20 EXAMPLE 3 Piperidin-4-ylmethyl-carbamic acid benzvl ester (4) To a solution of 3 (4.4 g, 13 mmol) in 90 ml of methylene 25 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. 30 1 H 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 -64- WO 98/57640 PCT/US98/12672 [1'-(2-Cyano-phenyl)-[1,4']bipiperidinyl-4-ylmethyl]-carbamic acid benzyl ester (6) To a solution of 2-(4-oxo-piperidin-1-yl)-benzonitrile (5) (653 5 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 10 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/CHC13) to give 15 the title compound. 1 H NMR (CDC13, 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 20 (m, 6H), 1.60-1.45 (m, 1H), 1.40-1.25 (m, 2H). EXAMPLE 5 2-(4-Aminomethv1-[ 1, 4'bipiperidinvy1- 1'-vl)-benzonitrile (7) 25 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. 1 H NMR (CDC13, 400 MHz) 7.53 (dd, 1H, J=7.69Hz, J=1.4Hz) 30 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 35 -65 - WO 98/57640 PCT/US98/12 6 72 3-{[1'-(2-Cyano-phenyl)- 1, 4 ']bipiperidinyl-4-ylmethyl]-carbamoyl}-4-(3,4 difluoro-phenyl)-6-methoxymethyl-2-oxo-1,2,3,4-tetrahydro-pvrimidine-5 carboxylic acid methyl ester trifluoroacetic acid salt (9) To a solution of 7 in 30 ml of chloroform was added dropwise 5 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/CHC13). 1H NMR (CD3OD, 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 10 (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 05 F2 0.80 H20, 1.40 TFA: C, 53.03; H, 5.10; N, 10.37 Found: C 53.03 H 5.12 N 10.37. 15 EXAMPLE 7 Toluene- 4 -sulfonic acid 1-benzhdrvl-azetidin- 3 -vI ester (11) To a cooled (00C) solution of 10 (7 g, 29 mmol) in 100 ml of 20 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 25 chromatography on silica gel to give the desired product as an oil. 1H NMR (CDC13, 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). 30 EXAMPLE 8 3-Azido-1-benzhvdrv1-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 35 cooling to room temperature the solvent was removed in vacuo and the -66- WO 98/57640 PCT/US98/12672 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. 5 1 H NMR (CDC13, 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 10 1-Benzhydrv1-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 CHC13: 15 MeOH:NH4OH). 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). -67- WO 98/57640 PCT/US98/12672 EXAMPLE 10 (1-Benzhydrv1-azetidin-3-vl)-carbamic acid tert-but1l ester (14) A solution of 13 (3.5 g, 14.7 mmol) di-tert-butyl dicarbonate 5 (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 10 compound. 1 H NMR (CDC13, 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 15 Azetidin-3-vl-carbamic acid tert-butyl 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 20 the solvents removed in vacuo to give the title compound. 1 H 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 25 {1-[1-(2-Cyano-phenyl)-piperidin-4-yl]-azetidin-3-yl}-carbamic acid tert butyl 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 30 of 6 to give the title compound. 1 H 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). 35 -68 - WO 98/57640 PCT/US98/12672 EXAMPLE 13 2-[4-(3-Amino-azetidin- 1-vl)-piperidin- 1-vll1-benzonitrile (17) The title compound was prepared from 16 (1.5 g) using the 5 procedure described for the preparation of 4. 1H NMR (CDC13, 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). 10 EXAMPLE 14 3- { 1-[1-(2-Cyano-phenyl)-piperidin-4-yl]-azetidin-3-ylcarbamoyl}-4-(3,4 difluoro-phenyl)-6-methoxymethyl-2-oxo-1,2,3,4-tetrahydro-pyrimidine-5 15 carboxylic acid methyl 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 (CDC13, 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), 20 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 05 F2 1.00 H20: 25 C, 58.81; H, 5.59, N, 13.72. Found: C, 58.58; H, 5.20; N, 13.59. -69 - WO 98/57640 PCT/US98/12672 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) 5 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. 1 H NMR (CD3OD, 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, 10 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 N5 03 F2 1.05 H20, 1.35 TFA: C, 50.84; H, 4.38; N, 10.70. Found: C, 50.83; H, 4.29; N, 11.09. 15 EXAMPLE 16 2-(3-Hvdroxvinethv1-[ 1 4'lbipiperidinv1- 1'-vl)-benzonitrile (22) The title compound was prepared from 21 (1.13 g, 5.6 mmol) 20 and 5 (750 mg, 3.75 mmol) using the procedure described in 16 to give the title compound. 1 H NMR (CDC13, 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). 25 EXAMPLE 17 p-Tolyl-methanesulfonic acid 1'-(2-cyano-phenyl)-[1,4']bipiperidinyl-3 ylmethyl ester (23) 30 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 (CDC13, 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, 35 2H), 3.63 (d, 2H, J=11.71Hz), 2.82-2.70 (m, 3H), 2.45 (s, 3H), 2.45-2.35 (m, - 70 - WO 98/57640 PCT/US98/12672 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 5 2-(3-Azidomethyl-[ 1.4'bipiperidiny1- 1'-vl)-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. 10 1 H NMR (CDC13, 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). 15 EXAMPLE 19 2-(3-Aminomethvl-[ 1.4'bipiperidinv1- 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 20 described for 13. 1 H NMR (CDC13, 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). 25 -71- WO 98/57640 PCT/US98/12672 EXAMPLE 20 3- {[ l'-(2-Cyano-phenyl)-[1,4']bipiperidinyl-3-ylmethyl]-carbamoyl}-4-(3,4 difluoro-phenyl)-6-methoxymethyl-2-oxo-1,2,3,4-tetrahydro-pvrimidine-5 5 carbox1ylic acid methyl 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. 1 H NMR (CD3OD, 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, 10 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 05 F2 0.35 H20, 1.65 TFA: C, 52.45; H, 4.89; N, 10.11. Found: C, 52.45; H, 4.88; N, 10.13. 15 EXAMPLE 21 4-(3,4-Difluoro-phenyl)-2-oxo-oxazolidine-3-carboxylic acid [1'-(2-cyano phenvl)-[1,4'lbipiperidinyl-3-v1methyll-amide trifluoroacetic acid salt (27) 20 The title compound was prepared from 25 (175 g, 0.58 mmol) and j19 (105 mg, 0.28 mmol) using the procedure described for 9. 1 H 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 25 1.57 (m, 8H), 1.23-1.03 (m, 1H). MS (FAB) 524 (M+1). Analysis calculated for C28 H31 N5 03 F2 1.30 TFA: C, 54.70; H, 4.85; N, 10.43. Found: C, 54.72; H, 4.77; N, 10.11. - 72 - WO 98/57640 PCT/US98/12672 EXAMPLE 22 4-(3,4-Difluoro-phenyl)-2-oxo-oxazolidine-3-carboxylic acid [1'-(2-cyano phenvl)-r[1,4'lbipiperidinv1-4-vlmethyll-amide triflouroacetic acid salt (28) 5 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. 1 H NMR (CD3OD, 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 10 (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 N5 03 F2 0.30 H20, 1.85 TFA: C, 51.45; H, 4.56; N, 9.47. Found: C, 51.47; H, 4.58; N, 9.36. 15 EXAMPLE 23

H

2 N- N 3-Aminomethyl N-diphenvylmethvl azetidine, (34) To a cooled solution of aluminum chloride (0.33 g, 2.41 20 mmol) in ether (50 mL) at -780 C was added lithium aluminum hydride (2.41 ml, 2.41 mmol). After stirring 15 minutes at -780 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 0oC and quenched with water (10 mL) dropwise 25 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. - 73 - WO 98/57640 PCT/US98/12672 1 H NMR (CDC1 3 , 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 BOCHN N 5 3-N-(1,1-dimethylethoxycarbonyl)aminomethyl N-diphenylmethyl azetidine, (35) The title compound was prepared from 34 using the procedure described for the preparation of 14. 10 1 H NMR (CDCl 3 , 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 15 BOCHN ' NH 3-N-[(1. 1-dimethylethoxycarbonyl)methyllaminomethyl azetidine. (36) The title compound was prepared from 35 using the procedure described for the preparation of 15. 1H NMR (CD 3 OD, 300 MHz) 4.92-4.85 (m, 4 H), 4.05 (br m, 2 20 H), 3.88-3.86 (br m, 2 H), 1.94-1.90 (m, 1 H), 1.46 (s, 9 H) EXAMPLE 26 -74- WO 98/57640 PCT/US98/12672 CN N NHBOC 2-[4-(3-N-(1,1-Dimethylethoxycarbonyl)aminomethyl-azetidin-1l-yl) piperidin-1-v11-benzonitrile, (37) The title compound was prepared from 36 using the 5 procedure described for the preparation of 16. 1 H NMR (CDC1 3 , 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). 10 EXAMPLE 27 CN N NH 2 2-[4-(3-Aminomethyl-azetidin-1-vl)-piperidin-1-yll-benzonitrile, (38) The title compound was prepared from 37 using the 15 procedure desrcibed for the preparation of 17. 1 H NMR (CDC1 3 , 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). 20 EXAMPLE 28 - 75 - WO 98/57640 PCT/US98/12672 CN F O 0 F /00 N 0 H NH N N N O Compound (39) The title compound 39 was prepared from 3 using the procedure described for the preparation of 18. 5 1 H NMR (CDC1 3 , 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). 10 MS (FAB) 609 (M+1) EXAMPLE 29 F F CN N H0 N NYN>O O O Compound (40) 15 The title compound 40 was prepared from 38 using the procedure described for the preparation of 20. 1 H NMR (CDC1 3 , 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 20 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). - 76- WO 98/57640 PCT/US98/12672 Anal. Called for C 26

