CA2253862A1 - Dihydropyrimidines and uses thereof - Google Patents

Dihydropyrimidines and uses thereof Download PDF

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CA2253862A1
CA2253862A1 CA002253862A CA2253862A CA2253862A1 CA 2253862 A1 CA2253862 A1 CA 2253862A1 CA 002253862 A CA002253862 A CA 002253862A CA 2253862 A CA2253862 A CA 2253862A CA 2253862 A1 CA2253862 A1 CA 2253862A1
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branched
straight chained
mmol
cycloalkyl
alkyl
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Wai C. Wong
Mohammad R. Marzabadi
Charles Gluchowski
Bharat Lagu
Dhanapalan Nagarathnam
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Synaptic Pharmaceutical Corp
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    • C07—ORGANIC CHEMISTRY
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    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/20—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D239/22—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms directly attached to ring carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/08—Drugs for disorders of the urinary system of the prostate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/06—Antiarrhythmics
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    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
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    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
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    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing aromatic rings
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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    • C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
    • C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
    • C07D451/04—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof with hetero atoms directly attached in position 3 of the 8-azabicyclo [3.2.1] octane or in position 7 of the 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring system
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    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems

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Abstract

This invention is directed to dihydropyrimidine compounds which are selective antagonists for human .alpha.1A receptors. This invention is also related to uses of these compounds for lowering intraocular pressure, inhibiting cholesterol synthesis, relaxing lower urinary tract tissue, the treatment of benign prostatic hyperplasia, impotency, cardiac arrhythmia and for the treatment of any disease where the antagonism of the .alpha.1A receptor may be useful. The invention further provides a pharmaceutical composition comprising a therapeutically effective amount of the above-defined compounds and a pharmaceutically acceptable carrier.

Description

D~ L~d vv~ im; dines and Uses Thereof Throughout this application, various references are referred to within parenthe9es- Disclosures of these publications in their entireties are here~y incorporated by reference into this application to more fully describe the state of the art to which this invention pertains.

Bach4~,d of the In~ention The designation ~lA~' is the appellation recently approved by the IUPHAR Nomenclature Co~mittee for the previously designated "~c" cloned subtype as outlined in the 1995 Receptor and Ion Channel Nomenclature Supplement (Watson and Girdlestone, 1995). The designation a~A is used throughout this application and the supporting tables and figures to refer to this receptor subtype. At the same time, the receptor formerly designated ~lA was renamed ~lD. The new nomenclature is used throughout this application.
Stable cell lines expressing these rece~tors are described hereini however, these cell lines were deposited with the American Type Culture Collection ~ATCC) under the old nomenclature (infra~.

Benign ProstatiC Hyperplasia (BPH), also called Benign Prostatic Hypertrophy~ is a progressive condition which is characterized by a nodular enlargement of prostatic tissue resulting in obstruction of the urethra. This results in increased frequency of urination, nocturia, a poor urine stream and hesitancy or delay in starting the urine flow. Chronic consequences of EPH can CA 022~3862 1998-11-09 W097/42956 -2- PCT~S97/08335 include hypertrophy of bladder smooth muscle, a decompensated bladder and an increased incidence of urinary tract infection. The specific biochemical, histological and pharmacological properties of the prostate adenoma leading to the bladder outlet obstruction are not yet known. However, the development of BPH is considered to be an inescapable phenomenon for the aging male population. BPH is observed in approximately 70~ of males over the age o~
70. Currently, in the United States, the method of choice for treating BPH is surgery (Lepor, H., Urol.
Clinics North Amer., 17, 651 ~1990)). Over 400,000 prostatectomies are performed annually (data from 1986). A medicinal alternative to surgery is clearly very desirable. The limitations of surgery for treating BPH include the morbidity rate of an operative procedure in elderly men, persistence or recurrence of obstructive and irritative symptoms, as well as the significant cost of surgery.
~-Adrenergic receptors (McGrath, et. al. Med. Res.
Rev., 9, 407-533, 1989) are specific neuroreceptor proteins located in the peripheral and central nervous systems on tissues and organs throughout the body.
These receptors are important switches for controlling many physiological functions and, thus, represent important targets for drug development. In fact, many ~-adrenergic drugs have been developed over the past 40 years. Examples include clonidine, phenoxybenzamine and prazosin (treatment of hypertension), naphazoline (nasal decongestant), and apraclonidine (treating glaucoma). ~-Adrenergic drugs can be broken down into two distinct classes: agonists (clonidine and naphazoline are agonists), which mimic the receptor activation properties of the endogenous neurotransmitter norepinephrine, and antagonists (phenoxybenzamine and prazosin are antagonists), which act to block the effects of norepinephrine. Many of these drugs are effective but also produce unwanted CA 022~3862 1998-11-09 W097/42956 PCT~S97/0~35 side effects (for example, clonidine produces dry mouth and sedation in addition to its antihypertensive effects).

During the past 15 years a more precise understanding of ~-adrenergic receptors and their drugs has evolved ~ through increased scientific scrutiny. Prior to 1977, only one ~-adrenergic receptor was known to exist.
Between 1977 and 19~8, it was accepted by the scientific community that at least two ~-adrenergic receptors--~l and ~2--existed in the central and peripheral nervous systems. Since 1988, new techniques in molecular biology have led to the identification of at least six ~-adrenergic receptors which exist throughout the central and peripheral nervous systems:
~lA (new nomenclature), ~ lD (new nomenclature), ~2A~
~2~ and ~2C (Bylund, D.B., FASEB J., 6, 832 (1992)). In many cases, it is not known precisely which physiological responses in the body are controlled by each of these receptors. In addition, current ~-adrenergic drugs are not selective for any particular ~-adrenergic receptor. Many of these drugs produce untoward side effects which may be attributed to their poor ~-adrenergic receptor selectivity.
Since the mid 1970's, nonselective ~-antagonists have been prescribed to treat BPH. In 1976, M. Caine, et al. (Brit. J. Urol., 48, 255 (1976)l, reported that the nonselective ~-antagonist phenoxybenzamine was useful in relieving the symptoms of BPH. This drug may produce its effects by interacting with ~-receptors located on the prostate. However, this drug also produces significant side effects such as dizziness and asthenia which severely limit its use in treating patients on a chronic basis. More recently, the ~-adrenergic antagonists prazosin and terazosin have also been found to be useful for treating BPH.

.... . ..

CA 022~3862 1998-11-09 W097t42956 PCT~S97/08335 However, these drugs also produce untoward side effects. It has recently been discovered that the ~lA
receptor is responsible for mediating the contraction of human prostate smooth muscle (Gluchowski, C. et.
al., WO 94/10989, 1994; Forray, C. et. al., Mol.
Pharmacol. 45, 703, 1994). This discovery indicates that the ~lA antagonists may be effective agents for the treatment of BPH with decreased side effects. Further studies have indicated that the ~lA receptor may also be present in other lower urinary tract tissues, such as urethral smooth muscle (Ford et al. Br. J. Pharmacol., 114, 24P, (1995)).

This invention is directed to dihydropyrimidine compounds which are selective antagonists for cloned human ~lA receptors. This invention is also related to uses of these compounds for lowering intraocular pressure (Zhan, et. al. O~hthalmol. Vis. Sci., 34 Abst.
#1133, 928, 1993), inhibiting cholesterol synthesis (D'Eletto and Javitt, J. Cardiovascular Pharmacol., 13 (Suppl. 2) S1-S4, 1989), benign prostatic hyperplasia, impotency (Milne and Wyllie, EP 0 459 666 A2, 1991), sympathetically mediated pain (Campbell, WO 92/14453, 1992), cardiac arrhythmia (Spiers, et. al.,J
Cardiovascular Pharmacol., 16, 824-830, 1990) and for the treatment of any disease where antagonism of the ~lA
receptor may be useful.

. _ W O 97/42956 PCTnUS97/08335 _5_ Summarv of the Invention This invention is directed to dihydropyrimidine compounds which are selective antagonists for human ~A
receptors. This invention is also related to uses o~
these compounds for lowering intraocular pressure, inhibiting cholesterol synthesis, relaxing lower urinary tract tissue, the treatment of ~enign prostatic hyperplasia, impotency, cardiac arrhythmia and for the treatment of any disease where antagonism of the ~lA
receptor may be useful. The invention further provides a pharmaceutical composition comprising a therapeutically effective amount of the above-defined compounds and a pharmaceutically acceptable carrier.

, W097/42956 PCT~S97/08335 Detailed Description of the Invention The present invention is directed to compounds having the structure:

1 1 1 N~ 4 R~ X R4 ~ ~ ~R4 R2 N X ~ or X ~ ~ ;
3 , R3 R R3 wherein A is ~ Y4 1 ~ y4 V2~ Yl ~

Yl- ~\ V r = N

/ ' X"' CA 022~3862 1998-11-09 W097/42956 PCT~S97/08335 wherein each of Yl, Y2, Y3, Y4 and Ys is independently -H; straight chained or branched Cl- C7 alkyl, monofluoroalkyl or polyfluoroalkyl;
straight chained or branched C2- C7 alkenyl or alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl~
polyfluorocycloalkyl or cycloalkenyl; -F, -Cl, -Br, or -Ii -NO2i -N3; -CN; -OR3, -OCOR3, -COR3, -CONHR3, -CON(R3)2, or -COOR3; or any two of Yl, Y2, Y3, Y4 and Y5 present on adjacent carbon atoms can constitute a methylenedioxy group;

wherein X is S; O; or NR3;

wherein Rl is -H; -NO2; -CN; straight chained or branched Cl-C7 alkyl, monofluoroalkyl or polyfluoroalkyli straight chained or branched C2-C7 alkenyl or alkynyl;. C3-C7 cycloalkyI, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; - N ( R3 ) 2 i - OR3; - ( CH2 ) pOR3; - COR3;
2 O COzR3; or - CON ( R3 ) 2i wherein R2 is -H; straight chained or branched Cl-C7 alkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, monofluoroalkyl or polyfluoroalkyl; straight 2 5 chained or branched C2- C7 alkenyl or alkynyl; C3 - C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; C3-Clo cycloalkyl-Cl-C1O-alkyl, C3-Clo cycloalkyl-Cl-C1O-monofluoroalkyl or C3-Clo cycloalkyl-Cl-Clo~
polyfluoroalkyl; - CN; - CH2XR3, - CH2X ( CH2 ) pNHR3, - ( CH2 ) nNHR3 ~ - CH2X ( CH2 ) pN ( R3 ) 2 ~ - CH2X ( CH2 ) pN3, or - CH2X ( CH2 ) pNHCXR7; or - OR3;

wherein each p is independently an integer from 1 to 7; wherein each n is independently an integer ~ from 0 to 5;

CA 022~3862 1998-11-09 W097/42956 PCT~S97/0833 wherein each R3 is independently -H; straight chained or branched Cl-C7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; c3-c7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;

wherein R4 is R ~ R6 R

R m~ V ~ l]m m[~V

wherein Z' is (CH2)o~ CO, (CH2)oCO~ or CO(CH2)o;

wherein each V is independently O; S; CH2; CRsR7;
C (R7) 2; or NR7;

wherein each m is independently an integer from 0 to 3; wherein o is an integer from 1 to 3;

wherein each R is independently -H; -F; straight chained or branched Cl-C7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; -N (R3) 2; -NO2; -CN; -CO2R3; or -OR3;
wherein R5 and R7 each independently may be -H; F;
C1; Br; I; -COR3; -CO2R3; -CON ( R3) 2; -CN; -NO2;
-N (R3)2; -OR3; -SR3; - (CH2)pOR3; - (CH2)pSR3; straight chained or branched C~-C7 alkyl, aminoalkyl, carboxamidoalkyl; straight chained or branched C2-C7 alkenyl or alkynyl, or C3-C7 cycloalkyl or cycloalkenyl; wherein the alkyl, aminoalkyl, carboxamidoalkyl, alkenyl, alkynyl, cycloalkyl or cycloalkenyl may be substituted with one or more CA 022~3862 1998-11-09 W 0971429S6 PCT~US97/08335 _g_ aryl or heteroaryl, wherein the aryl or heteroaryl may be substituted with -F, -C1, -Br, -I, -NO2, -CN, -OR3, -SR3, Cl-C3 alkyl, or carboxamido; aryl or heteroaryl, wherein the aryl or heteroaryl may be substituted with one or more -F, -C1, -Br, -I, COR3, CO2R3, -CON(R3)2, -CN, -NO2, -N~R3)2, -OR3, -SR3, (CH2)~OR3, ~CH2)0SR3; straight chained or branched C~- C7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl, C2-C7 alkynyl, C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; and wherein each R6 is independently -H; straight chained or branched C1-C7 alkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C, alkenyl or alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; or -OR3;

or a pharmaceutically acceptable salt thereof.

The invention further provides for the (+) enantiomer of any of the compounds described herein which is a cis isomer or a trans isomer. The invention also provides for the ~-) enantiomer of any of the compounds described herein which is a cis or a trans isomer.

The compounds of the present invention are preferably at least 80% pure, more preferably 90% pure, and most preferably 95% pure.

Ten fold selectivity differences are a minimum, but one 3~ skilled in the art will appreciate that compounds can be found that collectively have almost infinitely variable selective profiles. Compounds collectively having all possible combinations of selectivities are intended within the scope of this invention, provided , WO 97/42956 PCT~US97/08335 that each of these compounds has at least ten-fold greater affinity for the a,A receptor over the a~ and/or a~D receptors.

S In one embodiment of the present invention the compound has the structure:

m[ll~ \V

In one embodiment of the present invention Z' is CO and n is 0.

20 In another embodiment of the present invention the compounds have the structure:

o~o ~ ~ ~ N~

The invention provides for compounds having the following structures:
~P

o ~ O
H3C~o~NJ~N~/~N~ N~2 CA 02253862 l998-ll-09 ~ F

o ~ ~ N~ ~N

~F

~ ~ o 'O ~ ~N~,CN

H

[~F

~3,,F

H,C~ N ~ ~J3 and 0 F~ ~,F

H3C~o ' ,I' ~,N N~

W O 97/42956 PCT~US97/08335 The present invention is also directed to compounds having the structure:
A

A O A

R 2 N ~ XX ~ R or wherein A is ~ ~ Y4 y 2 ~ N~ Z ~ N ~ ,-Y3 Yl ~ NH

Yl I N ~ ~ / ~ N

~ ' X

wherein each of Y~, Y2, Y3, Y4 and Ys is independently -H; straight chained or branched C,-C7 alkyl, monofluoroalkyl or polyfluoroalkyl;
straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, CA 022~3862 l998-ll-09 W O 97/42956 PCTrUS97/08335 polyfluorocycloalkyl or cycloalkenyl; -F, -Cl, -Br, or - I; - NO2 i - N3; - CN i - OR3, - OCOR3, - COR3, -CONHR3, -CON tR3) 2, or - COOR3; or any two of Yl, Y., Y3, Y4 and Ys present on adjacent carbon atoms can constitute a methylenedioxy group;

wherein X is S; O; or NR3 i wherein R, is -H; -NO2; -CN; straight chained or branched Cl-C, alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3- C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyli - N ( R3 ) 2 i - OR3; - ~ CH2 ) pOR3; - COR3;
CO2R3; or - CON ( R3 ) 2 i wherein R2 is -H; straight chained or branched C~-C, alkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C, alkenyl or alkynyl; C3-C7 cycloalkyl, monof luorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; C3-Clo cycloalkyl-C,-C10-alkyl, C3 - Clo cycloalkyl-C1-CIc-monofluoroalkyl or C3-Clo cycloalkYl-Cl-clo~
polyfluoroalkyl; - CN; - CH2XR3, - CH2X ( CH2 ) pNHR3, - ( CH2 ) nNHR3, - CH2X ~ CH2 ) pN ( R3 ) 2 ~ - CH2X ( CH2 ) pN3, or - CH2X ( CH2 ) pNHCXR,; or - OR3;

wherein each p is independently an integer from 1 to 7; wherein each n is independently an integer from 0 to 5;

wherein each R3 is independently -H; straight chained or branched Cl-C7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyli W 0 97/42956 PCTrUS97/08335 wherein R4 is R ~ / 5 m / Z ~ N

~ ~ N

Y

0 ~ L

R ~ / R6 / Z

l ~ V

SU~S 111 ~JTE SHEET (RULE 26) W O 97142956 PCTrUS97/08335 Z [ ] n [ ~ [ ] n N V R5 R n R R ~ / R5 m --C H 2 [I ~]n Z [I ] N

2 0 R R ~Yl ~ N ~ Y2 2 5 R m D oY3 R R
3 0 Z ~ ] ~ X ~ ] R8 R R

3 5 z ~ R 8 SUBSTITUTE SHEET (RULE 26) CA 022~3862 1998-11-09 W O 97/42956 PCT~US97/08335 R R ~ , R5 Z- ~ W ~ N R6 or R ~ R6 ~]n N ~ V~ R]m m [ ~ V

wherein Z is C2-C7 alkenyl or alkynyl; CH2; O; CO;
CO2; CONR3; S; SO; SO2; or NR3;

wherein Z' is (CH2)o~ CO, (CH2)oCO~ or CO(CH2)o;

wherein each D is independently CH2; O; S; NR3; CO;
or CS;

wherein W is C=O; C=NOR3; substituted or unsubstituted phenyl, pyridyl, thiophenyl, furanyl, pyrazinyl, pyrryl, naphthyl, indolyl, imidazolyl, benzfurazanyl, benzfuranyl or benzyimidazolyl, wherein the phenyl, pyridyl, thiophenyl, furanyl, pyrazinyl, pyrryl, naphthyl, indolyl, imidazolyl, benzfurazanyl, benzfuranyl or benzyimidazolyl is substituted with -H, -F, -Cl, -Br, -I, -NO2, -CN, straight chained or branched C,-C7 alkyl, straight chained or branched C,-C7 monofluoroalkyl, straight chained or branched C,-C7 polyfluoroalkyl, straight chained or branched C2-C7 alkenyl, straight chained or branched C2-C~

SIJ~ 111 UTE SHEET (RULE 26) CA 022~3862 1998-11-09 W097/42956 PCT~S97108335 alkynyl, C3- C7 cycloalkyl, C3- C7 monofluorocycloalkyl, C3 ~ C7 polyfluorocycloalkyl, C3-C7 cycloalkenyl, -N(R3)2, -OR3~ -COR3, -CO2R~ or -CON~R3) 2i wherein each V is independently O; S; CH2; CRsR,;
C (R7) 2i or NR7; provided that when V is CRsR7 the rem~; ni ~g carbons on the ring may only be substituted with R
wherein each m is independently an integer from 0 to 3; wherein o is an integer from l to 3;

wherein each R is independently -H; -F; straight chained or branched Cl-C7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; -N(R3)2i -NO2; -CN; -CO2R3; or - OR3;

wherein Rs is aryl or heteroaryl substituted with one or more of F; Cl; Br; I; COR3; C02R3; ~ CON( R3 ) 2 i CN; - NO2; ~ N(R3) 2 i ~ OR3, ~ SR3; ( CH2) oOR3 i ( ~H2) CSR3;
straight chained or branched Cl- C7 alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or carboxamidoalkyli straight chained or branched C2-C7 alkenyl, C2-C7 alkynyl, C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;

wherein each R6 is independently -H; straight chained or branched Cl- C7 alkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, monofluoroalkyl or polyfluoroalkyli straight chained or branched C2-C7 alkenyl or alkynyl; c3 - c7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; or -OR3;

CA 022~3862 1998-11-09 W097/42956 PCT~S97/08335 wherein R, is aryl or heteroaryl substituted with one or more of F; Cl; Br; I; COR3; CO2R3; -CON(R3)2;
CN; -NO2; -N(R3)2; -OR3, -SR3; (CH2)0OR3; (CH2)0SR3;
straight chained or branched Cl-C, alkyl, ~ 5 monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained or branched C2-C, alkenyl, C2-C7 alkynyl, C3-C, cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; and wherein ~ is -H; substituted or unsubstituted benzyl, benzoyl, phenyl, pyridyl, thiophenyl, furanyl, pyrazinyl, pyrryl, naphthyl, indolyl, imidazolyl, benzfurazanyl, benzfuranyl, benzimidazolyl or 2-keto-1-benzimidazolinyl, wherein the benzyl, benzoyl, phenyl, pyridyl, thiophenyl, furanyl, pyrazinyl, pyrryl, naphthyI, indolyl, imidazolyl, benzfurazanyl, benzfuranyl, benzimidazolyl or 2-keto-1-benzimidazolinyl is substituted with -H, -F, -Cl, -Br, -I, -NO2, -CN, straight chained or branched Cl-C, alkyl, straight chained or branched Cl-C,monofluoroalkyl, straight chained or branched Cl-C7polyfluoroalkyl, straight chained or branched C2-C7 alkenyl, straight chained or branched C2-C, alkynyl, C3-C7 cycloalkyl, C3-C7 monofluorocycloalkyl, C3-C7 polyfluorocycloalkyl, C3-C7 cycloalkenyl, -N(R3) 2~ -OR3, -COR3, -CO2R3, or -CON(R3) 2; substituted or unsubstituted straight chained or branched Cl-C7 alkyl, monofluoroalkyl or polyfluoroalkyl; substituted or unsubstituted straight chained or branched C2-C7 alkenyl or alkynyl; C3-C, cycloalkyl or cycloalkenyl, wherein the alkyl, monofluoroalkyl, polyfluoroalkyl, alkenyl, alkynyl, cycloalkyl or cycloalkenyl is substituted with -H, phenyl, pyridyl, thiophenyl, furanyl, pyrazinyl, pyrryl, naphthyl, indolyl, imidazolyl, benzfurazanyl, benzfuranyl, W097l42956 PCT~S97/08335 benzimidazolyl, -N(R3) 2, -NO2, -CN, -CO2R3, -OR3;

~ = Y3 ~ R.j, or N ~ R7 or a pharmaceutically acceptable salt thereof.

In one embodiment of the present invention the compounds have the following structure:

[ ~ " R5 ~ ~ X 7 In a further embodiment of the present invention the compounds have the structure:
y3 Yl ~ 5 R [ ~ -~ ~R5 ~ ~ ~ N V

SU~:i 111 ~JTE SHEET (RULE 26) W097/42956 PCT~S97/08335 In one embodiment of the present invention the compounds have the structure:

o o R / R

R3 1 N N ~ N v wherein V is selected from CR5R7 or NR7 and p is selected from 1-3.

In a preferred embodiment of the present invention the compounds have the following structures:
p 20 ~ F
O ~ O

H ~ N ~ O ' "~'~
H

S~CH3 [ ~ ~,p N,< ~ ~ 5' and SUv~lllUTESHEET(RULE26) -II~C'~ N~ o ~

_ _ W 097/42956 PCTrUS97/08335 The present invention is also directed to compounds having the structure:
A A

Rl ~ ~R3 R1~N ~ R2 wherein A is ~ 3 ~ ~ ~ Y4 Y~ NH

Y2 ~/ 3 Y~, Y3 or Y~

wherein each of Y~, Y2, Y3, Y4 and Y5 is independently -H; straight chained or branched C~-C7 alkyl, monofluoroalkyl or polyfluoroalkyl;
straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, SUBSTITUTE SHEET (RULE 26) CA 022~3862 1998-11-09 polyfluorocycloalkyl or cycloalkenyl; -F, -Cl, -Br, or - I; - NO2 i - N3; -CN; - OR4 ~ ~ OCOR4 ~ ~ COR
-CONHR4, -CON (R4) 21 or -COOR4; or any two of Yl, Y~, Yl ~ Y4 and Ys present on adjacent carbon atoms can constitute a methylenedioxy group;

wherein X is S; O; or NR4;

wherein B is -H; straight chained or branched C.-C7 alkyl, monofluoroalkyl, polyfluoroalkyl, alkoxy or thioalkyl; straight chained or branched C2 - C7 alkenyl; - SCH2C6H40R4; ~ ~ CH2 ) nC6Hs; ~ CH2X ( CH2 ) nNHR4;
~ ( CH2 ) nNHR4; or - OR4;

wherein Rl is -H; -NO2; -CN; straight chained or branched Cl-C7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C, alkenyl or alkynyl; C3-C, cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; -N (R4) 2i -OR4; ~ (CH2) pOR4; -COR4;
CO2R4; or - CON ( R4 ) 2;

wherein R2 is -H; straight chained or branched Cl-C7 alkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl, monof luorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; c3-clo cycloalkyl-Cl-C,O-alkyl, C3-Clo cycloalkyl-Cl-C1O-monofluoroalkyl or C3-clo CyC loalkyl-C1-C10-polyfluoroalkyl; - CN i ~ CH2XR4, ~ CH2X ( CH2 ) pNHR4, - ( CH2 ) nNHR4 1 - CH2X ( CH2 ) pN ( R4 ) 2 1 ~ CH2X ~ CH2 ) pN3 ~ or ~ CH2X ( CH2) pNHCXR7; or - OR4;

wherein each p is independently an integer from 1 to 7; wherein each n is independently an integer from 0 to 5;

CA 022~3862 1998-11-09 W 097/42956 PCTrUS97/08335 wherein R3 is R ~ R5 / R

R ~ / Rs ~ 6 20~ ~t ~ ¦ : Y3 301~ , v SUBSTITUTE SHEET (RULE 26) WO 97142956 -2 6- ~CT/US97/08335 S R ~~ 6 R R ~3~ ~R5 CH2 [ I]n Z [ ] O N~

l~]v ~ ~YZ

D o Y3 Z--E~X~ ] RB

--Z--~3~ R

SUBSTITUTE SHEET (RULE 26) CA 022~3862 1998-11-09 W097/42956 - PCT~S97/08335 R R ~ / R5 - Z ~ W ~ N V

R ~ R6 [] m R

m[~ V

wherein Z is C2-C7 alkenyl or alkynyl; CH2; O; CO;
CO2; CON~; S; SO; SO2; or N~;
wherein Z' is ~CH2)o~ CO, (CH2)oCO~ or CO(CH2)o;

wherein each D is independently CH2; O; S; N~; CO;
or CS;
wherein W is C=O; C=NO~; substituted or unsubstituted phenyl, pyridyl, thiophenyl, furanyl, pyrazinyl, pyrryl, naphthyl, indolyl, imidazolyl, benzfurazanyl, benzfuranyl or benzyimidazolyl, wherein the phenyl, pyridyl, thiophenyl, furanyl, pyrazinyl, pyrryl, naphthyl, indolyl, imidazolyl, benzfurazanyl, benzfuranyl or benzyimidazolyl is substituted with -H, -F, -Cl, -Br, -I, -NO2, -CN, straight chained or branched C,-C7 alkyl, straight chained or branched Cl-C7 monofluoroalkyl, straight chained or branched C,-C7 polyfluoroalkyl, straight chained or branched C2-C7 SUBSTITUTE SHEET (RULE 26) CA 022~3862 1998-11-09 WO 97l42956 PCT/US97/08335 alkenyl, straight chained or branched C~- C7 alkynyl, C3-C7 cycloalkyl, C3-C7 monofluorocycloalkyl, C3-C7 polyfluorocycloalkyl, C3- C7 cycloalkenyl, -N (R4) 2, -OR4, -COR4, -CO2R4, or -CON (R4) 2i wherein each V is independently Oi S; CH2; CRsR7;
C(R7)2; or NR7; provided that when V is CRsR. the remaining carbons on the ring may only be substituted with R6;

wherein each m is independently an integer from 0 to 3; wherein o is an integer from 1 to 3;

wherein each R is independently -H; -F; straight chained or branched C1-C7 alkyl, monofluoroalkyl or polyfluoroalkyli straight chained or branched C2-C7 alkenyl or alkynyl; -N (R4) 2; -NO2; -CN; -CO2R4; or - OR4;
wherein each R4 is independently -H; straight chained or branched Cl-C7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C, alkenyl or alkynyl; C3-C, cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;

wherein Rs is aryl or heteroaryl substituted with one or more of F; Cl; Br; I; COR3; CO2R3; -CON (R3) 2;
CN; - NO2; - N ( R3 ) 2; - OR3 ~ - SR3; ( CH2 ) oOR3; ( CH2 ) oSR3;
straight chained or branched C1-C, alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained or branched C2-C7 alkenyl, C2-C7 alkynyl, C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;

CA 022~3862 1998-11-09 W097/42956 PCT~S97/08335 wherein each R6 is independently -H; straight chained or branched C1- C7 alkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, monofluoroalkyl or polyfluoroalkyli straight chained or branched C~-C-alkenyl or alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; or -OR4;

wherein R7 is aryl or heteroaryl substituted with one or more of F; Cl; Br; I; COR3 i CO2R3; - CON ( R3 ) 2i CN; -NO2; -N(R3) 2; -OR3~ -SR3; (CH2) oOR3; (CH2) oSR3;
straight chained or branched C1- C7 alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained or branched C2-C7 alkenyl, C2-C7 alkynyl, C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; and wherein R8 is -H; substituted or unsubstituted benzyl, benzoyl, phenyl, pyridyl, thiophenyl, furanyl, pyrazinyl, pyrryl, naphthyl, indolyl, imidazolyl, benzfurazanyl, benzfuranyl, benzimidazolyl or 2-keto-1-benzimidazolinyl, wherein the benzyl, benzoyl, phenyl, pyridyl, thiophenyl, furanyl, pyrazinyl, pyrryl, naphthyl, indolyl, imidazolyl, benzfurazanyl, benzfuranyl, benzimidazolyl or 2-keto-1-benzimidazolinyl is substituted with -H, -F, -Cl, -Br, -I, -NO2, -CN, straight chained or branched Cl-C7 alkyl, straight chained or branched Cl-C7monofluoroalkyl, straight chained or branched C1-C7polyfluoroalkyl, straight chained or branched C2-C7 alkenyl, straight chained or branched C2-C7 alkynyl, C3-C7 cycloalkyl, C3-C, monofluorocycloalkyl, C3-c7 polyfluorocycloalkyl, C3-C7 cycloalkenyl, -N(R4)2, -OR4, -COR4, -CO.R4, or -CON(R4)2; substituted or unsubstituted straight chained or branched Cl-C7 alkyl, monofluoroalkyl or ~30~
po}yfluoroalkyl; substituted or unsubstituted straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl or cycloalkenyl, wherein the alkyl, monofluoroalkyl, polyfluoroalkyl, alkenyl, alkynyl, cycloalkyl or cycloalkenyl is substituted with -H, phenyl, pyridyl, thiophenyl, furanyl, pyrazinyl, pyrryl, naphthyl, indolyl, imidazolyl, benzfurazanyl, benzfuranyl, benzimidazolyl, -N(~)2, -NO2, -CN, -C02~, -o~;
Yl m ~ R7 or N~ ~ R7 or a pharmaceutically acceptable salt thereof.

In one embodiment of the present invention the compounds have the following structure:

R~ ~I N R ~ R5 ~ R6 SUBSTITUTESHEET(RULE26) W097/42956 PCT~S97/08335 In a further embodiment of the present invention the compounds have the structure:

Y~ Y,~

Yl~Y5 loR4 ~ ~ R ,~ R5 Rz N B

The invention further provides for the embodiment having the following structures:

H ~ ~ N
¢~
p and 0 ~ '~'~ ~ N ~

O'CH3 SUtsS 111 ~JTE SHEET (RULE 26~

W097/42956 PCT~S97108335 The present invention is also directed to compounds having the structure:
A A

Rz N B 3 N R3 wherein A is Yl ~ Y4 Yl ~X /

Y2 ~ N q ~ ~ Y3 Yl ~ NH Yl ~X , Yl ~,0 ~r Yl~l ;

wherein each of Y1, Y2, Y3, Y4 and Y5 iS
independently -H; straight chained or branched C~-C7 alkyl, monofluoroalkyl or polyfluoroalkyl;
straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; -F, -Cl, -Br, or -I; -NO2; -N3; -CN; -OR4, -OCOR4, -COR4, SU~S 111 UTE SHEET (RULE 26) CA 022~3862 1998-11-09 ~33~
-CONHR4~ -CON (R4) 2, or -COOR4; or any two of Yl, Y2, Y3~ Y4 and Ys present on adjacent carbon atoms can constitute a methylenedioxy group;

wherein X is S; O; or NR4;

wherein B is -H; straight chained or branched Cl-C7 alkyl, monofluoroalkyl, polyfluoroalkyl, alkoxy or thioalkyl; straight chained or branched C2-C7 alkenyl; -SCH2C6H4OR4; ~ (CH2)nC6Hs; -CH2X (CH2)oNHR4;
~ (CH2)nNHR4; or -OR4;

wherein Rl is -H; -NO2; -CN; straight chained or branched Cl-C7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; c3-c7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; -N(R4)2; -OR4; ~ (CH2)pOR4; -COR4;
CO2R4; or -CON ( R4)2;
wherein R2 is -H; straight chained or branched Cl-C7 alkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2~C7 alkenyl or alkynyl; C3-C7 cycloalkyl, monof luorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; C3-Clo cycloalkyl-C~-C1O-alkyl, C3-CIo cycloalkyl-CI-ClO-monofluoroalkyl or C3-CIo cycloalkyl-CI-ClO-polyfluoroalkyl; -CN; -CH2XR4, -CH2X ( CH2)pNHR4, ~ (CH2)nNHR4~ -CH2X (CH2)pN (R4)2, -CH2X (CH2)pN3, or -CH2X (CH2)pNHCXR7; or -OR4;

wherein each p is independently an integer from 1 to 7; wherein each n is independently an integer from O to S;

Sl~ 1 1 UTE SHEET (RULE 26) CA 022~3862 1998-11-09 W O 97/42956 34 PCT~US97/08335 wherein R3 is R ~ R6 R

R m~ ~]m m[~V

wherein Z' is (CH2)o~ C0, (CH2)oC0~ or CO(CH2)o;

wherein each V is independently 0; S; CH2; CR5R7;
C(R7)2; or NR7;

~5 wherein each m is independently an integer from 0 to 3; wherein o is an integer from 1 to 3;

wherein each R is independently -H; -F; straight chained or branched C,-C7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; -N(R4)2; -N02; -CN; -C02R4; or -OR4;

wherein each R4 is independently -H; straight chained or branched C,-C7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;
wherein R5 and R7 each independently may be -H; F;
Cl; Br; I; -COR3; -CO2R3; -CON(R3)2; -CN; -NO2;
-N (R3) 2; -OR3; -SR3; - (CH2)pOR3; - (CH2)pSR3; straight chained or branched Cl-C7 alkyl, aminoalkyl, carboxamidoalkyl; straight chained or branched ~ C2-C7 alkenyl or alkynyl, or C3-C7 cycloalkyl or cycloalkenyl; wherein the alkyl, aminoalkyl, carboxamidoalkyl, alkenyl, alkynyl, cycloalkyl or cycloalkenyl may be substituted with one or more SIJL~S 1 l l UTE SHEET (RULE 26) . _ .

CA 022~3862 1998-11-09 W097l42956 PCT~S97/08335 aryl or heteroaryl, wherein the aryl or heteroaryl may be substituted with -F, -Cl, -Br, -I, -NO7, -CN, -OR3, -SR3, Cl-C3 alkyl, or carboxamido; aryl or heteroaryl, wherein the aryl or heteroaryl may be substituted with one or more -F, -Cl, -Br, - I, COR3, CO2R3, - CON ~ R3 ) 2~ - CN, -N02, -N~ R3 ) 2 ~ - OR3, -SR3, ~CH2)oOR3l ~CH2)oSR3; straight chained or branched Cl-C7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C7-C7 alkenyl, C2-C7 alkynyl, C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; and wherein each R6 is independently -Hi straight chained or branched C1-C7 alkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, monofluoroalkyl or polyfluoroalkyli straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; or -OR4;

or a pharmaceutically acceptable salt thereof.

In the present invention aryl includes phenyl, benzyl, benzoyl or naphthyl and heteroaryl includes pyrazinyl, pyrryl, furanyl, thiophenyl, pyridyl, imidazolyl, indolyl, aminophenyl, benzamidyl, benzimidazolyl, benzfurazanyl, benzfuranyl, 2-keto-1-benzimidazolinyl or quinolyl.
The invention further provides for a pharmaceutical composition comprising a therapeutically effective amount of any of the compounds described above and a pharmaceutically acceptable carrier. In the subject 3S invention a "therapeutically effective amount" is any amount of a compound which, when administered to a subject suffering from a disease against which the compounds are effective, causes reduction, remission, or regression of the disease. In one embodiment the CA 022~3862 1998-11-09 W097/42956 PCT~S97/08335 therapeutically effective amount is an amount from about 0.01 mg per subject per day to about 500 mg per subject per day, preferably from about 0.1 mg per subject per day to about 60 mg per subject per day and S most preferably from about 1 mg per subject per day to about 20 mg per subject per day. In the practice of this invention the "pharmaceutically acceptable carrier" is any physiological carrier known to those of ordinary skill in the art useful in formulating pharmaceutical compositions.

In one preferred embodiment the pharmaceutical carrier may be a liquid and the pharmaceutical composition would be in the form of a solution. In another equally preferred embodiment, the pharmaceutically acceptable carrier is a solid and the composition is in the form of a powder or tablet. In a further embodiment, the pharmaceutical carrier is a gel and the composition is in the form of a suppository or cream.
The invention provides a method of treating a subject suffering from benign prostatic hyperplasia which comprises administering to the subject any one of the compounds described herein effective to treat benign prostatic hyperplasia. In a preferred embodiment the compound of the pharmaceutical composition additionally does not cause a fall in blood pressure at dosages effective to alleviate benign prostatic hyperplasia.
In one preferred embodiment the compound effects treatment of benign prostatic hyperplasia by relaxing lower urinary tract tissue and in particular where lower urinary tract tissue is prostatic smooth muscle.

The invention further provides a method of treating a subject suffering from elevated intraocular pressure which comprises administering to the subject one of the compounds described herein effective to lower intraocular pressure.

CA 022~3862 1998-11-09 W097l42956 PCT~S97/08335 The invention further provides a method of treating a subject suffering from a disorder associated with elevated blood cholesterol which comprises administering to the subject one of the compounds ~ 5 described herein effective to inhibit cholesterol synthesis.

The invention also provides a method of treating a disease which is susceptible to treatment by antagonism of the ~lA receptor which comprises administering to the subject one of the compounds described herein effective to treat the disease.

The invention further provides a method of treating a subject suffering from impotency which comprises administering to the subject one of the compounds described herein effective to treat impotency.

The invention further provides a method of treating a subject suffering from sympathetically mediated pain which comprises administering to the subject one of the compounds described herein effective to treat sympathetically mediated pain.

The invention provides a method of treating a subject suffering from cardiac arrhythmia which comprises administering to the subject one of the compounds described herein effective to treat cardiac arrhythmia.

The invention provides a method of treating a subject suffering from benign prostatic hyperplasia which comprises administering to the subject one of the compounds described herein in combination with a 5 alpha-reductase inhibitor effective to treat benign prostatic hyperplasia. In one preferred embodiment the - 5-alpha reductase inhibitor is finasteride. The dosage administered to the subject is about 0.01 mg per subject per day to 50 mg per subject per day of finasteride in combination with an ~l~ antagonist. A

CA 022~3862 1998-11-09 W097/42956 PCT~S97/08335 more preferred dosage administered to the subject is about 1 mg per subject per day to 7 mg per subject per day of finasteride in combination with an antagonist. The most preferred dosage administered to the subject is about 5 mg per subject per day of finasteride in combination with an ~lA antagonist.

The invention also provides for a pharmaceutical composition comprising a therapeutically effective amount of a combination of any of the compounds described herein in combination with finasteride and a pharmaceutically acceptable carrier. In one embodiment the pharmaceutical composition is a therapeutically effective amount of a combination comprising an amount from about 0.01 mg per subject per day to about 500 mg per subject per day of any one of the compounds described herein and an amount of finasteride of about 5 mg per subject per day. A more preferred embodiment of the pharmaceutical composition is a therapeutically effective amount of a combination comprising an amount from about 0.1 mg per subject per day to about 60 mg per subject per day of any one of the compounds described herein and an amount of the finasteride of about 5 mg per subject per day. The most preferred embodiment of the pharmaceutical composition is a therapeutically effective amount of a combination comprising from about 1 mg per subject per day to about 20 mg per subject per day of any one of the compounds described herein and an amount of finasteride of about 5 mg per subject per day.

The invention further provides a method of relaxing lower urinary tract tissue which comprises contacting the lower urinary tract tissue with an amount of one of the compounds described herein effective to relax lower urinary tract tissue. In one embodiment the lower urinary tract tissue is prostatic smooth muscle. In one preferred embodiment the compound additionally does not cause a fall in blood pressure when it is effective CA 022~3862 1998-11-09 W097/42956 PCT~S97108335 to relax lower urinary tract tissue.

The invention provides a method of relaxing lower urinary tract tissue in a subject which comprises administering to the subject an amount of one of the compounds described herein effective to relax lower urinary tract tissue. In one preferred embodiment the compound does not cause a fall in blood pressure and the lower urinary tract tissue is prostatic smooth muscle.

The invention further provides for a method of inhibiting contraction of prostatic tissue, which comprises administering to the subject an amount of any lS of the compounds described herein effective to inhibit contraction of prostatic tissue. In one preferred embodiment the prostatic tissue is prostatic smooth muscle and the compound additionally does not cause a fall in blood pressure.
The invention provides for the use of the compounds described herein for the preparation of a pharmaceutical composition for lowering intraocular pressure, inhibiting cholesterol synthesis, and the treatment of: benign prostatic hyperplasia, impotency, cardiac arrhythmia and any disease where antagonism of the ~lA receptor may be useful. The invention provides for the use of the compounds described herein for the preparation of a pharmaceutical composition for ~30 relaxing lower urinary tract tissue and in particular prostatic smooth muscle. The invention further provides for the use of any of compounds described herein for the preparation of a pharmaceutical composition, where the compound additionally does not cause a fall in blood pressure at dosages effective tc lower intraocular pressure, to inhibit cholesterol synthesis, and for the treatment of: benign prostatic hyperplasia, impotency, cardiac arrhythmia and any disease where antagonism of the ~lA receptor may be CA 022~3862 1998-11-09 useful.

The invention provides for the use of the compounds described herein in the preparation of a medicament for lowering intraocular pressure, inhibiting cholesterol synthesis, and for the treatment of: benign prostatic hyperplasia, impotency, cardiac arrhythmia and any disease where antagonism of the ~A receptor may be useful. The invention provides for the use of the compounds described herein in the preparation of a medicament for relaxing lower urinary tract tissue and in particular prostatic smooth muscle. The invention further provides for the use of any of compounds described herein in the preparation of a medicament, where the compound additionally does not cause a fall in blood pressure at dosages effective to lower intraocular pressure, to inhibit cholesterol synthesis, and for the treatment of: benign prostatic hyperplasia, impotency, cardiac arrhythmia and any disease where antagonism of the ~lA receptor may be useful.

The invention provides for a drug which is useful for lowering intraocular pressure, inhibiting cholesterol synthesis, and the treatment of: benign prostatic hyperplasia, impotency, cardiac arrhythmia and any disease where antagonism of the ~lA receptor may be useful, the effective ingredient of the said drug being any of the compounds described herein. The invention further provides the drug described herein additionally does not cause a fall in blood pressure at dosages effective to lower intraocular pressure, to inhibit cholesterol synthesis, and for the treatment of: benign prostatic hyperplasia, impotency, cardiac arrhythmia and any disease where antagonism of the ~lA receptor may be useful.

The invention provides for a drug which is useful for relaxing lower urinary tract tissue and in particular prostatic smooth muscle, the effective ingredient of CA 022~3862 l998-ll-09 the drug being any of the compounds described herein.
The invention further provides the drug which is useful for relaxing lower urinary tract tissue additionally does not cause a fall in blood pressure at dosages effective to relax lower urinary tract tissue.

The invention also provides for the (-) and (+) enantiomers of all compounds of the subject application described herein. Included in this invention are pharmaceutically acceptable salts and complexes of all of the compounds described herein. The salts include but are not limited to the following acids and bases.
The following inorganic acids; hydrochloric acid, hydrofluoric acid, hydrobromic acid, hydroiodic acid, sulfuric acid and boric acid. The organic acids;
acetic acid, trifluoroacetic acid, formic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, maleic acid, citric acid, methanesulfonic acid, trifluoromethanesulfonic acid, benzoic acid, glycolic acid, lactic acid and mandelic acid. The following inorganic bases; ammonia, hydroxyethylamine and hydrazine. The following organic bases; methylamine, ethylamine, propylamine, dimethylamine, diethylamine, trimethylamine, triethylamine, ethylenediamine, hydroxyethylamine, morpholine, piperazine and guanidine. This invention further provides for the hydrates and polymorphs of all of the compounds described herein.

In one preferred embodiment the pharmaceutical carrier may be a liquid and the pharmaceutical composition would be in the form of a solution. In another equally preferred embodiment, the pharmaceutically acceptable carrier is a solid and the composition is in the form of a powder or tablet. In a further embodiment, the pharmaceutical carrier is a gel and the composition is in the form of a suppository or cream. In a further embodiment the compound may be formulated as a part of a pharmaceutically acceptable transdermal patch.

.

W097/42956 PCT~S97/0~3S

A solid carrier can include one or more substances which may also act as flavoring agents, lubricants, solubilizers, suspending agents, fillers, glidants, compression aids, binders or tablet-disintegrating agents; it can also be an encapsulating material. In powders, the carrier is a finely divided solid which is in admixture with the finely divided active ingredient.
In tablets, the active ingredient is mixed with a carrier having the necessary compression properties in suitable proportions and compacted in the shape and size desired. The powders and tablets preferably contain up to 99~ of the active ingredient. Suitable solid carriers include, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, polyvinylpyrrolidine, low melting waxes and ion exchange resins.

Liquid carriers are used in preparing solutions, suspensions, emulsions, syrups, elixirs and pressurized compositions. The active ingredient can be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, a mixture of both or pharmaceutically acceptable oils or fats. The liquid carrier can contain other suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, colors, viscosity regulators, stabilizers or osmo-regulators. Suitable examples of liquid carriers for oral and parenteral administration include water (partially containing additives as above, e.g.
cellulose derivatives, preferably sodium carboxymethyl cellulose solution), alcohols (including monohydric alcohols and polyhydric alcohols, e.g. glycols) and their derivatives, and oils (e.g. fractionated coconut oil and arachis oil). For parenteral administration, the carrier can also be an oily ester such as ethyl CA 022~3862 1998-11-09 W097/42956 PCT~S97/0~35 oleate and isopropyl myristate. Sterile liquid carriers are useful in sterile liquid form compositions for parenteral administration. The liquid carrier for pressurized compositions can be halogenated hydrocarbon or other pharmaceutically acceptable propellent.

Liquid pharmaceutical compositions which are sterile solutions or suspensions can be utilized by for example, intramuscular, intrathecal, epidural, intraperitoneal or subcutaneous injection. Sterile solutions can also be administered intravenously. The compounds may be prepared as a sterile solid composition which may be dissolved or suspended at the time of ~ n-stration using sterile water, saline, or other appropriate sterile injectable medium. Carriers are intended to include necessary and inert binders, suspending agents, lubricants, flavorants, sweeteners, preservati~es, dyes, and coatings.

The compound can be administered orally in the form of a sterile solution or suspension containing other solutes or suspending agents, for example, enough saline or glucose to make the solution isotonic, bile salts, acacia, gelatin, sorbitan monoleate, polysorbate (oleate esters of sorbitol and its anhydrides copolymerized with ethylene oxide) and the like.

The compound can also be administered orally either in liquid or solid composition form. Compositions suitable for oral administration include solid forms, such as pills, capsules, granules, tablets, and powders, and liquid forms, such as solutions, syrups, elixirs, and suspensions. Forms useful for parenteral administration include sterile solutions, emulsions, and suspensions.
.

Optimal dosages to be administered may be determined by CA 022~3862 1998-11-09 W097/42956 PCT~S97/08335 those skilled in the art, and will vary with the particular compound in use, the strength of the preparation, the mode of administration, and the advancement of the disease condition. Additional factors depending on the particular subject being treated will result in a need to adjust dosages, including sub~ect age, weight, gender, diet, and time of administration.

One skilled in the art will readily appreciate that appropriate biological assays will be used to determine the therapeutic potential of the claimed compounds for the treating the above noted disorders.

This invention will be better understood from the Experimental Details which follow. However, one skilled in the art will readily appreciate that the specific methods and results discussed are merely illustrative of the invention as described more fully in the claims which follow thereafter.

W O 97/42956 PCTrUS97/08335 Experimental Detail6 For Examples 1-92 Scheme l describes the general synthetic preparation. All NMRs were obtained using a 300MHz GE QEPLUS NMR machine.

