AU7976398A - Alpha 1a adrenergic receptor antagonists - Google Patents

Description

WO 98/57641 PCT/US98/12673 TITLE OF THE INVENTION ALPHA la ADRENERGIC RECEPTOR ANTAGONISTS This application claims the benefit of U.S. Provisional 5 Application No. 60/049,921, 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 32 subtypes. Functional differences between alpha 1 and alpha 2 receptors 35 have been recognized, and compounds which exhibit selective binding between these two subtypes have been developed. -1- WO 98/57641 PCT/US98/12673 For a general background on the alpha adrenergic receptors, the reader's attention is directed to Robert R. Ruffolo, Jr., a Adrenoreceptors: Molecular Biology, Biochemistry and Pharmacology, (Progress in Basic and Clinical Pharmacology series, Karger, 1991), 5 wherein the basis of alpha 1/alpha 2 subclassification, the molecular biology, signal transduction (G-protein interaction and location of the significant site for this and ligand binding activity away from the 3' terminus of alpha adrenergic receptors), agonist structure-activity relationships, receptor functions, and therapeutic applications for 10 compounds exhibiting alpha-adrenergic receptor affinity was explored. The cloning, sequencing and expression of alpha receptor subtypes from animal tissues has led to the subclassification of the alpha 1 receptors into alpha ld (formerly known as alpha la or la/ld), alpha lb and alpha la (formerly known as alpha 1c) subtypes. Each 15 alpha 1 receptor subtype exhibits its own pharmacologic and tissue specificities. The designation "alpha la" is the appellation recently approved by the IUPHAR Nomenclature Committee for the previously designated "alpha 1c" cloned subtype as outlined in the 1995 Receptor and Ion Channel Nomenclature Supplement (Watson and Girdlestone, 20 1995). The designation alpha la is used throughout this application to refer to this subtype. At the same time, the receptor formerly designated alpha la was renamed alpha ld. The new nomenclature is used throughout this application. Stable cell lines expressing these alpha 1 receptor subtypes are referred to herein; however, these cell lines were 25 deposited with the American Type Culture Collection (ATCC) under the old nomenclature. For a review of the classification of alpha 1 adrenoceptor subtypes, see, Martin C. Michel, et al., Naunyn Schmiedeberg's Arch. Pharmacol. (1995) 352:1-10. The differences in the alpha adrenergic receptor subtypes 30 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 severity with increasing age. The symptoms of the condition include, but are not limited to, increased difficulty in urination and sexual 35 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. -2- WO 98/57641 PCT/US98/12673 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. 5 In benign prostatic hyperplasia, the male hormone 5alpha 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 10 enlarged gland begins to obstruct the urethra with the pathologic symptoms noted above. The elucidation of the mechanism summarized above has resulted in the recent development of effective agents to control, and in many cases reverse, the pernicious advance of BPH. In the forefront of 15 these agents is Merck & Co., Inc's product PROSCAR® (finasteride). The effect of this compound is to inhibit the enzyme testosterone 5-a reductase, which converts testosterone into 5cc-dihydrotesterone, resulting in a reduced rate of prostatic enlargement, and often reduction in prostatic mass. 20 The development of such agents as PROSCAR® bodes well for the long-term control of BPH. However, as may be appreciated from the lengthy development of the syndrome, its reversal also is not immediate. In the interim, those males suffering with BPH continue to suffer, and may in fact lose hope that the agents are working sufficiently 25 rapidly. In response to this problem, one solution is to identify pharmaceutically active compounds which complement slower-acting therapeutics by providing acute relief. Agents which induce relaxation of the lower urinary tract tissue, by binding to alpha 1 adrenergic 30 receptors, thus reducing the increased adrenergic tone due to the disease, would be good candidates for this activity. Thus, one such agent is alfuzosin, which is reported in EP 0 204597 to induce urination in cases of prostatic hyperplasia. Likewise, in WO 92/0073, the selective ability of the R(+) enantiomer of terazosin to bind to adrenergic receptors 35 of the alphal subtype was reported. In addition, in WO 92/161213, combinations of 5a-reductase inhibitory compounds and alphal adrenergic receptor blockers (terazosin, doxazosin, prazosin, bunazosin, -3- WO 98/57641 PCT/US98/12673 indoramin, alfuzosin) were disclosed. However, no information as to the alpha ld, alpha lb, or alpha la subtype specificity of these compounds was provided as this data and its relevancy to the treatment of BPH was not known. Current therapy for BPH uses existing non-selective alpha 1 5 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 and syncope. 10 The recent cloning of the human alpha la adrenergic receptor (ATCC CRL 11140) and the use of a screening assay utilizing the cloned human alpha la receptor enables identification of compounds which specifically interact with the human alpha la adrenergic receptor. [PCT International Application Publication Nos. WO94/08040, 15 published 14 April 1994 and WO94/10989, published 26 May 1994] As disclosed in the instant patent disclosure, a cloned human alpha la adrenergic receptor and a method for identifying compounds which bind the human alpha la receptor has now made possible the identification of selective human alpha la adrenergic receptor antagonists useful for 20 treating BPH. The instant patent disclosure discloses novel compounds which selectively bind to the human alpha la receptor. These compounds are further tested for binding to other human alpha 1 receptor subtypes, as well as counterscreened against other types of receptors (e.g., alpha 2), thus defining the specificity of the compounds of 25 the present invention for the human alpha la adrenergic receptor. It is an object of the present invention to identify compounds which bind to the alpha la adrenergic receptor. It is a further object of the invention to identify compounds which act as antagonists of the alpha la adrenergic receptor. It is another object of the invention to 30 identify alpha la adrenergic receptor antagonist compounds which are useful agents for treating BPH in animals, preferably mammals, especially humans. Still another object of the invention is to identify alpha la adrenergic receptor antagonists which are useful for relaxing lower urinary tract tissue in animals, preferably mammals, especially 35 humans. It has now been found that the compounds of the present invention are alpha la adrenergic receptor antagonists. Thus, the -4- WO 98/57641 PCT/US98/12673 compounds of the present invention are useful for treating BPH in mammals. Additionally, it has been found that the alpha la adrenergic receptor antagonists of the present invention are also useful for relaxing lower urinary tract tissue in mammals. 5 SUMMARY OF THE INVENTION 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 10 receptor at nanomolar and subnanomolar concentrations while exhibiting at least ten fold lower affinity for the alpha ld and alpha lb 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 15 adrenergic blockade. Such side effects include hypotension, syncope, lethargy, etc. The compounds of the present invention have the structure: R24 M R15

R

16m R R JR nE

R

26 I R NC Q 1j I ~ 0 G

R

17 R 8 p o G R R1 L wherein Q is selected from -5- WO 98/57641 PCT/US98/12673 0RN R 5 L /oN H X)s s (X) s

R

7 /2R Ov3/ Ov 0 R5/ N N0O S R R 11 R R 12 O N R 0 N H H

R

1 3 0(X)s R 1 R 14 3 o R 0 H (Xs (Xs O O OR' R 12 E, G, L and M are each independently selected from hydrogen, C1-8 5 alkyl, C3-8 cycloalkyl, (CH2)0.4OR 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 6 or N N 5N NV S(CH2)4N R11 S N2N(R 1 9 )2; H R 12 H O ' 4 R -N (X s R ' 0 N or O '%0 E, G, L and M are each independently selected from hydrogen, C1-8 5 alkyl, C3-8 cycloalkyl, (CH2)0-40R6, (CH2)0-4N(R19)2, (CH2)0-4CN, (CH2)0-4CF3, (CH2)0-4CO2R19, (CH2)0-4CON(R19)2, (CH2)0-4SO2R6- o (CH2)0-4SO2N(R19)2, J is selected from hydrogen, C1-8 alkyl, C3-8 cycloalkyl, (CH2)1-.40R 6 , 10 (CH2)1-4N(R 1 9 )2, (CH2)1-4CN, (CH2)0-4CF3, (CH2)0-4CO2R 1 9 , -6- WO 98/57641 PCT/US98/12673 (CH2)0-4CON(R 1 9 )2, (CH2)0-4SO2R 6 , or (CH2)0-4SO2N(R 19 )2;

R

1 is selected from unsubstituted, mono- or poly-substituted phenyl wherein the substituents on the phenyl are independently selected from 5 halogen, CF3, cyano, nitro, OR 6 , N(R 1 9 )2, NR 1 9

COR

2 0 , NR19CON(R 2 0)2, NR 19 SO2R 6 , NR 1 9 SO2N(R 2 0 )2, (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, pyridyl N oxide (N-)O) pyrazinyl, thienyl, thiazolyl, furanyl, quinazolinyl or 10 naphthyl wherein the substituents on the pyridyl, pyrazinyl, thienyl, thiazolyl, furanyl, quinazolinyl, or naphthyl are independently selected from CF3, cyano, nitro, N(R 1 9 )2, (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; 15 R is selected from hydrogen, cyano, OR 6 , CO2R 1 9 , CON(R 1 9 )2, tetrazole, isooxadiazole, unsubstituted, mono- or poly-substituted phenyl wherein the substituents on the phenyl are independently selected from halogen, cyano, nitro, OR 6 , (CH2)0-4CO2R 1 9 , (CH2)0-4CON(R 19 )2, N(R 1 9 )2, 20 NR 1 9

COR

6 , NR 19

CON(R

2 0 )2, NR 1 9 SO2R 6 , NR 1 9 SO2N(R 2 0 )2, (CH2)0-4SO2N(R 1 9 )2, (CH2)0-4SO2R 6 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, (CH2)0-4CO2R 1 9 , (CH2)0-4CON(R 1 9 )2, 25 (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 and R 7 are each independently selected from hydrogen, C1-8 alkyl, C4-8 cycloalkyl, (CH2)0-4CO2R 1 9 , (CH2)0-4CON(R 1 9 )2, (CH2)0 30 4COR 6 , (CH2)2-4OR 6 , (CH2)1-4CF3, (CH2)0-4SO2R 6 , (CH2)0-4SO2N(R 1 9 )2 or (CH2)1-4CN;

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 35 (CH2)0-4SO2N(R 1 9 )2; -7- WO 98/57641 PCT/US98/12673

R

5 , 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; 5 R 6 is selected from hydrogen, C1-8 alkyl, C3-8 cycloalkyl or (CH2)0-4CF3;

R

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

CON(R

6 )2, (CH2)1-40R 6 or (CH2)0-4CF3; 10

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, 15 C3-8 cycloalkyl, (CH2)1-40R 6 , (CH2)0-4CF3, unsubstituted, mono- or poly-substituted phenyl wherein the substituents on the phenyl are independently selected from halogen, CF3, cyano, nitro, 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 20 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;

R

1 9 and R 2 0 are each independently selected from hydrogen, C1-8 alkyl, 25 C3-8 cycloalkyl or (CH2)1-4CF3;

R

2 2 is selected from hydrogen, C1-8 alkyl, C3-8 cycloalkyl, (CH2)0-4OR 6 or (CH2)0-4CF3; 30 R 2 4 and R 2 6 are each independently selected from hydrogen or OR 2 8 ;

R

2 8 is selected from hydrogen, C1-8 alkyl, C3-8 cycloalkyl or (CH2)0-4CF3; 35 W is O or NR 1 1 ; -8- WO 98/57641 PCT/US98/12673 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 6 or N; 5 Z is hydrogen, oxygen or sulphur; m, p and q are each independently an integer of from zero to two provided that when q is zero, R 2 6 is hydrogen; 10 n, o, s and t are each independently an integer of from zero to. four; v is an integer from zero to one; and the pharmaceutically acceptable salts thereof. A first embodiment of the invention is a compound having the structure 15 M R15 R 1 6 m 2 n E 1 R N C Q

R

1 J Rq)p 3 q o G R 17

R

18 L wherein R 1 is selected from unsubstituted, mono- or poly-substituted phenyl wherein the substituents on the phenyl are independently 20 selected from halogen, CF3, cyano, nitro, OR 6 , N(R 1 9 )2, NR 1 9

COR

2 0 ,

NR

1 9

CON(R

2 0 )2, NR 1 9 SO2R 6 , NR 1 9 SO2N(R 2 0 )2, (CH2)0-4CO2R 1 9 , (CH2)0-4CON(R 1 9 )2, (CH2)0-4SO2N(R 1 9 )2, (CH2)0-4SO2R 6 or 01-4 alkyl; or unsubstituted, mono- or poly-substituted pyridyl, pyrazinyl, thienyl, thiazolyl, furanyl, quinazolinyl or naphthyl 25 wherein the substituents on the pyridyl, pyrazinyl, thienyl, thiazolyl, furanyl, quinazolinyl, or naphthyl are independently selected from CF3, cyano, nitro, N(R 1 9 )2, (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; 30

R

4 is selected from (CH2)0.-4COR 6 , (CH2)0-4CN, (CH2)0-4CF3, -9- WO 98/57641 PCT/US98/12673 (CH2)0-4CO2R 1 9 , (CH2)0-4CON(R19)2, (CH2)0-4SO2R 6 or (CH2)0-4SO2N(R 19 )2; and

R

9 is selected from hydrogen, C1-8 alkyl, C3-8 cycloalkyl, (CH2)2-40R 6 or 5 (CH2)0-4CF3; all other variables are as originally defined above; and the pharmaceutically acceptable salts thereof. In a second embodiment of the invention is the compound of 10 the formula R24 M

R

15 R 1 m n E R2 R N C 0 RJ )P I R' R3 q o G R17R18 wherein E, G, L, M and J are each independently selected from hydrogen, 15 C1-8 alkyl, C3-8 cycloalkyl, or (CH2)0-4CF3;

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 , N(R 1 9 )2, NR 1 9

COR

2 0 , 20 NR 1 9

CON(R

2 0 )2, NR 1 9 SO2R 6 , NR 1 9 SO2N(R 2 0 )2, (CH2)0-4CO2R 1 9 , (CH2)0-4CON(R 1 9 )2, (CH2)0-4SO2N(R 19 )2, (CH2)0-4SO2R 6 or C1-4 alkyl; or unsubstituted, mono-, di- or tri-substituted pyridyl, pyridyl N-oxide (N-O), pyrazinyl, thienyl, thiazolyl, furanyl, quinazolinyl or naphthyl wherein the substituents on the pyridyl, pyrazinyl, thienyl, 25 thiazolyl, furanyl, quinazolinyl or naphthyl are independently selected from CF3, cyano, (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; - 10 - WO 98/57641 PCT/US98/12673 R is selected from hydrogen, cyano, OR 6 , CO2R 1 9 , CON(R 1 9 )2, tetrazole, isooxadiazole, unsubstituted, mono-, di- or tri-substituted phenyl wherein the substituents on the phenyl are independently selected from halogen, cyano, nitro, OR 6 , (CH2)0-4CO2R19, (CH2)0-4CON(R 19 )2, 5 N(R 1 9 )2, NR 1 9

COR

6 , NR 1 9

CON(R

2 0 )2, NR 1 9 SO2R 6 , NR 19 SO2N(R 2 0 )2, (CH2)0-4SO2N(R 1 9 )2, (CH2)0-4SO2R 6 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, (CH2)0-4CO2R 1 9 , (CH2)0-4CON(R 1 9 )2, 10 (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 and R 7 are each independently selected from hydrogen, C1-8 alkyl, C4-8 cycloalkyl or (CH2)1-4CF3; 15

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, OR 6 , 20 (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 C3-8 cycloalkyl; and 25 n and t are each independently an integer from zero to two; and all other variables are as originally defined above [previously]; and the pharmaceutically acceptable salts thereof. In a third embodiment of the invention is the compound of 30 formula M R15 R 1 6 m 2 nE R N C Q R' 1 )) 13 q G 17

R

18 LG R R" L - 11 - WO 98/57641 PCT/US98/12673 wherein 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 , N(R 1 9 )2, NR 1 9

COR

2 0 , 5 NR 1 9

CON(R

2 0 )2, NR 1 9 SO2R 6 , NR 1 9 SO2N(R 2 0 )2, (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-, di- or tri-substituted pyridyl, pyrazinyl, thienyl, thiazolyl, furanyl, quinazolinyl or naphthyl wherein the substituents on the pyridyl, pyrazinyl, thienyl, thiazolyl, furanyl, 10 quinazolinyl or naphthyl are independently selected from CF3, cyano, (CH2)0-4CO2R 19 , (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; and all other variables are as defined in the first embodiment; and the 15 pharmaceutically acceptable salts thereof. In a first class of the invention is the compound selected from R 24 R24 R N

R

26 R N CHg-Q (CH2)q-- Q , R 24 R N /(R 26 R

R

26 R N H2)q_ or N (CH 2 Q wherein Q is selected from - 12 - WO 98/57641 PCT/US98/12673 (X)s s s 0 O RN 4j Nk R8 N N R4R9 R N' N 7 N R7N or I49 -J N0.R1NR" r RO0 N R 5 0 o RO S H 1 R9o R

R

7

R

2 2 R13 ~~N (X)s t\ O 0

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 or C1-4 alkyl; or unsubstituted, mono-, or di-substituted pyridyl or pyridyl N-oxide, wherein the substituents on the pyridyl or pyridyl N-oxide are independently selected from halogen, CF3, cyano, OR 6 , (CH2)0-2CO2R 19 , (CH2)0-2CON(R 1 9 )2, (CH2)0-2SO2N(R 1 9 )2, 10 (CH2)0-2SO2R 6 or C1-4 alkyl; R is selected from hydrogen, cyano, OR 6 , CO2R 1 9 , CON(R 1 9 )2, or unsubstituted, mono- or di-substituted phenyl wherein the substituents on the phenyl are independently selected from halogen, cyano, nitro, 15 OR 6 , (CH2)0-2CO2R 1 9 , (CH2)0-2CON(R 1 9 )2 or C1-4 alkyl;

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)0-30R 6 or 20 (CH2)0-3CF3;

R

6 is selected from hydrogen, C1-6 alkyl, C3-6 cycloalkyl or (CH2)0-3CF3; 25 R 8 and R 1 0 are each independently selected from hydrogen, - 13

-

WO 98/57641 PCT/US98/12673 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; 5

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 selected from halogen, CF3, cyano, nitro, amino, OR 6 , CO2R 1 9 or C1-4 10 alkyl;

R

1 9 is selected from hydrogen, C1-6 alkyl, C3-6 cycloalkyl or (CH2)1-3CF3; and 15 R 2 2 is selected from hydrogen, C1-6 alkyl, C3-6 cycloalkyl, (CH2)0-40R 6 or (CH2)0-3CF3;

R

2 4 and R 2 6 are each independently selected from hydrogen or OR 2 8 , wherein R 2 8 is selected from hydrogen, C1-6 alkyl, C3-6 cycloalkyl or 20 (CH2)1-3CF3; s is an integer from zero to three; and all other variables are as defined above in the second embodiment; 25 and the pharmaceutically acceptable salts thereof. In a second class of the invention is the compound selected from (C H 2 )-Q R1 D NN2 R1._ NO(CH2Cq-Q R (CH2 R1 65 Njf or R N (CH 2 )q 0 - 14- WO 98/57641 PCT/US98/12673 wherein 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 5 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, 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 , C02R 1 9 , S02R 6 , or CON(R 1 9 )2; and all other variables are as defined above in the third embodiment; and the 15 pharmaceutically acceptable salts thereof. In a first subclass of the invention is the compound selected from N R224 R 26

(R

21 )r (CH 2 )-Q

R

24 NR

R

2 6 N

(CH

2 )-Q

(R

2 1) r A R 24 R N R26

(R

21 )r A "(CH2) Q or or R

R

26 N (CH2 Q

(R

21 r

N

A - 15 - WO 98/57641 PCT/US98/12673 wherein Q is selected from 0 0 )s O - O /- (X)s N N R4 N R 9 ~ N' O N R 5 or H R 13 H R is selected from hydrogen, OR 6 or cyano; 5 A is selected from C-R 2 1 or N or N4O;

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; each R 2 1 is independently selected from hydrogen, halogen, hydroxy, 15 cyano, OC1-4 alkyl, OCF3, OCH2CF3, CO2-C1-4 alkyl, CONH2, SO2NH2 or SO2C1-4 alkyl; and

R

2 4 and R 2 6 are each independently selected from hydrogen or OR 2 8 , wherein R 2 8 is selected from hydrogen, C1-4 alkyl, or (CH2)0-2CF3; 20 r is an integer from zero to two; and all other variables are as defined in the first class above; and the pharmaceutically acceptable salts thereof. In a second subclass of the invention is the compound 25 selected from - 16- WO 98/57641 PCT/US98/12673 / N

(R

21 )r

(CH

2 -Q R (R1R N (CH2 )-Q N3j or

(R

2 1 )r \: 2A RN

-(CH

2 ) -Q

(R

21 )Ar \:-A wherein A is selected from C-R 2 1 or N; 5 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 , CO2R 1 9 or C1-4 alkyl; 10 each X is a halogen; each R 2 1 is independently selected from hydrogen, halogen, hydroxy, cyano, OC1-4 alkyl, OCF3, OCH2CF3, CO2-C1-4 alkyl, CONH2, SO2NH2 15 or SO2C1-4 alkyl; r is an integer from zero to two; - 17- WO 98/57641 PCT/US98/12673 all other variables are as defined in the second class above; and the pharmaceutically acceptable salts thereof. In a first illustration of the invention is the compound wherein Q is selected from F F F F FF 0F F If" IR F J N N H N H Iii HO0O or H O N R 5 R13 5 H R is selected from hydrogen, hydroxy or cyano;

R

4 is CO2R 19 ; 10 R 5 is (CH2)0-30R 6 ; q is an integer from zero to one; and all other variables are as defined in the first subclass above; and the pharmaceutically acceptable salts thereof; provided that the 15 compound is not (4S)-trans-4-(3,4-difluorophenyl)-2-oxooxazolidine-3 carboxylic acid-[ 1-(4-hydroxy-4-pyridin-2-yl-cyclohexyl)-(3R)-pyrrolidin-3 yl]amide. In a second illustration of the invention is the compound wherein Q is selected from F F F F 0 F F H .. ,' or J'N ; 0 or H O0 N R 5 OR13 20 H R is selected from hydrogen, hydroxy or cyano; -18- WO 98/57641 PCT/US98/12673

R

4 is CO2R 1 9 ;

R

5 is (CH2)0-30R 6 ; 5 q is an integer from zero to one; and all other variables are as defined in the second subclass above; and the pharmaceutically acceptable salts thereof; provided that the compound is not (4S)-trans-4-(3,4-difluorophenyl)-2-oxooxazolidine-3 10 carboxylic acid-[ 1-(4-hydroxy-4-pyridin-2-yl-cyclohexyl)-(3R)-pyrrolidin-3 yl]amide. In a third illustration of the invention is the compound wherein 15 R is H or OH; Q is selected from F F F F orO ""NC'CR4N, R9 O. N HR HO HO 20

R

4 is H or CO2CH3;

R

5 is H, CH3, or CH2OCH3; 25 R 9 is H, CH3, cyclopropyl, CONH2, CH2OH, or COOCH3; q is an integer from zero to one; and all other variables are as defined in the first subclass above; and pharmaceutically acceptable salts thereof; provided that the compound is not (4S)-trans-4-(3,4-difluorophenyl)-2 -19- WO 98/57641 PCT/US98/12673 oxooxazolidine-3-carboxylic acid-[ 1-(4-hydroxy-4-pyridin-2-yl-cyclohexyl) (3R)-pyrrolidin-3-yl]amide hydrochloride. One aspect of the invention is the compound having the formula: 5 R N wherein 10 R is H or OH;

R

1 is suitably unsubstituted pyridyl, unsubstituted pyridyl N-oxide, unsubstituted phenyl, or mono- or poly-substituted phenyl; typically unsubstituted pyridyl, unsubstituted pyridyl N-oxide, unsubstituted 15 phenyl, or mono- or di-substituted phenyl; more typically 2-pyridyl, 2 pyridyl N-oxide, 4-substituted phenyl, 2-substituted phenyl, or 2,4 substituted phenyl; wherein the phenyl substituents are independently selected from fluorine, cyano, OH, OCH3, CO2CH2CH3, and CF3; and 20 Q is F F F F O 11 or O ,C R 4 R N 'N N N H H HO N Rs H O H O or more preferably is 25 -20- WO 98/57641 PCT/US98/12673 F F F F 9 or ,R4 4 R9 N 'CN N C N O' N R 5 O H wherein 5 R 4 is H or CO2CH3;

R

5 is H, CH3, or CH2OCH3; and

R

9 is H, CH3, cyclopropyl, CONH2, CH2OH, or COOCH3; provided that 10 the compound is not (4S)-trans-4-(3,4-difluorophenyl)-2-oxooxazolidine-3 carboxylic acid-[ 1-(4-hydroxy-4-pyridin-2-yl-cyclohexyl)-(3R)-pyrrolidin-3 yl]amide hydrochloride. Exemplifying the invention is the compound selected from 15 (4S)-3- {1-[4-(2-cyano-phenyl)-cyclohexyl]-(3R)-pyrrolidin-3-ylcarbamoyl)-4 (3,4-difluoro-phenyl)-6-methyoxymethyl-2-oxo- 1,2,3,4-tetra hydropyrimidine-5-carboxylic acid methyl ester; (4S)-cis-3-{1-[4-(2-cyano-phenyl)-cyclohexyl]-(3R)-pyrrolidin-3 20 ylcarbamoyl}-4-(3,4-difluoro-phenyl)-6-methyoxymethyl-2-oxo-1,2,3,4 tetrahydropyrimidine-5-carboxylic acid methyl ester; trans-4S-4-(3,4-difluorophenyl)-2-oxooxazolidine-3-carboxylic acid- {1-[4 (2- cyano-phenyl)-cyclohexyl]-3R-pyrrolidin-3-yl}amide; 25 (4S)-cis-4-(3,4-difluorophenyl)-2-oxooxazolidine-3-carboxylic acid- {1-[4-(2 cyano-phenyl)-cyclohexyl]-(3R)--pyrrolidin-3-yl} amide; -21- WO 98/57641 PCT/US98/12673 (4S)-trans-4-(3,4-difluoro-phenyl)-3-{1-[4-(2-ethoxycarbonyl-phenyl) cyclohexyl]-(3R)-pyrrolidin-3-ylcarbamoyl}-6-methoxymethyl-2-oxo 1,2,3,4-tetrahydropyrimidine-5-carboxylic acid methyl ester; 5 (4S)-cis-4-(3,4-difluoro-phenyl)-3-{1-[4-(2-ethoxycarbonyl-phenyl) cyclohexyl]-(3R)--pyrrolidin-3-ylcarbamoyl}-6-methoxymethyl-2-oxo 1,2,3,4-tetrahydropyrimidine-5-carboxylic acid methyl ester; (4S)-trans-4-(3,4-difluorophenyl)-2-oxo-oxazolidine-3-carboxylic acid-{1-[4 10 (2-ethoxycarbonylphenyl)-cyclohexyl]-(3R)-pyrrolidin-3-yl}amide; (4S)-cis-4-(3,4-difluorophenyl)-2-oxooxazolidine-3-carboxylic acid-{1-[4-(2 ethoxycarbonylphenyl)-cyclohexyl]-(3R)-pyrrolidin-3-yl}amide; 15 (4S)-trans-4-(3,4-difluorophenyl)-3-[1-(4-pyridin-2-yl-cyclohexyl)-(3R) pyrrolidin-3-ylcarbamoyl]-6-methoxymethyl-2-oxo-1,2,3,4-tetrahydro pyrimidine-5-carboxylic acid methyl ester; (4S)-cis-4-(3,4-difluorophenyl)-3-[1-(4-pyridin-2-yl-cyclohexyl)-(3R) 20 pyrrolidin-3-ylcarbamoyl]-6-methoxymethyl-2-oxo-1,2,3,4-tetrahydro pyrimidine-5-carboxylic acid methyl ester; (4S)-trans-4-(3,4-difluorophenyl)-2-oxo-oxazolidine-3-carboxylic acid-[1-(4 pyridin-2-yl-cyclohexyl)-(3R)-pyrrolidin-3-yl] amide; 25 (4S)-cis-4-(3,4-difluorophenyl)-2-oxooxazolidine-3-carboxylic acid-[1-(4 pyridin-2-yl-cyclohexyl)-(3R)-pyrrolidin-3-yl] amide; (4S)-trans-4-(3,4-difluorophenyl)-6-methoxymethyl-3-{1-[4-(2-methoxyl 30 phenyl)-cyclohexyl]-(3R)-pyrrolidin-3-ylcarbamoyl}-2-oxo-1,2,3,4 tetrahydro-pyrimidine-5-carboxylic acid methyl ester; (4S)-cis-4-(3,4-difluoro-phenyl)-6-methoxymethyl-3-{1-[4-(2-methoxyl phenyl)-cyclohexyl]-(3R)-pyrrolidin-3-ylcarbamoyl}-2-oxo-1,2,3,4 35 tetrahydro-pyrimidine-5-carboxylic acid methyl ester; -22 - WO 98/57641 PCT/US98/12673 (4S)-trans-4-(3,4-difluorophenyl)-2-oxooxazolidine-3-carboxylic acid-{1-[4 (2-methoxyphenyl)-cyclohexyl]-(3R)-pyrrolidin-3-yl} amide; (4S)-cis-4-(3,4-difluorophenyl)-2-oxooxazolidine-3-carboxylic acid-{1-[4-(2 5 methoxyphenyl)-cyclohexyl]-(3R)-pyrrolidin-3-yl}amide; (4S)-cis-4-(3,4-difluoro-phenyl) -3-[ 1-(4-hydroxy-4-pyridin-2-yl-cyclohexyl) (3R)-pyrrolidin-3-ylcarbamoyl]-6-methoxymethyl -2-oxo-1,2,3,4 tetrahydro-pyrimidine-5-carboxylic acid methyl ester; 10 (4S)-trans-4-(3,4-difluoro-phenyl) -3-[ 1-(4-hydroxy-4-pyridin-2-yl cyclohexyl)-(3R)--pyrrolidin-3-ylcarbamoyl]-6-methoxymethyl -2-oxo 1,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid methyl ester; 15 (4S)-cis-4-(3,4-difluorophenyl)-2-oxooxazolidine-3-carboxylic acid-[1-(4 hydroxy-4-pyridin-2-yl-cyclohexyl)-(3R)--pyrrolidin-3-yl]amide; (4S)-4-(3,4-difluoro-phenyl)-3-{1-[4-(2-hydroxy-phenyl)-cyclohexyl]-(3R) pyrrolidin-3-ylcarbamoyl}-6-methoxymethyl-2-oxo-1,2,3,4-tetrahydro 20 pyrimidine-5-carboxylic acid methyl ester; (4S)-cis-4-(3,4-difluoro-phenyl)-6-methoxymethyl-3-{1-[4-(2-hydroxy phenyl)-cyclohexyl]-(3R)--pyrrolidin-3-ylcarbamoyl})-2-oxo-1,2,3,4 tetrahydro-pyrimidine-5-carboxylic acid methyl ester; 25 (4S)-trans-4-(3,4-difluorophenyl)-2-oxooxazolidine-3-carboxylic acid-{1-[4 (2-hydroxyphenyl)-cyclohexyl]-(3R)--pyrrolidin-3-yl}amide; (4S)-cis-4-(3,4-difluorophenyl)-2-oxooxazolidine-3-carboxylic acid-{1-[4-(2 30 hydroxyphenyl)-cyclohexyl]-(3R)--pyrrolidin-3-yl}amide; and the pharmaceutically acceptable salts thereof. Also exemplifying the invention is the compound selected 35 from -23 - WO 98/57641 PCT/US98/12673 (4S)-trans-4-(3-,4-difluoro-phenyl)-3-(1-[4-(2-fluoro-phenyl)-cyclohexyl] (3R)-pyrrolidin-3-ylcarbamoyll-6-methoxymethyl-1,2,3,4-tetrahydro pyrimidine-5-carboxylic acid methyl ester; 5 (4S)-trans-4-(3,4-difluoro-phenyl)-2-oxo-oxazolidine-3-carboxylic acid -(1 [4-(2-fluoro-phenyl)-cyclohexyl]-(3R)-pyrrolidin-3-yl}-amide; (4S)-trans-4-(3,4-difluoro-phenyl)-3-{1-[4-(4-fluoro-2-methoxy-phenyl) cyclohexyl]-(3R)-pyrrolidin-3-ylcarbamoyl)-6-methoxymethyl-2-oxo 10 1,2,3,4-tetrahydro-pyrimidine-5-carbaxylic acid methyl ester; (4S)-trans-4-(3,4-difluoro-phenyl)-2-oxo-oxazolidine-3-carboxylic acid (1 [4-(4-fluoro-2-methoxy-phenyl)-cyclohexyll-(3R)-pyrrolidin-3-yl}-amide; 15 (4S)-4-(3,4-difluoro-phenyl)-3-{ 1-[4-(2-fluoro-phenyl)-4-hydroxy cyclohexyl]-(3R)-pyrroidin-3-ykcarbamoyll-6-methoxymethyl-1,2,3,4 tetrahydro-pyrimidine-5-carboxylic acid methyl ester; (4S)-4-(3,4-difluoro-phenyl)-2-oxo-oxazolidine-3-carboxylic acid -1-[4-(2 20 fluoro-phenyl)-4-hydroxy-cyclohexyl-(3R)-pyrrolidin-3-yl)-amide; (4S)-4-(3,4-difluorophenyl)-2-oxo-oxazolidine-3-carboxylic acid (1-[4 hydroxy-4-(2-trifluoromethylphenyl)-cyclohexyl]-(3R)-pyrrolidin-3-yl) amide; 25 (4S)-4-(3,4-difluorophenyl)-3-{1-[4-hydroxy-4-(2-trifluoromethylphenyl) cyclohexyl]-(3R)-pyrrolidin-3-ycarbamoyl}-6-methoxymethy-2-oxo 1,2,3,4-tetrahydropyrimidine-5-carboxylic acid methyl ester; 30 (4S)-4-(3,4-difluarophenyl)-2-oxo-oxazolidine-3-carboxylic acid (1-[4-(2 trifluoromethylphenyl)-cyclohexyll-(3R)-pyrrolidin-3-yl) amide; (4S)-4-(3,4-difluorophenyl)-6-methoxymethyl-2-oxo-3-(1-E4-(2 trifluoromethylphenyl)-cyclohexyl)-(3R)-pyrrolidin-3-ylcarbamoyl} 35 1,2,3,4-tetrahydropyrimidine-5-carboxylic acid methyl ester; (4S)-4-(3,4-difluorophenyl)-3-(1-[4-(4-fluorophenyl)-4-hydroxy-cyclohexylj -24- WO 98/57641 PCT/US98/12673 (3R)-pyrrolidin-3-ylcarbamoyl}-6-methoxymethyl-2-oxo- 1,2,3,4 tetrahydropyrimidine-5-carboxylic acid methyl ester; (4S)-4-(3,4-difluorophenyl)-2-oxo-oxazolidine-3-carboxylic acid{1-[4-(4 5 fluorophenyl)-4-hydroxy-cyclohexyl]-(3R)-pyrrolidin-3-yl}amide; (4S)-4 -(3,4-difluorophenyl)-3-{ 1-[4-(4-fluorophenyl)-4-hydroxy-cyclohexyl] (3R)-pyrrolidin-3-ylcarbamoyl}-6-methyl-2-oxo-1,2,3,4 tetrahydropyrimidine-5-carboxylic acid methyl ester; 10 (4S)-4 -(3,4-difluorophenyl)-3- { 1-[4-(4-fluorophenyl)-cyclohexyl]-(3R) pyrrolidin-3-ylcarbamoyl}-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5 carboxylic acid methyl ester; 15 (4S)-4 -(3,4-difluorophenyl)-3- { 1-[4-(4-fluorophenyl)-cyclohexyl]-(3R) pyrrolidin-3-ylcarbamoyl}-6-methoxymethyl-2-oxo-1,2,3,4 tetrahydropyrimidine-5-carboxylic acid methyl ester; (4S)-4 -(3,4-difluorophenyl)-2-oxo-oxazolidine-3-carboxylic acid{1-[4-(4 20 fluorophenyl)-cyclohexyl]-(3R)-pyrrolidin-3-yl}amide; (4S)-4 -(3,4-difluorophenyl)-3-{ 1-[4-(4-fluorophenyl)-4-hydroxy-cyclohexyl] (3R)-pyrrolidin-3-ylcarbamoyl}-2-oxo-1,2,3,4-tetrahydropyrimidine-5 carboxylic acid methyl ester; 25 (4S)-3-{1-[4-(4-cyanophenyl)-4-hydroxycyclohexyl]-(3R)-pyrrolidin-3 ylcarbamoyl}-4 -(3,4-difluorophenyl)-6-methoxymethyl-2-oxo-1,2,3,4 tetrahydropyrimidine-5-carboxylic acid methyl ester; 30 5-cyclopropyl-4-(3,4-difluorophenyl)-2-oxo-oxazolidine-3-carboxylic acid {1-[4-(2-fluorophenyl)-cyclohexyl]-(3R)-pyrrolidin-3-yl-amide; (4S, 5S)-5-cyclopropyl-4-(3,4-difluorophenyl)-2-oxo-oxazolidine-3 carboxylic acid{ 1-[4-(4-fluorophenyl)-4-hydroxy-cyclohexyl]-(3R) 35 pyrrolidin-3-yl}amide; - 25 - WO 98/57641 PCT/US98/12673 (4S, 5S)-5-cyclopropyl-4-(3,4-difluorophenyl)-2-oxo-oxazolidine-3 carboxylic acid{ 1-[4-(4-cyanophenyl)-cyclohexyl]-(3R)-pyrrolidin-3 yl}amide; 5 (4S)-4-(3,4-difluorophenyl)-2-oxo-oxazolidine-3-carboxylic acid{1-[4-(4 cyanophenyl)-4-hydroxy-cyclohexyl]-(3R)-pyrrolidin-3-yl} amide; (4S)-3-{ 1-[4-(4-cyanophenyl)-cyclohexyl]-(3R)-pyrrolidin-3-ylcarbamoyl}-4 (3,4-difluorophenyl)-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5 10 carboxylic acid methyl ester; (4S)-trans-4-(3,4-difluorophenyl)-3-[1-(4-pyridin-2-yl-cyclohexyl)-(3R) pyrrolidin-3-ylcarbamoyl]-6-methyl-2-oxo-1,2,3,4-tetrahydro-pyrimidine 5-carboxylic acid methyl ester; 15 (4S)-3- {1 -[4-(2-cyano-phenyl)-cyclohexyl]-(3R)-pyrrolidin-3- ylcarbamoyl} 4-(3,4-difluoro-phenyl)-6-methyl-2-oxo-1,2,3,4-tetrahydro-pyrimidine-5 carboxylic acid methyl ester; 20 (4S)-3- {1 -[4-(2-cyano-4-fluoro-phenyl)-cyclohexyl]-(3R)-pyrrolidin-3 ylcarbamoyl}-4-(3,4-difluoro-phenyl)-6-methoxymethyl-2-oxo-1,2,3,4 tetrahydro-pyrimidine-5-carboxylic acid methyl ester; (4S)-4-(3,4-difluoro-phenyl)-3-{ 1 -[4-(4-fluoro-2-hydroxy-phenyl) 25 cyclohexyl]-(3R)-pyrrolidin-3-ylcarbamoyl}-6-methoxymethyl-2-oxo 1,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid methyl ester; (4S)-4-(3,4-difluoro-phenyl)-2-oxo-oxazolidine-3-carboxylic acid {1-[4 -(4 fluoro-2-hydroxy-phenyl)-cyclohexyl]-(3R)-pyrrolidin-3- yl}-amide; 30 (4S)-4-(3,4-difluoro-phenyl)-2-oxo-oxazolidine-3-carboxylic acid {1-[4 -(2 cyano-4-fluoro-phenyl)-cyclohexyl]-(3R)-pyrrolidin-3-yl}-amide; (4S)-4-(3,4-difluoro-phenyl)-2-oxo-oxazolidine-3-carboxylic acid {(1-[4 -(2 35 cyano-4-fluoro-phenyl)-cyclohexyl]-(3R)-pyrrolidin-3-yl}-amide; -26- WO 98/57641 PCT/US98/12673 (4S,5S)-4-(3,4-difluoro-phenyl)-5-methyl-2-oxo-oxazolidine-3-carboxylic acid {1-[4 -(2-cyano-4-fluoro-phenyl)-cyclohexyl]-(3R)-pyrrolidin-3-yl} amide; 5 (4S,5S)-5-Cyclopropyl-4-(3,4-difluoro-phenyl)-2-oxo-oxazolidine-3 carboxylic acid {(1-[4 -(2-cyano-4-fluoro-phenyl)-cyclohexyl]-(3R) pyrrolidin-3yl}-amide; (4S)-4-(3,4-difluoro-phenyl)-3-{1-[4-(2-fluoro-phenyl)-4-hydroxy-cyclohex-1 10 yl]-(3R)-pyrrolidin-3-ylcarbamoyl}-6-methyl-2-oxo-1,2,3,4-tetrahydro pyrimidine-5-carboxylic acid methyl ester; (4S)-trans-4-(3,4-difluoro-phenyl)-3-{1-[4-(2-fluoro-phenyl)-cyclohexyl] (3R)-pyrrolidin-3-ylcarbamoyl}-6-methyl-2-oxo-1,2,3,4-tetrahydro 15 pyrimidine-5-carboxylic acid methyl ester; (4S)-cis-4-(3,4-difluoro-phenyl) -3-[ 1-(4-hydroxy-4-pyridin-2-yl-cyclohexyl) (3R)-pyrrolidin-3-ylcarbamoyl] -2-oxo-1,2,3,4-tetrahydro-pyrimidine-5 carboxylic acid methyl ester; 20 (4S)-trans-4-(3,4-difluorophenyl)-3-[1-(4-pyridin-2-yl-cyclohexyl)-(3R) pyrrolidin-3-ylcarbamoyl]-2-oxo- 1,2,3,4-tetrahydro-pyrimidine-5 carboxylic acid methyl ester; 25 (4S)-trans-3{1-[4-(2-cyano-phenyl)-piperidin-1-yl]-(3R)-pyrrolidin-3 ylcarbamoly}-4-(3,4-difluoro-phenyl)-2-oxo-1,2,3,4-tetrahydro-pyrimidine 5-carboxylic acid methyl ester; (4S,5S)-trans-5-cyclopropyl-4-(3,4-difluorophenyl)-2-oxo-oxazolidine-3 30 carboxylic acid {1-[ 4-(4-fluorophenyl)-cyclohexyl]-(3R)-pyrrolidin-3-yl amide; (4S)-4-(3,4-difluoro-phenyl) -3-[ 1-(4-hydroxy-4-pyridin-2-yl-cyclohexyl) (3R)-pyrrolidin-3-ylcarbamoyl]-6-methyl -2-oxo-1,2,3,4-tetrahydro 35 pyrimidine-5-carboxylic acid methyl ester; -27- WO 98/57641 PCT/US98/12673 (4S)-trans-4-(3,4-difluorophenyl)-5-methyl-2-oxooxazolidine-3-carboxylic acid-[ 1-(4-pyridin-2-yl-cyclohexyl)-(3R)-pyrrolidin-3-yl]amide; trans-4S-(3,4-difluorophenyl)-3-[1-(4-oxopyridin-2-yl-cyclohexyl)-3R 5 pyrrolidin-3-ylcarbamoyl]-6-methyl-2-oxo-1,2,3,4-tetrahydro-pyrimidine 5-carboxylic acid methyl ester; trans-2-(3,4-difluorophenyl)- 1-[1-(4-pyridin-2-yl-cyclohexyl)-3R pyrrolidin-3-ylcarbamoyl]-6-methoxymethyl-2-oxo-1,2,3,4-tetrahydro 10 pyrimidine; (4S,5R)-trans-4-(3,4-difluorophenyl-3-{1-[4-(4-fluoro-2 methoxycarbonylphenyl)-cyclohexyl]-(3R)-pyrrolidin-3-ylcarbamoyl}-2 oxo-oxazolidine-5-carboxylic acid methyl ester; 15 (4S,5R)-trans-4-(3,4-difluorophenyl)-3-(1-{4-[4-fluoro-2-(2,2,2 trifluoroethoxy)phenyl] cyclohexyl}-(3R)-pyrrolidin-3-ylcarbamoyl)-2-oxo oxazolidine-5-carboxylic acid methyl ester; 20 (4S,5R)-trans-4-(3,4-difluorophenyl)-2-oxo-3-[1-(4-pyridin-2-ylcyclohexyl) (3R)-pyrrolidin-3-ylcarbamoyl]-oxazolidine-5-carboxylic acid methyl ester; (4S,5R)-trans-4-(3,4-difluorophenyl)-3-{1-[4-(4-fluoro-2 25 methoxyphenyl)cyclohexyl]-(3R)-pyrrolidin-3-ylcarbamoyl]-2-oxo oxazolidine-5-carboxylic acid methyl ester; (4S,5R)-3-{1-[4-Cyano-4-(2-methoxyphenyl)cyclohexyl]-(3R)-pyrrolidin-3 ylcarbamoyl}-4-(3,4-difluorophenyl)-2-oxo-oxazolidine-5-carboxylic acid 30 methyl ester; (4S,5R)-3- {1-[4-Cyano-4-(2-fluorophenyl)cyclohexyl]-(3R)-pyrrolidin-3 ylcarbamoyl}-4-(3,4-difluorophenyl)-2-oxo-oxazolidine-5-carboxylic acid methyl ester; 35 -28 - WO 98/57641 PCT/US98/12673 (4S,5R)-trans-3-{ 1-[4-(2-cyanophenyl)cyclohexyl]-(3R)-pyrrolidin-3 ylcarbamoyl}- 4