H

2 7

N

5 0 3

F

2 * 0.25 CHC1 3 + 0.20 H 2 0: C = 61.94, H = 5.48, N = 13.87. Found: C = 61.97, H = 5.55, N = 13.50. MS (FAB) 496 (M+1) 5 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 F F 0 0 N O O~N O.. N.. 01O. H - 77 - WO 98/57640 PCTIUS98/12672 CD W Iq ~ ~ en C C\ b <~~ uuzc)o ) .0 -, - a z C) 00 6 lo 06 0 0 00 ,; W.; 00 00 o -78 - WO 98/57640 PCTIUS98/12672

=-

-> 0 .0 6. 00 U- L 0 -79 - WO 98/57640 PCT/US98/12672 00 0 ,O\Z 0 ,9 Z 'n RZ u0 u L) U a: - -) -\ r u oU Cu m~ .. L) U o U U z 0 -80 - WO 98/57640 PCTIUS98/12672 0 U Z = 0 \0 00 0 ) W 0 > 1 WO 98/57640 PCT/US98/12672 EXAMPLE 30 (4S, 5R)-4-(3,4-Difluorophenyl-3-(1-{1-[4-fluoro-2-(3-methyl 5 [1,2,4]oxadiazol-5-yl)phenyl]piperidin-4-yl}-(3R)-pyrrolidin-3 ylcarbamoyl)-2-oxo-oxazolidine-5-carboxylic acid methyl ester F F F_ N aN aN-AN CO2Me -N H O ON. M e 0 Step A: trans-3,4-Difluorocinnamic acid methyl ester 10 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 15 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. 1 H NMR dH (400 MHz, CDC1 3 ) 7.59 (d, 1H, J = 15.9), 7.34 (m, 1H), 20 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 25 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 -82 - WO 98/57640 PCT/US98/12672 (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, 5 103 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) 2 PHAL (1.3 g, 1.7 mmol) in 100 mL n-propanol. The suspension was added to the above reaction mixture and the residue 10 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) 15 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 20 (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 25 (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 30 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, 35 75% from trans-3,4-difluorocinnamic acid methyl ester). -83 - WO 98/57640 PCT/US98/12672 1 H NMR dH (400 MHz, CDC1 3 ) 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 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 0oC was added N,N-diisopropylethylamine (8.75 mL, 10 50 mmol) and triphosgene (2.48 g, 8.4 mmol). The reaction was stirred at O'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 15 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-5-carboxylic 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%) 20 1 H NMR dH (400 MHz, CDC1 3 ) 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 25 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 0 C under argon, was added a 1 M 30 solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (3.5 mL, 3.5 mmol) dropwise. The reaction mixture was warmed to 0 0 C in an ice bath, stirred 30 minutes, then returned to -78 0 C. In a separate flask, p nitrophenylchloroformate (714 mg, 3.54 mmol) was dissolved in anhydrous tetrahydrofuran (40 mL) under argon and cooled to -78 0 C. 35 The above prepared anion solution was added via cannula to the -84- WO 98/57640 PCT/US98/12672 chloroformate solution and the reaction mixture was stirred 1 h at 78 0 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 5 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%). 10 FAB MS: m/z=423 (M+H) Step F: (4S, 5R)-4-(3,4-Difluorophenyl-3-(1-{1-[4-fluoro-2-(3 methyl[1,2,4]oxadiazol-5-yl)phenyl]-piperidin-4-yl}-(3R) pyrrolidin-3-ylcarbamoyl)-2-oxo-oxazolidine-5-carboxylic 15 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 20 diisopropylethylamine (120 gL, 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) 25 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 30 according to standard procedures to afford (4S, 5R)trans-4-(3,4 difluorophenyl-3-(1-{1-[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 as a solid. HPLC retention time = 8.59 min, purity= 94% 35 FAB MS: m/z=629 (M+H) -85 - WO 98/57640 PCT/US98/12672 Analysis: Caled for C30H31N606F3*2HC1*0.2EtOAc C 51.44, H 4.85, N 11.69. Found: C 51.83, H 5.11, N 11.68. 5 The compounds in Examples 31 and 32 were prepared by procedures substantially as described above for Example 30, Step F. EXAMPLE 31 10 (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 F F N Na N .CO 2 Me OMeO 0 15 FAB MS: m/z=577 (M+H) Analysis: Calcd for C28H31N406F3*2F3CCO2H C 45.81, H 4.42, N 6.68. Found: C 45.85, H 4.54, N 6.62. 20 EXAMPLE 32 (4S, 5R)3- { 1-[ 1-(2-Cyanophenyl)piperidin-4-yl]-(3R)-pyrrolidin-3 ylcarbamoyl}-4-(3,4-difluorophenyl)-2-oxo-oxazolidine-5-carboxylic acid methyl ester F F NO N N ,C0 2 Me CN H O 25 O -86- WO 98/57640 PCT/US98/12672 FAB MS: m/z=554 (M+H) Analysis: Caled for C28H29N505F2 * HCl * 0.25H20 *0.75dioxane C 56.36, H 5.57, N 10.60. Found: C 56.33, H 5.39, N 10.61. 5 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 yl}amide F F N N N 'IO H CN H O 10 0 Step A: (4S, 5R) 4-(3,4-Difluorophenyl)-5-hydroxymethyl-oxazolidin 2-one 15 To a solution of (4S, 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 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 0 0 C, saturated sodium bicarbonate (20 mL) 20 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 25 mg, 0.8 mmol, 100%) 1 H NMR dH (400 MHz, CDC13) 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). 30 -87 - WO 98/57640 PCT/US98/12672 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 5 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 10 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 (3,4-difluorophenyl)-5-(tetrahydropyran-2-yloxymethyl)-oxazolidin-2-one 15 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 20 ester To a solution of (4S, 5R)-4-(3,4-difluorophenyl)-5-(tetrahydropyran 2-yloxymethyl)-oxazolidin-2-one (910 mg, 2.9 mmol) in anhydrous tetrahydrofuran (60 mL) cooled to -78 0 C under argon, was added a 1 M 25 solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (2.9 mL, 2.9 mmol) dropwise. The reaction mixture was warmed to 0oC in an ice bath, stirred 45 min, and then returned to -78 0 C. Meanwhile, in a separate dried flask, the p-nitrophenylchloroformate (586 mg, 2.9 mmol) was dissolved in anhydrous tetrahydrofuran (50 mL) under argon and 30 cooled to -78 0 C. The above prepared anion solution was added via cannula to the chloroformate solution and reaction mixture was stirred 1 h at -78 0 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 35 were removed under reduced pressure to give (4S, 5R)-4-(3,4 -88 - WO 98/57640 PCT/US98/12672 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) 5 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-yl}amide 10 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 jtL, 1.3 mmol) followed by (4S, 5R)-4-(3,4-difluorophenyl)-2-oxo-5 (tetrahydropyran-2-yloxymethyl)-oxazolidine-3-carboxylic acid 4 15 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 20 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 25 (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 30 4-yl]-(3R)-pyrrolidin-3-yl}amide To a solution of (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 (156 mg, 0.26 35 mmol) in methanol (5 mL) was added p-toluenesulfonic acid (50 mg, 0.26 - 89- WO 98/57640 PCT/US98/12672 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 5 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%) 10 HPLC: retention time= 7.20 min, purity=95% FAB MS: m/z=526 (M+H) 1 H NMR HC1 salt dH (400 MHz, CD3OD) 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), 15 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 (bin, 2H), 1.68 (bin, 1H) Analysis: Calcd for C27 H29 N5 04 F2*0.35 H20 20 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 25 silica gel chromatography using an elution system containing chloroform saturated with ammonia gas and methanol. F F F F ND N H Me . N NONH2 O O 0 0 30 EXAMPLE 34 -90 - WO 98/57640 PCT/US98/12672 (4S, 5R)3- { 1-[ 1-(2-Cyanophenyl)piperidin-4-yl]-(3R)-pyrrolidin-3 ylcarbamoyl}-4-(3,4-difluorophenyl)-2-oxo-oxazolidine-5-carboxamide F F E Q NN 2 N 5%IpCONH 2 CN H O O FAB MS: m/z=539 (M+H) 5 Analysis: Caled for C27H28N604F2*HC1*0.9H20 C 54.85, H 5.25, N 14.22. Found: C 54.83, H 5.02, N 14.05. EXAMPLE 35 10 (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 F F N Na N CONH 2 OMe H 0 0 FAB MS: m/z=562 (M+H) 15 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. 20 EXAMPLE 36 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 -91- WO 98/57640 PCT/US98/12672 F F F F ON HN H 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, 5 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 oC for 16 hours. After cooling to room temperature the solvent was removed in vacuo. The solid was dissolved in CH 2 C1 2 and H 2 0 then neutralized with 10% aqueous HC1 solution. The organic layer was dried over Na 2