Example 1 1,6-Dihydro-5-methoxycarh~nyl-2-l{(4-methoxyphenyl)me thyl}thio]-4-methyl-6-(4-nitrophenyl)-1-{N-[3-(4,4-diphenylpiperidin-1-yl)propyl]}carhnx~;do pyrimidine.

a. 4,4-Diphenylpiperidine hydrochloride. A mixture of 4-piperidone monohydrate hydrochloride (15.0 g, 0.0976 mol) and AlCl3 (130 g, 0.976 mol, 10.0 eq) in anhydrous benzene (600 mL) were stirred at reflux for 4 hours.
The mixture was cooled to room temperature, poured into ice (300 g) and water (50 mL), and filtered. The solid was washed with toluene and dried to afford 19.2 g (72~) of an off-white solid, which was characterized spectroscopically.

b. 3-(4,4-Diphenylpiperidin-1-yl)propionitrile. To a suspension of 4,4-diphenylpiperidine hydrochloride (0.195 g, 0.712 mmol) in EtOH (1.5 mL) was added Et3N
(0.25 mL, 1.8 mmol, 2.6 eq) followed by acrylonitrile (0.13 mL, 2.01 mmol, 2.8 eq). The resulting solution was stirred at room temperature under argon for 15 min and then concentrated. Water was added, and the mixture was extracted with EtOAc (3 X 10 mL). The combined organic extracts were dried ~MgSO4) and concentrated to give 170 mg (87%) of a tan solid, which was characterized spectroscopically and used in the next reaction without purification.
c. 3-(4,4-Diphenylpiperidin-l-yl)propylamine. To a stirred solution of 3-(4,4-diphenylpiperidin-1-W 097/42956 PCTrUS97/08335 yl)propionitrile (2.00 g, 6.89 mmol) in anhydrous THF
(20 mL) under argon was added a solution of BH3 in THF
(1.0 M, 24.1 mL, 24 mmol, 3.5 eq) at room temperature.
The mixture was refluxed for 4.5 hours and then cooled to room temperature. Aqueous HCl (6 N, 50 mL) was added and stirring was continued for 1 hour. The mixture was basified to pH 9 by addition of 6 N aq.
NaOH, extracted with CH2C12 (3 X 10 mL), dried (MgSO4) and concentrated. The residue was purified by flash chromatography (SiO2, EtOAc-MeOH-isopropylamine 9:1:0to 4:1:0.2) to give 1.35 g (66~) of tan solid, which was characterized spectroscopically.

d. 2-(4-Methoxybenzyl)-2-thiopseudourea hydrochloride.
To a well-stirred suspension of thiourea (7.6 g, 0.1 mol) in THF (50 mL) at 0 ~C, 4-methoxybenzyl chloride (16 g, 0.1 mol) was added in 10 min and the mixture was allowed to warm to room temperature. After 2 hours the mixture was heated to 65 ~C and kept at that temperature for 5 hours. It was cooled to room temperature and diluted with diethyl ether (200 mL). The white precipitate formed was filtered and dried (22.5 g, 96~); ~. p. 161-163 ~C.
e. Methyl 2-{(4-nitrophenyl)methylene}-3-oxobutyrate.A
mixture of 4-nitrobenzaldehyde (15.1 g, 0.1 mol), methyl acetoacetate (12.773 g, 0.11 mol), piperidine (0.41 g, 476 mL, 4.8 ~mol), and acetic acid (0.288 g, 274 mL, 4.8 mmol) in 2-propanol (400 mL) was stirred at room temperature for 48 hours. The white solid, methyl 2-{(4-nitrophenyl)methylene}-3-oxobutyrate, formed was filtered, washed with 2-propanol (2 X 50 mL) and dried (21.80 g, 93%).
f.l,6-Dihydro-5-methoxycarbonyl-2-[{(4-methoxyphenyl) methyl}th~o~-4-methyl-6-(4-nitrophenyl)pyrimidine. A

W097/429~6 PCT~S97/0833 mixture of methyl 2-{(4-nitrophenyl)methylene}-3-oxobutyrate (3:96 g, 0.04 mol), 2-(4-methoxybenzyl)-2-thiopseudourea hydrochloride (9.28 g, 0.04 mol), and NaOAc (3.28 g, 0.04 mol) in DMF (100 mL) was stirred and heated at 70-75 ~C for 4.5 hours. The mixture was cooled, poured into ice-water (300 mL), extracted with EtOAc (2 X 400 mL). The com~ined EtOAc extracts were washed with 10~ NaHCO3 solution (2 X 60 mL), brine (100 mL), and dried (MgSO4). Solvent was evaporated and the crude product was purified by flash column chromatography on silica gel using 10~ through 30%
EtOAc in hexane as the gradient eluent, to leave the product as an oil, which on trituration with EtOAc/hexane became a yellow solid (11.4 g, 66.7~);
m.p. 13B-139 ~C; lH-NMR (CDCl3): ~ 2.15 (s, 3 H), 3.62 (s, 3 H), 3.72 (s, 3 H), 4.05, 5.78 (s, d, J = 3 Hz, 1 H), 4.08, 4.20 (AB q, J = 12.5 Hz, 2 H), 4.21, 6.40 (s, d, J = 3 Hz, 1 H), 6.66 (2 d, J = 8.5 Hz, 2 H), 7.08 (2 d, J = 8.5 Hz, 2 H), 7.37 (2 d, J = 8.8 Hz, 2 H), 8.7 (2 d, J = 8.8 Hz, 2 H); Anal. Calcd. for C2lH2lN3O5S: C, 59.00; H, 4.95; N, 9.83. Found: C, 59.02; H, 4.93; N, 9.77.

g. 1,6-Dihydro-5-methoxycarbonyl-2-[{(4-methoxyphenyl) methyl}thio~-4-methyl-6-(4-nitrophenyl)-1-[(4-nitroph enyloxy)carbonyl]pyrimidine.
To a well-stirred mixture of 1,6-dihydro-5-methoxy car~onyl-2-[~(4-methoxyphenyl)methyl)thio]-4-methyl-6 -(4-nitrophenyl)pyrimidine (4.5 g, 0.0105 mol), NaHCO
(3.69 g, 0.044 mol), CH2C12 (200 mL), and water (50 mL) at 0-5 ~C, 4-nitrophenyl chloroformate (2.4 g, 0.0119 mol) was added in 5 min and the mixture was allowed to warm to room temperature. After 10 hours, the TLC
analysis of the reaction mixture showed the presence of a small amount of starting pyrimidine, therefore, more 4-nitrophenyl chloroformate (0.65 g, 0.C032 mol) was added and the stirring continued for an additional 4 W O g7/42956 PCTrUS97/08335 hours. The two layers were separated, the CH Cl2 layer was washed with saturated aqueous NaHCO3 solution ~3 X
50 mL), dried (MgSO4), and the solvent evaporated. The residue was recrystallized from CH2Cl2 and hexane to give the product as white crystals (5.5 g, 88.4%); m.p.
156-157 ~C; lH-NMR (CDCl3): ~ 2.53 ~s, 3 H), 3.70 (s, 3 H), 3.81 (s, 3 H), 4.06, 4.36 (AB q, J = 13.5 Hz, 2 H), 6.30 (s, 1 H), 6.78 (d, J = 8.7 Hz, 2 H), 7.17 (d, J =
8.5 Hz, 2 H), 7.20 (d, J = 8.7 Hz, 2 H), 7.32 (d, J =
8.8 Hz, 2 H), 7.97 (d, J = 8.8 Hz, 2 H), 8.25 (d, J =
8.8 Hz, 2 H); Anal. Calcd. for C2BH24N4O9S: C, 56.75; H, 4.08; N, 9.45. Found: C, 56.49; H, 4.28; N, 9.25.

h. 1,6-Dihydro-5-methoxycarbonyl-2-~{(4-methoxyphenyl) methyl}thio~-4-methyl-6-(4-nitrophenyl)-1-{N-[3-(4,4-diphenylpiperidin-1-yl)prop-yl]}carboxamido pyrimidine.
To a stirred solution of 1,6-dihydro-5-methoxycarbonyl -2-[{(4-methoxyphenyl)methyl)thio]-4-methyl-6-(4-nitr ophenyl)-1-[(4-nitrophenyloxy)carbonyl]pyrimidine (0.592 g, 1 mmol) in anhydrous TH~ (10 mL) at room temperature under argon atmosphere, a solution of 3-[4,4-diphenylpiperidin-1-yl]propylamine (0.441 g, 1.5 mmol, 1.5 eq) in THF (5 mL) was added and the stirring continued for 1 hours. Solvent was evaporated from the reaction mixture and the residue was redissolved in CH2C12 (50 mL), washed with 5% NaHCO3 (3 X 25 mL), brine (50 mL), and dried ~MgSO4). Solvent was evaporated and the residue was purified by flash chromatography on silica gel using 10% methanol in EtOAc as the eluent to give the desired product as an oil, which on trituration with hexane and drops of EtOAc became a white powder (0.32 g, 43%); m.p. 79-80 ~C; lH-NMR
~CDCl3): ~ 1.61-1.82 (m, 4 H), 2.27 (s, 3 H), 2.30-2.51 (m, 8 H), 3.19-3.36 (m, 1 H), 3.42-3.60 (m, 1 H), 3.68 (s, 3 H), 3.76 (s, 3 H), 3.95, 4.22 (AF3 q, J = 13.6 Hz, 2 H), 6.16 ~s, 1 H), 6.70 (d, J = 8.6 Hz, 2 H), 7.04 , . . ..

CA 022~3862 1998-11-09 W097/42956 PCT~S97/08335 (d, ~ = 8.6 Hz, 2 H), 7.11-7.29 (m, 12 H), 7.68 (br t, 1 H, NH), 7.91 (d, J = 8.8 Hz, 2 H); Anal. Calcd. for C42H45N5O6SØ33 CH2C12: C, 65.52; H, 5.93; N, 9.03 Found: C, 65.52; H, 6.01; N, 9.20.

- Example 2 1,6-Dihydro-5-methoxyC~r~nyl-2-~{(4-methoxyphenyl)me thyl}thio~-4-methyl-6-(4-nitrophenyl)-1-{N-[3-(4-phenylpiperidin-1-yl)propyl]}carboxamidopyrimidine.

a. 3-(4-Phenylpiperidin-1-yl)propionitrile.
Acrylonitrile (3.1 mL, 44 mmol, 2.5 eq) was added to a solution of 4-phenylpiperidine (3.0 g, 18 mmol) in EtOH
(40 mL) and the mixture was stirred at room temperature for 1.5 hours. The volatiles were removed to give 3.8 g of pure product (brown oil, 99~), which was characterized spectroscopically.

b. 3-(4-Phenylpiperidin-1-yl)propylamine. To a stirred solution of 3-(4-phenylpiperidin-1-yl)propionitrile (5.1 g, 24 mmol) in anhydrous THF ~20 mL) under argon was added a solution of BH3 in THF (1.0 M, 83 mL, 83 mmol, 3.5 eq) at room temperature. The mixture was re-fluxed for 4.5 hours and then cooled to roomtemperature. Aqueous HCl (6 N, 130 mL) was added and stirring was continued for 2 hours at 50-70 ~C. The mixture was basified to pH 9 by addition of 6 N aq.
NaOH and extracted with EtOAc (100 mL) and CH2Cl2 (3 x 100 mL). The combined organic extracts were dried (MgSO4) and concentrated. The residue was dissolved in CH2Cl2 (20 mL) and treated with HCl in ether (1.0 M, 50 mL). The solvents were removed, ether ~250 mL) was added, the mixture was filtered, and the filter cake was washed with ether. Water (60 mL) was added to the resulting white solid, the pH was adjusted to 10-11 with 1 N NaOH, and the aqueous phase was extracted with W O 97/42956 PCTrUS97/08335 CH2Cl2 t3 X 50 mL). The combined extracts were dried ~MgSO4) and the solvents evaporated to give 4.5 g ~87~) of pure product (light brown solid), which was characterized spectroscopically.

c. 1,6-Dihydro-5-methoxyrarho~yl-2-[{(4-methoxyphenyl) methyl}thio]-4-methyl-6-(4-nitrophenyl~-1-{N-~3-~4-phenylpiperidin-1-yl)propyl]}carboxamido pyrimidine. This compound was prepared from 1l6-dihydro-5-methoxycarbonyl-2-[~(4-methoxyphenyl) methyl~thio]-4-methyl-6-(4-nitrophenyl)-1-[~4-nitroph enyloxy)carbonyl]pyrimidine (0.77 g, 1.3 mmol), 3-~4-phenylpiperidin-1-yl] propylamine (0.34 g, 1.56 mmol, 1.2 eq) and purified using similar conditions described in Example 1 (0.63 g, 72~); m.p. 123-124 ~C; lH-NMR
(CDC13): ~ 1.65-2.10 (m, 8 H), 2.41 (s, 3 H), 2.41-2.55 (m, 3 H), 2.99-3.06 (m, 2 H), 3.2-3.35 (m, 1 H), 3.45-3.60 (m, 1 H), 3.67 (s, 3 H), 3.75 (s, 3 H), 4.10, 4.33 (AB q, J = 13.6 Hz, 2 H), 6.19 (s, 1 H), 6.71 (d, J =
8.6 Hz, 2 H), 7.09 (d, ~ = 8.6 Hz, 2 H), 7.20-7.34 (m, 7 H), 7.97 ~br t, 1 H, NH), 7.97 (d, J = 8.8 Hz, 2 H);
Anal. Calcd. for C36H4lNsO6SØ25 CH2Cl2: C, 62.82; H, 6.04; N, 10.11. Found: C, 62.54; H, 6.13; N, 10.03.

Example 3 1-{N-[3-(4-Cyano-4-phenylpiperidin-1-yl)propyl]}
carboxamido-1,6-dihydro-5-methoxycarbonyl-2-t{(4-meth oxyphenyl)methyl}thio]-4-methyl-6-(4-nitrophenyl) pyrimidine.

a. 3-(4-Cyano-4-phenylpiperidinlyl)propyl a~i ne . 4-Cyano-4-phenylpiperidine hydrochloride (5.01 g, 22.5 mmol) was added to water (100 mL~, and the solution was basified to pH 10-11 by addition of 6 N aqueous NaOH.
The mixtùre was extracted with CH2Cl2 (3 x 100 mL). The combined organic extracts were dried (MgSO4) and CA 02253862 l998-ll-09 W O 97142956 PCT~US97/08335 concentrated. To the residue were added 3-bromopropylamine hydrobromide ~4.92 g, 22.5 mmol), anhydrous K2CO3 (3.42 g, 24.8 mmol, 1.10 eq), and 1,4-dioxane (100 mL). The mixture was stirred at reflux for 24 hours under a CaSO4 drying tube. The solvent was evaporated, and the product was purified by flash chromatography (SiO2, CHCl3/MeOH/2 M NH3 in MeOH
(100:8:4 to 100:20:B) to give 3.23 g (59~) of colorless oil, which was characterized spectroscopically.
b. 1-{N- t3- (4-Cyano-4-phenylpiperidin-1-yl)propyl] }
carboxamido -1, 6 - dihydro - 5 -methoxycarbonyl - 2 [ { ( 4 -metho xy-phenyl)methyl}thiol -4-methyl-6- (4-nitrophenyl) pyrimidine .
This compound was prepared from 1,6-dihydro-5-methoxy carbonyl-2-[{(4-methoxyphenyl)methyl}thio]-4-methyl-6 -(4-nitrophenyl)-1-~(4-nitrophenyloxy)carbonyl~pyrimi dine (0.592 g, 1 mmol), 3-[4-cyano-4-phenyl piperidin-1-yl]propylamine (0.292 g, 1.2 mmol, 1.2 eq) and purified using similar conditions described in Example 1 (0.445 g, 64~); m.p. 143-144 ~C; lH-NMR
(CDCl3): ~ 1.70-1.86 (m, 2 H), 2.02-2.09 (m, 4 H), 2.38 (s, 3 H), 2.41-2.56 (m, 4 H), 2.95-3.02 (m, 2 H), 3.24-3.40 ~m, 1 H), 3.42-3.58 (m, 1 H), 3.68 (s, 3 H), 3.76 (s, 3 H), 4.08, 4.23 (AB q, J = 13.5 Hz, 2 H), 6.23 (s, 1 H), 6.72 (d, J = 8.6 Hz, 2 H), 6.94 (br t, 1 H, NH), 7.08 (d, J = 8.6 Hz, 2 H), 7.29 (d, ~ = 8.7 Hz, 2 H), 7.33-7.49 (m, 5 H), 7.94 (d, J = 8.8 Hz, 2 H); Anal.
Calcd. for C37H40N6O6S: C, 63.78; H, 5.79; N, 12.06.
Found: C, 63.86; H, 5.90i N, 11.92.

Example 4 1, 6 -Dihydro- 5 -methoxycarbonyl -1- {N- [ 3 - ( 4 -methoxycarbonyl - 4 -phenylpiperidin- 1 -yl ) propyl ] }
carboxsmido - 2 - [ { ( 4 -mothoxyphenyl ) methyl } thio~ - 4 -~nethyl -6 - ~ 4 -nitrophenyl ) pyrimidine .

W O 97/42956 . PCT~US97/08335 a. 4-Methoxycarbonyl-4-phenylpiperidine. T o a stirred solution of H2SO4 (16 mL) in MeO~ (400 mL), 4-phenyl-4-piperidinecarboxylic acid 4-methyl benzenesulfonate ~37.7 g, 0.1 mole) was added and the mixture was stirred and refluxed for 8 hours. Excess methanol was evaporated at reduced pressure and the residue was poured into a mixture of ice and 6 N NaOH.
The pH was adjusted to 10-11 by adding more 6 N NaOH
and extracted with CH2Cl2 (3 X 150 mL). The combined CH2Cl2 extracts were dried ~MgSO4) and the solvent evaporated to leave the desired product as a viscous oil. The product (20.2 g, 92%) was used without further purification.

b. 3-(4-Methoxycarbonyl-4-phenylpiperidin-1-yl)propylamine.
A mixture of 4-methoxycarbonyl-4-phenylpiperidine (8.5 g, 0.039 mol), 3-bromopropylamine hydrobromide (12.7 g, 0.058 mol), potassium carbonate (13.475 g, 0.0957 mole), and KI (3.24 g, 0.0195 mol) in 1,4-dioxane (200 mL) was stirred and refluxed for 24 hours. Dioxane was evaporated at reduced pressure, the residue was treated with ice-cold 6 N NaOH (400 mL) and extracted with CH2Cl2 t4 X 120 mL). Sol~ent was evaporated from the combined dried (K2CO3) extracts and the residue was purified by column chromatography on silica gel using CHCl3/MeOH/2 M NH3 in MeOH (20:2:1) as the eluent to afford the product as a viscous oil (7.8 g, 72~).

c. 1,6-Dihydro-5-methoxycarbonyl-1-{N-[3-(4-methoxycarbonyl-4-phenylpiperidin-1-yl)propyl~}carbox amido-2-~{(4-methoxyphenyl)methyl}thio]-4-methyl-6-(4-nitrophenyl)pyrimidine. This compound was prepared from 1,6-dihydro-~-methoxycarbonyl -2-[~(4-methoxyphenyl)methyl)thio]-4-methyl-6-(4-nitr ophenyl)-1-[(4-nitrophenyl-oxy)carbonyl]pyrimidine (1.0 g, 1.69 mmol), 3-[4-methoxycarbonyl-4-phenyl CA 022~3862 1998-11-09 W097/42956 PCT~S97/08335 piperidin-l-yl]propylamine (0.56 g, 2.03 mmol, 1.2 eq) and purified using similar conditions described in Example 1 (1.085 g, 88%); m.p. 140-141 ~C; ;H-NMR
(CDCl3): ~ 1.62-1.74 (m, 2 H), 1.82-2.18 (m, 4 H), 2.21 (s, 3 H), 2.35-2.58 (m, 4 H), 2.75-2.89 (m, 2 H), 3.18-3.30 (m, 1 H), 3.42-3.58 (m, 1 H), 3.61 (s, 3 H), 3.66 (s, 3 H), 3.75 (s, 3 H), 3.91, 4.15 (A~3 q, ~ = 13.6 Hz, 2 H), 6.14 (s, 1 H), 6.69 (d, J = 8.6 Hz, 2 H), 7.02 (d, J = 8.6 Hz, 2 H), 7.20-7.37 (m, 7 H), 7.56 (br t, 1 H, NH), 7.90 (d, J = 8.8 Hz, 2 H); Anal. Calcd. for C3eH43NsO8S: C, 62.54; H, 5.94; N, 9.60. Found: C, 62.41;
H, 6.06; N, 9.34.

Example 5 5-Methoxycarbonyl-4-methyl-6-(4-nitrophenyl)-1-{N-[3-(4,4-diphenyl-piperidin-1-yl)propyl~}carboxamido-1,2, 3,6-tetrahydro-2-thioxo-pyrimidine.
To a stirred solution of 1,6-dihydro-6-methoxycarbonyl-2-[{(4-methoxyphenyl)methyl~thio]-4-methyl-6-(4-nitro phenyl)-1-{N-[3-(4,4-diphenylpiperidin-1-yl)propyl]}
carboxamidopyrimidine (0.14 g, 0.187 mmol) and ethanethiol (0.5 mL) in CH2C12 (5 mL) at 5 ~C under argon, TFA (0.5 mL) was added and the mixture was allowed to warm to room temperature. After 3 hours, solvents were evaporated completely, the residue was redissolved in EtOAc (10 mL), washed with 5~ NaHCO~ (5 X 1 mL) and dried (MgSO4). Solvent was evaporated and the residue was purified ~y column chromatography using 1:1 hexane/EtOAc to 100% EtOAc as gradient eluent. The oily product was crystallized from hexane and EtOAc (0.096 g, 82~); m.p. 130-131 ~C; lH-NMR (CDCl3): ~ 1.65-1.80 (m, 2 H), 2.31 (s, 3 H), 2.31-2.49 (m, 10 H), 3.25-3.55 (m, 2 H), 3.76 (s, 3 H), 7.01 (s, 1 H), 7.09-7.29 (m, 6 H), 7.41 (d, J = 8.2 Hz, 2 H), 8.11 (d, J =
8.8 Hz, 2 H), 9.76 (br t, 1 H, NH); Anal. Calcd. for C34H3,N5O6SØ3 H2O: C, 64.50; H, 5.89; N, 11.06. Found:
C, 64.45; H, 6.05; N, 10.87.

W097/42956 PCT~S97/08335 Example 6 1-~N-[3-(4-(4-Methoxyphenyl)-4-phenylpiperidin-1-yl) propyl]}carboxamido-5-methoxycarbonyl-4-methyl-6-(4-nitrophenyl)-1,2,3,6-tetrahydro-2-thioxo pyrimidine.

a. 4-(4-Methoxyphenyl)-4-phenylpiperidine. 4-Hydroxy-4-phenylpiperidine (5.00 g, 28.2 mmol) was added to a suspension of AlCl3 (18.8 g, 0.141 mol, 5.00 e~ in anhydrous anisole (i00 mL). The mixture was stirred at room temperature for 1 hours and then heated to 50 ~C
for 3.5 hours. It was cooled to room temperature and poured cautiously into ice-water. The mixture was basified to pH 11 by addition of 6 N aqueous NaOH, and extracted with EtOAc (3 x 75 mL). The combined organic extracts were applied directly to a flash chromatography column, which was eluted with CH2Cl2/0.67 M NH3 in MeOH (4:1) to afford 1.683 g (22~) of light yellow oil, which was characterized spectroscopically.
b. 3-[4-(4-Methoxyphenyl)-4-phenylpiperidin-1-yl]propionitrile. Acrylonitrile (1.03 mL, 15.7 mmol, 2.50 eq) was added at 0 ~C to a solution of 4-(4-methoxyphenyl)-4-phenylpiperidine (1.68 g, 6.28 mmol) in EtOH (20 mL) and the resulting solution was stirred for 1.5 hours at room temperature. After removal of the solvent, the residue was purified by flash chromatography (SiO2, EtOAc-CHCl3 1:3) to give 1.41 g (70~) of colorless oil, which was characterized spectroscopically.

c. 3-~4-(4-Methoxyphenyl)-4-phenylpiperidin-1-yl]propylamine. To a stirred solution of 3-[4-(4-methoxyphenyl)-4-phenylpiperidin-1-yl]pro pionitrile (1.41 g, 4.40 mmol) in anhydrous THF (10 mL) under argon was added a solution of BH3 in TH~ (1.0 M, 11.0 m~, 2.5 eq) at room temperature. The mixture was CA 022~3862 1998-11-09 W097/429~ PCT~S97/0~35 refluxed for 4.5 hours and then cooled to room temperature. Aqueous HCl ~6 N, 15 mL) was added and stirring was continued for 2 h at 55-60 ~C. The mixture was basified to pH 9 by addition of 6 N a~.
NaOH and extracted with CH2Cl2 (3 x 75 mL). The combined organic solutions were dried (MgSO4) and concentrated. The residue was dissolved in CH2Cl2 (10 mL) and treated with HCl in ether (1.0 M, 9.0 mL, 2.0 eq). The solvents were removed, ether (30 mL) was added, the mixture was filtered, and the filter cake was washed with ether (2 x 10 mL). Water (20 mL) was added to the resulting white solid, the pH was adjusted to 10 with 1 N NaOH, and the aqueous phase was extracted with CH2Cl2 (3 x 40 mL). The combined organic extracts were dried (MgSO4) and concentrated to give 610 mg (43%) of white solid, which was characterized spectroscopically.

d. 1-{N-~3-~4-(4-Methoxyphenyl)-4-phenylpiperidin-l-yl) propyll}carboxamido-5-methoxycarbonyl-4-methyl-6-(4-nitrophenyl)-1,2,3,6-tetrahydro-2 -thio~Limidine.
To a stirred mixture of l,6-dihydro-S-methoxycarbonyl-2 -[~(4-methoxyphenyl)methyl}thio]-4-methyl-6-(4-nitrop henyl)-1-[(4-nitrophenyloxy)carbonyl]pyrimidine (0.592 g, 1 mmol) and K2CO3 (0.276 g, 2 mmol) in anhydrous THF
(10 mL) at room temperature under argon atmosphere, a solution of 3-[4-(4-methoxyphenyl)-4-phenyl piperidin-1-yl]propylamine t0.390 g, 1.2 mmol, 1.2 eq) in THF ~10 mL) was added and the stirring was continued for 1 hour. Solvent was evaporated from the reaction mixture and the residue was redissolved in CH2Cl2 (50 mL), washed with 5~ Na~CO3 (3 X 25 mL), brine (50 mL), and dried (MgSO4). The CH2C12 solution was filtered and cooled to S ~C. To this, ethanethiol (0.5 mL) and TFA
(0.5 mL) were added and the mixture was stirred and allowed to warm to room temperature. After 3 hours, CA 02253862 l998-ll-09 W 097/42956 PCT~US97/08335 solvents were evaporated completely, the residue was redissolved in EtOAc (10 mL), washed with 5g6 NaHCO3 (5 X 1 mL), and dried (MgSO4). Solvent was evaporated and the residue was purified by column chromatography using 1:1 hexane/~:tOAc to 100% EtOAc as gradient eluent. The oily product was crystallized from hexane and EtOAc (0.41 g, 62~); m.p. 120-121 ~C; lH-NMR (CDCl3): ~ 1.60-1.80 (m, 2 H), 2.31 (s, 3 H), 2.31-2.51 (m, 8 H), 3.32-3.43 (m, 2 H), 3.75 (S, 3 H), 3.76 (S, 3 H), 6.77 ~d, - J = 8.8 HZ, 2 H), 7.02 (S, 1 H), 7.12 (d, J = 8.6 HZ, 2 H), 7.20-7.27 (m, 6 H), 7.41 (d, J = 8.6 Hz, 2 H), 8.11 (d, J - 8.8 Hz, 2 H), 9.76 (br t, 1 H, NH); Anal.
Calcd. for C3sH39NsO6S: C, 63.91; H, 5. 98; N, ~0.65.
Found: C, 64.19; H, 6.22; N, 10.36.

Example 7 a. 4-Ethoxycarbonyl-4-phenylpiperidine. To a stirred solution of H2SO4 (1. 62 g, 16.56 mmol) in EtOH (200 mL~, 4-phenyl-4-piperidine-carboxylic acid 4-methyl benzenesulfonate (2S g, 66.23 mmol) was added and the mixture was stirred and refluxed for 12 hours. Excess ethanol was evaporated at reduced pressure and the residue was poured into a mixture of ice and 6 N NaOH.
The pH was adjusted to 10-11 by adding more 6 N NaOH
and extracted with CH2Cl2 (3 X 100 mL). The combined CH2Cl2 extracts were dried (MgSO4) and the solvent evaporated to leave the desired product as a colorless viscous oil, the lH-NMR showed it to be pure (14.68 g, 95~) and was used without any further purification.
b. 3-(4-Ethoxycarbonyl-4-phenylpiperidin-1-yl) propylamine.
A mixture of 4-ethoxycarbonyl-4-phenylpiperidine (30.5 g, 0.131 mol), 3-bromopropylamine hydrobromide (42.93 g, 0.196 mol), potassium carbonate (36.14 g, 0.241 mole), and KI (10.8 g, 0.065 mol) in 1,4-dioxane (500 mL) was stirred and refluxed for 24 hours. Dioxane was W097/42956 PCT~S97/08335 evaporated at reduced pressure, the residue was treated with ice-cold 6 N NaOH (400 mL) and extracted with CH2Cl2 (4 X 120 mL). Solvent was evaporated from the combined dried (K2CO3) CH2C12 extracts and the residue was purified by column chromatography on silica gel using CHCl3/MeOH/2 M NH3 in MeOH (20:2:1) as the eluen~
to afford the product as a viscous oil (24.2 g, 83.3~).

c. l-{N-[3-(4-EthoxycA~h~nyl-4-phenylpiperidin-l-yl) propyl~}caL~-o~ -;do-5-methoxycarbonyl-4-methyl-6-(4-nitrophenyl)-1,2,3,6-tetra-hydro-2-thiGxG~y~imidine. This compound was prepared from 1~6-dihydro-5-methoxycarbonyl-2-[{(4-methoxyphenyl)me thyl}thio]-4-methyl-6-(4-nitrophenyl)-1-[(4-nitrophen yloxy)carbonyl]pyrimidine (0.592 g, 1 mmol), K2CO, (0.276 g, 2 mmol), 3-[4-ethoxycarbonyl-4-phenyl piperidin-l-yl]propylamine (0.350 g, 1.2 mmol, 1.2 eq), ethanethiol (0.5 mL), and TFA (0.5 mL) using the procedure described in Example 7 and purified by flash column chromatography (0.295 g, 47~); m.p. 125-126 ~C
H-NM~ (CDC13): ~ 1.13 (t, J = 7 Hz, 3 H), 1.62-1.80 (m, 2 H), 1.87-2.0 (m, 2 H), 2.06-2.18 (m, 2 H), 2.31 (s, 3 H), 2.34-2.39 (m, 2 H), 2.50-2.55 (m, 2 H), 2.79-2.83 (m, 2 H), 3.30-3.51 (m, 2 H), 3.74 (s, 3 H), 4.07 (q, J = 7 Hz, 2 H), 7.03 (s, 1 H), 7.18-7.36 (m, 6 H), 7.40 (d, J = 8.8 Hz, 2 H), 8.08 (d, J = ~.8 Hz, 2 H), 9.78 (br t, 1 H, NH)i Anal. Calcd. for C3lH3,NsO7S: C, 59.70;
H, 5.98; N, 11.23. Found: C, 59.55; H, 5.99; N, 11.43.

Examplo 8 1,6-Dihydro-1-{N-[3-(4,4-diphenylpiperidin-1-yl)propy l~}carboxamido-2-methoxy-5-methoxycarbonyl-4-methyl-6-(4-nitrophonyl)pyrimidine. To a stirred mixture of 1~6-dihydro-2-methoxy-5-methoxycarbonyl-4-methyl -6-(4-nitrophenyl)-1-[(4-nitrophenyloxy)carbonyl]pyri midine (0.940 g, 2 mmol) and K2CO3 (0.552 g, 4 mmol) in anhydrous THF (20 mL) at room temperature under argon W097/42956 rcTrusg7/o83 atmosphere, a solution of 3[4,4-diphenylpiperidin-1-yl]
propylamine (0.882 g, 3 mmol, 1.5 eq) in THF (5 mL) was added and the stirring was continued for 1 hour.
Solvent was evaporated from the reaction mlxture, the residue was redissolved in CH2C12 (50 mL), washed with 5% NaHCO3 (3 X 25 mL), brine (50 mL), and dried (MgSO4).
Solvent was e~aporated and the residue was purified by flash chromatography on silica gel using 10% methanol in EtOAc as the eluent to give the desired product as an oil, which on trituration with hexane and drops of EtOAc became a white powder (1.10 g, 88%); m.p. 95-96 ~C; 1H-NMR (CDCl3): ~ 1.61-1.71 Im, 2 H), 2.26-2.33 (m, 2 H), 2.38 (S, 3 H), 2.39-2.50 (m, 8 H), 3.20-3.41 (m, 2 H), 3.65 (S, 3 ~I), 3.89 ~S, 3 H), 6.65 (S, 1 H), 6.84 (br t, 1 H, NH), 7.08-7.29 (m, 10 H), 7.40 (d, J = 8.7 Hz, 2 H), 8.03 (d, J = 8.6 Hz, 2 H); Anal. Calcd. for C3sH39N5O6Ø75 CH2Cl2: C, 62.28; H, 5.92; N, 10.16.
Found: C, 62.23; H, 5.76; N, 10.12.

Example 9 5-Methoxycarbonyl-4-methyl-6-(4-nitrophenyl)-1-{N-t3-(4,4-diphenyl-piperidin-1-yl)propyl]~carboxamido-2-oxo-1,2,3,6-tetrahydropyrimid-ine.

a 1,6-Dihydro-5-methoxycarbonyl-2-methoxy-4-methyl-6-~4-nitro-phenyl)pyrimidine.
A mixture of methyl 2-~ (4-nitrophen-yl)methylene}-3-oxobutyrate (12.46 g, 0. 05 mol), O-methylisourea hydrogen sulfate (10.32 g, 0.06 mol), and NaOAc ~9.84 g, 0.06 mol) in DMF (50 mL) was stirred and heated at 70-75 ~C for 4 hours. Tne mixture was cooled and poured into ice-water ~300 mL). The precipitate formed was filtered, washed with water, and dried. The crude 3 5 product was purified by flash column chromatography on silica gel using 10~ through 30~ EtOAc in hexane as the gradient eluent (9.8 g, 64%). The lH-NMR analysis of W097/42956 PCT~S97/08335 _59_ the product showed it to be a 19:1 mixture of the amine/imine tautomers which was used as such in the next step. lH-NMR (CDCl3): ~ 2.32, 2.38 (2 s, 3 H), 3.59, 3.70 (2 5, 3 H), 3.70, 3.85 ~2 s, 3 H), 5.40, 5.66 (s, d, J = 3 Hz, 1 H), 5.50, 6.08 (s, d, J = 3 Hz, 1 ~), 7.43, 7.45 (2 d, J = 9 Hz, 2 H), 8.10, 8.11 (2 d, J = 9 Hz, 2 H).

b.1,6-Dihydro-2-methoxy-5-methoxycarbonyl-4-methyl-6-(4-nitrophenyl)-1-[(4-nitrophenyloxy)carbonyl~
pyrimidine.
To a well-stirred mixture of 1,6-dihydro-2-methoxy-5-methoxycarbonyl-4-methyl-6-(4-nitrophenyl)pyrimidine (5.7 g, 0.0187 mol), NaHC03 ~6.27 g, 0.074 mol), CH.Cl~
(200 mL), and water (50 mL) at 0-5 ~C, 4-nitrophenyl chloroformate (3.76 g, 0.0186 mol) was added in 5 min and the mixture was allowed to warm to room temperature. After 10 hours, the TLC analysis of the reaction mixture showed the presence of a small amount of starting pyrimidine, therefore, more 4-nitrophenyl chloroformate (0.65 g, 0.0032 mol) was added and the stirring continued for an additional 4 hours. The two layers were separated, the CH2C12 layer was washed with saturated aqueous NaHCO~ solution (3 X 50 mL), dried (MgS04), and the solvent evaporated. The residue was recrystallized from CH2C12 and hexane to give the product as white crystals (12.8 g, 89%); lH-NMR (CDCl3):
~ 2.48 (s, 3 H), 3.69 ~s, 3 H), 3.94 (s, 3 H), 6.34 (s, 1 H), 7.36 (d, J = 9.1 Hz, 2 H), 7.46 (d, J = 8.7 Hz, 2 H), 8.14 (d, J = 8.7 Hz, 2 H), 8.26 (d, J = 9.1 Hz, 2 H); m.p. 168-169 ~C. Anal. Calcd. for C21H1~N4O9: C, 53.62; H, 3.86; N, 11.91. Found: C, 53.69; H, 3.92; N, 11.85.

c. 5-Methoxycarbonyl-4-methyl-6-(4-nitrophenyl)-1-{N-t3-(4,4-di-phenylpiperidin-1-yl)propyl~}
carboxamido-2-oxo-1,2,3,6-tetrahydro-pyrimidine.

CA 022~3862 1998-11-09 W 0 97/42956 PCTrU$97/08335 To a stirred solution of 1,6-dihydro-2-methoxy-6-methoxycarbonyl-4-methyl-6-(4-nitrophenyl)-1-~N-[3-(4,4-diphenylpiperidin-1-yl)propyl]~carboxamidopyrimi dine (0.208 g, 0.33 mmol) in THF (10 mL) at 5~C under argon, 3 N HCl (6 mL) was added and the mixture was allowed to warm to room temperature. After 2 hours, solvents were evaporated completely, the residue was treated with 40 mL of 10~ NaHCO3, the product was extracted with CH2C12 (2 X 15 mL) and the combined extracts were dried (MgSO4). Solvent was evaporated and the residue was crystallized from hexane and EtOAc (0.20 g, 97~); m.p. 197-198 ~C; lH-NM~ ~CDCl3): ~ 1.63-1.67 ~m, 2 H), 2.23-2.28 ~m, 2 H), 2.34 ~s, 3 H), 2.37-2.42 (m, 8 H), 3.20-3.41 (m, 2 H), 3.69 (s, 3 H), 6.75 (s, 1 H), 7.08-7.26 (m, 11 H), 7.46 (d, J = 8.7 Hz, 2 H), 8.08 (d, J = 8.7 Hz, 2 H), 8.77 (~r t, 1 H, NH);
Anal. Calcd. for C34H37N5O6: C, 66.76; H, 6.10; N, 11.45.
Found: C, 66.48; H, 5.97; N, 11.25.

Example 10 1-{N-[3-(4-(4-Methoxyphenyl)-4-phenylpiperidin-1-yl) propyl}~carboxamido-5-methoxycarbonyl-4-methyl-6 -(4-nitrophenyl)-2-oxo-1,2,3,6-tetrahydropyrimidine.
To a stirred mixture of 1,6-dihydro-2-meth-oxy-5-methoxycarbonyl-4-methyl-6-(4-nitrophenyl) -l-[(4-nitrophenyloxy)carbonyl]pyrimidine (0.47 g, mmol) and K2CO3 (0.552 g, 4 mmol) in anhydrous THF (10 mL) at room temperature under argon atmosphere, a solution of 3-[4-(4-methoxyphenyl)-4-phenyl piperidin-1-yl]propyl-amine (0.390 g, 1.2 mmol, 1.2 eq) in THF (10 mL) was added and the stirring was continued for 2 hours. The solid was removed by filtration and the solution was cooled to 0-5 ~C. 6N HCl (2 mL) was added to the solution and stirring was continued.
After 3 hours, solvents were evaporated completely, the residue was redissolved in CH2Cl2 (20 mL), washed with 10~ NaHCO3 (2 X 10 mL), and dried (MgSO4). Solvent was CA 02253862 l998-ll-09 evaporated and the residue was purified by column chromatography using l:1 hexane/EtOAc to 100% EtOAc as gradient eluent. The oily product was crystallized from hexane and EtOAc (0.55 g, 86%); m.p. 100-102 ~C;
lH-NMR (CDCl3): ~ 1.65-1.80 (m, 2 H), 2.26-2.31 (m, 2 H), 2.35 (s, 3 H), 2.39-2.44 (m, 6 H), 3.18-3.40 (m, 2 H), 3.69 (s, 3 H), 3.73 (s, 3 H), 6.75 (s, 1 H), ~7.60 (d, J = 8.7 Hz, 2 H), 6.84 (br s, 1 H, NH), 7.10 (d, J
8.7 Hz, 2 H), 7.18-7.26 (m, 5 H), 7.46 (d, J = 8.6 Hz, 2 H), 8.08 (d, J = 8.6 Hz, 2 H), 8.78 (br t, 1 H, NH); Anal. Calcd. for C3sH39NsO7Ø~ 2 CH2Cl2Ø12 EtOAc:
C, 64.54; H, 6.12; N, 10.57. Found: C, 64.44; H, 6.12;
N, 10.28.

Example 11 1-{N-[3-(4-Methoxycarbonyl-4-phenylpiperidin-1-yl)propyl~}carboxamido-5-methoxycarbonyl-4-methyl-6-(4-nitrophenyl)-2-oxo-1,2,3,6-tetrahydropyrimidine (Scheme 2).
To a stirred mixture of 1,6-dihydro-2-methoxy-5-methoxycarbonyl-4-methyl-6-(4-nitrophenyl)-1-[(4-nitrophenyloxy)carbonyl]pyrimidine (0.47 g, mmol), K2CO3 (0.276 g, 2 mmol) in anhydrous THF (10 mL) at room temperature under argon atmosphere, a solution of 3-[4-methoxycarbonyl-4-phenylpiperidin-l-yl]
propylamine (0.332 g, 1.2 mmol, 1.2 eq) in THF (10 mL) was added and the stirring was continued for 2 hours.
The solid was removed by filtration and the soiution was cooled to 0-5 ~C. To this, 6 N HCl (2 mL) was added and the stirring continued. After 3 hours, solvents were evaporated completely, the residue was redissolved in CH2Cl2 (20 mL), washed with 10% NaHCO3 (2 X 10 mL), and dried (MgSO4). Solvent was evaporated and the residue was purified by column chromatography using 1:1 hexane/EtOAc to 100% EtOAc as gradient eluent. The oily product was crystallized from hexane and EtOAc (0.55 g, 86%); m.p. lB0-181 ~C; ~H-NMR (CDCl3): ~ 1.60-, CA 022~3862 1998-11-09 W 097/429S6 PCT~US97/08335 1.80 (m, 2 H), 1.85-1.95 (m, 2 H), 2.03-2.10 (m, 2 H), 2.28-2.33 (m, 2 H), 2.35 (s, 3 H), 2.48-2.50 (m, 2 H), 3.20-3.40 (m, 2 H), 3.60 (s, 3 H), 3.68 (s, 3 H), 6.75 (s, 1 H), 7.20-7.34 (m, 6 H), 7.46 (d, J = 8.8 Hz, 2 H), 8.07 (d, ~ = 8.8 Hz, 2 H), 8.78 (br t, 1 ~, NH);
Anal. Calcd. for C3~H3sNsO8: C, 60.70; H, 5.94; N, 11.80.
Found: C, 60.71; H, 5.99; N, 11.43.

Examples lla ~ 11 b (+)-1-{N-~3-(4-Methoxycarbonyl-4-phenylpiperidin-1-yl) propyl]}~Arho~mido-5-methoxycarbonyl-4-methyl-6-(4-nitrophenyl)-2-oxo-1,2,3,6-tetrahydropyrimidine and (-)-1-{N-t3-(4-Methoxyc~h~nyl-4-phenyl-piperidin-1-yl) propyl]}carboxamido-5-methoxy~rhnnyl-4-methyl-6-(4-nitrophenyl)-2-oxo-1,2,3,6-tetrahydhv~yLi~dine (Scheme 3).

a. (-)-1,6-Dihydro-2-methoxy-5-methoxycarbonyl-4-methyl-6-(4-nitro-phenyl)-1-{N-[(2-phenyl)ethyl]}
carboxam;dopyrimidine and (+)-1,6-Dihydro-2-methoxy-5-methoxycarbonyl-4-methyl-6-(4-nitrophenyl)-1-{N-[(2-phenyl)ethyl]}carboxamidopyrimidine.
To a stirred solution of (+)-1,6-dihydro-2-methoxy-5-methoxycarbonyl-4-methyl-6-(4-nitrophenyl)-1-[(4-nitr ophenyloxy)carbonyl]pyrimidine (2.66 g, 5.6 mmol) in anhydrous THF (80 mL) at room temperature under argon atmosphere, a solution of (S)-(-)-a-methylbenzylamine (0.82 g, 6.78 mmol, 1.2 eq) in THF (5 mL) was added and the stirring was continued for 6 hours. Solvent was evaporated from the reaction mixture, the residue was redissolved in CH2Cl2 (50 mL), washed with 5~ NaHCO3 (3 X 25 mL), brine (50 mL), and dried ~MgSO4). Solvent was evaporated and the residue was purified by flash chromatography on silica gel using 5% to 30~ EtOAc in hexane as the gradient eluent. The first major product to elute was (~ 6-dihydro-2-methoxy-5-methoxy carbonyl-4-methyl-6-(4-nitrophenyl)-1-{N-[(2-phenyl) .

W O 97/42956 PCT~USg7/08335 ethyl~}carboxamidopyrimidine and this compound was crystallized from isopropyl ether (0.85 g, 33.6~); m.p.
119-120 ~C; [~]D = -329.32 (CH2Cl2, 10.3 g/100 mL); ~H-NMR (CDCl3): ~ 1.47 (d, J = 7 Hz, 3 H), 2.40 (s, 3 H), 3.61 (s, 3 H), 3.95 (s, 3 H), 4.96 (~uint, J = 6.5 Hz, 2 H), 6.66 (s, 1 H), 6.82 (d, J = 6.8 Hz, 1 H, NH), 7.22-7.36 (m, 5 H), 7.43 (d, J = 8.6 Hz, 2 H), 8.09 (d, J = 8.6 Hz, 2 H); Anal. Calcd. for C23H24N4O6: C, 61.06;
H, 5.35; N, 12.38. Found: C, 60.85; H, 5.13; N, 12.42.
The second major compound to elute was (+)-1l6-dihydro-2-methoxy-5-methoxycarbonyl-4-methyl-6 (4-nitrophenyl)-1-{N-[(2-phenyl)ethyl]}carboxamido pyrimidine and this compound was crystallized from isopropyl ether (0.92 g, 36.4~); m.p. 138-140 ~C; [a] D
= +171.81 (CH2Cl2, 11.31 g/100 mL); ~H-NMR (CDCl3):~ 1.47 (d, J = 7 Hz, 3 H), 2.42 (s, 3 H), 3.644 (s, 3 H), 3.917 (s, 3 H), 4.989 (quint, J = 6.5 Hz, 2 H), 6.70 (s, 1 H), 6.81 (d, J - 6.8 Hz, 1 H, NH), 7.22-7.35 (m, 5 H), 7.36 (d, J = 8.6 Hz, 2 H), 8.04 (d, J = 8.6 Hz, 2 H); Anal. Calcd. for C23H24N4O6: C, 61.06; H, 5.35; N, 12.38. Found: C, 60.95; H, 5.20; N, 12.38.

b. (+)-1-{N-~3-(4-~ethoxycarbonyl-4-phenyl piperidin-1-yl)propyl~}c~rho~mido-5-methoxyc~ho~yl-4-methyl-6-(4-nitrophenyl)-2-oxo-1,2,3,6-tetrahydro pyrimidine.
A solution of (+)-1,6-dihydro-2-methoxy-S-methoxy carbonyl-4-methyl-6-(4-nitrophenyl)-1-(N-[(2-phenyl) ethyl]}carboxamidopyrimidine (0.226 g, 0.5 mmol) and 1,8-diazabicyclo[5.4.0]-unde-7-ene (DBU) (0.076 g, 0.5 mmol) in CH2Cl2 (10 mL) was stirred and refluxed for 4 hours and the solvent evaporated. The product was purified by column chromatography using 30% EtOAc in hexane as the eluent. The product was found to be a mixture of the amine-imine tautomers (0.120 g, 78.7%);
[~] D = +14-5 (CH2C12, 6 g/100 mL).

, . ,, . _ CA 022~3862 1998-11-09 W O 97/42956 -64- PCTrUS97/08335 To a well-stirred solution of (+)-ll6-dihydro-5-methoxy carbonyl-2-methoxy-4-methyl-6-(4-nitrophenyl)pyrimidine (0.12 g, 0.393 mmol) and pyridine (0.5 mL) ln CH~Cl2 (10 mL) at 0-5 ~C, 4-nitrophenyl chloroformate (0.095 g, 0.472 mmol) was added in 5 min and the mixture was allowed to warm to room temperature. After 2 h, saturated aqueous NaHCO3 solution (10 mL) was added and the stirring continued for 30 min. The two layers were separated, the CH2Cl2 layer was washed with saturated aqueous NaHCO3 solution (3 X 5 mL), dried (Na2SO4), and the solvent evaporated. The residue was redissolved in THF ~10 mL) and mixed with K2CO3 (0.11 g, 0.8 mmol). To this, a solution of 3-[4-methoxycarbonyl-4-phenyl piperidin-l-yl]propylamine (0.138 g, 0.5 mmol) in THF
(5 mL) was added and the mixture was stirred for 2 hours. The solid was removed by filtration and the solution was cooled to 0-5 ~C. To this, 6 N HCl' (0.5 mL) was added and the stirring continued. After 3 hours, solvents were evaporated completely, the residue was redissolved in CH2C12 ~20 mL), washed with 10~
NaHCO3 (4 X 5 mL), and dried (MgSO4). Solvent was evaporated and the residue was purified by column chromatography using 1:1 hexane/EtOAc to 100~ EtOAc as gradient eluent. The oily product was crystallized from hexane and EtOAc (0.19 g, 82~); m.p. 138-~40 ~C;
[~]D = +lOB (CH2Cl2, 6.65 g/100 mL); lH-NMR (CDCl3):~
1.60-1.80 (m, 2 H), 1.85-1.95 (m, 2 H), 2.03-2.10 (m, 2 H), 2.28-2.33 (m, 2 H), 2.35 (s, 3 H), 2.48-2.50 (m, 2 H), 3.20-3.40 (m, 2 H), 3.60 (s, 3 H), 3.68 (s, 3 H), 6.75 (s, 1 H), 7.20-7.34 (~, 5 H), 7.46 (d, J = 8.8 Hz, 2 H), 7.60 (br s, 1 H, N H), 8.07 (d, J = 8.8 Hz, 2 H), 8.78 (br t, 1 H, NH); Anal. Calcd. for C30H35NsO~Ø2 CH2Cl2Ø2 EtOAc: C, 59.27; H, 5.94; N, 11.15. Found:
C, 59.07; H, 5.76; N, 10.99.
c. (~ {N-t3-(4-Methoxycarhonyl-4-phenyl piperidin-l-y~)propyl]}carbox~mido-5-methoxy CA 022~3862 1998-11-09 W 097/42956 PCTrUS97/08335 carbonyl - 4 -methyl - 6 - ( 4 - ni trop~enyl ) - 2 - oxo -1, 2, 3, 6 - tetrahydropyrimidine .
A solution of (-)-1,6-dihydro-2-methoxy-5-methoxy car~onyl-4-methyl-6-(4-nitrophenyl)-1-¦N-[t2-phenyl) ethyl]}carboxamidopyrimidine (0.35 g, 0.774 mmol) and 1~8-diazabicyclo[5.4.o]-unde-7-ene (DBU) (0.117 g, 0.774 mmol) in CH2Cl2 (10 mL) was stirred and refluxed for 8 hours and the solvent evaporated. The product was purified by column chromatography using 30~ EtOAc in hexane as the eluent. The product, (-)-1~6-dihydro-5-methoxycar~onyl-2-methoxy-4-methyl-6-(4-nitrophenyl)pyrimidine, was found to be a mixture of the amine-imine tautomers (0.170 g, 72~). To a well-stirred solution of (-)-l~6-dihydro-5-methoxy carbonyl-2-methoxy-4-methyl-6-(4-nitrophenyl)pyrimidine (0.152 g, 0.5 mmol) and pyridine (0.5 mL) in CH2Cl2 (10 mL) at 0-5 ~C, 4-nitrophenyl chloroformate (0.121 g, 0.6 mmol) was added in 5 min and the mixture was allowed to warm to room temperature. After 2 hours, saturated aqueous NaHCO3 solution ~10 mL~ was added and the stirring continued for 30 min. The two layers were separated, the CH2Cl2 layer was washed with saturated aqueous NaHCO3 solution (3 X 5 mL), dried (Na2SO4), and the solvent evaporated. The residue was redissolved in THF (10 mL) and mixed with K2CO3 (0.165 g, 1.2 mmol).
To this, a solution of 3-[4-methoxycarbonyl-4-phenylpiperidin-1-yl]propylamine (0.166 g, 0.6 mmol) in THF (5 mL) was added and the mixture was stirred for 2 hours. The solid was removed by filtration and the solution was cooled to 0-5 ~C. To this, 6 N HCl (0.5 mL) was added and the stirring continued. After 3 hours, solvents were evaporated completely, the residue was redissolved in CH2Cl2 (20 mL), washed with 10~
NaHCO3 (4 X 5 mL), and dried ~MgSO4). Solvent was evaporated and the residue was purified by column chromatography using 1:1 hexane/EtOAc to 100~ EtOAc as gradient eluent. The oily product was crystallized CA 022~3862 1998-11-09 W O 97/42956 rCT~US97/08335 from hexane and EtOAc (0.19 g, 64~); m.p. 138-140 ~C;
[~] D = -106 (CH2Cl2, 3.95 g/100 mL); lH-NMR (CDC13):~
1.60-1.80 (m, 2 H), 1.85-1.95 (m, 2 H), 2.03-2.10 (m, 2 H~, 2.28-2.33 (m, 2 H), 2.35 (s, 3 H), 2.48-2.50 (m, 2 H), 3.20-3.40 (m, 2 H), 3.60 (s, 3 H), 3.68 (s, 3 H), 6.75 (s, 1 H), 7.20-7.34 (m, 6 H), 7.46 (d, J = 8.8 ~z, 2 H), 8.07 (d, J = 8.8 Hz, 2 H), 8.78 (br t, 1 H, NH);
Anal. Calcd. for C30H3sNso8~o~4 CH2C12: C, 58.18; H, 5.75;
N, 11.16. Found: C, 58.25; H, 5.67; N, 10.98.
Example 12 5-Methoxycarbonyl-1-{N-~3-(4-methoxycarbonyl-4-phenylpiperidin-1-yl)propyl]}carh~Y~ido-4-methyl-6 -~3,4-methylenedioxyphenyl)-2-oxo-1,2,3,6-tetra l.y~y~imidine.
To a stirred solution of 5-benzyloxycarbonyl-1-{N-~3-(4-methoxycarbonyl-4-phenylpiperidin-1-yl)propyl]}
carboxamido-4-methyl-6-(3,4-methylenedioxyphenyl)-2-o xo-1,2,3,6-tetrahydropyrimidine (0.320 g, 0.48 mmol) in methanol (20 mL) and HCOOH (1 mL) at 0-5 ~C, 10~ Pd-C
(0.26 g) was added in portions and the cooling bath was removed. TLC analysis of the reaction mixture at frequent intervals showed the completion of the reaction after 2 hours. The catalyst was removed by filtration and the solvent was evaporated to leave 1-{N-[3-(4-methoxycarbonyl-4-phenylpiperidin-1-yl) propyl]}carboxamido-4-methyl-6-(3,4-methylenedioxy phenyl)-2-oxo-1,2,3,6-tetrahydropyrimidine-5-carboxylic acid as a white solid (0.275 g, 99~). The product was used in the next step without any further purification and characterization. A mixture of 1-{N-[3-(4-methoxycarbonyl-4-phenylpiperidin-1-yl)propyl]) carboxamido-4-methyl-6-(3,4-methylenedioxy phenyl)-2-oxo-1,2,3,6-tetrahydropyrimidine-5-carboxylic acid (0.2 g, 0.346 mmol), 1-(3-dimethylamino propyl)-3-ethylcarbodiimide hydrochloride (0.382 g, 2 mmol), and 4-(N,N-dimethylamino)pyridine (0.488 g, 4 W097/42~6 PCT~S97/08335 mmol), in methanol (20 mL) was stirred and refluxed for 5 h and the solvent evaporated. The residue was redissolved in CH2Cl2 (15 mL), washed with saturated aqueous ammonium chloride solution ~3 X 10 mL), and dried (Na2SO4). Evaporation of the solvent left the pure product as white powder (0.202 g, 99~); m.p. 139-141 ~C; lH-NMR (CDCl3):~ 1.62-1.80 (m, 2 H), 1.95-2.20 (m, 4 H), 2.35 (s, 3 H), 2.30-2.55 (m, 4 H), 2.76-2.90 (m, 2 H), 3.21-3.40 (m, 2 H), 3.61 (s, 3 H), 3.67 (s, 3 H), 5.89 (s, 2 H), 6.61-6.82 (m, 3 H), 6.63 (s, 1 H), 7.21-7.35 (m, 6 H), 8.79 (br t, 1 H, NH); Anal. Calcd.
for C3lH36N4O8Ø3 EtOAc: C, 62.47; H, 6.25; N, 9.05.
Found: C, 62.64; H, 6.25; N, 8.87.