-(

3

,

4 -difluorophenyl)-2-oxo-oxazolidine-5-carboxylic acid methyl ester; 5 (4S,5R)-trans-4-(3, 4 -difluorophenyl)-5-hydroxymethyl-2-oxo-oxazolidine 3-carboxylic acid {1-[4-(4-fluorophenyl)cyclohexyl]-(3R)-pyrrolidin-3-yl} amide; (4S,5R)-trans-4-(3, 4 -difluorophenyl)-5-hydroxymethyl-2-oxo-oxazolidine 10 3-carboxylic acid (1-[4-(4-fluoro-2-methoxyphenyl)cyclohexyl]-(3R) pyrrolidin-3-yl} amide; (4S,5R)-trans-4-(3,4-difluorophenyl)-3-{ 1-[4-(4-fluoro-2 methoxyphenyl)cyclohexyl]-(3R)-pyrrolidin-3-ylcarbamoyl]- 2 -oxo 15 oxazolidine-5-carboxamide; (4S,5R)-trans-4-(3,4-difluorophenyl)-3-{1-[4-(4-fluorophenyl)cyclohexyl]

(

3 R)-pyrrolidin-3-ylcarbamoyl]-2-oxo-oxazolidine-5-carboxamide; 20 (4S,5R)-trans-4-(3,4-difluorophe n yl)-3 - {1 - [4

-

(2

-

fluorophenyl)cyclohexyl ] (3R)-pyrrolidin-3-ylcarbamoyl]-2-oxo-oxazolidine-5-carboxamide; (4S,5R)-trans-3-{1-[4-(2-cyano-4-fluorophenyl)cy cl o h e x y l ]-(3 R )-p y r r o l i d i n 3-ylcarbamoyl}-4-(3, 4 -difluorophenyl)-2-oxo-oxazolidine-5-carboxamide; 25 and the pharmaceutically acceptable salts thereof. In a preferred embodiment the compound is selected from Compound A: F F Na FHN N N ... N H 30 O -29 - WO 98/57641 PCT/US98/12673 Compound B: F F .. /\H N CO 2 Me H Compound C: F F

NH

0 No 101N- N CO0 2 Me 0~ *,,,N ,,, 0 N Me H 5 and the pharmaceutically acceptable salts thereof. Another preferred embodiment is Compound A or a pharmaceutically acceptable salt thereof. Another preferred 10 embodiment is Compound B or a pharmaceutically acceptable salt thereof. Still another preferred embodiment is Compound C or a pharmaceutically acceptable salt 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 -30- WO 98/57641 PCT/US98/12673 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 5 reductase inhibitor. Preferably, the testosterone 5-alpha reductase inhibitor is a type 1, a type 2, both a type 1 and a type 2 (i.e., a three component combination comprising any of the compounds described above combined with both a type 1 testosterone 5-alpha reductase inhibitor and a type 2 testosterone 5-alpha reductase inhibitor) or a dual 10 type 1 and type 2 testosterone 5-alpha reductase inhibitor. More preferably, the testosterone 5-alpha reductase inhibitor is a type 2 testosterone 5-alpha reductase inhibitor. Most preferably, the testosterone 5-alpha reductase inhibitor is finasteride. More specifically illustrating the invention is a method of 15 treating benign prostatic hyperplasia in a subject in need thereof which comprises administering to the subject a therapeutically effective amount of any of the compounds (or any of the compositions) described above. Further exemplifying the invention is the method of 20 treating BPH wherein the compound (or composition) additionally does not cause a fall in blood pressure at dosages effective to alleviate BPH. Another illustration of the invention is the method of treating benign prostatic hyperplasia wherein the compound is administered in combination with a testosterone 5-alpha reductase 25 inhibitor. Preferably, the testosterone 5-alpha reductase inhibitor is finasteride. Further illustrating the invention is a method of inhibiting contraction of prostate tissue or relaxing lower urinary tract tissue in a subject in need thereof which comprises administering to the subject a 30 therapeutically effective amount of any of the compounds (or any of the compositions) described above. More specifically exemplifying the invention is the method of inhibiting contraction of prostate tissue or relaxing lower urinary tract tissue wherein the compound (or composition) additionally does not 35 cause a fall in blood pressures at dosages effective to inhibit contraction of prostate tissue. -31- WO 98/57641 PCT/US98/12673 More particularly illustrating the invention is the method of inhibiting contraction of prostate tissue or relaxing lower urinary tract tissue wherein the compound (or composition) is administered in combination with a testosterone 5-alpha reductase inhibitor; preferably, 5 the testosterone 5-alpha reductase inhibitor is finasteride. More particularly exemplifying the invention is a method of treating a disease which is susceptible to treatment by antagonism of the alpha la receptor which comprises administering to a subject in need thereof an amount of any of the compounds described above effective to 10 treat the disease. Diseases which are susceptible to treatment by antagonism of the alpha la receptor include, but are not limited to, BPH, high intraocular pressure, high cholesterol, impotency, sympathetically mediated pain, migraine (see, K.A. Vatz, Headache 1997:37: 107-108) and cardiac arrhythmia. 15 An additional illustration of the invention is the use of any of the compounds described above in the preparation of a medicament for: a) the treatment of benign prostatic hyperplasia; b) relaxing lower urinary tract tissue; or c) inhibiting contraction of prostate tissue; in a subject in need thereof. 20 An additional example of the invention is the use of any of the alpha la antagonist compounds described above and a 5-alpha reductase inhibitor for the manufacture of a medicament for: a) treating benign prostatic hyperplasia; b) relaxing lower urinary tract tissue; or c) inhibiting contraction of prostate tissue which comprises an effective 25 amount of the alpha la antagonist compound and an effective amount of 5-alpha reductase inhibitor, together or separately. DETAILED DESCRIPTION OF THE INVENTION Representative compounds of the present invention exhibit 30 high selectivity for the human alpha la adrenergic receptor. One implication of this selectivity is that these compounds display selectivity for lowering intraurethral pressure without substantially affecting diastolic blood pressure. Representative compounds of this invention display 35 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 -32- WO 98/57641 PCT/US98/12673 protein coupled human receptors. Particular representative compounds of this invention exhibit nanomolar and subnanomolar affinity for the human alpha la adrenergic receptor subtype while displaying at least 30 fold lower affinity for the human alpha ld and alpha lb adrenergic 5 receptor subtypes, and many other G-protein coupled human receptors (e.g., serotonin, dopamine, alpha 2 adrenergic, beta adrenergic or muscarinic receptors). These compounds are administered in dosages effective to antagonize the alpha la receptor where such treatment is needed, as in 10 BPH. For use in medicine, the salts of the compounds of this invention refer to non-toxic "pharmaceutically acceptable salts." Other salts may, however, be useful in the preparation of the compounds according to the invention or of their pharmaceutically acceptable salts. Suitable pharmaceutically acceptable salts of the compounds of this invention 15 include acid addition salts which may, for example, be formed by mixing a solution of the compound according to the invention with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, sulphuric acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid. 20 Furthermore, where the compounds of the invention carry an acidic moiety, suitable pharmaceutically acceptable salts thereof may include alkali metal salts, e.g. sodium or potassium salts; alkaline earth metal salts, e.g. calcium or magnesium salts; and salts formed with suitable organic ligands, e.g. quaternary ammonium salts. Thus, 25 representative pharmaceutically acceptable salts include the following: Acetate, Benzenesulfonate, Benzoate, Bicarbonate, Bisulfate, Bitartrate, Borate, Bromide, Calcium, Camsylate, Carbonate, Chloride, Clavulanate, Citrate, Dihydrochloride, Edetate, Edisylate, Estolate, Esylate, Fumarate, Gluceptate, Gluconate, Glutamate, 30 Glycollylarsanilate, Hexylresorcinate, Hydrabamine, Hydrobromide, Hydrochloride, Hydroxynaphthoate, Iodide, Isothionate, Lactate, Lactobionate, Laurate, Malate, Maleate, Mandelate, Mesylate, Methylbromide, Methylnitrate, Methylsulfate, Mucate, Napsylate, Nitrate, N-methylglucamine ammonium salt, Oleate, Pamoate 35 (Embonate), Palmitate, Pantothenate, Phosphate/diphosphate, Polygalacturonate, Salicylate, Stearate, Sulfate, Subacetate, Succinate, Tannate, Tartrate, Teoclate, Tosylate, Triethiodide and Valerate. -33 - WO 98/57641 PCT/US98/12673 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® 5 (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 10 nervous system events. The present invention includes within its scope prodrugs of the compounds of this invention. In general, such prodrugs will be functional derivatives of the compounds of this invention which are readily convertible in vivo into the required compound. Thus, in the 15 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 20 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 25 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, 30 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 35 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 -34- WO 98/57641 PCT/US98/12673 range (i.e., methyl, ethyl, 1-propyl, 2-propyl, n-butyl, s-butyl, t-butyl, etc.). The term "alkenyl" shall mean straight or branched chain alkenes of two to ten total carbon atoms, or any number within this 5 range. The term "aryl" as used herein, except where otherwise specifically defined, refers to unsubstituted, mono- or poly-substituted aromatic groups such as phenyl or naphthyl. The term "cycloalkyl" shall mean cyclic rings of alkanes of 10 three to eight total carbon atoms (i.e., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl). Whenever the term "alkyl" or "aryl" or either of their prefix roots appear in a name of a substituent (e.g., aralkoxyaryloxy) it shall be interpreted as including those limitations given above for "alkyl" and 15 "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 appears as its prefix root. The term "halogen" shall include iodine, bromine, chlorine 20 and fluorine. The term "substituted" shall be deemed to include multiple degrees of substitution by a named substituent. The term "poly substituted" as used herein shall include di-, tri-, tetra- and penta substitution by a named substituent. Preferably, a poly-substituted 25 moiety is di-, tri- or tetra-substituted by the named substituents, most preferably, di- or tri-substituted. It is intended that the definition of any substituent or variable (e.g., X, R 6 , R 1 9 ) at a particular location in a molecule be independent of its definitions elsewhere in that molecule. Thus, 30 N(R 1 9 )2 represents -NH2, -NHCH3, -NHC2H5, -N(CH3)C2H5, etc. and -35- WO 98/57641 PCT/US98/12673 R24 R4 represents for m=2 OH OH OH OH S S \etc. It is understood that substituents and substitution patterns on the compounds of the instant invention can be selected by one of ordinary skill in the art to provide compounds that are chemically stable and that 5 can be readily synthesized by techniques known in the art as well as those methods set forth below. Where multiple substituent moieties are disclosed or claimed, the substituted compound can be independently substituted by one or more of the disclosed or claimed substituent moieties, singly or plurally. 10 The term "Z is hydrogen," when refering to the "Q" group R13

N

8 0 R refers to the moiety R13 N R8 The term heterocycle or heterocyclic ring, as used herein, 15 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 20 may optionally be quaternized. The heterocyclic ring may be attached at -36 - WO 98/57641 PCT/US98/12673 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, 5 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, 10 and oxadiazolyl. Morpholino is the same as morpholinyl. 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 OF o SN

R

4 O N Rs 15 H for example: F F o o N O O N " H The term "activated (+)-DHP," as used herein, refers to a N 3-(activated)carbamate of the desired dihydropyrimidinone where the - 37- WO 98/57641 PCT/US98/12673 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 5 15. The term "(S)-oxa" as used herein, refers to an oxazolidinone group of the formula (X)q O R8 F 9 0 R1o O 0> for example, F F 100 10 O The term "activated (S)-oxa" as used herein, refers to an N (activated)carbamate of the desired oxazolidinone where the activating group is, for example, a p-nitrophenyloxy group. A specific example of an activated (S)-oxa group is 4-(3,4-difluorophenyl)-2-oxo-oxazolidine-3 15 carboxylic acid 4-nitrophenyl ester (i.e., compound 16). The term "lower urinary tract tissue," as used herein, 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, 20 preferably a mammal, most preferably a human, who has been the object of treatment, observation or experiment. -38 - WO 98/57641 PCT/US98/12673 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 term "selective alpha la adrenergic receptor antagonist," as used herein, refers to an alpha la antagonist compound which is at least ten fold selective for the human alpha la adrenergic 10 receptor as compared to the human alpha lb, alpha ld, alpha 2a, alpha 2b and alpha 2c adrenergic receptors. The present invention also provides pharmaceutical compositions comprising one or more compounds of this invention in association with a pharmaceutically acceptable carrier. Preferably 15 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 20 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 25 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 30 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 35 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 -39- WO 98/57641 PCT/US98/12673 tablets or pills of the novel composition can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action. For example, the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an 5 envelope over the former. The two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permits the inner component to pass intact into the duodenum or to be delayed in release. A variety of materials can be used for such enteric layers or coatings, such materials including a number of polymeric 10 acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol and cellulose acetate. As used herein, the term "composition" is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or 15 indirectly, from combination of the specified ingredients in the specified amounts. The liquid forms in which the novel compositions of the present invention may be incorporated for administration orally or by injection include aqueous solutions, suitably flavoured syrups, aqueous 20 or oil suspensions, and flavoured emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil or peanut oil, as well as elixirs and similar pharmaceutical vehicles. Suitable dispersing or suspending agents for aqueous suspensions include synthetic and natural gums such as tragacanth, acacia, alginate, dextran, sodium 25 carboxymethylcellulose, methylcellulose, polyvinyl-pyrrolidone or gelatin. Where the processes for the preparation of the compounds according to the invention give rise to mixtures of stereoisomers, these isomers may be separated by conventional techniques such as 30 preparative chromatography. The compounds may be prepared in racemic form, or individual enantiomers may be prepared either by enantiospecific synthesis or by resolution. The compounds may, for example, be resolved into their component enantiomers by standard techniques, such as the formation of diastereomeric pairs by salt 35 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 -40 - WO 98/57641 PCT/US98/12673 also be resolved by formation of diastereomeric esters or amides, followed by chromatographic separation and removal of the chiral auxiliary. Alternatively, the compounds may be resolved using a chiral HPLC column. 5 During any of the processes for preparation of the compounds of the present invention, it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups, such as those described in Protective Groups in Organic 10 Chemistry, ed. J.F.W. McOmie, Plenum Press, 1973; and T.W. Greene & 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 15 the alpha la receptor is shown by comparing affinity to membranes obtained from tranfected cell lines that express the alpha la receptor and membranes from cell lines or tissues known to express other types of alpha (e.g., alpha ld, alpha lb) or beta adrenergic receptors. Expression of the cloned human alpha ld, alpha lb, and alpha la receptors and 20 comparison of their binding properties with known selective antagonists provides a rational way for selection of compounds and discovery of new compounds with predictable pharmacological activities. Antagonism by these compounds of the human alpha la adrenergic receptor subtype may be functionally demonstrated in anesthetized animals. These 25 compounds may be used to increase urine flow without exhibiting hypotensive effects. The ability of compounds of the present invention to specifically bind to the alpha la receptor makes them useful for the treatment of BPH. The specificity of binding of compounds showing 30 affinity for the alpha la receptor is compared against the binding affinities to other types of alpha or beta adrenergic receptors. The human alpha adrenergic receptor of the la subtype was recently identified, cloned and expressed as described in PCT International Application Publication Nos. WO94/08040, published 14 April 1994 and 35 WO 94/21660, published 29 September 1994. The cloned human alpha la receptor, when expressed in mammalian cell lines, is used to discover ligands that bind to the receptor and alter its function. Expression of the -41- WO 98/57641 PCT/US98/12673 cloned human alpha ld, 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 compounds with predictable pharmacological activities. 5 Compounds of this invention exhibiting human alpha la adrenergic receptor antagonism may further be defined by counterscreening. This is accomplished according to methods known in the art using other receptors responsible for mediating diverse biological functions. [See e.g., PCT International Application Publication No. 10 WO94/10989, published 26 May 1994; U.S. Patent No. 5,403,847, issued April 4, 1995]. Compounds which are both selective amongst the various human alphal adrenergic receptor subtypes and which have low affinity for other receptors, such as the alpha2 adrenergic receptors, the 13 adrenergic receptors, the muscarinic receptors, the serotonin receptors, 15 and others are particularly preferred. The absence of these non-specific activities may be confirmed by using cloned and expressed receptors in an analogous fashion to the method disclosed herein for identifying compounds which have high affinity for the various human alphal adrenergic receptors. Furthermore, functional biological tests are used 20 to confirm the effects of identified compounds as alpha la adrenergic receptor antagonists. The present invention also has the objective of providing suitable topical, oral, systemic and parenteral pharmaceutical formulations for use in the novel methods of treatment of the present 25 invention. The compositions containing compounds of this invention as the active ingredient for use in the specific antagonism of human alpha la adrenergic receptors can be administered in a wide variety of therapeutic dosage forms in conventional vehicles for systemic administration. For example, the compounds can be administered in 30 such oral dosage forms as tablets, capsules (each including timed release and sustained release formulations), pills, powders, granules, elixirs, tinctures, solutions, suspensions, syrups and emulsions, or by injection. Likewise, they may also be administered in intravenous (both bolus and infusion), intraperitoneal, 35 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 -42- WO 98/57641 PCT/US98/12673 compound desired can be employed as an alpha la antagonistic agent. Advantageously, compounds of the present invention may be administered in a single daily dose, or the total daily dosage 5 may be administered in divided doses of two, three or four times daily. Furthermore, compounds for the present invention can be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal routes, using those forms of transdermal skin patches well known to those of ordinary skill in 10 that art. To be administered in the form of a transdermal delivery system, the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen. The dosage regimen utilizing the compounds of the present invention is selected in accordance with a variety of factors 15 including type, species, age, weight, sex and medical condition of the patient; the severity of the condition to be treated; the route of administration; the renal and hepatic function of the patient; and the particular compound thereof employed. A physician or veterinarian of ordinary skill can readily determine and prescribe the effective 20 amount of the drug required to prevent, counter or arrest the progress of the condition. Optimal precision in achieving concentration of drug within the range that yields efficacy without toxicity requires a regimen based on the kinetics of the drug's availability to target sites. This involves a consideration of the 25 distribution, equilibrium, and elimination of a drug. In the methods of the present invention, the compounds herein described in detail can form the active ingredient, and are typically administered in admixture with suitable pharmaceutical diluents, excipients or carriers (collectively referred to herein as 30 "carrier" materials) suitably selected with respect to the intended form of administration, that is, oral tablets, capsules, elixirs, syrups and the like, and consistent with conventional pharmaceutical practices. For instance, for oral administration in the form of a 35 tablet or capsule, the active drug component can be combined with an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like. Moreover, when desired or -43 - WO 98/57641 PCT/US98/12673 necessary, suitable binders, lubricants, disintegrating agents and coloring agents can also be incorporated into the mixture. Suitable binders include, without limitation, starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and 5 synthetic gums such as acacia, tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes and the like. Lubricants used in these dosage forms include, without limitation, sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like. 10 Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum and the like. The liquid forms in suitably flavored suspending or dispersing agents such as the synthetic and natural gums, for example, tragacanth, acacia, methyl-cellulose and the like. Other dispersing 15 agents which may be employed include glycerin and the like. For parenteral administration, sterile suspensions and solutions are desired. Isotonic preparations which generally contain suitable preservatives are employed when intravenous administration is desired. The compounds of the present invention can also be 20 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. Compounds of the present invention may also be 25 delivered by the use of monoclonal antibodies as individual carriers to which the compound molecules are coupled. The compounds of the present invention may also be coupled with soluble polymers as targetable drug carriers. Such polymers can include polyvinyl pyrrolidone, pyran copolymer, polyhydroxypropylmethacryl 30 amidephenol, polyhydroxy-ethylaspartamidephenol, or polyethyl eneoxidepolylysine substituted with palmitoyl residues. Furthermore, the compounds of the present invention may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyepsilon 35 caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydro-pyrans, polycyanoacrylates and cross-linked or amphipathic block copolymers of hydrogels. -44- WO 98/57641 PCT/US98/12673 Compounds of this invention may be administered in any of the foregoing compositions and according to dosage regimens established in the art whenever specific blockade of the human alpha la adrenergic receptor is required. 5 The daily dosage of the products may be varied over a wide range from 0.01 to 1,000 mg per adult human per day. For oral administration, the compositions are preferably provided in the form of tablets containing 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0 and 100 milligrams of the active ingredient for the symptomatic adjustment 10 of the dosage to the patient to be treated. A medicament typically contains from about 0.01 mg to about 500 mg of the active ingredient, preferably, from about 1 mg to about 100 mg of active ingredient. An effective amount of the drug is ordinarily supplied at a dosage level of from about 0.0002 mg/kg to about 20 mg/kg of body weight per day. 15 Preferably, the range is from about 0.001 to 10 mg/kg of body weight per day, and especially from about 0.001 mg/kg to 7 mg/kg of body weight per day. The compounds may be administered on a regimen of 1 to 4 times per day. Compounds of this patent disclosure may be used alone at 20 appropriate dosages defined by routine testing in order to obtain optimal antagonism of the human alpha la adrenergic receptor while minimizing any potential toxicity. In addition, co-administration or sequential administration of other agents which alleviate the effects of BPH is desirable. Thus, in one embodiment, this includes 25 administration of compounds of this invention and a human testosterone 5-a reductase inhibitor. Included with this embodiment are inhibitors of 5-alpha reductase isoenzyme 2. Many such compounds are now well known in the art and include such compounds as PROSCAR®, (also known as finasteride, a 4-Aza-steroid; see US Patents 4,377,584 and 30 4,760,071, for example). In addition to PROSCAR®, which is principally active in prostatic tissue due to its selectivity for human 5-ac reductase isozyme 2, combinations of compounds which are specifically active in inhibiting testosterone 5-alpha reductase isozyme 1 and compounds which act as dual inhibitors of both isozymes 1 and 2, are useful in 35 combination with compounds of this invention. Compounds that are active as 5c-reductase inhibitors have been described in WO93/23420, EP 0572166; WO 93/23050; WO93/23038,; WO93/23048; WO93/23041; -45 - WO 98/57641 PCT/US98/12673 W093/23040; W093/23039; WO93/23376; W093/23419, EP 0572165; W093/23051. The dosages of the alpha la adrenergic receptor and testosterone 5-alpha reductase inhibitors are adjusted when 5 combined to achieve desired effects. As those skilled in the art will appreciate, dosages of the 5-alpha reductase inhibitor and the alpha la adrenergic receptor antagonist may be independently optimized and combined to achieve a synergistic result wherein the pathology is reduced more than it would be if either agent were used alone. In 10 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 15 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 20 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 25 about 10 mg per subject per day, more preferably, about 1 to about 7 mg per subject to day, most preferably, about 5 mg per subject per day. For the treatment of benign prostatic hyperplasia, compounds of this invention exhibiting alpha la adrenergic receptor 30 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 4,7B-dimethyl-4-aza-5a-cholestan-3 one, in a single oral, systemic, or parenteral pharmaceutical dosage formulation. Alternatively, a combined therapy can be employed 35 wherein the alpha la adrenergic receptor antagonist and the 5u reductase 1 or 2 inhibitor are administered in separate oral, systemic, or parenteral dosage formulations. See, e.g., U.S. Patent -46- WO 98/57641 PCT/US98/12673 No.'s 4,377,584 and 4,760,071 which describe dosages and formulations for 5a-reductase inhibitors. Abbreviations used in the instant specification, particularly the Schemes and Examples, are as follows: 5 BCE = bromochloroethane Boc or BOC = t-butyloxycarbonyl BOPC1 = bis(2-oxo-3-oxazolidinyl)phosphinic chloride Cbz-Cl or CBZCI= benzyloxycarbonyl chloride 10 CSA = 10-Camphorsulfonic acid DAST = diethylaminosulfurtrifluoride DEAD = diethylazodicarboxylate DMF = N,N-dimethylformamide DMSO = dimethylsulfoxide 15 EDCI = 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride Et = ethyl Et3N = triethylamine EtOAc = ethyl acetate 20 EtOH = ethanol FABLRMS = fast atom bombardment low resolution mass spectroscopy HMPA = hexamethylphosporamide HPLC = high performance liquid chromatography 25 HOAc = acetic acid HOBt = 1-hydroxy benzotriazole hydrate i-PrOH = 2-propanol i-Pr2NEt = diisopropylethylamine LAH = lithium aluminum hydride 30 LDA = lithium diisopropyl amide mCPBA = meta-chloroperbenzoic acid Me = methyl MeOH = methanol NMR = nuclear magnetic resonance 35 PCTLC = preparative centrifugal thin layer chromatography PEI = polyethylenimine -47 - WO 98/57641 PCT/US98/12673 Ph = phenyl pTSOH = p-toluenesulfonic acid RT = retention time TEBAC = benzytriethylanunonium chloride 5 TFA = trifluoroacetic acid THF = tetrahydrofuran TLC = thin layer chromatography TMS = trimethylsilyl TMSCN = trimethylsilylcyanide 10 The compounds of the present invention can be prepared readily according to the following reaction schemes and examples, or modifications thereof, using readily available starting materials, reagents and conventional synthesis procedures. In these reactions, it 15 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. Many of the compounds claimed within this invention can be assembled as outlined in a general fashion in Scheme 1. Reductive 20 amination of a hydroxy amino derivative with a cycloalkanone provides an intermediate which can be carried on via either of the two outlined methods; conversion of the hydroxy group to a halide or tosylate and displacement with an anionic equivalent of one of the Q groups. Alternatively, the hydroxy group can be manipulated into an amino 25 group and acylated or alkylated to supply the desired amide as urea linked analogs. An example of this approach is highlighted where the central portion of the antagonist is assembled from N-protected 3 hydroxy azetidine. Conversion of the hydroxy to a protected amino group 30 and deprotection of the azetidine nitrogen provided the appropriate amine for reductive amination with a cycloalkanone, which after deprotection was acylated with an activated Q species. This was accomplished with the 3-aminnomethyl azetidine linker in an analogous fashion. 35 Derivatives where the central molecular framework is a 4-amino piperidine were prepared from isonipecotic acid via the sequence outlined in Scheme 2. Isonipecotic acid was converted to 4 -48- WO 98/57641 PCT/US98/12673 (tert-butoxycarbonyl)amino piperidine in three chemical steps. Reductive amination with 4-cyano 4-phenyl cyclohexanone provided a separable mixture of cis and trans products, which after Boc deprotection and acylation provided the desired antagonists. 5 The 3-amino piperidinyl bridged compounds were assembled in analogous fashion starting from nipecotic acid, Scheme 3. The corresponding 3-amino pyrroldinyl analogs were obtained by substituting the commercially available 3-(tert-butoxycaronyl)amino pyrrolidine for the corresponding piperidinyl material as shown in 10 Scheme 4. Selective acylation of the primary amines was accomplished by treatment of the amines with nearly equimolar quantities of the activated termini species (i.e., the "Q" groups). The activated termini species comprising the "Q" groups are readily prepared by one of 15 ordinary skill in the art. For example, unsubstituted, alkyl- and cycloalkyl-substituted oxazolidinones are prepared and activated in general by published and well developed chemistry, in particular, of Evans. [Evans, D.A.; Nelson, J.V.; Taber, T.R. Top. Stereochem. 13, 1 (1982)] The starting materials, in general, are natural and unnatural 20 amino acids. For instance, some of the preferred compounds are prepared from substituted phenyl glycine derivatives, which after reduction of the carboxylate and a phosgene equivalent mediated cyclization provides the substituted oxazolidinone ring system. Deprotonation with n-butyl lithium and addition to a THF solution of p 25 nitrophenylchloroformate produces the stable, isolable "activated"oxazolidinone (oxa). Oxazolidinones substituted with carboxylate, carboxamide, and hydroxymethyl are prepared by hydroxyamination of olefins to provide protected aminoalcohols, using procedures as described in 30 Sharpless et al., Angew. Chem. Int. Ed. Engl., 35, 2813 (1996). Deprotection under standard conditions followed by a phosgene equivalent to mediate cyclization provides the substituted oxazolidinone ring system. Deprotonation with a strong base, for example, lithium bis(trimethylsilyl)amide, and addition to a THF solution of p 35 nitrophenylchloroformate produces the stable, isolatable "activated" oxazolidinone. -49- WO 98/57641 PCT/US98/12673 Dihydropyrimidinones are prepared by condensation reaction of the aldehyde, urea and a 1,3-acetoacetate type derivative catalyzed by a Lewis Acid, a copper (I) species and acetic acid. Activation was accomplished by treatment with a strong base, for 5 instance, LiN(TMS)2, followed by addition to a THF solution of p nitrophenylchloroformate. Hydantoins and cycloimide were prepared in two chemical steps from ketones as outlined in the literature. More specifically, hydantoins were prepared according to known methodology, e.g., J.J. 10 Edmunds et al., J. Med. Chem. 1995, 38, pp. 3759-3771; J.H. Poupart et al., J. Chem. Res. 1979, pp. 174-175. Saccharins were prepared according to known methods, e.g., page 40 and Examples 21 and 22 of PCT International Application Publication No. WO96/25934, published August 29, 1996. 15 The dihydropyrimidinones and the unsubstituted, alkyl and cycloalkyl-substituted oxazolidinones were synthesized independently in racemic form, and then separated utilizing preparative chiral HPLC. Their optical rotations were recorded. Then they were activated and reacted with prerequisite amines. From the receptor 20 binding studies, a preferred isomer was identified, the (+) rotational isomer in each case. The absolute configurations were determined to be (S) for both the dihydropyrimidinones and oxazolidinones by correlating their optical rotations with x-ray crystal structures obtained of fragments involved in the production of the antagonists. 25 The oxazolidinones substituted with carboxylate, carboxamide, and hydroxymethyl were prepared in enantiomer enriched form and the assignments of (4S,5R) were made in accordance with Sharpless et al., Angew. Chem. Int. Ed. Engl., 35, 2813 (1996) Antagonists with cycloalkyl linking chains can be 30 assembled by reductive amination of the prerequisite amino alcohol and a ketone, for example, N-(2-cyanophenyl)piperidin-4-one, Scheme 5. Conversion of the hydroxy to a tosylate with tosyl anhydride, followed by displacement by the sodium or lithium salt of the desired Q group completes the synthesis of the targeted antagonists. 35 Some of the required ketones were readily assembled following the sequence outlined in Scheme 6. For example, a substituted benzyl nitrile, sulphone, etc. could be added to methyl acrylate (or other -50 - WO 98/57641 PCT/US98/12673 substituted acrylates), submitted to Dieckman cyclization, hydrolyzed and decarboxylated providing appropriately substituted ketones. Further modifications of the ketones can be accomplished following the Dieckman cyclization, which provides the -keto ester which can be 5 either: (a) submitted to a reductive amination and carried on to final product, (b) enolized and alkylated then reductively aminated, deprotected and further manipulated providing further substituted analogs; or (c) hydrolyzed and decarboxylated and run through the above described conditions producing the desired antagonists. 10 Another strategy for the synthesis of some geminally disubstituted cyclic ketones, in particular, 4,4-disubstituted cyclohexanones was accomplished as outlined in Schemes 7A and 7B starting from benzophenone derivatives and substituted methyl vinyl ketones which under basic conditions lead to the 4,4-aryl cyclohex-2-en-1 15 ones in good yield. Subsequent hydrogenation, reductive amination and deprotection provided the appropriate acylation/alkylation precursors. Alternatively, the 4,4-diaryl cyclohex-2-en-l-ones could be subjected to Michael addition of selected nucleophiles, alkylation or aldolyzation of the enolate of the resulting ketone then reductively aminated and carried 20 through the standard chemical transformation to provide further elaborated antagonists. The synthesis of some additional compounds of the present invention is described in Schemes 8-17. Schemes 16-17 describe the synthesis of the 3-aminomethyl-3-hydroxyazetidine and the 4-amino-3 25 hydroxypyrrolidine intermediates. The 3-aminomethyl-3 hydroxyazetidine was assembled from the commercially available N protected 3-hydroxyl azetidine as outlined Scheme 16. Swern oxidation of the alcohol with dimethylsulfoxide and oxalyl chloride provided the azetidinone. The zinc iodide catalyzed addition of TMSCN produced the 30 cyanohydrin. Subsequent LAH reduction of the nitrile and two protecting group manipulations yielded the key intermediate required for the reductive aminations with the cyclohexanones. Deprotection-of the N-BOC carbamate and acyclation with preferred activated "Q" groups furnished the final targets. The synthesis of the 4-amino-3 35 hydroxypyrrolidine intermediate began with 3,4-pyrroline. BOC protection of the amine followed by mCPBA oxidation provided the epoxidation. Subsequent sodium azide opening of the epoxide and -51- WO 98/57641 PCT/US98/12673 triphenylphosphine/water mediated reduction produced 4-amino-N-1 (1,1-dimethylethoxycarbonyl)-3-hydroxypyrrolidine. After two protecting manipulations the key amino intermediate was alkylated by reductive amination reactions with cyclohexanones. Following the cleavage of the 5 CBZ protecting group acyclation with preferred activated "Q"-groups furnished the final targets. -52- WO 98/57641 PCT/US98/12673 Scheme 1 'Rm OH CN HN O CN (R20) (R2 ) 2R3 m o ( O AcOH/MeOH 0 N OH A NaCNBH 3 P CBr 4 PPhs PPh 3 1 ) Tos20 CN 2) NaN 3 n 3) PPh 3