SO

4 , 10 concentrated, and purified by PCTLC (7% MeOH in CHC1, with 2%

NH

4 OH) to afford a 2.65 g mixture of the title compounds (71% yield). The 1 H NMR was consistent with the assigned structure. MS (FAB) 255 (M+1) 15 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 F F F F F ON HN H 20 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 -92- WO 98/57640 PCT/US98/12672 resulting mixture was refluxed at 90 oC for 16 hours. After cooling to room temperature the solvent was removed in vacuo. The solid was dissolved in CH 2 C1 2 and H20 then neutralized with 10% aqueous HC1 solution. The organic layer was dried over Na2SO4, concentrated, and 5 purified by PCTLC (7% MeOH in CHC1 3 with 2% NH 4 OH) to afford a 2.35 g mixture of the title compounds (54% yield). The 1 H NMR was consistent with the assigned structure. MS (FAB) 255 (M+1) 10 EXAMPLE 38 4S-4-(3,4-Difluorophenyl)-6-methoxymethyl-3-(4-nitrophenoxycarbonyl)-2 oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid methyl ester F F 02NO O N Oq H 15 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 20 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 25 tetrahydropyrimidine and 4R-4-(3,4-difluorophenyl)-6-methoxymethyl-2 oxo-2,3,4,5-tetrahydropyrimidine -93- WO 98/57640 PCT/US98/12672 F F F F 01N H 0 7N H The title compounds were prepared from 4R-4-(3,4 difluorophenyl)-6-methoxymethyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5 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 1 H NMR was consistent with the assigned structure. MS (FAB) 255 (M+1) 10 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 15 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 20 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. 25 EXAMPLE 40 N-(1-(1-(2-Cyanophenyl)piperidin-4-yl)azetidin-3-yl)-2-(3,4 difluorophenyl)acetamide -94- WO 98/57640 PCT/US98/12672 ON F CNN F H 1 H NMR (CDC1 3 , 400 MHz) consistent with assigned structure. FABLRMS m/e 411 g/mole (M++H, C 2 3

H

2 4

F

2

N

4 0 1 = 410.47 5 g/mole.) HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H 2 0 [0.1% H 3

PO

4 ] - CH 3 CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 ml/min flow rate) focus = 215 nm; >95% pure. Anal. Calcd for C 2 3

H

2 4

F

5

N

5 0 3 * 1.20 TFA: C = 55.74, H = 10 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 CN 0F ON N\3N F N F H 15 1 H NMR (CDC1 3 , 400 MHz) consistent with assigned structure. FABLRMS m/e 453 g/mole (M++H, C 2 6

H

3 0

F

2

N

4 0 1 = 452.23 g/mole.) -95- WO 98/57640 PCT/US98/12672 HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H 2 0 [0.1% H 3

PO

4 ] - CH 3 CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 ml/min flow rate) focus = 215 nm; >95% pure. Anal. Calcd for C 2 6

H

3 0

F

2

N

4 0 1 * 1.15 TFA * 0.15 H 2 0: C = 5 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 NN H F 10 F 1 H NMR (CDC1 3 , 400 MHz) consistent with assigned structure. FABLRMS m/e 482 g/mole (M++H, C 2 5

H

2 5

F

2

N

5 0 3 = 481.51 g/mole.) 15 HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H 2 0 [0.1% H 3

PO

4 ] - CH 3 CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 ml/min flow rate) focus = 215 nm; >99% pure. Anal. Calcd for C 2 5

H

2 5

F

2

N

5 0 3 1.35 TFA and 1.05 H 2 0: C = 50.84, H = 4.38, N = 10.70. Found: C = 50.83, H = 4.29, N = 11.09. 20 EXAMPLE 43 (4S)-3-{1-[1-(2-Cyanophenyl)piperidin-4-yl]azetidin-3-ylcarbamoyl}-4-(3,4 difluorophenyl)-6-methoxymethyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5 carboxylic acid methyl ester -96- WO 98/57640 PCT/US98/12672 CN N N NH H F CO 2 Me F 1 H NMR (CDC1 3 , 400 MHz) consistent with assigned structure. FABLRMS m/e 595 g/mole (M++H, C 3 0

H

3 2

F

2

N

6 0 5 = 594.62 5 g/mole.) HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H20 [0.1% H 3

PO

4 ] - CH 3 CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 ml/min flow rate) focus = 215 nm; >97% pure. Anal. Calcd for C 3 0

H

3 2

F

2

N

6 0 5 * 1.55 TFA and 1.30 H 2 0: C 10 = 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 Na CN 15 F 1H NMR (CDC1 3 , 400 MHz) consistent with assigned structure. -97 - WO 98/57640 PCT/US98/12672 FABLRMS m/e 425 g/mole (M++H, C 2 4

H

2 6

F

2

N

4 0 1 = 424.49 g/mole.) HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H 2 0 [0.1% H 3

PO

4 ] - CH 3 CN, 95% - 5%, 5% - 95%, over 16 5 minutes, 2 ml/min flow rate) focus = 215 nm; 99% pure. Anal. Calcd for C 2 4

H

2 6

F

2

N

4 0 1 * 0.05 CH 2 C1 2 : C = 67.37, H = 6.14, N = 13.07. Found: C = 67.53, H = 6.15, N = 13.40. EXAMPLE 45 10 N-(1-(1-(2-Cyanophenyl)piperidin-4-yl)azetidin-3-ylmethyl)-2,2 spirocyclopropyl-2-(3,4-difluorophenyl)acetamide CN ON N F 1 H NMR (CDC1 3 , 400 MHz) consistent with assigned structure. 15 FABLRMS m/e 451 g/mole (M++H, C 2 6

H

2 8

F

2

N

4 0 1 = 450.53 g/mole.) HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H 2 0 [0.1% H 3

PO

4 ] - CH 3 CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 ml/min flow rate) focus = 215 nm; 98% pure. 20 Anal. Calcd for C 2 6

H

2 8

F

2

N

4 0 1 * 1.9 HC1 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-ylmethylcarbamoyl} 25 4-(3,4-difluorophenyl)-6-methoxymethyl-2-oxo-1,2,3,4 tetrahydropyrimidine-5-carboxylic acid methyl ester -98- WO 98/57640 PCT/US98/12672 F F 0 OMe NIOMe NN N NH O O 1 H NMR (CDC1 3 , 400 MHz) consistent with assigned structure. FABLRMS m/e 609.26 g/mole (M++H, C 3 1

H

3 4

F

2

N

6 0 5 = 5 608.64 g/mole.) HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H 2 0 [0.1% H 3

PO

4 ] - CH 3 CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 ml/min flow rate) focus = 215 nm; 93.4% pure. 10 EXAMPLE 47 (4S)-4-(3,4-Difluorophenyl)-2-oxo-oxazolidine-3-carboxylic acid {1-[1-(2 cyanophenyl)-piperidin-4-yl] azetidin-3-ylmethyll-amide F I F NI CN 0 H O 0 1 H NMR (CDC1 3 , 400 MHz) consistent with assigned 15 structure. FABLRMS m/e 496.26 g/mole (M++H, C 2 6

H

2 7

F

2

N

5 0 3 = 495.53 g/mole.) HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H 2 0 [0.1% H 3

PO

4 ] - CH 3 CN, 95% - 5%, 5% - 95%, over 16 20 minutes, 2 ml/min flow rate) focus = 215 nm; 94.8% pure. -99- WO 98/57640 PCT/US98/12672 Anal. Calcd for C 29

H

3 2

F

5

N

5 0 5 * 0.05 CHC1 3 and 0.2 H 2 0: C = 61.94, H = 5.48, N = 13.87. Found: C = 61.97, H = 5.55, N = 13.50. EXAMPLE 48 5 (4S)-4-(3,4-Difluorophenyl)-2-oxo-oxazolidine-3-carboxylic acid {1-[1-(2 cyanophenyl)-piperidin-4-yl]-3-hydroxy-azetidin-3-ylmethyl}-amide F F CN CN N 0 OOH 0 1 H NMR (CDC1 3 , 400 MHz) consistent with assigned structure. 10 FABLRMS m/e 512 g/mole (M++H, C 2 6

H

2 7

F

2

N

5 0 4 = 511.52 g/mole.) HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H 2 0 [0.1% H 3