Example 13 (+)-5-Carboxamido-4-ethyl-1-{N-[3-(4-methoxycarbonyl-4-phenylpiperidin-1-yl)propyl~}carh~m;do-6-(4-nitro phenyl)-2-oxo-1,2,3,6-tetrhydropyrimidine (Scheme 4).

a. 2-Cyanoethyl 3-{(4-nitrophenyl)methylene~-4-oxopentanoate.
A mixture of ethyl propionylacetate (25 g, 0.173 mol) and 3-hydroxypropionitrile (18.48 g, 0.26 mol) was stirred and heated at 200-205 ~C for 2 h and the ethanol formed was remo~ed by distillation. The residue was subjected to high vacuum distillation and the fraction distilling at 120-125 ~C at 0.4 mm of Hg was collected to get 2-cyanoethyl propionylacetate (21.5 g, 73.4%).

A mixture of 4-nitrobenzaldehyde (14.46 g, 0.957 mol), 2-cyanoethyl propionylacetate ~17.0 g, 0.1005 mol), piperidine (0.41 g, 476 mL, 4.8 mmol), and acetic acid (0.288 g, 274 mL, 4.8 mmol) in 2-propanol (400 m~) was stirred at room temperature for 24 h. The white solid, 2-cyanoethyl 3-~(4-nitrophenyl)methylene}-4-oxo pentanoate, formed was filtered, washed with 2-propanol (2 X 50 mL) and dried (28.34 g, 97~); m.p. 98-100 ~C.

CA 022~3862 1998-11-09 b. 5-(2-Cyanoethoxycarbonyl)-1,6-dihydro-2-methoxy-4-ethyl-6-(4-nitrophenyl)pyrimidine.

A mixture of 2-cyanoethyl 3-{(4-nitrophenyl)methylene}
-4-oxopentanoate (5.00 g, 16.54 mmol), O-methylisourea hydrogen sulfate (3.422 g, 19.85 mmol), and NaHCO3 (2.78 g, 33.08 mol) in EtOH (70 mL) was stirred and heated at 85-90 ~C for 5 h. The solid was removed by filtration and ethanol was evaporated from the filtrate. The residue was redissolved in EtOAc (300 mL), washed with water (2 X 100 mL), dried (Na2SO4), and the solvent evaporated. The crude product was purified by flash column chromatography on silica gel using CHCl3/methanol (30:1) as the eluent, to leave the product as a white solid ~2.95 g, 50~). The lH-NMR analysis of the product showed it to be a 5:1 mixture of the amine/imine tautomers and was used as such in the next step.

c. 5-(2-CyanoethoxycArho~yl)-4-ethyl-1,6-d~hydro-2-methoxy-6-(4-nitrophenyl)-1-~(4-nitrophenyloxy) carbonyl]pyrimidine.

To a well-stirred solution of 5-(2-cyanoethoxy carbonyl)-4-ethyl-1,6-dihydro-2-methoxy-6-(4-nitrophenyl)pyrimidine (2.64 g, 7.36 mmol) and pyridine ~1.19 mL, 14.72 mmol) in CH2Cl2 (100 mL) at 0-5 ~C, 4-nitrophenyl chloroformate (1.485 g, 7.36 mmol) was added in 5 min and the mixture was allowed to warm to room temperature. After 16 h, saturated aqueous NaHCO
solution ~25 mL) was added and the stirring continued for 30 min. The two layers were separated, the CH2Cl layer was washed with saturated aqueous NaHCO3 solution (3 X 50 mL), dried (Na2SO4), and the solvent evaporated.
The crude product was purified by flash column chromatography on silica gel using CHCl3/EtOAc (25:1) as the eluent to give the product as a viscous oil (1.70 g, 44~ H-NMR (CDCl3): ~ 1.24 (t, J = 7 Hz, 3 H), CA 022~3862 1998-11-09 W097/42956 PCT~Sg7108335 2.61-2.68 (m, 2 H), 2.88-2.92 (m, 2 H), 3.97 (s, 3 H), 4.32 (t, J = 7 Hz, 2 H), 6.34 (s, 1 H), 7.37 (d, J =
9.2 Hz, 2 H), 7.50 (d, J c 8.7 Hz, 2 H), 8.18 (d, J =
8.7 Hz, 2 H), 8.28 (d, J = 9.2 Hz, 2 H).

d. S-(2-Cyanoethoxycar~onyl)-4-ethyl-1,6-dihydro-2-methoxy-6-(4-nitrophenyl)-1-{N-[(2-phenyl)ethyl]}
carboxamidopyrimidine.
To a stirred solution of 5-(2-cyanoethoxycarbonyl)-4-ethyl-1,6-dihydro-2-methoxy-6(4-nitrophenyl)-1-[(4-nitrophenyloxy)car~onyl]pyrimidine (17.5 g, 33.43 mmol) in anhydrous TH~ (200 mL) at room temperature under argon atmosphere, (R)-(~)-a-methylbenzylamine (4.86 g, 40.11 mmol) was added and the stirring was continued for 16 h. Solvent was evaporated from the reaction mixture and the residue was purified by flash chromatography on silica gel using toluene/EtOAc (20:3) as the eluent. The ~irst major product to elute was (+)-5-(2-cyanoethoxycarbonyl)-4-ethyl-1,6-dihydro-2 -methoxy-6-(4-nitrophenyl)-1-{N-I(2-phenyl)ethyl]}
carboxamidopyrimidine and obtained as a viscous oil (6.11 g, 36.2%); [~]D = +299.5 (c = 1.95, CHCl3); 'H-NMR
(CDCl3): ~ 1.18 (t, J = 7 Hz, 3 H), 1.47 (d, J = 7 Hz , 3 H), 2.61 (t, 2 H), 2.7-2.92 (m, 2 H), 3.98 (s, 3 H), 4.20-4.32 (m, 2 H), 4.96 (quint, J = 6.5 Hz, 2 H), 6.66 (s, 1 H), 6.82 (d, J = 6.8 Hz, 1 H, NH), 7.22-7.36 (m, 5 H), 7.45 (d, J = 8.6 Hz, 2 H), 8.11 (d, J = 8.6 Hz, 2 H). The second major compound to elute was (-) -5- (2-cyanoethoxycarbonyl)-4-ethyl-1,6-dihydro-2-methoxy-6-(4-nitrophenyl)-1- {N- [ (2-phenyl)ethyl]}
carboxamidopyrimidine and obtained as a viscous oil (5.92 g, 35~); [~]D = -105.1 (c = 3.9, CHCl3); 'H-NMR
(CDCl3): ~ 1.20 (t, J = 7 Hz, 3 H), 1.48 (d, J = 7 Hz, 3 H), 2.62 (t, 2 H), 2.82 (q, 2 H), 3.94 (s, 3 H), 4.20-4.32 (m, 2 H), 4.96 (quint, J = 6.5 Hz, 2 H), 6.69 - (s, 1 H), 6.84 (d, J = 6.8 Hz, 1 H, NH), 7.22-7.36 (m, 5 H), 7.39 (d, J = 8.6 Hz, 2 H), 8.06 (d, J = 8.6 Hz, CA 022~3862 1998-11-09 WO 97/42g56 PCT~US97/08335 2 H).

e.(+)-5-(2-Cyanoethoxycarbonyl)-1,6-dihydro-2-methoxy-4-ethyl-6-(4-nitrophenyl)pyrimidine.
To a stirred solution of (+)-5-(2-cyanoethoxycarbonyl)-4-ethyl-1,6-dihydro-2-methoxy-6-(4-nitrophenyl)-1-~N-[(2-phenyl)ethyl]}carboxamido pyrimidine (2.62 g, 5.182 mmol) in toluene (40 mL) was added 1~8-diazabicyclo[5~4~o]-undec-7-ene (0.237,1.55 mmol) at room temperature and the resulting solution was heated at 90 ~C for 3.5 minutes. The solvent was e~aporated and the residue was purified by flash column chromatography on silica gel using 9:1 CHCl3/EtOAc as the eluent, to give 1.32 g (71~)of (+)-5-(2-cyanoethoxycarbonyl)-1,6-dihydro-2-methoxy-4-ethyl-6-(4-nitrophenyl)pyrimidinei [~]D = +4.0 (c = 3.25, CHCl3).

f.(+)-5-~2-Cyanoethoxycarbonyl)-4-ethyl-1,6-dihydro-2-methoxy-6-(4-nitrophenyl)-1-[(4-nitrophenyloxy) carbonyl~pyrimidine.

To a well-stirred solution of 5-(2-cyanoethoxycarbonyl) -4-ethyl-1,6-dihydro-2-methoxy-6-(4-nitrophenyl) pyrimidine (1.62 g, 4.52 mmol) and 4-(N,N-dimethylamino)pyridine (0.663 g, 5.43 mmol) in CH2Cl2 (50 mL) at 0-5 ~C, 4-nitrophenyl chloroformate (1.094 g, 5.43 mmol) was added in 5 minutes and the mixture was allowed to warm to room temperature. After 3 hours the solvent evaporated and the product was purified by flash column chromatography on silica gel using CHCl3/EtOAc (25:1) as the eluent to give the product as a white solid (2.25 g, 95~ H-NMR (CDCl~ 1.24 (t, J = 7 Hz, 3 H), 2.61-2.68 (m, 2 H), 2.88-2.92 (m, 2 H), 3.97 (s, 3 H), 4.32 (t, J = 7 Hz, 2 H), 6.34 (s, 1 H), 7.37 (d, J = 9.2 Hz, 2 H), 7.50 (d, J = 8.7 Hz, 2 H), B.18 (d, J = 8.7 Hz, 2 H), 8.28 (d, J = 9.2 Hz, 2 H);

W O 97142956 PCT~US97tO8335 [~] D = +317. 2 (c = 3.9, CHCl3).

g.(+)-5-(2-cyanoethoxycarbonyl)-4-ethyl-l-{N-r3-(4 methoxycarbonyl-4-phenylpiperidin-1-yl)propyll}
c~r~oYamido-6-(4-nitrophenyl)-2-oxo-1,2.3,6-tetrhydro pyrimidine.

To a stirred mixture of (+) -5- (2-cyanoethoxycar}:onyl) -4-ethyl-1, 6-dihydro-2-methoxy-6- (4-nitrophenyl) -1- [ (4-nitrophenyloxy) carbonyl] pyrimidine (3.60 g, 6.878 mmol) in anhydrous THF ~100 mL) at room temperature under argon atmosphere, a solution of 3- [4-methoxycarbonyl - 4 -phenylpiperidin -1 -yl ] propylamine (2.47 g, 8.94 mmol, 1.3 eq) in THF (10 mL) was added and the stirring was continued for 12 hours. The mixture was cooled to 0 ~C and aqueous 6N hydrochloric acid ( lO mL) . The mixture was allowed to warm to room temperature and the stirring was continued for 5 h.
Solvent was e~raporated from the reaction mixture, the residue was purified by flash chromatography on silica gel using ethyl acetate ( 800 mL~ followed by chloroform-methanol-2M ammonia in methanol ~90/8/4) as the eluent, to obtain the desired product as a white powder (4.40 g, 98.5~ -NMR (CDC13): ~ 1.23 (t, LJ =
7 . 5 Hz, 3 H), 2 . 0-2 . 1 (m, 2 H), 2 . 40-2 . 95 (m, 12 H), 3.25-3.50 (m, 4 H), 3.6~ (s, 3 H), 4.27-4.32 (m, 2 H), 6 .64 (s, 1 H), 7.20-7.33 ~m, 5 H), 7 .49 (d, J = 7. 8 Hz, 2 H), 8.08 (d, J = 7.B ~Z, 2 H), 8.70-8.90 (m, 2 H);
[~¦D = +112.1 ~C = 2 . 15 , CHC13 ); This product was used in the next step without any additional analysis.

h.(+)-5-Carboxamido-4-ethyl-1-{N-[3-(4-methoxycarbonyl-4-phenylpiperidin-1-yl)propyl]}carboxamido-6-(4-nitro phenyl)-2-oxo-1,2,3,6-tetrhydropyrimidine.
To a stirred solution of 5- ~2-cyanoethoxycarbonyl) -4-ethyl~ N- [3- (4-methoxycarbonyl-4-phenyl CA 022~3862 1998-11-09 WO 97/42956 PCT~US97/08335 piperidin-1-yl)propyl]}carboxamido-6-~4-nitrophenyl)-2-oxo-l~2~3~6-tetrhydropyrimidine (4.40 g, 6.8 mmol) in acetone (50 mL) at 0 ~C, sodium hydroxide solution (1 N, 27.2 mL, 4 eq.) was added drop wise and the stirring was continued until the disappearance of the starting material (1 hour). Most of the acetone from the mixture was evaporated under reduced pressure while keeping the temperature at 0 ~C and the residue was adjusted to pH 7.0 by the addition of lN hydrochloric acid. The white precipitate of (+)-4-ethyl-1-~N-[3-(4-methoxycarbonyl-4-phenylpiperidin-1-yl)propyl]~
carboxamido-6-(4-nitrophenyl)-2-oxo-1,2,3,6-tetrhydro pyrimidine-5-carboxylic acid formed was filtered and dried under vacuum (3.59 g, 89%). lH-NMR (CDCl3):
1.07 (t, J = 7.5 Hz, 3 H), 1.55-1.70 (m, 2 H), 1.72-1.84 (m, 2 H), 1.84-2.15 (m, 2 ~), 2.20-2.40 (m, 4 H), 2.70-2.90 (m, 2 H), 3.10-3.40 (m, 4 H), 3.51 (s, 3 H), 6.54 (s, 1 H), 7.18-7.38 (m, 6 H), 7.41 (d, J = 7.8 Hz, 2 H), 8.15 (d, J = 7.8 Hz, 2 H), 8.79 (br t, 1 H, N H), 10.05 (br S, 1 H, COOH); This product was used in the next step without any additional analysis.

A mixture of (+)-4-ethyl-1-~N-[3-(4-methoxycarbonyl-4-phenylpiperidin-1-yl)propyl]}carboxamido-6-(4-nitro phenyl)-2-oxo-1,2,3,6-tetrhydropyrimidine-5-carboxylic acid (0.350 g, 0.59 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.2264 g, 1.181 mmol, 2eq.), and 4-(N,N-dimethylamino)pyridine (0.1443 g, 1.181 mmol, 2 eq) in anhydrous dichloromethane was stirred at room temperature for 2 h. To this, 40 aqueous ammonia (0.6 mL) was added and the stirring was continued for 12 h. The mixture was diluted with 100 mL of dichloromethane and washed with saturated aqueous ammonium chloride solution (3 X 20 mL). Solvent was evaporated from the dried ( magnesium sulfate) dichloromethane solution and the residue was purified by column chromatography on silica gel using W O 97/42956 PCT~US97/08335 chloroform-methanol-2M ~mmonia in methanol (500/16/8) as the eluent, to obtain the desired product as a white powder (0.24 g, 69~)i m.p. 107-109 ~CjlH-NMR (CDCl3):
1.20 (t, J = 7.5 Hz, 3 H), 1.66-1.72 (m, 2 H), 1.79-2.00 (m, 3 H), 2.00-2.20 (m, 2 H), 2.29-2.35 (m, 2 H), 2.42-2.60 (m, 2 H), 2.62-2.82 (m, 3 H), 3.20-3.40 (m, 2 H), 3.60 (8, 3 H), 5.70 (br m, 2 H, N~I2), 6.59 (s, 1 H), 7.20-7.39 (m, 6 H), 7.52 (d, J = 7.8 Hz, 2 H), 8.13 (d, ~ = 7.8 Hz, 2 H), 8.82 (t, 1 H) i [~]D = +115.71 (c = 1.4, CHC1 3); Anal. Calcd. for C30H36N6O7Ø~ H2O: C, 59.36; H, 6.24; N, 13.84. Found: C, 59.47; H, 6.07;
N, 13.64.

Example 14 (+)-5-Carboxamido-6-(3,4-difluorophenyl)-4-ethyl-1-{N-[3-(4-methoxycarbonyl-4-phenylpiperidin-1-yl) propyl]}carboxamido-2-oxo-1,2,3,6-tetrhydropyrimidine (Scheme 5).

a. Benzyl 3-~(3,4-difluorophenyl)methylene]-4-oxopentanoate. A solution of benzyl propionylacetate (36.3 g, 176 mmol), 3,4-difluorobenzaldehyde (25.0 g, 176 mmol), piperidine (0.86 mL, 9.0 mmol) and acetic acid (0.49 mL, 9.0 mmol) were refluxed with removal of water using Dean-Stark apparatus for 5h. The solvent was removed in vacuo and the residue was dissolved in EtOAc. It was washed with water (100 mL) followed by brine (100 mL) and dried over anhydrous Na2SO4. Solvent was evaporated to get pale yellow syrup (60.2 g). It was used in the next step without further purification.

- b. 5-~Benzyloxyca-ho~yl)-1,6-dihydro-2-methoxy-4-ethyl-6-(3,4-difluorophenyl)pyrimidine. A suspension of benzyl 3-~(3,4-difluorophenyl)methylene]-4-oxopentanoate (16.0 g, 48.0 mmol), O-methylisourea hydrogen sulfate (16.65 g, 97.02 mmol), NaHCO~ (16.3 g, . _ .

W O 971429S6 PCT~US97/08335 130.2 mmol) in DMF (190 mL) was stirred at 70~C for 20h.
After cooling to room temperature, the mixture was filtered and the filtrate was diluted with EtOAc (300 mL) and then washed with water (4X100 mL), brine (200 mL) and dried over Na2SO4. After removal of solvent, the residue was purified by column chromatography (SiO~, EtOAc/Hexane, 10%-30~) to get 5-(benzyloxycarbonyl)-1,6-dihydro-2-methoxy-4-methyl-6-(3,4-difluorophenyl)pyrimidine as a colorless oil (10.6 g, 58~). The NMR analysis showed it to be a mixture of amine/imine tautomers and was used as is in the next step.

c. 5-(Benzyloxyc~rhonyl)-4-ethyl-1,6-dihydro-2-methoxy-6-(3,4-difluorophenyl)-1-[(4-nitrophenyloxy~carbonyl]
pyrimidine. To a well stirred solution of 5-(benzyloxy carbonyl)-1,6-dihydro-2-methoxy-4-ethyl-6-(3,4-difluoro phenyl)pyrimidine (17.0 g, 44.04 mmol) and 4-dimethyl aminopyridine (6.99 g, 57.25 mmol) in CH2Cl2 (200 mL) was added a powder of 4-nitrophenyl chloroformate 11.54 g, 57.25 mmol) at room temperature. The reaction mixture was stirred for 12 hours and then the solvent was removed in vacuo. The residue was purified by chromatography (SiO2, EtOAc/Hexane 10-30~) to get 5-(benzyloxycarbonyl)-4~ethyl-1,6-dihydro-2-methoxy-6-( 3 , 4 - d i f l u o r o p h e n y l ) - 1 - [ ( 4 -nitrophenyloxy)carbonyl~pyrimidine as a colorless viscous oil(12.6 g, 50~).1H NM~ (CDCl3): ~ 1.24 (t, J=7.2 Hz, 3H), 2.81-2.98 (m, 3H), 3.97 (s, 3H), 5.14 (ABq~ ~A=5.08~ ~= 5.20, J= 12.3 Hz, 2H), 6.28 (s, 3H), 7.03-7.29 (m, 8H), 7.35 (d, J=9.2 Hz, 2H), 8.26 (d, J=9.2 Hz, 2H).

d. 5-~Benzyloxycarbonyl)-4-ethyl-1,6-dihydro-1-{N-e2-phenyl)ethyl]}c~QY~mido-2-methoxy-6-(3,4-difluoro phenyl)pyrimidine. To a stirred mixture of 5-(benzyloxycarbonyl)-4-ethyl-1,6-dihydro-2-methoxy-6-CA 022~3862 l998-ll-09 W O 97/42956 PCTrUS97/08335 ~3,4-difluorophenyl)-1-[(4-nitrophenyloxy)carbonyl]
pyrimidine (12.6 g, 22.86 mmol) in THF (150 mL) was added a solution of R-(+)-a-methyl benzylamine (3.53 mL, 27.44 mmol) at room temperature. The stirring was continued for 12 hours. Solvent was removed in vacuo.
The yellow residue was dissolved in chloroform (200 mL) and was washed with 10~ K2CO3 solution (2x30 mL). The organic layer was dried over Na2SO4, filtered and solvent was removed in ~acuo. The resulting mixture of diastereomers was separated by column chromatography over silica gel with 9:1 Pet. ether:Ether to 4:1 Pet.
ether:Ether. First major product to elute was (+)-5-(benzyloxycarbonyl)-4-ethyl-1,6-dihydro-l-{N-[2-phenyl)ethyl]~carboxamido-2-methoxy-6-(3,4-diflurophenyl)pyrimidine. Colorless oil, Rf= 0.31(4:1 Pet ether:ether), wt. = 3.8 g (60~), [~]~ = +267.05 (c =
0.76, CHCl3) lH NMR: ~i 1.22 (t, ~=7.5 Hz, 3H), 1.52 (d, J=6.9 Hz, 3H),2.88 (q, J=6.0 Hz, 2H), 3.99 (s, 3H), 4.99 (m, lH), 5.09 (ABq~ ~A=5.00, ~B= 5.19, J= 12.6 Hz, 2H), 6.66 (s, lH), 6.99-7.36 (m, 13H).; Second major product to elute was (-)-5-(benzyloxycarbonyl)-4-ethyl-1,6-dihydro-1-{N-[2-phenyl)ethyl])carboxamido-2-methoxy-6-(3,4-diflurophenyl)pyrimidine.Colorlessoil.
~f= 0.22(4:1 Pet ether:ether), wt.= 3.2 g (51.2~), [~]D
= -146.89 (c = 0.38, CHCl3), lH NMR: ~ 1.22 (t, J=7.2 Hz, 3H), 1.49 (d, J=6.6 Hz, 3H),2.88 (q, J=6.0 Hz, 2H), 3 94 (s 3H), 5 03 (m, lH), 5.11 (ABq~ ~A=5.02, ~B -5.19, J= 12.6 Hz, 2H), 6.68 (s, lH), 6.91-7.34 (m, 13H).
e. (+)-5-~Benzyloxycarbonyl)-1,6-dihydro-2-methoxy-4-ethyl-6-~3,4-diflurophenyl)pyrimidine. To a stirred solution of (+)-5-(benzyloxycarbonyl)-4-ethyl-1,6-dihydro~ N- [2-phenyl)ethyl]}carboxamido-2-methoxy-6-(3,4-diflurophenyl)pyrimidine (l.B3 mmol, 1.0 g) in toluene (10 mL) was added 1,8-diazabicyclo[5,4,0]-undec-7-ene (0.81 mmol,0.12 mL) at room temperature and CA 022s3862 1998-11-09 W 097/42956 PCT~US97/08335 the resulting solution was heated to reflux for 5h and then stirred for 12h at room temperature. The solvent was evaporated and the residue was purified by flash column chromatography on silica gel with 3:1 EtOAc/Hexanes as the eluting system. 0. 56 g of the (+)-5-(benzyloxycarbonyl)-1,6-dihydro-2-methoxy-4- ethyl-6-(3,4-diflurophenyl)pyrimidine was obtained (77%).

f. (+)-5-lLenzyloxycarbonyl)-4-ethyl-1,6-dihydro-2-methoxy-6-(3,4-diflurophenyl)-1-t(4-nitrophenyloxy) carbonyl~pyrimidine. To a well stirred solution of (+)-5-(benzyloxycarbonyl)-1,6-dihydro-2-methoxy-4-ethyl-6-(3,4-diflurophenyl)pyrimidine (17.0 g, 44.04 mmol) and 4-dimethylaminopyridine (6.99 g, 57.25 mmol) in CH2Cl2 (200 mL) was added a powder of 4-nitrophenyl chloroformate 11.54 g, 57.25 mmol) at room temperature.
The reaction mixture was stirred for 12 hours and then the solvent was removed in vacuo. The residue was purified by chromatography (Sio2, EtOAc/Hexane 10-30~) toget(+)-5-(benzyloxycarbonyl)-4-ethyl-1,6-dihydro-2-methoxy-6-(3,4-diflurophenyl)-1-[(4-nitrophenyloxy) carbonyl]pyrimidine as a colorless viscous oil(19.3 g, 76%).
g. (~) -5- (Benzyloxycarbonyl) -6- (3,4-difluorophenyl) -4-ethyl-1-{N- [3- (4-methoxycarbonyl-4-phenyl piperidin- 1 -yl ) propyl ] } carboxamido - 2 - oxo -1,2,3,6-tetrhydropyrimidine. To a stirred mixture of (+)-5-(benzyloxycarbonyl)-4-ethyl-1,6-dihydro-2-methoxy-6-(3,4-difluorophenyl)-1-[(4-nitrophenyloxy) carbonyl]pyrimidine (0.55 g, 1.12 mmol) in THF (5 mL) was added a solution of 3-[4-methoxycarbonyl-4-phenylpiperidin-1-yl]propylamine (0.31 g, 1.12 mmol) in THF (5 mL) at room temperature. The stirring was continued for 12 hours. A solution of 10% HCl in water (2 mL) was added and stirred for 2 h. The solvent was W097/42956 PCT~S97/08335 then removed in vacuo and the residue was extracted with ethyl acetate (3 X 10 mL). It was washed with 10~
aq. KOH solution, dried over Na2SO4 and solvent was removed in vacuo to obtain (+)-5-(benzyloxycarbonyl)-6-(3,4-difluorophenyl)-4-ethyl~ N-~3-(4-methoxycarbonyl-4-phenylpiperidin-1-yl)propyll}
carboxamido-2-oxo-1,2,3,6-tetrhydropyrimidine as a white foamy compound (0.73 g, 96.6%~ the purity of which was characterized as its HCl salt. It was used in the next step without further purification. Anal.
Calcd. for C37H4lClF2N4O6Ø5CHCl3:C, 58.43; H, 5.43; N, 7.27. Found: C, 58.11, H; 5.85; N, 7.64.

h. 6-(3,4-Difluorophenyl)-4-ethyl-1-{N-[3-(4-methoxy carbonyl-4-phenylpiperidin-1-yl)propyl~}carboxamido-1,2,3,6-tet hy~o-2-oxopyrimidine-5-carboxylicacid.To a suspension of 10~ Pd-C (0.14 g, 20~ by wt.) in MeOH
(3 mL) was added the solution of (+)-5-(benzyloxycarbonyl)-6-t3,4-difluorophenyl)-4-ethyl-l-{N-[3-(4-methoxycarbonyl-4-phenylpiperidin-l-yl) propyl]}carboxamido-2-oxo-1,2,3,6-tetrhydropyrimidine at room temperature with constant stirring. A balloon filled with H2 was attached and the reaction mixture was stirred for 48 hours. The black suspension was filtered through a pad of celite and the filtrate was concentrated in vacuo. The residue was purified by column chromatography (SiO2, 10% MeOH in EtOAc) to obtain (+)-6-(3,4-difluorophenyl)-4-ethyl-l-~N-[3-(4-methoxycarbonyl-4-phenylpiperidin-1-yl) propyl])carboxamido-1,2,3,6-tetrhydro-2-oxopyrimidine-5-carboxylic acid as a white solid. M.P. 184-186 ~C;
[~]D = +142.2 ~c = 0.25, CHCl3) The purity was checked by combustion analysis as a HCl salt. Anal. Calcd. for C30H3sClF2N4O6Ø3CHCl3:C, 55.40; H, 5.42; N, 8.53. Found:
C, 55.34; H; 5.80; N, 8.13.

i. (~)-5-Carboxamido-6-(3,4-difluorophenyl)-4-ethyl-CA 022~3862 1998-11-09 W O 97/42956 PCT~US97/0833S

1-{N-[3-~4-methoxycarbonyl-4-phenylpiperidin-1-yl) propyl]}carboxamido-2-oxo-1,2,3,6-tetrhydro pyrimidine.
To a solution of (+)-6-(3,4-difluorophenyl)-4-ethyl-l-{N-[3-(4-methoxycarbonyl-4-phenylpiperidin-l-yl) propyl]~carboxamido-1,2,3,6-tetrhydro-2-oxopyrimidine-5-carboxylic acid (0.22 g, 0.375 mmol) in CH2Cl2 ~3 mL) was added 4-N,N-dimethylamino pyridine (0.14 g, 1.12 mmol)andl-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.21 g, 1.12 mmol) under argon and the resulting solution was stirred at room temperature for 2h. Three drops of saturated NH40H was then added and the solution was stirred for 4~ h. The solution was washed with water (5 ml) and dried over Na2SO4. The solvent was removed in ~acuo and the residue was purified by-column chromatography (SiO2, 10~ MeOH in CHCl3)toobtain5-carboxamido-6-(3,4-difluorophenyl)-4-e t h y l - 1 - { N - [3 - (4 - m e t h o x y c a r b o n y l -4-phenylpiperidin-1-yl)propyl]~carboxamido-2-oxo-1,2,3,6-tetrhydropyrimidine as a beige solid ~0.1 g, 45~). Characterized as HCl salt. M.P. 136-138~C,, [~]D
= +111.44 (c = 0.18, MeOH): ~ 1.21 (t, J=7.5 Hz, 3H), 1.60-1.75 (m, 2H), l.g2-2.1 (m, 8H), 2.33 (t, J=6.6 Hz, 2H), 2.44-2.52 (m, 2~), 2.53-2.84 (m, 4H), 3.27-3.32 (m, 2H), 3.60 (s, 3H), 5.60 (br s,2H), 6.47 (s, lH), 7.05-7.33 (m, 8H), 8.80 (br t, lH), Anal. Calcd. for C30H35ClF2N4O6.1.0 CHCl3:C, 50.35; H, 5.04; N, 9.47.
Found: C, 50.40; H; 5.33; N, 9.13.

Example 15 6-(3,4-Difluoropheny~)-5-methoxycarbonyl-4-methyl-2-oxo-1-{N- [4- (2 -pyridyl) -p ip eridine-1-yl]propyl}carboxamido-1,2,3,6-tetrahydropyrimidine dihydrochloride ~Scheme 7).
a. 1-Benzyl-4-cyano-4-(2-pyridyl)piperidine. To a mixture of N,N-bis-(2-chloroethyl)benzylamine CA 022~3862 1998-11-09 W 097/42956 PCTrUS97/08335 (E.Szarvasi, Eur. J. Med. Chem. Chim. Ther. 11(2), 115-124, 1976) (60 g, 22 mmol), 2-pyridylacetonitrile (2.51 ml, 22 mmol) and tetrabutylammonium hydrogen sulfate (0.26 g, 0.7 mmol) in toluene (10 ml), sodium hydroxide solution (2.43 g in 4.86 ml H2O) was added over a 20 minute period. The reaction mixture was heated at 65 ~C for 4 hours. The reaction mixture was cooled to room temperature, 10 ml of water was added and the solution partitioned between ethyl acetate (45 ml) and water.
The organic layer was dried over sodium sulfate, filtered and concentrated. Purification of the crude product by column chromatography (hexane:EtOAc,2:3) gave 6.2 g (B7%) of the title compound as a red solid;
lH-NMR (CDCl3): ~ 2.05 (d, J = 13.1 Hz, 2 H), 2.30 (t, J = 13.2 Hz, 2 H), 2.4B (t, J = 13.2 Hz, 2 H), 2.97 (d, J = 12.1 Hz, 2 H), 3.57 (s, 2 H), 7.19-7.27 (m, 6 H), 7.30 (d, J = 7.6 Hz, 1 H), 7.60 (t, J = 7.6 Hz, 1 H), 8.58 (d, J - 4.6 Hz,lH).

b. 1-Benzyl-4-carboxamido-4-~2-pyridyl)piperidine. To 1-benzyl-4-cyano-4-(2-pyridyl)piperidine (4.5 g, 14.3 mmol), 10 ml of conc.H2SO4 was added and the solution was stirred at room temperature for 24 hours. It was cooled to 0 ~C, diluted with ice pieces and poured into crushed ice. The mixture was then carefully neutralized with 50 ~ NaOH solution. The reaction mixture was repeatedly extracted with chloroform (3 x 25 ml), dried over sodium sulfate, filtered and concentrated to gi~e 4.5 g (95%)of the crude product which was used as such for the subsequent step; 1H-NMR
(CDCl3): ~ Z.21-2.28 (m, 2 H), 2.47 (s, 6 H), 3.41 (s, 2 H), 5.23 (s, 1 H), 6.40 (s, 1 H), 7.12-7.29 (m, 6 H), 7.33 (d, J - 7.6 Hz, 1 H), 7.63 (t, J = 7.6 Hz, 1 H), 8.55 (d, J = 4.6 Hz, 1 H).
c. 1-Benzyl-4-(2-pyridyl)-piperidine. To l-benzyl-4-carboxamido-4-(2-pyridyl)piperidine (4.5 g, 13.5 mmol) CA 022~3862 l998-ll-09 W O 97/42956 PCT~US97/0833S

in anhydrous methanol (100 ml), HCl gas was bubbled through the solution at 0 ~C for 15 minutes. The reaction mixture was then refluxed for 24 hours. It was cooled to room temperature, concentrated, neutralized with 50 ~ NaOH and repeatedly extracted with chloroform ~3 x 25 ml). The combined organic layer was then dried over sodium sulfate, filtered and concentrated. Flash chromatography (hexane:ethylacetate, 1:4) of the crude product yielded 1.72 g (50%) of the product as a syrup; 'H-NMR (CDCl3):
1.8-1.94 (m, 4 H), 2.11 (t , J = 11.4 Hz , 2 H), 2.70 -2.72 (m, 1 H) ,3.02 (d, J = 11.4 Hz, 2 H), 3.54 (s, 2 H), 7.07-7.36 (m, 7 H), 7.58 (t, J = 7.6 Hz, 1 H), 8.52 (d, J = 4.6 Hz, 1 H).
d.3-~4-~2-Pyridyl)-piperidine-l-yl]propylamine(Scheme 6) . To 1-Benzyl-4- (2-pyridyl) -piperidine (3.26 g, 12.9 mmol) in dry methanol (25 ml), 1096 palladium hydroxide (1.9 g) was added and the solution was hydrogenated at 200 psi for 24 hours. The solution was filtered over celite, concentrated to give 2.1 g (99%) of 4- (2-pyridyl)-piperidine which was used as such for the subsequent step. A mixture of 3-bromopropylamine hydrobromide (20 g, 91.3 mmol), potassium carbonate ~37.85 g, 273.9 mmol) and di- tert-butyldicarbonate (21.90 g, 100 mmol) in methanol was stirred at room temperature for 24 hours. The reaction mixture was concentrated and partitioned between 250 ml EtOAc and 50 ml water, dried over sodium sulfate, filtered and concentrated. Purification of the crude product by column chromatography (Hexane: EtOAc, 4.5: 0.5) gave 17.5 g (80%) of the product as a pale yellow oil . To a stirred solution of the 4- (2-pyridyl) -piperidine (1.86 g, 11.4 mmol) in dioxane ( 20 ml), N- (tert-butoxycarbonyl)-3-bromopropylamine (2.82 g, 11.4 mmol) and potassium carbonate (3.16 g, 22.9 mmol) were added and the solution refluxed for 24 hours. The reaction CA 022~3862 1998-11-09 W097/429~6 PCT~S97/08335 mixture was cooled to room temperature, concentrated and partitioned between 40 ml chloroform and 5 ml water. The organic layer was dried over sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography (ethyl acetate:
methanol, 4:1) to yield 1.86 g (49 %) of the required product as a colorless oil; 1H-NM~ (CDC13): ~ 1.45 (s, 9 H),1.54-1.69 (m, 8 H), 2.21-2.68 (m, 2 H), 2.74-2.80 (m, 1 H), 3.02-3.22 (m, 4 H), 5.41 (s, lH), 7.13-7.17 (m, 1 H), 7.33 (d, J = 7.93 Hz, 1 H).7.63 (t, ~ = 7.6 Hz, 1 H), 8.54 (d, J = 4.6 Hz, 1 H). To N-(tert-butoxycarbonyl)-3-[4-(2-pyridyl)-piperidin-1-yl]propylamine (0.15g, 0.45 mmol) in 5 ml of dichloromethane, 1 ml of trifluoroacetic acid was added and the solution stirred at room temperature for 1 hour. The solution was concentrated, neutralized with 10 ~ KOH solution and extracted into 25 ml of dichloromethane. The organic layer was dried over sodium sulfate, filtered and concentrated to give 0.098 g (100~) of3-[4-(2-pyridyl)-piperidin-1-yl]propylamine which was used as such for the subsequent step (step h).

e. Methyl 2-{(3,4-difluorophenyl)methylene}-3-oxobutyrate. A mixture of 3,4-difluorobenzaldehyde (14.2 g, 0.1 mol), methyl acetoacetate (12.2 g, 0.10~
mol), piperidine (0.430 g, 5 mmol), and acetic acid (0.30 g, 5 mmol) in benzene (150 mL) was stirred and refluxed with a Dean-Stark trap for 8 hours. Benzene was evaporated, the residue was dissolved in ethyl acetate (200 mL) and washed with brine (50 mL), saturated potassium bisulfate solution (50 mL), and saturated sodium bicarbonate solution in sequence. The ethyl acetate solution was dried (magnesium sulfate), solvent removed under reduced pressure and the residue was purified by column chromatography (SiO2, EtOAc/hexane, 10~-15%). The product, methyl 2-~(3,4-CA 022~3862 1998-11-09 W O 97/42956 PCT~US97108335 difluorophenyl)methylene}-3-oxobutyrate, was obtained as a yellow oil ~0.98 g, 98.3~) and was used in the next step without any further characterization.

f . 6- ~3,4-Difluorophenyl)-1,6-dihydro-2-methoxy-5-methoxycarbonyl-4-methylpyrimidine. A mixture of methyl 2-{(3,4-difluorophenyl)methylene}-3-oxobutyrate (8.8 g, 36.6 mmol), O-methylisourea hydrogen sulfate (9.4 g, 55 mmol), and NaHCO3 (12.3 g, 0.146 mol) in DMF
(30 mL) was stirred and heated at 70 ~C for 16 hours.
The mixture was cooled, diluted with EtOAc (300 mL) and washed with water (5 X 300 mL), brine (300 mL), and dried (MgSO4). Solvent was evaporated and the crude product was purified by flash column chromatography on silica gel using 10~ through 20% EtOAc in hexane as the gradient eluent, to leave the product as an oil (3.82 g, 30.2~ H-NMR (CDC13):~ 2.32,2.39 (2 s, 3 H), 3.58, 3.64 (2 s, 3 H), 3.72, 3.85 (2 s, 3 H), 5.55 ( s, 1 H), 6.13-7.8 (m, 4 H).
g. 6-(3,4-Difluorophenyl)-1,6-dihydro-2-methoxy-5-methoxycarbonyl-4-methyl-1-[(4-nitrophenyloxy)car~o nyl]pyrimidine.
To a solution of 6-(3,4-difluorophenyl)-1,6-dihydro-2-methoxy-5-methoxycarbonyl-4-methylpyrimidine (2.82 g, 9.52 mmol) and 4-dimethylaminopyridine (1.16 g, 9.52 mmol) in CH2Cl2 (50 mL),at 0-5 ~C, 4-nitrophenyl chloroformate (1.82 g, 9.04 mmol) was added and the mixture was allowed to warm to room temperature. After 12 hours solvent was evaporated and the residue was purified by flash column chromatography (Sio2, EtOAc/hexane, 10%-15%)to obtain the product as white crystals (3.72, 84.7%); m.p. 172-174 ~C; 1H-NMR
(CDCl3):~ 2.51 (s, 3 H), 3.72 (s, 3 H), 3.97 (s, 3 H), 6.26 (s, 1 H), 7.0-7.3 (m, 3 H), 7.38 (d, J = 9.3 Hz, 2 H), 8.32 (d, J = 9.3 Hz, 2 H).
-CA 022~3862 1998-11-09 W O 97/42956 PCT~US97108335 h. 6-(3,4-Difluorophenyl)-5-methoxycarbonyl-4-methyl-2-oxo-l-{N-t4-(2-pyridyl)-piperidine-1-yl]propyl}
carboxamido-1,2,3,6-tetrahydropyrimidine dihydrochloride. To 6-(3,4-difluorophenyl)-1,6-dihydro-2-methoxy-5-methoxycarbonyl-4-methyl-1-(4-nitrophenoxy)carbonylpyrimidine (0.04 g,0.086 mmol~ ln 10 ml of dry dichloromethane, 3-[4- (2-pyridyl)-piperidine-1-yl]propylamine (0.038 g, 0.17 mmol) was added and the solution was stirred at room temperature for 24 hours. The reaction mixture was stirred for another 1 hour after addition of 2 ml of 6N HCl. After neutralization with 10% aqueous KOH solution, the reaction mixture was extracted into dichloromethane (3 x 10 ml). The organic layer was dried over sodium sulfate, filtered and concentrated. The crude product was purified by flash chromatography ( Et~Ac: MeOH, 4.5:0.5) to give 0.040 g (8996) as a syrup ; lH-NMR
(CDCl3): ~ 1.73-2.11 (m, 7 H), 2.41 (s, 6 H), 2.69 (m, 1 H), 3.04 (d, J = 12.1 Hz, 2 H) , 3.31-3.48 (m, 2 H), 3.71 ( s, 3 H3, 6.70 (s, 1 H), 7.24-7.27 (m, 5 H), 7.61 ( t, J = 8.0 Hz, 2 H), 8.51 (d, J = 4.6 Hz, 1 H), 8.89 (t, J = 5.1 Hz, 2 H).

To the free base (0.04g, 0.07 mmol) in 4 ml of dichloromethane, 5 ml of lN HCl in ether was added, and the solution concentrated under reduced pressure.
Recrystallization from ether gave 0.046 g (98%) of 6-(3,4-difluorophenyl)-5-methoxycarbonyl-4-methyl-2-oxo-l-~N-[4-(2-pyridyl)-piperidine-l-yl~propyl)carboxamido-1,2,3,6-tetrahydropyrimidine dihydrochloride as a white solid; m.p. 170-174 ~C; Anal. Calcd. for C27H33C12F2N5O4.1.0 H2O: C, 52-43; H,5.70, N 11.30. Found:
C, 52.16; H 5.35; N 11.10.

Example 16 6-(3,4-Benzofurazan-5-yl)-5-methoxycarbonyl-4-methyl-2-oxo-1-{N-t4-(2-pyridyl)-piperidin-1-yllpropyl}carbox .

CA 022~3862 1998-11-09 amido-1,2,3,6-tetrahydropyrimidine dihydrochloride (Scheme B).

5-Methylbenzfuroxan. 4-Methyl-2-nitroaniline (100 g, 0.650 mol~ was suspended in saturated alcoholic sodium hydroxide solution (1.50 l). To this suspension was added with cooling (5 ~C) commercial aqueous sodium hypochlorite till the red color disappeared. The fluffy yellow precipitate formed was filtered, washed with cold water and recrystallized from ethanol to get 5-Methylbenzfuroxan (88.2 g, 89 % yield) as a pale solid.

5-Methylbenzofurazan. To 5-Methylbenzfuroxan (88.2 g, 0.59. mol) in refluxing EtOH (75 ml) was added dropwise P(OEt)3 (150 ml ). When addition was complete, refluxing was continued for 1 more hour. The solvent was removed by rotary evaporation and the residue shaken with water (200 mL) and allowed to stand overnight at (0-5 ~C). The brown solid so obtained was filtered, washed with water and chromatograghed on silica gel to yield 5-Methylbenzofurazan (70 g, 87 ~) as white needle.

5-Dibromomethylbenzofurazan. 5-Methylbenzofurazan (70 g, 0.52 mol), NBS (325 g), and benzoyl peroxide (0.5 g) were refluxed with stirring in carbon tetrachloride (1.5 ~) with exclusion of moisture for 30 hours. The reaction mixture was washed with water (2X0.5L), dried (NaSO4), and the solvent was removed in vacuo. The residue was chromatographed (silica, EtOAc-hexane, 1:150) to give 122 g (80~) of the title compound. The resulting white solid was used in the next step without any further characterization.
5-Formylbenzofurazan. To a refluxing mixture of the dibromomethylbenzofurazan (122 g, 418 mmol) in EtOH (1 CA 022~3862 1998-11-09 L) was added AgNO3 (163 g) in 2 L of water. Refluxing was continued for 2 hours. The mixture was cooled and the AgBr was removed by filtration through Celite, and the solvent was concentrated to a small volume. The resulting solution was extracted with toiuene (10 X
100 mL), dried (MgSO4), and the solvent was removed in vacuo. The residue was chromatographed on silica (EtOAc-hexane, 8:1000) to give 48.2 g of the title aldehyde (78~) as a white solid.

a.Methyl2-{(benzofuran-5-yl)methylene}-3-oxobutyrate.

A mixture of 5-Formylbenzofurazan (0.6 g, 4.1 mmol), methyl acetoacetate (0.52 g, 4.5 mmol), piperidine (0.019 g, 0.225 mmol), and acetic acid (0.014 g, 0.225 mmol) in benzene (30 mL) was stirred and refluxed with a Dean-Stark trap for 8 h. Benzene was evaporated, the residue was dissolved in ethyl acetate (80 mL) and washed with brine (50 mL), saturated potassium bisulfate solution (50 mL), and saturated sodium bicarbonate solution in sequence. The ethyl acetate solution was dried (magnesium sulfate), solvent removed under reduced pressure and the residue was purified by column chromatography (SiO2, EtOAc/hexane, 10~-15%).
The product, methyl 2-~(benzofuran-5-yl)methylene)-3-oxobutyrate, was obtained as an oil (0.98 g, 98.3~) and was used in the next step without any further characterization.

b. 6-(Benzofurazan-5-yl)-1,6-dihydro-2-methoxy-5-methoxycarbonyl-4-methylpyrimidine. A mixture of methyl 2-{(benzofuran-5-yl)methylene~-3-oxobutyrate (1.02 g, 4.1 mmol), O-methylisourea hydrogen sulfate (1.06 g, 6.2 mmol), and NaHCO3 (1.3 g, 16.4 mmol) in DMF
(15 mL) was stirred and heated at 70 ~C for 16 h. The mixture was cooled, diluted with EtOAc (50 mL) and washed with water (5X 50 mL), brine (50 mL), and dried .. ..