/H

2 0

(R

2 0 )r m 4) 0 / 112 o N- Br LG Q' P (R 20 )r EDCI, HOBT H-Q CN CN R2~m o //20 1n o 1 ,0 NA (R20r R2 R m N Q, o Np Q (X)s P LG = leaving group, e.g., ' -N (X)Me COe N~ N COMe NX 0 N O O -53 -50 WO 98/57641 PCTIUS98/12673 Scheme 1 (cont'd) CN AcOH/MeOH C

(R

20 ) r 0aNH (R20) o(A 0HNC>NHBOC HBO i)Ts 2 OCN EtOAC 3) PPh 3 a/H 2 0 () 4)Boc2O NJ\ P h h>-N>0I-H 0 PhC N LG 0

(R

20 ) rO -54- WO 98/57641 PCT/US98/12673 Scheme 1 (cont'd) CN CN n AcOH/MeOH ON n (R20)r NaCNBH 3 (R 2)r o N o A O HN ' o N NHBOC NHBOC 1) LAH HC 2) Boc 2 0 EtOAc 3 H 2 /Pd-C EtOAc Ph -- CN CNN P h CN // n (R20)r o ('"" N N H 2 0 N

NH

2 CN. O n LG Q (R20)r 0 -55N -55 - WO 98/57641 PCT/US98/12673 SCHEME 2 Ti(OiPr) 4 CN NaCNBH 3 HCI CN MeOH EtOAc 0 HNN H O HN\CN NHBOC N NHBOC /NH 1) CBZCI 2) DPPA N

CO

2 H Et 3 N/tBuOH NHBOC 3) H 2 /Pd-C C lOCN F F CN CN FF N a 1) 3,4-F 2 PhCO 2 H N a NH 2 EDCI 1 2 HOBt C 2) HCI/EtOAc CN N NH 2 O 'N" O F L"AN H 2 -56- WO 98/57641 PCT/US98/12673 SCHEME 3 Ti(OiPr) 4 CN NaCNBH30 CN MeOH CNHBOC SHN CN EtOAc NH C H 1) CBZCI NHBOC 2) DPPA N NB

CO

2 H Et 3 N/tBuOH 3) H 2 /Pd-C F I CN

CO

2 Me ' F \ O e CN HFN N yN NH

NH

2 0 0 S15 3 CN N N H 2 e F O N

CO

2 Me F CNFM K,-J, N N N NH 0 0 0 15= O CO 2 Me 4 15 =N 0 2 N -57 - WO 98/57641 PCT/US98/12673 Scheme 3 (cont'd) CN HO F "a NH 2 F EDGI CN HOBt SNHF2 N F2N H F **N F 16 O ON 0 F 0 2 N - O 0 H N F O F 3Q 6 F8 H O NNN 0 0 7 F CN F t2111"N H 0 .N NO 0 0 8 -58 - WO 98/57641 PCT/US98/12673 SCHEME 4 Ti(OiPr)4 CN NaCNBH3 .. CN MeOH NHBOC %/NHBOC L HCI oN HNL NHBOC CN EtOAc ,,N , NHBOC CN F

CO

2 Me oF tI~~uIJ~ ~ NH tII~ L r NH NL~r 15 CN L N F

CO

2 Me F 1 ,/ NH2 N YN NH 10 -59- WO 98/57641 PCT/US98/12673 SCHEME 4 (Cont'd) CN

R

13 F N *'rNH 2 HO 13 CN NH 2 HO F R 3 =HoriPr "" jj r N2 0 EDCI, HOBt CN

R

13 F 16 F O CN 11 F H F ,, N N 0 0 13 -- F H 0

Y

~N

' 0 0 14 -60 - WO 98/57641 PCT/US98/12673 SCHEME 5 AcOH or Ti(OiPr) 4 CN CN NaCNBH 3 MeOH 1-2 (CH 2

)

0

-

2 0H 1-2 N O (C H2)0-20 H, HN 00-2 F 0-2 Tos20 F CN 1-2 HN N (CH 2

)

0

-

2 0Tos 0 F ) 0-2 N N F \ 1-2 N 0-2 N 0-2 0 -61- WO 98/57641 PCT/US98/12673 SCHEME 5 (cont'd) N I ON R13 R \ CN R14 O H, 1" 1-2 R Z N o N 0

-

2 Y

NR

8 R 0-2 Z R0 0-2 z

R

13 N H N 0 .- 2 N 14 NX 0-2 1-2 0( -, 6 2 N 0-2 N% - 062- WO 98/57641 PCT/US98/12673 SCHEME 6 For example, -uCO 2 Me R KOtBu R , / / CO2Me (R2)r Triton-B (R21)r- THF -, tBuOH THF or heteroaryl or heteroaryl

CO

2 Me R = CN, SO 2 alk, others R R AcOH 2 / CO 2 Me (R21 R) (R2)r (R1r Aq HCI r or heteroaryl O or heteroaryl A -63- WO 98/57641 PCT/US98/12673 SCHEME 7A II - \o o O - H 2 /Pd-C Base 0 HNJ -N NHP HN NHBOC AcOH/MeOH NaCNBH 3 P = BOC HCI P = H*HCI EtOAc FF 0 EDCI 'NJ" 7 N F H HO F HOBt -64- WO 98/57641 PCT/US98/12673 SCHEME 7B II \O 0

H

2 /Pd-C Base H 0 H 2 N -- N- NHBO C IH AcOH/MeOH NaCNBH 3 P = BOC HCI P = H*HCI EtOAc OFH 0 F HO F EON N F EDCI F H HOF HOBt S- 65 - WO 98/57641 PCT/US98/12673 Scheme 8 O LDA, PhN(SO 2 0F 3

)

2 0 O F 3 Cas O 0 (R21 ,ZnI

R

2 1 = H, CN, CO 2 Et, F, CF 3 , OMe, OR 6 ' THF Pd[P(Ph) 3

]

4

(R

21 ) O (R21)

H

2 , Pd/C EtOAc 1 N HCI 1. Dioxane HNG NHBOC 0 NaCNBH 3 N,) NH3

(R

21 )r THF, MeOH (Ri) r | 2. HCI(g), EtOAc -66 - WO 98/57641 PCT/US98/12673 SCHEME 8 (Cont'd)

N

2 1 ) N NH 3 CI (R21 )r 0 2 N O Q, o TEA, DMF H (R 21)r ,, (X)s (X)s N C0 2 Me N O~ OMe O O NJ H 0 -67 - WO 98/57641 PCT/US98/12673 Scheme 9 .0 _°> SLDA, PhN(SO 2

CF

3 ) 0 O THF,-78 0 C C 'O

(R

2 1 )r ZnI

R

2 1 = H, CN, CO 2 Et, F, CF 3 , OMe, OR 6 \ THF -N Pd[P(Ph) 3

]

4

(R

21 )r ( )r O1

H

2 , Pd/C EtOAc 1 N HCI Dioxane ( 1 r0O : NHBOC

(R

21 Nr 1 N) N NH 3 CI NaCNBH 3

(R

2 Nr THF, MeOH 2. HCI(g), EtOAc N -68 - WO 98/57641 PCT/US98/12673 SCHEME 9 (Cont'd)

(R

2 1 )r ND

NH

3 CI . TEA, DMF O 0 N 0 kN N 0 2 N O , H

(R

21 ) 1 (X)s (X)s CO 2M e N NN O, N OMe O0 H O - 69 - WO 98/57641 PCT/US98/12673 Scheme 10 (R21 (R 21)r O

(R

21 )r Br 1. n-BuLi, THF, -780C O 2. O OH

R

2 1 = H, CN, Me, OMe, j O

S

O 1 N HCI CF3, F, OR 6 Dioxane 0O O (R 2 1 )r

(R

2 1 )r O

H

2 , Pd/C r z EtOAc 1HN NHBOC NaCNBH 3 THF, MeOH O Q' 2. HCl(g), EtOAc 0

NII§\NH

3 CI 0 2 NN' N

(R

21 )r H TEA, DMF 21I (X)s (X)s (R 21 1 N CO 2 Me N ON NOMe Q' =I 1 K(OMe O O N H 0 -70 - WO 98/57641 PCT/US98/12673 Scheme 11 O Br 1. n-BuLi, THF, -78C O ,N 2. O-N OH CI O Dioxane O 1. NHBOC ' HN OH ,N NaCNBH 3 THF, MeOH N'I\ NHBoc NQ:

NH

3 CI HCI(g) OH OH N EtOAc N O TEA, DMF 0 2 N-- OJ-Q, o (X)s \ (X) N N H O OH

CO

2 Me O COMe 0 N O H 0 -71- WO 98/57641 PCT/US98/12673 Scheme 12

(R

2 1 )r O Br 1. n-BuLi, THF, -78C O I OOH

(R

2 1 )r 2O 1 N HCI O Dioxane I

.

O 0

(R

21 ) NHBOC OH NaCNBH 3 THF, MeOH rNDNH3CI N'7 NHBoc

(R

2 1 HCI(g) OH 1 OH EtOAc

(R

21 )r /0 ]TEA, DMF 0 2 N- O - Q, o (X (Xs Nr, N Q (R H)r OH IN CO 2 Me N 9J OMe 0 N O H 0 WO 98/57641 PCT/US98/12673 Scheme 13 HO OH O S Br 1. n-BuLi, THF, -78oC O R21 2. O0 R21 OH O

K

2

CO

3

R

21 = H, ON, Me, OMe, BnBr

CF

3 , F, OR 6 DMF 0 0 1 N HCI Dioxane 0

R

2 1

R

2 1

H

2 , Pd/C EtOAc 0 HO HN NHBOC N' NH 3 CI NaCNBH 3 HO

R

21 THF,MeOH \/ 2. HCI(g), EtOAc

R

21 - 73 - WO 98/57641 PCT/US98/12673 Scheme 13 (cont'd)

N'I

1 - NH 3 CI HO \ TEA, DMF O O R102N-- O , O'N N Q' HO H (X)s (X)s / R21 (x)\\ R C02Me

CO

2 Me O N /O H 7 •- 74 - WO 98/57641 PCT/US98/1 2673 Scheme 14 00 NnBr H 2 ,Pd (10%) Pd(PPh 3

)

4 , THE EtOH 0_ OTf .HrD--NHBoc mCPBA HCI, HOAc, H 2 0 INaCNBH 3 , MeOH

CHC

3 N0 2. chromatography 0 0_50 0 HCI(g); Na 2

CO

3 I sscINHBoc 0 0C ONH 2 F OJNAL N C 2 Me F 0"'N'Me 'N DMF N-kN C0 2 Me 0 lMe -75- WO 98/57641 PCT/US98/12673 Scheme 15 0 0 0 A'NH 0 0BnOCONH 2 r~ o H 0 H MeOH Me tBuOCINaOHMe F- H2SO4- F-f

(DHQ)

2 PHAL

K

2 OsO 2

(OH)

2 F NH2 O F

H

2 , Pd/C Me triphosge 02M LiHMDS E. e H triphosgene *4O2Me F 'Pr 2 NEt H p-NO 2 PhOCOCI O

O

2 Me 1 Pr 2 NEt NH2 ~,,,D .. NO¢sCO2Me FO FF

R

2 1 F R 2 1 CHC1 3

/NH

3 ' ,HiO2Me 4 02,N O 0 ,ONH 2 sii0 gel 00 O O 5 10 15 20 -76- WO 98/57641 PCT/US98/12673 Scheme 15 (cont'd) F F F F F F\ LiBH 4 2,3 dihydropyran H N CO 2 Me H N -OH CSA, CH 2

CI

2 HN HN '0 TI-N HNo dO}" F R21 LiHMDS 2 N F -NH2 p-NO 2 PhOCOCl O iPr 2 NEt F F R 2FR"F & _ mN -O pTsOH a - H ,,,NN ) ,N ' L' H N tO' MeOH O - 77 -77 - WO 98/57641 PCT/US98/12673 SCHEME 16 Ph Swern Ph TMSCN Ph N< Oxidatn Ph NZnl2 OH 0O Ph Ph LAH BOC20 Ph N C AICI3 Ph N NH2 CN OH OH Ph H2/Pd-C HNhNHBOC Ph N NHBOC EtOH NHBOC OH OH NaCNBH3 +/ CN AcOH,MeOH 0 1) HCI-EtOAc Final . Products CN 2) Activated Products IN (+)-DHP NHBOC or OH (S)-OXA -78- WO 98/57641 PCT/US98/12673 SCHEME 17 HN BOC20 BOCN mCPBA NaHCO3 BOCN a- NaN3 BOCN -OH PPh3 DMF H20 N3 BOCN -OH CBZCI BOCN -OH HCI NH2 NHCBZ EtOAc HN -OH NaCNBH3 NHCBZ CN AcOH, MeOH NHOBZ ONO 1) H2/Pd-C Final Q~. Products CN 2) Activated Products N -OH (+)-DHP or NHCBZ (S)-OXA - 79 - WO 98/57641 PCT/US98/12673 The following examples are provided to further define the invention without, however, limiting the invention to the particulars of these examples. 5 Examples 1-12 were prepared according to Schemes 8 and 9. EXAMPLE 1 (4S)-3-{ 1-[4-(2-Cyano-phenyl)-cyclohexyl]-(3R)-pyrrolidin-3-ylcarbamoyl} 4-(3,4-difluoro-phenyl)-6-methyoxymethyl-2-oxo-1,2,3,4-tetra 10 hydropyrimidine-5-carboxylic acid methyl ester hydrochloride F CN .,,, Na O0 F NA N H O / CO 2 Me H OMe *-HC1 Step A: Trifluoromethanesulfonic acid 1,4-dioxa-spiro[4.5]dec-7-en 8-yl ester 15 To a solution of diisopropylamine (7.6 mL, 54.3 mmol) in 200 mL THF cooled to -78 0 C was added n-butyllithium (21.8 mL 2.5 M in hexane, 54.3 mmol) under argon.The solution was stirred for 10 minutes, then a solution of 1,4-cyclohexanedione monoethylene ketal (8.5 g, 54.3 mmol) in 75 mL THF was added slowly. The solution was stirred 20 for 10 min, then a solution of N-phenyltrifluoromethane sulfonamide (19.5 g, 54.3 mmol) in 150 mL THF was added slowly. The reaction solution was warmed to r.t., poured onto saturated sodium bicarbonate, and extracted with ethyl acetate. The combined organic layers were washed with saturated sodium chloride, dried with magnesium sulfate, 25 and concentrated in vacuo. The crude material was passed through silica (3% methanol, dichloromethane) to give the product as an oil. H NMR 8H (CDC1 3 ) 5.7-5.6 (m, 1H), 4.1-4.0 (m, 4H), 2.6-2.5 (m, 2H), 2.5-2.4 (m, 2H), 1.9 (t, 2H, J 6.6). -80 - WO 98/57641 PCT/US98/12673 Step B: 2-(1,4-Dioxaspiro[4.5]dec-7-en-8-yl)benzonitrile To a solution of trifluoromethanesulfonic acid 1,4-dioxa spiro[4.5]dec-7-en-8-yl ester (12.5 g, 45.2 mmol) in THF (100 mL) at room 5 temperature was added a solution of iodozinc benzonitrile (100 mL of a 0.5 N solution in THF, 50 mmol) and palladium tetrakistriphenylphophine (1 g, 0.8 mmol). The reaction was heated to 80'C for 1 hour. The reaction was cooled to room temperature and poured into saturated sodium bicarbonate (1L), and extracted with ethyl 10 acetate. The combined organic layers were washed with saturated sodium chloride, dried with magnesium sulfate, and concentrated in vacuo. The crude material was chromatographed over silica gel eluting with 25% ethylacetate/hexane to give the product as a pale yellow oil. H NMR 8 H (CDC1 3 ) 7.7-7.6 (m, 1H), 7.52 (dt, 1H, J = 2, 7 15 Hz),7.4-7.26 (m, 2H), 5.95-5.88 (m, 1H), 4.05-4.0 (m, 4H), 2.7-2.6 (m, 2H), 2.55-2.48 (m, 2H), 1.95 (t, 2H, J = 6.6 Hz). Step C: 2-(1,4-Dioxaspiro[4.5]dec -8-yl)benzonitrile 20 To a suspension of 10% palladium on carbon (1.5g) in ethyl acetate (200mL) at room temperature under argon was added a solutioin of 2-(1,4-Dioxaspiro[4.5]dec-7-en-8-yl)benzonitrile (8.9 g, 36.7 mmol) in ethyl acetate (50 mL). Hydrogen gas was then bubbled into the reaction mixture until all the starting material was consumed. The reaction was 25 filtered through celite to remove the catalyst and the solution concentrated to give the product as a colorless oil. H NMR 8 H (CDC1 3 ) 7.65-7.6 (m, 1H), 7.54 (dt, 1H, J = 2, 7 Hz),7.46 (br d, 2H, J = 7 Hz), 7.28 (dt, 1H, J = 2, 7 Hz), 4.05-4.0 (m, 4H), 3.1 3.0 (m, 1H), 2.0-1.7 (m, 8H) 30 Step D: 2-(4-Oxocyclohexyl)benzonitrile To a stirring solution of 2-(1,4-Dioxaspiro[4.5]dec -8 yl)benzonitrile (8.7 g, 35.7 mmol) in dioxane (200 mL) was added 1N HC1 35 (200 mL) and the reaction heated to 80'C for 2 hours. The reaction was cooled to room temperature and poured into water (1 L) the mixture was -81- WO 98/57641 PCT/US98/12673 extracted with ethyl acetate (3 X 250 mL). The combined organics were washed with brine (200 mL) and then dried over anhydrous magnesium sulfate, filtered and concentrated at reduced pressure to give the product. 5 1H NMR 8H (CDC13) 7.65-7.6 (br d, 1H, J = 7 Hz), 7.59 (br t, 1H, J = 7 Hz),7.40-7.30 (m, 2H), 3.5 (tt, 1H, J = 3, 10 Hz), 2.7-2.5 (m, 4H), 2.35-2.2 (m, 2H), ), 2.05-1.90 (m, 2H) Step E: cis and trans 2-[4-(3R-3-Amino-pyrrolidin-1-yl)-cyclohexyl] 10 benzonitrile dihydrochloride To a solution of 2-(4-Oxocyclohexyl)benzonitrile (0.921 g, 4.63 mmol) and acetic acid (1.0 mL 17.5 mmol) in 30 mL methanol was addded (3R)-(+)-3-(tert-butoxycarbonylamino)-pyrrolidine (1.29g, 6.95 15 mmol) under argon. The solution was stirred for 2h, then sodium cyanoborohydride (6.95 mL 1M in THF, 6.95 mmol) was added dropwise. The solution was poured onto saturated sodium bicarbonate, and extracted with ethylacetate. The combined organic layers were washed with saturated sodium chloride, dried with magnesium sulfate, and 20 concentrated in vacuo. The crude material was passed through silica (5% methanol, ethylactate) to give 2:1 trans:cis 2-[4-(3 tertbutoxycarbonylamino-pyrrolidin-1-yl)-cyclohexyl]-benzonitrile. The trans-2-[4-(3-tertbutoxycarbonylamino-pyrrolidin-1-yl)-cyclohexyl] benzonitrile (1.1 g, 2.98mmol) was dissolved in 100 mL ethylacetate, and 25 HC1 gas was bubbled through the solution for 30 min. The solution was concentrated in vacuo to give the trans product. 1H NMR 8 H (CDC1 3 ) 7.75-7.60 (m, 2H), 7.55-7.45 (m, 1H), 7.40-7.35 (m, 1H), 4.20-3.20 (m, 7H), 3.15-3.00 (m, 2H), 2.80-2.50 (m, 1H), 2.40-2.00 (m, 5H), 1.90-1.60 (m, 4H). 30 The cis-2- [4- (3-tert -butoxycarbonylamino-pyrrolidin-1-yl) cyclohexyl]- benzonitrile (0.60 g, 1.6 mmol) was dissolved in 100 mL ethylacetate, and HC1 gas was bubbled through the solution for 30 min. The solution was concentrated in vacuo, swished with hot ethyl acetate, and filtered to give the cis product - 82 - WO 98/57641 PCT/US98/12673 H NMR H (CDC1 3 ) 8.00-7.90 (m, 1H), 7.70-7.60 (m, 2H), 3.40-3.30 (m, 1H), 4.30-3.80 (m, 6H), 3.70-3.10 (m, 3H), 2.85-2.70 (m, 1H), 2.55-1.75 (m, 9H). 5 Step F: 3- 1-[4-(2-Cyano-phenyl)-cyclohexyl]-3R-pyrrolidin-3 ylcarbamoyl]-4-(3,4-difluoro-phenyl)-6-methoxymethyl-2 oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid methyl ester hydrochloride 10 To a solution of trans-2-[4-(3R-3-Amino-pyrrolidin-1l-yl) cyclohexyl]-benzonitrile dihydrochloride (300 mg, 0.880 mmol) and triethylamine (0.37 mL, 2.64 mmol) in 3.0 mL DMF was added (+)-3-(4 nitrophenoxycarbonyl)-4-(3,4-difluorophenyl)-6-methoxymethyl-2-oxo 1,2,3,4-tetrahydropyrimidine-5-carboxylic acid methyl ester (462 mg, 15 0.968 mmol) under argon. The solution was stirred for 2 hour, poured onto saturated sodium bicarbonate, and extracted with ethylacetate. The combined organic layers were washed with saturated sodium chloride, dried with magnesium sulfate, and concentrated in vacuo. The crude material was passed through silica (3% methanol, dichloromethane) 20 and washed with sodium carbonate. To a solution of the free base in ethylacetate was added excess hydrogen chloride (1M in diethylether). This solution was concentrated in vacuo to give the product. Anal. Calcd. for C 32

H

35

F

2

N

5 0 5 sHC1: C, 59.67; H, 5.63; N, 10.87. Found: C, 60.10; H, 5.13; N, 11.16%. 25 The following compounds were prepared by procedures substantially as described above for step F from either the cis or trans product of step E. In the case of Examples 3 and 4, the (+)-(S)-3-(4 nitrophenoxycarbonyl)-4-(3,4-difluorophenyl)-oxazolidin-2-one was 30 substituted for the (+)-3-(4-nitrophenoxycarbonyl)-4-(3,4-difluorophenyl) 6-methoxymethyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid methyl ester -83 - WO 98/57641 PCT/US98/12673 EXAMPLE 2 (4S)-cis-3- { 1-[4-(2-Cyano-phenyl)-cyclohexyl]-(3R)-pyrrolidin-3 ylcarbamoyl}-4-(3,4-difluoro-phenyl)-6-methyoxymethyl-2-oxo-1,2,3,4 tetrahydropyrimidine-5-carboxylic acid methyl ester hydrochloride F CN NN F N N N H /. C02Me N 5 H OMe *HCI Analysis: Calcd. for C 3 2

H

3 5

F

2

N

5 0 5 * HC1 * 0.4 H 2 0 C, 59.01; H, 5.70; N,10.75 Found: C, 59.04; H, 5.65; N,10.47 10 EXAMPLE 3 trans-4S-4-(3,4-Difluorophenyl)-2-oxooxazolidine-3-carboxylic acid- {1-[4 (2-Cyano-phenyl)-cyclohexyl]-3R-pyrrolidin-3-yl}amide hydrochloride F CN - N' H NF O O * HC1 Analysis: Calcd. for C 2 7

H

28

F

2

N

4 0 3 * HC1 * 0.2 H 2 0 * 0.25 EtOAc 15 C, 60.41; H, 5.69; N,10.07 Found: C, 60.42; H, 5.62; N,10.10 EXAMPLE 4 - (4S)-cis-4-(3,4-Difluorophenyl)-2-oxooxazolidine-3-carboxylic acid-{1-[4-(2 20 Cyano-phenyl)-cyclohexyl]-(3R)--pyrrolidin-3-yl} amide hydrochloride -84- WO 98/57641 PCT/US98/12673 F CN 6-N NO / H N O O HCI Analysis: Calcd. for C 2 7

H

28

F

2

N

4 0 3 * HC1 * 0.1 H 2 0 * 0.95 EtOAc C, 60.00; H, 6.02; N,9.09 Found: C, 60.02; H, 5.75; N,9.06 5 The following Examples were prepared by procedures substantialy as described above for Examples 1-4 except substituting the appropriate halozine reagent (purchased from RIEKE Chemical) in step B. 10 EXAMPLE 5 (4S)-trans-4-(3,4-Difluoro-phenyl)-3-{1-[4-(2-ethoxycarbonyl-phenyl) cyclohexyl]-(3R)-pyrrolidin-3-ylcarbamoyl}-6-methoxymethyl-2-oxo 1,2,3,4-tetrahydropyrimidine-5-carboxylic acid methyl ester 15 hydrochloride F C ), NN

-

F N CO2Et O

CO

2 Me H OMe *HC1 Analysis: Calcd. for C 34

H

4 0

F

2

N

4 0 5 * HCl * 0.75 H 2 0 * 0.05 EtOAc C, 58.01; H, 5.96; N,7.91 Found: C, 57.89; H, 5.99; N,8.31 20 EXAMPLE 6 (4S)-cis-4-(3,4-Difluoro-phenyl)-3-{1-[4-(2-ethoxycarbonyl-phenyl) cyclohexyl]-(3R)--pyrrolidin-3-ylcarbamoyl}-6-methoxymethyl-2-oxo -85

-

WO 98/57641 PCT/US98/12673 1,2,3,4-tetrahydropyrimidine-5-carboxylic acid methyl ester hydrochloride F / \ N- O F C- 2 Et H N O= / CO 2 Me H OMe * HC1 Analysis: Caled. for C 34

H

40

F

2

N

4 0 5 * HC1 * 0.75 H20 * 0.05 EtOAc 5 C, 57.20; H, 6.16; N,7.80 Found: C, 57.21; H, 6.00; N,8.46 EXAMPLE 7 (4S)-trans-4-(3,4-Difluorophenyl)-2-oxo-oxazolidine-3-carboxylic acid-{1 10 [4-(2-ethoxycarbonylphenyl)-cyclohexyl]-(3R)-pyrrolidin-3-yl}lamide hydrochloride F 0- Na0

CO

2 Et H N S O* HCI Analysis: Calcd. for C 29

H

33

F

2

N

3 0 5 * HC1 * 0.15 H 2 0 * 0.05 EtOAc C, 59.93; H, 5.98; N,7.18 15 Found: C, 59.94; H, 5.78; N,7.52 EXAMPLE 8 (4S)-cis-4-(3,4-Difluorophenyl)-2-oxooxazolidine-3-carboxylic acid-{1-1-4-(2 ethoxycarbonylphenyl)-cyclohexyl]-(3R)-pyrrolidin-3-yl}amide 20 hydrochloride -86- WO 98/57641 PCT/US98/12673 F /\ NO / F - N"