PO

4 ] - CH 3 CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 ml/min flow rate) focus = 215 nm; 95% pure. 15 EXAMPLE 49 (4S)-3-{1-[1-(2-Cyanophenyl)piperidin-4-yl]-3-hydroxy-azetidin-3 ylmethylcarbamoyl}-4-(3,4-difluorophenyl)-6-methoxymethyl-2-oxo 1,2,3,4-tetrahydropyrimidine-5-carboxylic acid methyl ester F F 0 OMe N/ OMe N N NH CNN OH N, N N 20 0 0 - 100- WO 98/57640 PCT/US98/12672 1 H NMR (CDC1 3 , 400 MHz) consistent with assigned structure. FABLRMS m/e 625 g/mole (M++H, C 3 1

H

3 4

F

2

N

6 0 6 = 624.64 g/mole.) 5 HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H 2 0 [0.1% H 3

PO

4 ] - CH 3 CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 ml/min flow rate) focus = 215 nm; 98% pure. Anal. Caled for C 3 1

H

3 4

F

2

N

6 0 6 * 1.65 HC1 and 0.2 Et 2 0: C = 54.59, H = 5.42, N = 12.01. Found: C = 54.65, H = 5.25, N = 11.99. 10 EXAMPLE 50 (3R)-N-(1-(1-(2-Nitrophenyl)piperidin-4-yl)pyrrolidin-3-yl)-2-(3,4 difluorophenyl)acetamide

NO

2 N N N0 F 15 1 H NMR (CDC1 3 , 400 MHz) consistent with assigned structure. FABLRMS m/e 445 g/mole (M++H, C 2 3

H

2 6

F

2

N

4 0 3 = 444.485 g/mole.) HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; 20 gradient = H 2 0 [0.1% H 3

PO

4 ] - CH 3 CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 ml/min flow rate) focus = 215 nm; 98% pure. Anal. Calcd for C 2 3

H

2 6

F

2

N

4 0 3 * 1.75 HCI: C = 54.35, H = 5.50, N = 11.02. Found: C = 54.29, H = 5.51, N = 10.63. 25 EXAMPLE 51 (Dias A) (3R)-N-(1-(1-(2-Nitrophenyl)piperidin-4-yl)pyrrolidin-3-yl)-2-(3,4 difluorophenyl)acetamide -101- WO 98/57640 PCT/US98/12672

NO

2 N Nc-Na R) 0 F N H \/F 1 H NMR (CDC1 3 , 400 MHz) consistent with assigned structure. FABLRMS m/e 487 g/mole (M++H, C 2 6

H

3 2

F

2

N

4 0 3 = 486.567 5 g/mole.) HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H 2 0 [0.1% H 3

PO

4 ] - CH 3 CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 ml/min flow rate) focus = 215 nm; 100% pure. Anal. Calcd for C 2 6

H

3 2

F

2

N

4 0 3 1.4 HCl: C = 58.08, H = 10 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 F CN 0 N F H 15 1 H NMR (CDC1 3 , 400 MHz) consistent with assigned structure. FABLRMS m/e 467 g/mole (M++H, C 2 7

H

3 2

F

2

N

4 0 1 = 466.577 g/mole.) 20 HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H 2 0 [0.1% H 3

PO

4 ] - CH 3 CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 ml/min flow rate) focus = 215 rnm; 95.4% pure. EXAMPLE 53 - 102- WO 98/57640 PCT/US98/12672 (Diast B)(3R)-N-(1-(1-(2-Cyanophenyl)piperidin-4-yl)pyrrolidin-3-yl)-2 (3,4-difluorophenyl)acetamide F CN N F No N F H 1 H NMR (CDC1 3 , 400 MHz) consistent with assigned 5 structure. FABLRMS m/e 467 g/mole (M++H, C 2 7

H

3 2

F

2

N

4 0 1 = 466.577 g/mole.) HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H 2 0 [0.1% H 3

PO

4 ] - CH 3 CN, 95% - 5%, 5% - 95%, over 16 10 minutes, 2 ml/min flow rate) focus = 215 nm; 95.8% pure. EXAMPLE 54 (3R,4S)-4-(3,4-Difluorophenyl)-2-oxo-oxazolidine-3-carboxylic acid {1-[1-(2 nitrophenyl)-piperidin-4-yl]pyrrolidin-3-yl}-amide F F

NO

2 O 15 1 H NMR (CDC1 3 , 400 MHz) consistent with assigned structure. FABLRMS m/e 516 g/mole (M++H, C 2 5

H

2 7

F

2

N

5 0 5 = 515.522 g/mole.) 20 HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H 2 0 [0.1% H 3

PO

4 ] - CH 3 CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 ml/min flow rate) focus = 215 nm; 100% pure. - 103- WO 98/57640 PCT/US98/12672 Anal. Calcd for C 2 5

H

2 7

F

2

N

5 0 5 * 1.35 HCI: C = 53.17, H = 5.06, N = 12.40. Found: C = 53.26, H = 5.09, N = 12.08. EXAMPLE 55 5 (3R,4S)-4-(3,4-Difluorophenyl)-2-oxo-oxazolidine-3-carboxylic acid {1-[1-(2 [N-1l-(N-3-methylureyl)]phenyl)-piperidin-4-yl]pyrrolidin-3-yl}-amide F F HN-CH3 NH OO 1 H NMR (CDC1 3 , 400 MHz) consistent with assigned structure. 10 FABLRMS m/e 543 g/mole (M++H, C 2 7

H

3 2

F

2

N

6 0 4 = 542.591 g/mole.) HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H 2 0 [0.1% H 3

PO

4 ] - CH 3 CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 ml/min flow rate) focus = 215 nm; 95% pure. 15 Anal. Calcd for C 2 7

H

3 2

F

2

N

6 0 4 * 2.15 HCI: 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-carboxylic acid {1-[1-(2 20 (N-3-dimethylsulfonamido)aminophenyl)-piperidin-4-yl]pyrrolidin-3-yl} amide - 104- WO 98/57640 PCT/US98/12672 F

CH

3 F HC-N ,}Q 0" NH N(, N N O O 0 1 H NMR (CDC1 3 , 400 MHz) consistent with assigned structure. FABLRMS m/e 593 g/mole (M++H, C 2 7

H

3 4

F

2

N

6 0 5 S = 5 592.666 g/mole.) HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H 2 0 [0.1% H 3

PO

4 ] - CH 3 CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 ml/min flow rate) focus = 215 nm; 99.1% pure. Anal. Calcd for C 2 7

H

3 4

F

2

N

6 0 5 S * 1.90 HCl: C = 48.99, H = 10 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-carboxylic acid {1-[1-(2 (N-1-methanesulfonyl)aminophenyl)-piperidin-4-yl]pyrrolidin-3-yl} 15 amide F F

H

3 C,, S IF O NH N N N H 0 1 H NMR (CDC1 3 , 400 MHz) consistent with assigned structure. FABLRMS m/e 564 g/mole (M++H, C 2 6

H

3 1

F

2

N

5 0 5 S = 20 563.624 g/mole.) - 105- WO 98/57640 PCT/US98/12672 HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H 2 0 [0.1% H 3

PO

H

3 1

F

2

N

5 0 5 S * 2.0 HCI: C = 49.05, H = 5 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-carboxylic acid {1-[1-(2 (N-1-acetyl)aminophenyl)-piperidin-4-yl]pyrrolidin-3-yll-amide F F

H

3 NH N N 10 1 H NMR (CDC1 3 , 400 MHz) consistent with assigned structure. FABLRMS m/e 528 g/mole (M++H, C 2 7

H

3 1

F

2

N

5 0 4 = 527.576 g/mole.) 15 HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H 2 0 [0.1% H 3

PO

4 ] - CH 3 CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 ml/min flow rate) focus = 215 nm; 95.7% pure. 20 EXAMPLE 59 (4S)-3-{ 1-[ 1-(2-Nitrophenyl)piperidin-4-yl]-pyrrolidin-3-ylcarbamoyl}-4 (3,4-difluorophenyl)-6-methoxymethyl-2-oxo-1,2,3,4 tetrahydropyrimidine-5-carboxylic acid methyl ester - 106- WO 98/57640 PCT/US98/12672 F F

NO

2 0 H 1 H NMR (CDC13, 400 MHz) consistent with assigned structure. FABLRMS m/e 629 g/mole (M++H, C 3 0

H

3 4

F

2

N

6 0 7 = 628.64 5 g/mole.) HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H 2 0 [0.1% H 3

PO

4 ] - CH 3 CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 ml/min flow rate) focus = 215 nm; 100% pure. 10 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 F HN.CH3 F 0 NH '' 0 O OrH 0 , N OCH 3 ON H 15 1 H NMR (CDC1 3 , 400 MHz) consistent with assigned structure. FABLRMS m/e 656 g/mole (M++H, C 3 2