WO 97/42956 PCT~US97/08335 (MgSO4). Solvent was evaporated and the crude product was purified by flash column chromatography on silica gel using 10~ through 20~ EtOAc in hexane as the gradient eluent, to leave the product as an oil (0.52 g, 4396); lH-NMR (CDCl3):~ 2.38,2.42 (2 s, 3 H), 3.60, 3.66 (2 s, 3 H), 3.74, 3.82 (2 s, 3 H), 5.53, 5.68 (2 s, 1 H), 6.31, 6.32 (br s, 1 H), 7.0-7.8 (m, 3 H).

c. 6-~enzofurazan-5-yl)-1,6-dihydro-2-methoxy-5-methoxycarbonyl-4-methyl-1-[(4-nitrophenyloxy)carbo nyl~pyrimidine.
To a solution of 6-(benzofuran-5-yl)-1,6-dihydro-2-methoxy-5-methoxycarbonyl-4-methylpyrimidine (0.485 g, 1.6 mmol) and 4-dimethylaminopyridine (0.2 g, 1.6 mmol) in CH2Cl2 (20 mL),at 0-5 ~C, was added 4-nitrophenyl chloroformate (0.307 g, 1.52 mmol) and the mixture was allowed to warm to room temperature. After 12 hours solvent was evaporated and the residue was purified by flash column chromatography (SiO2, EtOAc/hexane, 10~-15~)to obtain the product as white crystals (0.665 g, 89~); m.p. 180-183 ~C; lH-NMR (CDCl3):~ 2.54 (s, 3 H), 3.75 (s, 3 H), 3.98 (s, 3 H), 6.37 (s, 1 H), 7.40 (d, J = 9.3 Hz, 2 H), 7.52 (d, ~ = 9.0 Hz, 1 H), 7.68 (s, 1 H), 7.84 (d, J = 9.0 Hz, 1 H), 8.32 (d, ~ = 9.3 Hz, 2 H).

d . 6 - ( 3, 4 -Benzofurazan- 5 -yl ) - 5 -methoxycar}~onyl - 4 -methyl-2-oxo-1-{N- [4- (2-pyridyl) -piperidin-1-yl]propyl}
carboxamido- 1, 2, 3, 6 - tetrahydropyrimidine dihydrochloride. To 6-(benzofurazan-5-yl)-1,6-dihydro-2-methoxy-5-methoxycarbonyl-4-methyl-1-(4-nitrophenoxy)carbonylpyrimidine (0.04 g,0.085 mmol) in 10 ml of dry dichloromethane, 3-[4-(2-pyridyl)-piperidine-1-yl]propylamine (0.037 g, 0.17 mmol) was added and the solution was stirred at room temperature for 24 hours. The reaction mixture was stirred for another 1 hour after addition of 2 ml of 6N HCl. After CA 022~3862 1998-11-09 W 097/42956 PCT~US97/08335 neutralization with 10~ aqueous KOH solution, the reaction mixture was extracted into dichloromethane (3 x 10 ml). The organic layer was dried over sodium sulfate, filtered and concentrated. The crude product was purified by flash chromatography ( EtOAc: MeOH, 4.5:0.5) to give 0.040 g (89~) as a syrup; lH-NMR
(CDC13): ~ 1.74-2.10 (m, 7 H), 2.46 (s, 6 H), 2.70-2.72 (m, 1 H), 3.05 (d, J = 12.1 Hz , 2 H), 3.34 -3.48 (m, 2 H), 3.76 ( s, 3 H), 6.82 (s, 1 H), 7.11-7.32 (m, 3 H), 7.54-7.78 (m, 4 H), 8.53 (d, J = 4.6 Hz, 1 H), 8.89 ( t, J = 5.16 Hz, 2 H) .

To the free base ( 0.04g, 0.07 mmol) in 4 ml of dichloromethane, 5 ml of lN HCl in ether was added, and the solution concentrated under reduced pressure.
Recrystallization from ether gave 0.040 g (87~6) of 6-(3,4-benzofurazan-5-yl) -5-methoxycarbonyl-4-methyl-2-oxo-1- {N- [4- (2-pyridyl) -piperidine-l-yl] propyl}
carboxamido-1, 2, 3, 6-tetrahydropyrimidine dihydrochloride as a white solid; m.p. 200-204 ~C; Anal.
Calcd. for C27H33Cl2N70s. 2.5 H2O: C, 49.77; H,5.88. Found:
C, 49.41; H 5.20.

Example 17 6-(3,4-Difluorophenyl)-1,6-dihydro-5-methoxycarbonyl-1-(5-(4-methoxycarbonyl-4-phenylpiperidin-1-yl)-pentyl)-2,4-dimethylpyrimidine (Scheme 9).

a. 6-(3,4-D~fluorophenyl)-1,6-dihydro-2,4-dimethyl-5-methoxycarbony}pyrimidine. To a solution of acetamidine hydrochloride (1. 53 g, 16.2 mmol . ) in DMF
(10 mL) were added a solution of potassium tert-butoxide (1.33 g, 11.8 mmol. ) in DMF (10 mL) and a solution of methyl ~2- (3,4-difluorophenyl) methylene~ -- 35 3-oxobutanoate (2.6 g, 10. 8 mmol . ) in DMF (10 mL) at 0~C. After the mixture was stirred for 0.5 hour at 0~C, p-toluenesulfonic acid monohydrate (4.1 g, 21.5 mmol . ) CA 022~3862 1998-11-09 W O 97/42956 PCTrUS97/08335 was added. The mixture was heated at 100-120~C for 2 hrs. The reaction mixture was cooled to room temperature, quenched with a~ueous NaOH solution (2N, 60 mL), and extracted with ether. The organic layer was dried over Na2SO4 and evaporated. The residue was flash chromatographed over silica gel (eluent: ethyl acetate) to give the product in 59~ yield (1.8 g) as a yellow solid: lH NMR (300 MHz, CDC13) ~ 1.98 ~3H, s), 2.31 (3H, s), 3.59 (3H, s), 5.47 (lH, s), 7.03-7.05 (3H, m).
(5-Chloropentyl) -6- (3, 4-difluorophenyl) -1, 6-dihydro-2,4-dimethyl-5-methoxycarbony}pyrimidine. To a suspension of NaH (90 mg, 60~ dispersion in mineral oil, 2.25 mmol.) in THF (7 mL) was added a solution of the above yellow solid (0.6 g, 2.14 mmol.) in THF (8 mL) at 0~C. After 2D min, 1-bromo-5-chloropentane (1 mL, d 1.408, 7.59 mmol.) was added. The reaction mixture was then refluxed overnight. After the removal of the solvent, the residue was flash chromatographed over silica gel (eluent: ethyl acetate) to give the product in 75% yield (0.614 g) as a yellow oil: lH NMR (~00 MHz, CDC13) ~ 1.42-1.75 (6H, m), 2.17 ~3H, s), 2.28 (3H, s), 3.05-3.45 (2H, m), 3.49 (2H, t, ~=5.88Hz), 3.63 (3H, s), 5.23 (lH, s), 7.01-7.15 (3H, m).
c . 6 - ( 3, 4 -Dif luorophenyl ) -1, 6 - dihydro - 5 -methoxycarbonyl-1- (5- (4-methoxycarbonyl-4-phenylpiperidin-1-yl) -pentyl) -2, 4-dimethylpyrimidine .
A mixture of the above yellow oil (0.667 g, 1.73 mmol.), 4-methoxycarbonyl-4-phenyl piperidine (0.76 g, 3.47 mmol.), potassium carbonate (0.96 g, 6.95 mmol.), sodium iodide (0.52 g, 3.47 mmol.) and 1,4-dioxane (15 mL) was refluxed overnight. The undissolved solid was then filtered off and the solvent was evaporated. The residue was flash chromatographed over silica gel (eluent: 80:20 v/v ethyl acetate-2M ammonia in methanol) to give the title compound in 78~ yield .

CA 022~3862 1998-11-09 W O 97/42956 PCT~US97/08335 (0.768 g) as a yellow oil: CIMS, m/z 568 (MH~); iH NMR
(300 MHz, CDCl3) ~ 1.23-1.28 (2H, m), 1.43-1.51 (2H, m), 1.77-2.13 (8H, m), 2.16 (3H, s), 2.28 (3H, s), 2 47-2.55 (2H, m), 2.74-2.81 (2H, m), 3.00-3.12 (lH, m), 3.22-3.38 (lH, m), 3.613 (3H, s), 3.615 (3H, s), 5.22 (lH, s), 6.99-7.35 (3H, m).

Treatment of the free base with 2 equivalents of lM HCl in ether gave the HCl salt as a yellow foam: m.p. 170-176~C. Anal. Calc. for C32H39F2N3O42HCl 2.3H2O: C, 56.35;
H, 6.74; N, 6.16; Found: C, 56.34; H, 6.62; N, 5.86.

Example 18 (+)-6-~3,4-Difluorophenyl)-5-methoxycarbonyl-4-methyl-2-oxo-1-{N-~3-(4-(2-pyridyl)-4-hydroxypiperidin-1-yl)propyl~}carboxamido-1,2,3,6-tetrahydropyrimidine dihydrochloride.
A solution of (+)-6-~3,4-difluorophenyl)-1,6-dihydro-2-methoxy-5-methoxycarbonyl-4-methyl-1-(4-nitrophenoxy) carbonylpyrimidine (0.894 g, 2 mmol), 3-[4-(2-pyridyl~-4-hydroxypiperidin-1-yl]propylamine (0.517 g, 2.2 mmol) in tetrahydrofuran (100 mL) was stirred at room temperature for 24 hours. The reaction mixture was stirred for another 1 hour after addition of 2 ml of 6N
HCl. Solvent was evaporated at reduced pressure and the residue was basified by treatment with 10% aqueous KOH solution, extracted with dichloromethane (3 x 10 mL). The combined extracts were dried over potassium carbonate, and solvent evaporated. The crude product was purified by flash chromatography on silica gel (dichloromethane:MeOH:2M ammonia in MeOH,90:8:4) to give 1.20 g (97~) as a syrup. The free base was dissolved in 20 mL anhydrous ether, cooled to 0-5 ~C and treated with 10 mL of lN HCl in ether. The white powder was filtered and dried to give 6-(3,4-difluorophenyl)-5-methoxycarbonyl-4-methyl-2-oxo-1-{N-[3-(4-~2-pyridyl)-4-hydroxypiperidin-1-yl)propyl]}carboxamido-W097/429s6 PCT~S97/08335 1~2~3t6-tetrahydropyrimidine dihydrochloride; m.p. 200-206 ~C; [~] D = +91 (C = 1.15 g, in 100 mL of chloroform). Anal. Calcd. for C27H33C12F2NsO4Ø4CHCl3: C, 48.18; H, 4.92; N, 10.18. Found: C, 48.34; H, 5.01; N, 10.08.

Example 19 (+)-1,2,3,6-Tetrahydro-l-{N-t4-(2-pyridyl)-piperidin-l-yl]-(2-hydroxypropyl)}carboxamido-5-methoxycar~onyl lo -2-oxo-6-(3,4-difluorophenyl)-4-methylpyrimidine dihydrochloride a) 3 -[ 4-~2-Pyridyl)- piperidin-1-yl](2-hydroxypropyl) phthalimide A mixture of 4-(2-pyridyl)piperidine (3.25 g, 19.90 mmol) and 2,3-epoxypropylphthalimide (4.449 ~, 21.89 mmol) in DMF (20 mL) was stirred and heated at 70 ~C for 48 h. The solvent was evaporated under reduced pressure and the residue was purified by column chromatography on silica gel using chloroform-methanol-2M ammonia in methanol (1000/28/14) as the eluent, to obtain the desired product as a viscous oil (6.15 g, 84%).

b) 3-~4-(2-Pyridyl)-piperidin-l-yl]-2-hydroxy propylamine A mixture of 3 -[ 4-(2-pyridyl)- piperidin-1-yl](2-hydroxypropyl)phthalimide (1.35 g, 3.68 mmol) and hydrazine (0.588 g, 18.4 mmol) in methanol (15 mL) was stirred and refluxed for 4.5 h. It was cooled, filtered, and the solid was washed with methanol (30 mL). Evaporation of solvent from the filtrate gave the product as a viscous oil (0.85 g, 98%).

c)(+)-1,2,3,6-Tetrahydro-1-{N-t4-(2-pyridyl)-piperidi n-1-yl]-(2-hydroxypropyl)}carboxamido-5-methoxycarbon yl-2-oxo-6-(3,4-difluorophenyl~-4-methylpyrimidine W097/42956 PCT~S97/08335 dihydrochloride A solution of (+)-6-(3,4-difluorophenyl)-1,2,3,6-tetrahydro-2-oxo-5-methoxycarbonyl-4-methyl-1-(4-nitrophenoxy) carbonylpyrimidine (105 mg, 0.23 mmol), 3-[4-(2-pyridyl)piperidin-1-yl]-2-hydroxypropylamine (50 mg, 0.23 mmol~ in tetrahydrofuran (20 mL) was stirred at room temperature for 24 hours. Solvent was evaporated at reduced pressure and the residue was basified by treatment with 10% aqueous KOH solution, extracted with dichloromethane (3 x 10 mL). The com~ined extracts were dried over potassium carbonate, and solvent evaporated. The crude product was purified by fiash chromatography (dichloromethane:MeoH:2M
ammonia in MeOH,90:8:4) to give 120 mg (g7~) as a syrup; The HCl salt was prepared by treatment with lN
HCl in ether; m.p. 215-220 ~C; [~]D = +41 (c = 1.15 g, in 100 mL of methanol). Anal. Calcd. for C27H33NsO6F2C12Ø8 MeOH: C, 52.00i H, 5.68; N, 10.90. Found: C, 52.08; H;
5.70; N, 10.53.
Example 20 and Example 21 (+)-1,2,3,6-Tetrahydro-1-{N-[3-~4-(2-pyridyl)-piperidin-l-yl)-(2-fluoro)propyl]}carboxamido-5-metho xycarbonyl-2-oxo-6-(3,4-difluorophenyl)-4-methylpyrim idine dihydrochloride A mixture of (+)-1,2,3,6-tetrahydro-1-{N-I3-(4-(2-pyridyl)-piperidine-1-yl)-(2-hydroxy)propyl~ca rboxamido-5-methoxycarbonyl-2-oxo-6-(3,4-difluorophen yl)-4-methylpyrimidine (0.50 g, 0.92 mmol), diethylaminosulfur trifluoride (DAST, 0.222 g, 1.38 mmol, 1.5 eq.), and benzene (50 mL) was stirred at 70 ~C under dry argon atmosphere for 24 h. The TLC analysis of reaction mixture showed the complete disappearance of the starting material. Solvent was evaporated under - 35 reduced pressure and the residue was purified by column chromatography on silica gel (20 g), using chloroform/methanol/2 M ammonia in methanol (500tl6/8) CA 022~3862 1998-11-09 W097/42956 PCT~S97/08335 as the eluent to give two products as a mixture of two diastereomers. These diastereomers were purified by chiral HPLC separation on Chiralpak A3, 4. 6 X 250 mm column, using isocratic condition ~90% hexane and 10~
ethanol containing 0. 5~ DEA). The retention time for the first product (example 26) was 12. 97 minutes and for the second product (example 27) was 16.18 minutes.
The combined yield of these products is (65 mg + 65 mg~
24%. The HC1 salt was prepared by treatment with lN
HCl in ether; Example 20: m.p. 132-134 ~C; [~] D = +108 (c = 0.715 g, in 100 mL of chloroform). Anal. Calcd.
for C2~H32NsO4F3Cl2.2.0 H2O: C, 53.38; H, 5.60; N, 11.12.
Found: C, 53.28; H; S.89; N, 10.96. Example 21: m.p.
130-132 ~C; [~] D = +100 (C = O . 7 g, in 100 mL of chloroform). Anal. Calcd. for C2~H32NsO4F3Cl2.1.5 H2O: C, 54.15; H, 5.52; N, 11.28. Found: C, 54.17; H; 5.57; N, 11 . 00 .
Note: Examples 14 and 15 are two diastereomeric products derived from the (+)enantiomer at the pyrimidine part and the two possible enantiomeric compounds with respect to the fluoromethylene chiral center.

Example 22 (I)-5-Carboxamido-6-(2,4-difluorophenyl)-4-ethyl-1-{N-~3-(4-cyano-4-phenylpiperidin-1-yl)propyl]}
carboxamido-2-oxo-1,2,3,6-tetrahydropyrimidine.

a) 3-(4-Cyano-4-phenylpiperidin-1-yl)propylphthal;mide.
A mixture of 4-cyano-4-phenylpiperidine hydrochloride (lll g, 0.5 mol), 3-~romopropylphthalimide (135.39 g, 0.505 mol), potassium carbonate (276.42 g, 2 mol), and potassium iodide (5.4 g) in DMF (1 L) was stirred and heated at lO0-110 ~C for 8 h. About 80~ of the solvent was evaporated at reduced pressure, the residue was diluted with dichloromethane (1 L) and washed with brine (3 X 300 mL) and dried (Na2SOq). Solvent was CA 022~3862 1998-11-09 W097/42956 PCT~S97/~35 evaporated from the dichloromethane solution and the residue was treated with isopropanol (400 mL) and cooled. The pale yellow crystalline product formed was filtered, washed with ice-cold isopropanol and dried (168.6 g, 90~); M.p. 96-98 ~C.

b) 3-(4-Cyano-4-phenylpiperidin-1-yl)propylamine.
To a solution of 3-(4-cyano-4-phenylpiperidin-l-yl) propylphthalimide (112 g, 0.3 mol) in methanol (1. 5 L), hydrazine ~30 mL) was added and the mixture was stirred and refluxed for 20 h. It was cooled, the white solid formed was filtered and washed with more methanol (200 mL). Solvent was evaporated from the filtrate and residue was dried under vacuum for 4 h.
Chloroform (500 mL) was added to this, stirred for 1 h and filtered. The white solid was washed with more chloroform (200 mL), the solvent was evaporated from the combined filtrates to leave the product as an oil (70 g, 96%).
c) Benzyl 2-[(2,4-difluorophenyl)methylene]-3-oxopentanoate. A solution of benzyl propionylacetate (157 g, 0.758 mol), 2,4-difluorobenzaldehyde (107.65 g, 0.758 mol), and piperidinium acetate (5.49 g, 38 mmol) in benzene (1 L) were stirred at room temperature for 96 h. The mixture was washed with water (2 X 100 mL), dried (magnesium sulfate) and the solvent evaporated under reduced pressure to get the product as a pale yellow syrup (251.2 g). It was used in the next step without further purification.

d) 5-(Benzyloxyc~rhonyl)-1,6-dihydro-2-methoxy-4-ethyl-6-(2,4-difluorophenyl)pyrimidine.
A suspension of benzyl 2-[(2,4-difluorophenyl) methylene]-3-oxopentanoate (80.0 g, 0.241 mol), O-methylisourea hemisulfate (63.8 g, 0.362 mol, 1.5 eq.), NaHCO3 (60.48 g, 0.72 mol) in ethanol (800 mL) was CA 022~3862 1998-11-09 W 097/42956 PCT~US97/08335 stirred at 60-70 ~C for 20 h. After cooling to room temperature, the mixture was filtered, and the solid was washed with ethanol (200 mL). The solvent was evaporated from the combined filtrates and the residue was purified by column chromatography (SiO2, EtOAc/Hexane, 10~-30%) to get 5-(benzyloxycarbonyl)-1l6-dihydro-2-methoxy-4-ethyl-6-(2~4-difluorophenyl) pyrimidine as a pale yellow oil (39 g, 42~). The lH-NMR
analysis showed it to be a mixture of amine/imine tautomers and was used as is in the next step.

e) 5-(~enzyloxycarbonyl)-4-ethyl-1,6-dihydro-2-methoxy-6-(2,4-difluorophenyl)-1-[(4-nitrophenyloxy)carbonyl]
pyrimidine.
To a well stirred solution of 5-(benzyloxycarbonyl)-1~6-dihydro-2-methoxy-4-ethyl-6-(2~4-difluorophenyl) pyrimidine (22.5 g, 59.3 mmol) and 4-(N,N-dimethyl amino)pyridine (9.3 g, 75.8 mmol) in CH2C12 (200 mL) was added a powder of 4-nitrophenyl chloroformate (15.3 g, 75.8 mmol) at 0 ~C. The reaction mixture was stirred for 12 h at room temperature and then water (50 mL) was added. The pH of the aqueous layer was adjusted to 10-ll by the addition of 6 N sodium hydroxide. The dichloromethane layer was separated and dried (Na2SO4).
Solvent was evaporated in vacuo and the residue was purified by column chromatography (SiO2, dichloromethane /hexane, 20%-50%) to give the product as a viscous oil (32.0 g, 98%).

f) 5- (Benzyloxycarbonyl) -4-ethyl-1, 6-dihydro-1-{N- [2-phenyl) ethyl] }carboxamido- 2 -methoxy- 6 - ( 2, 4 -di f luorophenyl ) pyrimidine .
To a stirred solution of 5-(benzyloxycarbonyl)-4-ethyl-1~6-dihydro-2-methoxy-6-(2~4-difluoropheny~ -[(4 nitrophenyloxy)carbonyl]pyrimidine (32 g, 58.11 mmol) in dichloromethane (200 mL) was added R-(+)-~-methylbenzylamine (9.16, 75.6 mmol) at room temperature ~ . .

CA 022~3862 l998-ll-o9 WO 97/42956 PCTrUS97/08335 and the stirring was continued for 12 h. The mixture was diluted with more dichloromethane (200 mL) and washed with 0.5 N NaOH solution (2 x 60 mL). The organic layer was dried over Na2SO4, filtered and solvent was evaporated. The resulting mixture of diastereomers was separated by column chromatography(SiO2, 3~ EtOAc in toluene). The first major product to elute was (+)-5-(benzyloxycarbonyl)-4-ethyl-1,6-dihydro-1-{N-[2-phenyl)ethyl]}carboxamido-2-methoxy-6-(2,4-difluorophenyl~pyrimidine (12.15 g, 38~). [~] D = +214 (c = 1.5 g in 100 mL CHCl3); The second major product to elute was the other diastereomer and no effort was made to isolate it.

g) (I)-5-(Benzyloxycarbonyl)-1,6-dihydro-2-methoxy-4-ethyl-6-(2,4-difluorophenyl)pyrimidine.
To a stirred solution of (+)-5-(benzyloxycarbonyl)-4-ethyl-1,6-dihydro-1-{N-[2-phenyl)ethyl]}carboxamido-2-methoxy-6-(2,4-difluorophenyl)pyrimidine (11.15 g, 20.41 mmol) in toluene (250 mL) was added 1,8-diazabicyclo~5,4,0]-undec-7-ene (4.04 g, 26.53 mmol) and the mixture was stirred at room temperature for 14 h. The solvent was evaporated and the residue was purified by flash column chromatography on silica gel with 3:1 EtOAc/hexane as eluent to give (+)-5-(benzyloxycarbonyl)-1,6-dihydro-2-methoxy-4-ethyl-6-(2,4-difluorophenyl)pyrimidine as a viscous oil (6.15 g, 78~).

h) (I)-5-~Benzyloxycarbonyl)-4-ethyl-1,6-dihydro-2-methoxy-6-(2,4-difluorophenyl)-1-[(4-nitrophenyloxy) carbonyl~pyrimidine.
To a well stirred solution of (+)-5-(benzyloxycarbonyl) -l~6-dihydro-2-methoxy-4-ethyl-6-(2~4-difluorophenyl) - 35 pyrimidine (4.1 g, 10.62 mmol) and 4-(N,N-dimethylamino)pyridine (1.69 g, 13.80 mmol) in CH2Cl2 (200 mL) was added a powder of 4-nitrophenyl ~, . _ . . , W 097/42956 PCT~US97/08335 chloroformate ~2.78 g, 13.80 mmol) at room temperature.
The reaction mixture was stirred for 12 h and washed with 0.5 N NaOH solution (2 X 50 mL). The organic layer was separated and dried (Na2SO4;. The solvent was evaporated and ~he residue was purified by column chromatography on silica gel using dichloromethane/hexane (20~-50~) as the eluent to glve (+)-5-(benzyloxycarbonyl)-4-ethyl-1,6-dihydro-2-met ho x y- 6- (2, 4 - dif luo rop he n y l) - 1 - [(4 -nitrophenyloxy)carbonyl~pyrimidine (5.37 g, 92%) as a viscous oil.

i) (+)-5-(Benzyloxycarbonyl)-6-(2,4-difluorophenyl)-4-ethyl-l-{N-~3-(4-cyano-4-phenylpiperidin-1-yl)propyl]}
carboxamido-2-oxo-1,2,3,6-tetrahydropyrimidine.
A mixture of (+)-5-(benzyloxycarbonyl)-4-ethyl-l~6-dihydro-2-methoxy-6-(2,4-difluorophenyl)-1-[(4-nitrophenyloxy)carbonyl]pyrimidine (6.50 g, 11.81 mmol) and3-[4-cyano-4-phenylpiperidin-1-yl]propylamine (3.60 g, ~5.36 mmol) in THF (500 mL) was stirred at room temperature for 18 h. It was cooled to O ~C and 10% HCl in water (2 mL) was added and stirred for 2 h. The mixture was washed with 0.5 N aq. NaOH solution (30 mL), dried over Na2SO4 and the solvent evaporated. The residue was purified by column chromatography on SiO2 using CHCl3/MeOH/2M NH3 in MeOH (100/2/1) as eluent to obtain (+)-5-(benzyloxycarbonyl)-6-(2,4-difluorophenyl)-4-ethyl-1-(N- [3-(4-cyano-4-phenylpiperidin-1-yl)propyl]}carboxamido-2-oxo-1~2~3~6-tetrahydropyrimidine as a white foamy solid (7.05 g, 93~).

;) 6-~2,4-Difluorophenyl)-4-ethyl-1-{N-[3-(4-cyano-4-phenylpiper~din-1-yl)propyl]}carboxamido-1,2,3,6-tetrahydro-2-oxopyrimidine-5-carboxylic acid.

To a suspension of 10~ Pd-C (2.1 g) in MeOH (100 mL) _,, ~

CA 022~3862 1998-11-09 and H2O (20 mL) was added a solution of (+)-5-(benzy~oxycarbonyl)-6-(2,4-dlfluorophenyl)-4-ethyl-l-~N-[3-(4-cyano-4-phenylpiperidin-l-yl)propyl]}
carboxamido-2-oxo-1,2,3,6-tetrahydropyrimidine( 7. 55g, 11.2 mL) in methanol (100 mL) and the mixture was hydrogenated at 80 psi for 14 h. The black suspension was filtered through a pad of celite and washed thoroughly with MeOH (2.0 L) and methanol/chloroform (1:2, 200 mL). Solvent was evaporated from the combined filtrate to leave the product (+)-6-(2,4-difluorophenyl)-4-ethyl-1-{N- [3-(4-cyano-4-phenylpiperidin-1-yl)propyl]}carboxamido-1l2~3l6-tetrahydro-2-oxopyrimidine-5-carboxylicacidas a white solid (6.06 g, 98~). It was used in the next step without further purification.

k) (+)-5-CarhnYa~;do-6-(2,4-difluorophenyl)-4-ethyl-1-{N-t3-(4-cyano-4-phenylpiperidin-1-yl)propyl]}
carboxamido-2-oxo-1,2,3,6-tetrahydropyrimidine.
A mixture of (+)-6-(2,4-difluorophenyl)-4-ethyl-l-~N-[3-(4-cyano-4-phenylpiperidin-1-yl)propyl]}
carboxamido-1,2,3,6-tetrahydro-2-oxopyrimidine-5-carboxylic acid (6.30 g, 11~18 mmol), 1-(3-dimethylaminopropyl)-3-ethylcar~odiimide hydrochloride (4.29 g, 22.36 mmol, 2 eq.), and 4-(N,N-dimethylamino)pyridine (3.41 g, 27.95 mmol, 2.5 eq) in anhydrous dichloromethane (400 mL) was stirred at room temperature for 2 h. To this, 40~ aqueous ammonia (6.13 g, 5 eq) was added and the stirring was continued for 12 h. The mixture was diluted with 200 mL of dichloromethane and washed with saturated aqueous ammonium chloride solution (3 X 200 mL). Solvent was evaporated from the dried (sodium sulfate) dichloromethane solution and the residue was purified by column chromatography on silica gel using chloroform-methanol-2M ammonia in methanol (100/2/l) as the eluent, to obtain the desired product as a white W O 97/42956 PCTnUS97/08335 powder (5.45 g, 87%); m.p. 210-211 ~C; Part of the compound (300 mg) was dissolved in dichloromethane (3 mL), cooled to 0-5 ~C and treated with lN HCl in ether ~10 mL) followed by anhydrous ether (20 mL). The white powder formed was filtered, washed with ether (100 mL) and dried (320 mg, 100g~); m.p. 196-97 ~C; [~Y] D = +126 (c 0.505 g, in 100 mL of 1:1 chloroform/MeOH).Anal.
Calcd. for C29H33N6O3F2Cl: C, 59.27; H, 5.78; N, 14.24.
Found: C, 59.33; H; 5.67i N, 14.32.

Example 23 (+) - S - Carboxamido - 6 - (3, 4 - di f luorophenyl ) - 4 -methoxymethyl-1-{N- [3- (4 (2-pyridyl)piperidin-1-yl) propyl~}carboxamido-2-oxo-1,2,3,6-tetrahydropyrimidine dihydrochloride.
a) 2-Cyanoethyl 4-methoxyacetoacetate.
A mixture of methyl 4-methoxyacetoacetate ~50 g, 0.342 mol) and 3-hydroxypropionitrile (31.61 g, 0.444 mol) was heated to 160-180 ~C in a distillation set-up. It was kept at that temperature for 2 h until the distillation of the methanol stopped. The residual yellow oil of 2-cyanoethyl 4-methoxyacetoacetate (56.4 g, go~) was used as is without any further purification.
b) 2-Cyanoethyl 2- [(3,4-difluorophenyl)methylene] -3-oxo-4-methoxybutyrate.
A solution of 2-cyanoethyl 4-methoxyacetoacetate (17.8 g, 0.125 mol), 3,4-difluorobenzaldehyde (25.5 g, 6.26 mmol), acetic acid (0.376 g, 6.26 mmol), and piperidine (0.533 g, 6.26 mmol) in benzene (500 mL) were added molecular sieves (200 g) and the mixture was stirred at room temperature for 24 h. Then the solvent was evaporated under reduced pressure and the residue was purif ied by column chromatography using chloroform/ethyl acetate (100:5) to get the product as an oil (29 g, 75~).

CA 022~3862 1998-11-09 W 097/42956 PCT~US97/08335 _ 99 _ c) 5-(2-Cyanoethoxycarbonyl)-1,6-dihydro-2-methoxy-4-methoxymethyl-6-(3,4-difluorophenyl)pyrimidine.
A suspension of 2-cyanoethyl 2-[(3,4-difluorophenyl)methylene]-3-oxo-4-methoxybutyrate ~29 g, 0.094 mol), O-methylisourea hemisulfate (21 g, 0.121 mol, 1.3 eq.), dimethylaminopyridine (29.67 g, 0.243 mol, 2.5 eq.) in ethanol (400 mL) was stirred at 50-55 ~C for 6 h. The solvent was evaporated from the combined filtrates and the residue was purified by 10 column chromatography (Sio2~ EtOAc/hexane, 10%-30%) to get 5-(2-cyanoethoxycarbonyl)-1,6-dihydro-2-methoxy-4-methoxymethyl-6-(3,4-difluorophenyl)pyrimidine as a pale yellow oil (10.5 g, 31%). The lH-NMR analysis showed it to be a mixture of amine/imine tautomers and 15 was used as is in the next step.

d) 5-(2-Cyanoethoxycarbonyl)-4-methoxymethyl-1,6-dihydro-2-methoxy-6-(3,4-difluorophenyl)-1-~(4-nitrophenyloxy)carbonyl]pyrimidine.
20 To a well stirred solution of 5-(2-cyanoethoxy carbonyl)-1,6-dihydro-2-methoxy-4-methoxymethyl-6-(3,4-dif1uorophenyl)pyrimidine (10.5 g, 28.74 mmol) and 4-(N,N-dimethylamino)pyridine (6.95 g, 34.49 mmol) in CH2Cl2 (100 mL) was added a powder of 4-nitrophenyl chloroformate (4.21 g, 34.49 mmol) at 0 ~C. The reaction mixture was stirred for 12 h at room temperature and then the solvent was evaporated. The residue was purified by column chromatography (SiO2, ~ dichloromethane/hexane, 20%-50%) to give the product as a viscous oil (6.5 g, 43%).

e) 5-(2-Cyanoethoxycarbonyl)-4-methoxymethyl-1,6-dihydro-l-{N-~2-phenyl)ethyl]}carboxamido-2-methoxy-6-(3,4-difluorophenyl)pyrimidine.
~ 35 To a stirred solution of 5-(2-cyanoethoxycarbonyl)-4-methoxymethyl-1,6-dihydro-2-methoxy-6-(3,4-difluorophenyl)-1-[(4-nitrophenyloxy)carbonyl~
-CA 022~3862 1998-11-09 W O 97/429~6 PCT~US97/08335 pyrimidine (6.5 g, 12.25 mmol) in dichloromethane ~150 mL) was added ~-(+)-~-methylbenzylamine (1.78 g, 14.7 mmol) at room temperature and the stirring was continued for 12 h. Solvent was evaporated and the residue was purified by column chromatography (SiO2, 10-20~ EtOAc in hexane). The first major product to elute was (+)-5-(2-cyanoethoxycarbonyl)-4- methoxmethyl-1,6-dihydro-l-~N-[2-phenyl)ethyl])carboxamido-2-methoxy-6-(3,4-difluorophenyl)pyrimidine (2.54 g, 44-5~)-[~]D =
10 +177.8 (c = 9.2 g in 100 mL CHC13); The second major product to elute was the other diastereomer and no effort was made to isolate it.

f) (I)-5-(2-Cyanoethoxycarbonyl)-1,6-dihydro-2-methoxy-15 4-ethyl-6-(3,4-difluorophenyl)pyrimidine.
To a stirred solution of (+)-5-(2-cyanoethoxycarbonyl)-4-methoxymethyl-1,6-dihydro-1-{N-[2-phenyl)ethyl]}
car~oxamido-2-methoxy-6-(3,4-difluorophenyl)pyrimidine (2.80 g, 5.46 mmol) in toluene (80 m~) was added 1,8-20 diazabicyclo[5,4,0]-undec-7-ene (0.250 g, 1.64 mmol) and the mixture was stirred at 75 ~C for 1 h. The solvent was evaporated and the residue was purified ~y flash column chromatography on silica gel with 3:1 EtOAc/hexane as eluent to give (+)-5-(2-25 cyanoethoxycarbonyl)-1,6-dihydro-2-methoxy-4-methoxymethyl-6-(3,4-difluorophenyl)pyrimidine as a viscous oil (0.82 g, 40.5%).

g) (~)-5-~2-Cyanoethoxycarbonyl)-4-methoxymethyl-1,6-30 dihydro-2-methoxy-6-(3,4-difluorophenyl)-1-[(4-nitrophenyloxy)carbonyl]pyrimidine.
To a well stirred solution of ~+)-5-(2-cyanoethoxycarbonyl)-1,6-dihydro-2-methoxy-4-methoxymethyl-6-(3,4-difluorophenyl)pyrimidine(0.82g, 35 2.24 mmol) and 4-(N,N-dimethylamino)pyridine (0.329 g, 2.69 mmol) in CH2Cl2 (200 mL~ was added a powder of 4-nitrophenyl chloroformate (0.543 g, 2.69 mmol) at room CA 022~3862 1998-11-09 W 097/42956 PCT~US97/08335 temperature. The solvent was evaporated and the residue was purified by column chromatography on silica gel using dichloromethane/hexane ~20~-50~) as the eluent to give (+)-5-(2-cyanoethoxycarbonyl)-4-methoxymethyl-1,6-dihydro-2-methoxy-6-(3,4-difluorophenyl)-1-[~4-nitrophenyloxy)carbonyl]
- pyrimidine (0.80 g, 67%) as a viscous oil.

h ) ( + ) - 5 - ( 2 - Cyanoe thoxyc arbonyl ) - 6 - ( 3, 4 -difluorophenyl) -4 -methoxymethyl-1- {N- [3 - (4 - (2 -pyridyl) piperidin-1-yl) propyl] }carboxamido-2 -oxo-1, 2, 3, 6 - tetral~yd~y ~ imidine .
A mixture of (+)-5-(2-cyanoethoxycarbonyl)-4-methoxymethyl-1,6-dihydro-2-methoxy-6-~3,4-difluorophenyl)-1-[(4-nitrophenyloxy)carbonyl~
pyrimidine (0.44 g, 0.83 mmol) and 3-[4-(2-pyridyl)piperidin-1-yl]propylamine (0.218 g, 0.996 mmol) in THF (15 mL) was stirred at room temperature for 12 h. It was cooled to 0 ~C and 10~ HCl in water (2 mL) was added and stirred for 2 h. Solvent was evaporated and the residue was purified by column chromatography on SiO2 using CHCl3/MeOH/2M NH3 in MeOH
(100/2/1) as eluent to obtain (+)-5-(2-cyanoethoxycarbonyl)-6-(3,4-difluorophenyl)-4-methoxymethyl-1-~N-[3-(4-(2-pyridyl)piperidin-1-yl) propyl]~carboxamido-2-oxo-1,2,3,6-tetrahydropyrimidine as a white foamy solid (0.41 g, 83~).

i) 6-(3,4-Difluorophenyl)-4-methoxymethyl-1-{N-[3-(4-(2-pyridyl)piperidin-1-yl)propyl~}carboxamido-1,2,3,6-tetrahydro-2-oxopyrimidine-5-carboxylic acid.

To a stirred solution of (+)-S-(2-cyanoethoxycarbonyl)-6-~3,4-difluorophenyl)-4-methoxymethyl-1-{N-[3-(4-(2-pyridyl)piperidin-1-yl)propyl]~car~oxamido-2-oxo-~ 1~2~3~6-tetrahydropyrimidine (0.34 g, 0.57 mmol) in acetone ~5 mL) at 0 ~C, sodium hydroxide solution (1 N, CA 022~3862 1998-11-09 W O 97/42956 PCT~US97/08335 1.71 mL) was added drop wise and the stirring was continued until the disappearance of the starting material (1 hour). Most of the acetone from the mixture was evaporated under reduced pressure while keeping the temperature at 0 ~C and the residue was adjusted to pH 7.0 by the addition of lN hydrochloric acid. The white precipitate of 6-(3,4-difluorophenyl)-4-methoxymethyl-1-~N-[3-(4- (2-pyridyl)piperidin-l-yl)propyl])carboxamido-lo 1~2~3~6-tetrahydro-2-oxopyrimidine-5-carboxylic acid formed was filtered and dried under vacuum (0.30 g, g6~) .

j) (I)-5-Carboxamido-6-(3,4-difluorophenyl)-4-methoxymethyl-1-{N-~3-(4-~2-pyridyl)piperidin-1-yl) propyl]}carbox~;do-2-oxo-1,2,3,6-tetr~,~ ~y imidine.

A mixture of (+)-6-(3,4-difluorophenyl)-4-methoxymethyl-l-~N-[3-(4-(2-pyridyl)piperidin-1-yl) propyl]}carboxamido-1,2,3,6-tetrahydro-2-oxopyrimidine-5-carboxylic acid (0.30 g, 0.55 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.212 g, 1.1 mmol, 2 eq.), and 4-(N,N-dimethylamino)pyridine (0.134 g, 1.1 mmol, 2 eq) in anhydrous dichloromethane (20 mL) was stirred at room temperature for 2 h. To this, 40~ aqueous ammonia (0.64 g, 10 eq) was added and the stirring was continued for 12 h. The mixture was diluted with 20 mL of dichloromethane and washed with saturated aqueous ammonium chloride solution (3 X 200 mL). Solvent was evaporated from the dried ~sodium sulfate) dichloromethane solution and the residue was purified by column chromatography on silica gel using chloroform-methanol-2M ammonia in methanol (100/2/1) as the eluent, to obtain the desired product as a white powder (0.232 g, 78~)i The HCl salt of this compound was prepared by treatment with 1 N HCl in ether. m.p.

W097/42956 PCT~S97/08335 95-97 ~C; [~] D = +139 (c = 2.1 g, in lOo mL of chloroform). ~nal. Calcd. for C27H34N6O4F2C12.2.2 H2O: C, 49.50; H, 5.91; N, 12.83. Found: C, 49.50; H, 5.89; N, 12.43.

Example 24 (+)-5-Methoxycarbonyl-6-(3,4-difluorophenyl)-4-methoxymethyl-1-{N-[3-(4-(2-pyridyl)piperidin-1-yl) propyl]}carboxamido-2-oxo-1,2,3,6-tetrahydropyrimidine.

A mixture of (+)-6-~3,4-difluorophenyl)-4-methoxymethyl~ N-[3-(4-(2-pyridyl)piperidin-1-yl) propyl]~carboxamido-1,2,3,6-tetrahydro-2-oxopyrimidine-5-carboxylic acid (0.30 g, 0.55 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.212 g, 1.1 mmol, 2 eq.), and 4-(N,N-dimethylamino) pyridine (0.134 g, 1.1 mmol, 2 eq) in methanol (20 mL) was stirred at room temperature for 20 h. Solvent was evaporated and the residue was dissolved in 20 mL of dichloromethane and washed with saturated a~ueous ammonium chloride solution (3 X 200 mL). Solvent was evaporated from the dried (sodium sulfate) dichloromethane solution and the residue was purified by column chromatography on silica gel using chloroform-methanol-2M ammonia in methanol (100/2/1) as the eluent, to obtain the desired product as a white powder (278 mg, 91%); The HCl salt of this compound was prepared by treatment with 1 N HCl in ether. m.p. 180-184 ~C; [~]D = +122 (c = 1.25 g, in 100 mL of methanol).
Anal. Calcd. for C28H3sNsosF2cl2~l.o H2O: C, 51.86; H, 5.75; N, 10.80. Found: C, 52.14; H, 5.72; N, 10.53.

Example 25 (+)-1,2,3,6-Tetrahydro-l-{N-t3-(4-(2-pyridyl)-piperidine-1-yl)-(2-oxo)propyll}carboxamido-5-methoxy car~onyl-2-oxo-6-(3,4-difluorophenyl)-4-methoxymethyl pyrimidine dihydrochloride CA 022~3862 1998-11-09 W O 97/42956 PCT~US97108335 a) Methyl 2-[(3,4-difluorophenyl) methylene~-3-oxo-4-methoxy~utyrate.
A solution of methyl 4-methoxyacetoacetate (84 . 32 g, 0.577 mol), 3,4-difluorobenzaldehyde (82 g, 0.577 mmol), and piperidinium acetate (5 . 86 g, 0 . 068 mol) in benzene (1.5 L) were added molecular sieves (400 g) and the mixture was stirred at room temperature for 48 h.
The molecular sieves were removed by filtration and the solvent was evaporated ~rom the f iltrate under reduced pressure. The residue was purified by column chromatography on silica gel using chloroform/ethyl acetate ( 100: 3 ) to get the product as an oil ( 67 g, 47g~) -b) 5-Methoxycarbonyl-1,6-dihydro-2-methoxy-4-methoxymethyl-6-(3,4-difluorophenyl)pyrimidine.
A suspension of methyl 2-[(3, 4-difluorophenyl) methylene] -3-oxo-4-methoxybutyrate (7 . 50 g, 27 . 75 mmol), O-methylisourea hemisulfate (7.17 g, 41.63 mmol, 1.5 eq.), sodium bicarbonate (6.99 g, 83.25 mmol, 3 eq. ) in ethanol (400 mL) was stirred at 50-55 ~C for 6 h . The solvent was evaporated f rom the combined f iltrates and the residue was purif ied by column chromatography (SiO2, EtOAc/hexane, 10g6-30~) to get 5-methoxycarbonyl-1, 6-dihydro-2-methoxy-4-methoxymethyl-6- (3,4-difluorophenyl)pyrimidine as a pale yellow oil (4 . 3 g, 47~? . The lH-NMR analysis showed it to be a mixture of amine/imine tautomers and was used as is in the next step.
c) 5-Methoxycarbonyl-4-methoxymethyl-1,6-dihydro-2-methoxy-6-(3,4-difluorophenyl)-1-l(4-nitrophenyloxy) carbonyl]pyrimidine.
To a well stirred solution of 5-methoxycarbonyl-1, 6-dihydro-2-methoxy-4-methoxymethyl-6 - (3, 4-difluorophenyl)pyrimidine (4.3 g, 13.18 mmol) and 4-(N,N-dimethylamino)pyridine (2.09 g, 17.13 mmol) in W 097/42956 PCTnUS97108335 -105-CH2Cl2 (100 mL) was added a powder of 4-nitrophenyl chloroformate (3.45 g, 17.13 mmol) at 0 ~C. The reaction mixture was stirred for 12 h at room temperature and the solid formed was removed by filtration. Solvent was evaporated from the filtrate and the residue was purified by column chromatography - (SiO2, dichloromethane/heY~ne, 20~-50%) to give the product as a viscous oil (3.85 g, 59~).

d) 5-Methoxycarbonyl-4-methoxymethyl-1,6-dihydro-1-{N-[2-phenyl)ethyl]}carboxamido-2-methoxy-6-(3,4-difluorophenyl)pyrimidine.
To a stirred solution of 5-methoxycarbonyl-4-methoxymethyl-1,6-dihydro-2-methoxy-6-(3,4-difluorophenyl)-1-[(4-nitrophenyloxy)carbonyl]
pyrimidine (3.82 g, 7.77 mmol) in THF (140 mL) was added R-(+)-~-methylbenzylamine (1.13 g, 9.33 mmol, 1.2 eq.) at room temperature and the stirring was continued for 12 h. Solvent was evaporated and the residue was purified by column chromatography (SiO2, 10-20~ ~tOAc in hexane). The first major product to elute was (+)-5-methoxycarbonyl-4-methoxmethyl-1,6-dihydro-1-{N-[2-phenyl)ethyl])carboxamido-2-methoxy-6-(3,4-difluorophenyl)pyrimidine (1.74 g, 44-5%)-~]D = +205.5 (c = 5.1 g in 100 mL CHCl3); The second major product to elute was the other diastereomer and no effort was made to isolate it.

e) (+)-5-Methoxycarbonyl-1,6-dihydro-2-methoxy-4-methoxymethyl-6-(3,4-difluorophenyl)pyrimidine.
To a stirred solution of ~+)-5-methoxycarbonyl-4-methoxymethyl-1,6-dihydro~ N-I2-phenyl)ethyl]) carboxamido-2-methoxy-6-(3,4-difluorophenyl)pyrimidine (1.74 g, 3.67 mmol) in toluene (40 mL) was added 1,8-diazabicyclo[5,4,0]-undec-7-ene (0.250 g, 1.64 mmol) and the mixture was stirred at 70-80 ~C for 1.5 h. The solvent was e~aporated and the residue was purified by CA 022~3862 1998-11-09 WO 97/42956 PCr/US97/08335 flash column chromatography on silica gel with 9 :1 CHC13/EtOAc as eluent to give ( + ) - 5 -methoxycarbonyl - i, 6 -dihydro-2 -methoxy-4 -methoxymethyl - 6 - ( 3, 4 -difluorophenyl)pyrimidine as a viscous oil (1.11 g, 92 . 5~) .

f) (+)-5-Methoxyc~rhrnyl-4-methoxymethyl-1,6-dihydro-2-methoxy-6-(3,4-difluorophenyl)-1-~(4-nitrophenyloxy) carbonyl]pyrimidine.
To a well stirred solution of (+)-5-methoxycarbonyl-1, 6 -dihydro- 2 -methoxy- 4 -methoxymethyl - 6 - ( 3, 4 -dif luorophenyl ) pyrimidine ( 1 . ll g, 3 . 4 mmol ) and 4 -(N,N-dimethylamino)pyridine (0.54 g, 4.42 mmol) in CH2Cl2 (200 mL) was added a powder of 4-nitrophenyl chloroformate (0.891 g, 4.42 mmol) at room temperature.
The solvent was evaporated and the residue was purified by column chromatography on silica gel using CHCl3/EtOAc ( 2 0 ~ - 5 0 ~6 ) as the e luent to give ( + ) - 5 - methoxycarbonyl -4-methoxymethyl-1, 6-dihydro-2-methoxy-6- (3, 4-difluorophenyl) -1- [ (4-nitrophenyloxy) carbonyl]
pyrimidine (1.30 g, 78g6) as a viscous oil. [~]D = +262.2 (c = 2 . 3 g in 100 mL CHCl3) .

g) (+)-1,2,3,6-Tetrahydro-l-{N-13-(4-~2-pyridyl)-piperidine-1-yl)-(2-hydroxy)propyl]}carboxamido-5-met hoxycarbonyl-2-oxo-6-(3,4-difluorophenyl)-4-methoxyme thylpyrimidine.
A solution of (+) -6- (3, 4-difluorophenyl) -1, 6-dihydro-2-methoxy- 5 -methoxycarbonyl -4 -methoxymethyl - l - ( 4 -nitrophenoxy)carbonylpyrimidine (0.450 g, 0.91 mmol), 3 - [4 - ( 2 -pyridyl ) piperidin- l -yl] - 2 -hydroxypropylamine (0.280 g, 1.19 mmol) in tetrahydrofuran (100 mL) was stirred at room temperature for 24 hours. The reaction mixture was stirred for another 1 hour after addition 3 5 of 2 ml of 6N HCl . Solvent was e~aporated at reduced pressure and the residue was basif ied by treatment with 10~ aqueous KOH solution, extracted with dichloromethane (3 x 10 mL). The combined extracts were dried over potassium carbonate, and solvent evaporated. The crude product was purified by flash chromatography (dichloromethane:MeOH:2M am~nonia in MeOH,90:8:4) to give 0.514 ~ (989~) as a syrup.

h) (+)-1,2,3,6-Tetrahydro-1-{N- ~3- (4-(2-pyridyl) -piperidine-l-yl)- (2-oxo)propyl~ }carboxamido-5-methoxy carbonyl-2-oxo-6- ~3,4-d~fluorophenyl) -4-methoxymethyl pyrimidine dihydrochloride To a stirred solution of DMSO (0.174 g, 2.23 mmol) in dichloromethane (5 mL) at -78 ~C, oxalyl chloride (0.135 g, 1.07 mmol) in dichloromethane (5 mL) was added and the mixture was stirred for 3 min. To this, a solution of (l)-1,2,3,6-tetrahydro-1-{N- [3-(4-(2-pyridyl)-piperidine-1-yl)- (2-hydroxy)propyl])carboxamido-5-met hoxycarbonyl-2-oxo-6- (3,4-difluorophenyl)-4-methoxyme thylpyrimidine (0.51 g, 0.889 mmol) in dichloromethane (5 mL) was added and the stirring was continued for 15 min. It was warmed to room temperature and added 5 mL
of water. The pH of the mixture was adjusted to 10-11 by adding lN NaOH and the dichloromethane layer was separated. The aqueous layer was extracted with more dichloromethane (3 X 10 mL). The combined dichloromethane extracts were dried (magnesium sulfate), solvents evaporated, and the residue was purif ied by f lash chromatography (dichloromethane:MeOH:2M ammonia in MeOH,90:8:4) to give 0.32 g (63%) of the product as a syrup. [~]~, = +122 (c = 0.55 g in 100 mL CHCl3); Anal. Calcd. for C29H33NsO6F2Cl2.2.5 H2O: C, 48.77; H, 5.55; N, 10.16.
Found: C, 48.71i H, 5.72; N, 9.87.