CO

2 Et H o O * HCI Analysis: Calcd. for C 29

H

33

F

2

N

3 0 5 * HC1 * 0.85 H 2 0 * 0.05 EtOAc C, 58.67; H, 6.09; N,7.03 Found: C, 58.63; H, 5.86; N,7.05 5 EXAMPLE 9 (4S)-trans-4-(3,4-Difluorophenyl)-3-[ 1-(4-pyridin-2-yl-cyclohexyl)-(3R) pyrrolidin-3-ylcarbamoyl]-6-methoxymethyl-2-oxo-1,2,3,4-tetrahydro pyrimidine-5-carboxylic acid methyl ester F Na 0 F N.,& N A F HN O4 / CO 2 Me 10 H OMe *HCI Analysis: Calcd. for C3 0

H

35

F

2

N

5 0 5 * HC1 * 0.45 H 2 0 * 0.2 EtOAc C, 57.28; H, 6.01; N,10.84 Found: C, 57.25; H, 5.73; N,10.85 15 EXAMPLE 10 (4S)-cis-4-(3,4-Difluorophenyl)-3-[ 1-(4-pyridin-2-yl-cyclohexyl)-(3R) pyrrolidin-3-ylcarbamoyl]-6-methoxymethyl-2-oxo-1,2,3,4-tetrahydro pyrimidine-5-carboxylic acid methyl ester -87 - WO 98/57641 PCT/US98/12673 F Na 0 F NN N ON HO C0 2 Me N H OMe *HCI Analysis: Calcd. for C 30

H

3 5

F

2

N

5 0 5 * HC1 * 0.35 EtOAc C, 57.93; H, 6.01; N,10.76 Found: C, 58.17; H, 5.80; N,10.73 5 EXAMPLE 11 (4S)-trans-4-(3,4-Difluorophenyl)-2-oxo-oxazolidine-3-carboxylic acid-[1 (4-pyridin-2-yl-cyclohexyl)-(3R)-pyrrolidin-3-yl]amide hydrochloride F ..... N

HNN

O O * HCI 10 Analysis: Caled. for C 25

H

28

F

2

N

4 0 3 * HC1 * 2.5 H20 * 0.05 EtOAc C, 51.05; H, 6.02; N,9.45 Found: C, 50.90; H, 5.30; N,9.40 EXAMPLE 12 15 (4S)-cis-4-(3,4-Difluorophenyl)-2-oxooxazolidine-3-carboxylic acid-[1-(4 pyridin-2-yl-cyclohexyl)-(3R)-pyrrolidin-3-yl] amide hydrochloride F Na 0 F C N N O '/F H N O<O * HCI - 88- WO 98/57641 PCT/US98/12673 Analysis: Calcd. for C 25

H

28

F

2

N

4 0 3 * HC1 * 1.65 H20 * 0.1 EtOAc C, 55.92; H, 6.12; N,10.27 Found: C, 55.92; H, 5.85; N,10.22 5 Examples 13 - 17 were prepared according to Scheme 10. EXAMPLE 13 (4S)-trans-4-(3,4-Difluorophenyl)-6-methoxymethyl-3-{1-[4-(2-methoxyl phenyl)-cyclohexyl]-(3R)-pyrrolidin-3-ylcarbamoyl}- 2 -oxo-1,2,3,4 10 tetrahydro-pyrimidine-5-carboxylic acid methyl ester hydrochloride F OMe ..... ) N0F N N H O / CO 2 Me N H OMe *HC1 Step A: 8-(2-Methoxy-phenyl)-1,4-dioxa-spiro[4.5]decan-8-ol To a solution of 2-Bromoanisole (1.87g, 10.0 mmol) in 10 mL 15 THF under Argon was added n-butyllithium (4.0 mL 2.5M in hexane, 10.0 mmol) cooled to -78 0 C. The solution was stirred 10 min. at -780 C, and a solution of 1,4-Cyclohexanedione mono-ethylene ketal (1.56g, 10.0 mmol) in 10 mL THF was added slowly. The solution was warmed to r.t. and stirred for 60 min., then poured onto saturated sodium bicarbonate 20 and extracted with ethylacetate. The combined organic layers were washed with saturated sodium chloride, dried with magnesium sulfate, and concentrated in vacuo. The crude solid was crystallized with hexane/diethylether 2:1 to give 8-(2-Methoxy-phenyl)-1,4-dioxa spiro[4.5]decan-8-ol as a white solid. 25 H NMR 8H (CDC13) 7.4-7.2 (m, 2H), 7.0-6.9 (m, 2H), 4.1-3.9 (m, 4H), 3.9 (s, 3H), 2.3-2.0 (m, 6H), 1.7-1.6 (m, 2H). Step B: 4- (2-Methoxy-phenyl)-cyclohex-3-enone and 4-(2-Methoxy phenyl)-cyclohex-2-enone -89- WO 98/57641 PCT/US98/12673 To a solution of 8-(2-Methoxy-phenyl)-1,4-dioxa spiro[4.5]decan-8-ol (100mg, 0.379 mmol) in 10 mL THF was added HC1 (1.4 mL 6M, 8.4 mmol). The solution was heated to 80 0 C for 45 min, then 5 poured onto saturated sodium bicarbonate and extracted with ethylacetate. The combined organic layers were washed with saturated sodium chloride, dried with magnesium sulfate, and concentrated in vacuo. The crude material was passed through silica (dichloromethane/ 3% methanol as eluent) to give 4-(2-Methoxy-phenyl)-cyclohex-3-enone 10 1 H NMR 5 H (CDC1 3 ) 7.3-7.1 (m, 2H), 7.0-6.9 (m, 2H), 5.9-5.8 (m, 1H), 3.9-3.8 (s, 3H), 3.1-3.0 (m, 2H), 2.9-2.8 (m, 2H), 2.7-2.5 (m, 2H) and 4-(2-Methoxy-phenyl)-cyclohex-2-enone. 1H NMR 6 H (CDC1 3 ) 7.3-7.2 (m, 1H), 7.2-7.1 (m, 1H), 7.0-6.9 (m, 3H), 6.2-6.1 (m, 1H), 4.2-4.1 (m, 1H), 3.8 (s, 3H), 2.6-2.4 (m, 2H), 2.4 15 2.2 (m, 1H), 2.1-1.9 (m, 1H). Step C: 4- (2-Methoxy-phenyl)-cyclohexanone To a suspension of palladium on carbon (3.75 g, 25% wt) in 20 200 mL ethylacetate was added a 1:2 mixture of 4-(2-Methoxy-phenyl) cyclohex-3-enone and 4-(2-Methoxy-phenyl)-cyclohex-2-enone (15 g, 75.0 mmol) under argon. The suspension was stirred under a hydrogen at 1 atm. for 6.5 h, filtered through celite,concentrated in vacuo, and crystallized from ethylacetate to give 4- (2-Methoxy-phenyl) 25 cyclohexanone. H NMR 6 H (CDC1 3 ) 7.3-7.1 (m, 2H), 7.0-6.9 (m, 2H), 3.88 (s, 1H), 3.6-3.4(m, 1H), 2.6-2.4 (m, 4H), 2.3-2.2 (m, 2H), 2.0-1.8 (m, 2H). The title compound of Example 13 was prepared from the 30 product of step C by procedures identical to that described above for EXAMPLE 1 Steps E + F. trans-4-(3,4-Difluoro-phenyl)-6-methoxymethyl-3-{1-[4-(2-methoxyl phenyl)-cyclohexyl]-3R-pyrrolidin-3-ylcarbamoyl)-2-oxo-1,2,3,4 35 tetrahydro-pyrimidine-5-carboxylic acid methyl ester hydrochloride -90- WO 98/57641 PCT/US98/12673 Analysis Calcd. for C 32

H

38

F

2

N

4 0 6 * HC1 * 0.45 H 2 0 C, 58.56; H, 5.98; N, 8.54 Found: C, 58.55; H, 6.59; N, 8.15 5 The following Examples were prepared from the product of step C above by procedures substantially as described above for Example 1 steps E + F. EXAMPLE 14 10 (4S)-cis-4-(3,4-Difluoro-phenyl)-6-methoxymethyl-3-{1-[4-(2-methoxyl phenyl)-cyclohexyl]-(3R)-pyrrolidin-3-ylcarbamoyl}-2-oxo-1,2,3,4 tetrahydro-pyrimidine-5-carboxylic acid methyl ester hydrochloride F F 0

CO

2 Me OMe HOMe H * HC1 Analysis: Calcd. for C3 2 H38F 2

N

4 0 6 * HC1 * 0.7 H 2 0 15 C, 57.96; H, 6.25; N, 8.19 Found: C, 58.66; H, 6.05; N, 8.19 EXAMPLE 15 (4S)-trans-4-(3,4-Difluorophenyl)-2-oxooxazolidine-3-carboxylic acid-{1-[4 20 (2-methoxyphenyl)-cyclohexyl]-(3R)-pyrrolidin-3-yl}amide hydrochloride - 91 - WO 98/57641 PCT/US98/12673 F F I N N N OM H -O 0 HCI Analysis: Calcd. for C 32 H38F 2

N

4 0 6 * HC1 * 0.7 H 2 0 * 0.25 EtOAc C, 60.42; H, 5.69; N,10.07 Found: C, 60.42; H, 5.62; N,10.10 5 EXAMPLE 16 (4S)-cis-4-(3,4-Difluorophenyl)-2-oxooxazolidine-3-carboxylic acid-{1-[4-(2 methoxyphenyl)-cyclohexyl]-(3R)-pyrrolidin-3-yl}amide hydrochloride F F NQ) N N OMe H O \ 0 * HC1 10 Analysis: Calcd. for C 32

H

3 8

F

2

N

4 0 6 * HC1 * 0.1 H 2 0 * 0.95 EtOAc C, 60.00; H, 6.02; N,9.09 Found: C, 60.02; H, 5.75; N,9.06 Examples 17 - 20 prepared according to Scheme 11. 15 -92- WO 98/57641 PCT/US98/12673 EXAMPLE 17 (4S)-cis-4-(3,4-Difluoro-phenyl) -3-[ 1-(4-hydroxy-4-pyridin-2-yl-cyclohexyl) (3R)-pyrrolidin-3-ylcarbamoyl]-6-methoxymethyl -2-oxo-1,2,3,4 tetrahydro-pyrimidine-5-carboxylic acid methyl ester hydrochloride F H / F OK / C N 5 H OMe *HC1 Step A: 8-(2-Pyridyl)-1,4-dioxaspiro[4,5]decan-8-ol To a solution of 2-bromo-pyridine (10 g, 63. 3mmol) in tetrahydrofuran (200 mL) at -78 oC under an argon atmosphere was 10 added a solution of n-butyllithium ( 26 mL of 2.5N solution, 65 mmol). The solution was stirred at -78oC for 10 minutes and then a solution of cyclohexanedione monoethylene ketal ( 10 g, 64 mmol) in tetrahydrofuran(50 mL) was added. The reaction was allowed to warm to room temperature and poured into a saturated solution of sodium 15 bicarbonate (mL) the mixture was extracted with ethyl acetate. The combined ethyl acetate fractions were dried over anhydrous sodium sulfate, filtered, and concentrated at reduced pressure. The residue was chromatographed over silica gel eluting with 25% to 50% ethyl acetate/hexane to give the product. 20 1 H NMR (CDC13, 300 MHz) 8 8.5 (m, 1H), 7.69 (dt, J = 2, 7.5 Hz, 1H), 7.40 (dt, J = 7.5, 1 Hz, 1H), 7.2 (ddd, J = 1.5, 4.5, 7 Hz, 1H), 5.25 (s, 1H ex), 4.0 (m, 4H), 2.3-2.0 (m, 4H), 1.8-1.65 (m, 4H).. Step B: 4-Hydroxy-4-(2-pyridyl)-cyclohexanone 25 A solution of the product of step A (8-(2-pyridyl)-1,4 dioxaspiro[4,5]decan-8-ol) ( 8.3 g, 35.5 mmol) in dioxane (150 mL) was treated with 6 N HC1 ( 60 mL) and stirred at room temperature for 0.5 hr. The reaction was carefully poured into cold saturated sodium - 93 - WO 98/57641 PCT/US98/12673 bicarbonate (1 L). The mixture was extracted with ethyl acetate (3 X 200 mL) and the combined extracts were dried over anhydrous sodium sulfate, filtered, and concentrated at reduced pressure to give 5.3 g of the product. 5 1H NMR (CDC13, 300 MHz) 8 8.6 (br d, 1H), 7.8-7.7 (m, 1H), 7.35 (d, J = 5 Hz, 1H), 7.3-7.25 (m, 1H), 5.52 (s, 1H ex), 3.2-2.95 (m, 2H), 2.48-2.35 (m, 2H). 2.35-2.20 (m, 2H). 2.1-2.0 (m, 2H). The title compound of Example 17 was prepared from the 10 product of step B by procedures identical to those described above for EXAMPLE 1 Steps E + F Analysis Calcd. for C 3 0

H

3 5

F

2

N

5 0 6 * HC1 * 0.1 H 2 0 C, 58.94; H, 5.99; N,11.46 15 Found: C, 58.59; H, 5.59; N,11.24 The following Examples were prepared from the product of step B above by procedures substantially as described above for Example 1 steps E + F. 20 EXAMPLE 18 (4S)-trans-4-(3,4-Difluoro-phenyl) -3-[ 1-(4-hydroxy-4-pyridin-2-yl cyclohexyl)-(3R)--pyrrolidin-3-ylcarbamoyl]-6-methoxymethyl -2-oxo 1,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid methyl ester 25 hydrochloride F HO N N F NN N OH/

CO

2 Me N H OMe *HC1 Analysis: Calcd. for C 3 oH 3 5

F

2

N

5 0 6 * HCI * 0.55 H 2 0 * 0.1CH 2

CI

2 C, 58.87; H, 5.83; N,11.39 Found: C, 58.88; H, 5.68; N,11.25 -94- WO 98/57641 PCT/US98/12673 EXAMPLE 19 (4S)-cis-4-(3,4-Difluorophenyl)-2-oxooxazolidine-3-carboxylic acid-[1-(4 hydroxy-4-pyridin-2-yl-cyclohexyl)-(3R)--pyrrolidin-3-yl] amide 5 hydrochloride F HO N N O F HN O 0 * 2 HC1 Analysis: Calcd. for C 25

H

2 8

F

2

N

5 0 4 * 2 HC1 * 0.05 H 2 0 * 0.25 EtOAc C, 53.62; H, 5.56; N,9.62 Found: C, 54.30; H, 5.66; N,9.60 10 EXAMPLE 20 (4S)-trans-4-(3,4-Difluorophenyl)-2-oxooxazolidine-3-carboxylic acid-[1-(4 hydroxy-4-pyridin-2-yl-cyclohexyl)-(3R)-pyrrolidin-3-yl]amide hydrochloride F HO N N N N-/ 15 O O 2 HCI Analysis: Calcd. for C 25

H

28

F

2

N

5 0 4 * 2 HC1 * 0.3 H 2 0 * 0.25 EtOAc C, 53.21; H, 5.60; N,9.55 Found: C, 54.18; H, 5.57; N,9.29 20 Examples 21 - 24 were prepared according to Scheme 13. -95 - WO 98/57641 PCT/US98/12673 EXAMPLE 21 (4S)-4-(3,4-Difluoro-phenyl)-3-{ 1-[4-(2-hydroxy-phenyl)-cyclohexyl]-(3R) pyrrolidin-3-ylcarbamoyl)-6-methoxymethyl-2-oxo-1,2,3,4-tetrahydro pyrimidine-5-carboxylic acid methyl ester 5 F F .. ,Na N /, F OH O / CO 2 Me N H OMe Step A: 8-(2-Benxyloxy-phenyl)-1,4-dioxa-spiro[4.5]decan-8-ol 10 To a solution of 8-(2-Hydroxy-phenyl)-1,4-dioxa spiro[4.5]decan-8-ol (2.0g, 7.9 mmol) in 10 mL DMF was added potassium carbonate (3.91g, 28.3 mmol) and benzyl bromide (1.35g, 1.9 mmol) under argon. The suspension was stirred for 1.5 h, poured onto 10% potassium hydrogen sulfate, and extracted with ethylacetate. The 15 combined organic layers were washed with saturated sodium chloride, dried with magnesium sulfate, and concentrated in vacuo to give the product (2.76g, 100%). 1H NMR 8H (CDC1 3 ) 8.02 (bs,1H), 7.45-7.35 (m, 2H), 7.25-7.20 (m, 2H), 7.05-6.95 (m, 1H), 5.18 (s, 2H), 4.00-3.90 (m, 4H), 2.20-2.10 (m, 20 4H), 1.70-1.60 (m, 4H). Step B: 4-(2-Benzyloxy-phenyl)-4-hydroxy-cyclohexanone To a solution of of 8-(2-Hydroxy-phenyl)-1,4-dioxa 25 spiro[4.5]decan-8-ol (2.76 g, 8.12 mmol) in 70 mL 1,4-dioxane was added aqueous hydrogen chloride (40.6 mL 1M, 40.6 mmol). The solution was stirred for 30 min., poured onto saturated sodium bicarbonate, and extracted with ethylacetate. The combined organic layers were washed -96- WO 98/57641 PCT/US98/12673 with saturated sodium chloride, dried with magnesium sulfate, and concentrated in vacuo to give the product (1.96 g, 82%). 1H NMR8H (CDC1 3 ) 7.35-7.25 (M, 2H), 7.10-7.00 (m, 2H), 5.20 (s, 2H), 4.44 (s, 1H), 3.00-2.85 (m, 2H), 2.55-2.40 (m, 2H), 2.35-2.15 (m, 4H). 5 Step C: 4-(2-Benzyloxy-phenyl)-cyclohex-3-enone and 4-(2-Benzyloxy phenyl)-cyclohex-2-enone To a solution of 4-(2-Benzyloxy-phenyl)-4-hydroxy 10 cyclohexanone (1.9 g, 6.42 mmol) in 70 mL benzene was added p toluenesulfonic acid monohydrate (0.070 g, 0.368 mmol). The solution was warmed to 60 0 C, stirred for 1 h, then poured onto saturated sodium bicarbonate, and extracted with ethylacetate. The combined organic layers were washed with saturated sodium chloride, dried with 15 magnesium sulfate, and concentrated in vacuo to give a mixture of enone products (1.7 g, 100%). 1H NMR 8H (CDC13) 7.45-7.20 (m, 7H), 7.00-6.90 (m, 2H), 5.83 (s, 1H), 5.13 (s, 2H), 3.03 (bs, 2H), 2.83 (bt, 2H, J 6.35 Hz), 2.52 (bt, 2H, J 6.83). 20 Step D: 4-(2-Hydroxy-phenyl)-cyclohexanone To a solution of a mixture of 4-(2-Benzyloxy-phenyl) cyclohex-3-enone and 4-(2-Benzyloxy-phenyl)-cyclohex-2-enone (1.7 g, 25 6.12 mmol) in 25 mL ethylacetate under argon was added 10% palladium on carbon (0.425 g, 25 wt. %). The suspension was stirred under hydrogen at 1 atm. for 24 h, filtered through celite, and concentrated in vacuo to give the product (1.13 g, 97%). 1 H NMR 8 H (CDCl 3 ) 7.20-7.05 (m, 2H), 6.92 (t, 1H, J 7.56 Hz), 30 6.75 (d, 1H, J 8.06 Hz), 3.35-3.45 (m, 1H), 2.65-2.45 (m, 4H), 2.30-2.20 (m, 2H), 2.0- 1,85 (m, 2H). The title compound of Example 21 was prepared from the product of step D by procedures identical to that described in EXAMPLE 35 1 StepsE + F -97- WO 98/57641 PCT/US98/12673 Analysis Calcd. for C 3 1

H

36

F

2

N

5 0 6 0.9 H 2 0 * 0.4 CH 2 Cl 2 C, 58.12; H, 6.00; N, 8.64 Found: C, 58.21; H, 5.72; N, 8.66 5 The following examples were prepared from the product of step D above by procedures substantially as described above for Example 1 steps E + F. 10 EXAMPLE 22 (4S)-cis-4-(3,4-Difluoro-phenyl)-6-methoxymethyl-3-{ 1-[4-(2-hydroxy phenyl)-cyclohexyl]-(3R)--pyrrolidin-3-ylcarbamoyl}-2-oxo-1,2,3,4 tetrahydro-pyrimidine-5-carboxylic acid methyl ester F /\N O a NAN oF OH H C2 N H -- OMe 15 Analysis: Calcd. for C 31 H36F 2

N

5 0 6 * 0.4 H 2 0 * 0.1 CH 2 C1 2 C, 61.00; H, 5.76; N, 9.15 Found: C, 61.01; H, 5.77; N, 8.91 EXAMPLE 23 20 (4S)-trans-4-(3,4-Difluorophenyl)-2-oxooxazolidine-3-carboxylic acid-{1-[4 (2-hydroxyphenyl)-cyclohexyl]-(3R)--pyrrolidin-3-yl}amide F 0- Na0 N/ \ F OH H N O~O Analysis: Calcd. for C 26

H

29

F

2 N30 4 * 0.5 H 2 0 * 0.2 CH 2 Cl 2 -98- WO 98/57641 PCT/US98/12673 C, 61.50; H, 5.99; N, 8.22 Found: C, 61.42; H, 5.76; N, 8.32 EXAMPLE 24 5 (4S)-cis-4-(3,4-Difluorophenyl)-2-oxooxazolidine-3-carboxylic acid- {1-[4-(2 hydroxyphenyl)-cyclohexyl]-(3R)--pyrrolidin-3-yl}amide F N 0 / F - N' OH H N OO Analysis: Calcd. for C 26

H

29

F

2

N

3 0 4 * 0.3 H 2 0 * 0.15 CH 2 C1 2 C, 62.35; H, 5.98; N, 8.34 10 Found: C, 62.73; H, 5.81; N, 8.30 Utilizing the methodology described in detail herein, the following additional compounds shown in Tables 1-3 were prepared. -99- WO 98/57641 PCTIUS98/12673 ~~0 -- CD. co 0 C)) II a.-N -0000 ~CYN LA( ZI -100 WO 98/5764 1 PCT/US9/12673 o =o N-1 00 o o Qq 00 LACIA CD C -4 -A 0 0

-

-3 ;Q0 0 f-P

L

0 0 LALA cQ- : ("AOO

.

"p CN 1011 LApw 00 110 ~04 . 000 LA L A~ * L~ 0 WO 98/57641 PCT/US98/12673 o 0o 0 0 00 00 o 0 CDCD Jo c 00 0 0(00\9 9 90 cQ,~ -- u z~ w1 o~ - 102 - WO 98/57641 PCT/US98/12673 0 0 -n1 -n -n -ni CA 00 00 0 000 oZ0 CCD 00 -~1 o~ 0C)C 000# t*C, C Lo C)< C) U -L 0. ) 0 q 00~ A~ A -0- 0 ut0 11 ;, 0000 000 000 -103- WO 98/57641 PCT/US98/12673 o riA >0 0 00 0-, ON O- -ON CD CD CD CD 0 ~~r-4 * CD i f LA L0 LA 3 _ C CNI CD- 9oQ 9o ON 0 oO c~~ 10 Z" , WO 98/57641 PCT/US98/12673 0 0 -n -n -n -n 0) 00 00 S. 0n C) cin I0i(:7 lpii CD CD 0t .P, 00 t E- 10 - WO 98/57641 PCTIUS98/12673 tzC 0 -n -n 00 S. -. 00 00 C00 - 16D WO 98/57641 PCT/US98/12673 EXAMPLE 25 (4S)-trans-4-(3-,4-Difluorophenyl)-3-{ 1-[4-(2-fluorophenyl)-cyclohexyl] 5 (3R)-pyrrolidin-3-ylcarbamoyl}-6-methoxymethyl-1,2,3,4-tetrahydro pyrimidine-5-carboxylic acid methyl ester hydrochloride F F \O / 0 H O-X O O H H F H 10 Step A: 8-(2-Fluorophenyl)-1,4-dioxa-spiro[4.5]decan-8-ol To a solution of 2-fluoro-1-Iodobenzene (11.1g, 50.0 mmol) in 50 mL THF, cooled to -78oC under argon, was added n-butyllithium (20.0 15 mL 2.5M in hexane, 50.0 mmol). The solution was stirred 10 min. at -780 C, and a solution of 1,4-cyclohexanedione mono-ethylene ketal (7.81g, 50.0 mmol) in 50 mL THF was added slowly. The solution was warmed to r.t. and stirred for 60 min., then poured onto saturated sodium bicarbonate and extracted with ethylacetate. The combined organic 20 layers were washed with saturated sodium chloride, dried with magnesium sulfate, and concentrated in vacuo. The crude solid was crystallized from dichloromethane / hexane to give 8-(2-Fluoro-phenyl) 1,4-dioxa-spiro-[4.5]decan-8-ol (3.8g, 30%). 1 H NMR 6 (CDC1 3 ) 7.54-7.47 (m, 1H), 7.28-7.20 (m, 1H), 7.15 25 7.00 (m, 2H) 4.01 (s, 4H), 2.39-2.28 (m, 2H), 2.18-2.07 (m, 2H), 1.95 -1.85 (m, 2H), 1.75-1.60 (m, 2H). Step B: 4-(2-Fluorophenyl)-4-hydroxy-cyclohexanone - 107- WO 98/57641 PCT/US98/12673 To a solution of 8-(2-fluorophenyl)-1,4-dioxa-spiro[4.5]decan 8-ol (5.8 g, 23 mmol) in dioxane (100 mL), cooled to 0OC was added hydrogen chloride (1M in water, 75 ml, 75 mmol). The reaction mixture was stirred for 2 hour at room temperature, extracted with ethyl ether 5 (2x 200 mL) and washed with saturated bicarbonate solution, water and brine. Drying and solvent evaporation gave 4-(2-Fluorophenyl)-4 hydroxy-cyclohexanone in quantitative yield. 1H NMR (CDC13) 1H NMR d (CDC13) 7.60-7.50 (m, 1H), 7.40-7.00 (m, 3H), 3.0-2.8 (m, 2H), 2.6-2.3 (m, 4H), 2.3-2.2 (m, 2H). 10 Step C: 4- (2-Fluorophenyl)-cyclohexanone: 4-(2-Fluorophenyl)-4-hydroxy-cyclohexanone from Step B 15 was added to trifluoroacetic acid at 0OC and the reaction was stirred for 30 minutes and then poured onto saturated sodium bicarbonate and extracted with ethylacetate. The combined organic layers were washed with saturated sodium chloride, dried with magnesium sulfate, and concentrated in vacuo. to give the mixture of olefins, 4- (2-Fluorophenyl) 20 cyclohex-3-enone and 4-(2-Fluorophenyl)-cyclohex-2-enone (5.2 g) To a suspension of palladium on carbon (1.1 g) in 100 mL ethylacetate was added the mixture of 4-(2-Fluoro-phenyl)-cyclohex-3 enone and 4-(2-Fluorophenyl)-cyclohex-2-enone (5.1 g) under argon. The suspension was placed under 50 psi hydrogen for 36 h, filtered through 25 celite, concentrated in vacuo, and passed through silica (10% ethylacetate,hexane) to give 4-(2-fluorophenyl)-cyclohexanone (3.5 g). 1 H NMR 5, (CDC13) 7.29-7.20 (m, 2H), 7.15-7.04 (m, 2H), 3.44 3.34 (m, 1H), 2.64-2.41 (m, 4H), 2.26-2.21 (m, 2H), 2.06-2.01 (m, 2H). 30 Step D: cis and trans -1-[4-(2-Fluorophenyl)-cyclohexyl]-pyrrolidin 3-ylamine dihydrochloride To a solution of 4- (2-Fluorophenyl)-cyclohexanone (1.2 g, 6.25 mmol) and acetic acid (1.3 mL 22.75 mmol) in 30 mL methanol was 35 addded (3R)-(+)-3-(tert-butoxycarbonylamino)-pyrrolidine (1.74 g, 9.38 mmol) under argon. The solution was stirred for 2h, then sodium cyanoborohydride (9.36 mL 1M in THF, 9.38 mmol) was added dropwise. - 108- WO 98/57641 PCT/US98/12673 The solution was poured onto saturated sodium bicarbonate, and extracted with ethylacetate. The combined organic layers were washed with saturated sodium chloride, dried with magnesium sulfate, and concentrated in vacuo. The crude material was passed through silica 5 (3% methanol, ethylactate) to give 2:1 trans:cis 1-tertbutoxycarbonyl-[4 (2-fluoro-phenyl)-cyclohexyl]pyrrolidin-3-ylamine (2.3 g, 100%). The trans- 1-tertbutoxycarbonyl-[4-(2-fluoro-phenyl)-cyclohexyl]pyrrolidin-3 ylamine (1.53 g, 4.23 mmol) was dissolved in 100 mL ethylacetate, and HC1 gas was bubbled through the solution for 20 min. The solution was 10 concentrated in vacuo to give trans -1-[4-(2-Fluorophenyl)-cyclohexyl] pyrrolidin-3-ylamine dihydrochloride (1.4 g, 100%). 1 H NMR 6 H

(CD

3 OD) 7.31-7.26 (m, 2H), 7.29-7.03 (m, 2H), 4.15 (m, 1H), 3.90-3.45 (m, 2H), 3.42-3.25 (m, 2H), 3.0-2.85 (m, 1H), 2.70-2.45 (m, 1H), 2.40-2.20 (m, 2H), 2.05-2.02 (d, 2H, J= 9.5 Hz), 1.79-1.67 (m, 4H). 15 Step E: trans-4-(3-,4-Difluorophenyl)-3- { 1-[4-(2-fluorophenyl) cyclohexyl]-pyrrolidin-3-ylcarbamoyl}-6-methoxymethyl 1,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid methyl ester hydrochloride 20 To a solution of trans- 1-[4-(2-fluoro-phenyl)-cyclohexyl] pyrrolidin-3-ylamine dihydrochloride (100 mg, 0.299 mmol) and triethylamine (0.125 mL, 0.897 mmol) in 3.0 mL DMF was added (+)-3-(4 nitrophenoxycarbonyl)-4-(3,4-difluorophenyl)-6-methoxymethyl-2-oxo 25 1,2,3,4-tetrahydropyrimidine-5-carboxylic acid methyl ester (477 mg, 0.329 mmol) under argon. The solution was stirred for 2h, poured onto saturated sodium bicarbonate, and extracted with ethylacetate. The combined organic layers were washed with saturated sodium chloride, dried with magnesium sulfate, and concentrated in vacuo. The crude 30 material was passed through silica (3% methanol, dichloromethane) and washed with sodium carbonate. To a solution of the free base in ethylacetate was added excess hydrogen chloride (IM in diethylether). This solution was concentrated in vacuo to give the product (133 mg, 67%). 35 Analysis: Calcd. for C3,H 35

F

3

N

4 05-HCl*0.55 H20 C, 57.54; H, 5.78; N, 8.66. - 109- WO 98/57641 PCT/US98/12673 Found: C, 57.58; H, 5.91; N, 8.79 The compounds set forth in Examples 26-42 below were prepared by procedures substantially the same as described above in 5 Example 25. Additional preparative details are provided in certain Examples as deemed appropriate. EXAMPLE 26 (4S)-trans-4-(3,4-Difluoro-phenyl)-2-oxo-oxazolidine-3-carboxylic acid -{1 10 [4-(2-fluoro-phenyl)-cyclohexyl]-(3R)-pyrrolidin-3-yl}-amide hydrochloride 0 N O 0 F *HCI I F 'F F 15 Analysis: Calcd. for C 31

H

3

FN

4 0 5 s*HC1*0.35 H20*0.20 EtOAc C, 58.74; H, 5.76; N, 7.67 Found: C, 58.74; H, 5.82; N, 7.50 EXAMPLE 27 20 (4S)-trans-4-(3,4-Difluoro-phenyl)-3-{1-[4-(4-fluoro-2-methoxy-phenyl) cyclohexyl]-(3R)-pyrrolidin-3-ylcarbamoyl}-6-methoxymethyl-2-oxo 1,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid methyl ester hydrochloride - 110- WO 98/57641 PCT/US98/12673 F F O0 0 H H NN

H

3 CO H *HCI Analysis: Calcd. for C 32

H

3 7

F

3

N

4 0 6 *HC *1.35 H 2 0*0.20 EtOAc 5 C,57.00; H, 6.32; N, 8.11 Found: C, 57.03; H, 5.95; N, 7.88 EXAMPLE 28 (4S)-trans-4-(3,4-Difluoro-phenyl)-2-oxo-oxazolidine-3-carboxylic acid {1 10 [4-(4-fluoro-2-methoxy-phenyl)-cyclohexyl]-(3R)-pyrrolidin-3-yl}l-amide hydrochloride O 0 H F /0

H

3 CO H *HCI \ F F F 15 Analysis: Calcd. for C 27

H

3 ,oF 3

N

3 0 4 *HCl*0.40 H 2 0*0.45 EtOAc C,57.56; H, 5.94; N, 6.99 Found: C, 57.56; H, 5.68; N, 7.00 EXAMPLE 29 20 (4S)- 4-(3,4-Difluoro-phenyl)-3- { 1-[4-(2-fluoro-phenyl)-4-hydroxy cyclohexyl]-(3R)-pyrrolidin-3-ylcarbamoyl}-6-methoxymethyl-1,2,3,4 tetrahydro-pyrimidine-5-carboxylic acid methyl ester hydrochloride -111 - WO 98/57641 PCT/US98/12673 Prepared from the product of Example 25, Step B by procedures similar to those described for Steps D and E of Example 25. F F O f 0 H O F OH *HCI Analysis: Calcd. for C 3 1 H3F3N 4 0 6 *HC1 1.00 H 2 00.05 ether 5 C,55.53; H,5.75; N, 8.30 Found: C, 55.53; H, 5.60; N, 8.34 EXAMPLE 30 (4S)-4-(3,4-Difluoro-phenyl)-2-oxo-oxazolidine-3-carboxylic acid -{1-[4-(2 10 fluoro-phenyl)-4-hydroxy-cyclohexyl]-(3R)-pyrrolidin-3-yl}-amide hydrochloride 0 HO o F OH *HCI F F Analysis: Calcd. for C 26

H

28

F

3

N

3 0 4 *HC1*0.40 H 2 0 15 C,57.07; H, 5.49; N,7.68 Found: C,57.03; H, 5.32; N, 7.42 EXAMPLE 31 20 (4S)-4-(3,4-Difluorophenyl)-2-oxo-oxazolidine-3-carboxylic acid {1-[4 hydroxy-4-(2-trifluoromethylphenyl)-cyclohexyl]-(3R)-pyrrolidin-3-yl} amide - 112- WO 98/57641 PCT/US98/12673 F

CF

3 F N HO HOH 0oO Analysis: Calculated for C 27

H

28

N

3 0 4

F

5 0.15 EtOAc: 5 C, 58.49; H, 5.19; N, 7.41 Found: C, 58.50; H, 4.98; N, 7.13 EXAMPLE 32 10 (4S)-4-(3,4-Difluorophenyl)-3- { 1-[4-hydroxy-4-(2-trifluoromethylphenyl) cyclohexyl]-(3R)-pyrrolidin-3-ylcarbamoyl}-6-methoxymethyl-2-oxo 1,2,3,4-tetrahydropyrimidine-5-carboxylic acid methyl ester F F