H

3 9

F

2

N

7 0 6 = 655.709 g/mole.) - 107- WO 98/57640 PCT/US98/12 6 7 2 HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H 2 0 [0.1%

H

3 PO4] - CH 3 CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 ml/min flow rate) focus = 215 nm; 96.8% pure. 5 EXAMPLE 61 (4S)-3-{ 1-[1-(2-(N-3-dimethylsulfonamido)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 F CH3 F

H

3 CK N ,O O O NH H OOC0H 3 O' N H 10 1 H NMR (CDC1 3 , 400 MHz) consistent with assigned structure. FABLRMS m/e 706 g/mole (M++H, C 3 2

H

4 1

F

2

N

7 07S = 705.783 g/mole.) HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; 15 gradient = H 2 0 [0.1% H 3 PO4] - CH 3 CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 ml/min flow rate) focus = 215 nm; 99.1% pure. Anal. Calcd for C 3 2

H

4 1

F

2 N707 2.10 HCL: C = 49.12, H = 5.55, N = 12.53. Found: C = 49.12, H = 5.60, N = 12.44. 20 EXAMPLE 62 (4S)-3-{1-[1-(2-(N-1-acetyl)aminophenyl)pip e r i din -4 -yl] -p y r r olidin-3 ylcarbamoyl}- 4

-(

3 ,4-difluorophenyl)-6-methoxymethyl-2-oxo-1,2,3,4 tetrahydropyrimidine-5-carboxylic acid methyl ester - 108 - WO 98/57640 PCT/US98/12672 F F

OCH

3 O N N O -0 N OCH 3 H 1 H NMR (CDC1 3 , 400 MHz) consistent with assigned structure. FABLRMS m/e 641 g/mole (M++H, C 3 2

H

3 8

F

2 N606 = 640.693 5 g/mole.) HPLC (Vydac; C18; diameter = 4.6 nmm; length = 150 mm; gradient = H 2 0 [0.1% H 3

PO

4 ] - CH 3 CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 ml/min flow rate) focus = 215 nm; 100% pure. 10 EXAMPLE 63 (4S)-3- {1-[1-(2-(N-1-methanesulfonyl)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 F F H 3 C\s/ F,,0 0 NH 'I

OCH

3 -. , H 0, ' OCH 3 ON H 15 1 H NMR (CDC1 3 , 400 MHz) consistent with assigned structure. FABLRMS m/e 677 g/mole (M++H, C 3 1

H

3 8

F

2 N607S = 676.747 g/mole.) - 109- WO 98/57640 PCT/US98/1267 2 HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H 2 0 [0.1% H 3 P04] - CH 3 CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 ml/min flow rate) focus = 215 nm; 99.9% pure. 5 EXAMPLE 64 (Diast A) (4S)-4-(3, 4 -Difluorophenyl)-2-oxo-oxazolidine-3-carboxylic acid{1-[ l-( 2 -cyanophenyl)piperidin-4-yl]-3-hydroxy-pyrrolidin-4-yl} amide F F ,OH No N N O ONO H 0 1 H NMR (CDC1 3 , 400 MHz) consistent with assigned 10 structure. FABLRMS m/e 512 g/mole (M++H,

C

2 6

H

2 7 F2N504 = 511.52 g/mole.) HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H 2 0 [0.1% H 3 PO4] - CH 3 CN, 95% - 5%, 5% - 95%, over 16 15 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 -p y r r olidin -4 -y l }lamide F F N1 H pH _0 20 - 110 - WO 98/57640 PCT/US98/12672 1 H NMR (CDC1 3 , 400 MHz) consistent with assigned structure. FABLRMS m/e 512 g/mole (M++H, C 2 6

H

2 7

F

2

N

5 0 4 = 511.52 g/mole.) 5 HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H 2 0 [0.1% H 3

PO

4 ] - CH 3 CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 ml/min flow rate) focus = 215 nm; 98% pure. EXAMPLE 66 10 (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-carboxylic acid methyl ester F F ,OH CN N H 15 1H NMR (CDC13, 400 MHz) consistent with assigned structure. FABLRMS m/e 625.4 g/mole (M++H, C 3 1

H

3 4

F

2

N

6 06 = 624.64 g/mole.) HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; 20 gradient = H 2 0 [0.1% H 3

PO

4 ] - CH 3 CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 ml/min flow rate) focus = 215 nm; 100% pure. EXAMPLE 67 (Dias A) (4S)-3-{1-[1-(2-Cyanophenyl)piperidin-4-yl]-3-hydroxy-pyrrolidin 25 4-ylcarbamoyl}- 4

-(

3 ,4-difluorophenyl)-6-methoxymethyl- 2 -oxo- 1,2,3,4 tetrahydropyrimidine-5-carboxylic acid methyl ester -111- WO 98/57640 PCT/US98/12 6 7 2 F F ,OH CN 1 \NJ OMe H H 1 H NMR (CDC1 3 , 400 MHz) consistent with assigned structure. FABLRMS m/e 625.4 g/mole (M++H, C 3 1

H

3 4

F

2 N606 = 5 624.64 g/mole.) HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H 2 0 [0.1% H 3 PO4] - CH 3 CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 ml/min flow rate) focus = 215 nm; 100% pure. 10 EXAMPLE 68 (Dias B) (4S)-3-{1-[l-( 2 -Cyanophenyl)piperidin-4-yl]-3-hydroxy-pyrrolidin 4-ylcarbamoyl}-4-(3,4-difluorophenyl)-6-methoxymethyl-2-oxo -1,2,3,4 tetrahydropyrimidine-5-carboxylic acid methyl ester F F C\N NN OMe H 15 1H NMR (CDC1 3 , 400 MHz) consistent with assigned structure. FABLRMS m/e 625.4 g/mole (M++H, C 3 1

H

3 4 F2N606 = 624.64 g/mole.) - 112- WO 98/57640 PCT/US98/12 6 7 2 HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H 2 0 [0.1% H 3 PO4] - CH 3 CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 ml/min flow rate) focus = 215 nm; 100% pure. 5 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 F CN N 0 N N/N ON 1 H NMR (CDC1 3 , 400 MHz) consistent with assigned 10 structure. FABLRMS m/e 510.34 g/mole (M++H, C 2 7

H

2 9

F

2 N503 = 509.55 g/mole.) HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H 2 0 [0.1% H 3 PO4] - CH 3 CN, 95% - 5%, 5% - 95%, over 16 15 minutes, 2 ml/min flow rate) focus = 215 nm; 96% pure. EXAMPLE 70 (racemic) (4S)-3-{l-[l-(2-Cyanophenyl)piperidin-4-yl]pyrrolidin-3 ylmethylcarbamoyl}-4-(3,4-difluorophenyl)-6-methoxymethyl-2-oxo 20 1,2,3,4-tetrahydropyrimidine-5-carboxylic acid methyl ester N F I N H NH N 0 - 113 - WO 98/57640 PCT/US98/12672 1 H NMR (CDC1 3 , 400 MHz) consistent with assigned structure. FABLRMS m/e 623.5 g/mole (M++H, C 3 2

H

3 6

F

2

N

6 0 5 = 622.67 g/mole.) 5 HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H 2 0 [0.1% H 3

PO

4 ] - CH 3 CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 ml/min flow rate) focus = 215 nm; 92% pure. EXAMPLE 71 10 Diast A (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 N F 0 F-0 0 / o0 N H NH N N 0 0 1H NMR (CDC1 3 , 400 MHz) consistent with assigned 15 structure. FABLRMS m/e 623.5 g/mole (M++H, C 3 2

H

3 6

F

2 N605 = 622.67 g/mole.) HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H 2 0 [0.1% H 3

PO

4 ] - CH 3 CN, 95% - 5%, 5% - 95%, over 16 20 minutes, 2 ml/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 25 1,2,3,4-tetrahydropyrimidine-5-carboxylic acid methyl ester -114- WO 98/57640 PCT/US98/12672 N F O U 0 C O/ 00 N NH NH 1 H NMR (CDC1 3 , 400 MHz) consistent with assigned structure. FABLRMS m/e 623.5 g/mole (M++H, C 3 2

H

3 6

F

2

N

6 05 = 5 622.67 g/mole.) HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H 2 0 [0.1% H 3 PO4] - CH 3 CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 ml/min flow rate) focus = 215 nm; 92% pure. 10 EXAMPLE 73 (Racemic) (4S)-4-(3,4-Difluorophenyl)-2-oxo-oxazolidine-3-carboxylic acid 1-[ 1-(2-cyanophenyl)-piperidin-4-yl]piperidin-3-ylmethyl} -amide F F CN No f HN 0 o0 o 1 H NMR (CDC1 3 , 400 MHz) consistent with assigned 15 structure. FABLRMS m/e 524 g/mole (M++H, C 2 8