Example 26 and Example 27 Syn and anti i~omers of (1)-1,2,3,6-tetrahydro-1-{N-[3-(4-(2-pyridyl)-piperidine-1-yl)-(2-hydroYim;no)propyl ] }carboxamido-5-methoxycarbonyl-2-oxo-6-(3,4-difluoro W O 97/42956 PCTnUS97/08335 phenyl)-4-methoxymethylpyrimidine dihydrochloride A solution of ~+)-1,2,3,6-tetrahydro~ N-[3-(4-(2-pyridyl)-piperidin-1-yl)-(2-oxo)propyl]}carboxa mido-5-methoxycarbonyl-2-oxo-6-(3,4-difluorophenyl)-4 -methoxymethylpyrimidine (0.14 g, 0.22 mmol), hydroxylamine hydrochloride (19.6 mg, 0.28 mmol), and sodium acetate (74.8 mg, 0.55 mmol) in methanol (5 mL) was stirred at room temperature for 24 h. Solvent was evaporated at reduced pressure, the residue was mixed with dichloromethane (30 mL) and washed with water.
The dichloromethane solution was dried (sodium sulfate) and the solvent evaporated. The residue was purified by column chromatography on silica gel tchloroform:MeOH:2M ammonia in MeOH,90:8:4). The first product to elute was Example 26, syn isomer with respect to oxime hydroxyl and piperidine ~30 mg); [O~] D
+94.1 (c = 0.528 g in 100 mL CHCl3); The HCl salt was prepared by treatment with lN HCl in et}ler; m.p. 90-92 ~C; Anal. Calcd. for C28H34N6O6F2C12.1.5 H2OØ6 CH2Cl2: C, 47.65; H, 5.35; N, 11.26. Found: C, 47.67; H; 5.56; N, 11.36.

The second product to elute was example 33, anti isomer with respect to oxime hydroxyl and piperidine (70 mg);
[CY~D = +104 (c = 0.3 g in 100 mL CHCl3)i The HCl salt was prepared by treatment with lN HCl in ether; m.p.
103-105 ~C; Anal. Calcd. for C28H34N6O6F2Cl2.2.2 H2OØ22 CH2Cl2: C, 47.74; H, 5.51; N, 11.84. Found: C, 48.01;
H, 5.72; N, 11.57.
Example~ 28 (+) -1, 2,3, 6-Tetrahydro-l-{N- [3- (4- (2-pyridyl) -piperidine-1-yl)-(2-methoximino)propyl]}carboxamido-5 -methoxycarbonyl-2-oxo-6-(3,4-difluorophenyl)-4-metho xymethylpyrimidine dihydrochloride A solution of (+)-1,2,3,6-tetrahydro-1-{N-[3-(4-(2-pyridyl)-piperidine-l-yl)-(2-oxo)propyll}carbox W O 97/42956 PCT~US97/08335 amido-5-methoxycarbonyl-2-oxo-6-(3,4-difluorophenyl~-4-methoxymethylpyrimidine (30 mg, 0.047 mmol), O-methoxylamine hydrochloride (7.78 mg, 0.093 mmol), and sodium acetate (32 mg, 0.24 mmol) in methanol (5 mL) was stirred at room temperature for 24 h. Solvent was evaporated at reduced pressure, the residue was mixed with dichloromethane (30 mL) and washed with water.
The dichloromethane solution was dried (sodium sulfate) and the solvent e-~aporated. The residue was purified by column chromatography on silica gel (chloroform:MeOH:2M ammonia in MeOH,90:8:4). Only one isomeric product was detected by this purification (20 mg, 71~); [~x] D = +98 (c = 0.4 g in 100 mL CHCl3); The HCl salt was prepared by treatment with lN HCl in ether; m.p. 109-112 ~C; Anal. Calcd. for C29H36N6O6F2C12.2.3H2OØ46 CH2C12: C, 46.93; ~, 5.55; N, 11.15. Found: C, 47.08; H, 5.66; N, 10.88.

Example 29 ( + ) - 1 , 2 , 3 , 6 - T e t r a h y d r o - 1 - { N - [ 3 (4- (2-car~oxamidophenyl)-piperazin-1-yl)-propyl] }carb oxamido-5-acetyl-2-oxo-6-(3,4,5-trifluorophenyl)-4-me thylpyrimidine dihydrochloride a) 3-{(3,4,5-Trifluorophenyl)methylene}-2,4-pentan~lione.
A mixture of 3,4,5-trifluorobenzaldehyde (4.2 g, 26.2 mmol), 2,4-pentanedione (2.62 g, 26.2 mmol), piperidine (0.430 g, 5 mmol)in benzene (150 mL) was stirred and refluxed with a Dean-Stark trap for 8 hours. Benzene was evaporated, the yellow oily residue, 2-~(3,4,5-trifluorophenyl)methylene}-2,4-pentanedione, was used in the next step without any further purification.

b) 6-(3,4,5-Trifluorophenyl)-1,6-dihydro-2-methoxy-5-acetyl-4-methylpyrimldine.
A mixture of 2-{(3,4,5-trifluorophenyl)methylene}-2,4-, W097/42g56 PCT~S97tO8335 pentanedione ~26.2 mmol), O-methylisourea hydrogen sulfate (3.22 g, 39.3 mmol), and NaHCO3 (6.6 g, 78.6 mmol) in EtOH (400 mL) was stirred and heated at 95-100 ~C for 6 hours. The mixture was filtered, the solid residue was washed with ethanol ~100 mL). Solvent was evaporated from the combined filtrate and the crude product was purified by flash column chromatography on silica gel using 10% through 25~ EtOAc in hexane as the gradient eluent, to leave the product as an oil (2.80 g, 36~).

c) 6-~3,4,5-Trif~uorophenyl)-1,6-dihydro-2-methoxy-5-acetyl-4-methyl-1-[(4-nitrophenyloxy)carbonyl]
pyrimidine To a solution of 6-(3,4,5-trifluorophenyl)-1l6-dihydro-2-methoxy-5-acetyl-4-methylpyrimidine (2.8 g, 9.38 mmol) and pyridine (10 mL) in CH2Cl2 (200 mL) at 0-5 ~C, 4-nitrophenyl chloroformate (1.886 g, 9.38 mmol) was added and the mixture was allowed to warm to room temperature. After 12 hours solvent was evaporated and the residue was purified by flash column chromatography (SiO2, dichloromethane/EtOAc, 10~-15~)to obtain the product as a white powder (4.0 g, 92~).

d) 6-(3,4,5-Trifluorophenyl)-1,2,3,6-tetrahydro-2-oxo-5-acetyl-4-methyl-1-[(4-nitrophenyloxy)carbonyl]pyrim idine.
To a well-stirred solution of 6-(3,4,5-trifluorophenyl)-1,6-dihydro-2-methoxy-5-acetyl-4-methyl-1-~(4-nitrophenyloxy)carbonyl]pyrim idine (4.0 g, 8.63 mmol) in THF (100 mL) at 0-5 ~C, 6N
aqueous HCl (4 m~) was added and the mixture was allowed to warm to room temperature. After 2 h, sol~ent was evaporated and the product dried under vacuum. The product was obtained as a pure single component and no need for further purification (3.88 g, 100~).

W097/429S6 PCT~S97/08335 e) (I) - 1, 2, 3, 6- T e tr a h y d r o- 1 - { N - ~3 -(4-(2-carboxamidophenyl)-piperazin-1-yl)-propyl]}carb oxamido-5-acetyl-2-oxo-6-(3,4,5-trifluorophenyl)-4-me thylpyrimidine dihydrochloride A mixture of 6-(3,4,~-difluorophenyl)-1,2,3,6-tetra hydro-2-oxo-5-acetyl-4-methyl-1-[~4-nitrophenyloxy) carbonyl]pyrimidine (44.9 mg, 0.1 mmol) and 3-[4-(2-carboxamidophenyl)-piperazin-1-yl]-propylamine ~26.2 mg, 0.1 mmol) in THF (10 mL) was stirred at room temperature for 10 h and the solvent evaporated. It was redissolved in dichloromethane ~10 mL), washed with ice-cold 0.5 N NaOH (2 X 5 mL), dried and solvent evaporated. The residue was purified by preparative thin layer chromatography on silica gel using chloroform-methanol-2M ammonia in methanol (100/2/1) as the eluent to afford the product as a white powder (60 mg, 93~); The HCl salt was prepared by treatment with lN HCl in ether to give the product as a dihydrochloride salt. Anal. Calcd. for C2~H33N6O4Cl2F30.4 H2O: C, 51.52; H, 5.22; N, 12.88. Found: C, 51.70; H, 5.25; N, 12.53.

Example 30 1,2,3,6-Tetrahydro-l-{N-[3-(4-(4-~luorobenzoyl) piperidin-1-yl)ethyl]}carhoxa~;do-5-methoxycarbonyl-4 -methyl-6-(3,4-difluorophenyl)-2-oxopyrimidine hydrochloride a) 6-(3,4-Difluorophenyl)-1,2,3,6-tetrahydro-2-oxo-5-methoxycarbonyl-4-methyl-1-(4-nitrop~n~Yy) carbonylpyrimidine.

A well stirred solution of 6-(3l4-difluorophenyl)-l~6-dihydro-2-methoxy-5-methoxycarbonyl-4-methyl-1-(4-nitrophenoxy)carbonylpyrimidine (10 g) in THF (200 mL) at room temperature, aqueous 6N hydrochloric acid (10 mL) was added and the stirring was continued for 3 h.

CA 022~3862 1998-11-09 W O 97/42956 PCT~US97/08335 Solvent was evaporated and the residue was dried under vacuum to obtain the product as a white powder (9.7 g, 100~); m.p. 185-186 ~C.

b) 6-(3,4-Difluorophenyl)-1,2,3,6-tet~ahydro-2-oxo-5-methoxycarbonyl-4-methyl-1-(2-bromoethylamino ~hQ~yl)pyr~idine.

A mixture of6-(3,4-difluorophenyl)-1,2,3,6-tetrahydro-2-oxo-5-methoxycarbonyl-4-methyl-1-(4-nitrophenoxy) carbonylpyrimidine (0.5 g, 1.118 mmol), 2-bromoethylamine hydrobromide ~0.458 g, 2.237 mmol), and potassium carbonate ~2.0 g) in THF/water (50 mL/5 mL) were stirred at room temperature for lh. Then most of the solvent was evaporated at reduced pressure. The residue was partitioned between dichloromethane and water (100 mL and 100 mL). The dichloromethane layer was separated, washed with ice-cold 0.5 N NaOH (2 X 50 mL) and dried (sodium sulfate). Evaporation of the solvent gave the product as a single product (0.48 g, 100~) as a white powder; m.p. 159-160 ~C.
c ) 1 , 2 , 3 , 6 - T e t r a h y d r o - 1 - { N - [ 2 -(4-(4-fluorobenzoyl)piperidin-1-yl)ethyl~}carboxamido -5-methoxycarbonyl-4-methyl-6-(3,4-difluorophenyl)-2-~u~ imidine hydrochloride A mixture of6-(3,4-difluorophenyl)-1,2,3,6-tetrahydro-2-oxo-5-methoxycarbonyl-4-methyl-1-~2-bromoethylamino carbonyl)pyrimidine (43 mg, 0.1 mmol), 4-(4-fluorobenzoyl)piperidine p-toluene sulfonate (57 mg, 0.15 mmol), potassium carbonate (300 mg), and potassium iodide (30 mg) in THF(10 mL) was stirred at room temperature for 20 h. The solid material was removed by filtration, the solvent from the filtrate was evaporated, and the residue was purified by preparative thin layer chromatography on silica gel using chloroform-methanol-2M ~mmQni a in methanol (100/2/1) as .

W097/42g~6 PCT~S97/08335 the eluent to afford the product as a viscous oil which was converted to the HC1 salt by treatment with lN HCl in ether; m.p. 159-160 ~C; Anal. Calcd. for C29H29N4O5F3.1HClØ8Et2O: C, 57.27; H, 5.85; N, 8.56.
Found: C, 57.31; H; 5.75; N, 8.79.
Example 31 1,2,3,6-Tetrahydro-l-{N-~3-(4-(4-fluorophenyl)-4-hydroxypiperidin-l-yl)propyl]}carboxamido-5-methoxyca rbonyl-4-methyl-6-(3,4-difluorophenyl)-2-oxopyrimidine hydrochloride a) 6-(3,4-D~fluorophenyl)-1,2,3,6-tetrahydro-2-oxo-5-methoxyca~hQ~yl-4-methyl-1-t3-bromopropylamino c~r~nyl) pyri~ 9-A mixture of 6-(3,4-difluorophenyl)-1,2,3,6-tetrahydro-2-oxo-5-methoxycarbonyl-4-methyl-1-(4-nitrophenoxy) carbony~pyrimidine (1.0 g, 2.237 mmol), 3-bromopropylamine hydrobromide (0.979 g, 4.474 mmol), and potassium carbonate (4.0 g) in THF/water (100 mL/10 mL) were stirred at room temperature for lh. Then most of the solvent was evaporated at reduced pressure. The residue was partitioned between dichloromethane and water (100 mL and 100 mL). The dichloromethane layer was separated, washed with ice-cold 0.5 N NaOH (2 X 50 mL) and dried (sodium sulfate). Evaporation of the solvent ga~e the product as a single product (0.98 g, 100~) as a white powder and confirmed by lH-NMR.
b) 1,2,3,6-Tetrahydro-1-{N-t3-(4-~4-fluorophenyl)-4-hydroxypiperidin-1-yl)propyl~}carboxamido-5-methoxyca rbonyl-4-methyl-6-(3,4-difluorophenyl)-2-ox~ imidine hydrochloride A mixture of 6-(3,4-difluorophenyl)-1,2,3,6-tetrahydro-2-oxo-5-methoxycarbonyl-4-methyl-1-(3-bromopropylamino 3~ carbonyl)pyrimidine (44.6 mg, 0.1 mmol), 4-(4-fluorophenyl)-4-hydroxypiperidine (28.7 mg, 0.15 mmol), potassium carbonate (300 mg), and potassium iodide (30 mg) in THF(10 mL) was stirred at room temperature for CA 022~3862 l998-ll-09 W O 97/42956 PCTrUS97tO8335 -114-20 h. The solid material were removed ~y filtration, the solvent from the filtrate was evaporated, and the residue was purified by preparative thin layer chromatography on silica gel using chloroform-methanol-2M ammonia in methanol (100/2/1) as the eluent to afford the product as a viscous oil which was converted to the HCl salt by treatment with lN HCl in ether; m.p.
160-164 ~C; Anal. Calcd. for C29H29N4O5F3.lHClØ8Et2O: C, 57.27; H, 5.85; N, 8.56. Found: C, 57.31; H; 5.75; N, 8.79.

Example 32 a) (-) -S- (Elenzylo~cycarbonyl) -4-ethyl-1, 6-dihydro-2-methoxy- 6 - ( 3, 4 - di f luorophenyl ) -1 -me thoxy -carbonyll pyrimidine .
To a well stirred solution of (-)-5-(benzyloxycarbonyl)-1,6-dihydro-2-methoxy-4-ethyl-6-(3,4-diflurophenyl)pyrimidine (0.6 g, 1.5 mmol) and 4-(N,N-dimethylamino)pyridine (0.32 g, 2.66 mmol) in CH2Cl2 (6 mL) was added methyl chloroformate (0.2 mL, 2.66 mmol) at room temperature. The solvent was removed in vacuo and the residue was purified by column chromatography on silica gel with 3:1 Petroleum ether/EtOAC as the eluting system to obtain 0.45 g (78%
yield) of (-)-5-(benzyloxycarbonyl)-4-ethyl-1,6-dihydro-2-methoxy-6-(3,4-difluorophenyl)-1-[methoxy-carbonyl]pyrimidine as a colorless oil.

b) ( - ) -1, 2, 3, 6-Tetrahydro-4-ethyl-2 -oxo-6 - (3, 4-difluorophenyl) -1- ~methoxycarbonyl] pyrimidine - 5 -carboxylic acid.
To a solution of (-)-5-(benzyloxycarbonyl)-4-ethyl-1, 6-dihydro-2-methoxy-6-(3,4 -difluorophenyl) -1-[methoxycarbonyl]pyrimidine (0.45 g, 1.18 mmol) in 20 mL of MeOH was added 0.05 g of 10% Pd on carbon and the resulting suspension was hydrogenated under 100 psi for 12 h. The catalyst was then filtered through a pad of CA 022~3862 1998-11-09 W097/42956 PCT~S97/08335 celite and was washed thoroughly with MeOH. A~l the MeOH washings were collected and the solvent was removed in vacuo to obtain 0.42 g (99% yield) of (-)-1~2~3~6-tetrahydro-4-ethyl-2-oxo-6-(3~4-difluorophenyl)-1-[methoxycarbonyl]pyrimidine-5-carboxylic acid as a white solid which was used in the - next reaction without further purification.

c) (-)1,2,3,6-Tetrahydro-5-{N-~3-(4-methoxyc~hnnyl)-4-phenyl-piperidin-1-yl]propyl}-carboxamido-1-methoxycarbonyl-4-ethyl-6-(3,4-difl~orophenyl)-2-oxo-pyrimidine.
To a solution of (-)-1,2,3,6-tetrahydro-4-ethyl-2-oxo-6-(3,4-difluorophenyl)-1-[methoxycarbonyl]pyrimidine-5-carboxylic acid (1.18 mmol, 0.4 g) and 3-[4-methoxycarbonyl-4-phenylpiperidin-1-yl)propylamine (1.23 mmol, 0.34 g) in 20 mL CH2C12 was added 4-(N,N-dimethylamino)-pyridine (1.16 mmol, 0.15 g), followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (1.84 mmol, 0.54 g) and the resulting solution was stirred at room temperature under argon for 2 days. The solution was then transferred into a separatory funnel, extracted with CH2C12, washed with sat. NH4Cl solution (2 X 20 mL) and then with brine (20 mL). The organic layer was separated and dried over Na2SO4, filtered and the solvent was evaporated in vacuo to obtain an off-white solid. It was purified by column chromatography on silica gel with 10~ MeOH in EtOAc as the solvent system to obtain (-)1,2,3,6-tetrahydro-5-{N-[3-(4-methoxycarbonyl)-4-phenyl-piperidin-l-yl]propyl}-carboxamido-l-methoxycarbonyl-4-ethyl-6-(3,4-difluorophenyl)-2-oxo-pyrimidine as a white solid (0.55 g, 79~ yield). M.P. 53-55~C; I~ID = -48.5 (c = 0.43, CHCl3). It was characterized as HC1 salt. Anal. Calcd.
For C31H3~N4O6F2ClØ4 CHCl3: C, 55.23; H, 5.52; N, 8.20.
Found: C, 55.29; H, 5.35; N, 7.99.

._ ~ . , CA 022~3862 1998-11-09 WO 97/42956 PCTrUS97/08335 Example 33 (+)-1-3-{[4-(3,4-Difluorophenyl)-2,5-dioxo-1,2,5,7-tetrahydro-4H-furo[3,4-d]-pyr~midine-3-c~h~yl]smino}-propyl-4-phenyl-piperidine-5-carboxylic acid methyl ester.
a) (I)-6-(3,4-Difluorophenyl)-1,6-dihydro-2-oxo-5-methoxy-carbonyl-4-bromomethyl-1-[(4-nitrophenyl-oxy)carbonyl]pyrimidine.
To a well stirred solution of (+) -6-(3, 4-difluorophenyl)-1,6-dihydro-2-methoxy-5-methoxycarbonyl-4-methyl-1-[~4-nitrophenyloxy) carbonyl]pyrimidine tl.5 mmol, 0.66 g~ in 5 mL of chloroform was added a solution of bromine (1.5 mmol, 0.09 mL) in 3 mL of chloroform at 0~C and the solution was allowed to attain room temperature over 1.5 h. The solvent was removed in vacuo and the residue was again dissolved in CHCl3 ~20 mL) and washed with brine. The organic layer was separated, dried over Na2S04, filtered and the solvent was removed in vacuo to get 0.81 g of (+) -6- (3, 4-difluorophenyl)-1, 2,3, 6-tetrahydro-2-oxo-5-methoxycarbonyl-4-bromomethyl-1-[(4-nitrophenyloxy) carbonyl]pyrimidine as a yellow foam. It was used in the next step without any purification.

b) (+) -4-(3,4-Difluorophenyl)-2,5-dioxo-1,2,4,5,6,7-hexahydro-cyclopentapyrimidine-3-carboxylic acid-4-nitrophenyl ester.
(+)-6-(3,4-Difluorophenyl)-1,6-dihydro-2-oxo-5-methoxy-carbonyl-4-bromomethyl-1-[(4-nitrophenyloxy) carbonyl]pyrimidine (1.5 mmol, 0.81 g) was heated in oil bath for 3 h (bath temperature 130~C). The brown residue thus obtained was washed with CHCl3 and (+)-4-(3, 4-difluoro-phenyl)-2,5-dioxo-1,2,4,5,6,7-hexahydro-cyclopenta pyrimidine-3-carboxylic acid-4-nitrophenyl ester was obtained as a pale brown solid which was used in the next step without further purification (crude wt. O.S1 g).

W ~ 97/4t956 PCT~US97/08335 c)(~ 3-{[4-~3,4-Difluorophenyl)-2,5-dioxo-1,2,5,7-tetrahydro-4H-furo[3,4-d]-pyrimidine-3-cArho~yl]a~ino}-propyl-4-phenyl-piperidine-5-carboxylic acid methyl ester.
A solution of (+)-4-(3,4-difluorophenyl)-2,5-dioxo-1~2~4~5~6l7-hexahydro-cyclopenta pyrimidine-3-carboxylic acid-4-nitrophenyl ester ((0.30 mmol, 0.13 g) and 3-[4-methoxycarbonyl-4-phenylpiperidin-l-yl)propylamine (0.32 mmol, 0.09 g) in 10 m~ of anhydrous THF was stirred overnight at room temperature. The solvent was remo~ed in vacuo and the residue was purified by column chromatography ~CH2Cl2 followed by 9:1 CH2Cl2/MeOH) to obtain (+)-1-3-~[4-(3,4-difluorophenyl)-2,5-dioxo-1,2,5,7-tetrahydro-4H-furo[3,4-d]-pyrimidine-3-carbonyl]amino~-propyl-4-phenyl-piperidine-5-carboxylic acid methyl ester as a pale yellow solid (0.12 g, 70%). [~]D = 128.1 (c =
0.525, CHCl3). It was characterized as HCl salt. M.P.
142-145~C; Anal. Calcd. For C29H31N4O6F2C1Ø23 CHCl3: C, 55.55; H, 4.98; N, 8.87. Found: C, 55.25; H, 5.03; N, 8.52.

Example 34 (-)-1-3-{t4-(3,4-Difluorophenyl)-2,5-dioxo-1,2,5,7-tetrahydro-4H-furo[3,4-d]-pyr~ ;ne-3-c~rhnnyl]amino}-propyl-4-phenyl-piperidine-5-carboxylic acid methyl ester. In a similar way, (-)-1-3-{[4-~3,4-difluorophenyl)-2,5-dioxo-1,2,5,7-tetrahydro-4H-furo[3,4-d]-pyrimidine-3-carbonyl]amino}-propyl-4-phenyl-piperidine-5-carboxylic acid methyl ester was prepared starting with (-)-6-(3,4-difluorophenyl)-1,6-dihydro-2-methoxy-5-methoxycarbonyl-4-methyl-1-[(4-nitrophenyloxy)carbonyl]pyrimidine (overall yield 27~).
M.P. 162-165 ~C [~]D = -121.3 (c = 0.52, CHCl3).
Example 35 ~ 1 , 2 , 3 , 6 - T e t r a h y d r o - 1 - { N - t4 - ( 2 -CA 022~3862 1998-11-09 W097/42956 PCT~S97/08335 c~ phenyl)piperaz~n-lyl]propyl}-carh~Y~;do-4-methyl-6-(3,4-difluorophenyl)-2-oxo-pyrimidine a)1-(2-Carboxami~p~nyl)piperazine Concentrated sulfuric acid (15 mL) was added to ~-(2-cyanophenyl)piperazine (1.5 g, 8.0 mmol) placed in a round bottom flask and the resulting slurry was stirred at room temperature for 48 h. The reaction mixture was poured on crushed ice very slowly and then basified (pH
9) with 50~ solution of NaOH. The aqueous layer was extracted several times with EtOAc, dried over K2CO3, filtered and the solvent was evaporated. 1-(2-carboxamidophenyl)piperazine was obtained as an off-white solid (1.2 g, 73~). It was used in the next step without further purification. Mass spectrum 206 (M +
l, 100~); Combustion analysis was obtained on its hydrochloride salt. Anal. Calcd. for Cl~Hl,N3OClØ3 CHC13: C, 43.23; H, 5.55; N, 13.30. Found: C, 43.58; H, 5.70; N, 12.79.
b) (+) - 1,2,3, 6 -Te trahy d ro-1 -{~- [4 - (2 -~hoy~midophenyl)piperazin-lyl]propyl}-carboxamido-4-methyl-6-(3,4-difluorophenyl)-2-oxo-pyrimidine.
To a solution of (+)-6-(3~4-difluorophenyl)-l~2~3~6 tetrahydro-2-oxo-5-methoxycarbonyl-4-methyl-1-(3-bromopropylaminocarbonyl)pyrimidine (0.435 g, 1.0 mmol) and 1-(2-carboxamidophenyl)piperazine (0.4 g, 2.0 mmol) in 25 mL of anhydrous acetone was added powdered K2CO~
(0.69 g, 5.0 mmol) and KI (0.17 g, 1.0 mmol) and the resulting suspension was heated to reflux for 10 h.
TLC indicated complete formation of the product (~f =
0.4, 3:0.5 EtOAc/MeOH). The solvent was evaporated and the residue was dissolved in water (10 mL). The aqueous layer was extracted in EtOAc (3 X 30 mL), the separated organic extract was dried over Na2SO4 and the ~ solvent was removed in vacuo. The residue thus obtained was purified by column chromatography on .. . . ..

W097/42956 PCT~S97/08335 silica gel with ÉtOAc/MeOH (5:1) as the eluting system.
(+)-l~2~3~6-tetrahydro-l-{N-[4-(2-carboxamido phenyl)piperazin-lyl]propyl}-carboxamido-4-methyl-6-(3,4-difluorophenyl)-2-oxo-pyrimidine was obtained as light yellow powder (0.48 g, 84~ yield). The product was analyzed as its dihydrochloride salt. M.P. 190-193 ~Ci [~]D = 98.8 (c = 0.31, MeOH); Anal calcd. for C2BH34N6F20sCl20.35 EtOAc: C, 52.16; H, 5.50; N, 12.46.
Found: C, 51.84; H, 5.67; N, 12.05.

Example 36 1,2,3,6-Tetrahydro-l{N-[4-(N-benzimidazolyl)-piperidin-l-yl]propyl}-carboxamido-4-methyl-6-(3,4-difluorophenyl)-2-oxo-pyrimidine.
15 To a solution of 6-(3,4-difluorophenyl)-1,2,3,6-tetrahydro-2-oxo-5-methoxycarbonyl-4-methyl-1-(3-bromopropylaminocarbonyl)pyrimidine (43 mg, 0.1 mmol) in 10 mL of anhydrous acetone was added 4-(N-benzimidazolyl)-piperidine (32.6 mg, 0.15 mmol) 20 followed by NaHCO3 (41 mg, 0.3 mmol) and KI (16 mg, 0.1 mmol). The resulting suspension was heated to reflux for 10 h and then cooled to room temperature. The solvent was removed in vacuo and the residue was purified by flash column chromatography on silica gel 25 with EtOAc followed by 10% MeOH in EtOAc to obtain 1~2~3l6-tetrahydro-l{N-[4-(N-benzimidazolyl)-piperidin-l-yl]propyl~-carboxamido-4-methyl-6-(3,4-difluorophenyl)-2-oxo-pyrimidine as an oil (15 mg, 26~
yield). The product thus obtained was then dissolved 30 in 2 mL of chloro~orm and 0.5 mL of HCl in Et20 ~1 M) was added at room temperature. The solvent was removed in vacuo and the HCl salt was characterized by combustion analysis. M.P. 168-172 ~C. Anal calcd. for C29H33N6F205Cl:0.75 CHCl3: C, 50.43; H, 4.90; N, 11.86.
35 Found: C, 50.84; H, 5.44; N, 11.46.
.

Example 37 (-)-6-(Benzoll, 2,5iQYa~;~701-5-yl) -1-carboxamido-4-et . . .

CA 022~3862 1998-11-09 W097/42956 PCT~S97/0833S

hyl-5-{N-t3-(4-methoxycarbonyl-4-phenylpiperidin-1-yl )propyl]}carboxamido-2- oxo-1,2,3,6-tetrahydro pyrimidine.
a) 5-Methylbenzfuroxan.
4-~ethyl-2-nitroaniline (100 g, 0.650 mol) was suspended in saturated alcoholic sodium hydroxide solution (1.50 l). To this suspension was added with cooling (5 ~C) commercial aqueous sodium hypochlorite until the red color disappeared. The fluffy yellow precipitate formed was filtered, washed with cold water and recrystallized from ethanol to get 5-methylbenzfuroxan (88.2 g, 89 ~ yield) as a pale solid.

b) 5-Methylbenzofurazan.
To 5-methylbenzfuroxan (88.2 g, 0.59 mol) in refluxing EtOH ~75 ml) was added dropwise P(OEt)3 ~150 ml). When addition was complete, refluxing was continued for l more hour. The solvent was removed by rotary evaporation and the residue shaken with water (200 ml) and allowed to stand overnight at (0-5~C). The brown solid so obtained was filtered , washed with water and chromatographed on silica gel to yield 5-methylbenzofurazan (70 g, 87 ~) as white needles.

c) 5-Dibromomethylbenzofurazan.
5-Methylbenzofurazan (70 g, 0.52 mol), NBS (325 g), and benzoyl peroxide (0.5 g) were refluxed with stirring in carbon tetrachloride (1.5 l) with exclusion of moisture for 2 days. The reaction mixture was washed with water (2 X 0.5 l), brine, dried (Na2SO4), and the solvent removed in vacuo. The residue was chromatographed on silica (hexane/ EtOAc = 150/1) to get 122 g (80~) of the title compound as a pink solid. 5-Triblo,,lul,~cthylbenzofurazan (17 g, 9~) was also isolated as a pink solid.

d) 5-Formylbenzofurazan.

W O 97/42956 PCTnUS97/08335 -12}-To a refluxing mixture of 5-dibromo methylbenzofurazan (122 g, 418 mmol) in EtOH ~1 1) was added AgNOl (163 g) in 2 l of water. When addition was complete, refluxing was continued for 2 hours. The mixture was cooled and the Ag~r formed was removed by filtration.
The resulting solution was concentrated to a small volume and extracted with toluene (10 X 300 ml). The extract was concentrated and the residue collected was chromatographed on silica gel (3 kg), ~EtOAc / hexane = 8/1000 ) to get the title compound (48.2 g, 78~) as a white solid.

e) 2-Cyanoethyl 3-benzo[1,2,5~oxadiazol-5-yl-2-propionyl-acrylate.
A mixture of 5-formylbenzofurazan (25.0 g, 168.s mmol), 2-cyanoethyl 3-oxo-pentanoate (31.4 g, 203 mm~l), and piperidinium acetate (1.22 g, 8.40 mmol) in benzene (1.5 l ) was refluxed with a Dean-Stark trap for 24 hours. Benzene was evaporated, and the residue was chromatographed on silica (200 g) (EtOAc / CHCl3 =
5 / 100) to get the title compound (32.36, 62.1 yield) as a orange oil.

f)2-Cyanoethyl 6-benzo~1,2,5]oxadiazol-5-yl-4-ethyl-2-methoxy-1,6-dih~lG~r~imidine-5-carboYylate.
A mixture of 2-cyano-ethyl 3-benzo[1,2,5]oxadiazol-5-yl-2-propionyl-acrylate (19 g, 63.48 mmol), o-methylisourea hydrogen sulfate (15.3 g, 88.9 mmol~, and 4-dimethylaminopyridine (21.3 g, 175 mmol) in THF
(200 ml) was stirred at 65 ~C for 6 hours. The solvent was evaporated and the residue was chromatographed on silica gel (-300 g) (hexane / EtOAc = 2 / 1) to get 8 g of the title compound as an orange oily solid. This reaction was repeated for many times and the yields were between 5% and 38%.

g)6-~enzo[1,2,5]oYA~;A~ol-5-yl-4-ethyl-2-methoxy-6~I-CA 02253862 l998-ll-09 pyrimidine-1,5-dicarboxylic acid 5-(2-cyan-ethyl) ester 1-(4-nitro-phenyl) ester.
To a solution of 2-cyanoethyl 6-benzo [1, 2, 5] oxadiazol-5-yl-4-ethyl-2-methoxy-1,6-dihydropyrimidine-5-carboxylate (3.62 g, 10.19 mmol) and 4-dimethylaminopyridine ~1.49 g, 12.2 mmol) in CH2Cl2 (75 ml), at 0 ~C, was added 4-nitrophenylchloroformate (2.46 g, 12.22 mmol). The reaction mixture was slowly warmed to r.t. at which it was stirred for 20 hours. Then, the solvent was evaporated and the residue was purified by flash column chromatography (~60 g of SiO2, CHC13 / EtOAc = 100 / 3) to get the title compound (1.96 g, 37 % yield) as a yellow solid.
h)2-Cyanoethyl ester 6-benzoll,2,5]oxadiazol-5-yl-4-ethyl-2-methoxy-1-(1-phenyl- ethyl carbamoyl)-1,6-dihydro-pyrimidine-5-carboxylate.
A solution of 6-benzo[1,2,5]oxadiazol-5-yl-4-ethyl-2-methoxy-6H-pyrimidine-1,5-dicarboxylic acid 5-(2-cyanoethyl) ester l-(4-nitrophenyl) ester ( 2.2 g, 4.22 mmol ) and (R)-(+)-~- methylbenzylamine (1.36 ml, 10.6 mmol) in CH2Cl2 (30 ml) was stirred at room temperature for 10 hours. The solvent was evaporated, and the residue was chromatographed on silica gel (100 g) (CHC13 / EtOAc = 30 / 1) to get the two diasteromers of the title compound (}.03 g in total, 49%).

i) (-)-2-Cyanoethyl 6-benzo~1,2,5]oxadiazol-5-yl-4-ethyl-2-methoxy-1,6-dihydropyrimidine-5-carboxylate.
A mixture of (-)-2-cyanoethyl ester 6-benzo~l,2,5]oxadiazol-5-yl-4-ethyl-2-methoxy-1-(1-phenyl- ethyl carbamoyl)-1,6-dihydro-pyrimidine-5-carboxylate (557 mg, 1.11 mmol) and 1,8-diazabicyclo[5,4,0]undec-7-ene (82.5 ml, 0.55 mmol) in benzene (15 ml) was stirred at 50 ~C for 1 hour. The solvent was evaporated, and the residue was W O 97/42956 PCT~US97/08335 chromatographed on silica gel (~30 g) (CHC13 / EtOAc /
2 N NH3 in MeOH = 40 / 10 / 1) to get the title compound (270 mg, 68.5 % yield) as a yellow solid. No rotation was observed for this compound.

j) (-)-6-Benzo[1,2,5~QYa~ia~ol-5-yl-4-ethyl-2-methoxy-6H-pyrimidine-1,5-dicarboxylic acid 5-~2-cyanoethyl) ester 1-(4-nitro-phenyl) ester.
To a solution of (-)-2-cyanoethyl 6-benzo[l,2,5]oxadiazol-5-yl-4-ethyl-2-methoxy-1,6-dihydropyrimidine-5-carboxylate (220 mg, 0.62 mmol) and 4-dimethylaminopyridine (99 mg, 0.81 mmol) in CH2Cl2 (12 ml), at 0 ~C, was added 4-nitrophenylchloroformate (164 mg, 0.81 mmol). The reaction mixture was slowly warmed to r.t. at which it was stirred for 24 hours.
The solvent was evaporated and the residue was purified by flash column chromatography (-30 g of SiO2, CHCl3 /
EtOAc = 38/1) to get the title compound (301 mg, 93 yield) as a yellow solid.
k)(-)-6-(Be~zo[1, 2,5]n~ 3;Azol-5-yl) -l-carho~ido-4-ethyl-5-{N-~3-(4-methoxycarbonyl-4-phenylpiperidin-1-yl)propyl~}
carboxamido-2- oxo-1,6-dihydropyrimidine.
To (-)-6-benzo[1,2,5]oxadiazol-5-yl-4-ethyl-2-methoxy-6H-pyrimidine-1,5-dicarboxylic acid 5-(2-cyanoethyl) ester 1-(4-nitrophenyl) ester (100 mg, 0.19 mmol) in dry THF (10 ml) ~o~ia (gas) was introduced with a balloon at room temperature. It was stirred at room temperature for 14 hours. TLC and l~ NMR of the reaction mixture showed that the reaction was complete.
NaOH (1 N, 3 ml) was added at room temperature. After it was stirred for 6 hours, HCl solution (6 N, 4 ml) was added. It was stirred at room temperature for 14 hours. The solvent was evaporated to get a white solid which was used directly in the next step.

CA 022~3862 1998-11-09 W097/42956 PCT~S97/08335 A mixture of the crude product from the above step, 4-dimethyl aminopyridine (61mg, 0.5 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (96 mg, 0.5 mmol) in CH2C12 (15 ml) was stirred at room temperature for 4 hours. Methyl 1-(3-amino-propyl)-4-phenyl-piperidine-4-carboxylate (140 mg, 0.5 mmol) was added. The reaction mixture was stirred at room temperature for 16 hours. The solvent was evaporated and the residue was chromatographed on silica gel (5 g) (CHCl3 / MeOH / 2 N NEI3 in MeH = 250 / 2 / 1) to get the title compound as a white solid (10.8 mg, 10 ~ yield over 3 steps). [~] D = -303.9- Hydrochloride of the title compound was made with HCl in ether. M.P. of the salt: 140-143~C. Calculated for C30H3sN7O6 + l.OHCl + 0.6 ether: C, 58.03 ~; H, 6.31 ~; N, 14.62 ~. Found: C, 58.07 ~; H, 6.08 %; N,14.66 %.

Example 38 6-(3,4-Difluoro-phenyl)-1-t3-(3',6'-dihydro-~2,4']bip yridinyl-1'-yl)-propylcarbamoyl]-4-methyl-5-methoxycarbonyl-2-oxo-1,2,3,6-tetrahydropyrimidine hydrochloride.
a) 1-(3-Aminopropyl)-4-[pyrid-2-yl~pyridinium bromide hydrobromide.
A solution of 2,4'-dipyridyl (5.0 g, 32.0 mmol) and 3-bromopropylamine hydrobromide (7.0 g, 32.0 mmol) in DMF
(50.0 mL) and acetonitrile (50.0 mL) was heated at 90-95~C for l h. After cooling, the white solid that came out was filtered, washed with Et20 and dried. The mother liquor was concentrated to remove Et20 and then heated to 90-95~C for 4 h. The solvent was evaporated and the white residue was triturated with Et20 (lOO.o mL) and filtered. The combined weight of the salt was 11.6 g (97~).
b) 3-(3',6'-Dihydro-2'-H-l2,4']bipyridinyl-1'-yl)-propylamine.

.

W097/429S6 PCT~S97/08335 To a solution of 1-(3-aminopropyl)-4-[pyrid-2-yl]pyridinium bromide hydrobromide (0.66 g, 1.75 mmol) n 20.0 mL MeOH was added NaBH4 (0.101 g, 2.62 mmol) in small portions. The reaction mixture was stirred for 30 min and then quenched with 6M HCl solution. The solution was concentrated to 20.0 mL and basified with 50% NaOH solution to pH 12. Extracted witn CHCl3 (5 x 30.0 mL), dried over MgSOq and the solvent was removed togive3-~3~6~-dihydro-2~-H-[2~4~bipyridinyl-l~-yl)-propylamine as an oil ~0.37 g, 96~ yield). It is used in the next step immediately without purification.

c)6-(3,4-Difluoro-phenyl~ t3-(3',6'-dihydro-[2,4'~b ipyridinyl-1'-yl)-propylcarbamoyl~-4-methyl-5-methoxycarbonyl-2-oxo-1,2,3,6-tetrahydro-pyrimidine hydrochloride.
A solution of 6-(3,4-difluorophenyl)-4-methyl-5-methoxycarbonyl-1-(4-nitrophenoxy)carbonyl-2-oxo-1,2,3,6- tetrahydro-pyrimidine (20 mg, 0.045 mmol) and 3-(3', 6'-dihydro-2'H-[2,4']bipyridyl-1-yl)propylamine (9.7 mg, 0.045 mmol) in CH2Cl2 (10 ml) was stirred at room temperature for 3 days. The solvent was removed in vacuum. The residue was separated on preparative TLC (CHCl3 / MeOH = 100 / 15) to get the title compound (21mg, 89 ~~ yield) as a yellow solid. Hydrochloride salt was made with HCl in ether. M.P. of the salt: 242-244~C. Calcd for C27H29N5OqF2 ~ 2.0 HCl ~ 1.05 CHC13 + 1.05 ether: C, 48.32 %; H, 5.35 ~; N, 8.74 ~. Found: C, 48.10 ~; H, 5.13 %; N, 8.72 ~.

Example 39 6-(3,4-Difluorophenyl)-1-(3-imidazol-1-yl-propylcarba moyl)-4-methyl-2-oxo-1,2,3,6-tetrahydro-pyrimidine-5-carboxylic acid methyl ester.
A solution of 6-~3,4-difluorophenyl)-4-methyl-5-methoxycarbonyl-l-(4-nitrophenoxy)carbonyl-2-oxo-W O 97/42956 PCTrUS97/08335 1~2~3~6-tetrahydro-pyrimidine (100 mg, 0.22 mmol) and l-(3-aminopropyl)imidazole (40 ml, 0.34 mmol) in CH2Cl~
(10 ml) was stirred at room temperature for 3 hours.
The solvent was removed in vacuum. The residue was separated on preparative TLC (CHCl3 / MeOH = 100 / 15) to get the title compound (80 mg, 84 % yield) as a white solid. Hydrochloride of title compound was made with HCl in ether. Calcd for C20HzlNsO4F2 + 0.3 H.O: C, 54.74 ~; H, 4.99 ~i N, 15.89 %. Found: C, 54.92 ~;H, 4.65 %; N, 15.77 %. M.P. of the salt: 221-224~C.

E x a m p l e 4 o 6-(3,4-Difluorophenyl)-1-{N-~3-(2-phenylimidazol-l-yl )propyl]}carboxamido-4-methyl-5-methoxycarbonyl-2-oxo -1,2,3,6-tetrahydropyrimidine hydrochloride.
A mixture of 6-~3,4-difluorophenyl)-1,2,3,6-tetrahydro-2-oxo-5-methoxycarbonyl-4-methyl-1-(3-bromopropylamino carbonyl)pyrimidine (100 mg, 0.22 mmol), 2-phenylimidazole (32.3 mg, 0.22 mmol), and CsC03 (358 mg, 1.1 mmol) in DMF (10 ml) was stirred at room temperature for 2 days. The solid was filtered out.
The solution was concentrated and separated on preparative TLC (EtOAc / hexane = 3 / 1) to get the title compound (41 mg, 37 % yield) as a white oily solid. Hydrochloride of title compound was made with HCl in ether. M.P. of the salt: 278-282 ~C.
Calculated for C26H25NsO4F2 + 2.0 HCl + 0.25 H2O: C, 52.23 %; H, 4.60 %; N, 11.60 %. Found: C, 52.21 ~; H, 4.69 %; N, ll.11 %.
Example 41 and Example 42 (+)-, and (-)-3,6-Dihydro-l-{N-~4-(2-pyridyl)-piperidine-1-yl] propyl}car~oxamido-5- methoxy carbonyl-2-oxo-6-(3,4,5- trifluorophenyl)-4-methyl pyrimidine dihydrochloride.
.

a) Methyl2-acetyl-3-(3,4,5-trifluoro-phenyl)-acrylate.

W O 97/42956 PCTrUS97/08335 -127-A mixture of 3,4,5-trifluorobenzaldehyde (1.0 g, 6.3 mmol), methyl acetoacetate ( 0.81 ml, 7.5 mmol), and piperidinium acetate (45 mg, 0.31 mmol) in benzene ~lQ
ml) was refluxed with a Dean-Stark trap for 12 hours.
The solvent was e~aporated, and the residue was chromatographed on silica gel (~50 g) (EtOAc / hexane = 1 / 6) to get the title compound (825 mg, 51 ~ yield) as a mixture of cis and trans isomers (yellow oil).

b) Methyl 2-methoxy-4-methyl-6-(3,4,5-trifluoro-phenyl)-1,6-dihydro-pyrimidane-5-carboxylate.
A mixture of methyl 2-acetyl-3-(3,4,5-trifluoro-phenyl)-acrylate (670 mg, 2.60 mmol), O-methylisourea hydrogen hemisulfate (448 mg, 3.63 mmol), and 4-dimethylaminopyridine (407 mg, 3.63 mmol) in ethanol (20 ml) was stirred at 65 ~C for 2 days. The solid formed was filtered out. The filtrate was concentrated and chromatographed on silica gel (30 g) (CH2Cl2 / EtOAc = 9 / 1) to get the title compound (390 mg, 48 % yield) as a pale yellow oil. Calculated for Cl4Hl3N2O3F3; C, 53.50 %; H, 4.20 ~; N, 8.90 ~. Found: C, 53.24 ~i H, 4.20 %; N, 8.60 ~.

c) 1,6-Dihydro-5-methoxycarbonyl-2-msthoxy-4-methyl-1-(4-nitro phenyloxy)carbonyl -6-(3,4,5-trifluorophenyl) -pyrimidine.
To a solution of methyl l,6-dihydro-2-methoxy-4-methyl-6-(3,4,5-trifluoro-phenyl)-pyrimidine-5-carboxylate (385 mg, 1.23 mmol) and 4-dimethylaminopyridine (195 mg, 1.60 mmol) in CH2Cl2 (15 ml), at room temperature, was added 4-nitrophenyl chloroformate (322 mg, 1.60 mmol). The reaction solution was stirred at room temperature for 2 days.
The white solid formed was filtered out. The filtrate was concentrated and chromatographed on silica gel (~20 g) (CHCl3 / CH30H = 9 / 1) to get the titled compound (206 mg, 35 ~ yield) as a white solid. Calculated for .

WO 97l42956 PCr/US97108335 C2lH16N3O7F3 + 1.0 H2O: C, 50.71 %; H, 3.65 %; N, 8.45 9~. Found: C, 50.83~; H, 3.29 %; N, 8.33 ~.

d) 1,6-Dihydro-2-methoxy-5-methoxycarbonyl-4-methyl-1-S {N-~4-(2-~yridyl)-piperidin-1-yl]-propyl}carbamoyl-6-(3,4,5-trifluoro-phenyl)-pyrimidine.

A mixture of 1,6-dihydro-5- methoxycarbonyl -2-methoxy- (4-nitrophenyloxy) carbonyl-6-(3,4,5-trifluorophenyl) - 4-methyl-pyrimidine ~25 mg, 0.05 mmol) and 3- [4- (2-pyridyl) -piperidin-1-yl] -propylamine (16 mg, 0.078 mmol) was stirred at room temperature for 12 hours. The solvent was evaporated and the residue chromatographed on silica gel (~5 g) (CHCl3 / EtOAc = 30 / 1 ) to get the title compound (16 mg, 57 ~ yield) as a pale solid.

e) 1,2,3,6-Tetrahydro-5-methoxycarbonyl-4-methyl-2-oxo-1-{N-t4-(2-pyridyl)-piperidine-1-yl]-propyl}carboxam~do-6-(3,4,5-trifluorophenyl)-pyrimidine dihydrochloride.
1,6-Dihydro- 2 -methoxy-5-methoxycarbonyl-4-methyl-1- {N-[4 - (2 -pyridyl ) -piperidin- 1 -yl] -propyl ~ carbamoyl - 6 -(3,4,5-trifluoro-phenyl) -pyrimidine from the previous step was dissolved in CH2C12 (5 ml) and concentrated HCl solution (0.5 ml ) was added . The reaction mixture was stirred at room temperature for 1 hour. NaOH solution (1 N) was added to neutralized the reaction mixture .
It was extracted with CH2C12. The extractant was dried ( Na2SO4) and concentrated to get the title compound (16 mg, quantitative ) as a pale solid . Hydrochloride of the title compound was made with HCl in ether.
Calculated for C2,H29NsO4F~ + 2.0 HCl + 4.0 THF ~ 0.8 CH2Cl2: C, 54.02 %; H, 6.69 %; N, 7.19 %. Found:
C, 54.00 %; H, 6.48 %; N, 7.42 %.

f) (+) -, and (-) -3,6-Dihydro-1-{N- t4- (2-pyridyl) -W097/42956 PCT~S97/08335 piperidine-l-yl] propyl}carboxamido-5- methoxy carbonyl-2-oxo-6-~3,4,5- trifluorophenyl)-4-methyl pyrimidine dihydrochloride.
The enantiomers were separated by chiral HPLC
separation (column: chiralpak AS) of the racemic 1,2,3,6-tetrahydro~ N-~4-(2-pyridyl)-piperidine-1-y l]propyl}carboxamido-5-methoxycarbonyl-2-oxo-6-(3,4,s -trifluorophenyl)-4-methylpyrimidine dihydrochloride which was synthesized in the previous step. The (~) isomer: [a~D = +80.4 (c = 0.2 g in 100 ml dichloromethane): The (-) isomer: [a]D = -82.2 Hydrochloride salts of the title compounds was made with HCl in ether.