CF

3 F ,HO N N COOMe H OMe O N 15 H Analysis: Calculated for C 32

H

35

N

4 0 6

F

5 0.30 EtOAc: C, 57.53; H, 5.44; N, 8.08 20 Found: C, 57.92; H, 5.43; N, 7.82 EXAMPLE 33 (4S)-4-(3,4-Difluorophenyl)-2-oxo-oxazolidine-3-carboxylic acid {1-[4-(2 25 trifluoromethylphenyl)-cyclohexyl]-(3R)-pyrrolidin-3-yl} amide -113- WO 98/57641 PCT/US98/12673 F

CF

3 F 0 H O O Analysis: Calculated for C 27

H

28

N

3 0 3

F

5 : 5 C, 60.32; H, 5.26; N, 7.82 Found C, 60.36; H, 5.29; N, 7.50 EXAMPLE 34 10 (4S)-4-(3,4-Difluorophenyl)-6-methoxymethyl-2-oxo-3-{1-[4-(2 trifluoromethylphenyl)-cyclohexyl]-(3R)-pyrrolidin-3-ylcarbamoyl} 1,2,3,4-tetrahydropyrimidine-5-carboxylic acid methyl ester F F CF3 N NCOOMe N N0 H OMe 0 N 15 H Analysis: Calculated for C, 32

H

35

N

4 0 5

F

5 - 0.15 CHC1 3 : C, 57.75; H, 5.30; N, 8.38 20 Found: C, 57.53; H, 5.30; N, 8.51 - 114- WO 98/57641 PCT/US98/12673 EXAMPLE 35 (4S)-4-(3,4-Difluorophenyl)-3-{1-[4-(4-fluorophenyl)-4-hydroxy-cyclohexyl] (3R)-pyrrolidin-3-ylcarbamoyl}-6-methoxymethyl-2-oxo-1,2,3,4 tetrahydropyrimidine-5-carboxylic acid methyl ester hydrochloride 5 F F NHO N COOMe H OMe HCI N Step A.: 8-(4-Fluorophenyl)-1,4-dioxa-spiro[4.5]decan-8-ol 10 To a solution of 1,4-cyclohexanedione mono-ethylene ketal (25 g, 0.16 mol) in diethylether (750 ml), cooled to -78 0 C was added 4-fluorophenyl magnesium bromide (1 M in tetrahydrofuran, 190 ml, 0.19 mol) dropwise. The reaction mixture was warmed to room temperature, quenched with water and extracted twice with ethyl acetate. Washing 15 with brine, drying and solvent evaporation gave 8-(4-fluorophenyl)-1,4 dioxa-spiro[4.5]decan-8-ol (38 g, 95%). 1H NMR (CDC13) 5 7.55-7.40 (m, 2H) 7.05-6.95 (m, 2H), 3.95 (m, 4H), 2.20 1.90 (m, 4H), 1.90-1.60 (m, 4H), 1.50 (s, 1H) 20 Step B: 4-(4-Fluorophenyl)-4-hydroxy-cyclohexanone To a solution of 8-(4-fluorophenyl)-1,4-dioxa-spiro[4.5]decan-8-ol (38 g, 0.15 mol) in dioxane (900 ml), cooled to 0oC was added hydrogen chloride (1M in water, 1.5 L, 1.5 mol). The reaction mixture was stirred 25 for 2 hour at RT and extracted twice with ethyl acetate. The ethyl acetate layer was washed with saturated sodium bicarbonate solution, water and brine. Drying and solvent evaporation gave 4-(4-fluorophenyl)-4 hydroxy-cyclohexanone (24.8 g, 79 %); 1H NMR (CDC13) 5 7.55-7.45 (m, 2H) 7.16-7.0 (m, 2H), 3.0-2.85 (m, 2H), 2.18-2.38 (m, 6H), 1.85 (s, 1H) 30 - 115- WO 98/57641 PCT/US98/12673 Step C: 4-(3-(3R)-tert-Butoxycarbonylamino-pyrrolidin-1-yl)- 1-(4 fluorophenyl)- cyclohexanol F ~HN~ NHBoc HO NaCNBH 3 , MeCOOH HO 0 MeOH N 5 NHBoc To a solution of 4-(4-Fluorophenyl)-4-hydroxy-cyclohexanone 10 (2.0 g, 9.6 mmol) and acetic acid (2.6 ml, 48 mmol) in methanol (60 ml) was added (3R)-(+)-3-(tert-butoxycarbonylamino) pyrrolidine (2.6 g, 14.4 mmol). After stirring for 2 hours at room temperature, sodium cyanoborohydride (1M in tetrahydrofuran, 14.4 ml, 14.4 mmol) was added dropwise. The reaction mixture was stirred for 45 minutes, 15 concentrated, diluted with 10% potassium hydrogen sulfate and extracted twice with ether. The aqueous solution was basified with 1N sodium hydroxide and extracted with ethyl acetate three times. Washing with brine, drying and solvent evaporation gave an oil. Flash chromatography (silica gel, 2-propanol-ethyl acetate, 4:96 increasing to 20 8:92) gave 4-(3-(3R)-tert-Butoxycarbonylamino-pyrrolidin-1-yl)-1-(4 fluorophenyl)- cyclohexanol (2.0 g, 56%); 'H NMR (CDC13) 5 7.46(m, 2H), 7.02 (m, 2H), 4.89 (m, 1H), 4.18 (m, 1H), 2.94 (m, 1H), 2.71 (m, 2H), 2.42 (m, 1H), 2.26 (m, 1H), 2.13 (m, 1H), 1.83 (m, 9H), 1.63 (m, 1H), 1.44 (s, 9H), 25 A less polar isomer was also isolated. Step D: 4-[(3R)-3-Aminopyrrolidin-1-yl]- 1-(4-fluorophenyl) cyclohexanol dihydrochloride - 116 - WO 98/57641 PCT/US98/12673 F F HO HCI HO N EtOAc N NHBoc 2 HCI NH 2 To a solution of 4-((3R)-3-tert-Butoxycarbonylamino-pyrrolidin-1 yl)-1-(4-fluorophenyl) cyclohexanol (1.05 g, 2.8 mmol) in ethyl acetate (50 5 ml), cooled to 0oC was added hydrogen chloride gas, bubbled in gently for 5-10 minutes. The reaction mixture was stirred for 20 minutes at O'C and the above procedure was repeated twice. Concentration and flushing with ethyl acetate three times gave 4-((3R)-3-aminopyrrolidin-1 yl)-1-(4-fluorophenyl) cyclohexanol dihydrochloride (0.87 g, 89%); 1 H 10 NMR (DMSO) 8 11.33 (bd, 1H)), 8.60 (bd, 3H), 7.52 (m, 2H), 7.14 (m,2H), 5.12 (bs, 1H), 3.35-4.04 (m, 6H), 1.76-2.27 (m, 10H). Step E: 4-(3,4-Difluorophenyl)-3-{ 1-[4-(4-fluorophenyl)-4-hydroxy cyclohexyl]-(3R)-pyrrolidin-3-ylcarbamoyl}-6 15 methoxymethyl-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid methyl ester hydrochloride was prepared by a procedure substantially as described above for the preparation of Example 25 20 Mass Spectrum: 617.4 (M+1), FAB EXAMPLE 36 (4S)-4-(3,4-Difluorophenyl)-2-oxo-oxazolidine-3-carboxylic acid{1-[4-(4 25 fluorophenyl)-4-hydroxy-cyclohexyl]-(3R)-pyrrolidin-3-yl} amide - 117 - WO 98/57641 PCT/US98/12673 F \F HO N N N H L/_ HOHO HCI Mass Spectrum: 504.3 (M+1), FAB 5 EXAMPLE 37 (4S)-4 -(3,4-Difluorophenyl)-3- { 1-[4-(4-fluorophenyl)-4-hydroxy cyclohexyl]-(3R)-pyrrolidin-3-ylcarbamoyl}-6-methyl-2-oxo-1,2,3,4 10 tetrahydropyrimidine-5-carboxylic acid methyl ester hydrochloride F F HO HNN COOMe H HCI 0 N CH 3 H 15 Analysis: Calculated for C 30

H

33

N

4 0 5

F

3 HCL 1.5 H 2 0: C, 55.43; H, 5.74; N, 8.62 Found: C, 55.43; H, 5.48; N, 8.56 20 EXAMPLE 38 (4S)-4 -(3,4-Difluorophenyl)-3-{ 1-[4-(4-fluorophenyl)-cyclohexyl]-(3R) pyrrolidin-3-ylcarbamoyl}-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5 carboxylic acid methyl ester hydrochloride - 118- WO 98/57641 PCT/US98/12673 F F F N N N COOMe H I SHCI 0 N CH 3 H 5 Analysis: Calculated for Co 3 0

H

33

N

4 0 4

F

3 HCL 0.75 H 2 0: C, 58.06; H, 5.77; N, 9.03 Found: C, 58.09; H, 5.90; N, 8.86 10 EXAMPLE 39 (4S)-4 -(3,4-Difluorophenyl)-3-{1-[4-(4-fluorophenyl)-cyclohexyl]-(3R) pyrrolidin-3-ylcarbamoyl-6-methoxymethyl- 2 -oxo-1,2,3,4 tetrahydropyrimidine-5-carboxylic acid methyl ester hydrochloride F F F F N N COOMe N N H , OMe HCI 0 N 15 H Analysis: Calculated for C 31

H

35

,N

4 0 5

F

3 - HCL 0.45 H 2 0: C, 57.70; H, 5.76; N, 8.68 20 Found: C, 57.77; H, 5.75; N, 8.29 -119- WO 98/57641 PCT/US98/12673 EXAMPLE 40 (4S)-4 -(3,4-Difluorophenyl)-2-oxo-oxazolidine-3-carboxylic acid{1-[4-(4 fluorophenyl)-cyclohexyl]-(3R)-pyrrolidin-3-yl}amide 5 F \F F N jN H 0 _O Analysis: Calculated for C 26

H

28

N

3 0 3

F

3 : 10 C, 64.04; H, 5.80; N, 8.62 Found: C, 63.93; H, 5.79; N, 8.58 EXAMPLE 41 15 (4S)-4 -(3,4-Difluorophenyl)-3- { 1-[4-(4-fluorophenyl)-4-hydroxy cyclohexyl]-(3R)-pyrrolidin-3-ylcarbamoyl}-2-oxo-1,2,3,4 tetrahydropyrimidine-5-carboxylic acid methyl ester F F F N COOMe HO N N COMe H 0 N H 20 H Analysis: Calculated for C2 9

H

31

,N

4 0F 3 0.30 CHC1 3 : C, 57.84; H, 5.19; N, 9.21 25 Found: C, 57.95; H, 5.54; N, 8.92 - 120 - WO 98/57641 PCT/US98/12673 EXAMPLE 42 (4S)-3-{ 1-[4-(4-Cyanophenyl)-4-hydroxycyclohexyl]-(3R)-pyrrolidin-3 5 ylcarbamoyl}-4 -(3,4-difluorophenyl)-6-methoxymethyl-2-oxo-1,2,3,4 tetrahydropyrimidine-5-carboxylic acid methyl ester hydrochloride F F NC0 HOC N N N COOMe H O Me HCI H 10 Analysis: Calculated for C32H355NO6F2 HCL 0.75 H 2 0: C, 57.05; H, 5.61; N, 10.40 Found: C, 56.75; H, 5.68; N, 10.79 15 EXAMPLE 43 5-Cyclopropyl-4-(3,4-difluorophenyl)-2-oxo-oxazolidine-3-carboxylic acid {1-[4-(2-fluorophenyl)-cyclohexyl]-(3R)-pyrrolidin-3-yl-amide F F F _a NN) N ' NO H 0 20 0 Step A 2-(3,4-difluorophenyl)-3-cyclopropyl-3-hydroxy-propionic acid - 121 - WO 98/57641 PCT/US98/12673 A solution of 3,4-difluorophenylacetic acid (2.9 g, 16.8 mmol) in 80 mL dry THF was cooled to -78 *C and treated with LDA (2.0 M heptane/THF/ethylbenzene, 42 mmol, 21 mL) for 15 minutes. Then cyclopropylcarboxaldehyde (17 mmol, 1.27 mL, 1.19 g) was added via 5 syringe and the reaction warmed slowly to room temperature over 1 hr.. The reaction mixture was diluted with 5 % aqueous potassium hydrogen sulfate (50 mL), and extracted with ethyl acetate (2 x 150 mL). The combined extracts were dried (Na2SO4), filtered and concentrated in vacuo. The lower rf material crystallized to give 1.4 g of solid. 10 1 H NMR (CDCl3, 300 MHz) 8 7.40 - 7.00 (m, 3H, Ar-H), 3.75-3.60 (br m, 1H), 3.50-3.40 (m, 1H), 0.95-0.70 (m, 1H), 0.5-0.20 (m, 4H) Step B 4-(3,4-difluorophenyl)-5-cyclopropyl-oxazolidin-2-one 15 The resulting hydroxy acids (7.95 g, 32 mmole) without further purification, were dissolved in dry degassed DMF (100 mL) and treated with solid NaHCO3 (14.0 g) and diphenylphosphorylazide (DPPA, 9.9 g, 36 mmol, 7.74 mL) at room temperature for 1 hr. The reaction was then heated on a steam bath for 15 min. Signs of nitrogen evolution were 20 immediately apparent. The reaction mixture was poured into saturated sodium bicarbonate and extracted with ethyl acetate. The organics were dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo and purified by chromatography (SiO2, 8 mm, 0 - 50% EtOAc/hexanes) affording the (±)-trans diastereomer (4.9 g) followed by 25 the (±)-cis diastereomer (1.5 g). The trans isomer was resolved by HPLC on a Chiralcel OD eluting with 10% ethanol hexanes containing 1% diethylamine. For the cis isomer. 1 H NMR (CDC13, 300 MHz) 8 7.35 - 7.20 (m, 2H, Ar-H), 7.10-7.05 (br m, 30 1H, Ar-H), 5.70 (br s, 1H, NH), 4.95 (d, 1H, J = 7.5 Hz, CH(Ar)), 4.10 (t, 1H, J = 7.5 Hz, CHcycpr), 0.6-0.50 (m, 1H), 0.5-0.4 (m, 1H), 0.4-0.3 (m, 1H), 0.2-0.1 (m, 1H) For the trans isomer: 1 H NMR (CDC13, 300 MHz) 8 7.30 - 7.15 (m, 2H, Ar-H), 7.15-7.08 (br m, 35 1H, Ar-H), 5.85 (br s, 1H, NH), 4.75 (d, 1H, J = 7.2 Hz, CH(Ar)), 3.65 (t, 1H, J = 7.2 Hz, CHcycpr), 1.3-1.15 (m, 1H), 0.75-0.6 (m, 1H), 0.5-0.4 (m, 1H), 0.22-0.14 (m, 1H) - 122 - WO 98/57641 PCT/US98/12673 SteIDC 4-(3,4-Difluorophenyl)-5-cyclopropyl-2-oxo-oxazolidine-3-carboxylic acid 5 4-nitro-phenyl ester To a solution of 4-(3,4-difluorophenyl)-5-cyclopropyl-oxazolidin-2-one (2 g, 8.3 mmol) in 100 mL THF was added a solution of n-butyllithium in hexane (9.1 mmol) dropwise via a syringe under an argon atmosphere at -780C. The resulting yellow solution was stirred at -78 0 C for 10 min. To 10 this solution was then added dropwise via syringe 4 nitrophenylchloroformate (1.03 g, 5.1 mmol) in 20 mL of THF. The reaction was stirred at -78 ° for 10 min. The reaction mixture was poured into saturated sodium bicarbonate and extracted with ethyl acetate (2 X 200 mL). The organic extracts were washed with brine, and the organic 15 layer was dried over Na 2

SO

4 . The solvent was removed after filtration, and the residue was purified by column chromatography on silica gel 30% ethyl acetate hexane. The material was rechromatographed on silica gel eluting with 2% acetone/ methylene chloride to give 1.2 g the product as a thick syrup which solidified upon standing. 20 1H NMR (CDCI 3 , 300 MHz) 8 8.22 (d, J = 9.0 Hz, 2 H), 7.34 (d, J = 9.0 Hz, 2 H), 7.35-7.05 (m, 3 H), 5.19 (d, J = 5.0 Hz, 1 H),3.80 (dd, J = 5.0,8.6 Hz, 1 H), 1.35-1.15 (m, 1H), 0.85-0.7 (m, 1H), 0.6-0.5 (m, 1H), 0.35-0.2 (m, 1H) Ste DD. 25 5-cyclopropyl-4-(3,4-difluorophenyl)-2-oxo-oxazolidine-3-carboxylic acid (1-[4-(2-fluorophenyl)-cyclohexyl]-pyrrolidin-3-yl-amide The title compound was prepared from the reaction of the product of Step C above and trans -1-[4-(2-fluoro-phenyl)-cyclohexyl]-pyrrolidin-3 ylamine dihydrochloride 30 - 123 - WO 98/57641 PCT/US98/12673 F SF Fo H O 0 Calcd. for C,,H,,N,0,F,*0.3 H 2 0 5 65.35 6.17 7.88 Found 65.38 6.02 8.05 The compounds set forth in Examples 44 and 45 below were 10 prepared by procedures substantially as described above for Example 43. EXAMPLE 44 (4S, 5S)-5-Cyclopropyl-4-(3,4-difluorophenyl)-2-oxo-oxazolidine-3 carboxylic acid({1-[4-(4-fluorophenyl)-4-hydroxy-cyclahexyl]-(3R) 15 pyrrolidin-3-yl)amide hydrochloride This compound was prepared from the product of Example 35, Step D and the product of Example 43, Step C by a procedure similar to that described in Example 25, Step E. 20 F \F F N N N , H O HCI H Analysis: Calculated for CH 32

N

3 04F, - HCL: - 124- WO 98/57641 PCT/US98/12673 C, 60.04; H, 5.74; N, 7.24 Found: C, 59.74; H, 5.76; N, 7.45 Mass Spectrum: 544.3 (M+1), FAB 5 EXAMPLE 45 (4S, 5S)-5-Cyclopropyl-4-(3,4-difluorophenyl)-2-oxo-oxazolidine-3 carboxylic acid{ 1-[4-(4-cyanophenyl)-cyclohexyl]-(3R)-pyrrolidin-.3.

yl}amide 10 F \F NC O m H

O

O Analysis: Calculated for Ca H, 2

N

4 0sF 2 0.15 CHC1,: C, 65.54; H, 5.87; N, 10.14 15 Found: C, 65.85; H, 5.80; N, 10.10 The compounds set forth in Examples 46-64 below were prepared using procedures substantially the same as described in the preceding 20 Examples. EXAMPLE 46 (4S)-4-(3,4-difluorophenyl)-2-oxo-oxazolidine-3-carboxylic acid(1-[4-(4 25 cyanophenyl)-4-hydroxy-cyclohexyl]-(3R)-pyrrolidin-3-y1)amide hydrochloride - 125 - WO 98/57641 PCT/US98/12673 F N 0F NC N N N .H HCI Analysis: Calculated for C 27

H

28

N

4 0 4 F2 HCL 0.75 H 2 0: 5 C, 57.85; H, 5.48; N, 10.00 Found: C, 57.88; H, 5.79; N, 9.97 EXAMPLE 47 (4S)-3- { 1-[4-(4-Cyanophenyl)-cyclohexyl]-(3R)-pyrrolidin-3-ylcarbamoyl}-4 10 (3,4-difluorophenyl)-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5 carboxylic acid methyl ester F F NC N COOMe H U 0 N CH 3 H 15 Analysis: Calculated for ClH33N504F2: C, 64.45; H, 5.77; N, 12.12 20 Found: C, 64.04; H, 5.73; N, 11.82 - 126- WO 98/57641 PCT/US98/12673 EXAMPLE 48 (4S)-trans-4-(3,4-Difluorophenyl)-3-[1-(4-pyridin-2-yl-cyclohexyl)-(3R) pyrrolidin-3-ylcarbamoyl]-6-methyl-2-oxo-1,2,3,4-tetrahydro-pyrimidine 5-carboxylic acid methyl ester 5 F F /0 NN N H N

CO

2 Me H To a solution of dry acetonitrile (20 mL) containing 666 mg (1.141 mmole) of trans-4-(3,4-difluorophenyl)-3-[1-(4-pyridin-2-yl-cyclohexyl)-3R 10 pyrrolidin-3-ylcarbamoyl]-6-methoxymethyl- 2 -oxo-1,2,3,4-tetrahydro pyrimidine-5-carboxylic acid methyl ester (the preparation of which is described in Example 9) was added 0.676 ml (5.33 mmole) of chlorotrimethylsilane and 0.8 g (5.33 mmole) of sodium iodide. The reaction vessel was fitted with an efficient reflux condenser and the 15 reaction mixture was heated to 650 C for 30 minutes. The reaction mixture was subsequently heated to reflux for 30 minutes more. After one hour, an additional 5.33 mmole each of chlorotrimethylsilane and sodium iodide were added and then the same amount, once more, after three hours. The reaction was terminated after six hours. All volatiles 20 were removed under reduced pressure and the residue was partitioned between ethyl acetate (200 mL) and water. The organic phase was washed with water and brine, then dried (sodium sulfate) and concentrated to yield an amorphous solid. The crude product was purified via preparative centrifugal chromatography (4 mm plate 25 thickness, 2-20% methanol/chloroform gradient); repurification via preparative thick layer chromatography (1 mm plate thickness, 88:121.2 chloroform/methanol/conc. ammonium hydroxide elution, v/v) yielded 212 mg (34%) of the title compound in analytically pure form. This material was converted to its salt form with HC1 (gas) in ethyl acetate: 30 HPLC = >99% pure at 215 nm & 255 nm. -127- WO 98/57641 PCT/US98/12673 NMR(CDC1 3 , 400 MHz): Consistent with structure assignment and confirms presence of solvent. FAB MS: 554 (M+ + 1). Analysis for C 2 9

H

3 3

F

2

N

5 04 * 2HC1 0.7H20: 5 Calculated: C, 54.49; H, 5.74; N, 10.96. Found: C, 54.46; H, 5.73; N, 10.64. EXAMPLE 49 10 (4S)-3-({1 -[4-(2-Cyano-phenyl)-cyclohexyl]-(3R)-pyrrolidin-3- ylcarbamoyl} 4-(3,4-difluoro-phenyl)-6-methyl-2-oxo-1,2,3,4-tetrahydro-pyrimidine-5 carboxylic acid methyl ester Hydrochloride. F H F -j CN H N N OCH 3 *HCI H 0 N CH 3 H 15 Analysis: Calcd. for C3H 33 F2N 5 0 4 *HC1l0.75H 2 0 C, 59.32; H, 5.70; N, 11.16 Found: C, 59.08; H, 5.89; N, 10.87 20 EXAMPLE 50 (4S)-3-{1 -[4-(2-Cyano-4-fluoro-phenyl)-cyclohexyl]-(3R)-pyrrolidin-3 ylcarbamoyl}-4-(3,4-difluoro-phenyl)-6-methoxymethyl-2-oxo-1,2,3,4 25 tetrahydro-pyrimidine-5-carboxylic acid methyl ester Hydrochloride. -128- WO 98/57641 PCT/US98/12673 F F F N O O CN H .%%H N N "OCH, oHCI H N 0 N H Analysis: Calcd. for C 32

H

34

F

3 50NO*HC1*1.5H 2 0 5 C, 55.77; H, 5.56; N, 10.16 Found: C, 55.52; H, 5.63; N, 10.02 EXAMPLE 51 10 (4S)-4-(3,4-Difluoro-phenyl)-3- 1 -[4-(4-fluoro-2-hydroxy-phenyl) cyclohexyl]-(3R)-pyrrolidin-3-ylcarbamoyl}-6-methoxymethyl-2-oxo 1,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid methyl ester Hydrochloride. F F .H F N" 000H OH H ,H N N OCH 3 *HCI H j I O N H O 15 Analysis: Calcd. for C3,H 35 F3N40 6 *HCl*0.85H 2 0*0.25C 4

H,

1 Q C, 55.95; H, 5.90; N, 8.16 Found: C, 56.17; H, 5.51; N, 7.81 20 -129- WO 98/57641 PCT/US98/12673 EXAMPLE 52 (4S)-4-(3,4-Difluoro-phenyl)-2-oxo-oxazolidine-3-carboxylic acid {1-[4 -(4 fluoro-2-hydroxy-phenyl)-cyclohexyl]-(3R)-pyrrolidin-3- yl}-amide Hydrochloride. 5 F F F H F N~O OH H N N *HCI H O Analysis: Calcd. for C 26

H

28

F

3

N

3 0 4 HC1*0.10H 2 0 10 C, 57.64; H, 5.43; N, 7.76 Found: C, 57.42; H, 5.22; N, 7.88 EXAMPLE 53 15 (4S)-4-(3,4-Difluoro-phenyl)-2-oxo-oxazolidine-3-carboxylic acid {1-[4 -(2 cyano-4-fluoro-phenyl)-cyclohexyl]-(3R)-pyrrolidin-3-yl}-amide. F F F N y CN H H O 20 Analysis: Calcd. for C 27

H

2 7

F

3

N

4 0 3 0.35H 2 0 C, 62.50; H, 5.38; N, 10.80 Found: C, 62.87; H, 5.53; N, 10.42 25 -130- WO 98/57641 PCT/US98/12673 EXAMPLE 54 (4S)-4-(3,4-Difluoro-phenyl)-2-oxo-oxazolidine-3-carboxylic acid {1-[4 -(2 cyano-4-fluoro-phenyl)-cyclohexyl]-(3R)-pyrrolidin-3-yl}-amide 5 Hydrochloride. F : IF F N\ F NQ ON H *HCI 0O 10 Analysis: Calcd. for C 27

H

2 7 F3N 4 0 3 *HC1 C, 59.07; H, 5.14; N, 10.21 Found: C, 59.38; H, 5.42; N, 9.87 15 EXAMPLE 55 (4S,5S)-4-(3,4-Difluoro-phenyl)-5-methyl-2-oxo-oxazolidine-3-carboxylic acid {1-[4 -(2-cyano-4-fluoro-phenyl)-cyclohexyl]-(3R)-pyrrolidin-3-yl} amide Hydrochloride. 20 F S*HCI F I F , C N / \Q N H H 0 0 ""CH3 0 - 131- WO 98/57641 PCT/US98/12673 Analysis: Caled. for C 28

H

29

F

3

N

4 0 3 ,*HCl 1.25H20 C, 57.43; H, 5.59; N, 9.57 Found: C, 57.19; H, 5.68; N, 9.79 5 EXAMPLE 56 (4S,5S)-5-Cyclopropyl-4-(3,4-difluoro-phenyl)-2-oxo-oxazolidine-3 carboxylic acid {(1-[4 -(2-cyano-4-fluoro-phenyl)-cyclohexyl]-(3R) pyrrolidin-3yl}-amide Hydrochloride. 10 F -HCI F CN /\ F NN F N N H 0 X 15 Analysis: Calcd. for Co 30 H3F3N403*HCl*0.55H 2 0 C, 60.15; H, 5.57; N, 9.35 Found: C, 59.85; H, 5.77; N, 9.14 20 EXAMPLE 57 (4S)-4-(3,4-Difluoro-phenyl)-3-{1-[4-(2-fluoro-phenyl)-4-hydroxy-cyclohex 1-yl]-(3R)-pyrrolidin-3-ylcarbamoyl}-6-methyl-2-oxo-1,2,3,4-tetrahydro pyrimidine-5-carboxylic acid methyl ester hydrochloride - 132- WO 98/57641 PCT/US98/12673 F HOF HCO HOH F Analysis: Calcd. for CooH 33

F

3

N

4 0 5 *HCl*0.60 H 2 0*0.35 EtOAc 5 C,56.73; H,5.76; N, 8.43 Found: C, 56.73; H,5.83; N, 8.45 EXAMPLE 58 10 (4S)-trans-4-(3,4-Difluoro-phenyl)-3-{1-[4-(2-fluoro-phenyl)-cyclohexyl] (3R)-pyrrolidin-3-ylcarbamoyl}-6-methyl-2-oxo-1,2,3,4-tetrahydro pyrimidine-5-carboxylic acid methyl ester hydrochloride F F 0 / 0 H *HCI O H F Analysis: Calcd. for C 3 oHF 32 N3 4 0 4 *HCl*0.85 H 2 O*0.10 EtOAc 15 C, 57.94; H, 5.68; N, 8.89 Found: C, 57.93; H,5.91; N, 8.94 - 133 - WO 98/57641 PCT/US98/12673 EXAMPLE 59 (4S)-cis-4-(3,4-Difluoro-phenyl) -3-[ 1-(4-hydroxy-4-pyridin-2-yl-cyclohexyl) (3R)-pyrrolidin-3-ylcarbamoyl] -2-oxo-1,2,3,4-tetrahydro-pyrimidine-5 carboxylic acid methyl ester hydrochloride F F O0 HO O F \ON C,51.80; H,5.4; N,10.79 Found: C, 51.79; H,5.60; N, 10.86 10 EXAMPLE 60 (4S)-trans-4-(3,4-Difluorophenyl)-3-[1-(4-pyridin-2-yl-cyclohexyl)-(3R) pyrrolidin-3-ylcarbamoyl]-2-oxo-1,2,3,4-tetrahydro-pyrimidine-5 15 carboxylic acid methyl ester F H N 0 H HO O2C N ',N Analysis: Calcd. for C 28 H3,F2N 504*0.75 H 2 0 C,60.80; H,5.92; N,12.66 20 Found: C, 60.74; H,5.72; N,13.05 - 134 - WO 98/57641 PCT/US98/12673 EXAMPLE 61 (4S)-trans-3 {1-[4-(2-Cyano-phenyl)-piperidin-1-yl]-(3R)-pyrrolidin-3 ylcarbamoly}-4-(3,4-difluoro-phenyl)-2-oxo-1,2,3,4-tetrahydro-pyrimidine 5-carboxylic acid methyl ester F F \O 0 H /NN 0 5 CN Analysis: Calcd. for C 3 oHa 3

,F

2

N

5 0 4 .0.75 H 2 0 C, 62.43; H, 5.68; N, 12.14 Found: C, 62.43; H, 5.45; N, 12.27 10 EXAMPLE 62 (4S,5S)-trans-5-Cyclopropyl-4-(3,4-difluorophenyl)-2-oxo-oxazolidine-3 carboxylic acid {1-[ 4-(4-fluorophenyl)-cyclohexyl]-(3R)-pyrrolidin-3-yl 15 amide F F- .,,.. N- N O 0 F N/ ' F H N Calcd. for C 29 H32N30F 3 0.35 H 2 0*0.1 CH 2

C

2 20 C, 64.44; H, 6.11; N, 7.75 Found C, 64.39; H, 5.97; N, 7.77 - 135 - WO 98/57641 PCT/US98/12673 EXAMPLE 63 (4S)-4-(3,4-Difluoro-phenyl) -3-[ 1-(4-hydroxy-4-pyridin-2-yl-cyclohexyl) (3R)-pyrrolidin-3-ylcarbamoyl]-6-methyl -2-oxo-1,2,3,4-tetrahydro pyrimidine-5-carboxylic acid methyl ester hydrochloride F HO / F O- / CO 2 Me * 2 HCI N 5 H Me Analysis: Calcd. for C 2 9

H

3 3

F

2

N

5 05 6 * 2 HC1 C, 50.26; H, 5.91; N,10.11 Found: C, 50.24; H, 5.72; N, 9.82 10 EXAMPLE 64 (4S)-trans-4-(3,4-Difluorophenyl)-5-methyl-2-oxooxazolidine-3-carboxylic acid-[ 1-(4-pyridin-2-yl-cyclohexyl)-(3R)-pyrrolidin-3-yl]amide hydrochloride F Na 0 F N,, N O / F H N "-Me 15 0 O 2 HC1 Mass Spectrum (FAB) Calcd. for C 26