H

3 1

F

2 N503 = 523.58 g/mole.) HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H 2 0 [0.1% H 3

PO

4 ] - CH 3 CN, 95% - 5%, 5% - 95%, over 16 20 minutes, 2 ml/min flow rate) focus = 215 nm; >95% pure. - 115- WO 98/57640 PCT/US98/12672 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 F F CN IN N NN N 5 1 H NMR (CDC13, 400 MHz) consistent with assigned structure. FABLRMS mn/e 524 g/mole (M++H, C 2 8

H

3 1

F

2

N

5 0 3 = 523.58 g/mole.) 10 HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H 2 0 [0.1% H 3

PO

4 ] - CH 3 CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 ml/min flow rate) focus = 215 nm; >95% pure. EXAMPLE 75 15 (Dias B) (4S)-4-(3,4-Difluorophenyl)-2-oxo-oxazolidine-3-carboxylic acid {1 [1-(2-cyanophenyl)-piperidin-4-yl]piperidin-3-ylmethyl)-amide F F ON Na H CNN NN ~ rl N N y O 1 H NMR (CDC1 3 , 400 MHz) consistent with assigned structure. -116- WO 98/57640 PCT/US98/12672 FABLRMS m/e 524 g/mole (M++H, C 2 8

H

3 1

F

2

N

5 0 3 = 523.58 g/mole.) HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H 2 0 [0.1% H 3

PO

4 ] - CH 3 CN, 95% - 5%, 5% - 95%, over 16 5 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 10 1,2,3,4-tetrahydropyrimidine-5-carboxylic acid methyl ester F F 00 0 N 1 H NMR (CDC1 3 , 400 MHz) consistent with assigned structure. FABLRMS m/e 637 g/mole (M++H, C 3 3

H

3 8

F

2

N

6 0 5 = 622.67 15 g/mole.) HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H 2 0 [0.1% H 3

PO

4 ] - CH 3 CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 ml/min flow rate) focus = 215 nm; >95% pure. 20 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 -117- WO 98/57640 PCT/US98/12672 F F [/ 02Me N N N NH 1H NMR (CDC1 3 , 400 MHz) consistent with assigned structure. FABLRMS m/e 637 g/mole (M++H, C 3 3

H

38

F

2

N

6 0 5 = 622.67 5 g/mole.) HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H 2 0 [0.1% H 3

PO

4 ] - CH 3 CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 ml/min flow rate) focus = 215 nm; >95% pure. 10 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 F 2 F

CO

2 Me HN N NH 15 1 H NMR (CDC1 3 , 400 MHz) consistent with assigned structure. FABLRMS m/e 637 g/mole (M++H, C 3 3

H

3 8

F

2

N

6 0 5 = 622.67 g/mole.) -118- WO 98/57640 PCT/US98/12672 HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H 2 0 [0.1% H 3

PO

4 ] - CH 3 CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 ml/min flow rate) focus = 215 nm; >95% pure. 5 EXAMPLE 79 (4S)-4-(3,4-Difluorophenyl)-2-oxo-oxazolidine-3-carboxylic acid {1-[1-(2 cyanophenyl)-piperidin-4-yl]piperidin-4-ylmethyl}-amide N '* F N H 0 OO 1 H NMR (CDC1 3 , 400 MHz) consistent with assigned 10 structure. FABLRMS m/e 524 g/mole (M++H, C 2 8

H

3 1

F

2

N

PO

4 ] - CH 3 CN, 95% - 5%, 5% - 95%, over 16 15 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 20 1,2,3,4-tetrahydropyrimidine-5-carboxylic acid methyl ester -119- WO 98/57640 PCT/US98/12672 CN F N 02 N N HN~ NH 0 0 1 H NMR (CDC1 3 , 400 MHz) consistent with assigned structure. FABLRMS m/e 637 g/mole (M++H, C 3 3

H

3 8

F

2

N

PO

4 ] - CH 3 CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 ml/min flow rate) focus = 215 nm; >99% pure. 10 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-yl}-amide F F

CO

2 Me 0 1 H NMR (CDC1 3 , 400 MHz) consistent with assigned 15 structure. HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H 2 0 [0.1% H 3

PO

4 ] - CH 3 CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 ml/min flow rate) focus = 215 nm; 100% pure. Anal. Calcd for C 28

H

32

F

2

N

4 0 5 * 1.25 EtOAc and 1.85 H 2 0: 20 C = 57.77, H = 6.71, N = 8.17. Found: C = 57.75, H = 6.95, N = 8.16. - 120- WO 98/57640 PCT/US98/12672 EXAMPLE 82 (3R,4S,5R)-5-Carboxymethyl-4-(3,4-difluorophenyl)-2-oxo-oxazolidine-3 carboxylic acid {1-[1-(2-carboxymethylphenyl)-piperidin-4-yl]pyrrolid-3 5 yl}-amide F F CO

NCO

2 Me' -CO 2 Me ND H _ 1 H NMR (CDC1 3 , 400 MHz) consistent with assigned structure. 10 HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; gradient = H 2 0 [0.1% H 3

PO

4 ] - CH 3 CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 ml/min flow rate) focus = 215 nm; 96% pure. Anal. Calcd for C 2 9

H

3 2

F

2

N

4 0 7 * 2.1 HC1 and 0.7 Et 2 0: C = 53.41, H = 5.79, N = 7.84. Found: C = 53.39, H = 5.56, N = 7.82. 15 EXAMPLE 83 As a specific embodiment of an oral composition, 100 mg of the compound of Example 6 (i.e., Compound 9) is formulated with 20 sufficient finely divided lactose to provide a total amount of 580 to 590 mg to fill a size O hard gel capsule. EXAMPLE 84 25 Screening assay: Alpha la Adrenergic Receptor Binding Membranes prepared from the stably transfected human alpha la cell line (ATCC CRL 11140) were used to identify compounds -121- WO 98/57640 PCT/US98/12672 that bind to the human alpha la adrenergic receptor. These competition binding reactions (total volume = 200 p1) contained 50 mM Tris-HC1 pH. 7.4, 5 mM EDTA, 150 mM NaC1, 100 pM [125 I]-HEAT, membranes prepared from the alpha la cell line and increasing amounts of 5 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 10 were found to have Ki values < 50 nM. EXAMPLE 85 Selective Binding assays 15 Membranes prepared from stably transfected human alpha ld and alpha lb 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 l) contained 50 mM Tris-HC1 pH. 7.4, 5 mM EDTA, 150 20 mM NaC1, 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 25 harvester. Filters were washed three times with ice cold buffer and bound radioactivity was determined (Ki). EXAMPLE 86 30 EXEMPLARY COUNTERSCREENS 1. Assay Title: Dopamine D2, D3, D4 in vitro screen Objective of the Assay: - 122- WO 98/57640 PCT/US98/12672 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. 5 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 10 buffer (10mM Tris-HC1/5mM Mg, pH 7.4). Pellets obtained after centrifuging these membranes (15' at 24,450 rpm) are resuspended in 50mM Tris-HC1 pH 7.4 containing EDTA, MgCl[2], KC1, NaC1, CaCl[2] and ascorbate to give a 1 Mg/mL suspension. The assay is initiated by adding 50-75 tg membranes in a total volume of 500 tl containing 0.2 nM 15 [3H]-spiperone. Non-specific binding is defined using 10 gfM 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-HC1 pH 7.4. 20 2. Assay Title: Serotonin 5HT1a Objective of the Assay The objective of this assay is to eliminate agents which specifically affect binding to cloned human 5HT1a receptor 25 Method: Modified from Schelegel and Peroutka Biochemical Pharmacology 35: 1943-1949 (1986). Mammalian cells expressing cloned human 5HT1a 30 receptors are lysed in ice-cold 5 mM Tris-HC1 , 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 35 mM Tris-HC1, 4 mM CaC12 and 1mg/ml ascorbate. Non-specific binding - 123- WO 98/57640 PCT/US98/12672 is defined using 10 tM propranolol. The assay is terminated after a 1 hour incubation at room temperature by rapid filtration over GF/Cfilters EXAMPLE 87 5 EXEMPLARY FUNCTIONAL ASSAYS In order to confirm the specificity of compounds for the human alpha la adrenergic receptor and to define the biological activity 10 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 15 (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 20 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 25 Krebs solution [NaC1, 118 mM; KC1, 4.7 mM; CaC12, 2.5 mM; KH2PO4, 1.2 mM; MgSO4, 1.2 mM; NaHCO3, 2.0 mM; dextrose, 11 mM] warmed to 37 0 C. 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 30 buffer at 37 0 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. - 124- WO 98/57640 PCT/US98/12672 After a single priming dose of 3 gM (for rat), 10 gM (for dog) and 20 gM (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 5 allowed to incubate for one hour, then another cumulative concentration response curve to the agonist is generated. EC50 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 10 concentrations of antagonist are tested, Kb values are calculated according to the following formula Kb = F[B, x-1 where x is the ratio of EC50 of agonist in the presence and absence of antagonist and [B] is the antagonist concentration. 15 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 20 prostatic urethra from increased prostate mass as well as active obstruction due to prostatic 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 25 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 30 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 - 125- WO 98/57640 PCT/US98/12672 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 5 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 10 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 15 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 20 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 prostatic 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 25 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 30 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 35 package) with a four paramenter logistic equation constraining the - 126- WO 98/57640 PCT/US98/12672 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 ED50's for the respective curves. These dose-ratios are then used to 5 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 10 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 15 increasing intra-urethral pressure is also present in the systentic 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. 20 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 25 modifications as come within the scope of the following claims and their equivalents. - 127-