Example 43 ~ 1,2,3,6-Tetrahydro-5-methoxycarbonyl-4-methoxymethyl-2-oxo-1-{N-~4-~2-pyridyl)-p i p e r i d~ n e - 1 - y l] -p r o p y l } c a rb o x a m i d o -6-(3,4,5-trifluorophenyl)-pyrimidine dihydrochloride.
a) Methyl 2-methoxyacetyl-3-(3,4,5-trifluoro-phenyl)-acrylate.
A mixture of 3,4,5-trifluoro benzaldehyde (10 g, 62.5 mmol), methyl 4-methoxyacetoacetate (9.7 ml, 75.0 mmol), and piperidinium acetate (450 mg, 3.1 mmol) in benzene (100 ml) was refluxed with a Dean-Stark trap for 8 hours. The white solid formed ( some side product) was filtered out. The solvent was evaporated, and the residue was chromatographed on silica gel (- 1 Kg) (toluene / t-butyl methyl ether = 8 / 1) to get the title compound (4.5 g, 25% yield) as a mixture of cis and trans isomers (white solid).

b) 1,6-Dihydro-2-methoxy-5-methoxycarbonyl-4-methoxymethyl-6-(3,4,5-trifluoro-phenyl)-pyrimidine.
A mixture of methyl 2-methoxyacetyl-3-(3,4,5-- trifluoro-phenyl)-acrylate (6.0 g, 20.8 mmol~, 0-methylisourea hydrogen hemisulfate ~3.6 g, 29.2 mmol), CA 022~3862 1998-11-09 W O 97t42956 PCTAUS97/08335 and 4-dimethylaminopyridine ~3.6 g, 29.2 mmol) in ethanol (20 ml) was stirred at 65 ~C for 12 hours. The solid formed was filtered out. The filtrate was concentrated and chromatographed on silica gel (~1 kg) (hexane / ether = 2 / 1) to get the title compound (4.0 g, 56 ~ yield) as a pale colorless oily solid.

c ) 1, 6 -Dihydro- 2 -methoxy- S -methoxycarbonyl - 4 -methoxymethyl - 1- ( 4 -ni trophenyloxy) carbonyl - 6 - ( 3, 4, 5 - trif luorophenyl ) -pyrimidine .
To a solution of 1,6-dihydro-2-methoxy-5-methoxycarbonyl-4-methoxymethyl-6-(3,4,5-trifluoro-phenyl)-pyrimidine (3.24 g, 9.41 mmol) and 4-dimethylaminopyridine (1.38 g, 11.3 mmol) in CH2C12 ~20 ml), at room temperature, was added 4-nitrophenyl chloroformate (2.28 g, 11.3 mmol). The reaction solution was stirred at room temperature for 2 days.
The white solid formed was filtered out. The filtrate was concentrated and chromatographed on silica gel (hexane / ether = 1 / 1) to get the title compound (3.70 g, 77 ~ yield) as a yellow solid.

d)(+)-, and (-)-1,6-Dihydro-2-methoxy-5-methoxycarbonyl-4-methoxymethyl-1-[N-~2-methylbenzyl )]carbamoyl-6-(3,4,5-trifluoro-phenyl)-pyrimidine.
A mixture of 1,6-dihydro-2-methoxy-5-methoxycarbonyl-4-methoxymethyl~ 4-nitrophenyloxy)carbonyl-6-(3,4,5-trifluorophenyl)-pyrimidine (3.80 g, 7.46 mmol) and (R)-(+)-~-methylbenzylamine (2.02 mg, 16.4 mmol) in CH2Cl2 was stirred at room temperature for 2 days. The solvent was evaporated and the residue chromatographed on silica gel (toluene /t-butyl methyl ether = 5 / 1) to get the title compound as yellow oil solids. For the less polar isomer (1.81 g, 50 ~yield): [~]D = +164.3. For the more polar isomer (1.79 g, 50 ~ yield): [~] D = -86.2.

W O 97/42956 PCTnUS97/08335 -131-e)~ 1,6-dihydro-2-methoxy-5-methoxycarbonyl-4-methoxymethyl-6-(3,4,5-trifluoro-phenyl)-pyrimidine.
A mixture of (+)-1,6-dihydro-2-methoxy-5-methoxycarbonyl-4-methoxymethyl-1-~N-(2-methylbenzyl )]carbamoyl-6-(3,4,5-trifluoro-phenyl)-pyrimidine (1.81 g, 3.81 mmol) and 1,8-diazabicyclo~5,4,0]undec-7-ene (0.28 ml, 1.90 mmol) in benzene (10 ml) was stirred at room temperature for 4 days. The solvent was evaporated, and the residue was chromatographed on 0 silica gel (~500 g) (hexane / ether = 2.5 / 1) to get the title compound (1.2 g, 91 ~ yield) as a yellow oil.
No rotation was observed for this compound.

f ) ( + ) -1, 6 - D ihydro - 2 - me thoxy - 5 - me thoxyc a rb ony l - 4 -methoxymethyl -1- ( 4 -ni trophenyloxy) carbonyl - 6 - ( 3, 4, 5 - trif luorophenyl) -pyrimidine .
To a solution of 1,6-dihydro-2-methoxy-5-methoxycar~onyl-4-methoxymethyl-6-(3,4,5-trifluoro-phenyl)-pyrimidine (1.20 g, 3.49 mmol) and 4-dimethylaminopyridine (0.51 g, 4.18 mmol) in CH2Cl2 (20 ml), at room temperature, was added 4-nitrophenyl chloroformate (0.84 g, 11.3 mmol). The reaction solution was stirred at room temperature for 12 hours.
The white solid formed was filtered out. Trials to purify the crude product on silica gel only hydrolyzed the desired product to the start materials. The crude product was used in the next step without any further purification.

g)(l)-1,6-Dihydro-2-methoxy-5-methoxycarbonyl-4-methoxymethyl-l-{N-14-(2-pyridyl)-piperidin-1-yl]-propyl}carbamoyl-6-~3,4,5-trifluoro-phenyl)-pyrimidine.

A mixture of (+)-1,6-dihydro-2-methoxy-5-methoxy carbonyl-4-methoxymethyl-1-~4-nitrophenyloxy) carbonyl-6- ~3,4,5-trifluorophenyl)-pyrimidine and 3-[4-(2-pyridyl)-piperidin-1-yl]-propylamine (215 mg, 1.05 mmol) was stirred at room temperature for 12hours. The solvent was evaporated and the residue chromatographed on prep. TLC (CHCl3 / MeOH = 100 / 15~
to get the title compound (115 mg, 22 ~ yield over 2 steps) as a yellow oil.

h) (+) -1, 2, 3, 6-Tetrahydro-5-methoxycarbonyl -4-methoxymethyl-2-oxo-1- {N- [4- (2-pyridyl) -piperidine -1 -yl~ -propyl } carboxamido -6- (3, 4, 5-trifluorophenyl) -pyrimidine dihydrochloride .

1,6-Dihydro-2-methoxy-5-methoxycarbonyl-4-methoxymethyl-1-{N-[4-(2-pyridyl)-piperidin-1-yl]-propyl~carbamoyl-6-(3,4,5-trifluoro-phenyl)-pyrimidine from the previous step was dissolved in CH2Cl2 (5 ml) and HCl solution (6 N,0.5 ml) was added. The reaction mixture was stirred at room temperature for 4 hour.
KOH solution (1 N) was added to neutralize the reaction mixture. It was extracted with CH2C12. The extractant was dried ( Na2SO4) and concentrated to get the title compound (106 mg, 94 % yield) as a pale oily solid.
[~] D = + 78.6 (c = 0.5 g in 100 ml dichloromethane).
Hydrochloride of the title compound was made with HCl in ether. Calculated for C28H32NsOsF3 + 3.8 HCl+1.8 EtOAc: C, 48.44~; H, 5.80%; N, 8.02 ~. Found: C, 48.19 %; H, 5.38 ~; N, 8.32~.

Example 44 ( - ) -1, 2, 3, 6-Tetrahydro-5-methoxycarbonyl-4-me thoxyme thyl - 2 - oxo - 1 - { N - [ 4 - ( 2 - pyr i dyl ) -piperidine -1 -yl] -propyl}carboxamido-6 - ( 3, 4, 5 - tri f luorophenyl ) -pyrimidine dihydrochloride .
a) ( -) -1, 6-Dihydro-2-methoxy-5-methoxycarbonyl-4 -methoxymethyl - 6 - ( 3, 4, 5 - tri f luoro -phenyl ) -pyrimidine .
A mixture of (-)-1,6-dihydro-2-methoxy-5-methoxycarbonyl-4-methoxymethyl-1- [N-(2-methylbenzyl)~carbamoyl-6-~3,4,5-trifluoro-phenyl)-W097/42956 PCT~S97/08335 pyrimidine (1.79 g, 3.B0 mmol) and 1,8-diazabicyclo[5,4,01undec-7-ene (0.28 ml, 1.90 mmol) in benzene (10 ml) was stirred at room temperature for 4 days. The solvent was evaporated, and the residue was chromatographed on silica gel (~500 g) (hexane / ether = 2.5 / 1) to get the title compound (0.92 g,70 ~) as a yellow oil. No rotation was observed for this compound.

b) (~) -1, 6-Dihydro-2-methoxy-5-methoxycarbonyl-4-methoxymethyl-1- (4-nitrophenyloxy) carbonyl -6- ~3,4,5-trlfluorophenyl) -pyrimidine.
To a ~olution of 1,6-dihydro-2-methoxy-5-methoxycarbonyl-4-methoxymethyl-6-(3,4,5-trifluoro-phenyl)-pyrimidine (0.92 g, 2.67 mmol) and 4-dimethylaminopyridine ~0.46 g, 3.74 mmol) in CH,Cl2 (20 ml), at room temperature, was added 4-nitrophenyl chloroformate (0.75 g, 3.74 mmol). The reaction solution was stirred at room temperature for 2 days.
The white solid formed was filtered out. The filtrate was concentrated and chromatographed on silica gel (hexane / ether = 3 / 1) to get the title compound (1.01 g, 79 % yield) as a yellow solid.

c) (-)-1,6-Dihydro-2-methoxy-5-methoxycarbonyl-4-methoxymethyl-1-{N-14-(2-pyridyl)-piperidin-1-yl]-propyl}carbamoyl-6-(3,4,5-trifluorophenyl)-pyrimidine.
A m i x t u r e o f ( - ) -1,6-dihydro-2-methoxy-5-methoxycarbonyl-4-methoxymethyl-1-(4-nitrophenyloxy)carbonyl-6-~3,4,5-trifluorophenyl)-pyrimidine (300 mg, 0.59 mmol) and 3-~4-(2-pyridyl)-piperidin-1-yll-propylamine (160 mg, 0.77 mmol) was stirred a~ room temperature for 12 hours. The solvent was evaporated and the residue chromatographed on prep. TLC (CHC13 / MeOH / 2 N NH3 in MeOH = 20 / 2 / 1) to get the title compound (290 mg, 83 ~ yield) as a yellow oil.

W O 97/42956 PCT~US97/08335 d) (-)-1,2,3,6-Tetrahydro-5-methoxycarbonyl-4-methoxymethyl-2-oxo-1-{N-[4-(2-pyridyl)-piperidine-1-yl] -propyl}carboxamido-6-(3,4,5-trifluorophenyl)-pyrimidine dihydrochloride.
(-)l~6-dihydro-2-methoxy-5-methoxycarbonyl-4-methoxymethyl-l-{N-[4-(2-pyridyl)-piperidin-1-yl]-propyl}carbamoyl-6- (3,4, 5-trifluoro-phenyl)-pyrimidine (290 mg, 0.49 mmol) was dissolved in CH2Cl2 (5 ml) and HCl solution (6 N, 2 ml) was added. The reaction mixture was stirred at room temperature for 10 hour.
KOH solution (1 N) was added to neutralized the reaction mixture. It was extracted with CH2Cl2. The extractant was dried ( Na2SO4) and concentrated to get the title compound (180 mg, 64 ~ yield) as a pale oily solid. [CY]D = - 31.4 (c = 0.44 g in 100 ml dichloromethane). Hydrochloride of the title compound was made with HCl in ether. Calculated for C28H32NsO5F3 + 2.0 HCl + 0.8 ether + 0.8 CH2Cl2: C, 50.59 %; H, 5.78 ~; N, 9.22 ~. Found: C, 50.86 ~; H, 5.82 ~;
N, 8.75 ~.

Example 45 1,2,3,6-Tetrahydro-5-methoxycarbonyl-4-methyl-2-oxo-1-{N-[4-(2-pyridyl)- piperidine-1-yl]-propyl}cA~ do-6-(2,4,5-trifluorophenyl- pyrimidine dihydrochloride.
a)Methyl2-acetyl-3-(2,4,5-trifluoro-phenyl)-acrylate.
A mixture of 2,4,5-trifluorobenzaldehyde (1.0 g, 6.3 mmol), methyl acetoacetate ( 0.81 ml, 7.4 mmol), and piperidinium acetate(38 mg, 0.26 mmol) in benzene (10 ml) was stirred at room temperature for 2 days. The solvent was evaporated, and the residue was chromatographed on silica gel (-50 g) ( hexane / ether = 5 / 1) to get the title compound (1.60 g, quantitative ) as a mixture of cis and trans isomers (colorless oil).

W O 971429~6 rCTrUS97/08335 -135-b) 1,6-Dihydro-2-methoxy-5-methoxycarbonyl-4-methyl-6-(2,4,5-trifluoro-phenyl)-pyrimidine.
A mixture of methyl 2-acetyl-3-~2,4,5-trifluoro-phenyl)-acrylate (1.60 g, 6.20 mmol), O-methylisourea hydrogen hemisulfate (1.07 g, 8.68 mmol), and 4-dimethylaminopyridine (1.06 g, 8.68 mmol) in ethanol ~10 ml) was stirred at 65 ~C for 2 days. The solid formed was filtered out. The filtrate was concentrated and chromatographed on silica gel (-50 g) (CH2Cl. /
EtOAc = 9 / 1) to get the title compound (982 mg, 50 yield) as a pale colorless oily solid.

c) 1,6-Dihydro-5-methoxycarbonyl-2-methoxy-4-methyl-1-(4-nitro phenyloxy)carbonyl -6-(2,4,~-trifluorophenyl) -pyrimidine.
To a solution of 1,6-dihydro-2-methoxy-5-methoxycarbonyl-4-methyl-6-(2,4,5-trifluoro-phenyl)-pyrimidine (600 mg, 1.91 mmol) and 4-dimethylaminopyridine (280 mg, 2.29 mmol) in CH2Cl2 (8 ml), at room temperature, was added 4-nitrophenyl chloroformate (462 mg, 2.29 mmol). The reaction solution was stirred at room temperature for 18 hours.
The white solid formed was filtered out. The filtrate was concentrated and chromatographed on silica gel (~50 g) (hexane t ether = 4 / l) to get the title compound (143 mg, 16 % yield) as a white solid.

d) 1,6-Dihydro-2-methoxy-5-methoxycarbonyl-4-methyl-1-{N-[4-(2-pyridyl)-piperidin-1-yl]-propyl}c~bA~yl-6-(2,4,5-trifluoro-phenyl)-pyrimidine.
A mixture of 1,6-dihydro-5-methoxycarbonyl-2-methoxy-4-methyl-1-(4-nitrophenyloxy)carbonyl-6-(2,4,5-trifluorophenyl)-pyrimidine (70 mg, 0.146 mmol) and 3-[4-(2-pyridyl)-piperidin-1-yl]propylamine (46 mg, 0.220 mmol) was stirred at room temperature for 12 hours. The solvent was evaporated and the residue separated on preparative TLC (CHC13 / MeOH / 2 N NH3 in W O 97t42956 rCT~US97/08335 MeOH = 20 / 2 / 1) to get the title compound (59 mg, 72 ~6 yield ) as a yellow oil.

e) 1,2,3,6-Tetrahydro-5-methoxycarbonyl-4-methyl-2-oxo-1-{N- [4- (2-pyridyl)- piperidine-1-yl] -propyl}~h~Yamido-6-(2,4,5-trifluorophenyl- pyrimidine dihydrochloride.
1~6-Dihydro-2-methoxy-5methoxycarbonyl-4-methyl-l-{N-[4 - (2-pyridyl)-piperidin-1-yl] -propyl}carbamoyl-6-(2,4,5-trif~uoro-phenyl)-pyrimidine (59 mg, 0.11 mmo') was dissolved in THF (3 ml) and HCl solution (6 N, 2 ml) was added. The reaction mixture was stirred at room temperature for 6 hour. KOH solution ~1 N) was added to neutralized the reaction mixture. It was extracted with CHzCl2. The extractant was dried (Na2SO4) and concentrated to get the title compound (50 mg, 87 ~ yield) as a white solid. Hydrochloride of the title compound was made with HCl in ether. Calculated for C27H3~NsOgF2 + 2.0 HCl + 1.0 C6Hl2 + 1.0 CHCl3: C, 49.68 ~; H, 5.52 ~; N, 8.52 ~. Found: C, 49.22 ~; H, 6.11 9~; N, 8.59 ~. M.P. of the salt: 239-243 ~C.

Example 46 4- (3,4-Difluorophenyl)-3- [3-(3-hydroxy-3-phenyl-8-aza bicyclo ~3.2.1] oct-8-yl)propylcarbamoyl] -6-methyl-2-ox o-1,2,3,6-tetrahydro-pyrimidine-5-carboxylic acid methyl eE~ter a) 8-Benzyl-3-phenyl-8-azabicyclo t3.2.1~ octan-3-ol:
N-benzyltropinone (14.4 g, 66.7 mmol) was added dropwise (neat) to a solution of phenyl magnesium bromide (100 mL, 0.1 M in THF). The addition was continued as such a rate to maintain a gentle reflux.
Once the addition was complete, the reaction mixture was heated at reflux temperature for 19 hours, cooled to room temperature, poured over 200 mL of crushed ice, saturated with Ammor-ium chloride, and extracted with 3 X 100 mL of ethyl acetate. The combined organic .

W097/42956 PCT~S97/08335 extracts were dried (K2CO3), solvent removed in Vacuo, and the crude product was chromatographed on 500 g of silica pac~ed with CHC13. The column was eluted with CHCl3 (1 L), 5~EtOAc-CHCl3 (1 L), 10% (1 L), 20%, (1 L), 30% (1 L), 50~ (1 L), 100~ EtOAc (1 L), and 10~ MeOH-EtOAc (2 ~), to give 11.8 g (40~) of the desired product as a slightly yellow oily solid. Anal. Calc.
for C2DH23NIOl: C, 81.87; H, 7.90; N, 4.77. Found: C, 81.63; H, 8.01; N, 4.70.

b) 3-Phenyl-8-azabicyclo13.2.1~octan-3-ol:
A mixture of 5.10 g of 8-benzyl-3-phenyl-8-azabicyclo 13.2.1]octan-3-ol (17-4 mmol), 3.15 g of 10~ Pd/C in 50 mL of 95~ ethanol was hydrogenated in a pressurized bomb (200 psi) at 60-70 ~C (bath temperature) for 16 hours. The reaction mixture was filtered through a pad of Celite, and the solids were washed with 5 X 30 mL of methanol. The combined organic extracts were concentrated, and the crude product was chromatographed on 300 g of silica packed with EtOAc-MeOH-isopropanol (30:2:1). The column was eluted with EtOAc-MeOH-isopropanol 25:2:1 (1 L), 20:2:1 (1 L), and 15:2-1 (1 L) to give 3.16 g (89~) of the desired product as a slightly yellow oily solid. Anal. Calc. for C,3Hl7N1Ol:
C, 76.81; H, 8.43; N, 6.89. Found: C, 76.57; H, 8.53;
N, 6.80.

c)4-~3,4-Difluorophenyl)-3-[3-(3-hydroxy-3-phenyl-8-a zabicyclo~3.2.1]oct-8-yl)propylcarbamoyl}-6-methyl-2-oxo-1,2,3,6-tetrahydro-pyrimidine-5-carboxylic acid methyl ester.
A mixture of 243 mg of 3-phenyl-8-azabicyclo[3.2.l]
octan-3-ol (1.2 mmol), 640 mg of 1,2,3,6-tetra hydro-1-~3- bromopropyl}carboxamido-5-methoxy carbonyl-4-methyl-6-~3,4-difluorophenyl)-2-oxo pyrimidine (1.44 mmol), 197 mg of K2CO3 (1.44 mmol), catalytic amounts (a few crystals) of KI in 10 mL of CA 022~3862 1998-11-09 WO 97/42956 PCT~US97/08335 -138-ethanol were heated at reflux temperature for 4 hours.
The reaction mixture was cooled to room temperature, and the crude product was purified with preparative TLC
(2000 microns, 10~ MeOH-EtOAc) to give 290 mg (43%) of the desired product as a slightly yellow viscous oil.
Anal. Calc. For C30H34F2N4Os+ 1.0 Methanol: C, 61.99; H, 6.38; N, 9.33. Found: C, 62.12; H, 6.02; N, 9.58. The hydrochloride salt was prepared by dissolving 150 mg o~
the free base in minimum EtOAc and excess lN HCl in ether was added. The solvent was decanted and the separated oil was triturated with ether to give the hydrochloride as a slightly yellow powder: Anal. Calc.
for C30H34F2N4Os+ 1.0 HCl + 1.2 H2O: C, 57.50; H, 6.01; N, 8.94. Found: C, 57.76; H, 5.82; N, 8.50.
Example 47 and Example 48 1, 2, 3, 6-Tetrahydro-1- (N- (3 - (3 -imidazol-1-yl) propyl) am ino ) propylcarboxamido - 5 -methoxycarbonyl - 2 - oxo - 6 - ( 3, 4 -difluorophenyl)-4-methylpyrimidine dihydrochloride and 1, 2, 3, 6-Tetrahydro-1- (N- (3 - (2-indol-3-yl) ) ethyl) amino) propylca ~ ; do-5-methoxycarbonyl-2 -oxo-6- (3,4-difluorophenyl) -4-methylpyrimidine hydrochloride In two separate reaction vessels, a mixture of 89 mg of 1~2~3~6-tetrahydro-l-{3-bromopropyl}carboxamido-5-met hoxy carbonyl-4-methyl-6-(3,4-difluorophenyl)-2-oxo pyrimidine t0.200 mmol), 0.200 mmol of the following nucleophiles (25.0 mg of 1-(3-aminopropyl)imidazole, 25 mg of tryptamine), 89 mg of K2CO3, in 1 mL of acetonitrile were heated at reflux temperature for 2-5 days, applied to the preparative-TLC and eluted with CHCl3-MeOH-2N NH3 in MeOH (10:1:1) to give the title compounds. The hydrochlorides were prepared by dissolving the title compounds in minimum EtOAc, and excess lN HCl in ether was added until no more precipitate was apparent. The solids were filtered, washed with ether, and dried under high vacuum.

CA 02253862 l998-ll-09 W O 97/42956 PCT~US97/08335 1,2,3,6-Tetrahydro-l- ~N- (3- (3-imidazol-l-yl)propyl)am ino ) propylcarboxamido - 5 -methoxycarbonyl - 2 - oxo - 6 - ( 3, 4 -difluorophenyl) -4-methylpyrimidine dihydrochloride ( 12 mg): Anal. Calc. for C23H2BF2N604 1 2.0 HCl + 0.6 ether + 0.3 CH2Cl2: C, 49.31; H, 5.76; N, 13.12. Found: C, 49.07; H, 5.78; N, 13.28.
1, 2, 3, 6-Tetrahydro-1- (N- (3- (2-indol-3 -yl) ) ethyl) amino) propyl~rhQ~mido-5-methoxycarbonyl-2 - oxo - 6 - ( 3, 4 - dif luorophenyl ) - 4 -methylpyrimidine 1 0 hydrochloride (23 mg); Anal. Calc. for C27H29F2NsO4+ 1.0 HCl + 3.7 THF:
C, 60.58; H, 7.25; N, 8.45. Found: C, 60.84; H, 7.21;
N, 8.48.

Example 49 6- (3,4-Difluorophenyl)-1,6-dihydro-1-methoxycarbonyl-5-( 3 - ( 4 -methoxycarbonyl - 4 -phenylpiperidin -1 -yl ) -propyla~ n~a rbonyl ) - 2, 4 - dime thylpyrimidine a) Benzyl 3-oxo-2- ~3,4-difluorobenzylidenyl)butanoate.
A mixture of 3,4-difluorobenzaldehyde (7.1 g, 50 mmol.), benzyl acetoacetate (12 .48 g, 65 mmol.), acetic acid (0.15 g, 2.5 mmol.), piperidine (0.212 g, 2.5 mmol.) and benzene (300 mL) was refluxed under a dean-stark trap overnight. After the removal of solvent, the residue was then dissolved in ethyl acetate and washed with saturated KHS04 ~ saturated NaHCO3, water and then dried over Na2SO4. The solvent was evaporated, and the residue was flash chromatographed over silica gel (eluent: 1:1 v/v ethyl acetate-hexane) t~ give the product in 87~ yield (13.7 g) as a yellow solid.

b) 5-Benzyloxycarbonyl-6- ~3, 4-difluorophenyl) -1, 6-dihydro- 2, 4 - dimethylpyrimidine .
To a stirred solution of acetamidine hydrochloride (1.42 g, 15 mmol.) in DMF (10 mL) were added a solution of potassium tert-butoxide (1.23 g, 11 mmol.) in DMF
(lOmL) and a solution of the above yellow solid (3.16 CA 022~3862 1998-11-09 W O 97/42956 PCT~US97/08335 g, 10 mmol.) in DMF (10 mL) at 0~C. After the mixture was stirred for 15 min at 0~C, p-toluenesulfonic acid monohydrate (3.8 g, 20 mmol.) was added. The mixture was heated at 100-110~C for 2 hrs. After cooling, it was quenched with 2N aqueous NaOH solution and extracted with ether. The organic layer was dried over Na2SO~ and evaporated. The residue was flash chromatographed over silica gel (eluent: 100:5 v/v ethyl acetate-2M ammonia in methanol) to give the product in 42% yield (1.5 g) as an off-white solid.

c) 5-Renzyloxycarbonyl-6- (3,4-difluorophenyl) -1, 6-dihydro - l -methoxycarbonyl - 2, 4 - dimethylpyrimidine .
To a stirred slurry of NaH (59 mg, 60~ in mineral oil, 1.47mmol.) in THF ~5 mL) was added a solution of the above off-white solid ~0.S g, 1.4 mmol.) in THF (10 mL) at 0~C. After 5 min, methyl chloroformate (0.16 g, 1.7 mmol.) was added at 0~C. Stirring was continued at room temperature for 30 min. The mixture was quenched with brine and extracted with ethyl acetate. The organic layer was dried over Na2SO4 and evaporated to give a quantitative yield of the product as a yellow solid.

d) 5 ~ Ca rhoxy- 6 - ( 3, 4 - di f luorophenyl ) -1, 6 - dihydro -1-methoxycarbonyl-2, 4-dimethylpyrimidine.
A solution of the above yellow solid ~0.63 g, 1.52 mmol) in methonal (20 mL) was subjected to hydrogenation with a H2 balloon in the presence of palladium (63 mg, 5% on C). The reaction was carried out at room temperature for 30 min. The catalyst was then filtered off and the solvent was removed in vacuo to give the product in 99~ yield (0.487 g) as an off-white solid.

e) 6-(3, 4 -Di f luorophenyl ) - 1, 6 - dihydro -1-methoxycarbonyl - 5 - ( 3 - ( 4 -methoxycarbonyl - 4 -phenylpiperidin- 1 -yl) -propylaminocarbonyl ) - 2, 4 -W O 97142956 PCTrUS97/0833S
dimethylpyrimidine.
A mixture of the above off-white solid (0.070 g, 0.~2 mmol.), 4-dimethylaminopyridine (0.040 g, 0.33 mmol.), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.060 g, 0.30 mmol.) and CH2Cl2 (5 mL) was stirred at room temperature for 0.5 hr. After the ~ addition of 3-(4-methoxycarbonyl-4-phenylpiperidin-l-yl)propylamine (0.075 g, 0.27 mmol.), the mixture was refluxed overnight. To the mixture was added another 25 mL of CH2Cl2 and washed with saturated NH4Cl solution.
After the removal of the solvent, the residue was flash chromatographed over silica gel (eluent: 85:15 v/v ethyl acetate-methonal) to give the title compound in 42~ yield (O.052 g) as a white solid: mp 55-57~C. Anal.
Calcd. for C3lH36F2N4O50.5CH2C12: C, 60.52; H, 5.97; N, 8.96. Found: C, 60.61; H, 6.09; N, 8.94.

Example 50 6 - ( 3, 4 -Dif luorophenyl ) -1, 6 - dihydro - 5 - ( 3 - ( 4 -m e t h o x y c a r b o n y 1 - 4 - p h e n y 1 p i p e r i d i n - 1 -yl) propylaminocarbonyl ) -1 -methoxymethyl - 2, 4 -dimethylpyrimidine a) 5 ~Benzyloxy~honyl- 6 - (3, 4 -dif luorophenyl) -1, 6 -dihydro- 1 -methoxymethyl - 2, 4 - dimethylpyrimidine .
To a stirred slurry of NaH (24 mg, 60~ in mineral oil, 0.6 mmol.) in THF (5 mL) was added a solution of 5-benzyloxycarbonyl-6-(3,4-difluorophenyl)-1,6-dihydro-2,4-dimethylpyrimidine (0.2 g, 0.56 mmol.) in THF (10 mL) at 0~C. After 10 min, chloromethyl methyl ether (0.043 mL, 0.57 mmol.) was added at 0~C. Stirring was continued at room temperature for 3 hrs. The mixture was quenched with brine and extracted with ethyl acetate. The organic layer was dried over Na2SO4 and evaporated to give the product in 44.5~ yield as a yellow oil.
.

b) S -Carboxy- 6 - ( 3, 4 -dif luorophenyl) -1, 6 -dihydro- 1-CA 02253862 l998-ll-09 methoxymethyl-2, 4-dimethylpyrimidine .
A solution of the above yellow oil (0.17 g, 0.43 mmol) in methanol (20 mL) was subjected to hydrogenation with a H2 balloon in the presence of palladium (34 mg, 5~ on C). The reaction was carried out at room temperature for 0.5 hr. The catalyst was ~hen filtered off and the solvent was removed in vacuo to give the product in 100~ yield (0.13 g) as an off-white solid.

c) 6 - (3, 4-Difluorophenyl) -1, 6-dihydro-5- (3 - (4 -me thoxycarbonyl - 4 -phenylpiperidin - 1 -yl ) propylaminocarbonyl ) -1 -methoxymethyl - 2, 4 -dimethylpyrimidine .
A mixture of 5-carboxy-6-(3,4-difluoro-phenyl)-1,6-dihydro-1-methoxymethyl-2,4-dimethylpyrimidine(0.13g, 0.42 mmol.), 4-dimethylaminopyridine (0.1 g, 0.84 mmol.), 1-~3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.16 g, 0.82 mmol.) and CH2Cl2 (5 mL) was stirred at room temperature for 0.5 hr. After the addition of 3-(4-methoxycarbonyl-4-phenylpiperidin-1-yl)propylamine (0.17 g, 0.62 mmol.), the mixture was refluxed o~ernight. To the mixture was added another 25 mL of CH2Cl2 and washed with saturated NH4Cl solution.
After removal of the solvent, the residue was flash chramotographed o~er silica gel (eluent: 80:20 v/v ethyl acetate- methanol) to give the title compound in 32~ yield (0.075 g) as a pale yellow solld: mp 53-57~C.
Anal. Calcd. for C3~H38F2N40g0~25CHCl3 C, 62.71; H, 6.44;
N, 9.36. Found: C, 62.62; H, 6.79; N, 9.19.
Example 51 1,6-Dihydro-5-methoxycarbonyl-1-(5-(4-methoxycarbonyl - 4 - p h e n y l p i p e r i d i n - 1 - y l ) p e n t y 1 ) -4-me~hyl-6-(4-nitrophenyl)-pyrimidine a) 1,6-Dihydro-5-methoxycarbonyl-4-methyl-6-(4-nitrophenyl)-pyrimidine.
Sodium (0.55 g, 23.9 mmol) was allowed to react with CA 022S3862 l998-ll-09 W O 97/42956 PCTrUS97/08335 anhydrous EtOH (100 mL). Then the solution was cooled by an ice water bath when formamidine acetate (2.29 g, 2 2 . 0 m m o l ) a n d m e t h y l 2 - ~ 4 -nitrobenzylidenyl)acetoacetate (5.00 g, 20.1 ~mol) were added. The mixture was stirred at room temperature for 3 h. The product was filtered off as a ye~low powder (4.68 g, 80~). It was mixed with p-toluenesulfonic acid monohydrate ~6.7 g, 35.2 mmol) in dry DMSO (125 mL) and heated at 110~C for 3 h. Ice water (450 mL) was added and the product as a tosylate was filtered off as an off-white solid (5.55 g, 78%).

b) 1-(s-chloropentyl)-l~6-dihydro-5-methoxycarbonyl-4 methyl-6-(4-nitrophenyl)pyrimidine.
The above solid (2.44 g, 5.45 mmol) was added to dry TH~ (50 mL) containing sodium hydride (60~ oil dispersion, 480 mg, 12.0 mmol) and cooled by an ice water bath. Then l-bromo-5-chloropentane (3 mL, 22.8 mmol) was added. The mixture was stirred at room temperature for 7 h before ice water was added.
Extraction with EtOAc gave a dark oil (4.455 g) which was flash chromatographed over silica gel (120 g) eluting with EtOAc/hexane/Et3N (15:15:1) to afford a brown oil (1.43 g, 69%).
c)1,6-Dihydro-5-methoxycarbonyl-1-(5-(4-methoxycarbon yl-4-phenyl-piperidin-1-yl)pentyl)-4-methyl-6-(4-nitrophenyl)-pyrimidine.
The above oil t220 mg, 0.58 mmol) was mixed with 4-methoxy-carbonyl-4-phenylpiperidine (127 mg, 0.58 mmol) and potassium iodide (106 mg, 0.64 mmol) in dry glyme (4 mL) cooled by an ice water bath. Then sodium hydride (24 mg, 60% oil dispersion, 0.60 mmol) was ~ added. The mixture was heated at reflux overnight and more KI (106 mg) was added. Reflux was continued for two more days. Ice water was added. Extraction with EtOAc (3 x 3 mL) gave a brown oil (158 mg). It was W097t42956 PCT~S97/08335 dissolved in CHCl3/EtOAc and flash chromatographed over sllica gel (16 g) eluting with EtOAc/MeOH/Et3N (20:1:1) to afford a yellow oil (89 mg, 27%). Anal. Calcd. for C3lH3jN4O63/4H2O: C, 64.62; H, 6.91; N, 9.72. Found: C, 64.56; H, 6.84; N, 9.76.

Example 52 6-~2,4-Difluorophenyl)-1,6-dihydro-1-(5-(4-methoxycarbonyl-4-phenylpiperidin-1-yl)-pentyl)-2,4-dimethyl-5-methylaminoca-bonyl-pyrimidine a) Benzyl 3-oxo-2-~2,4-difluorobenzylidenyl)butanoate.
A mixture of 2,4-difluorobenzaldehyde (7.1 g, So mmol.), benzyl acetoacetate (12.48 g, 65 mmol.), acetic acid (0.15 g, 2.5 mmol.), piperidine (0.212 g, 2.5 mmol.) and 2-propanol (300 mL) was stirred at room temperature for two days. After the removal of solvent, the residue was then dissolved in ethyl acetate and washed with saturated KHSO4, saturated NaHCO3, water and then dried over Na2SO4. The solvent was evaporated, and the residue was flash chromatographed over silica gel (eluent: 1:5 v/v ethyl acetate-hexane) to give the product in 91~ yield (14.3 g) as a yellow solid.

b) 5-Benzyloxycarbonyl-6-(2,4-difluorophenyl)-1,6-dihydro-2,4-dimethylpyrimidine. To a stirred solution of acetamidine hydrochloride (2.84 g, 30 mmol.) in DMF
(20 mL) were added a solution of potassium tert-~utoxide (2.46 g, 22 mmol.) in DMF (20mL) and a solution of the above yellow solid (6.32 g, 20 mmol.) in DMF (20 mL) at 0~C. After the mixture was stirred for 15 min at 0~C, p-toluenesulfonic acid monohydrate (7.6 g, 40 mmol.) was added. The mixture was heated at 100-t 10~C for 2 hrs. After cooling, it was quenched with 2N
aqueous NaOH solution and extracted with ether. The organic layer was dried over Na2SO4 and evaporated. the residue was flash chromatographed over silica gel (eluent: 100:5 v/v ethyl acetate-2M ammonia in WO 97/42956 PCT~US97/08335 -~45-Methanol) to give the product in 42% yield (1.5 g) as an off-white solid.

c) 5-Benzyloxycarbonyl-1-(5-bromopentyl)-6-(2,4-difluorophenyl)-1,6-dihydro-2,4-dimethylpyrimidine. To a suspension of NaH (123 mg, 60% dispersion in mineral - oil, 3.08 mmol.) in THF (5 mL) was added a solution of the above off-white solid (1.0 g, 2.8 mmol.) and HMPA
(0.5 g, 2.8 mmol.) in THF (5 mL) at 0~C. After 15 min, 1,5-dibromopentane (1.53 mL, 11.2 mmol.) was added.
The mixture was then refluxed for 30 min. The solid was filtered off. After the removal of the solven~, the residue was flash chromatographed over silica gel (eluent: ethyl acetate) to give the product in 78 yield (1.1 g) as a yellow oil.

dJ 5-Benzyloxycarbonyl-6-(2,4-difluorophenyl)-1,6-dihydro-1-(5-(4-methoxycar~onyl-4-phenylpiperidin-1-yl)pentyl)-2,4-dimethyl-pyrimidine. A mixture of the above yellow oil (1.62 g, 3.2 mmol.), 4-methoxycarbonyl-4-phenyl piperidine (1.4 g, 6.4 mmol.), potassium carbonate (1.76 g, 12.7 mmol.), sodium iodide (0.45 g, 3.0 mmol.) and 1,4-dioxane ~15 mL) was refluxed overnight. The undissolved solid was then filtered off and the solvent was evaporated. The residue was flash chromatographed over silica gel (eluent: 80:20 v/v ethyl acetate-2M ammonia in methanol) to give the product in 66~ yield (1.36 g) as a yellow oil.
e~ 5-Carboxy-6-(2,4-difluorophenyl)-1,6-dihydro-1-(~-~4-mothoxycarbonyl-4-phenylpiperidin-1-yl)pentyl)-2,4-dimethyl-pyrimidine. A solution of the above yellow oil (0.36 g, 0.5~ mmol) in methanol ~20 mL) was subjected to hydrogenation with a H2 balloon in the presence of palladium (36 mg, 5% on C). The reaction was carried out at room temperature for 30 min. The CA 022~3862 1998-11-09 W O 97/42956 rCTrUS97/08335 catalyst was then filtered off and the solvent was removed in vacuo to give the product in quantitative yield (0.31 g) as an off-white solid.

f) 6-(2,4-Difluorophenyl)-1,6-dihydro-1-(5-(4-methoxycarbonyl-4-phenylpiperidin-1-yl)-pentyl)-2,4-dimethyl-5-methylaminocarbonyl-pyrimidine. A mixture of the above off-white solid (0.244 g, 0.44 mmol.), 4-dimethylaminopyridine (0.26 g, 2.12 mmol.), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.13 g, 0.66 mmol.) and CH2C12 (10 mL) was stirred at room temperature for 2 hrs. After the addition of methyl amine hydrogen chloride (0.089 g, 1.32 mmol.), the mixture was stirred at room temperature overnight.
To the mixture was added another 25 mL of CH2Cl2 and washed with saturated NH4Cl solution. After removal of the solvent, the residue was flash chramotographed over silica gel (eluent: 100:20 v/v ethyl acetate-2M ammonia in methanol) to give the title compound in 22% yield (0.055 g) as a yellow oil. Treatment of the free base with 2 equivalents of lM HCl in ether gave the HCl salt as a pale yellow solid: mp 152-155~C. Anal. Calcd. for C32H40F2N4O32HCl 1.6H2O 0.8CHCl3: C, 51.57; H, 6.07; N, 7.33. Found: C, 51.38; H, 5.91; N, 7.27.
Exa~npl e 5 3 6 (R, S ) - ( 3, 4 - Di f luorophenyl ) - 1, 6 - dihydro - 5 -methoxycarbonyl -1- ( 5 - ( 4 -me thoxycarbonyl - 4 -phenylpiperidin -1 -yl ) - 4 (S ) -methyl ) pentyl - 2, 4 -dimethylpyrimidine a) (S) - (+) -3-Methylpiperidine. A mixture of (~)-mandelic acid (45.64 g, 0.3 mol) in ethyl acetate ~300 mL) was heated to solution and treated with 3-methylpiperidine (2g.75 g, 0.3 mol). The mi~ture was allowed to come to room temperature before filtration.
The crystalline material was washed with 1:1 ethyl acetate-ether (400 mL). Two recrystallizations of this .

W O 97/42956 PCTrUS97/08335 -147-salt from ethyl acetate gave the optically pure salt in 56~ yield (21.7 g).

b) (S)-(~)-N-Benzoyl-3-methylpiperidine. The above salt ~21 g, 0.088 mol) was dissolved in sodium hydroxide solution (1.0 N, 200 mL). The solution was cooled tO
3~C, and benzoyl chloride (12.5 g, 0.089 mol) was added dropwise over 10 min. After the addition was complete, the mixture was transferred to a separatory funnel and extracted with ether. The combined extracts were dried (Na2SO4) and concentrated to give the pure amide in 98 yield ( 17.2 g): [~]D +45.9 (c 1.00, CH30H).

c) (S)~ 2-Methyl-l,S-dibromopentane. To the above amide powder was added phosphorus tribromide (7.81 mL, d 2.85, 0.082 mol) at 5~C over 20 min with vigorous stirring. After the addition, the mixture was warmed to room temperature, and Br2 (4 mL, 0.082 mol) was added dropwise over 10 min. The mixture was then allowed to stand at room temperature overnight and distilled under vacuum (0.5-1 mm Hg) until the head temperature reached 80~C. The distillate was dissolved in hexane (100 mL) and washed successively with water t20 mL), concentrated sulfuric acid (4x30 mL), water (20 mL), NaOH solution (lN, 2x40 mL), and water (20 mL). The hexane solution was then dried (Na2SO4) and concentrated to give the product in 31~ yield (6.4 g) as a light yellow liquid.

d) 1-(5-Bromo-4(S)-methylpentyl)-6(R,S)-(3,4-difluorophenyl)-1,6-dihydro-5-methoxycarbonyl-2,4-dimethylpyrimidine. To a suspension of NaH (47mg, 60 dispersion in mineral oil, 1.17 mmol.) in THF (3 mL) was added a solution of 6-(3,4-difluoro-phenyl)-1,6-dihydro-5~methoxycarbonyl-2,4-dimethylpyrimidine (0.3 g, 1.07 mmol.) and HMPA (0.193 g, 1.07 mmol.) in THF (4 mL) at 0~C. After 10 min, a solution of (-)-2-methyl-W 097/42956 PCT~US97/08335 1,5-dibromopentane (0.86 g, 3.53 mmol.) in THF (~ mL) was added. The mixture was then refluxed for 10 min.
The solid formed was filtered off. After the removal of the solvent, the residue was flash chromatographed over S silica gel (eluent: 100:5 v/v ethyl acetate-2.OM
ammonia in methanol) to give the product in 36% yield (0.169 g) as a yellow oil.

e) 6(R,S)-~3,4-Difluorophenyl)-1,6-dihydro-5-methoxycarbonyl -1- ( 5 - ( 4 -me thoxycarbonyl - 4 -phenylpiperidin - 1 -yl ) - 4 ( S ) -me thyl ) pentyl - 2, 4 -dimethylpyrimidine. A mixture of the above yellow oil (0.169 g, 0.38 mmol.), 4-methoxycarbonyl-4-phenyl piperidine (0.167 g, 0.76 mmol.), potassium carbonate (0.21 g, 1.52 mmol.), sodium iodide (0.057 g, 0.38 mmol.) and 1,4-dioxane (8 mL) was refluxed overnight.
The undissolved solid was then filtered off and the solvent was evaporated. The residue was flash chromatographed over silica gel (eluent: 100:5 v/v ethyl acetate-2M ammonia in methanol) to give the title compound in 11% yield (0.025 g) as a yellow oil.
Treatment of the free base with 2 equivalents of lM HCl in ether gave the HCl salt as a light yellow solid: mp 155-158~C. Anal. Calcd. for C33H41F2N3042HCl 0.5H20: C, 59.72; H, 6.64; N, 6.33. Found: C, 59.47; H, 6.66; N, 6.10.

Example 54 6- (3,4-Difuorophenyl) -1, 6-dihydro-5-methoxycarbonyl-1-(3- (4-methoxycarbonyl-4-phenylpiperidin-1-yl ) methyl ) benzyl - 2, 4 - dimethylpyrimidine a) 1- (3-Bromomethylbenzyl) -6- (3, 4-difluorophenyl) -1, 6-dihydro-~-methoxycarbonyl-2,4-dimethylpyrimidine. To a suspension of NaH ~31 mg, 60% dispersion in mineral oil, 0.77 mmol.) in THF (5 mL) was added a solution of 6-(3,4-difluorophenyl)-1,6-dihydro-5-methoxycarbonyl-2,4-dimethylpyrimidine (0.3 g, 1.07 mmol.) and HMPA

W097/429s6 PCT~S97/08335 (0.193 g, 1.07 mmol.~ in THF (5 mL~ at 0~C. After 15 min, ~,~'-dibromo-m-xylene (0.99 g, 3.75 mmol.) was added. The mixture was then refluxed for 15 min. The solid was filtered off. After the removal of the solvent, the residue was flash chromatographed over silica gel (eluent: ethyl acetate~ to give the product in 91~ yield (0.45 g~ as a yellow oil.

b) 6- (3,4-Difluorophenyl) -1,6-dihydro-5-methoxycarbonyl-1- ~3- (4-methoxycarbonyl-4-phenyl-4-phenylpiperidin -1- yl ) me thyl ) benzyl - 2, 4 -dimethylpyrimidine .
A mixture of the above yellow oil (0.45 g, 0.97 mmol.), 4-methoxycarbonyl-4-phenyl piperidine (0.42 g, 1.9 mmol.), potassium carbonate (0.67 g, 4.86 mmol.), sodium iodide ~0.14 g, 0.97 mmol.) and 1,4-dioxane (10 mL) was refluxed overnight. The undissolved solid was then filtered off and the solvent was evaporated. The residue was flash chromatographed over silica gel (eluent: 100:5 v/v ethyl acetate-2M ammonia in methanol) to give the title compound in 17~ yield tO.10 g) as a yellow oil. Treatment of the free base with 2 equivalents of lM HCl in ether gave the HCl salt as an off-white solid: mp 181-183~C. Anal. Calcd. for C3sH37F2N3042HCl l.OH20: C, 60.69; H, 5.97; N, 6.07.
Found: C, 60.73; H, 5.77; N, 5.94.

Example 55 6-(3,4-Difluorophenyl)-1,6-dihydro-5-methoxycarbonyl-2,4-dimethyl-1-(5-(3-phenylpropylamino)pentyl)-pyrimidine A mixture of 1-(5-bromopentyl)-6~(3,4-difluorophenyl)-1,6-dihydro-5-methoxycarbonyl-2,4-dimethylpyrimidine (0.186 g, 0.433 mmol.), 3-phenyl-1-propylamine (0.12 g, 0.89 mmol.), potassium carbonate (0.3 g, 2.17 mmol.), sodium iodide (70 mg, 0.46 mmol.) and 1,4-dioxane (8 mL) was refluxed overnight. The undissolved solid was W097/42956 PCT~S97/08335 then filtered off and the solvent was evaporated. The residue was flash chromatographed over silica gel (eluent: 100:20:10 v/v/v CHCl3-methanol-2M ammonia in methanol) to give the product in 54% yield (0.114 g) as a yellow oil. Treatment of the free base with 2 equivalents of lM HCl in ether gave the HCl salt as a white solid: mp 95-97~C. Anal. Calcd. for C28H3~F2N3022HCl 0.5CH2C12: C, 57.15; H, 6.39; N, 7.02.
Found: C, 57.09; H, 6.65; N, 6.85.
Example 56 ~+)-6-(3,4-Difluorophenyl)-1,6-dihydro-1-(4-hydroxy-5-(4-~2-pyridyl)piperidin-1-yl)pentyl)-5-methoxycarbonyl-2,4-dimethylpyrimidine a) 3-BromG~ lepoxide.
To a solution of 5-~romo-1-pentene (2.15 g, 14.4 mmol.) in CH2C12 (40 mL) was added MCPBA (3.0 g, 17.3 mmol.) at 0~C slowly. After stirred at room temperature overnight, the mixture was poured into a mixture of ice and 2N
NaOH solution. The separated aqueous layer was extracted with CH2Cl2. The combined organic layer was then washed with water, brine and dried over Na2SOg. The concentrated mixture was flash chromatographed over silica gel (eluent: CH2C12) to give the product in 92 yield (2.19 g) as a pale yellow liquid.

b) 1-(4,5-Epoxypentyl)-6-~3,4-difluorophenyl)-1,6-dihydro-5-methoxycarbonyl-2,4-dimethylpyrimidine.
To a suspension of NaH (78 mg, 60~ dispersion in mineral oil) in THF (10 mL) was added a solution of 6-(3,4-difluorophenyl)-1,6-dihydro-5-methoxycarbonyl-2,4-dimethylpyrimidine (0.5 g, 1.78 mmol.) and HMPA (0.3 mL, 1.78 mmol.) in THF (5 mL) at 0~C. After 20 min, the above pale yellow li~uid (0.6 g, 3.6 mmol.) was added.
The mixture was then refluxed 2hrs. After the removal of the solvent, the residue was flash chromatographed over silica gel (eluent:100:5 v/v ethyl acetate-2.OM

W O 97t42956 PCTrUS97tO8335 -151-ammonia in methanol~ to give the product in 62% yield (0.4 g) as a yellow oil.

c) 6-(3,4-Difluorophenyl)-1,6-dihydro-1-(4-hydroxy-5-(4-(2-pyridyl)piperidin-1-)ylpentyl)-5-methoxycarbonyl-2,4-dimethylpyrimidine.
A mixture of the above yellow oil (0.48 g, 1.32 mmol.~.
4-~2-pyridyl)piperidine (0.32 g, 1.98 mmol.) and 1,4-dioxane (10 mL) was refluxed overnight. The concentrated mixture was then flash chromatographed over silica gel (eluent: 80:20 v/v ethyl acetate-2.0M
ammonia in methanol) to give all four diastereomers in 43~ yield (0.3 g). Chiral HPLC separation gave the title enantiomer which was converted to a HCl salt: [~]~
= 120.6 (c 0.7, MeOH); mp 163-165~C. Anal. Calcd. for C29H36F2N4O33HCl 0.7CHCl~: C, 49.57; H, 5.56; N, 7.79.
Found: C, 49.41; H, 5.96; N, 7.38.

Example 57 6-(3,4-Difluorophenyl)-1,6-dihydro-5-methoxycarbonyl-2,4-dimethyl-1-(5-(4-(2-pyridyl)piperidin-1-yl)-4-oxo)pentyl pyrimidine To a solution of oxalyl chloride (8 mg, 0.06 mmol.) in CH2Cl2 (0.25 mL) was added a solution of DMSO (10 mg, 0.14 mmol.) in CH2Cl2 (0.3 mL) at -78~C. After 3 min, a solution of 6-(3,4-difluorophenyl)-1,6-dihydro-1-(4-hydroxy-5-(4-(2-pyridyl)-piperidin-1-yl)pentyl)-5-methoxycarbonyl-2,4-dimethylpyrimidine (30 mg, 0.057 mmol.) in CH2C12 (1 mL) was added to the mixture which was stirred for another 15 min. The mixture was treated with triethylamine (0.04 mL) and stirred for another 5 min. Then it was allowed to warm up to room temperature. After the addition of water, it was washed with lN NaOH and water. The organic layer was dried over Na2SO4 and concentrated. The residue was purified by preparative TLC (eluent: 100:20 v/v ethyl acetate-2.0M ~on~a in methanol) to give the title compound in CA 022~3862 1998-11-09 WO 97/42956 PCTrUS97/08335 43~ yield (13 mg) as a yellow oil. Treatment of the free base with 3 equivalents of lM HCl in ether gave the HCl salt as a pale yellow solid: mp 135-137~C.
Anal. Calcd. for C29H34F2N4O33HC1 2H2O 0.9CH2Cl2: C, 48.11;
H, 5.78; N, 7.51. Found: C, 47.~9; H, 6.03; N, 7.35.