H

27

F

2

N

4 03 Found: 485 (M+1) 20 EXAMPLE 65 trans-4S-(3,4-Difluorophenyl)-6-methyl-2-oxo-3-{1-[4-(1-oxopyridin-2-yl) cyclohexyl]-3R-pyrrolidin-3-ylcarbamoyl}-1,2,3,4-tetrahydropyrimidine-5 carboxylic acid methyl ester hydrochloride - 136- WO 98/57641 PCT/US98/12673 F F HO ,,"N , N C 0 2 Me 0N 0N O "Me H Step A: 2-(1,4-Dioxaspiro[4.5]dec-7-en-8-yl)pyridine 5 To a solution of trifluoromethanesulfonic acid 1,4-dioxa spiro[4.5]dec-7-en-8-yl ester (25.41 g, 88.15 mmol) in THF (266 mL) at room temperature was added palladium tetrakistriphenylphosphine (5.08 g, 4.4 mmol) under an inert atmosphere. To this mixture was added a solution of 2-pyridyl zinc bromide (264.4 mL of a 0.5 N solution 10 in THF, 132.2 mmol) resulting in a slight exotherm. The resulting reaction mixture was then stirred 15 minutes. The reaction was quenched with the addition of 200 mL of saturated sodium bicarbonate solution. After stirring 5 minutes more, the phases were separated and the aqueous layer was extracted with ethyl acetate The combined 15 organic extracts were washed with saturated sodium chloride, dried with sodium sulfate, and concentrated in vacuo. The crude material was chromatographed over silica gel eluting with 25% ethyl acetate/hexane to give 14.6 (76%) of homogeneous product. 20 Step B: 2-(1,4-Dioxaspiro[4.5]dec-8-yl)pyridine To a solution of 14.6 g (67.19 mmol) of 2-(1,4 dioxaspiro[4.5]dec-7-en-8-yl)pyridine in ethyl acetate (400 mL) was added 4.6 g of 10% palladium on carbon catalyst. The resulting suspension was 25 then hydrogenated at ambient temperature and atmospheric pressure until all the starting material was consumed (10.5 hr). The reaction mixture was filtered through celite and the filtrate was concentrated to give the product as an oily solid. -137- WO 98/57641 PCT/US98/12673 Step C: 2-(1,4-Dioxaspiro[4.5]dec-8-yl)pyridine N-oxide To an ice cold solution of 3 g (13.68 mmol) of 2-(1,4 5 dioxaspiro[4.5]dec-8-yl)pyridine in chloroform (46 mL) was added 4.51 g (14.36 mmol) of meta-chloroperoxybenzoic acid (50-60%). The reaction mixture was stirred and allowed to come to room temperature over a four hour period. The volume of the reaction mixture was reduced by approximately 75% under reduced pressure and the residual material 10 was partitioned between ethyl acetate and 1 N aqueous sodium hydroxide solution. The organic phase was separated and washed with water and brine, then dried (sodium sulfate) and concentrated to yield 3 g of the product as an oil. 15 Step D: 2-(4-Oxocyclohexyl)pyridine N-oxide 2-(1,4-Dioxaspiro[4.5]dec-8-yl)pyridine N-oxide (3 g, 12.75 mmol) was combined with glacial acetic acid (20 mL), concentrated hydrochloric acid (10 mL), and water (10 mL). The resulting mixture 20 was heated to 45 0 C for 24 hours. The reaction was cooled to 0oC and the pH was adjusted to 6 with 20% sodium hydroxide solution. The phases were separated and the aqueous layer was extracted with ethyl acetate (3 X 100 mL). The combined organic extracts were washed with water and brine, then dried (sodium sulfate), and concentrated under reduced 25 pressure to yield 1.8 g of the product as an oil. Step E: 2-[trans-4-(3R-3-Aminopyrrolidin-1-yl)-cyclohexyl]pyridine N-oxide 30 To a solution of 17.8 mL of methanol containing 2-(4 oxocyclohexyl)pyridine N-oxide (1.8 g, 9.41 mmol) and 1.75 g (9.41 mmol) of (3R)-(+)-3-(tert-butoxycarbonylamino)-pyrrolidine was added 3.23 mL (56.4 mmol) of glacial acetic acid under an inert atmosphere. The resulting solution was stirred at ambient temperature for 20 minutes, 35 cooled to 0oC, and treated with four equal portions of solid sodium cyanoborohyride (total: 296 mg, 4.71 mmol). The reaction mixture was stirred at 0 0 C for 20 minutes more. All volatiles were removed under - 138- WO 98/57641 PCT/US98/12673 reduced pressure and the residue was taken up in 200 mL of ethyl acetate. The organic layer was washed with 10% sodium carbonate solution and brine, then dried (sodium sulfate) and concentrated to yield 2.86 g of the crude product as an oil. The desired trans-2-[4-(3-tert 5 butoxycarbonylaminopyrrolidin-1-yl)-cyclohexyl]-pyridine N-oxide was obtained via preparative centrifugal chromatography on silica gel (chloroform-methanol gradient elution). A portion of this material (544 mg, 1.505 mmol) was dissolved in 300 mL ethyl acetate at 0oC, and HC1 gas was bubbled through the solution for 10 min. The reaction mixture 10 was allowed to come to room temperature over a 1 hour period. All volatiles were rotoevaporated under reduced pressure to give a white solid. This material was resuspended in 200 mL of ethyl acetate and treated with 10 ml of 10% sodium carbonate solution. After 10 minutes the phases were separated and the organic layer was dried (sodium 15 sulfate). The aqueous layer was concentrated to dryness and the residue was stirred with a chloroform-methanol mixture (4:1, v/v). The suspension was filtered and the filtrate was combined with the ethyl acetate extracts. The combined organic extracts were then concentrated and azeotropically dried with toluene to give 400 mg of the title compound 20 as a tan powder. Step F: trans-4S-(3,4-Difluorophenyl)-6-methyl-2-oxo-3- {1-[4-(1 oxopyridin-2-yl)-cyclohexyl]-3R-pyrrolidin-3-ylcarbamoyl} 1,2,3,4-tetrahydropyrimidine-5-carboxylic Acid Methyl Ester 25 Hydrochloride 2-[trans-4-(3R-3-Aminopyrrolidin-1-yl)-cyclohexyl]pyridine N-oxide (300 mg, 1.148 mmol) and (+)-3-(4-nitrophenoxycarbonyl)-4S-(3,4 Sdifluorophenyl)-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic 30 acid methyl ester (514 mg, 1.148 mmol) were combined in 20 mL of dry tetrahydrofuran at room temperature under nitrogen. The solution was stirred for 10 minutes, an additional 50 mg of (+)-3-(4 nitrophenoxycarbonyl)-4S-(3,4-difluorophenyl)-6-methyl-2-oxo-1,2,3,4 tetrahydropyrimidine-5-carboxylic acid methyl ester was added, and 35 stirring was continued for 1 hour. The reaction mixture was concentrated in vacuo and the residue was purified directly via preparative centrifugal chromatography on silica gel (first ethyl acetate - 139- WO 98/57641 PCT/US98/12673 and then chloroform-methanol gradient elution: CHC1,/MeOH, 100%/0% to 85%/15%) to give the title compound as the free base. The hydrochloride salt was prepared by dissolving the chromatographed product in ice cold ethyl acetate and treating this solution with a solution 5 of ethyl acetate saturated with HC1 gas. In this way, the title compound was obtained analytically pure as an off-white solid: m.p. 195-200 0 C. Anal. Calcd. for C 29

H

3 3F 2

N

5 0 5 s*HC1*2.2H 2 0: C, 53.78; H, 5.60; N, 10.59. Found: C, 53.94; H, 5.60; N, 10.59%. 10 EXAMPLE 66 trans-2-(3,4-Difluorophenyl)- 1-[1-(4-pyridin-2-yl-cyclohexyl)-3R pyrrolidin-3-ylcarbamoyl]-6-methoxymethyl- 2 -oxo-1,2,3,4-tetrahydro 15 pyrimidine F \F H~< 0 N O H The title compound was prepared in accordance with the following scheme: 20 -140- WO 98/57641 PCT/US98/12673 F F F F F / ONaOH . + ,* MeOH H 54 - 71% OHN HN H H 17 18 19 F 02YL 0 N o cO N O H 20 F \ F

NH

2 N N 21 0 N H Step A: To a solution of (+)-DHP 17 (4.63 g, 14.7 mmol) in a methanol (100 ml) was added sodium hydroxide (2.94 g, 73.6 mmol). The resulting 5 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 Cl 2 and H 2 0 then neutralized with 10% aqueous HC1 solution. The organic layer was dried over Na 2

SO

4 , concentrated, and purified by PCTLC (7% MeOH in CHC1 3 with 2% NH 4 OH) to afford a 2.65 g mixture 10 of 18 and 19 (71% yield). The 1H NMR was consistent with the assigned structure. MS (FAB) 255 (M+1) Step B (alternative to Step A): To a solution of (+)-DHP 17 (5.36 g, 17.0 15 mmol) in a methanol (150 ml) was added 1N NaOH (10 ml). The resulting mixture was refluxed at 90 OC for 16 hours. After cooling to - 141 - WO 98/57641 PCT/US98/12673 room temperature the solvent was removed in vacuo. The solid was dissolved in CH 2 2and H20 then neutralized with 10% aqueous HC1 solution. The organic layer was dried over Na2SO4, concentrated, and purified by PCTLC (7% MeOH in CHC1 3 with 2% NH 4 OH) to afford a 2.35 5 g mixture of 18 and 19 (54% yield). The 'H NMR is consistent with the assigned structure. MS (FAB) 255 (M+1) Step C: The title compound was prepared by reacting a mixture of 10 18 and 19 (1.93 g, 7.59 mmol) with 4-nitrophenoxycarbonyl chloride (1.5 equivalents) in LDA (1.1 equivalents) at -78oC until the reaction was completed as determined by GLC. 0.488 g (15% yield) of 20 was obtained. The 1 H NMR was consistent with the assigned structure. 15 Step D: The title compound was obtained from 20 (0.119 g, 0.284 mmol) using the procedure described for step F in Example 1. The 1 H NMR was consistent with the assigned structure.

C

28

H

33

F

2

N

5 0 3 MS (FAB) 526 (M+H). 20 EXAMPLE 67 (4S,5R)-trans-4-(3,4-Difluorophenyl-3-{1-[4-(4-fluoro-2 methoxycarbonylphenyl)-cyclohexyl]-(3R)-pyrrolidin-3-ylcarbamoyl}-2 oxo-oxazolidine-5-carboxylic acid methyl ester 25 F F F m0N N ,0C0 2 Me

CO

2 Me H O 0 Step A: trans-3,4-Difluorocinnamic acid methyl ester 30 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 -142- WO 98/57641 PCT/US98/12673 in vacuo. The residue was taken up in ethyl acetate (500 mL) and washed with saturated sodium bicarbonate (2 x 100 mL), brine (1 x 100 mL), dried with magnesium sulfate, and concentrated in vacuo to provide trans-3,4-difluorocinnamic acid methyl ester (10.7 g, 54 mmol, 5 100%) as a white solid. 1 H NMR dH (400 MHz, CDC1 3 ) 7.59 (d, 1H, J = 15.9), 7.34 (m, 1H), 7.24 (m, 1H) 7.18 (dd, 1H, J = 9.9, 2.0), 6.35 (d, 1H, J = 16.1), 3.81 (s, 3H). Step B: (2R, 3S)-N-Benzyloxycarbonyl-3-amino-3-(3,4 10 difluorophenyl)-2-hydroxypropionic acid methyl ester A solution of NaOH (4.1 g, 103 mmol) was prepared in 175 mL water. Potassium osmate dihydrate (491 mg, 1.3 mmol) was dissolved in 35 mL of this NaOH solution, resulting in a dark pink homogeneous 15 mixture. To a 1000 mL round bottom flask is added the remaining NaOH solution prepared above, 135 mL n-propanol and benzyl cabamate (9.8 g, 110 mmol). The suspension was stirred at ambient temperature for 30 min wherein the mixture was nearly homogeneous. The reaction flask was placed in a room temperature water bath and the surrounding 20 lights were turned off. Freshly prepared t-butylhypochlorite (11.2 mL, 103 mmol) was added dropwise with vigorous stirring, and the reaction stirred an additional 15 min. In a separate 250 mL round bottom flask was suspended trans-3,4-difluorocinnamic acid methyl ester (6.6 g, 33.3 mmol) and (DHQ) 2 PHAL (1.3 g, 1.7 mmol) in 100 mL n-propanol. The 25 suspension was added to the above reaction mixture and the residue rinsed into the reaction flask (2 x 10 mL). To the reaction was added the above prepared solution of potassium osmate dihydrate. The resulting green solution became amber/brown over 1 h. Sodium metabisulfite (66 g, 347 mmol) was added and the resulting suspension stirred 3 h when it 30 was poured into a separatory funnel containing ethyl acetate (200 mL) and the layers separated. The aqueous layer was extracted with ethyl acetate (150 mL) and the combined organics washed with brine (100-mL), dried with magnesium sulfate, and concentrated in vacuo to provide a pale yellow solid. The crude material was passed through silica (25% 35 ethyl acetate/hexane) to give (2R, 3S)-N-benzyloxycarbonyl-3-amino-3 (3,4-difluorophenyl)-2-hydroxypropionic acid methyl ester contaminated with benzyl carbamate. - 143- WO 98/57641 PCT/US98/12673 Step C: (2R, 3S)-3-Amino-3-(3,4-difluorophenyl)-2-hydroxypropionic acid methyl ester 5 (2R, 3S)-N-benzyloxycarbonyl-3-amino-3-( 3 ,4-difluorophenyl)-2 hydroxypropionic acid methyl ester (>12.2 g, 33.3 mmol maximum) was dissolved in 750 mL ethanol. The flask was purged and filled with argon three times. Palladium on carbon (2 g, 10% wt) was added under argon and the suspension was again purged and filled with argon three times. 10 The suspension was then purged, filled with hydrogen, and stirred 16 h. The suspension was purged, filled with argon three times, filtered through celite and concentrated in vacuo to give (2R, 3S)-3-amino-3-(3,4 difluorophenyl)-2-hydroxypropionic acid methyl ester (5.8 g, 25 mmol, 75% from trans-3,4-difluorocinnamic acid methyl ester). 15 'H NMR dH (400 MHz, CDC13) 7.26 (m, 1H), 7.15-7.08 (m, 2H), 4.28 (s, 2H), 3.82 (s, 3H), 2.48 (bs, 2H). Ste D: (4S,5R)-4-(3,4-Difluorophenyl)-2-oxo-oxazolidine-5-carboxylic acid methyl ester 20 To a solution of (2R, 3S)-3-amino-3-(3,4-difluorophenyl)-2 hydroxypropionic acid methyl ester (5.8 g, 25 mmol) in 250 mL tetrahydrofuran at 0 0 C was added N,N-diisopropylethylamine (8.75 mL, 50 mmol) and triphosgene (2.48 g, 8.4 mmol). The reaction was stirred 25 at 0OC for 30 min when it was poured over ethyl acetate (200 mL) and saturated sodium carbonate solution (100 mL). The layers were separated, the organic layer washed with saturated sodium carbonate solution (1 x 100 mL), dried with magnesium sulfate, and concentrated in vacuo to provide a pale yellow oil. The material was triturated with 30 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%) 1H NMR dH (400 MHz, CDC13) 7.25-7.20 (m, 2H), 7.15 (m, 1H), 6.33 35 (bs, 1H), 4.98 (d, 1H, J = 5.1), 4.72 (d, 1H, J = 5.3), 3.89 (s, 3H). FABMS M+H = 258 - 144- WO 98/57641 PCT/US98/12673 Step E: (4S,5R)-4-(3-,4-difluorophenyl)-2-oxo-oxazolidine-3,5 dicarboxylic acid methyl ester 3-(4-nitrophenyl) ester To a solution of (4S,5R)-4-(3,4-difluorophenyl)-2-oxo-oxazolidine-5 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 THF solution of lithium bis(trimethylsilyl)amide (3.5 mL, 3.5 mmol) dropwise. The reaction mixture was warmed to 0oC in an ice bath, stirred 30 minutes, then returned to -78 0 C. In a separate flask, p 10 nitrophenylchloroformate (714 mg, 3.54 mmol) was dissolved in anhydrous tetrahydrofuran (40 mL) under argon and cooled to -78 0 C. The above prepared anion solution was added via cannula to the 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 15 the resulting solution was washed with water (1 x 150 ml), brine (1 x 150 ml) and dried over magnesium sulfate and filtered. The volitiles were removed under reduced pressure and the resulting oil was triturated with diethyl ether. Ether was twice decanted from the resulting pale yellow solid to give (4S,5R)-4-(3-,4-difluorophenyl)-2-oxo 20 oxazolidine-3,5-dicarboxylic acid methyl ester 3-(4-nitrophenyl) ester (1.3 g, 3.1 mmol, 87%). FAB MS: m/z=423 (M+H) Step F: (4S,5R)-trans-4-(3,4-Difluorophenyl-3- 1-[4-(4-fluoro-2 25 methoxycarbonylphenyl)-cyclohexyl]-(3R)-pyrrolidin-3 ylcarbamoyl}-2-oxo-oxazolidine-5-carboxylic acid methyl ester To a solution of trans-2-[4-(3-amino-(3R)-pyrrolidin- 1 30 yl)cyclohexyl]-5-fluorobenzoic acid methyl ester (145 mg, 0.37 mmol) in dry, degassed N,N-dimethylformamide (3 mL) was added N,N diisopropylethylamine (130 pL, 0.74 mmol) followed (4S,5R)-4-(3-,4 difluorophenyl)-2-oxo-oxazolidine-3,5-dicarboxylic acid methyl ester 3-(4 nitrophenyl) ester (156 mg, 0.37 mmol). The reaction mixture was 35 stirred at ambient temperature for 4 h. The volatiles were removed under reduced pressure and residue dissolved in ethyl acetate, washed with 10% aqueous sodium carbonate solution (8 x 100 ml), brine (1 x 100 - 145- WO 98/57641 PCT/US98/12673 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 (2-5% methanol in ethyl acetate) to afford (4S,5R)-trans-4-(3,4-difluorophenyl-3- {1-[4-(4-fluoro-2 5 methoxycarbonylphenyl)-cyclohexyl]-(3R)-pyrrolidin-3-ylcarbamoyl}-2 oxo-oxazolidine-5-carboxylic acid methyl ester as a white foamy solid. The hydrochloride salt was prepared according to standard procedures and isolated as a white solid (125 mg, 0.2 mmol, 56%). 10 'H NMR dH (400 MHz, CD 3 OD) 7.46 (m, 2H), 7.33 (m, 2H), 7.24 (m, 2H), 5.54 (dd, J= 3.85, 1.83 Hz, 1H), 5.03 (dd, J= 3.84, 2.01 Hz, 1H), 3.89 (s, 3H), 3.87 (s,3H), 3.82-3.20 (m, 8H), 2.57 (m, 1H), 2.30 (m, 3H), 1.65 (m, 4H). Analysis: Calcd for C30 H32 N3 07 F3*HC1*0.15 Et20*0.85 H20, 15 C 55.14, H 5.47, N 6.31. Found: C 55.13, H 5.44, N 6.16 HPLC retention time = 9.082 min, purity= 96% FAB MS: m/z=604 (M+H) 20 The compounds in Examples 68-73 were prepared by procedures substantially as described above for Example 67, Step F. EXAMPLE 68 25 (4S,5R)-trans-4-(3,4-Difluorophenyl)-3-(1-{4-[4-fluoro-2-(2,2,2 trifluoroethoxy)phenyl]cyclohexyl}-(3R)-pyrrolidin-3-ylcarbamoyl)-2-oxo oxazolidine-5-carboxylic acid methyl ester F F F * I~ 0 ,C 2 F *"N NCO 2 Me

OCH

2

CF

3 H O H O 0 30 FAB MS: m/z=644 (M+H) Analysis: Calcd for C30H31N306F6*F3CCO2H, C 50.73, H 4.26, N 5.55. - 146- WO 98/57641 PCT/US98/12673 Found: C 50.34, H 4.13, N 5.50. EXAMPLE 69 (4S,5R)-trans-4-(3,4-Difluorophenyl)-2-oxo-3-[1-(4-pyridin-2-ylcyclohexyl) 5 (3R)-pyrrolidin-3-ylcarbamoyl]-oxazolidine-5-carboxylic acid methyl ester F F N CO 2 Me HO 0 FAB MS: m/z=529 (M+H) Analysis: Caled for C27H30N405F2 * 2HCl * 0.95H20 * 0.3EtOAc 10 C 52.85, H 5.80, N 8.55 Found: C 52.86, H 5.45, N 8.55 EXAMPLE 70 (4S,5R)-trans-4-(3,4-Difluorophenyl)-3-{1-[4-(4-fluoro-2 15 methoxyphenyl)cyclohexyl]-(3R)-pyrrolidin-3-ylcarbamoyl]-2-oxo oxazolidine-5-carboxylic acid methyl ester F F F mINa N

CO

2 Me F-QQ0 3AIN OMe H O 0 FAB MS: m/z=576 (M+H) 20 Analysis: Calcd for C29H32N306F3*HCl0.25H20 C 56.49, H 5.48, N 6.82. Found: C 56.52, H 5.50, N 7.03. - 147 - WO 98/57641 PCT/US98/12673 EXAMPLE 71 (4S,5R)-3-{ 1-[4-Cyano-4-(2-methoxyphenyl)cyclohexyl]-(3R)-pyrrolidin- 3 ylcarbamoyl}-4-(3,4-difluorophenyl)-2-oxo-oxazolidine-5-carboxylic acid methyl ester 5 F F N N N CO 2 Me OMe H N O H O 0 FAB MS: m/z=583 (M+H) Analysis: Calcd for C30H32N406F2 * F3CCO2H *0.6CH2C12 C 52.37, H 4.61, N 7.49. 10 Found: C 52.32, H 4.37, N 7.24. EXAMPLE 72 (4S,5R)-3-{ 1-[4-Cyano-4-(2-fluorophenyl)cyclohexyl]-(3R)-pyrrolidin-3 15 ylcarbamoyl}-4-(3,4-difluorophenyl)-2-oxo-oxazolidine-5-carboxylic acid methyl ester F F NC ' N ,CO 2 Me F H O 0 FAB MS: m/z=571 (M+H) Analysis: Calcd for C29H29N405F3*HCl*0.65H20 20 C 56.30, H 5.10, N 9.06. Found: C 56.33, H 5.22, N 8.83. EXAMPLE 73 25 (4S,5R)-trans-3-{1-[4-(2-Cyanophenyl)cyclohexyl]-(3R)-pyrrolidin-3 ylcarbamoyl}-4-(3,4-difluorophenyl)-2-oxo-oxazolidine-5-carboxylic acid methyl ester -148- WO 98/57641 PCT/US98/12673 F F *O*N N 'N CO 2 Me 0 FAB MS: m/z=553 (M+H) Analysis: Calcd for C29H30N405F2*HC1*0.5H20 C 58.24, H 5.39, N 9.37. 5 Found: C 58.23, H 5.42, N 9.07. EXAMPLE 74 (4S,5R)-trans-4-(3,4-difluorophenyl )-5-hydroxymethyl-2-oxo-oxazolidine 10 3-carboxylic acid {(1-[4-(4-fluorophenyl)cyclohexyl]-(3R)-pyrrolidin-3-yl} amide F F F -* i *N N ;.- 0 H H 0 15 Step A: (4S,5R) 4-(3,4-Difluorophenyl)-5-hydroxymethyl-oxazolidin 2-one 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 67, Step D] in tetrahydrofuran (10 mL) at 0OC was added a 2 M solution of 20 lithium borohydride in tetrahydrofuran (0.4 mL, 0.8 mmol). After stirring for 20 min at 0OC, saturated sodium bicarbonate (20 mL) was added and the mixture stirred at ambient temperature for 20 min. Ethyl acetate (50 mL) was added and the layers separated. The organic layer was washed with brine (1 x 10 mL), dried with magnesium sulfate, 25 filtered and concentrated in vacuo to provide (4S,5R) 4-(3,4 difluorophenyl)-5-hydroxymethyl-oxazolidin-2-one as a white solid (180 mg, 0.8 mmol, 100%) - 149- WO 98/57641 PCT/US98/12673 'IH NMR dH (400 MHz, CDClI) 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). 5 Step B: (4S,5R) 4-(3,4-Difluorophenyl)-5-(tetrahydropyran-2 yloxymethyl)-oxazolidin-2-one To a solution of (4S,5R) 4-(3,4-difluorophenyl)-5-hydroxymethyl oxazolidin-2-one (695 mg, 3.0 mmol) in dry dichloromethane (30 mL) 10 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) and washed with saturated sodium bicarbonate solution (2 x 100 ml), brine (1 x 100 ml), dried over 15 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 as a colorless oil (750 mg, 2.4 mmol, 80%). 20 FAB MS: m/z=314 (M+H*) Step C: ( 4 S,5R)-4-(3,4-Difluorophenyl)-2-oxo-5-(tetrahydropyran-2 yloxymethyl)-oxazolidine-3-carboxylic acid 4-nitrophenyl ester 25 To a solution of (4S,SR)-4-(3,4-difluorophenyl)-5-(tetrahydropyran 2-yloxymethyl)-oxazolidin2-one (910 mg, 2.9 mmol) in anhydrous tetrahydrofuran (60 mL) cooled to -78 0 C under argon, was added a THF solution of lithium bis(trimethylsilyl)amide (2.9 mL, 2.9 mmol) 30 dropwise. The reaction mixture was warmed to 0*C in an ice bath and stirred 45 min, and then returned to -78'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 cooled to -78*C. Then the above prepared anion solution was added via cannula 35 to the chloroformate solution and reaction mixture was stirred I h at 78'C. The reaction mixture was treated with ethyl acetate (150 mL). The resulting solution was washed with water (1 x 150 nml), brine (1 x 150 - 150- WO 98/57641 PCT/US98/12673 mL), dried over magnesium sulfate and filtered. The volatiles were removed under reduced pressure to give (4S,5R)-4-(3,4-difluorophenyl)-2 oxo-5-(tetrahydropyran-2-yloxymethyl)-oxazolidine-3-carboxylic acid 4 nitrophenyl ester as a yellow foam (1.3g, 2.8 mmol, 96%). 5 FAB MS: m/z=479 (M+H) Step D: (4S,5R)-trans-4-(3,4-Difluorophenyl)-5-(tetrahydropyran-2 yloxymethyl-2-oxo-oxazolidine-3-carboxylic acid {1-[4-(4 fluorophenyl)cyclohexyl]-(3R)-pyrrolidin-3-yl} amide 10 To a solution of trans- 1-[4-(4-fluorophenyl)cyclohexyl]-(3R) pyrrolidin-3-ylamine dihydrochloride (210 mg, 0.63 mmol) in dry tetrahydrofuran (4 mL) was added N,N-diisopropylethylamine (219 gL, 1.26 mmol) followed by (4S,5R)-4-(3,4-difluorophenyl)-2-oxo-5 15 (tetrahydropyran-2-yloxymethyl)-oxazolidine-3-carboxylic acid 4 nitrophenyl ester (300 mg, 0.63 mmol). The reaction mixture was stirred at ambient temperature for 18 h when the volatiles were removed under reduced pressure and residue dissolved in ethyl acetate (100 mL) and washed with 10% aqueous sodium carbonate solution (8 x 100 ml), brine 20 (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 (3:1 then 1:0 ethyl acetate:hexane to afford (4S,5R)-trans-4-(3,4-difluorophenyl)-5 (tetrahydropyran-2-yloxymethyl-2-oxo-oxazolidine-3-carboxylic acid {1-[4 25 (4-fluorophenyl)cyclohexyl]-(3R)-pyrrolidin-3-yl} amide as a white foam (153 mg, 0.25 mmol, 40%). Step E: (4S,5R)-trans-4-(3,4-Difluorophenyl)-5-hydroxymethyl-2-oxo oxazolidine-3-carboxylic acid {1-[4-(4 30 fluorophenyl)cyclohexyl]-(3R)-pyrrolidin-3-yl} amide To a solution of (4S,5R)-trans-4-(3,4-difluorophenyl)-5 (tetrahydropyran-2-yloxymethyl-2-oxo-oxazolidine-3-carboxylic acid {1-[4 (4-fluorophenyl)cyclohexyl]-(3R)-pyrrolidin-3-yl} amide (153 mg, 0.26 35 mmol) was dissolved in methanol (5 mL) and p-toluenesulfonic acid (50 mg, 0.26 mmol) was added. The reaction mixture was stirred at ambient temperature for 17 h. The volatiles were removed under reduced - 151- WO 98/57641 PCT/US98/12673 pressure and the residue was taken up in ethlyl acetate (100 mL) and washed with saturated sodium carbonate solution (3 x 100 ml), brine (1 x 100 ml), dried over magnesium sulfate and filtered. The volatiles were removed under reduced pressure to afford an oil which was lyophilized 5 at reduced pressure from acetonitrile and HC1 (1N aqueous solution) to afford (4S,5R)-trans-4-(3,4-difluorophenyl)-5-hydroxymethyl-2-oxo oxazolidine-3-carboxylic acid {1-[4-(4-fluorophenyl)cyclohexyl]-(3R) pyrrolidin-3-yl} amide. 10 HPLC: retention time= 8.05 min, purity=94% FAB MS: m/z=571 (M+H) Analysis: Calcd for C27 H30 N3 04 F3*HCl0.9 H 2 0 C 56.87, H 5.80, N 7.37. Found: C 56.68, H 5.40, N 7.66. 15 The compound of Example 75 was prepared by procedures substantially as described above for Example 74, Steps E and F. 20 EXAMPLE 75 (4S,5R)-trans-4-(3,4-Difluorophenyl)-5-hydroxymethyl-2-oxo-oxazolidine 3-carboxylic acid {1-[4-(4-fluoro-2-methoxyphenyl)cyclohexyl]-(3R) pyrrolidin-3-yl} amide F F F ,N N 4-0 H N U OMe H O 25 0 FAB MS: m/z=548 (M+H) Analysis: Calcd for C28H32N305F3 HCl*0.7H20 C 56.36, H 5.81, N 7.04. Found: C 56.35, H 5.82, N 6.76. 30 - 152- WO 98/57641 PCT/US98/12673 EXAMPLE 76 (4S,5R)-trans-4-(3,4-Difluorophenyl)-3-{1-[4-(4-fluoro-2 methoxyphenyl)cyclohexyl]-(3R)-pyrrolidin-3-ylcarbamoyl]- 2 -oxo oxazolidine-5-carboxamide F F F ,( :N 0 ,CONH2 OMe H -O 5 O The title compound was prepared by the procedure described in Example 67, followed by pressurized silica gel chromatography using an elution system containing chloroform saturated with ammonia gas and methanol. 10 F F F " N N ,CO2Me OMe H O 0 F F F , / N N N ,CONH2 OMe H ) O H O 0 FAB MS: mlz=561 (M+H) WO 98/57641 PCT/US98/12673 Analysis: Calcd for C28H31N405F3 C 59.99, H 5.57, N 9.99. Found: C 59.84, H 5.47, N 9.85. 5 The compounds of Examples 77- 79 were prepared using procedures substantially as described above for Example 76. EXAMPLE 77 10 (4S,5R)-trans-4-(3,4-Difluorophenyl)-3-{1-[4-(4-fluorophenyl)cyclohexyl] (3R)-pyrrolidin-3-ylcarbamoyl]-2-oxo-oxazolidine-5-carboxamide F F F ,,/~Nc N N

CONH

2 H )/O O FAB MS: m/z=531 (M+H) Analysis: Calcd for C27H29N404F3 .0.05H20 15 C 61.02, H 5.52, N 10.54. Found: C 61.07, H 5.47, N 10.51. EXAMPLE 78 20 (4S,5R)-trans-4-(3,4-Difluorophenyl)-3-{1-[4-(2-fluorophenyl)cyclohexyl] (3R)-pyrrolidin-3-ylcarbamoyl]-2-oxo-oxazolidine-5-carboxamide F F Q O ,"'Na N N ,,,,CONH 2 F H O O 0- 154 - 154 - WO 98/57641 PCT/US98/12673 Analysis: Calcd for C27H29N404F3 C 61.12, H 5.51, N 10.56. Found: C 61.20, H 5.67, N 10.46. 5 EXAMPLE 79 (4S,5R)-trans-3-{1-[4-(2-Cyano-4-fluorophenyl)cyclohexyl]-(3R)-pyrrolidin 3-ylcarbamoyl}-4-(3,4-Difluorophenyl)-2-oxo-oxazolidine-5-carboxamide F F F ,,N N ,CONH 2 CN H >- O 10 O FAB MS: m/z=556 (M+H) Analysis: Caled for C28H28N504F3 .HCl * 0.85H20 * 0.35EtOAc C 55.33, H 5.29, N 10.98. Found: C 55.33, H 4.90, N 10.65. 15 EXAMPLE 80 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 20 oxo-2,3,4,5-tetrahydropyrimidine F F F F O N HN H - 155 - WO 98/57641 PCT/US98/12673 To a solution of (+)-4-(3,4-difluorophenyl)-6-methoxymethyl 2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid methyl ester (4.63 g, 14.7 mmol) in a methanol (100 ml) was added sodium hydroxide (2.94 g, 73.6 mmol). The resulting mixture was refluxed at 90 OC for 16 hours. 5 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 Na 2

SO

4 , concentrated, and purified by PCTLC (7% MeOH in CHC1 3 with 2%

NH

4 OH) to afford a 2.65 g mixture of the title compounds (71% yield). 10 The 1 H NMR was consistent with the assigned structure. MS (FAB) 255 (M+1) EXAMPLE 81 Mixture of 4S-4-(3,4-difluorophenyl)-6-methoxymethyl-2-oxo-1,2,3,4 15 tetrahydropyrimidine and 4S-4-(3,4-difluorophenyl)-6-methoxymethyl-2 oxo-2,3,4,5-tetrahydropyrimidine F F F F O N OHN O N 0 N N 0N H 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, 20 17.0 mmol) in a methanol (150 ml) was added 1N NaOH (10 ml). 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 H20 then neutralized with 10% aqueous HC1 solution. The organic layer was dried over Na 2 S0 4 , concentrated, and 25 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) - 156- WO 98/57641 PCT/US98/12673 EXAMPLE 82 4S-4-(3,4-Difluorophenyl)-6-methoxymethyl-3-(4-nitrophenoxycarbonyl)- 2 oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid methyl ester F F 0 2 N O , ON H 5 The title compound was prepared by treating the mixture obtained from Example 80 or Example 81 (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 10 was obtained in a 15% yield. The 1 H NMR was consistent with the assigned structure. EXAMPLE 83 Mixture of 4R-4-(3,4-difluorophenyl)-6-methoxymethyl- 2 -oxo-1,2,3,4 15 tetrahydropyrimidine and 4R-4-(3,4-difluorophenyl)-6-methoxymethyl-2 oxo-2,3,4,5-tetrahydropyrimidine F F F F O NO-N O N H The title compounds were prepared from 4R-4-(3,4 difluorophenyl)-6-methoxymethyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5 20 carboxylic acid methyl ester (5.0 g, 17.7 mmol) using the procedure described in Example 80. A mixture of 2.0 g of the title compounds was - 157- WO 98/57641 PCT/US98/12673 obtained in 50% yield. The 1 H NMR was consistent with the assigned structure. MS (FAB) 255 (M+1) 5 Compounds of the invention can be prepared by reacting the products obtained in Example 82 with an aminopiperidine, e.g., in accordance with Scheme 3. Compounds of the invention can also be prepared by preparing a nitrophenoxy derivative of the compound of Example 83 in accordance with the procedure set forth in Example 82 10 and then reacting the derivative with an aminopiperidine in accordance with Scheme 3. The following compounds were prepared in accordance with 15 procedures set forth in the preceding Examples and Schemes. EXAMPLE 84 trans-(4S)-3-{1-[4-(2-Methoxyphenyl)cyclohexyl]azetidin-3 20 ylmethylcarbamoyl}-4-(3,4-difluorophenyl)-6-methoxymethyl-2-oxo 1,2,3,4-tetrahydropyrimidine-5-carboxylic acid methyl ester hydrochloride O F 1H NMR (CDC13, 400 MHz) consistent with assigned 25 structure. FABLRMS m/e 613.4 g/mole (M++H, C32H38F2N40 6 = 612.67 g/mole.) - 158 0 0 Hi

NH

N 1 H NMR (CDCl 3 , 400 MHz) consistent with assigned 25 structure. FABLRMS m/e 613.4 g/mole (M++H, C 3 2

H

3 8

F

2

N

4 0 6 = 612.67 g/mole.) -158- WO 98/57641 PCT/US98/12673 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; 97% pure. Anal. Calcd for C 3 2

H

3 8

F

2

N

4 0 6 * 1.0 HC1, 0.3 CHC1 3 and 5 0.35 H 2 0: C = 57.45, H = 5.97, N = 8.30. Found: C = 57.48, H = 5.97, N = 8.40. EXAMPLE 85 10 trans-(4S)-4-(3,4-Difluorophenyl)-2-oxo-oxazolidine-3-carboxylic acid{1-[4 (2-methoxyphenyl)-cyclohexyl] azetidin-3-ylmethyl-amide hydrochloride F F N~N 0 0 1 H NMR (CDC1 3 , 400 MHz) consistent with assigned structure. 15 FABLRMS m/e 500.3 g/mole (M++H, C 2 7

H

3 1

F

2

N

3 0 4 = 499.45 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% pure. 20 Anal. Calcd for C 2 7

H

3 1

F

2

N

3 0 4 1.35 HC1 and 1.1 Et 2 0: C = 59.83, H = 6.93, N = 9.56. Found: C = 60.17, H = 6.57, N = 6.28.