Claims

1. A compound of the formula: M R15 16 R 24 M R is.i6 m -" ( n E 2 6 R N C Q R1-N ) q G RR 18 L 5 wherein Q is selected from (Xs (Xs (Xs R 4 R 8R9 N N R ((X)s R 8 2 8 N~(~ N N R7 ' ON SR R 11R _, Rio 0' N/ R50 0 i R9 H Si - (X)s N NR 8 0 NR 8 7 R 5 N "NO H (X)s (X)s O O O R 11 R12 R"1 N N N R7 W R7 W O N R0 O N H R12 H O - 128- WO 98/57640 PCT/US98/12672 R 1 3 R13(X) s 8 R , o0. RN Z~N 0 R 8 N or O " E, G, L and M are each independently selected from hydrogen, C1-8 alkyl, C3-8 cycloalkyl, (CH2)0-40R 6 , (CH2)0-4N(R 1 9)2, (CH2)0-4CN, (CH2)0-4CF3, (CH2)0-4CO2R 1 9 , (CH2)0-4CON(R 1 9)2, (CH2)0-4SO2R 1 9 , or 5 (CH2)0-4SO2N(R 1 9 )2; J is selected from hydrogen, C1-8 alkyl, C3-8 cycloalkyl, (CH2)1-40R 6 , (CH2)1-4N(R 1 9 )2, (CH2)1-4CN, (CH2)0-4CF3, (CH2)0-4CO2R 1 9 , (CH2)0-4CON(R 1 9 )2, (CH2)0-4SO2R 19 , or (CH2)0-4SO2N(R 1 9)2; 10 R 1 is selected from unsubstituted, mono- or poly-substituted phenyl wherein the substituents on the phenyl are independently selected from halogen, CF3, cyano, nitro, N(R 1 9 )2, NR 19 COR 2 0 , NR 1 9 CON(R 2 0 )2, NR 1 9 SO2R 2 0 , NR 1 9 SO2N(R 2 0 )2, OR 6 , (CH2)0-4CO2R 1 9 , oxadiazolyl-, C1 15 4 alkyl oxadiazolyl-, (CH2)0-4CON(R 1 9 )2, (CH2)0-4SO2N(R 1 9 )2, (CH2)0 4SO2R 6 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, 20 cyano, nitro, (CH2)0-4CO2R 1 9 , (CH2)0-4CON(R 1 9 )2, (CH2)0-4SO2N(R 1 9 )2, (CH2)0-4SO2R 6 , phenyl, OR 6 , halogen, C1-4 alkyl or C3-8 cycloalkyl; R 2 , R 3 , R 8 , R 1 0 , R 1 5 , R 1 6 , R 1 7 and R 1 8 are each independently selected from hydrogen, C1-8 alkyl, C3-8 cycloalkyl, (CH2)2-40R 6 or (CH2)0-4CF3; 25 R 4 is selected from hydrogen, (CH2)0-4COR 6 , (CH2)0-4CN, (CH2)0-4CF3, (CH2)0-4CO2R 1 9 , (CH2)0-4CON(R 1 9 )2, (CH2)0-4SO2R 6 or (CH2)0-4SO2N(R 1 9 )2; - 129- WO 98/57640 PCT/US98/12672 R 5 is selected from hydrogen, C1-8 alkyl, C3-8 cycloalkyl, (CH2)1-40R 6 or (CH2)0-4CF3; 5 R 6 is selected from hydrogen, C1-8 alkyl, C3-8 cycloalkyl or (CH2)0-4CF3; R 7 is selected from hydrogen, C1-8 alkyl, C4-8 cycloalkyl, (CH2)0-4CO2R 1 9 , (CH2)0-4CON(R 1 9 )2, (CH2)0-4COR 1 9 , (CH2)2-40R 6 , 10 (CH2)1-4CF3, (CH2)0-4SO2R 6 , (CH2)0-4SO2N(R 1 9)2 or (CH2)1-4CN; R 9 is selected from hydrogen, C1-8 alkyl, C3-8 cycloalkyl, CO2R 6 , CON(R 6 )2, (CH2)1-40R 6 or (CH2)0-4 CF3; 15 R 1 1 and R 1 2 are each independently selected from hydrogen, C1-8 alkyl or C3-8 cycloalkyl; R 1 3 and R 1 4 are each independently selected from hydrogen, C1-8 alkyl, C3-8 cycloalkyl, (CH2)1-40R 6 , (CH2)0-4CF3, unsubstituted, mono- or 20 poly-substituted phenyl wherein the substituents on the phenyl are independently selected from halogen, CF3, cyano, nitro, amino, OR 6 , (CH2)0-4CON(R 1 9 )2, (CH2)0-4CO2R 1 9 or C1-4 alkyl; or unsubstituted, mono- or poly-substituted: pyridyl, thienyl, furanyl or naphthyl wherein the substituents on the pyridyl, thienyl, furanyl or naphthyl are 25 independently selected from CF3, phenyl, OR 6 , halogen, C1-4 alkyl or C3-8 cycloalkyl; R 1 9 and R 2 0 are each independently selected from hydrogen, C1-8 alkyl, C3-8 cycloalkyl or (CH2)1-4CF3; 30 R 2 2 is selected from hydrogen, C1-8 alkyl, C3-8 cycloalkyl, (CH2)0-40R 6 or (CH2)0-4CF3; R 2 4 and R 2 6 are each independently selected from hydrogen or OR 2 8 ; - 130- WO 98/57640 PCT/US98/12672 R 2 8 is selected from hydrogen, C1-8 alkyl, C3-8 cycloalkyl, or (CH2)0-4CF3; 5 W is O or NR 1 1 ; each X is independently selected from halogen, cyano, nitro, C1-8 alkyl, C3-8 cycloalkyl, (CH2)0-40R 6 or (CH2)0-4CF3; 10 Y is C-R 1 9 or N; Z is hydrogen, oxygen or sulphur; m, p and q are each independently an integer from zero to two, provided 15 that when q is zero, R 2 6 is hydrogen; n, o, and s are each independently an integer from zero to four; and v is an integer from zero to one; or a pharmaceutically acceptable salt thereof. 20

2. The compound of Claim 1, of the formula M R15R 16 m R 2 (n E I R'-N ) q J pR 3 q o G R 1 7 R 18 L wherein R 1 is selected from unsubstituted, mono- or poly-substituted phenyl wherein the substituents on the phenyl are independently 25 selected from halogen, CF3, cyano, nitro, N(R 1 9 )2, NR 1 9 COR 2 0 , NR 1 9 CON(R 2 0 )2, NR 1 9 SO2R 2 0 , NR1 9 SO2N(R 2 0 )2, OR 6 , (CH2)0 4CO2R 1 9 , (CH2)0-4CON(R 1 9 )2, (CH2)0-4SO2N(R 1 9 )2, (CH2)0-4SO2R 6 or C1-4 alkyl; or unsubstituted, mono- or poly-substituted pyridyl, pyrazinyl, thienyl, thiazolyl, furanyl, quinazolinyl or naphthyl wherein -131- WO 98/57640 PCT/US98/12672 the substituents on the pyridyl, pyrazinyl, thienyl, thiazolyl, furanyl, quinazolinyl or naphthyl are independently selected from CF3, cyano, nitro, (CH2)0-4CO2R 1 9 , (CH2)0-4CON(R 1 9 )2, (CH2)0-4SO2N(R 1 9 )2, (CH2)0-4SO2R 6 , phenyl, OR 6 , halogen, C1-4 alkyl or C3-8 cycloalkyl; 5 R 4 is selected from (CH2)0-4COR 6 , (CH2)0-4CN, (CH2)0-4CF3, (CH2)0-4CO2R 1 9 , (CH2)0-4CON(R 1 9 )2, (CH2)0-4SO2R 6 or (CH2)0-4SO2N(R 1 9 )2; 10 R 5 is selected from hydrogen, C1-8 alkyl, C3-8 cycloalkyl, (CH2)2-40R 6 or (CH2)0-4CF3; R 9 is selected from hydrogen, C1-8 alkyl, C3-8 cycloalkyl, (CH2)2-40R 6 or (CH2)0-4 CF3; 15 or a pharmaceutically acceptable salt thereof.