Example 58 ~ 4-(3,4,5-Trifluorophenyl)-3,4-dihydro-5-methoxyc~onyl-6-methyl-3-(5-(4-(2-pyridyl)piperidin-1-yl)-pentyl-2(lH)-pyrimidone a) 3-(5-Bromopentyl)-4-(3,4,5- trifluorophenyl)-3,4-dihydro-5-methoxycarbonyl-6-methyl-2(lH)-pyrimidone.
To a suspension of NaH (0.23 g, 60~ dispersion in mineral oil, 5.8 mmol.) in THF (40 mL) was added a solution of 6-(3,4,5-trifluorophenyl-1,6-dihydro-2-methoxy-5-methoxycarbonyl-4-methyl-pyrimidine (0.6 g, 1.9 mmol.) and HMPA (0.33 mL, 1.9 mmol.) in THF (10 mL) at 0~C. After 20 min, 1,5-dibromopentane (1.75 g, 9.4 mmol.) was added. The mixture was then refluxed for 2 hrs and quenched by water. The mixture was partitioned between ethyl acetate and water. The organic layer was separated, treated with 6N HC1 ~10 mL) solution and stirred at room temperature for 1 hr. It was then separated and dried over Na2SO4. After the removal of solvent, the residue was flash chromatographed over silica gel (eluent: 80:20 v/v hexane-ethyl acetate) to give the product in 73~ yield (0.62 g) as a yellow oil.

b)(+)-4-(3,4,5-Trifluorophenyl)-3,4-dihydro-5-methG~yc~ yl-6-methyl-3-(5-(4-(2-pyridyl)piperidin-1-yl)-pentyl-2(lH)-pyrimidone. A mixture of 3-(5-bromopentyl)-4-(3,4,5-trifluorophenyl)-3,4-dihydro-5-methoxycarbonyl-6-methyl-2(lH)-pyrimidone (0.3 g, 0.7 mmol.), 4-(2-pyridyl) piperidine (0.22 g, 1.4 mmol.), potassium carbonate ~0.5 g, 3.6 mmol.), sodium iodide (O.lg, 0.7 mmol.) and acetone (20 mL) was refluxed overnight. The undissolved solid was then filtered off CA 02253862 l998-ll-09 W O 97142956 PCTrUS97/08335 -153-and the solvent was evaporated. The residue was flash chromatographed over silica gel (eluent: 80:20 v/v ethyl acetate-2.OM ammonia in Methanol) to give the racemic product in 85% yield (0.3 g) as a yellow oil.
Chiral HPLC separation afforded the title enantiomer which was converted to a HCl salt: [~] D = 122 (c 4.1, - MeOH); mp 125-127~C. Anal. Calcd. for C2aH33F3N4O3 2HCl 2H2O 0 2Et2~: C, 52.86; H, 6.32; N, 8.56.
Found: C, 52.66; H, 6.37; N, 8.15.
E x a m p l e S 9 4-(3,4,5-Trifluorophenyl)-3,4-dihydro-5-methoxycarbon yl-6-methyl-3-(3-(4-~2-pyridyl)piperidin-1-yl)propylo xycarbonyl)-2(1N)-pyrimidone.
a) 1-(3-Hydroxypropyl)-4-(2-pyridyl~piperidine.
A mixture of 4-(2-pyridyl)piperidine ~200 mg, 1.23 mmol), 3-bromopropanol (135 mL, 1.49 mmol), potassium carbonate (620 mg, 4.49 mmol) and a catalytic amount of sodium iodide in acetone (10 mL) was heated at reflux overnight. Filtration followed by evaporation of the solvent gave a light brown oil (324 mg) which was dissolved in CHCl3 and flash chromatographed over silica gel (20 g) eluting with EtOAc/MeOH/Et3N (20:1:1) to afford a light brown solid (166 mg, 61~).
b 4-~3,4,5-Trifluorophenyl)-3,4-dihydro-5-methoxycarbon yl-6-methyl-3-(3-(4-~2-pyridyl)piperidin-1-yl)propylo xycarbonyl)-2(lH)-pyrimidone.
A mixture of 1-(3-hydroxypropyl)-4-(2-pyridyl)-piperidine (72 mg, 0.33 mmol) and 4-(3,4,5-trifluorophenyl)-3,4-dihydro-5-methoxycarbonyl-6-methyl-3-(4-nitrophenoxycarbonyl)-2(lH)-pyrimidine (lS2 mg, 0.33 mmol) in dry THF (8 mL) was heated at reflux overnight. The residue obtained after evaporation of the solvent was dissolved in EtOAc and flash chromatographed over silica gel (18 g) eluting with W097/42956 PCT~S97/08335 EtOAc/MeOH/Et3N (100:3:3) to afford an off-white solid (133 mg, 75~). It was dissolved in CH2Cl2 and treated with lM HCl in ether (0.6 mL) to give an off-white solid: mp 154~C (dec.). Anal. Calcd. fcr C27H2gF3N4Os2HCl 2H2O: C, 49.47; H, 5.38; N, 8.55. Found:
C, 49.48; H, 5.16; N, 8.35.

Ex_mple 60 ~ 1,2,3,6-Tetrahydro-l-{N-t4-cyano-4-(phenyl)cycloh ex-1-yl]ethyl}carboxa~ido-5-methoxy carbonyl-4-methoxy methyl-6-(3,4-difluorophenyl)-2-oxopyrimidine hydrochloride.
a) 2-~4-Cyano-4-(phenyl)cyclohex-1-yl]ethylamine.
A mixture of 4-phenyl-4-cyanocyclohexanone (5.00 g, 25.09 mmol) and ethylenediamine (5.58) and p-toluene sulfonic acid in benzene (200 mL) were refluxed for 4 h in a Dean-Stork set-up to remove the water formed.
Solvent was e~aporated and the residue was redissolved in methanol and cooled to 0 ~C. To this, sodium borohydride tl.5 g) was added in portions and the mixture was stirred at room temperature for 3 h.
Solvent was evaporated, the residue was dissolved in dichloromethane (300 mL), washed with brine (2 X 200 mL) and dried (sodium sulfate). Sclvent was evaporated and the residue was dried under vacuum to leave the product as an oil ( 5.2 g). The lH-NMR showed this product to be pure and found to contain the cis/trans isomers in the ratio of about 9:1. It was used as was in the next step.
b)(+)-1,2,3,6-Tetrahydro-1-{N-[4-cyano-4-(phenyl)cycl ohex-1-yl]ethyl}carboxamido-5-methoxyca~h~yl-4-methoxy methyl-6-(3,4-difluorophenyl)-2-oxopyrimidine hydrochloride.
A solution of (+)-6-(3,4-difluorophenyl)-1,6-dihydro-2-methoxy-5-methoxycarbonyl-4-methoxymethyl-1-(4-nitrophenoxy)carbonylpyrimidine t0.220 g, 0.448 CA 022~3862 l998-ll-09 W O 97142956 PCTrUS97/08335 mmol),2- [4-cyano-4- (phenyl) cyclohex-l-yl] ethylamine (0.130 g, 0.538 mmol) in tetrahydrofuran (100 mL) was stirred at room temperature for 24 hours. The reaction mixture was stirred for another 1 hour after addition of 2 mL of 6N HCl. Sol~ent was evaporated at reduced pressure and the residue was basified ~y treatment with 10% aqueous KOH solution, extracted with dichloromethane (3 x 10 mL). The com}~ined extracts were dried over potassium carbonate, and solvent evaporated. The crude product was purified by preparative thinlayer chromatography (dichloromethane:MeOH:2M ammonia in MeOH,90:8:4) . The two possible isomer were obtained in the order of less polar compound as the minor product and the more polar compound as the major component (yields: 16 mg minor and 160 mg major isomer). The HCl salts were obtained by treatment with lN HCl in ether. The minor isomer HCl salt:m.p. 124-126 ~C; [a!]D = +112 (c = 0.21 g in 100 mL
CHCl3); Anal. Calcd. for C30H34NsO5F2ClØ5 chloroform.
0.5 ether: C, 54.61; H, 5.57; N, 9.80. Found: C, 54.43; H, 5.29; N, 9.54. The major isomer HCl salt: m.
p. 136-138 ~C; [~Y]D = +142 (c = 0.21 g in 100 mL CHCl3);
Anal. Calcd. for C3UH34NsosF2cl~o~4 chloroform: C, 54.84i H, 5.21; N, 10.52. Found: C, 55.16; H, 5.39; N, 10.42.

CA 022~3862 1998-11-09 General Procedure for the Preparation of 4,4-Diarylpiperidine~:
A mixture of 0.5 g of 4-aryl-4-hydroxy piperidine, 3 mL of the aromatic substrate, and 1 g of aluminu n chloride was stirred at room temperature for 3 days.
The reaction mixture was poured over 10 mL of ice, diluted with t-butyl-methyl ether, the resulting hydrochloride salt was filtered, washed with water and ether, dried, and used in the next step after spectral characterization.
4-Phenyl-4- (4-thiomethoxy-phenyl)-piperidine hydrochloride:
From 4-phenyl-4-hydroxy-piperidine and thioanisole (82~), Anal. Calc. for C1eH2lN1Sl+HCl+0.2H2O: C, 66. 83;
H, 6.98; N, 4.33. Found: C, 66.71; H, 6.81; N, 4.24.
4-(4-Fluorophenyl-4-(4-thiomethoxy-phenyl)-piperidine hydrochloride:
From 4-(4-fluoro-phenyl-4-hydroxy-piperidine and thioanisole (59~6), Anal. Calc. for C18H2oF1N1S1+HCl+0.35CH2Cl2: C, 60 .14; H, 5.56; N, 3.90.
Found: C, 59.96; H, 5.95; N, 3.81.
4-(4-Fluorophenyl-4-(2-methoxy-5-fluoro-phenyl)-piperidine hydrochloride:
From 4-(4-fluorophenyl)-4-hydroxy-piperidine and 4-fluoroanisole (78 ~ ), Anal. Calc. for C18H1gN1F201+HCl+0.2H2O: C, 62.96; H, 5.99; N, 4. 08.
Found: C, 62.72; H, 6.06; N, 4.06.
Bis-4-(4-Chlorophenyl)-piperidine hydrochloride:
From 4-(4-chlorophenyl~-4-hydroxy-piperidine and chlorobenzene (92%), Anal. Calc. for C17H17N1Cl2+HCl: C, 59.58; H, 5.29; N, 3.90. Found: C, 59.58; H, 5.28; N, 3.90.
4-Phenyl-4-(4-Hydroxy-phenyl)-piperidine hydrochloride:
From 4-phenyl-4-hydroxy-piperidine and phenol (5B~6).
General Procedure for the preparation of 4,4-diaryl-N-(3-amino)-propylpiperidinec:

W O 97/42956 PCT~US97/08335 -157-A mixture of 4,4-diarylpiperidine hydrochloride (0.100 mmol), ~3-bromopropyl)-carbamic acid tert-butyl ester (0.100 mmol), diisopropylethylamine (l mL), and dioxane (2 mL) were heated at reflux temperature for 2 days, cooled, chromatographed (silica prep-TLC plates) to give the BOC protected 4,4-diaryl-N-aminopropylpiperidine.
The BOC protected amine was dissolved in 1:1 TFA-dichloromethane, stirred for 6 hours, concentrated in vacuo, and the crude product was chromatographed (silica gel prep-TLC plates) to give 4,4-diaryl-N-(3-amino)propylpiperidines which were used after spectral characterization.

General Procedure for the Preparation of Dihydropyrimi~;~oneP:
Method A: Reaction of piperidines with bromopropylcarbamoyl-dihydropyrimi~; no~es:
A mixture of the 3-~3-~romopropylcarbamoyl}-4-~3,4-difluoro-phenyl)-6-methyl-2-oxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid methyl ester (45 mg, 0.1 mmol) and 0.1 mmol of 4,4-diarylpiperidine hydrochloride in a mixture of dioxane-diisopropylethylamine (2-0.5 mL) was heated at reflux temperature for 2 days, cooled, applied to a preparative-TLC plate and eluted with MeOH-EtOAc (2-3%) to give the dihydro-pyrimidine free base as the product. The free base was dissolved in a minimum of EtOAc and excess 1 N HCl in ether was added. The product was filtered, washed with ether, and dried.
Example 61:
3-{3-l(4-phenyl)-4-(4-thiomethoxy-phenyl)-piperidin-1 -yl]-propyl-carbamoyl}-4-(3,4-difluoro-phenyl)-2-oxo-1,2,3,4-tetr ahydro-pyrimidine-S-carh~xylic acid methyl ester .

W097/429S6 PCT~S97/08335 hydrochloride.
Prepared by method A. 63~ yield. Anal. Calc. for C35H3~N4~2O4Sl+HCl+0.2CHCl3: C, 59.62; H, 5.57; N, 7.90.
Found: C, 60.07; H, 6.27; N, 7.40.
Example 62:
3-{3-[(4-phenyl)-4-(4-thiomethoxy-phenyl)-piperidin-1 -yl] -propylcarbamoyl}-4-(3,4-di~luorophenyl)-2-oxo-1,2,3,4 -tetrahydro-pyrimidine-5-carboxylic acid methyl ester hydrochloride.
Prepared by method A. 63~ yield. Anal. Calc. for C3sH37N4F3O4S1+HCl+ether: C, 60.26; H, 6.22; N, 7.21.
Found: C, 60.46; H, 6.58; N, 7.41.
Example 63:
3-{3-14-(4-Fluorophenyl)-4-(2-methoxy-5-methyl-phenyl )piperidin-1-yl-propylcarbamoyl}-4-(3,4-difluoro-phenyl)-2-oxo-1 ,2,3,4-tetrahyd v~y~imidine-5-carboxylic acid methyl ester hydrochloride.
Prepared by method A. 63% yield. Anal. Calc. for C35H36N4F4O5+HCl+H20: C, 58.13; H, 5.44; N, 7.75. Found:
C, 57.97; H, 5.55; N, 7.31.
Example 64:
3-{3-~Bis-4-(4-Chlorophenyl)piperidin-1-yl-propylcarbamoyl}-4-(3,4-difluorophenyl)-2-oxo-1,2,3,4-tetrahydro-pyrim idine-5-car~oxylic acid methyl ester hydrochloride.
Prepared by method A. 71~ yield. Anal. Calc. for C34H34Cl2N4F204+HCl+ether: C, 58.35; H, 5.80; N, 7.16.
Found: C, 5B.23; H, 5.71; N, 7.39.
Example 65:
3-{3-t(4-phenyl)-4-(4-hyd G~y~henyl)piperidin-l-yl]pr opyl-carbamoyl}-4-(3,4-difluorophenyl)-2-oxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid methyl ester hydrochloride.

W O 97/42956 PCTrUS97/08335 -159-Prepared by method A. 63~ yield. Anal. Calc. for C34H36N4F20s~+HCl+1.4ethanol: C, 61.08; H, 6.61; N, 7.75. Found: C, 60.86; H, 6.77; N, 7.32.
Method B. Reaction of 4,4-diaryl-~-(3-aminopropyl)piperidines with p-nitrophenylcarbamoyldihydropyrimi~;~o~s:
Example 66:
3,6-Dihydro-5-methoxycarbonyl-4-methoxymethyl-2-oxo-1-{N-[4,4-bis-(4-fluorophenyl)-piperidine-1-yl]-propyl}carboxamido-6-(2,3,6-trifluorophenyl)-pyrimidine dihydrochloride.
a) Methyl 2-methoxyacotyl-3-(2,3,6-trifluorophenyl)acrylate. A mixture of 2,3,6-trifluorobenzaldehyde (5.2 g, 33 mmol ), methyl 4-methoxyacetoacetate ( 5.7 ml, 39 mmol~, and piperidinium acetate (catalytic amount) in benzene (10 ml) was stirred at room temperature for 3 days.
The solvent was evaporated, and the residue was chromatographed on silica gel (hexane/ether = 7/1) to yield the title compound (3.4 g, 36~) as a mixture of cis and trans isomers as a colorless oil .
b) 1,6-dihydro-2-methoxy-5-methoxycarbonyl-4-methoxymethyl-6-(2,3,6-trifluorophenyl)pyrimidine.
A mixture of methyl 2-methoxyacetyl-3-~2,3,6-trifluorophenyl)-acrylate (3,4 g, 11.8 mmol), 0-methylisourea hydrogen hemisulfate (2.3 g, 16.5 mmol), and 4-dimethylaminopyridine (32.0 g, 16.5 mmol) in ethanol (lO ml) was stirred at 65 ~C for 24 hours, cooled and filtered . The filtrate was concentrated and chromatographed on silica gel (hexane/ether = 2/1) to yield the title compound (0.78 g, 20 ~ yield) as a colorless oil.
c) 1,6-Dihydro-2-methoxy-5-methoxycarbonyl-4-methoxymethyl-1-(4-nitrophenyloxy)carbonyl-6-(2,3,6-trifluorophenyl)-pyrimidine.

CA 022~3862 1998-11-09 W097/42956 PCT~S97/0833S

To a solution of 1,6-dihydro-2-methoxy-5-methoxycarbonyl-4-methoxymethyl-6-(2,3,6-trifluoro-phenyl)-pyrimidine (0.76 g, 2.2 mmol) and 4-dimethylaminopyridine (0.33 g, 2.7 mmol) in CH~C1. (5 ml), at room temperature, was added 4-nitrophenyl chloroformate (0.54 g, 2.7 mmol). The reaction solution was stirred at room temperature for 24 hours. It was filtered. The filtrate was concentrated and chromatographed on silica gel (hexane/ether = 2/1) to give the title compound (0.98 g, 87 ~ yield) as a pale yellow solid.
d) 3,6-D~hydro-5-methoxycarbonyl-4-methoxymethyl-2-oxo-1-{N-t4,4-bis-(4-fluoro-phenyl)-piperidine-1-yl]-propyl}carboxamido-6-(2,3,6-trifluorophenyl)-pyrimidine dihydrochloride.
A mixture of 1,6-Dihydro-2-methoxy-5-methoxycarbonyl-4-methoxy-methyl-1-(4-nitrophenyloxy)carbonyl-6-(2,3,6-trifluoro-phenyl)pyrimidine ~25 mg, 0.05 mmol) and 3-[4~4-bis-(4-fluoro-phenyl)-piperidin-l-yl]-propylamine (20 mg, C.06 mmol) in CH2Cl2 ( 3 ml ) was stirred at room temperature for 12 hours. HCl solution (6 N, 2 ml) was added. The reaction mixture was stirred at room temperature for 6 hour. KOH
solution (1 N) was added to neutralize the reaction mixture, and was extracted with CH2C12. The extracts were dried (Na2SO4), concentrated and the product was chromatographed on prep. TLC (CH2Cl2 : CH30H : 2 N NH3 in CH30H = 40:2:1) to obtain the title compound (18 mg, 53~) as a colorless oil. The hydrochloride of the title compound was synthesized using HCl in ether. Calculated for C3sH3sNso4F5 + 2.0 HCl: C,55.06~;
H,4.63~; N, 7.16~. Found: C,55.34~; H,4.91~;
N,7.38~.
Example 67:
3,6-Dihydro-5-methoxyr~ho~yl-4-methoxymethyl-2-oxo-1-{N-[4-(4-chloro-phenyl)-4-(5-fluoro-2-CA 02253862 l998-ll-09 W O 97/42956 PCTrUS97/08335 methoxy-phenyl)-piperidine-l-yl]-propyl}carboxamido-6-(3,5-difluorophenyl)-pyrimidine dihydrochloride.
a) Methyl 2-methoxyacetyl-3-~3,5-difluoro-phenyl)-acrylate.
~ mixture of 3,5-difluorobenzaldehyde (10 g, 70 mmol ), methyl 4-methoxyacetoacetate ( 11 ml, 80 mmol), and piperidinium acetate (catalytical amount) in benzene (100 ml) was stirred at room temperature for 3 days. The solvent was evaporated, and the residue was chromatographed on silica gel (hexane/ether =
5/1) to give the cis and trans mixture of the title compound (3.7 g, 20~ yield) as a yellow oil .
b) l,6-dihydro-2-methoxy-5-methoxycarbonyl-4-methoxymethyl-6-~3,5-difluoro-phenyl)-pyrimidine.
A mixture of methyl 2-methoxyacetyl-3-(3,5-difluoro-phenyl)-acrylate (3.74 g, 13.8 mmol), O-methylisourea hydrogen hemisulfate (2.68 g, 19.4 mmol), and 4-dimethylaminopyridine (2.37 g, 19.4 mmol) in ethanol (30 ml) was stirred at 65 ~C for 2 days, cooled and filtered . The filtrate was concentrated and chromatographed on silica gel (hexane/ether = 3/1) to get the title compound (1.7 g, 38 ~ yield) as a yellow solid.
c) l,6-Dihydro-2-methoxy-5-methoxycarbonyl-4-methoxymethyl-1-(4-nitrophenyloxy)carbonyl-6-(3,5-difluorophenyl)-pyr imidine.
To a solution of 1,6-dihydro-2-methoxy-5-methoxycarbonyl-4-methoxymethyl-6-(3,5-difluorophenyl)pyrimidine (1.67 g, 5.10 mmol) and 4-dimethylaminopyridine (0.75 g, 6.1 mmol) in CH2Cl2 (10 ml), at room temperature, was added 4-nitrophenyl chloroformate ~1.24 g, 6.1 mmol). The reaction solution was stirred at room temperature for 24 hours, and filtered. The filtrate was concentrated - and chromatographed on silica gel (hexane/ether =
2/1) to yield the title compound (1.82 g, 72 ~ yield) W 097142956 PCT~US97/08335 as a white solid.
d) 3,6-Dihydro-5-methoxycarbonyl-4-methoxymethyl-2-oxo-1-{N-l4-(4-chloro-phenyl)-4-(5-fluoro-2-methoxy-phenyl)-piperidine-l-yl]-propyl}ca hO~ i do-6-(3,5-difluorophenyl)-pyrimidine dihydrochloride.
A mixture of 1,6-dihydro-2-methoxy-5-methoxycarbonyl-4-methoxy-methyl-1-(4-nitrophenyloxy)carbonyl-6-(3,5-difluoro-phenyl)pyrimidine (25 mg, 0.050 mmol) and 3-[4-(4-chloro-phenyl)-4-(5-fluoro-2-methoxy-phenyl)-piperidin-1-yl]-propylamine (23 mg, 0.060 mmol) in CH2Cl2 ( 3 ml ) was stirred at room temperature for 12 hours. HCl solution (6 N, 2 ml) was added. The reaction mixture was stirred at room temperature for 6 hour. KOH solution ~l N) was added to neutralize the reaction mixture, and extracted with CH2Cl2. The extracts were dried (Na2SO4), concentrated and chromatographed on prep. TLC ( CH2Cl2: CH30H: 2 N NH3 in CH30H = 40:2:1) to give the title compound (18 mg, 50~) as a colorless oil. The hydrochloride of the title compound was synthesized using HCl in ether.
Anal. Calculated for C36H3~ClN4O6F3 + 1.0 HCl + O. 5 CHC13: C, 54.45~; H,4.68~; N,6.36~. Found: C, 54.04~;
H, 4.91~; N, 6.91%.
Example 68:
(+)-1-(5-(4-Cyano-4-phenylpiperidin-1-yl)-4(S)-methyl)pentyl-6-(3,4-difluorophenyl)-1,6-dihydro-5-(methoxycarbonyl)-4-methyl-2-pyrimidine.
a) (+)-1-(5-Lromo-4(S)-methyl)pentyl-6-(3,4-difluorophenyl)-1,6-dihydro-5-methoxycarbonyl-4-methyl-2-pyrimidone.
To a suspension of NaH (18 mg, 60~ dispersion in mineral oil, 0.45 mmol.) in THF (5 mL) was added a solution of (+)-6-(3,4-difluorophenyl-1,6-dihydro-2-methoxy-5-methoxycarbonyl-4-methyl-pyrimidine (0.12 g, 0.4 mmol.) and HMPA (0.07 mL, 0.4 mmol.) in THF
(15 mL) at 0~C. After 20 min, 2(5)-methyl-1, 5-W O 97/429S6 PCTrUS97/08335 dibromopentane (0.2 mg, 0.82 mmol.) was added. The reaction mixture was then refluxed for 2 h and quenched by water. It was partitioned bewteen ethyl acetate and water. The organic layer was separated, treated with 6N HCl (5 mL) solution and stirred at room temperature for 1 h. 'rhe organic layer was then separated and dried over Na2SO4. After the removal of solvent, the residue was flash chromatographed over silica gel (eluent: 1:1 hexane/ethyl acetate) to give the product in 81% yield (0.15 g) as a yellow oil.
b) (~)-1-(5-(4-Cyano-4-phenylpiperidin-1-yl)-4(S)-methyl)pentyl-6-(3,4-difluorophenyl)-1,6-dihydro-5-(methoxycarhonyl)-4-methyl-2-pyrimidone.
A mixture of (+)-1-(5-Bromo-4(S)-methyl)pentyl-6-(3,4-difluorophenyl)-1,6-dihydro-5-methoxycarbonyl-4-methyl-2-pyrimidone (0.138g, 0.31 mmol.), 4-cyano-4-phenylpiperidine hydrochloride (0.13B 9, 0.62 mmol.), potassium carbonate (0.22 g, 1.6 mmol.), sodium iodide (47 mg, 0.31 mmol.) and dioxane (8 mL) was refluxed overnight. The undissolved solid was then filtered off and the solvent was evaparated. The residue was purified by flash chromatographed over silica gel (eluent: ethyl acetate) to give the product in 18~ yield (0.030 g) as a yellow oil.
Treatment of the free base with one equivalent of lM
HCl in ether gave the ~ICl salt as a light yellow solid: mp 133-135~Ci [~!]D = 87.4 (1.75 mg/mL, MeOH).
Anal. Calc. for C31H36F2N4O3.HClØ3CHCl3: C, 60.35; H, 6.04; N, 8.99. Found: C, 60.26; H, 6.29; N, 8.67.
Example 69:
1-(5-(4-(2-Aminocarbonyl)phenylpiperazin-1-yl)-4(S)-methyl)pentyl-6-(3,4-difluorophenyl)-1,6-dihydro-5-methoxy-carbonyl-4-methyl-2-pyrimidone.
A mixture 1-(5-bromo-4(S)-methyl)pentyl-6-(3,4-difluorophenyl)-1,6-dihydro-5-methoxycarbonyl-4-methyl-2-pyrimidone (0.lg, 0.22 mmol.), 4-(2-aminocarbonylphenyl)piperazine (0.070 g, 0.34 mmol.), CA 02253862 l998-ll-09 W O 97/42956 PCTrUS97/08335 potassium carbonate (0.16 g, 1.2 mmol.), sodium iodide (33 mg, 0.22 mmol.) and dioxane (8 mL) was refluxed overnight. The undissolved solid was then filtered off and the solvent was evaparated. The residue was purified by flash chromatographed over silica gel (eluent: 20:1 ethy; acetate/2M ammonia in methanol) to give the product in 41~ yield (0.052 g) as a yellow oil. Treatment of the free base with one equivalent of lM HCl in ether gave the HCl salt as a pale yellow solid: mp 168-171~C; [CY]D = 83.5 (2 mg/mL, MeOH). Anal. Calc. for C30H37F2NsO42HCl 0.5CH2Cl2: C, 53.48; H, 5.89; N, 10.22. Found: C, 53.74; H, 5.94;
N, 9.99.
Example 70:
1-(5-(4-Cyano-4-phenyl)piperidin-1-yl)pentyl-6-(3,4-difluoro-phenyl)-1,6-dihydro-5-methoxycarbonyl-2-methoxymethyl-4-methyl-pyrimidine.
a) 6-(3,4-Di~luorophenyl)-1,6-dihydro-5-methoxycarbonyl-2-methoxy-methyl-4-methylpyrimidine.
To a solution of 2-methoxyacetamidine hydrochloride tl.4 g, 11.2 mmol.) in DMF (6 mL) were added a solution of potassium tert-butoxide (0.69 g, 6.1 mmol.) in DMF (6 mL) and a solution of methyl ~2-(3,4-difluorophenyl) methylene}-3-oxobutanoate (1.4 g, 5.8 mmol.) in DMF (6 mL) at 0~C. After the mixture was stirred for 0.5 hr at 0~C, p-toluenesulfonic acid monohydrate (2.2 g, 11.6 mmol.) was added. The mixture was heated at 100-120~C for 2.5 hrs. The mixture was cooled to room temperature, quenched with aqueous NaOH solution (2N, 30 mL), and extracted with ether. The organic layer was dried over Na2SO4 and evaporated. The residue was flash chromatographed over silica gel (eluent: ethyl acetate) to give the product in 44~ yield (0.8 g) as a yellow oil.
b) 1-(5-~romopentyl)-6-(3,4-difluorophenyl)-1,6-dihydro-5-methoxycarbonyl-2-methoxymethyl-4-methylpyrimidine.

To a suspension of NaH (0.11 g, 609~ dispersion in mineral oil, 2.8 mmol.) in THF (20 mL) was added a solution of 6-(3,4-difluorophenyl)-1,6-dihydro-5-methoxycarbonyl-2-methoxymethyl-4-methylpyrimidine (0.8 g, 2.6 mmol.) in THF (5 mL) at 0~C. After 20 min, 1,5-dibromopentane (O.7 TnD, 5.2 mmol.) was added. The mixture was then refluxed overnight. After the removal of solvent, the residue was flash chromatographed over silica gel (eluent: ethyl acetate) to give the product in quantitative yield (1.2 g) as a yellow oil.
c) 1-(5-(4-Cyano-4-phenyl)piperidin-1-yl)pentyl-6-(3,4-difluorophenyl)-1,6-dihydro-5-methoxycarbonyl-2-methoxymethyl-4-methylpyrimidine.
A mixture of 1-(5-~romopentyl)-6-(3,4-difluorophenyl)-1,6-dihydro-5-methoxycarbonyl-2-methoxymethyl-4-methylpyrimidine (0.15 g, 0.33 mmol.), 4-cyano-4-phenylpiperidine hydrochloride (0.15 g, 0.67 mmol.), potassium carbonate (0.23 g, 1.7 mmol.), sodium iodide (50 mg, 0.33 mmol.) and acetone (6 mL) was refluxed overnight. The undissolved solid was then filtered off and the solvent was evaporated. The residue was flash chromatographed over silica gel (eluent: 10:1 ethyl acetate/2M ammonia in methanol) to give the title compound in 44~ yield (0.080 g) as a yellow oil.
Treatment of the free base with 2 equi~alents of lM
HCl in ether gave the HCl salt as an off-white solid:
mp 98-101~C. Anal. Calc. for C32H38F2N4O3 2HCl l.lCHCl3:
C, 51.70; H, 5.39; N, 7.29. Found: C, 51.56; H, 5.52;
N, 7.27.
Example 71:
(I)-6-(3,4-Difluorophenyl)-16-dihydro-5-methoxycarbonyl-2,4-dimethyl-1-(4~S)-methyl-5-(4-(2-methylphenyl)-4-(4-methyl-phenyl)piperidin-1-yl)pentyl)pyrimidine.
a) (I)-1-(5-Bromo-4(S)-methylpentyl)-6-~3,4-CA 022~3862 1998-11-09 WO 97/42956 PCTrUS97/0833S

difluorophenyl)-1,6-dihydro-5-methoxycarbonyl-2,4-dimethylpyrimidine.
To a suspension of NaH (47 mg, 6096 dispersion in mineral oil, 1.17 mmol.) in THF (3 mLJ was added a solution of 6-(3, 4-difluorophenyl)-1,6-dihydro-5-methoxycarbonyl-2,4-dimethyl-pyrimidine (0.3 g, 1.07 mmol.) and HMPA (0.193 g, 1.07 mmol.) in THF (4 mL) at 0~C. After 10 min, a solution of (-)-2-methyl-1,5-dibromopentane (0.86 g, 3.53 mmol.) in THF (5 mL) was added. The reaction mixture was then refluxed for 10 min. The solid formed was filtered off. After the removal of solvent, the residue was flash chromatographed over silica gel (eluent: 20:1 ethyl acetate/2M ammonia in methanol) to give the product in 3696 yield (0.169 g) as a yellow oil. Chiral HPLC
separation of the above diastereomers (Column:
Chiralcel OD 20 x 250 mm. Eluent: 2-propanol/hexane/diethylamine 10:90:0.1) gave the desired enantiomer: ~]D = 200.9 (25.5 mg/mL, CH2C12).
b) (+)-6-(3,4-Difluorophenyl)-1,6-dihydro-5-methoxycarbonyl-2,4-dimethyl-1-(4(S)-methyl-5-(4-(2-methylphenyl)-4-(4-methyl-phenyl)piperidin-1-yl)pentyl)pyrimidine.
A mixture of (+)-1-(5-bromo-4(S)-methylpentyl)-6-(3,4-difluorophenyl)-1,6-dihydro-5-methoxycarbonyl-2,4-dimethyl-pyrimidine (0.1 g, 0.23 mmol.), 4-(2-methylphenyl)-4-(4-methylphenyl)piperidlne hydrochloride (0.08 g, 0.26 mmol.), potassium carbonate (0.18 g, 1.3 mmol.), sodium iodide (0.033 g, 0.26 mmol.) and acetone (8 mL) was refluxed overnight. The undissolved solid was then filtered off and the solvent was evaporated. The residue was flash chromatographed over silica gel (eluent: 10:1 ethyl acetate/2M ammonia in methanol) to give the title compound in 64~ yield (0.090 g) as a yellow oil. Treatment of the free base with 2 equivalents of lM HCl in ether gave the HCl salt as a light ~. .

CA 02253862 lsss-ll-os W O 97/42956 PCTrUS97/08335 yellow solid: mp 130-133~C; [tY]D = 62.4 (1.85 mg/mL, MeOH). Anal. Calc. for C39H47F2N3O22HCl 2H2O 0.65CHCl3:
C, 58.48; H, 6.64; N, 5.16. Found: C, 58.27; H, 6.46;
N, 5.40.
Example 72:
(+)-6-(3,4-Difluorophenyl)-1,6-dihydro-5-~ethoxycarbonyl-2-methoxymethyl-4-methyl-1-(5-(4-~2-methylphenyl)-4-(4-methyl-phenyl)piperidin-1-yl)pentyl)pyrimidine.
a) (+)-1-(5-Bromopentyl)-6-(3,4-difluorophenyl)-1,6-dihydro-5-methoxycar~onyl-2-methoxymethyl-4-methylpyrimidine.
To a suspension of NaH (0.11 g, 60~ dispersion in mineral oil, 2.8 mmol.) in THF (20 mL) was added a solution of 6-(3,4-difluorophenyl)-1,6-dihydro-5-methoxycarbonyl-2-methoxymethyl-4-methylpyrimidine (0.8 g, 2.6 mmol.) in THF (5 mL) at 0~C. After 20 min., 1,5-di~romopentane (0.7 mL, 5.2 mmol.) was added. The mixture was then refluxed overnight. After the removal of the solvent, the residue was flash chromatographed over silica gel (eluent: ethyl acetate) to give the product in quantitative yield (1.2 g) as a yellow oil. Chiral HPLC separation (Column: Chiralcel OD 20 x 250 mm. Eluent: 2-propanol/hexane/diethylamine 10:90:0.1) gave the title enantiomer: [a]D = 190.5 (55 mg/mL, CH2Cl2).
~) (+)-6-(3,4-Difluorophenyl)-1,6-dihydro-5-methoxycarbonyl-2-methoxymethyl-4-methyl-1-(5-(4-(2-methylphenyl)-4-(4-methyl-phenyl)piperidin-1-yl)pentyl)pyrimidine.
A mixture of (~)-1-(5-bromopentyl)-6-(3,4-difluorophenyl)-1, 6 -dihydro-5-methoxycarbonyl-2-methoxymethyl-4-methylpyrimidine (0.08 g, 0.17 mmol.), 4-(2-methylphenyl)-4-(4-methylphenyl)piperidine hydrochloride (0.063 g, 0.21 mmol.), potassium carbonate (0.14 g, 1.0 mmol.), sodium iodide (26 mg, 0.17 mmol.) and acetone (6 mL) W O 97/42956 PCTrUS97/08335 -168-was refluxed overnight. The undissolved solid was then filtered off and the sol~ent was evaporated.
The residue was flash chromatographed over silica gel (eluent: 10:1 ethyl acetate/2M ammonia in methanol) to give the title compound in 89~ yield (0.1 g) as a yellow oil. Treatment of the free base with 2 equivalents of lM HCl in ether gave the HCl salt as a pale yellow solid: mp 137-140~C; [~]~ = 56.5 (1.65 mg/mL, MeOH). Anal. Calc. for C39H47F2N3O32HCl 2H2O 0.75CHC13: C, 56.68; H, 6.43; N, 4.99. Found: C, 56.55i H, 6.19; N, 5.02.
Example 73:
~ 1,2,3,6-Tetrahydro-l-{N-[3-~4,4-diphenylpiperidin-1-yl)-propyl]}ca~hoY~mido-5-methoxycarbonyl-2-oxo-6-~3,4-difluoro-phenyl)-4-methoxymethylpyrimidine hydrochloride.
A solution of (+)-6-(3,4-difluorophenyl)-1,2,3,6-tetrahydro-2-oxo-5-methoxycarbonyl-4-methoxymethyl-1-(4-nitrophenoxy)-carbonylpyrimidine (0.160 g) and 3-(4,4-diphenyl-piperidin-1-yl)propylamine(0.150 g) in tetrahydrofuran (10 mL) was stirred at room temperature for 14 hours. The product was purified by preparative thin layer chromatography on silica gel using ethyl aceate as eluent to give 0.22 g of the product as a syrup, which was converted to the hydrochloride salt by treatment with lN HCl in ether;
m.p. 178-181 ~C; [~]D = +99.6 (c = 0.24, MeOH). Anal.
Calcd. for C3sH39ClF2N4OsØ2CH2Cl2: C, 60.93; H, 5.74;
N, 8.06. Found: C, 60.73; H, 5.89; N, 7.92.
Example 74:
(+)-1,2,3,6-Tetrahydro-l-{N-[3-(4,4-diphenylpiperidinl-yl)-propyll}carboxamido-5-acetyl-2-oxo-6-(3,4,5-trifluorophenyl)-4-methylpyrimidine dihydrochloride.
A mixture of 6-(3,4,5-difluorophenyl)-1,2,3,6-tetrahydro-2-oxo-W097/429~6 PCT~S97/08335 5-acetyl-4-methyl-1-[(4-nitrophenyloxy)carbonyl]pyrim idine (0.150 g) and 3-(4,4-diphenylpiperidin-1-yl)propylamine~0.180 g) in T~F
(10 mL) was stirred at room temperature for 14 h. The product was purified by preparative thin layer chromatography on silica gel using ethyl aceate as eluent to gi~e 0.23 g of the product as a syrup, which was converted to the hydrochloride salt by treatment with lN HCl in ether; m.p. 180-182 ~C.
Anal. Calcd. for C34H36ClF3N4O3.1CH2C12: C, 57.90; H, 5.28; N, 7.72. Found: C, 57.54; H, 5.10; N, 7.79.
Example 75:
(+)-1,2,3,6-Tetrahydro-1-{N-~3-~4-(2-methylphenyl)-4-(4-methylphenyl)piperidin-l-yl)-propyl]}carboxamido-5-ac etyl-2-oxo-6-(3,4,5-trifluorophenyl)-4-methylpyrimidine hydrochloride.
A mixture of 6-(3,4,5-difluorophenyl)-1,2,3,6-tetrahydro-2-oxo-5-acetyl-4-methyl-1-[(4-nitrophenyloxy)carbonyl]pyrim idine (0.02 g) and 3-[4-(2-methylphenyl)-4-(4-methylphenyl)-piperidin-1-yl]-propylamine(0.02 g) in THF (1 mL) was stirred at room temperature for 14 h.
The product was purified by preparative thinlayer chromatography on silica gel using ethyl aceate as eluent to give 0.03 g of the product as a syrup, which was converted to the hydrochloride salt by treatment with lN HCl in ether; m.p. 180-184 ~C.
Anal. Calcd. for C36H4CClF3N4O3Ø4CH2C12: C, 62.18; H, 5.85; N, 7.97. Found: C, 62.42; H, 6.00; N, 7.88.
Example 76:
(+)-6-(3,4-Difluorophenyl-1-[{N-~4-cyano-4-phenyl-piperidin-l-yl]-2,2-diflu~.o~ l}carboxamido]-5-methoxycarbonyl-4-methoxymethyl-2-oxo-1,2,3,6-tetrahydro-pyrimidine.
a) 3-~4-Cyano-4-phenyl-piperidin-1-yl](2-. . . ~ , .

hydroxypropyl)-phtha}imide.
A mixture of 4-cyano-4-phenylpiperidine (10 g, 44.9 mmol) and 2,3-epoxypropylphthalimide ~10.94 g, 53.9 mmol) in DMF (100 mL) was stirred and heated at 70 ~C
for 72 h. The solvent was evaporated under reduced pressure and the residue was purified by column chromatography on silica gel using chloroform-methanol-2M ~mmo~ia in methanol (1000/28/14) as the eluent, to obtain the desired product as a viscous oil (16.45 g, 86~).
b) 3-[4-Cyano-4-phenyl-piperidin-1-yl](2-G~ J~Y1) phthalimide.
To a stirred solution of DMSO (3.6 mL, 51.07 mmol) in dichloromethane (100 mL) at -78 ~C, oxalyl chloride (2.18 mL, 24.5 mmol) in dichloromethane ~15 mL) was added and the mixture was stirred for 3 min. To this, a solution of 3-[4-cyano-4-phenyl-piperidin-1-yl](2-hydroxypropyl)phthalimide (8.70 g, 20.42 mmol) in dichloromethane (25 mL) was added and the stirring was continued for 15 min. It was warmed to room temperature and added 5 mL of water.
The p~ of the mixture was adjusted to 10-11 by adding lN NaOH and the dichloromethane layer was separated.
The aqueous layer was extracted with more dichloromethane (3 X 100 mL). The combined dichloromethane extracts were dried (magnesium sulfate), solvents evaporated, and the residue was purified by flash chromatography on silica gel using ethyl acetate/hexane as eluent (6.05 g, 70%).
c) 3-~4~Cyano-4-phenyl-piperidin-1-yl](2,2-difluo~ G~yl)-phthalimide.
To a well stirred solution of 3-[4-cyano-4-phenyl-piperidin-1-yl]-(2-oxopropyl)phthalimide (0.22 g, 0.52 mmol) in anhydrous dichloromethane (25 mL) at -78~C, under argon atmosphere was added ~ diethyaminosulfur trifluoride (DAST) (0.251 mg, 1.56 mmol) and the mixture was allowed to warm to room CA 022~3862 1998-11-09 W097/42956 PCT~S97/08335 temperature. After 36 h, the reaction mixture was cooled to 0-5 ~C and to this saturated sodium bicarbonate solution (20 mL) was added cautiously.
The dichloromethane layer was separated, dried (sodium sulfate), and the solvent was evaporated.
The product was purified by flash column chromatography on silica gel using 30~ ethyl acetate in hexanes as eluent (80 mg, 38~ H-NMR was in agreement with the product.
d) 3-~4-Cyano-4-phenylpiperidin-1-yl](2,2-dif}uoro)propylamine.
A mixture of 3-[4-cyano-4-phenyl-piperidin-1-yl](2,2-difluoro-propyl)phthalimide (120 mg, 0.29 mmol) and hydrazine (0.5 mL g) in methanol (15 mL) was stirred and refluxed for 4.5 h. It was cooled, filtered, and the solid was washed with methanol (30 mL).
Evaporation of solvent from the filtrate gave the product as a viscous oil (60 mg, 73%) which was used in the next step without any further purification.
e) (~)-6-(3,4-Difluorophenyl-l-l{N-[4-cyano-4-phenyl-piperidin-1-yl~-2,2-difluoropropyl}-carboxamido]-5-methoxycarbonyl-4-methoxymethyl-2-oxo-1,2,3,6-tetrahydro-pyrimidine.
A solution of (+)-5-methoxycarbonyl-4-methoxymethyl-1~2~3~6-tetrahydro-2-oxo-6-(3~4-difluorophenyl)-l-[(4-nitrophenyloxy)-carbonyl]pyrimidine (38 mg, 0.077 mmol) and 3-[4-cyano-4-phenyl-piperidin-l-yl](2~2 difluoropropyl)propylamine (30 mg, 0.107 mmol) in dichloromethane (3 mL) was stirred at room temperature for 12 hours. The mixture was purified by preparative tlc on silica gel (60~ ethyl acetate in hexanes) to give 38 mg (81~) as a white powder.
The HCl salt was prepared by treatment of a solution of the free base in ether with lN HCl in ether. The white powder was dried and recrystallized from anhydrous 2-propanol. M.P. 184-186 DC; [alD = +96.36 (c = O.55, dichloromethane). Anal. Calcd. for . . , CA 022~3862 1998-11-09 WO 97/42956 PCTrUS97/08335 C30~32NsOsF4Cl:C, 55.12i H, 4.87; N, 9.95. Found: C, 55.09; H; 4.93; N, 9.71.
Example 77:
(+)-1,2,3,6-Tetrahydro-1-{N-14-(4-methoxycar~onyl-4-phenyl-piperidin-1-yl)-piperidinyl]}carbonyl-5-methoxycarbon yl-2-oxo-6-(3,4,5-trifluorophenyl)-4-methoxymethylpyrimidi ne hydrochloride.
a) 1-~enzyl-4-(4-Methoxycarbonyl-4~
phenylpiperidinl-yl)-piperidine.
A mixture of 4-methoxycarbonyl-4-phenylpiperidine (6.50 g, 0.0296 mol), N-benzyl-4-piperidone (5.62 g), and p-toluenesulfonic acid (100 mg) in benzene (100 mL) was heated at 110 ~C for 14 h with a Dean-Stark trap to remove the water that formed. Solvent was evaporated and the residue was redissolved in methanol ~20 mL). To this, sodium cyanoborohydride (1.86 g) was added in portions and the mixture was stirred at room temperature for 6 h. Solvent was evaporated, the residue was mixed with lN NaOH (10 mL) and the resultant mixture was extracted with ether (4 X 20 mL). The combined extracts were washed with brine (20 mL), dried (sodium sulfate), and the solvent evaporated. The residue was purified by column chromatography on silica gel using dichloro-methane/methanol/2M ammonia in methanol (50/20/10) as eluent. The product was obtained as a viscous oil (~.5 g), which on trituration with hexane became a white powder.
b) 4-(4-Methoxycarbonyl-4-phenylpiperidin-1-yl)-piperidine.
A mixture of 1-benzyl-4-(4-Methoxycarbonyl-4-phenylpiperidin-1-yl)piperidine (3.92 g) and 10% Pd-C
(0.4 g) in ethanol (200 m~) was hydrogenated at 80 psi for 12h. The catalyst was removed by filtration and the solvent was evaporated from the filtrate to . _, , W 097/42956 PCTrUS97/08335 leave the product (2.9 g, 96%) as a white powder.
c) (+)-1,2,3,6-Tetrahydro-1-{N-14-(4-methoxycarbonyl-4-phenyl-piperidin-l-yl)-piper~dinyl~}carbonyl-S-methoxycarbon yl-2-oxo-6-~3,4,5-trifluorophenyl)-4-methoxymethylpyrimidine hydrochloride.
A solution of (+)-6-(3l4~5-trifluorophenyl)-l~2~3~6-tetrahydro-2-oxo-5-methoxycarbonyl-4-methoxymethyl-1-(4-nitrophenoxy)-carbonylpyrimidine ~50 mg, prepared similarly to (+)-6-(3,4-difluorophenyl)-1,2,3,6-tetrahydro-2-oxo-5-methoxycarbonyl-4-methoxy-methyl-1-(4-nitrophenoxy)carbonylpyrimidine) and 4-(4-methoxycarbonyl-4-phenylpiperidin-1-yl)piperidine(50 mg) in THF (2 mL) was stirred at room temperature for 14 hours. The product was purified by preparative thin layer chromatography on silica gel using ethyl aceate as eluent to give 70 mg of the product as a syrup, which was converted to the hydrochloride salt by treatment with lN HCl in ether; m.p. 178-181 ~C;
[~D = +135 (c = 0.65, MeOH). Anal. Calcd. for C3sH38ClF3N4O7Ø4CH2Cl2: C, 55.02; H, 5.36; N, 7.68.
Found: C, 55.22; H, 5.48; N, 7.56.
Example 78:
(+)-1,2,3,6-Tetrahydro-l-{N-[2-(4-phenyl-4-methoxyc~rh~nyl)-piperidin-1-yl)ethyl]}acetamido-5-methoxycarbonyl-2-oxo-6-(3,4-difluorophenyl)-4-methylpyrimidine hydrochloride.
a) (~)-1,2,3,6-Tetrahydro-1-~bezyloxycarbonylmethyl)-5-met~oxy-carbonyl-2-oxo-6-(3,4-difluorophenyl)-4-methylpyrimid ine .
A mixture of (+)-1,6-dihydro-5-methoxycarbonyl-2-methoxy-6-(3,4-difluorophenyl)-4-methylpyrimidine (0.296 g), W097/42956 PCT~S97/08335 benzyl bromoacetate (0.229 g~, potassium carbonate (0.600 g), and potassium iodide (30 mg) in acetone (20 mL) was he~ted under reflux for 14 h. It was filtered, washed with acetone (15 mL). To the combined filtrates 6N HCl (0.5 mL) was added and stirred for 4 h. Solvent was evaporated and the product was purified by preparati~e thin layer chromatography on silica gel using hexane/ethyl acetate (1:1) to give the product as a foam (0.20 g) which was used in the next step without further characterization.
b) (+)-1,2,3,6-Tetrahydro-5-methoxyc~rho~yl-2-oxo-6-(3,4-difluorophenyl)-4-methylpyrimidine-1-acetic acid .
To a suspension of 10~ Pd-C (20 mg) in MeOH (10 mL) and H2O (2 mL) was added a solution of (+)-1,2,3,6-tetrahydro-1-(benzyloxy-carbonylmethyl)-5-methoxycarbonyl-2-oxo-6-(3,4-difluorophenyl)-4-methylpyrimidine (200 mg) in methanol (1 mL) and the mixture was hydrogenated at 80 psi for 4 h. The black suspension was filtered through a pad of Celite and washed thoroughly with MeOH (100 mL). Solvent was evaporated from the combined filtrate to yield the product (+)-1,2,3,6-tetrahydro-1-5-methoxycarbonyl-2-oxo-6-(3,4-difluorophenyl)-4-methylpyrimidine-1-acetic acid as a white solid (0.15 g). It was used in the next step without further purification.
c) (~)-1,2,3,6-Tetrahydro-1-{N-[2-(4-phenyl-4-methoxycarbonyl)-piperidin-1-yl)ethyl~}acetamido-5-methoxycarh~nyl-2-oxo-6-(3,4-difluorophenyl)-4-methylpyrimidine hydrochloride.
A mixture of (+)-1,2,3,6-tetrahydro-1-5-methoxycarbonyl-2-oxo-6-(3,4-difluorophenyl)-4-methylpyrimidine-1-acetic acid ~20 mg), 2-(4-phenyl-4-W O 97/42956 PCTrUS97/08335 methoxycarbonyl)piperidin-l-yl)ethylamine ~20 mg), l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride ~20 mg), and 4-(N,N-dimethylamino)pyridine (20 mg) in anhydrous dichloromethane (4 mL) was stirred at room temperature for 12 h. The reaction mixture was purified by preparative thin layer chromatography on silica gel using ethyl acetate as the eluent. The product was dissolved in ether (0.5 mL), cooled to 0-5 ~C and treated with lN HCl in ether (10 mL) and the solvents evaporated to leave the product as a white powder ~25 mg); mp 2~7-250~C; [a3D = ~108.2 (c = 0.50, MeOH). Anal. Calcd. for C30H3sN4O6F~Cl: C, 58.02; H, 5.68; N, 9.02. Found: C, ~8.21; H; 5.70; N, 8.92.
Example 79:
1,6-Dihydro-l-{N-[2-(4-phenyl-4-methoxy~ar~nyl)piperidin-l-yl)-ethyl]}acetamido-5-methoxycarbonyl-6-(3,4,5-trifluorophenyl)-2,4-dimethylpyr~midine dihydrochloride.
a) 6-~3,4,5-trifluorophenyl)-1,6-dihydro-5-methoxyca~ yl-2,4-dimethylpyrim~dine.
To a solution of acetamidine hydrochloride (1.41 g, 14.9 mmol.) In DMF (10 mL) was added a solution of potassium tert-butoxide (12 mL, 1.0 M in THF ) at 0~C.
After stirred for 10 minutes, a solution of methyl {2-(3,4,5-trifluorophenyl)methylene}-3-oxobutanoate (2.10 g, 10.0 mmol) in DMF (10 mL) was added and the mixture was stirred for 2 hours while warmed up to room temperature. p-Toluenesulfonic acid monohydrate (4.50 g, 23.6 mmol) was added to the solution and the reaction mixture was heated at 110-120 ~C for 2 hours.
The mixture was cooled to room temperature and poured into ice (100 g) and aqueous NaOH solution (3 N, 200 mL), and extracted with ether ~3x100 mL). The organic layers were combined, dried (K2CO3) and e~aporated.
The residue was purified by flash chromatography o~er silica gel (eluent: 10-15~ MeOH in methylene chloride) to afford the product in 47~ yield ( 1.4 g )as an oil.
b) 1,6-Dihydro-1-{bezyloxycarbonylmethyl)-5-methoxycarbonyl-6-(3,4,5-trifluorophenyl)-2,4-dimethylpyrimidine. A
mixture of 1,6-dihydro-5-methoxycarbonyl-6-(3,4,5-trifluorophenyl)-2,4-dimethylpyrimidine (0.298 g), benzyl bromoacetate (0.229 g), potassium carbonate (0.600 g), and potassium iodide (30 mg) in acetone (20 mL) was heated under reflux for 14 h. It was filtered, washed with acetone (15 mL). Solvent was evaporated and the product was purified by preparative thin layer chromatography on silica gel using hexane/ethyl acetate (l:1) to give the product as a foam (0.34 g).
NMR confirmed it to be the desired product which was used in the next step without any further characterization.
c) 1,6-Dihydro-5-methoxyc a ~honyl-6-(3,4,5-trifluorophenyl)-2,4-d~methylpyrimidine-1-acetic acid. To a suspension of 10~ Pd-C (30 mg) in MeOH ~10 mL) and H2O (2 mL) was added a solution of 1,6-dihydro~ bezyloxycarbonylmethyl)-5-methoxycarbonyl-6-(3,4,5-trifluorophenyl)-2,4-dimethylpyrimidine (300 mg) in methanol (1 mL) and the mixture was hydrogenated at 80 psi for 4 h. The black suspension was filtered through a pad of Celite and washed thoroughly with MeOH (100 mL). Solvent was evaporated from the combined filtrate to leave the product 1,6-dihydro-5-methoxycarbonyl-6-(3,4,5-trifluorophenyl)-2,4-dimethy lpyrimidine-1-acetic acid as a white solid (0.225 g)~
It was used in the next step without further purification.
d) 1,6-Dihydro-1-{N-l2-(4-phenyl-4-, . , Wog7/429~6 PCT~S97108335 methoxycarbonyl)piperidin-l-yl)ethyl]}acetamido-5-methoxy~rh~nyl-6-(3,4,5-trifluoro-phenyl)-2,4-dimethylpyrimidine dihydrochloride.
A mixture of l,6-dihydro-5-methoxycarbonyl-6-(3,4,5-trifluoro-phenyl)-2,4-dimethylpyrimidine-l-acetic acid (20 mg), 2-(4-phenyl-4-methoxycarbonyl)piperidin-l-yl)ethylamine (20 mg), l-(3-dimethyl-aminopropyl)-3-ethylcarbodiimide hydrochloride ~20 mg), and 4-(N,N-dimethylamino)pyridine (20 mg) in anhydrous dichloromethane (4 mL) was stirred at room temperature for 12 h. The reaction mixture was purified by preparative thin layer chromatography on silica gel using ethyl acetate as the eluent. The product was dissolved in ether (0.5 mL), cooled to 0-5 ~C and treated with lN HCl in ether (l0 mL) and the solvents evaporated to leave the product as a white powder (25 mg); m.p. 187-l90 ~C; Anal. Calcd. for C31H3,N4O5F3Cl2: C, 55.28; H, 5.54; N, 8.32. Found: C, 55.36; H; 5.80; N, 8.41.
Example 80:
(+)l,2,3,6-Tetrahydro-l-{N-[4-(2-ni~rophenyl)piperazin-l-yl]-propyl}-carhox~;do-4-methyl-6-(3,4-difluorophenyl)-2-oxo-pyrimidine.
a) l-(2-nitrophenyl)-piperazine.
A heterogenous reaction mixture containing 2-bromo-l-nitrobenzene (2.02 g, l0.0 mmol) and piperazine (4.3 g, 50.0 mmol) was heated at 100~C for l0 h. The orange-red solid was extracted with ethyl acetate and washed thoroughly with 3 N NaOH solution followed by brine. The organic layer was separated and dried over Na2SO4, filtered and the solvent was removed in vacuo. The resulting red oil was purified by column chromatography on silica gel (l:l hexane/EtOAc followed by 4:l EtOAc/MeOH) to yield l-(2-nitro-~ phenyl)-piperazine as an orange-red oil (l.90 g, 92%). It was converted to its hydrochloride salt.