WO 98/57641 PCT/US98/12673 EXAMPLE 86 trans-(4S)-3- { 1-[4-(2-Cyanophenyl)cyclohexyl]azetidin-3 ylmethylcarbamoyl}-4-(3,4-difluorophenyl)-6-methoxymethyl-2-oxo 1,2,3,4-tetrahydropyrimidine-5-carboxylic acid methyl ester 5 hydrochloride CN F o N H NH O 1 H NMR (CDC1 3 , 400 MHz) consistent with assigned structure. FABLRMS m/e 608 g/mole (M++H, C 3 2

H

3 5

F

2

N

5 0 5 = 607.65 10 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; 97% pure. Anal. Calcd for C 3 2

H

3 5

F

2

N

5 0 5 * 1.0 HC1 and 0.8 H 2 0: C = 15 58.36, H = 5.76, N = 10.64. Found: C = 58.40, H = 5.80, N = 10.42. EXAMPLE 87 trans-(4S)-4-(3,4-Difluorophenyl)-2-oxo-oxazolidine-3-carboxylic acid {1 20 [4-(2-cyanophenyl)-cyclohexyl]azetidin-3-ylmethyl-amide hydrochloride SF CN Na H 0 0 - 160- WO 98/57641 PCT/US98/12673 1 H NMR (CDC1 3 , 400 MHz) consistent with assigned structure. FABLRMS m/e 495 g/mole (M++H, C 2 7

H

2 8

F

2

N

4 0 3 = 494.54 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; >97% pure. Anal. Called for C 2 7

H

2 8

F

2

N

4 0 3 * 1.0 HC1 and 0.85 H 2 0: C = 59.36, H = 5.66, N = 10.26. Found: C = 59.48, H = 5.84, N = 9.87. 10 EXAMPLE 88 (High Rf) (4S)-3-{1-[4-(2-pyridyl)cyclohexyl]azetidin-3-1methylcarbamoyl} 4-(3,4-difluorophenyl)-6-methoxymethyl-2-oxo-1,2,3,4 15 tetrahydropyrimidine-5-carboxylic acid methyl ester hydrochloride \ F 0 0 /O N 0 N H NH O 1 H NMR (CDC1 3 , 400 MHz) consistent with assigned structure. FABLRMS m/e 584 g/mole (M++H, C 3 0

H

3 5

F

2

N

5 0 5 = 583.63 20 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 inm; 99% pure. Anal. Calcd for C 3 0

H

35

F

2

N

5 0 5 * 2.0 HC1, 0.5 CHC1 3 and 25 0.75 Et 2 0: C = 52.19, H = 5.75, N = 9.09. Found: C = 52.21, H = 5.88, N = 9.12. - 161- WO 98/57641 PCT/US98/12673 EXAMPLE 90 (High Rf) (4S)-4-(3,4-Difluorophenyl)-2-oxo-oxazolidine-3-carboxylic acid {1-[4-(2-pyridyl)-cyclohexyl] azetidin-3-ylmethyl-amide hydrochloride F F N O 0 5 1 H NMR (CDC1 3 , 400 MHz) consistent with assigned structure. FABLRMS m/e 471 g/mole (M++H, C 2 5

H

2 8

F

2

N

4 0 3 = 470.51 g/mole.) HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; 10 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 8

F

2

N

4 0 3 * 2.0 HC1, 0.4 CHC1 3 and 0.45 Et 2 0: C = 52.31, H = 5.63, N = 8.97. Found: C = 52.33, H = 5.60, N = 9.15. 15 EXAMPLE 91 (Low Rf) (4S)-3-{1-[4-(2-pyridyl)cyclohexyl]azetidin-3-ylmethylcarbamoyl} 4-(3,4-difluorophenyl)-6-methoxymethyl-2-oxo-1,2,3,4 20 tetrahydropyrimidine-5-carboxylic acid methyl ester hydrochloride F 0 N 0 N H NH N - 162 - WO 98/57641 PCT/US98/12673 1 H NMR (CDC1 3 , 400 MHz) consistent with assigned structure. FABLRMS m/e 584 g/mole (M++H, C 3 0

H

3 5

F

2

N

5 0 5 = 583.63 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; 99% pure. Anal. Calcd for C 3 0

H

3 5

F

2

N

5 0 5 * 2.0 HC1 and 2.35 Et 2 0: C = 51.63, H = 5.88, N = 10.04. Found: C = 51.63, H = 5.83, N = 10.20. 10 EXAMPLE 92 (Low Rf) (4S)-4-(3,4-Difluorophenyl)-2-oxo-oxazolidine-3-carboxylic acid {1-[4-(2-pyridyl)-cyclohexyl]azetidin-3-ylmethyl-amide hydrochloride F F N OaN H0 15 O 1 H NMR (CDC1 3 , 400 MHz) consistent with assigned structure. FABLRMS mn/e 471 g/mole (M++H, C 2 5

H

2 8

F

2

N

4 0 3 = 470.51 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; 99% pure. Anal. Calcd for C 2 5

H

2 8

F

2

N

4 0 3 * 2.0 HC1, 0.15 CHC1 3 and 1.5 H 2 0: C = 51.34, H = 5.68, N = 9.52. Found: C = 51.34, H = 5.63, N = 25 9.64. - 163 - WO 98/57641 PCT/US98/12673 EXAMPLE 93 trans-(4S)-3-{1-[4-(2-Cyanophenyl)cyclohexyl]azetidin-3-ylcarbamoyl}-4 (3,4-difluorophenyl)-6-methoxymethyl-2-oxo-1,2,3,4 tetrahydropyrimidine-5-carboxylic acid methyl ester CN ,, F N0 N 0 Oo/AI. O NH N O OO NO 5 H 1 H NMR (CDC1 3 , 400 MHz) consistent with assigned structure. FABLRMS m/e 594 g/mole (M++H, C 3 1

H

3 3

F

2

N

5 0 5 = 593.63 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; 100% pure. Anal. Calcd for C 3 1

H

3 3

F

2

N

5 0 5 * 0.3 H 2 0: C = 62.15, H = 5.65, N = 11.69. Found: C = 62.19, H = 5.75, N = 11.39. 15 EXAMPLE 94 trans-(4S)-4-(3,4-Difluorophenyl)-2-oxo-oxazolidine-3-carboxylic acid {1 [4-(2-cyanophenyl)-cyclohexyl]azetidin-3-yl-amide CN F IIIF F N, NH M 0 0 20 0 - 164- WO 98/57641 PCT/US98/12673 1 H NMR (CDC1 3 , 400 MHz) consistent with assigned structure. FABLRMS m/e 481 g/mole (M++H, C 2 6

H

2 6

F

2

N

4 0 3 = 480.51 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; 100% pure. Anal. Calcd for C 2 6

H

2 6

F

2

N

4 0 3 * 0.2 CHC1 3 and 0.2 H 2 0: C = 63.84, H = 5.44, N = 11.43. Found: C = 63.85, H = 5.30, N = 11.41. 10 EXAMPLE 95 trans-(4S)-3-{ 1-[4-(2-Methoxyphenyl)cyclohexyl] azetidin-3-ylcarbamoyl}-4 (3,4-difluorophenyl)-6-methoxymethyl-2-oxo-1,2,3,4 15 tetrahydropyrimidine-5-carboxylic acid methyl ester 0 F F N O OO N H 1 H NMR (CDC1 3 , 400 MHz) consistent with assigned structure. FABLRMS m/e 599 g/mole (M++H, C 3 1

H

3 6

F

2

N

4 0 6 = 598.64 20 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 3 1

H

3 6

F

2

N

4 0 6 : C = 62.19, H = 6.06, N = 25 9.35. Found: C = 62.18, H = 5.96, N = 9.28. - 165- WO 98/57641 PCT/US98/12673 EXAMPLE 96 trans-(4S)-4-(3,4-Difluorophenyl)-2-oxo-oxazolidine-3-carboxylic acid {1 [4-(2-methoxyphenyl)-cyclohexyl]azetidin-3-yl-amide 0 F F NH O0 O 5 1 H NMR (CDC1 3 , 400 MHz) consistent with assigned structure. FABLRMS m/e 486 g/mole (M++H, C 2 6

H

2 9

F

2

N

3 0 4 = 485.53 g/mole.) HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 mm; 10 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; 100% pure. Anal. Calcd for C 2 6

H

2 9

F

2

N

3 0 4 : C = 64.31, H = 6.02, N = 8.65. Found: C = 64.28, H = 6.04, N = 8.68. 15 EXAMPLE 97 (Low Rf) (4S)-3-{1-[4-(2-pyridyl)cyclohexyl]azetidin-3-ylcarbamoyl}-4-(3,4 difluorophenyl)-6-methoxymethyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5 carboxylic acid methyl ester hydrochloride F 0F N NH C N 0 0N 20 H - 166- WO 98/57641 PCT/US98/12673 1 H NMR (CDC1 3 , 400 MHz) consistent with assigned structure. FABLRMS m/e 570 g/mole (M++H, C 2 9

H

3 3

F

2

N

5 0 5 = 466.577 g/mole.) 5 HPLC (Vydac; C18; diameter = 4.6 mm; length = 150 nunmm; 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 9

H

3 3

F

2

N

5 0 5 : C = 61.12, H = 6.04, N = 11.88. Found: C = 61.14, H = 5.90, N = 11.88. 10 EXAMPLE 98 (Lower Rf) (4S)-4-(3,4-Difluorophenyl)-2-oxo-oxazolidine-3-carboxylic acid {1-[4-(2-pyridyl)-cyclohexyl]azetidin-3-ylmethyl-amide F F NNNH ONO 15 O 1H NMR (CDC13, 400 MHz) consistent with assigned structure. FABLRMS m/e 457 g/mole (M++H, C 24

H

26

F

2

N

4 0 4 = 456.49 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. Anal. Calcd for C 2 4

H

2 6

F

2

N

4 0 4 * 0.2 CHC13 and 0.45 EtOAc: C = 60.05, H = 5.78, N = 10.77. Found: C = 59.92, H = 5.77, N = 25 10.79. -167- WO 98/57641 PCT/US98/12673 EXAMPLE 99 trans-(4S)-3-{1-[4-(2-Carboxymethoxyphenyl)cyclohexyl]azetidin-3 ylmethylcarbamoyl}-4-(3,4-difluorophenyl)-6-methoxymethyl-2-oxo 1,2,3,4-tetrahydropyrimidine-5-carboxylic acid methyl ester SF N H 0 OO N 0' 5 H 1 H NMR (CDC13, 400 MHz) consistent with assigned structure. FABLRMS m/e 641 g/mole (M++H, C 3 3

H

38

F

2

N

4 0 7 = 640.69 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; 97% pure. Anal. Calcd for C 3 3

H

3 8

F

2

N

4 0 7 * 0.2 CHC1 3 and 0.25 EtOAc: C = 59.82, H = 5.90, N = 8.16. Found: C = 59.81, H = 5.80, N = 8.13. 15 EXAMPLE 100 trans-(4S)-4-(3,4-Difluorophenyl)-2-oxo-oxazolidine-3-carboxylic acid {1 [4-(2-carboxymethoxyphenyl)- cyclohexyl]azetidin-3-ylmethyl-amide F I/ F N2 H 20 0 - 168 - WO 98/57641 PCT/US98/12673 1 H NMR (CDC1 3 , 400 MHz) consistent with assigned structure. FABLRMS m/e 528 g/mole (M++H, C 2 8

H

3 1

F

2

N

3 0 5 = 527.57 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. Calcd for C 2 8

H

3 1

F

2

N

3 0 5 * 0.35 CHC1 3 and 0.1 EtOAc: C = 59.72, H = 5.61, N = 7.27. Found: C = 59.72, H = 5.78, N = 7.37. 10 EXAMPLE 101 trans-(4S)-3-{1-[4-(2-Carboxyethoxyphenyl)-cyclohexyl]azetidin-3 ylmethylcarbamoyl}-4-(3,4-difluorophenyl)-6-methoxymethyl-2-oxo 15 1,2,3,4-tetrahydropyrimidine-5-carboxylic acid methyl ester F F F N H N O 0O N Os0 H 1 H NMR (CDC1 3 , 400 MHz) consistent with assigned structure. FABLRMS m/e 655 g/mole (M++H, C 3 4

H

4 0

F

2

N

4 0 7 = 654.71 20 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. Anal. Calcd for C 3 4

H

4 0

F

2

N

4 0 7 0.3 EtOAc: C = 62.06, 1-= 25 6.27, N = 8.23. Found: C = 61.91, H = 6.09, N = 8.25. - 169- WO 98/57641 PCT/US98/12673 EXAMPLE 102 trans-(4S)-3-{1-[4-(2-Carboxyethoxyphenyl)-cyclohexyl]azetidin-3 ylmethylcarbamoyl}-4-(3,4-difluorophenyl)-2-oxo-1,2,3,4-tetrahydro-4H furo[3,4-d]pyrimidine O0 H N O ON 2F 5 H 1 H NMR (CDC1 3 , 400 MHz) consistent with assigned structure. FABLRMS m/e 609 g/mole (M++H, C 3 2

H

3 4

F

2

N

4 0 6 = 608.64 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; 98% pure. Anal. Calcd for C 3 2

H

3 4

F

2

N

4 0 6 0.4 EtOAc: C = 62.67, H = 5.82, N = 8.70. Found: C = 62.31, H = 5.71, N = 8.83. 15 EXAMPLE 103 trans-(4S)-4-(3,4-Difluorophenyl)-2-oxo-oxazolidine-3-carboxylic acid {1 [4-(2-carboxyethoxyphenyl)-cyclohexyl]azetidin-3-ylmethyl-amide F N H N 20 O - 170 - WO 98/57641 PCT/US98/12673 1 H NMR (CDC1 3 , 400 MHz) consistent with assigned structure. FABLRMS m/e 542 g/mole (M++H, C 2 9

H

3 3

F

2

N

3 0 5 = 541.59 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. Calcd for C 2 9

H

3 3

F

2

N

3 0 5 0.3 EtOAc: C = 63.85, H = 6.28, N = 7.40. Found: C = 63.54, H = 6.12, N = 7.43. 10 EXAMPLE 104 (Diast A) (4S)-4-(3,4-Difluorophenyl)-2-oxo-oxazolidine-3-carboxylic acid{ 1-[4-(2-pyridyl)cyclohexyl]-3-hydroxy-pyrrolidin-4-yl}amide F N ~.."OH H N 15 O 1 H NMR (CDC1 3 , 400 MHz) consistent with assigned structure. FABLRMS m/e 487.2 g/mole (M++H, C 2 5

H

2 8

F

2

N

4 0 4 = 486.51 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. 25 EXAMPLE 105 (Diast B) (4S)-4-(3,4-Difluorophenyl)-2-oxo-oxazolidine-3-carboxylic acid{ 1-[4-(2-pyridyl)cyclohexyl]-3-hydroxy-pyrrolidin-4-yl}amide - 171- WO 98/57641 PCT/US98/12673 0.0 N '~ F F HN 0 1 H NMR (CDC1 3 , 400 MHz) consistent with assigned structure. FABLRMS m/e 487.2 g/mole (M++H, C 25

H

2 8

F

2

N

4 0 4 = 5 486.51 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 106 (Diast A) (4S)-4-(3,4-Difluorophenyl)-2-oxo-oxazolidine-3-carboxylic acid{ 1-[4-(2-cyanophenyl)cyclohexyl]-3-hydroxy-pyrrolidin-4-yl}lamide -CN F F N..aOH I H N O 0 15 1 H NMR (CDC1 3 , 400 MHz) consistent with assigned structure. FABLRMS m/e 511 g/mole (M++H, C 2 7

H

28

F

2

N

4 0 4 = 510.54 g/mole.) -172- WO 98/57641 PCT/US98/12673 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 7

H

2 8

F

2

N

4 0 4 * 0.5 H 2 0 and 0.25 Et 2 0: C 5 = 62.50, H = 5.90, N = 10.41. Found: C = 62.55, H = 5.69, N = 10.36. EXAMPLE 107 (Diast B) (4S)-4-(3,4-Difluorophenyl)-2-oxo-oxazolidine-3-carboxylic 10 acid{ 1-[4-(2-cyanophenyl)cyclohexyl]-3-hydroxy-pyrrolidin-4-yll}amide ";: CN F F N -

"

OH ' HN OO 0 O 0 1 H NMR (CDC1 3 , 400 MHz) consistent with assigned structure. FABLRMS m/e 511 g/mole (M++H, C 2 7

H

2 8

F

2

N

4 0 4 = 510.54 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; 99% pure. Anal. Called for C 2 7

H

2 8

F

2

N

4 0 4 * 0.4 H 2 0 and 0.4 Et 2 0: C = 20 62.75, H = 6.04, N = 10.24. Found: C = 62.77, H = 5.71, N = 10.23. - 173- WO 98/57641 PCT/US98/12673 EXAMPLE 108 (Racemic @ pyrrolidine) (4S)-3- {1-[4-(2-Pyridyl)-cyclohexyl]-3-hydroxy pyrrolidin-4-ylcarbamoyl}-4-(3,4-difluorophenyl)-6-methyl-2-oxo-1,2,3,4 tetrahydropyrimidine-5-carboxylic acid methyl ester U. FF N

....

oH H N O H N, < NN 0~~ o O) N 5 H 1 H NMR (CDC1 3 , 400 MHz) consistent with assigned structure. FABLRMS m/e 600 g/mole (M++H, C 3 0

H

3 5

F

2

N

5 0 6 = 599.63 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; 98% pure. Anal. Calcd for C 3 0

H

3 5

F

2

N

5 0 6 * 0.55 H 2 0 and 0.35 Et 2 0: C = 59.34, H = 6.28, N = 11.02. Found: C = 59.32, H = 5.99, N = 10.98. 15 EXAMPLE 109 trans-(4S,5S)-4-(3,4-Difluorophenyl)-5-methyl-2-oxo-oxazolidine-3 carboxylic acid {1-[4-(2-cyanophenyl)-cyclohexyl]3-hydroxy-azetidin-3 20 ylmethyl-amide ,CN F .. F N N H OH 0 - 174- WO 98/57641 PCT/US98/12673 1 H NMR (CDC1 3 , 400 MHz) consistent with assigned structure. FABLRMS m/e 525.0 g/mole (M++H, C 2 8

H

3 0

F

2

N

4 0 4 = 524.56 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; 99% pure. Anal. Calcd for C 2 8

H

3 0

F

2

N

4 0 4 * 0.40 H 2 0 and 1.30

CH

2 C1 2 : C = 54.80, H = 5.24, N = 8.73. Found: C = 54.78, H = 5.25, N = 10 8.67. EXAMPLE 110 trans-(4S,5S)-4-(3,4-Difluorophenyl)-5-methyl-2-oxo-oxazolidine-3 15 carboxylic acid {1-[4-(2-pyridyl)-cyclohexyl]3-hydroxy-azetidin-3-ylmethyl amide F OF 0 O 1 H NMR (CDC1 3 , 400 MHz) consistent with assigned structure. 20 FABLRMS m/e 485 g/mole (M++H, C 2 6

H

3 0

F

2

N

4 0 3 = 484.54 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; 97% pure. 25 Anal. Calcd for C 2 6

H

3 0

F

2

N

4 0 3 * 0.15 CH 2 C1 2 : C = 63.15, H = 6.14, N = 11.27. Found: C = 63.40, H = 6.00, N = 11.24. - 175- WO 98/57641 PCT/US98/12673 EXAMPLE 111 trans-(4S,5S)-4-(3,4-Difluorophenyl)-5-methyl-2-oxo-oxazolidine-3 carboxylic acid {1-[4-(2-cyanophenyl)-cyclohexyl]azetidin-3-ylmethyl amide CN F Na, H N~ N> 5 0O 1 H NMR (CDC1 3 , 400 MHz) consistent with assigned structure. FABLRMS m/e 509 g/mole (M++H, C 2 8

H

3 0

F

2

N

4 0 3 = 508.56 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; 97% pure. Anal. Calcd for C 2 8

H

3 0

F

2

N

4 0 3 * 0.05 Et 2 0 and 0.10

CH

2 C1 2 : C = 65.27, H = 5.94, N = 10.76. Found: C = 65.36, H = 65.36, N = 15 10.73. EXAMPLE 112 trans-(4±)-3-{ 1-[4-(2-Cyanophenyl)cyclohexyl]azetidin-3 20 ylmethylcarbamoyl}-4-(3,4-difluorophenyl)-2-oxo-1,2,3,4 tetrahydropyrimidine-5-carboxylic acid methyl ester - 176- WO 98/57641 PCT/US98/12673 CN F I C F F Co0 H 1 H NMR (CDC1 3 , 400 MHz) consistent with assigned structure. FABLRMS m/e 564 g/mole (M++H, C 3 0

H

3 1

F

2

N

5 0 4 = 563.60 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; 98% pure. Anal. Calcd for C 3 0

H

3 1

F

2

N

5 0 4 * 0.15 Et 2 0 and 0.15 10 CH 2 C1 2 : C = 62.86, H = 5.63, N = 11.92. Found: C = 62.88, H = 5.74, N = 11.99. EXAMPLE 113 15 trans-(4±)-3-{1-[4-(2-Cyanophenyl)cyclohexyl]3-hydroxy-azetidin-3 ylmethylcarbamoyl}-4-(3,4-difluorophenyl)-2-oxo-1,2,3,4 tetrahydropyrimidine-5-carboxylic acid methyl ester CN F F " N " H ' 0 CN I 0F OH 0o H 1 H NMR (CDC1 3 , 400 MHz) consistent with assigned 20 structure. - 177 - WO 98/57641 PCT/US98/12673 FABLRMS m/e 580 g/mole (M++H, C 3 0

H

3 1

F

2

N

5 0 5 = 579.60 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; 98% pure. Anal. Calcd for C 3 0

H

3 1

F

2

N

5 0 5 * 0.05 CH 2 C1 2 : C = 61.81, H = 5.37, N = 12.00. Found: C = 61.61, H = 5.57, N = 12.22. 10 EXAMPLE 114 trans-(4±)-3-{1-[4-(2-Pyridyl)cyclohexyl]3-hydroxy-azetidin-3 ylmethylcarbamoyl}-4-(3,4-difluorophenyl)-2-oxo-1,2,3,4 tetrahydropyrimidine-5-carboxylic acid methyl ester F F H 0 O N H 15 1H NMR (CDC1 3 , 400 MHz) consistent with assigned structure. FABLRMS m/e 540 g/mole (M++H, C 2 8

H

3 1

F

2

N

5 0 4 = 539.58 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; 95% pure. Anal. Calcd for C 2 8

H

3 1

F

2

N

5 0 4 * 0.05 Et 2 0 and 0.45

CH

2 Cl 2 : C = 59.17, H = 5.62, N = 12.04. Found: C = 59.18, H = 5.62, N = 12.04. 25 EXAMPLE 115 trans-(3R,4S,5S)-4-(3 ,4-Difluorophenyl)-5-methyl-2-oxo-oxazolidine-3 carboxylic acid {1-[4-(2-pyridyl)-cyclohexyl]azetidin-3-ylmethyl-amide - 178- WO 98/57641 PCT/US98/12673 F SH

CH

3 1 H NMR (CDCl 3 , 400 MHz) consistent with assigned structure. FABLRMS m/e 485 g/mole (M++Hl, C 2 6

H

3 0

F

2

N

4 0 3 = 484.548 5 g/mole.) HPLC (Vydac; 018; diameter = 4.6 rmm; length = 150 mm; gradient = H 2 0 [0.1% H 3

PO

4 1 - CH 3 CN, 95% - 5%, 5% - 95%, over 16 minutes, 2 ml/min flow rate) focus = 215 nm; 96.4% pure. 10 EXAMPLE 116 As a specific embodiment of an oral composition, 100 mg of the compound of Example 1 is formulated with sufficient finely divided lactose to provide a total amount of 580 to 590 mg to fill a size O hard gel 15 capsule. EXAMPLE 117 20 Screening assay: Alpha la Adreneric Receptor Bindine Membranes prepared from the stably transfected human alpha la cell line (ATCC CRL 11140) were used to identify compounds that bind to the human alpha la adrenergic receptor. These competition binding reactions (total volume = 200 p.l) contained 50 mM Tris-HCI pH. 25 7.4, 5 mM EDTA, 150 mM NaCI, 100 pM [125 J]-HEAT, membranes prepared from the alpha la cell line and increasing amounts of unlabeled ligand. Reactions were incubated at room temperature for one hour with shaking. Reactions were filtered onto Whatman GF/C glass fiber filters with a Inotec 96 well cell harvester. Filters were 30 washed three times with ice cold buffer and bound radioactivity was - 179- WO 98/57641 PCT/US98/12673 determined (Ki). Representative compounds of the present invention were found to have Ki values < 50 nM. EXAMPLE 118 5 Selective Binding assays 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 10 alpha la adrenergic receptor. These competition binding reactions (total volume = 200 Pl) contained 50 mM Tris-HC1 pH. 7.4, 5 mM EDTA, 150 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 15 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). All of the compounds of the present invention prepared in 20 the foregoing Examples were found to have alpha la Ki values of less than 50 nM as determined via the screening assay described in Example 117, except for Examples 12 (<200 nM), 16 (ca. 800 nM) and 20 (inactive). All of the compounds were further found to be at least about 50-fold more selective in binding to alpha la receptors versus binding to the alpha lb 25 and alpha ld receptors, as determined via the selective binding assay described in the preceding paragraph, except for Examples 12 (at least about 3-fold), 16 (at least about 8-fold), 20, and 78 (about 37-fold). All of the compounds except for those of Examples 8, 12, 14, 16, 19, 20, 21, 24, 30, 40, 47, 50, 51, 52, 67, 69, 70, 76, 77 and 78 were at least about 100-fold more 30 selective in binding to alpha la receptors versus alpha lb and ld receptors. - 180- WO 98/57641 PCT/US98/12673 EXAMPLE 119 EXEMPLARY COUNTERSCREENS 5 1. Assay Title: Dopamine D2, D3, D4 in vitro screen Objective of the Assay: The objective of this assay is to eliminate agents which specifically affect binding of [3H] spiperone to cells expressing human 10 dopamine receptors D2, D3 or D4. Method: Modified from VanTol et al (1991); Nature (Vol 350) Pg 610 613. 15 Frozen pellets containing specific dopamine receptor subtypes stably expressed in clonal cell lines are lysed in 2 ml lysing buffer (10mM Tris-HCl/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] 20 and ascorbate to give a 1 Mg/mL suspension. The assay is initiated by adding 50-75 gg membranes in a total volume of 500 gl containing 0.2 nM [3H]-spiperone. Non-specific binding is defined using 10 gM 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, 25 using 50mM Tris-HC1 pH 7.4. 2. Assay Title: Serotonin 5HT1a Objective of the Assay 30 The objective of this assay is to eliminate agents which specifically affect binding to cloned human 5HT1a receptor Method: Modified from Schelegel and Peroutka Biochemical 35 Pharmacology 35: 1943-1949 (1986). Mammalian cells expressing cloned human 5HT1a receptors are lysed in ice-cold 5 mM Tris-HC1, 2 mM EDTA (pH 7.4) and -181- WO 98/57641 PCT/US98/12673 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 5 mM Tris-HC1, 4 mM CaC12 and 1mg/ml ascorbate. Non-specific binding is defined using 10 jtM propranolol. The assay is terminated after a 1 hour incubation at room temperature by rapid filtration over GF/Cfilters EXAMPLE 120 10 EXEMPLARY FUNCTIONAL ASSAYS In order to confirm the specificity of compounds for the human alpha la adrenergic receptor and to define the biological activity 15 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 20 (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 25 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 30 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 35 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 - 182 - WO 98/57641 PCT/US98/12673 one hour. Contractions are recorded on a Hewlett-Packard 7700 series strip chart recorder. After a single priming dose of 3 gM (for rat), 10 gM (for dog) and 20 gM (for human) of phenylephrine, a cumulative concentration 5 response curve to an agonist is generated; the tissues are washed every 10 minutes for one hour. Vehicle or antagonist is added to the bath and allowed to incubate for one hour, then another cumulative concentration response curve to the agonist is generated. EC50 values are calculated for each group using GraphPad 10 Inplot software. pA2 (-log Kb) values were obtained from Schild plot when three or more concentrations were tested. When less than three concentrations of antagonist are tested, Kb values are calculated according 15 to the following formula Kb =EMl, x-1 where x is the ratio of EC50 of agonist in the presence and absence of antagonist and [B] is the antagonist concentration. 20 2. Measurement of Intra-Urethral Pressure in Anesthetized Dogs PURPOSE: Benign prostatic hyperplasia causes a decreased urine flow rate that may be produced by both passive physical obstruction of the prostatic urethra from increased prostate mass as well as active 25 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 antagonists which also have pronounced vascular effects. Because we 30 have identified the alpha la receptor subtype as the predominent subtype in the human prostate, it is now possible to specifically target this receptor to inhibit prostatic contraction without concomitant changes-in the vasculature. The following model is used to measure adrenergically mediated changes in intra-urethral pressure and arterial pressure in 35 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 - 183

-

WO 98/57641 PCT/US98/12673 contraction and vascular responses, and 2) use this model to evaluate novel selective alpha adrenergic antagonists. Novel and standard alpha adrenergic antagonists may be evaluated in this manner. 5 METHODS: Male mongrel dogs (7-12 kg) are used in this study. The dogs are anesthetized with pentobarbital sodium (35 mg/kg, i.v. plus 4 mg/kg/hr iv infusion). An endotracheal tube is inserted and the animal ventilated with room air using a Harvard instruments positive displacement large animal ventilator. Catheters (PE 240 or 260) are 10 placed in the aorta via the femoral artery and vena cava via the femoral veins (2 catheters, one in each vein) for the measurement of arterial pressure and the administration of drugs, respectively. A supra-pubic incision -1/2 inch lateral to the penis is made to expose the urethers, bladder and urethra. The urethers are ligated and cannulated so that 15 urine flows freely into beakers. The dome of the bladder is retracted to facilitate dissection of the proximal and distal urethra. Umbilical tape is passed beneath the urethra at the bladder neck and another piece of umbilical tape is placed under the distal urethra approximately 1-2 cm distal to the prostate. The bladder is incised and a Millar micro-tip 20 pressure transducer is advanced into the urethra. The bladder incision is sutured with 2-0 or 3-0 silk (purse-string suture) to hold the transducer. The tip of the transducer is placed in the prostatic urethra and the position of the Millar catheter is verified by gently squeezing the prostate and noting the large change in urethral pressure. 25 Phenylephrine, an alpha 1 adrenergic agonist, is administered (0.1-100 ug/kg, iv; 0.05 ml/kg volume) in order to construct dose response curves for changes in intra-urethral and arterial pressure. Following administration of increasing doses of an alpha adrenergic antagonist (or vehicle), the effects of phenylephrine on 30 arterial pressure and intra-urethral pressure are re-evaluated. Four or five phenylephrine dose-response curves are generated in each animal (one control, three or four doses of antagonist or vehicle). The relative antagonist potency on phenylephrine induced changes in arterial and intra-urethral pressure are determined by Schild analysis. The family 35 of averaged curves are fit simultaneously (using ALLFIT software package) with a four paramenter logistic equation constraining the slope, minimum response, and maximum response to be constant -184- WO 98/57641 PCT/US98/12673 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 construct a Schild plot and the Kb (expressed as ug/kg, iv) determined. 5 The Kb (dose of antagonist causing a 2-fold rightward shift of the phenylephrine dose-response curve) is used to compare the relative potency of the antagonists on inhibiting phenylephrine responses for intra-urethral and arterial pressure. The relative selectivity is calculated as the ratio of arterial pressure and intra-urethral pressure 10 Kb's. Effects of the alpha 1 antagonists on baseline arterial pressure are also monitored. Comparison of the relative antagonist potency on changes in arterial pressure and intra-urethral pressure provide insight as to whether the alpha receptor subtype responsible for increasing intra-urethral pressure is also present in the systemic 15 vasculature. According to this method, one is able to confirm the selectivity of alpha la adrenergic receptor antagonists that prevent the increase in intra-urethral pressure to phenylephrine without any activity at the vasculature. While the foregoing specification teaches the principles of 20 the present invention, with examples provided for the purpose of illustration, it will be understood that the practice of the invention encompasses all of the usual variations, adaptations and/or modifications as come within the scope of the following claims and their equivalents. - 185 -

Claims (31)

1. A compound of the formula: R24 M R1s R1m R 5 wherein Q is selected from N RRo HH (X)s R 2 O13 R7 O OR R186 N 4N N R 7 W R7 ( W 0 0i 0 R 9 1 1 0 N 0 N H RH - 186 - WO 98/57641 PCT/US98/12673 RN3 R 1 4 8 R1 R 1 4 0SNs 0 N ~N oi or O0 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 6 or 5 (CH2)0-4SO2N(R 19 )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 6 , or (CH2)0-4SO2N(R 19 )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, OR 6 , N(R 1 9 )2, NR 1 9 COR 2 0 , NR 1 9 CON(R 2 0 )2, NR 1 9 SO2R 6 , NR1 9 SO2N(R 2 0)2, (CH2)0-4CO2R 1 9 , 15 (CH2)0-4CON(R 19 )2, (CH2)0-4SO2N(R 1 9 )2, (CH2)0-4SO2R 6 or C1-4 alkyl; or unsubstituted, mono- or poly-substituted pyridyl, pyridyl N oxide (N-4O), pyrazinyl, thienyl, thiazolyl, furanyl, quinazolinyl or naphthyl wherein the substituents on the pyridyl, pyrazinyl, thienyl, thiazolyl, furanyl, quinazolinyl, or naphthyl are independently selected 20 from CF3, cyano, nitro, N(R 1 9 )2, (CH2)0-4CO2R 19 , (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 is selected from hydrogen, cyano, OR 6 , CO2R 1 9 , CON(R 1 9 )2, tetrazole, 25 isooxadiazole, unsubstituted, mono- or poly-substituted phenyl wherein the substituents on the phenyl are independently selected from halogen, cyano, nitro, OR 6 , (CH2)0-4CO2R 1 9 , (CH2)0-4CON(R 1 9 )2, N(R 1 9 )2, NR 19 COR 6 , NR 1 9 CON(R 2 0 )2, NR 1 9 SO2R 6 , NR 1 9 SO2N(R 2 0 )2, (CH2)0-4SO2N(R 1 9)2, (CH2)0-4SO2R 6 or C1-4 alkyl; or unsubstituted, 30 mono- or poly-substituted pyridyl, thienyl, furanyl or naphthyl wherein the substituents on the pyridyl, thienyl, furanyl or naphthyl are independently selected from CF3, (CH2)0-4CO2R 1 9 , (CH2)0-4CON(R 1 9 )2, - 187- WO 98/57641 PCT/US98/12673 (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 and R 7 are each independently selected from hydrogen, C1-8 5 alkyl, C4-8 cycloalkyl, (CH2)0-4CO2R 1 9 , (CH2)0-4CON(R 19 )2, (CH2)0 4COR 6 , (CH2)2-40R 6 , (CH2)1-4CF3, (CH2)0-4SO2R 6 , (CH2)0-4SO2N(R 1 9 )2 or (CH2)1-4CN; R 4 is selected from hydrogen, (CH2)0-4COR 6 , (CH2)0-4CN, (CH2)0-4CF3, 10 (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 , 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 15 (CH2)0-4CF3; R 6 is selected from hydrogen, C1-8 alkyl, C3-8 cycloalkyl or (CH2)0-4CF3; 20 R 9 is selected from hydrogen, C1-8 alkyl, C3-8 cycloalkyl, CO2R 6 , CON(R 6 )2, (CH2)1-40R 6 or (CH2)0-4CF3; R 1 1 and R 1 2 are each independently selected from hydrogen, C1-8 alkyl or C3-8 cycloalkyl; 25 R 1 3 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 independently selected from halogen, CF3, cyano, nitro, OR 6 , 30 (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 - independently selected from CF3, phenyl, OR 6 , halogen, C1-4 alkyl or C3-8 cycloalkyl; 35 -188- WO 98/57641 PCT/US98/12673 R 1 9 and R 2 0 are each independently selected from hydrogen, C1-8 alkyl, C3-8 cycloalkyl or (CH2)1-4CF3; R 2 2 is selected from hydrogen, C1-8 alkyl, C3-8 cycloalkyl, (CH2)0-40R 6 5 or (CH2)0-4CF3; R 2 4 and R 2 6 are each independently selected from hydrogen or OR 2 8 ; R 2 8 is selected from hydrogen, C1-8 alkyl, C3-8 cycloalkyl or 10 (CH2)0-4CF3; W is 0 or NR 1 1 ; each X is independently selected from halogen, cyano, nitro, C1-8 alkyl, 15 C3-8 cycloalkyl, (CH2)0-4OR 6 or (CH2)0-4CF3; Y is C-R 6 or N; Z is hydrogen, oxygen or sulphur; 20 m, p and q are each independently an integer of from zero to two provided that when q is zero, R 2 6 is hydrogen; n, o, s and t are each independently an integer of from zero to four; v is an integer from zero to one; 25 or a pharmaceutically acceptable salt thereof.