3. The compound of Claim 1, of the formula M R 1 5R 6 mR 24 ( n E 26 1 N C OQ R 1 -N \ J Rp 3 q G R 17 R 18 L 20 wherein E, G, L, M and J are each independently selected from hydrogen, C1-8 alkyl, C3-8 cycloalkyl, or (CH2)0-4CF3; 25 R 1 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(R 1 9 )2, NR 1 9 COR 2 0 , NR 1 9 CON(R 2 0 )2, NR 1 9 SO2R 2 0 , NR 1 9 SO2N(R 2 0 )2, OR 6 , (CH2)0-4CO2R 1 9 , oxadiazolyl-, - 132- WO 98/57640 PCT/US98/12672 C1-4 alkyl oxadiazolyl-, (CH2)0-4CON(R 1 9 )2, (CH2)0-4SO2N(R 1 9 )2, (CH2)0-4SO2R 6 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, 5 thiazolyl, furanyl, quinazolinyl or naphthyl are independently selected from CF3, cyano, nitro, (CH2)0-4CO2R 1 9 , (CH2)0-4CON(R 1 9 )2, (CH2)0 4SO2N(R 19 )2, (CH2)0-4SO2R 6 , phenyl, OR 6 , halogen, C1-4 alkyl or C3-8 cycloalkyl; 10 R 7 is selected from hydrogen, C1-8 alkyl, C4-8 cycloalkyl or (CH2)1-4CF3; R 13 and R 1 4 are each independently selected from hydrogen, C1-8 alkyl, C3-8 cycloalkyl, (CH2)1-4OR 6 , (CH2)0-4CF3, unsubstituted, mono-, di- or 15 tri-substituted phenyl wherein the substituents on the phenyl are independently selected from halogen, CF3, cyano, nitro, amino, OR 6 , (CH2)0-4CON(R 1 9 )2, (CH2)0-4CO2R 1 9 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 20 independently selected from CF3, phenyl, OR 6 , halogen, C1-4 alkyl or C3-8 cycloalkyl; and n is an integer from zero to two; 25 or a pharmaceutically acceptable salt thereof.

4. The compound of Claim 3, selected from - 133- WO 98/57640 PCT/US98/12672 R'-N N 26 R2R26 (CH2)qA Q R 1 -N N (CH2 )q - Q R 2 4 R 1 -N N R 26 r R 26 ( H 2 )q__ Q O RI N (CH2q Q wherein Q is selected from (X s (XNs R 7 N ,. R ,O Ro R O R9NS 0 0 0 ' o N R 5 R0 H 1 0 0 RoR9 R7 R22 R1P I <,N or -(1 0 _(X)S 5 R 1 is selected from unsubstituted, mono-, di- or tnri-substituted phenyl wherein the substituents on the phenyl are independently selected from halogen, CF3, cyano, nitro, OR 6 , (CH2)0-2CO2R 1 9 , (CH2)0-2CON(R 1 9 )2, (CH2)0-2SO2N(R 1 9 ) 2 , (CH2)0-2SO2R 6 , C1-4 alkyloxadiazolyl or C1-4 alkyl; or unsubstituted, mono-, or di-substituted pyridyl wherein the 10 substituents on the pyridyl are independently selected from halogen, CF3, cyano, nitro, OR 6 , (CH2)0-2CO2R 1 9 , (CH2)0-2CON(R 1 9 )2, (CH2)0-2SO2N(R 1 9 )2, (CH2)0-2SO2R 6 or C1-4 alkyl; R 4 is selected from hydrogen, COR 6 , CO2R 1 9 , S02R 6 or CON(R 1 9 )2; - 134- WO 98/57640 PCT/US98/12672 R 5 is selected from hydrogen, C1-6 alkyl, C3-6 cycloalkyl, (CH2)0-30R 6 or (CH2)1-3CF3; 5 R 6 is selected from hydrogen, C1-6 alkyl, C3-6 cycloalkyl or (CH2)0-3CF3; R 8 and R 1 0 are each independently selected from hydrogen, C1-6 alkyl, C3-6 cycloalkyl, (CH2)2-40R 6 or (CH2)0-3CF3; 10 R 9 is selected from hydrogen, C1-6 alkyl, C3-6 cycloalkyl, CO2R 6 , CON(R 6 )2, (CH2)1-40R 6 or (CH2)0-3CF3; R 1 3 is selected from hydrogen, C1-6 alkyl, C3-6 cycloalkyl, 15 (CH2)2-40R 6 , (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, OR 6 , CO2R 1 9 or C1-4 alkyl; 20 R 1 9 is selected from hydrogen, C1-6 alkyl, C3-6 cycloalkyl or (CH2)1-3CF3; R 2 2 is selected from hydrogen, C1-6 alkyl, C3-6 cycloalkyl, (CH2)0-40R 6 or (CH2)0-3CF3; 25 R 2 8 is selected from hydrogen, C1-6 alkyl, C3-6 cycloalkyl, or (CH2)0-3CF3; q is an integer from zero to two; 30 s is an integer from zero to three; and or a pharmaceutically acceptable salt thereof.

5. The compound of Claim 4, wherein Q is selected from - 135- WO 98/57640 PCT/US98/12672 (X)s s O (X)s 0 9 0N HNR H N 9 O R H N O N R 5 O0 or H R13 H R 1 3 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, OR 6 , 5 CO2R 19 or C1-4 alkyl; each X is a halogen; 10 or a pharmaceutically acceptable salt thereof.

6. The compound of Claim 5, selected from (R 21 )r N N 24 \(CH2)qQ (R 2 1 )r R24 N 1R 26 A \ND - 1N3 (CH-Q - 136 - WO 98/57640 PCT/US98/12672 (R 2 1 )r ( 2 4 1 )r S N N R 26 (CH 2 q wherein A is C-R 2 1 or N; each R 2 1 is independently selected from hydrogen, halogen, cyano, 5 OC1-4 alkyl, OCF3, OCH2CF3, CO2CH3, CONH2, SO2NH2 or SO2C1-4 alkyl; R 2 4 and R 2 6 are each independently selected from hydrogen or OR 2 8 , wherein R 2 8 is hydrogen or C1-4 alkyl; 10 each X is fluorine; r is an integer from zero to two; and q is an integer from zero to one; 15 or a pharmaceutically acceptable salt thereof.

7. The compound of Claim 5, wherein Q is selected from - 137- WO 98/57640 PCT/US98/12672 F F F \ F F O O F F H' N RH R 13 o N" "" H R 4 is CO2R 1 9 ; and R 5 is (CH2)1-30R 6 ; 5 or a pharmaceutically acceptable salt thereof.

8. A pharmaceutical composition comprising the compound of Claim 1 and a pharmaceutically acceptable carrier. 10

9. A pharmaceutical composition made by combining a compound of Claim 1 and a pharmaceutically acceptable carrier.

10. A process for making a pharmaceutical composition comprising combining a compound of Claim 1 and a pharmaceutically 15 acceptable carrier.

11. The composition of Claim 8 further comprising a testosterone 5-alpha reductase inhibitor. 20

12. The composition of Claim 11, wherein the testosterone 5 alpha reductase inhibitor is a type 1, a type 2, both a type 1 and a type 2 or a dual type 1 and type 2 testosterone 5-alpha reductase inhibitor.

13. The composition of Claim 12, wherein the 25 testosterone 5-alpha reductase inhibitor is a type 2 testosterone 5-alpha reductase inhibitor. - 138- WO 98/57640 PCT/US98/12672

14. The composition of Claim 13, wherein the testosterone 5-alpha reductase inhibitor is finasteride.

15. A method of treating benign prostatic hyperplasia in 5 a subject in need thereof which comprises administering to the subject a therapeutically effective amount of the compound of Claim 1.

16. The method of Claim 15, wherein the compound additionally does not cause a fall in blood pressure at dosages effective to 10 alleviate benign prostatic hyperplasia.

17. The method of Claim 15, wherein the compound is administered in combination with a testosterone 5-alpha reductase inhibitor. 15

18. The method of Claim 17, wherein the testosterone 5 alpha reductase inhibitor is finasteride.

19. A method of treating benign prostatic hyperplasia in a 20 subject in need thereof which comprises administering a therapeutically effective amount of the composition of Claim 8.

20. The method of Claim 19, wherein the composition further comprises a therapeutically effective amount of a testosterone 5 25 alpha reductase inhibitor.

21. A method of relaxing lower urinary tract tissue in a subject in need thereof which comprises administering to the subject a therapeutically effective amount of the compound of Claim 1. 30

22. The method of Claim 21, wherein the compound additionally does not cause a fall in blood pressure at dosages effective to relax lower urinary tract tissue. - 139- WO 98/57640 PCT/US98/12672

23. The method of Claim 21, wherein the compound is administered in combination with a testosterone 5-alpha reductase inhibitor. 5

24. The method of Claim 23, wherein the testosterone 5 alpha reductase inhibitor is finasteride.

25. A method of treating a condition which is susceptible to treatment by antagonism of the alpha la receptor which comprises 10 administering to a subject in need thereof an amount of the compound of Claim 1 effective to treat the condition.

26. A method of eliciting an alpha la antagonizing effect in a mammal in need thereof, comprising administering to the 15 mammal a therapeutically effective amount of the compound of Claim 1. - 140-