2. The compound of Claim 1, having the structure M R15sR 16 2 _n E I R NC Q 0 G R17R18 L wherein R 1 is selected from unsubstituted, mono- or poly-substituted 30 phenyl wherein the substituents on the phenyl are independently -189- WO 98/57641 PCT/US98/12673 selected from halogen, CF3, cyano, nitro, OR 6 , N(R 1 9)2, NR 1 9 COR 2 0 , NR 1 9 CON(R 2 0 )2, NR 1 9 SO2R 6 , NR1 9 SO2N(R 2 0)2, (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, 5 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, N(R 1 9 )2, (CH2)0-4CO2R 1 9 , (CH2)0-4CON(R 19 )2, (CH2)0-4SO2N(R 1 9 )2, (CH2)0-4SO2R 6 , phenyl, OR 6 , halogen, C1-4 alkyl 10 or C3-8 cycloalkyl; 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; and 15 R 9 is selected from hydrogen, C1-8 alkyl, C3-8 cycloalkyl, (CH2)2-40R 6 or (CH2)0-4CF3; or a pharmaceutically acceptable salt thereof. 20

3. The compound of Claim 1, of the formula R24 M R15 Rm R n E R 26 I R N C Q RI 1 3 S o L G R17R18 wherein 25 E, G, L, M and J are each independently selected from hydrogen, C1-8 alkyl, C3-8 cycloalkyl, or (CH2)0-4CF3; R 1 is selected from unsubstituted, mono-, di- or tri-substituted phenyl wherein the substituents on the phenyl are independently selected from - 190- WO 98/57641 PCT/US98/12673 halogen, CF3, cyano, nitro, OR 6 , N(R 1 9)2, NR 1 9 COR 2 0 , NR 1 9 CON(R 2 0 )2, NR 1 9 SO2R 6 , NR1 9 SO2N(R 2 0)2, (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-, di- or tri-substituted pyridyl, pyridyl 5 N-oxide (N-O), 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, (CH2)0-4CO2R 1 9 , (CH2)0-4CON(R 1 9)2, (CH2)0 4SO2N(R 1 9)2, 10 (CH2)0-4SO2R 6 , phenyl, OR 6 , halogen, C1-4 alkyl or C3-8 cycloalkyl; R is selected from hydrogen, cyano, OR 6 , CO2R 1 9 , CON(R 1 9 )2, tetrazole, isooxadiazole, unsubstituted, mono-, di- or tri-substituted phenyl wherein the substituents on the phenyl are independently selected from 15 halogen, cyano, nitro, OR 6 , (CH2)0-4CO2R 1 9 , (CH2)0-4CON(R 1 9 )2, N(R 1 9 )2, NR 1 9 COR 6 , NR 1 9 CON(R 2 0 )2, NR 1 9 SO2R 6 , NR 1 9 SO2N(R 2 0 )2, (CH2)0-4SO2N(R 1 9)2, (CH2)0-4SO2R 6 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, (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 and R 7 are each independently selected from hydrogen, C1-8 25 alkyl, C4-8 cycloalkyl or (CH2)1-4CF3; R 1 3 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 tri-substituted phenyl wherein the substituents on the phenyl are 30 independently selected from halogen, CF3, cyano, nitro, 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 35 C3-8 cycloalkyl; and - 191- WO 98/57641 PCT/US98/12673 n and t are each independently an integer from zero to two; or a pharmaceutically acceptable salt thereof. 5

4. The compound of Claim 3, selected from R 24R 24 N 2 4 R R 26 RN R R1- N (CHg-Q (CH2)q-- , R 2 4 R 3N / 6 or R R 26 2 ( H)Q (CH 2 ) wherein Q is selected from (X)s Xs (X)s 0 ~ 00 O 4 kNK R 8 R N N R4 R 9 R N7 N0 R7 N ON S RO N Rs R70 O1 Rio RO S9 or H Rio R9 R 7 R 22 R13 N s t\ O 0 R 1 is selected from unsubstituted, mono-, di- or tri-substituted phenyl 10 wherein the substituents on the phenyl are independently selected from halogen, CF3, cyano, nitro, OR 6 , (CH2)0-2CO2R 19 , (CH2)0-2CON(R 1 9)2, (CH2)o0-2SO2N(R 19 )2, (CH2)0-2SO2R 6 or C1-4 alkyl; or unsubstituted, mono-, or di-substituted pyridyl or pyridyl N-oxide, wherein the substituents on the pyridyl or pyridyl N-oxide are independently selected 15 from halogen, CF3, cyano, OR 6 , (CH2)o0-2CO2R 19 , (CH2)0-2CON(R 19 )2, (CH2)0-2SO2N(R 19 )2, - 192 - WO 98/57641 PCT/US98/12673 (CH2)0-2SO2R 6 or C1-4 alkyl; R is selected from hydrogen, cyano, OR 6 , CO2R 1 9 , CON(R 1 9 )2, or unsubstituted, mono- or di-substituted phenyl wherein the substituents 5 on the phenyl are independently selected from halogen, cyano, nitro, OR 6 , (CH2)0-2CO2R 1 9 , (CH2)0-2CON(R 1 9 )2 or C1-4 alkyl; R 4 is selected from hydrogen, COR 6 , CO2R 1 9 , SO2R 6 or CON(R 1 9)2; 10 R 5 is selected from hydrogen, C1-6 alkyl, C3-6 cycloalkyl, (CH2)0-3OR 6 or (CH2)0-3CF3; R 6 is selected from hydrogen, C1-6 alkyl, C3-6 cycloalkyl or (CH2)0-3CF3; 15 R 8 and R 1 0 are each independently selected from hydrogen, C1-6 alkyl, C3-6 cycloalkyl, (CH2)2-4OR 6 or (CH2)0-3CF3; R 9 is selected from hydrogen, C1-6 alkyl, C3-6 cycloalkyl, CO2R 6 , 20 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, (CH2)2-4OR 6 , (CH2)0-2CF3 or unsubstituted, mono- or di-substituted phenyl wherein the substituents on the phenyl are independently 25 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; and 30 R 2 2 is selected from hydrogen, C1-6 alkyl, C3-6 cycloalkyl, (CH2)0-4OR 6 or (CH2)0-3CF3; R 2 8 is selected from hydrogen, C1-6 alkyl, C3-6 cycloalkyl or 35 (CH2)1-3CF3; -193- WO 98/57641 PCT/US98/12673 s is an integer from zero to three; or a pharmaceutically acceptable salt thereof.

5 5. The compound of Claim 4, selected from RR 2 4 N I R 2 6 (R 2 1 )r A (CH 2 )-Q R24 N R 26 N (CH 2 )q Q (R 21 ) r A R 2 4 R R 2 6 (R 21 ) r \A "(0H2)q-Q or N (CH 2 -Q (R 21 )r A wherein Q is selected from (X)s s o - (X)s R 4 N N R4 N R9 H I HIN H N RO or H 13 H 10 R is selected from hydrogen, OR 6 or cyano; - 194- WO 98/57641 PCT/US98/12673 A is selected from C-R 2 1 or N or N-O; R 1 3 is selected from hydrogen, C1-4 alkyl or unsubstituted, mono- or di substituted phenyl wherein the substituents on the phenyl are 5 independently selected from halogen, CF3, cyano, nitro, amino, OR 6 , C02R 1 9 or C1-4 alkyl; each X is a halogen; 10 each R 2 1 is independently selected from hydrogen, halogen, hydroxy, cyano, OC1-4 alkyl, OCF3, OCH2CF3, CO2-C1-4 alkyl, CONH2, SO2NH2 or SO2C1-4 alkyl; and R 2 8 is selected from hydrogen, C1-4 alkyl, or (CH2)0-2CF3; 15 r is an integer from zero to two; or a pharmaceutically acceptable salt thereof.

6. The compound of Claim 5, wherein 20 Q is selected from F F F F SF F O / O F R 4 NN H JjO N & H o r H O N R 5 O O or H R 13 H R is selected from hydrogen, hydroxy or cyano; 25 A is selected from C-R 2 1 or N; R 4 is CO2R 1 9 ; R 5 is (CH2)0-30R 6 ; and - 195 - WO 98/57641 PCT/US98/12673 q is an integer from zero to one; or a pharmaceutically acceptable salt thereof; provided that the compound is not (4S)-trans-4-(3,4-difluorophenyl)-2-oxooxazolidine-3 5 carboxylic acid-[ 1-(4-hydroxy-4-pyridin-2-yl-cyclohexyl)-(3R)-pyrrolidin-3 yl]amide.

7. The compound of Claim 6, selected from 10 (4S)-3- { 1-[4-(2-cyano-phenyl)-cyclohexyl]-(3R)-pyrrolidin-3-ylcarbamoyl}-4 (3,4-difluoro-phenyl)-6-methyoxymethyl-2-oxo-1,2,3,4-tetra hydropyrimidine-5-carboxylic acid methyl ester; (4S)-cis-3- {1-[4-(2-cyano-phenyl)-cyclohexyl]-(3R)-pyrrolidin-3 15 ylcarbamoyl}-4-(3,4-difluoro-phenyl)-6-methyoxymethyl-2-oxo-1,2,3,4 tetrahydropyrimidine-5-carboxylic acid methyl ester; trans-4S-4-(3,4-difluorophenyl)-2-oxooxazolidine-3-carboxylic acid-{1-[4 (2-cyano-phenyl)-cyclohexyl]-3R-pyrrolidin- 3 -yl}amide; 20 (4S)-cis-4-(3,4-difluorophenyl)-2-oxooxazolidine-3-carboxylic acid-{1-[4-(2 cyano-phenyl)-cyclohexyl]-(3R)--pyrrolidin-3-yl} amide; (4S)-trans-4-(3,4-difluoro-phenyl)-3-{1-[4-(2-ethoxycarbonyl-phenyl) 25 cyclohexyl]-(3R)-pyrrolidin-3-ylcarbamoyl}-6-methoxymethyl-2-oxo 1,2,3,4-tetrahydropyrimidine-5-carboxylic acid methyl ester; (4S)-cis-4-(3,4-difluoro-phenyl)-3-{1-[4-(2-ethoxycarbonyl-phenyl) cyclohexyl]-(3R)--pyrrolidin-3-ylcarbamoyl}-6-methoxymethyl-2-oxo 30 1,2,3,4-tetrahydropyrimidine-5-carboxylic acid methyl ester; (4S)-trans-4-(3,4-difluorophenyl)-2-oxo-oxazolidine-3-carboxylic acid-{1-[4 (2-ethoxycarbonylphenyl)-cyclohexyl]-(3R)-pyrrolidin-3-yl}amide; 35 (4S)-cis-4-(3,4-difluorophenyl)-2-oxooxazolidine-3-carboxylic acid- {1-[4-(2 ethoxycarbonylphenyl)-cyclohexyl]-(3R)-pyrrolidin-3-yl}amide; - 196- WO 98/57641 PCT/US98/12673 (4S)-trans-4-(3,4-difluorophenyl)-3-[1-(4-pyridin-2-yl-cyclohexyl)-(3R) pyrro1idin-3-ylcarbamoyl]-6-methoxymethyl-2-oxo-1,2,3,4-tetrahydro pyrimidine-5-carboxylic acid methyl ester; 5 (4S)-cis-4-(3,4-difluorophenyl)-3-[1-(4-pyridin-2-yl-cyclohexyl)-(3R) pyrrolidin-3-ylcarbamoyl]-6-methoxymethyl-2-oxo-1,2,3,4-tetrahydro pyrimidine-5-carboxylic acid methyl ester; (4S)-trans-4-(3,4-difluorophenyl)-2-oxo-oxazolidine-3-carboxylic acid-[1-(4 10 pyridin-2-yl-cyclohexyl)-(3R)-pyrrolidin-3-yl] amide; (4S)-cis-4-(3,4-difluorophenyl)-2-oxooxazolidine-3-carboxylic acid-[1-(4 pyridin-2-yl-cyclohexyl)-(3R)-pyrrolidin-3-yl]amide; 15 (4S)-trans-4-(3,4-difluorophenyl)-6-methoxymethyl-3-{1-[4-(2-methoxyl phenyl)-cyclohexyl]-(3R)-pyrrolidin-3-ylcarbamoyl}-2-oxo-1,2,3,4 tetrahydro-pyrimidine-5-carboxylic acid methyl ester; (4S)-cis-4-(3,4-difluoro-phenyl)-6-methoxymethyl-3-{1-[4-(2-methoxyl 20 phenyl)-cyclohexyl]-(3R)-pyrrolidin-3-ylcarbamoyl)-2-oxo-1,2,3,4 tetrahydro-pyrimidine-5-carboxylic acid methyl ester; (4S)-trans-4-(3,4-difluorophenyl)-2-oxooxazolidine-3-carboxylic acid- { 1-[4 (2-methoxyphenyl)-cyclohexyl]-(3R)-pyrrolidin-3-yll amide; 25 (4S)-cis-4-(3,4-difluorophenyl)-2-oxooxazolidine-3-carboxylic acid-{1-[4-(2 methoxyphenyl)-cyclohexyl]-(3R)-pyrrolidin-3-yl}amide; (4S)-cis-4-(3,4-difluoro-phenyl) -3-[ 1-(4-hydroxy-4-pyridin-2-yl-cyclohexyl) 30 (3R)-pyrrolidin-3-ylcarbamoyl]-6-methoxymethyl -2-oxo-1,2,3,4 tetrahydro-pyrimidine-5-carboxylic acid methyl ester; (4S)-trans-4-(3,4-difluoro-phenyl) -3-[ 1-(4-hydroxy-4-pyridin-2-yl cyclohexyl)-(3R)--pyrrolidin-3-ylcarbamoyl]-6-methoxymethyl -2-oxo 35 1,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid methyl ester; -197- WO 98/57641 PCT/US98/12673 (4S)-cis-4-(3,4-difluorophenyl)-2-oxooxazolidine-3-carboxylic acid-[1-(4 hydroxy-4-pyridin-2-yl-cyclohexyl)-(3R)--pyrrolidin-3-yl] amide; (4S)-4-(3,4-difluoro-phenyl)-3-{ 1-[4-(2-hydroxy-phenyl)-cyclohexyl]-(3R) 5 pyrrolidin-3-ylcarbamoyl}-6-methoxymethyl- 2 -oxo-1,2,3,4-tetrahydro pyrimidine-5-carboxylic acid methyl ester; (4S)-cis-4-(3,4-difluoro-phenyl)-6-methoxymethyl-3-{ 1-[4-(2-hydroxy phenyl)-cyclohexyl]-(3R)--pyrrolidin-3-ylcarbamoyl}-2-oxo-1,2,3,4 10 tetrahydro-pyrimidine-5-carboxylic acid methyl ester; (4S)-trans-4-(3,4-difluorophenyl)-2-oxooxazolidine-3-carboxylic acid-{1-[4 (2-hydroxyphenyl)-cyclohexyl]-(3R)--pyrrolidin-3-yl}lamide; 15 (4S)-cis-4-(3,4-difluorophenyl)-2-oxooxazolidine-3-carboxylic acid- {1-[4-(2 hydroxyphenyl)-cyclohexyl]-(3R)--pyrrolidin- 3 -yl)amide; and the pharmaceutically acceptable salts thereof. 20

8. The compound of claim 5, wherein R is H or OH; Q is selected from 25 F F F F 9 or 0 H, R 5 H C 'N R9 H H O N Rs H O O R 4 is H or CO2CH3; 30 R 5 is H, CH3, or CH2OCH3; - 198- WO 98/57641 PCT/US98/12673 R 9 is H, CH3, cyclopropyl, CONH2, CH2OH, or COOCH3; q is an integer from zero to one; or a pharmaceutically acceptable salt 5 thereof; provided that the compound is not (4S)-trans-4-(3,4 difluorophenyl)-2-oxooxazolidine-3-carboxylic acid-[ 1-(4-hydroxy-4 pyridin-2-yl-cyclohexyl)-(3R)-pyrrolidin- 3 -yl] amide.

9. The compound of claim 8, selected from 10 (4S)-trans-4-(3-,4-difluoro-phenyl)-3-{1-[4-(2-fluoro-phenyl)-cyclohexyl] (3R)-pyrrolidin-3-ylcarbamoyl}-6-methoxymethyl-1,2,3,4-tetrahydro pyrimidine-5-carboxylic acid methyl ester; 15 (4S)-trans-4-(3,4-difluoro-phenyl)-2-oxo-oxazolidine-3-carboxylic acid -{1 [4-(2-fluoro-phenyl)-cyclohexyl]-(3R)-pyrrolidin-3-yl}-amide; (4S)-trans-4-(3,4-difluoro-phenyl)-3-{1-[4-(4-fluoro-2-methoxy-phenyl) cyclohexyl]-(3R)-pyrrolidin-3-ylcarbamoyl}-6-methoxymethyl-2-oxo 20 1,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid methyl ester; (4S)-trans-4-(3,4-difluoro-phenyl)-2-oxo-oxazolidine-3-carboxylic acid {(1 [4-(4-fluoro-2-methoxy-phenyl)-cyclohexyl]-(3R)-pyrrolidin-3-yl)-amide; 25 (4S)-4-(3,4-difluoro-phenyl)-3-{ 1-[4-(2-fluoro-phenyl)-4-hydroxy cyclohexyl]-(3R)-pyrrolidin-3-ylcarbamoyl}-6-methoxymethyl-1,2,3,4 tetrahydro-pyrimidine-5-carboxylic acid methyl ester; (4S)-4-(3,4-difluoro-phenyl)-2-oxo-oxazolidine-3-carboxylic acid -{1-[4-(2 30 fluoro-phenyl)-4-hydroxy-cyclohexyl]-(3R)-pyrrolidin-3-yl}-amide; (4S)-4-(3,4-difluorophenyl)-2-oxo-oxazolidine-3-carboxylic acid {1-[4- - hydroxy-4-(2-trifluoromethylphenyl)-cyclohexyl]-(3R)-pyrrolidin-3-yl} amide; 35 - 199- WO 98/57641 PCT/US98/12673 (4S)-4-(3,4-difluorophenyl)-3-{1-[4-hydroxy-4-(2-trifluoromethylphenyl) cyclohexyl]-(3R)-pyrrolidin-3-ylcarbamoyl}-6-methoxymethyl-2-oxo 1,2,3,4-tetrahydropyrimidine-5-carboxylic acid methyl ester; 5 (4S)-4-(3,4-difluorophenyl)-2-oxo-oxazolidine-3-carboxylic acid {(1-[4-(2 trifluoromethylphenyl)-cyclohexyl]-(3R)-pyrrolidin-3-yl} amide; (4S)-4-(3,4-difluorophenyl)-6-methoxymethyl-2-oxo-3- {1-[4-(2 trifluoromethylphenyl)-cyclohexyl]-(3R)-pyrrolidin-3-ylcarbamoyl} 10 1,2,3,4-tetrahydropyrimidine-5-carboxylic acid methyl ester; (4S)-4-(3,4-difluorophenyl)-3-{1-[4-(4-fluorophenyl)-4-hydroxy-cyclohexyl] (3R)-pyrrolidin-3-ylcarbamoyl}-6-methoxymethyl-2-oxo-1,2,3,4 tetrahydropyrimidine-5-carboxylic acid methyl ester; 15 (4S)-4-(3,4-difluorophenyl)-2-oxo-oxazolidine-3-carboxylic acid{1-[4-(4 fluorophenyl)-4-hydroxy-cyclohexyl]-(3R)-pyrrolidin-3-yl} amide; (4S)-4 -(3,4-difluorophenyl)-3-{ 1-[4-(4-fluorophenyl)-4-hydroxy-cyclohexyl] 20 (3R)-pyrrolidin-3-ylcarbamoyl}-6-methyl-2-oxo-1,2,3,4 tetrahydropyrimidine-5-carboxylic acid methyl ester; (4S)-4 -(3,4-difluorophenyl)-3-{ 1-[4-(4-fluorophenyl)-cyclohexyl]-(3R) pyrrolidin-3-ylcarbamoyl}-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5 25 carboxylic acid methyl ester; (4S)-4 -(3,4-difluorophenyl)-3- {1-[4-(4-fluorophenyl)-cyclohexyl]-(3R) pyrrolidin-3-ylcarbamoyl}-6-methoxymethyl-2-oxo-1,2,3,4 tetrahydropyrimidine-5-carboxylic acid methyl ester; 30 (4S)-4 -(3,4-difluorophenyl)-2-oxo-oxazolidine-3-carboxylic acid {1-[4-(4 fluorophenyl)-cyclohexyl]-(3R)-pyrrolidin-3-yl}amide; (4S)-4 -(3,4-difluorophenyl)-3-{1-[4-(4-fluorophenyl)-4-hydroxy-cyclohexyl] 35 (3R)-pyrrolidin-3-ylcarbamoyl}-2-oxo-1,2,3,4-tetrahydropyrimidine-5 carboxylic acid methyl ester; - 200 - WO 98/57641 PCT/US98/12673 (4S)-3-{1-[4-(4-cyanophenyl)-4-hydroxycyclohexyl]-(3R)-pyrrolidin-3 ylcarbamoyl}-4 -(3,4-difluorophenyl)-6-methoxymethyl-2-oxo-1,2,3,4 tetrahydropyrimidine-5-carboxylic acid methyl ester; 5 5-cyclopropyl-4-(3,4-difluorophenyl)-2-oxo-oxazolidine-3-carboxylic acid {1-[4-(2-fluorophenyl)-cyclohexyl]-(3R)-pyrrolidin-3-yl-amide; (4S, 5S)-5-cyclopropyl-4-(3,4-difluorophenyl)-2-oxo-oxazolidine-3 carboxylic acid{ 1-[4-(4-fluorophenyl)-4-hydroxy-cyclohexyl]-(3R) 10 pyrrolidin-3-yl}amide; (4S, 5S)-5-cyclopropyl-4-(3,4-difluorophenyl)-2-oxo-oxazolidine-3 carboxylic acid{ 1-[4-(4-cyanophenyl)-cyclohexyl]-(3R)-pyrrolidin-3 yl}amide; 15 (4S)-4-(3,4-difluorophenyl)-2-oxo-oxazolidine-3-carboxylic acid {1-[4-(4 cyanophenyl)-4-hydroxy-cyclohexyl]-(3R)-pyrrolidin-3-yl}amide; (4S)-3- { 1-[4-(4-cyanophenyl)-cyclohexyl]-(3R)-pyrrolidin-3-ylcarbamoyl}-4 20 (3,4-difluorophenyl)-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5 carboxylic acid methyl ester; (4S)-trans-4-(3,4-difluorophenyl)-3-[ 1-(4-pyridin-2-yl-cyclohexyl)-(3R) pyrrolidin-3-ylcarbamoyl]-6-methyl-2-oxo-1,2,3,4-tetrahydro-pyrimidine 25 5-carboxylic acid methyl ester; (4S)-3-{1 -[4-(2-cyano-phenyl)-cyclohexyl]-(3R)-pyrrolidin-3- ylcarbamoyl} 4-(3,4-difluoro-phenyl)-6-methyl-2-oxo-1,2,3,4-tetrahydro-pyrimidine-5 carboxylic acid methyl ester; 30 (4S)-3- { 1 -[4-(2-cyano-4-fluoro-phenyl)-cyclohexyl]-(3R)-pyrrolidin-3 ylcarbamoyl}-4-(3,4-difluoro-phenyl)-6-methoxymethyl-2-oxo-1,2,3,4-- tetrahydro-pyrimidine-5-carboxylic acid methyl ester; 35 (4S)-4-(3,4-difluoro-phenyl)-3-{1 -[4-(4-fluoro-2-hydroxy-phenyl) cyclohexyl]-(3R)-pyrrolidin-3-ylcarbamoyl}-6-methoxymethyl-2-oxo 1,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid methyl ester; -201- WO 98/57641 PCT/US98/12673 (4S)-4-(3,4-difluoro-phenyl)-2-oxo-oxazolidine-3-carboxylic acid {1-[4 -(4 fluoro-2-hydroxy-phenyl)-cyclohexyl]-(3R)-pyrrolidin-3- yl}-amide; 5 (4S)-4-(3,4-difluoro-phenyl)-2-oxo-oxazolidine-3-carboxylic acid {1-[4 -(2 cyano-4-fluoro-phenyl)-cyclohexyl]-(3R)-pyrrolidin-3-yll-amide; (4S)-4-(3,4-difluoro-phenyl)-2-oxo-oxazolidine-3-carboxylic acid {1-[4 -(2 cyano-4-fluoro-phenyl)-cyclohexyl]-(3R)-pyrrolidin-3-yl}-amide; 10 (4S,5S)-4-(3,4-difluoro-phenyl)-5-methyl-2-oxo-oxazolidine-3-carboxylic acid {1-[4 -(2-cyano-4-fluoro-phenyl)-cyclohexyl]-(3R)-pyrrolidin-3-yl} amide; 15 (4S,5S)-5-Cyclopropyl-4-(3,4-difluoro-phenyl)-2-oxo-oxazolidine-3 carboxylic acid {(1-[4 -(2-cyano-4-fluoro-phenyl)-cyclohexyl]-(3R) pyrrolidin-3yl}-amide; (4S)-4-(3,4-difluoro-phenyl)-3-{1-[4-(2-fluoro-phenyl)-4-hydroxy-cyclohex-1 20 yl]-(3R)-pyrrolidin-3-ylcarbamoyl}-6-methyl- 2 -oxo-1,2,3,4-tetrahydro pyrimidine-5-carboxylic acid methyl ester; (4S)-trans-4-(3,4-difluoro-phenyl)-3-{1-[4-(2-fluoro-phenyl)-cyclohexyll] (3R)-pyrrolidin-3-ylcarbamoyl}-6-methyl-2-oxo-1,2,3,4-tetrahydro 25 pyrimidine-5-carboxylic acid methyl ester; (4S)-cis-4-(3,4-difluoro-phenyl) -3-[1-(4-hydroxy-4-pyridin-2-yl-cyclohexyl) (3R)-pyrrolidin-3-ylcarbamoyl] -2-oxo-1,2,3,4-tetrahydro-pyrimidine-5 carboxylic acid methyl ester; 30 (4S)-trans-4-(3,4-difluorophenyl)-3-[1-(4-pyridin-2-yl-cyclohexyl)-(3R) pyrrolidin-3-ylcarbamoyl]-2-oxo-1,2,3,4-tetrahydro-pyrimidine-5 carboxylic acid methyl ester; 35 (4S)-trans-3 {1-[4-(2-cyano-phenyl)-piperidin-1-yl]-(3R)-pyrrolidin-3 ylcarbamoly}-4-(3,4-difluoro-phenyl)-2-oxo-1,2,3,4-tetrahydro-pyrimidine 5-carboxylic acid methyl ester; -202- WO 98/57641 PCT/US98/12673 (4S,5S)-trans-5-cyclopropyl-4-(3,4-difluorophenyl)-2-oxo-oxazolidine-3 carboxylic acid {1-[ 4-(4-fluorophenyl)-cyclohexyl]-(3R)-pyrrolidin-3-yl amide; 5 (4S)-4-(3,4-difluoro-phenyl) -3-[ 1-(4-hydroxy-4-pyridin-2-yl-cyclohexyl) (3R)-pyrrolidin-3-ylcarbamoyl]-6-methyl -2-oxo-1,2,3,4-tetrahydro pyrimidine-5-carboxylic acid methyl ester; 10 (4S)-trans-4-(3,4-difluorophenyl)-5-methyl-2-oxooxazolidine-3-carboxylic acid-[ 1-(4-pyridin-2-yl-cyclohexyl)-(3R)-pyrrolidin-3-yl] amide; trans-4S-(3,4-difluorophenyl)-3-[1-(4-oxopyridin-2-yl-cyclohexyl)-3R pyrrolidin-3-ylcarbamoyl]-6-methyl-2-oxo-1,2,3,4-tetrahydro-pyrimidine 15 5-carboxylic acid methyl ester; trans-2-(3,4-difluorophenyl)- 1-[1-(4-pyridin-2-yl-cyclohexyl)-3R pyrrolidin-3-ylcarbamoyl]-6-methoxymethyl-2-oxo-1,2,3,4-tetrahydro pyrimidine; 20 (4S,5R)-trans-4-(3,4-difluorophenyl-3-{1-[4-(4-fluoro-2 methoxycarbonylphenyl)-cyclohexyl]-(3R)-pyrrolidin-3-ylcarbamoyl}-2 oxo-oxazolidine-5-carboxylic acid methyl ester; 25 (4S,5R)-trans-4-(3,4-difluorophenyl)-3-(1-{4-[4-fluoro-2-(2,2,2 trifluoroethoxy)phenyl]cyclohexyl}-(3R)-pyrrolidin-3-ylcarbamoyl)- 2 -oxo oxazolidine-5-carboxylic acid methyl ester; (4S,5R)-trans-4-(3,4-difluorophenyl)-2-oxo-3-[1-(4-pyridin-2-ylcyclohexyl) 30 (3R)-pyrrolidin-3-ylcarbamoyl]-oxazolidine-5-carboxylic acid methyl ester; (4S,5R)-trans-4-(3,4-difluorophenyl)-3-{1-[4-(4-fluoro-2 methoxyphenyl)cyclohexyl]-(3R)-pyrrolidin-3-ylcarbamoyl]-2-oxo 35 oxazolidine-5-carboxylic acid methyl ester; - 203 - WO 98/57641 PCT/US98/12673 (4S,5R)-3- { 1-[4-Cyano-4-(2-methoxyphenyl)cyclohexyl]-(3R)-pyrrolidin-3- ylcarbamoyl}-4-( 3 ,4-difluorophenyl)-2-oxo-oxazolidine-5-carboxylic acid methyl ester; 5 (4S,5R)-3- {1-[4-Cyano-4-(2-fluorophenyl)cyclohexyl]-(3R)-pyrrolidin-3 ylcarbamoyl}-4-(3,4-difluorophenyl)-2-oxo-oxazolidine-5-carboxylic acid methyl ester; (4S,5R)-trans-3-{1-[4-(2-cyanophenyl)cyclohexyl]-(3R)-pyrrolidin-3 10 ylcarbamoyl}-4-(3,4-difluorophenyl)-2-oxo-oxazolidine-5-carboxylic acid methyl ester; (4S,5R)-trans-4-(3,4-difluorophenyl)-5-hydroxymethyl-2-oxo-oxazolidine 3-carboxylic acid {(1-[4-(4-fluorophenyl)cyclohexyl]-(3R)-pyrrolidin-3-yl) 15 amide; (4S,5R)-trans-4-(3,4-difluorophenyl)-5-hydroxymethyl-2-oxo-oxazolidine 3-carboxylic acid {1-[4-(4-fluoro-2-methoxyphenyl)cyclohexyl]-(3R) pyrrolidin-3-yl} amide; 20 (4S,5R)-trans-4-(3,4-difluorophenyl)-3-{1-[4-(4-fluoro-2 methoxyphenyl)cyclohexyl]-(3R)-pyrrolidin-3-ylcarbamoyl]-2-oxo oxazolidine-5-carboxamide; 25 (4S,5R)-trans-4-(3,4-difluorophenyl)-3-{1-[4-(4-fluorophenyl)cyclohexyl] (3R)-pyrrolidin-3-ylcarbamoyl]-2-oxo-oxazolidine-5-carboxamide; (4S,5R)-trans-4-(3,4-difluorophenyl)-3-{ 1-[4-(2-fluorophenyl)cyclohexyl] (3R)-pyrrolidin-3-ylcarbamoyl]-2-oxo-oxazolidine-5-carboxamide; 30 (4S,5R)-trans-3-{1-[4-(2-cyano-4-fluorophenyl)cyclohexyl]-(3R)-pyrrolidin 3-ylcarbamoyl}-4-(3,4-difluorophenyl)-2-oxo-oxazolidine-5-carboxamide; and pharmaceutically acceptable salts thereof. 35 -204- WO 98/57641 PCT/US98/12673

10. The compound of claim 8, which is Compound A: F /F F N

11 HO N N H O ;or a pharmaceutically acceptable salt thereof. 5 11. The compound of claim 8, which is Compound B: F F .\N N CO 2 Me H -N O N H ;ora pharmaceutically acceptable salt thereof.

12. The compound of claim 8, which is Compound C: F F NHO ,"N "*NC " O 2 Me O N Me H 10 or a pharmaceutically acceptable salt thereof.

13. A pharmaceutical composition comprising the compound of Claim 1 and a pharmaceutically acceptable carrier. 15 -205- WO 98/57641 PCT/US98/12673

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

15. A process for making a pharmaceutical composition 5 comprising combining a compound of Claim 1 and a pharmaceutically acceptable carrier.

16. The composition of Claim 13 further comprising a testosterone 5-alpha reductase inhibitor. 10

17. The composition of Claim 16, 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. 15

18. The composition of Claim 17, wherein the testosterone 5-alpha reductase inhibitor is a type 2 testosterone 5-alpha reductase inhibitor.

19. The composition of Claim 18, wherein the 20 testosterone 5-alpha reductase inhibitor is finasteride.

20. A method of treating benign prostatic hyperplasia in a subject in need thereof which comprises administering to the subject a therapeutically effective amount of the compound of Claim 1. 25

21. The method of Claim 20, wherein the compound additionally does not cause a fall in blood pressure at dosages effective to alleviate benign prostatic hyperplasia. 30

22. The method of Claim 20, wherein the compound is administered in combination with a testosterone 5-alpha reductase inhibitor.

23. The method of Claim 22, wherein the testosterone 5 35 alpha reductase inhibitor is finasteride. - 206 - WO 98/57641 PCT/US98/12673

24. A method of treating benign prostatic hyperplasia in a subject in need thereof which comprises administering a therapeutically effective amount of the composition of Claim 13. 5

25. The method of Claim 24, wherein the composition further comprises a therapeutically effective amount of a testosterone 5 alpha reductase inhibitor.

26. A method of relaxing lower urinary tract tissue in a 10 subject in need thereof which comprises administering to the subject a therapeutically effective amount of the compound of Claim 1.

27. The method of Claim 26, wherein the compound additionally does not cause a fall in blood pressure at dosages effective to 15 relax lower urinary tract tissue.

28. The method of Claim 26, wherein the compound is administered in combination with a testosterone 5-alpha reductase inhibitor. 20

29. The method of Claim 28, wherein the testosterone 5 alpha reductase inhibitor is finasteride.

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

31. A method of eliciting an alpha la antagonizing effect 30 in a mammal in need thereof, comprising administering to the mammal a therapeutically effective amount of the compound of Claim 1. -207-