CA 022~3862 1998-11-09 W0~7/429S6 PCT~$97/0~35 Anal. calcd. for CloH14N3O2Cl 0.10 C~Cl3: C, 47.46; H, 5.56; N, 16.44. Found: C, 47.63; H, 5.69; N, 16.42.
b) (+)-1,2,3,6-Tetrahydro-1-{N-~4-(2-nitrophenyl)piperazin-1-yl~propyl}-carboxamido-4-methyl-6-(3,4-difluorophenyl)-2-oxo-pyrimidine.
To a solution of (+)-1-(3-bromo-propylcarbamoyl)-6-(3,4-difluoro-phenyl)-4-methyl-2-oxo-1,6-dihydro-pyrimidine-5-carboxylic acid methyl ester (0.22 g, 0.5 mmol) and 1-(2-nitro-phenyl)-piperazine (0.15 g, 0.75 mmol) in 20 mL of anhydrous acetone was added powdered K2CO3 ~0.34 g, 3.5 mmol) and KI (0.07 g, 0.5 mmol) and the resulting suspension was heated to reflux for 10 h. The suspension was cooled, filtered and the solvent was evaporated and the residue was purified by column chromatography on silica gel with EtOAc/MeOH (5:1) as the eluting system. (+)-1,2,3,6-tetrahydro-1-{N-4-(2-nitrophenyl)piperazin-1-yl]propyl~-carboxamido-4-methyl-6-(3,4-difluorophenyl)-2-oxo-pyrimidine was obtained as a yellow oil (0.08 g, 29~ yield). The product was analyzed as its hydrochloride salt. M.P. 133-136~C;
[~D = +56.7 (c = 0.11, MeOH). Anal. calcd. for C27H3lN6F2O6Cl 0.20 CH2Cl2: C, 51.62; H, 4.97; N, 13.28.
Found: C, 51.35; H, 5.18; N, 11.99.
Example 81:
(+)-1,2,3,6-Tetrahydro-1-{N-[4-(2-amino-phenyl)piperazin-1-yl~propyl}-car~oxamido-4-methyl-6-(3,4-difluorophenyl)-2-oxo-pyrimidine.
To a cooled suspension of 10~ palladium on carbon (40 mg) in methanol (25 mL) was added a solution of (+)-1,2,3,6-tetrahydro-1-{N-4-(2-nitrophenyl)piperazin-lyl]propyl}-carboxamido-4-methyl-6-(3~4-difluorophenyl)-2-oxo-pyrimidine (50 mg, 0.09 mmol) in methanol (5 mL) and the resulting suspension was hydrogenated at 100 psi at room temperature for 3 h.
The suspension was filtered through a pad of celite and washed with 50 mL of methanol. The solvent was ~ . .

CA 022~3862 l998- 1 1 - os WO 97l42956 PCT/US97/0833S

removed in vacuo from the combined filtrate to get 0.03 g (6096) of (+)-1,2,3,6-tetrahydro-1-{N-l4-(2-amino-phenyl)-piperazin-1-yl]propyl}-carboxamido-4-methyl-6- (3,4-difluoro-phenyl)-2-oxo-pyrimidine as a yellow oil. No purification was performed on this material and it was characterized as its dihydrochloride salt. Mass spectrum (low res.) 543 (M+l, 100~); [a]D = + 75.1 (c = 0.41, MeOH); Anal calcd. for C27H34N6F2O4Cl2 0.03 CHCl3: C, 52.48; H, 5.54;
N, 13.59. Found: C, 52.35; H, 5.83; N, 12.50.
Example 82:
1,2,3,6-Tetrahydro-l-{N-[4-(6-(nitro)pyrid-2-yl)piperazin-1-yl] propyl}-carboxamido-4-methyl-6-(3,4-difluorophenyl)-2-oxo-pyrimidine.
a) 1-16-tn~ tro)pyrid-2-yl]piperazine.
To a solution of 2-chloro-3-nitropyridine (1.58 g, 10.0 mmol) in 1,4-dioxane (50 mL) was added piperazine (4.3 g, 50.0 mmol) and powdered K2CO3 (50.0 mmol, 6.9 g) and the resulting suspension was heated at reflux for 10 h. After the suspension was cooled, it was extracted with ethyl acetate (2 X 50 mL) and washed successively with 3 N NaOH (20 mL) and water (20 mL). The organic layer was dried over Na2SO4, ~iltered and the solvent was removed in vacuo. The resulting residue was purified by column chromatography on silica gel (1:1 hexane/EtOAc followed by 4:1 EtOAc/MeOH) to yield 1- [6-(nitro)pyrid-2-yl] piperazine as a yellow solid. It was charcterized as a hydrochloride salt.
Anal calcd. for CgH12N4O2Cl 0.25 CHCl3: C, 40.47; H, 4.86; N, 20.41. Found: C, 40.72; ~I, 4.97; N, 20.50.
b) 1,2,3,6-Tetrahydro-1-{N-[4-(6-(nitro)pyrid-2-yl)piperazin-1-yl~propyl}-ca~ i do-4-methyl-6-(3,4-difluorophenyl~-2-oxo-pyrimidine.
To a solution of 1-(3-bromo-propylcarbamoyl)-6-(3,4-difluoro-phenyl)-4-methyl-2-oxo-1,6-dihydro-pyrimidine-5-carboxylic acid methyl ester (0.04 g, W097/42g56 PCT~S97/08335 0.1 mmol) and 1-[6-(nitro)pyrid-2-yl]-piperazine (0.03 g, 0.15 mmol) in 10 mL of anhydrous acetone was added powdered K2CO3 (0.06 g, 0.6 mmol) and KI (0.01 g, 0.10 mmol) and the resulting suspension was heated to reflux for 10 h. The suspension was cooled, filtered and the solvent was evaporated in vacuo. The residue was purified by column chromatography on silica gel with EtOAc/MeOH (5:1) as the eluting system. 1,2,3,6-tetrahydro-1-~N-[4-(6-(nitro)pyrid-2-yl)-piperazin-1-yl]propyl}-carboxamido-4-methyl-6-~3,4-difluoro-phenyl)-2-oxo-pyrimidine was obtained as a yellow oil (0.04 g, 70~ yield). The product was analyzed as its hydrochloride salt. M.P. 142-145~C;
Anal calcd. for C26H30N7F2O6Cl 0.30 CH2Cl2: C, 48.91; H, 4.74; N, 15.18. Found: C, 48.94; H, 4.94; N, 13.29.
Example 83:
~+)-1,2,3,6-Tetrahydro-1-{N-~2-(S)-methyl)-4-(2-nitrophenyl)-piperazin-l-yl]propyl}-carboxamido-4-methyl-6-~3,4-difluoro-phenyl)-2-oxo-pyrim~dine.
a) (S)-(+)-3-methyl-1-(2-nitrophenyl)piperazine.
To a solution of 2-bromo-1-nitrobenzene (0.6 g, 3.0 mmol) in 1,4-dioxane (15 mL) was added ~S)-(+)-2-methylpiperazine (0.5 g, 0.5 mmol) and powdered K2CO3 (15.0 mmol, 1.5 g) and the resulting suspension was heated at reflux for 10 h. After the suspension was cooled, it was filtered through a sintered glass funnel and the solvent was evaporated in vacuo. The resulting residue was purified by column chromatography on silica gel (1 1 hexane/EtOAc followed by 4:1 EtOAc/MeOH) to yield (S)-(+)-3-methyl-1-(2-nitrophenyl)-piperazine as an orange oil (0.53 g, 80%).
b) (I)-1,2,3,6-Tetrahydro-l-{N-[2-(S)-methyl)-4-(2-nitrophenyl)-piperazin-1-yl]propyl}-carboxamido-4-methyl-6-(3,4-difluoro)-phenyl-2-oxo-pyrimidine.
To a solution of (+)-1-(3-bromopropylcarbamoyl)-6-(3,4-difluorophenyl)-4-methyl-2-oxo-1,6-dihydro-CA 02253862 1998-ll-09 W O 97/42956 rcTrusg7/08335 pyrimidine-5-carboxylic acid methyl ester (0.2 g, 0.5 mmol) and (S)-(+)-3-methyl-1-(2-nitrophenyl)piperazine (0.17 g, 0.75 mmol) in 20 mL
of anhydrous acetone was added powdered K2CO3 (0.34 g, 3.5 mmol) and KI ~0.07 g, 0.5 mmol) and the resulting suspension was heated to reflux for 10 h. TLC
~ indicated a new spot for the product (Rf = 0.3, 3:0.5 EtOAc/MeOH) and mostly the starting material. The suspension was cooled, filtered and the solvent was evaporated and the residue was purified by column chromatography on silica gel with EtOAc/MeOH (5:1) as the eluting system. (+)-1,2,3,6-Tetrahydro-l-~N-[2-(S)-methyl)-4-(2-nitrophenyl)piperazin-1-yl~propyl}-carboxamido-4-methyl-6-~3,4-difluorophenyl)-2-oxo-pyrimidine was obtained as yellow oil (0.03 g, 10 yield). The product was analyzed as its hydrochloride salt. M.P. 150-153~C; E~]D = 58.3 (c =
0.3, MeOH); Anal calcd. for Cz~H33N6F2O6Cl 0.20 CH2Cl2:
C, 52.92; H, 5.26; N, 13.13. Found: C, 52.84; H, 5.68; N, 12.94.
Example B4:
A)(+)-1,2,3,6-Tetrahydro-5-methoxycarhonyl-4-methyl-2-oxo-1-{N-[2-(R)-methyl)-4-(2-nitrophenyl)piperazin-1-yl]propyl}-6-(3,4-difluorophenyl)pyrimidine.
a) (R)-(+)-3-methyl-1-(2-nitrophenyl)piperazine.
To a solution of 2-bromo-nitrobenzene (0.4 g, 2.0 mmol) in 1,4-dioxane ~10 mL) was added (R)-(+)-2-methylpiperazine (0.25 g, 0.25 mmol) and powdered K2CO3 (7.5 mmol, 0.8 g) and the resulting suspension was heated at reflux for 10 h. After the suspension was cooled, it was filtered through a sintered glass funnel and the solvent was evaporated in vacuo. The resulting residue was purified by column chromatography on silica gel (1:1 hexane/EtOAc followed by 4:1 EtOAc/MeOH) to yield (R)-(+)-3-- methyl-1-(2-nitrophenyl)-piperazine as an orange-red oil (0.26 g, 78~).

, W O 97142956 PCTrUS97/08335 b) (+)-1,2,3,6-Tetrahydro-5-methoxycarbonyl-4-methyl-2-oxo-1-{N-t2-(R)-methyl)-4-(2-nitrophenyl)piperazin-1-yl]propyl}-6-~3,~-difluorophenyl)pyrimidine.
To a solution of (+)-1-(3-bromo-propylcarbamoyl)-6-(3,4-difluorophenyl)-4-methyl-2-oxo-1,6-dihydro-pyrimidine-S-carboxylic acid methyl ester (0.11 g, 0.25 mmol) and (R)-(+)-3-methyl-1-(2-nitrophenyl)-piperazine (0.11 g, 0.50 mmol) in 20 mL of anhydrous acetone was added powdered K2CO3 (0.34 g, 3.5 mmol) and KI (0.07 g, 0.5 mmol) and the resulting suspension was heated to reflux for 10 h. TLC
indicated a new spot for the product (Rf = 0.3, 3:0.5 EtOAc/MeOH) and mostly the starting material. The suspension was cooled, filtered and the solvent was evaporated and the residue was purified by column chromatography on silica gel with EtOAc/MeOH (5:1) as the eluting system.(+)-1,2,3,6-Tetrahydro-5-methoxycarbonyl-4-methyl-2-oxo-1-{N-[2-(R)-methyl)-4-(2-nitrophenyl)piperazin-1-yl]propyl~-6-(3,4-difluorophenyl)-pyrimidine was obtained as yellow oil (0.02 g, 14~ yield). The product was analyzed as its hydrochloride salt. M.P. 135-138~C; ~] D = + 63.5 (c = 0.2, MeOH); Anal calcd. for C28H33N6F2O6C1 1.0 CHCl3:
C, 46.g2; H, 4.62; N, 11.32. Found: C, 46.94; H, 4.97; N, 11.47.
Example 85:
~ 1,2,3,6-Tetrahydro-5-methoxycarbonyl-4-methoxymethyl-2-oxo-1-{N-~4-(2-methoxy-5-methyl)phenyl-4-phenyl-piperidin-1-yl]propyl}-6-(3,4-difluorophenyl) pyrimidine.
a) 4-(2-Nethoxy-5-methyl)phenyl-4-phenylpiperidine hyd Gchloride.
To a 100 mL round bottom flask equipped with a rubber septum and a stirring bar was added 4-hydroxy-4-phenyl-piperidine (1.25 g, 7.0 mmol) followed by 10 mL of 4-methylanisole. The resulting solution was stirred at room temperature under argon atmosphere ..

W097/42956 PCT~S97/08335 and then AlCl3 (2.82 g, 21.0 mmol) was added in one portion. An exotherm was observed. The reaction mixture was stirred for 8 h and then poured carefully over 150 ml of ice-water. The white solid that precipitated out was filtered and washed thoroughly with water followed by diethyl ether to obtain 4-(2-methoxy-5-methyl)-phenyl-4-phenyl-piperidine hydrochloride ~1.59 g, 50%) as a white solid. Mass spectrum: 282 (M+1, 100~). Anal calcd. for ClgH24NOCl 0.15 CH2Cl2: C, 69.57; H, 7.41; N, 4~24.
Found: C, 69.62; H, 7.31; N, 4.36.
b) 3-l4-(2-methoxy-5-methyl)phenyl-4-phenyl-piperidin-l-yl~-propylamine.
To a solution of 4-(2-methoxy-5-methyl)-phenyl-4-phenyl-piperidine (0.6 g, 2.1 mmol) in 30 mL dioxane was added 3-bromo-N-tert-butoxycarbonyl-propylamine (0.6 g, 2.5 mmol) and K2CO3 (0.6 g, 6.0 mmol) and the resulting suspension was heated to reflux for 10 h.
The suspension was allowed to cool, filtered and the solvent was evaporated to obtain yellow residue which was purified by column chromatography (Rf = 0.4, 3:1 EtOAc/MeOH) to obtain 3-[4-(2-methoxy-5-methyl)phenyl-4-phenyl-piperidin-l-yl~-N-tert-butoxycarbonyl-propylamine as a yellow oil (0.35 g).
It was dissolved in 15 mL of CH2Cl2 and 3.0 mL of trifluoroacetic acid was added with stirring at room temperature under argon atmosphere for l h. The solvent was evaporated in vacuo and the residue was basified to pH 10 by adding minimum amount of 1 N KOH
solution. The product was extracted with CH2Cl2 (3 X
25 mL), dried over MgSO4, filtered and the solvent was remo~ed in ~acuo to obtain 3-[4-(2-methoxy-5-methyl)phenyl-4-phenyl-piperidin-1-yl]propylamine as a yellow oil (0.25 g, 35~ for two steps). It was used in the next step without further purification.
- c) (~)-1,2,3,6-Tetrahydro-5-methoxycarbonyl-4-methoxymethyl-2-oxo-l-{N-~4-(2-methoxy-5-W097/42956 PCT~S97/08335 methyl)phenyl-4-phenyl-piperidin-1-yl3propyl}-6-(3,4-difluorophenyl) pyrimidine.
To a solution of 3-[4-(2-methoxy-5-methyl)phenyl-4-phenyl-piperidin-1-yl]propylamine (0.12 g, 0.36 mmol' in 5.0 mL THF was added (+)l~6-dihydro-5-methoxycarbonyl-4-methoxymethyl-2-oxo-1-(4-nitrophenyloxy)carbonyl-6-(3,4-difluorophenyl)pyrimidine (0.12 g, 0.33 mmol) at room temperature and the resulting yellow solution was stirred for 6 h. The solvent was removed in vacuo and the resulting residue was subjected to column chromatography over silica gel (1:1 hexane/EtOAc to EtOAc to g:1 EtOAC/MeOH) to obtain (+)-1,2,3,6-tetrahydro-5-methoxycarbonyl-4-methoxymethyl-2-oxo-1-~N-[4-(2-methoxy-5-methyl)phenyl-4-phenyl-piperidin-1-yl]propyl}-6-(3,4-difluorophenyl)pyrimidine (0.12 g, 65~ as a yellow oil. It was converted into its HCl salt (pale yellow powder). M.P. 102-105~C- [~] D
= + 49.4 (c = 0.65, MeOH) Anal calcd. for C32H36N3O4F2Cl 1.5 CH2Cl2: C, 55.31; H, 5.40; N, 5.78.
Found: C, 55.55; H, 5.06; N, 6.08.
Example 86:
(+)-1,2,3,6-Tetrahydro-5-methoxycarbonyl-4-methoxymethyl-2-oxo-1-{N-[4-(4-methyl)-phenyl-4-(2-methyl)phenyl piperidin-1-yl~-propyl}-6-~3,4-difluorophenyl) pyrimidine.
a) 4-(4-methyl)phenyl-4-(2-methyl)phenylpiperidine hydrochloride.
To a 100 mL round bottom flask equipped with a rubber septum and a stirring bar was added 4-hydroxy-4-(4-methyl)phenyl-piperidine (1.25 g, 6.54 mmol) followed by 20 mL of anhydrous toluene. The resulting solution was stirred at room temperature under argon atmosphere and then AlCl3 ~1.4 g, 10.2 mmol) was added in one portion. An exotherm was observed. The reaction mixture was stiired for 10 h and then poured carefully over 100 ml of ice-water. The white solid W097/429S6 PCT~S97/08335 that precipitated out was filtered and washed thoroughly with water followed by diethyl ether ~o obtain 4-(4-methyl)phenyl-4-(2-methyl)phenylpiperidine hydrochloride (1.95 g, 99~) as a white solid. Mass spectrum: 266 (M+1, 100%).
Anal calcd. for C19H24NCl 0.15 CH2C12: C, 73.11; H, ~ 7.79; N, 4.45. Found: C, 73.33; H, 7.B2; N, 3.92.
b) 3-~4-(4-methyl)phenyl-4-(2-methyl)phenylpiperidin-1-yl~-propylamine.
To a solution of 4-(4-methyl)-phenyl-4-(2-methyl)phenyl piperidine hydrochloride (2.6 g, 9.8 mmol) in 100 ~L dioxane was added 3-bromo-N-tert-butoxycarbonyl-propylamine (2.57 g, 10.8 mmol) and K2CO3 (4.06 g, 29.4 mmol) and the resulting suspension was heated to reflux for 10 h. The suspension was allowed to cool, filtered and the solvent was evaporated to obtain a yellow residue which was purified by column chromatography over silica gel (Rf = 0.4, 3:1 EtOAc/MeOH) to give 3-14-(4-methyl)phenyl-4-(2-methyl)phenylpiperidin-1-yl]-N-tert-butoxycarbonyl-propylamine as a yellow oil (2.30 g).
It was dissolved in 60 mL of CH2C12 and 10.0 mL of trifluoroacetic acid was added with stirring at room temperature under argon atmosphere for l h. The solvent was evaporated in vacuo and the residue was basified to pH 10 by adding minimum amount of l N KOH
solution. The product was extracted with CH2Cl2 (3 X
25 mL~, dried over MgSO4, filtered and the solvent was removed in vacuo to obtain 3-[4-(4-methyl)-phenyl-4-(2-~ethyl)phenyl piperidin-1-yl]propylamine as a yellow oil (1.39 g, 44% for two steps). It was used in the next step without further purification.
C) (t )-1,2,3,6-Tetrahydro-5-methoxycarbonyl-4-methoxymethyl-2-oxo-1-{N-l4-(4-methyl)-phenyl-4-(2-methyl)phenylpiperidin-1-yl~-propyl}-6-(3,4-difluorophenyl)pyrimidine.
To a solution of 3-[4-(4-methyl)phenyl-4-(2-methyl)phenyl- piperidin-l-yl]propylamine ~0.10 g, 0.31 mmol) in 10.0 mL THF was added (+)-1,6-Dihydro-5-methoxycarbonyl-4-methoxymethyl-2-oxo-1-(4-nitrophenyloxy)carbonyl-6-(3,4-difluorophenyl)pyrimidine (0.10 g, 0.28 mmol) at room temperature and the resulting yellow solution was stirred for 8 h. The solvent was removed in vacuo and the resulting residue was subjected to column chromatography over silica gel ~1:1 hexane/EtOAc to EtOAc to 9:1 EtOAC/MeOH) to obtain (+)-1,2,3,6-Tetrahydro-s-methoxycarbonyl-4-methoxymethyl-2 {N-[3-[4-(4-methyl)phenyl-4-(2-methyl)phenylpiperidin-l-yl]propyl}-6-(3,4-difluorophenyl)pyrimidine (0.11 g, 70~) as a yellow oil. It was converted into its HCl salt (pale yellow powder). M.P. 103-107~C. [~]D = + 104.8 (c = 0.31, MeOH) Anal calcd. for C38H46N4OsF2Cl 0.66 CH2C12: C, 60.44; H, 6.32; N, 6.71. ~ound: C, 60.44; H, 6.21; N, 7.19.
Example 87:
(+)-1,2,3,6-Tetrahydro-5-methoxycarbonyl-4-methyl-2-oxo-l-{N-[3-(4-(4-methyl)phenyl-4-(2-methyl)phenylpiperidin-l-yl]propyl}-6-~3,4-difluorophenyl)pyrimidine.
To a solution of 3-[4-(4-methyl)phenyl-4-(2-methyl)phenyl-piperidin-1-yl]propylamine (0.25 g, 0.78 mmol) in 10.0 mL THF was added (+)-1,6-dihydro-5-methoxycarbonyl-4-methyl-2-oxo-1-(4-nitrophenyloxy)carbonyl-6-(3,4-difluorophenyl)pyrimidine (0.22 g, 0.67 mmol) at room temperature and the resulting yellow solution was stirred for 8 h. The solvent was removed in vacuo and the resulting residue was subjected to column chroma~ography over silica gel ~1:1 hexane/EtOAc to EtOAc to 9:1 EtOAC/MeOH) to obtain (+)-1,2,3,6-Tetrahydro-5-methoxycarbonyl-4-methyl-2-oxo-1-~N-~3-E4-(4-methyl)phenyl-4-(2-methyl)phenylpiperidin-1-, W 097/42g56 PCT~US97/08335 yl]-propyl~-6-(3,4-difluorophenyl)pyrimidine (0.19 g, 64~) as a yellow oil. It was converted into its HCl salt (pale yellow powder). M.P. 143-147~C. [~]~ = +
79.8 (c = O.25, MeOH). Anal. calcd. for C37H44N4O4F2Cl 0.50 CH2Cl2: C, 62.19; H, 6.26; N, 7.73.
Found: C, 62.15; H, 5.92; N, 7.21.
~ Example B8:
1,2,3,6-Tetrahydro-1-{[4-ben~;do-piperidin-1-yl]propyl}-c~h~Yamido-4-methyl-6-t3,4-difluorophenyl)-2-oxo-pyrimidine.
a) 4-Amino-l-benzylpiperidine.
To a solution of hydroxylamine hydrochloride (3.67 g, 52.8 mmol) in water ~10 mL) and ethyl alcohol (80 mL) was added 1-benzyl piperidone (10.0 g, 52.8 mmol) at room temperature. The reaction mixture was heated to reflux for 4 h and then stirred at room temperature overnight. The resulting white solid was filtered, washed with ether and dried (8.4 g, 80~). It was added in small portions to a suspension of lithium aluminum hydride (2.3 g, 60.0 mmol) in diethyl ether (150 mL) at room temperature and the suspension was heated to reflux for 8 h. The reaction mixture was cooled to 0~C and quenched with successive addition of water (3 mL), 3 N NaOH (3 mL) and water (9 mL). The white suspension was filtered and the filtrate was dried over MsSO4. The solvent was removed in vacuo after filtration. 4-Amino-1-benzyl-piperidine was obtained as a colorless oil (6.0 g). It was used in the next step without purification.
b) 1-Benzyl-4-ben~ dopiperidine.
To a biphasic solution of 4-amino-1-benzylpiperidine (6.0 g, 31.6 mmol), K2CO3 (8.71 g, 63.1 mmol) in CH2Cl2 (200 mL) and water (100 mL) was added ~enzoyl chloride (4.86 g, 34.7 mmol) in 20 mL of CH2Cl2 at 0~C
with stirring. After stirring for 4 h at room temperature, the layers were separated. The organic layer was washed with water, dried over MgSO4 and filtered. The solvent was removed in vacuo to obtain l-benzyl-4-benzamidopiperidine (8.16 g, B7~ yield) as a white solid. It was used in the next step without purification.
c) 4-Benzamido-piperidine.
To a suspension of 10% palladium on carbon (0.2 g) in 30 mL of ethyl alcohol was added a solution of 1-benzyl-4-benzamido- piperidine (0.5 g, 1.79 mmol) ln ethyl alcohol (10 mL). The resulting suspension was hydrogenated at 100 psi at 50~C for 30 h after which it was filtered through a pad of celite and the solvent was removed in vacuo to obtain 0.34 g (100%) of 4-bp~m;dopiperidine as a white solid. It was used in the next step without purification.
d) 1,2,3,6-Tetrahydro-1-{[4-benzamido-piperidin-1-yl]propyl}-carboxamido-4-methyl-6-(3,4-difluorophenyl)-2-oxo-pyr$midine.
To a solution of 1-(3-bromopropylcarbamoyl)-6-(3,4-difluoro-phenyl)-~-methyl-2-oxo-1,6-dihydropyrimidine-5-carboxylic acid methyl ester (0.04 g, 0.10 mmol) and 4-benzamidopiperidine (0.03 g, 0.15 mmol) in 15 mL of anhydrous THF was added triethylamine ~2 mL) and the resulting solution was heated to reflux for 10 h. The suspension was cooled, filtered and the solvent was evaporated. The residue was purified by column chromatography on silica gel with EtOAc/MeOH (5:1) as the eluting system. 1,2,3,6-tetrahydro-1-{[4-benzamidopiperidin-1-yl]propyl}carboxamido-4-methyl-6-(3~4-difluorophenyl)-2-oxo-pyrimidine was obtained as a yellow oil (0.02 g, 37% yield). The product was analyzed as its hydrochloride salt. M.P. 121-125~C.
Anal calcd. for C29H34NsF2OsCl 0.53 CHCll: C, 53.03; H, 5.20; N, 10.37. ~ound: C, 52.90; H, 5.61; N, 9.97.
Example 89:
4-(3,4-Difluorophenyl)-6-methoxymethyl-2-oxo-3-~3-(4-phenyl-4-(thiophen-2-yl)piperidin-1-yl)-- r -W097/42956 PCT~S97/0~35 propylcarbamoyl}-1,2,3,4-tetrahyd G~y~ imidine-5-carboxylic acid methyl ester.
a) 4-Phenyl-4-(thiophen-2-yl)piperidine.
To a solution of 4-hydroxy-4-phenylpiperidine (1.0 g, 5.6 mmol) and thiophene to.88 ml, 11 mmol) in 20 ml of CH2Cl2 was added AlCl3 (0.75 g, 5.6 mmol) at -78 ~C
- and the resulting reaction mixture was stirred for 1 h. The reaction mixture was basified with sat~d aqueous NaHCO3 and extracted with EtOAc. The organic layer was dried over Na2CO3 and concentrated in ~acuo to provide the product as a colorless oil which was subjected to the following reaction without further purification.
b) 3-(4-Phenyl-4-(thiophen-2-yl)piperidin-1-yl)propylamine.
A solution of 4-phenyl-4-(thiophen-2-yl)piperidine and 3-Boc-aminopropylbromide (1.0 g, 4.4 mmol) with 1 g of K2CO3 in 20 ml of dioxane was stirred at reflux for 12 h. The reaction mixture was diluted with water and extracted with EtOAc. The organic solution was dried over Na2SO4 and concentrated in vacuo to yield an oil which was subjected to column chromatography over silica gel (EtOAc) to provide 0.43 g (1.1 mmol, 20% for two steps) of 3-(4-phenyl-4-(thiophene-2-yl)piperidin-1-yl)-propylcarbamic acid tert-butyl ester as colorless oil. The ester in 5 ml of CH2Cl2 was added with 1 ml of CF3CO2H and resulting solution was stirred for 1 h at 25 ~C. The reaction mixture was concentrated in vacuo to yield oily mixture, which was dissolved in EtOAc and washed with aqueous NaHCO3. Concentration of the reaction mixture provided the desired product as an oil (0.29 g, 0.96 mmol, 88%) which was used in the next step without further purification.
c) 4-(3,4-Difluorophenyl)-6-methoxymethyl-2-oxo-3-[3-(4-phenyl-4-(thiophen-2-yl)piperidin-1-yl)~pylcarbamoyl}-l~2~3~4-tetrahydropyrimidine -W097l42956 Pcr/uS97tO8335 carboxylic acid methyl e~ter.
To a solution of 6-(3,4-difluorophenyl)-4-methoxymethyl-2-oxo-3,6-dihydro-2H-pyrimidine-1,5-dicarboxylic acid 5-methyl ester 1-(4-nitrophenyl)ester (29 mg, 0.06 mmol) in 2 ml of CH7Cl.
was added 3-(4-phenyl-4-thiophen-2-yl-piperidin-1-yl)propylamine (20 mg, 0.07 mmol) and the resulting solution was stirred for 2 h at 25 ~C. The reaction mixture was concentrated in vacuo to provide an oil which was subjected to column chromatography over silica gel (5~ MeOH/CHCl3) to yield 25 mg (64~) of the desired product which was converted to a HCl salt and recrystallized from EtOAC-Et20 to afford 22 mg of the product as a white solid: mp 157-159~C; Anal. Calc.
For C33H36F2N40sS requires C, 58.6; H, 5.33; N, 8.29.
Found: C, 57.3; H, 5.45; 7.90.
Example 90:
4-(3,4-Difluorophenyl)-6-methoxymethyl-2-oxo-3-[3-(4-phenyl-4-(furan-2-yl)piperidin-1-yl)propyl]carbamoyl-1,2,3,4-tetrahydropyri~idine-5-carboxylic acid methyl e~ter.
a) 4-Phenyl-4-(furan-2-yl)piperidine.
To a solution of 4-hydroxy-4-phenyl-piperidine (0.3 g, 1.7 mmol) and furan (0.50 ml, 6.8 mmol) in 20 ml of C~I2Cl2 was added AlC13 (0.50 g, 3.7 mmol) at 25 ~C
and the resulting reaction mixture was stirred for h. The reaction mixture was basified with sat'd aqueous NaHCO3 and extracted with EtOAc. The organic layer was dried over Na2CO3 and concentrated in vacuo to provide a colorless oil which was identified as the desired product by NMR analysis and subjected to the following reaction without further purification.
b) 3-(4-Phenyl-4-(furan-2-yl)piperidin-1-yl)propylam~ne.
A solution of 4-phenyl-4-furan-2-yl-piperidine and 3-Boc-aminopropylbromide (0.30 g, 1.3 mmol) with 0.5 g of K2C03 in 20 ml of dioxane was stirred at reflux for W097/429S6 PCT~S97/08335 12 h. The reaction mixture was diluted with water and extracted with EtOAc. The organic solution was dried over Na2SO4 and concentrated in vacuo to yield an oil which was subjected to column chromatography over silica gel (EtOAc) to provide 0.21 g (0.54 ~mol, 32~ for two steps) of 3-(4-phenyl-4-(furan-2-~ yl)piperidin-1-yl)propylcar~amic acid tert-butyl ester as a colorless oil. The ester in 5 ml of CH2Cl2 was added with 1 ml of CF3CO2H and resulting solution was stirred for 1 h at 25 ~C. The reaction mixture was concentrated in vacuo to yield oily mixture, which was dissolved in EtOAc and washed with aqueous NaHCO3. Concentration of the reaction mixture pro~ided the desired product as an oil (0.13 g, 0.45 mmol, 84%).
c) 4-~3,4-Difluorophenyl)-6-methoxymethyl-2-oxo-3-t3-(4-phenyl-4-(furan-2-yl)piperidin-1-yl)propylcarbamoyl}-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid methyl ester.
To a solution of 6-(3,4-difluorophenyl)-4-methoxymethyl-2-oxo-3,6-dihydro-2H-pyrimidine-1,5-dicarboxylic acid 5-methyl ester 1-(4-nitrophenyl)ester (20 mg, 0.04 mmol) in 2 ml of CH2Cl2 was added 3-(4-phenyl-4-furan-2-yl-piperidin-1-yl)-propylamine (12 mg, 0.04 mmol) and resulting solution was stirred for 2 h at 25 ~C. The reaction mixture was concentrated in vacuo to provide an oil which was subjected to column chromatography over silica gel (5% MeOH/CHCl3) to yield 22 mg (85%) of the desired product, which was converted to HCl salt and recrystallized from EtOAC-Et2O to afford 18 mg of the product as a white solid: mp 153-155 ~C; Anal. Calc.
For C33~36F2N4O6 requires C, 60.1; H, 5.46; N, 8.49.
Found: C, 58.9; H, 5.53; 8.45.
Example 91:
~ 4-(3,4-Difluorophenyl)-6-methoxymethyl-2-oxo-3-{3-[4-phenyl-4-~l-methylpyrrol-2-yl)-piperidin-1-yl]-WO 97/42956 PCTrUS97/08335 propylcarbamoyl}-1,2,3,4-tetrahyd,u~y.imidine-5-carboxylic acid methyl ester.
a) 4-Phenyl-4-(1-methylpyrrol-2-yl)piperidine.
To a solution of 4-hydroxy-4-phenylpiperidine (0.5 g, 2.8 mmol) and l-methylpyrrole (0.50 ml, 5.6 mmol) 1n 20 ml of CH2Cl2 was added AlC13 (O. 75 g, 5.6 mmol) at 25 ~C and the resulting reaction mixture was stirred for 1 h. The reaction mixture was basified with sat'd aqueous NaHCO3 and extracted with EtOAc. The organic layer was dried over Na2CO3 and concentrated in vacuo to pro~ide the desired product as a colorless oil.
b) 3-t4-Phenyl-4-(1-methylpyrrol-2-yl)piperidin-1-yl]-propylamine.
A solution of 4-phenyl-4-(1-methylpyrrol-2-yl)-piperidine and 3-Boc-aminopropylbromide (1.0 g, 4.5 mmol) with 1.5 g of K2CO3 in 20 ml of dioxane was stirred at reflux for 12 h. The reaction mixture was diluted with water and extracted with EtOAc. Organic solution was dried over Na2SO4 and concentrated in vacuo to yield an oil which was subjected to column chromatography over silica gel (EtOAc) to provide 0.44 g (1.1 mmol, 20~ for two steps) of 3-[4-phenyl-4-(l-methylpyrrol-2-yl)-piperidin-l-y])-propylcarbamic acid tert-butyl ester as a colorless oil. The ester in 10 ml of CH2Cl2 was added with 1 ml of CF3CO2H and resulting solution was stirred for 1 h at 25 ~C. The reaction mixture was concentrated in ~-acuo to yield an oily mixture, which was dissolved in EtOAc and washed with aqueous NaHCO3.
Concentration of the reaction mixture provided an oil (0.26 g, 0.87 mmol, 79%) which was identified as the desired product.
c) 4-(3,4-Difluorophenyl)-6-methoxymethyl-2-oxo-3-{3-[4-phenyl-4-(1-methylpyrrol-2-yl)-piperidin-1-yl~propylcarbamoyl}-1,2,3,4-tetrahydropyrimidine-5-car~oxylic acid methyl ester.

W097/429~6 PCT~S97/08335 -lg3-To a solution of 6-(3,4-difluorophenyl)-4-methoxymethyl-2-oxo-3,6-dihydro-2H-pyrimidine-1,5-dicarboxylic acid 5-methyl ester 1-(4-nitrophenyl)ester (24 mg, 0.05 mmol) in 2 ml of CH.Cl~
was added 3-[4-phenyl-4-(1-methylpyrrol-2-yl)-piperidin-l-yl]-propylamine (15 mg, 0.05 mmol) and resulting solution was stirred for 2 h at 25 ~C.
Reaction mixture was concentrated in vacuo to provide an oil which was subjected to column chromatography over silica gel ~5~ MeO~/CHCl3) to yield 22 mg ~69%) of the desired product, which was converted to HCl salt and recrystallized from EtOAC-Et2O to afford 16 mg of the product as a white solid: mp 139-142~C.

Exam~le 92 As a specific embodiment of an oral composition of a compound of this invention, lOOmg of one of the compounds described herein is formulated with sufficient finely divided lactose to provide a total amount of 5~0 to 590 mg to fill a size 0 hard gel capsule.

CA 022~3862 1998-11-09 W O 97/42956 PCTnUS97/08335 Pharmacoloaical Profiles of the Com~ounds in Cloned H~ n Adrener~ic Receptors.

Binding affinities were measured for selected compounds of the invention at six cloned human alpha-1 and alpha-2 receptor subtypes, as well as at the L-type calcium channel. The protocols for these experiments are given below.

Protocol for the Determination of the Poten~y of Antaqonists The activity of compounds at the different human receptors was determined in vitro using cultured cell lines that selectively express the receptor of interest. These cell lines were prepared ~y transfecting the cloned cDNA or cloned genomic DNA or constructs containing both genomic DNA and cDNA
encoding the human ~-adrenergic receptors as follows:

~ Human Adrenergic Receptor: The entire coding region of ~lD (1719 bp), including 150 base pairs of 5' untranslated sequence (5' UT) and 300 bp of 3' untranslated sequence (3' UT), was cloned into the BamHI and ClaI sites of the polylinker-modified eukaryotic expression vector pCEXV-3, called EXJ.~R.
The construct involved the ligation of partial overlapping human lymphocyte genomic and hippocampal cDNA clones: 5' sequence were contained on a 1.2-kb SmaI-XhoI genomic fragment (the vector-derived BamHI
site was used for subcloning instead of the internal insert-derived SmaI site) and 3' sequences were contained on an 1.3 kb XhoI-ClaI cDNA fragment (the ClaI site was from the vector polylinker). Stable cell lines were obtained by cotransfection with the plasmid ~lA/EXJ (expression vector containing the ~lA receptor gene (old nomenclature)) and the plasmid pGCcos3neo (plasmid containing the aminoglycoside transferase .

W097/429S6 PCT~S97/08335 gene) into LM(tk-) cells using calcium phosphate technique. The cells were grown, in a controlled environment (37~C., 5% CO2), as monolayers in Dulbecco's modified ~agle's Medium (GIBCO, Grand Island, NY) containing 25mM glucose and supplemented with 10 bovine calf serum, 100 units/ml penicillin g, and 100 ~g/ml streptomycin sulfate. Stable clones were then selected for resistance to the antibiotic G-418 (1 mg/ml), and me~branes were harvested and assayed for their ability to bind [3H]prazosin as described below (see "Radioligand Binding assays"~.

The cell line expressing the human ~lD receptor used herein was designated L a1A (old nomenclature) and was deposited with the American Type Culture Collection, 12301 Parklawn Drive, Rockville, Maryland 20852, U.S.A.
under the provisions of the Budapest Treaty for the International Recognition of the Deposit of Microorganisms for the Purposes of Patent Procedure.
The cell line expressing the human ~lD receptor, was accorded ATCC Accession No. CRL 11138, and was deposited on September 25, 1992.

a~s Human Adrenergic Receptor: The entire coding region of al~ (1563 bp~, including 200 base pairs and 5' untranslated sequence (5' UT) and 600 bp of 3' untranslated sequence (3' UT), was cloned into the EcoRI site of pCEXV-3 eukaryotic expression vector.
The construct involved ligating the full-length containing EcoRI brainstem cDNA fragment from ~ ZapII
into the expression vector. Stable cell lines were selected as described above. The cell line used herein was designated L~ and was deposited with the American Type Culture Collection, 12301 Parklawn Drive, Rockville, Maryland 20852, U.S.A. under the provisions of the Budapest Treaty for the International Recognition of the Deposit of Microorganisms for the .. .. .

CA 022~3862 1998-11-09 W 097/42956 PCTrUS97/08335 Purposes of Patent Procedure. The cell line L-CY1E was accorded ATCC Accession No. CR 11139, on September 29, 1992.

~ Human Adrenergic Receptor: The entire coding region of ~lA (1401 bp), including 400 base pairs of 5~
untranslated sequence (5' UT) and 200 bp of 3' untranslated sequence (3' UT), was cloned into the KpnI
site of the polylinker-modified pCEXV-3-derived eukaryotic expression vector, EXJ.RH. The construct involved ligating three partial overlapping fragments:
a 5' 0.6kb HincII genomic clone, a central 1.8 EcoRI
hippocampal cDNA clone, and a 3' 0.6Kb PstI genomic clone. The hippocampal cDNA fragment overlaps with the lS 5' and 3' genomic clones so that the HincII and PstI
sites at the 5' and 3' ends of the cDNA clone, respectively, were utilized for ligation. This full-length clone was cloned into the KpnI site of the expression vector, using the 5' and 3' KpnI sites of the fragment, derived from vector (i.e., pBluescript) and 3'-untranslated sequences, respectively. Stable cell lines were selected as described above. The stable cell line expressing the human ~lA receptor used herein was designated L-~lC (old nomenclature) and was deposited with the American Type Culture Collection, 12301 Parklawn Drive, Rock~ille, Maryland 20852, U.S.A.
under the provisions of the Budapest Treaty for the International Recognition of the Deposit of Microorganisms for the Purposes of Patent Procedure.
The cell line expressing the human ~lA receptor was accorded Accession No. CR 11140, on September 25, 1992.

Radioligand ~ ing A~says: Transfected cells from culture flasks were scraped into 5ml of 5mM Tris-HCl, 5mM EDTA, pH 7.5, and lysed by sonication. The cell lysates were centrifuged at 1000 rpm for 5 min at 4~C, and the supernatant was centrifuged at 30,000 x g for .

CA 022~3862 1998-11-09 W O 97/42956 PCT~US97/08335 -197-20 min at 4~C. The pellet was suspended in 50mM Tris-HCl, lmM MgCl2, and 0.1~z ascorbic acid at pH 7.5.
Binding of the ~1 antagonist [3H]prazosin ~0.5 nM, specific activity 76.2 Ci/mmol) to membrane preparations of LM(tk-) cells was done in a final volume of 0.25 ml and incubated at 37~C for 20 min.
Nonspecific binding was determined in the presence of - 10 ~M phentolamine. The reaction was stopped by filtration through GF/B filters using a cell harvester.
Inhibition experiments, routinely consisting of 7 concentrations of the tested compounds, were analyzed using a non-linear regression curve-fitting computer program to obtain Ki values.

~2 Human Adrenergic Receptors: To determine the potency of ~1 antagonists at the ~2 receptors, LM ( tk-) cell lines stably transfected with the genes encoding the ~2A~ ~2~, and ~2C receptors were used. The cell line expressing the ~2A receptor is designated L-~2A~ and was deposited on November 6, 1992 under ATCC Accession No.
CRL 11180. The cell line expressing the ~2~ receptor is designated L-NGC-~2~, and was deposited on October 25, 1989 under ATCC Accession No. CRL10275. The cell line expressing the ~2C receptor is designated L-~2C, and was deposited on November 6, 1992 under ATCC Accession No.
CRL-11181. All the cell lines were deposited with the American Type Culture Collection, 12301 Parklawn Drive, Rockville, Maryland 20852, U.S.A. under the provisions of the Budapest Treaty for the International Recognition of the Deposit of Microorganisms for the Purposes of Patent Procedure. Cell lysates were prepared as described above (see Radioligand Binding Assays), and suspended in 25mM glycylglycine buffer (pH
7.6 at room temperature). Equilibrium competition binding assay were performed using [3H]rauwolscine - (O.SnM), and nonspecific binding was determined by incubation with lO~M phentolamine. The bound CA 022~3862 1998-11-09 W097/429~ PCT~S97/08335 radioligand was separated by filtration through GF/B
filters using a cell harvester.

Det~r~;nAtion of the Activity of ~l Antagonists at S Calcium ~h~nn~ls The potency of ~l antagonists at calcium channels may be determined in competition binding assays of [3H]nitrendipine to membrane fragments of rat cardiac muscle, essentially as described by Glossman and Ferry (Methods in Enzymology 109:513-550, 1985). Briefly, the tissue is minced and homogenized in 50mM Tris-HCl (pH 7.4) containing O.lmM phenylmethylsulfonyl fluoride. The homogenates are centrifuged at 1000 g for 15 minutes, and the resulting supernatant centrifuged at 45,000 g for 15 minutes. The 45,000 g pellet is suspended in buffer and centrifuged a second time. Aliquots of membrane protein are then incubated for 30 minutes at 37~C in the presence of [3H]nitrendipine (lnM), and nonspecific binding determined in the presence of lO~M nifedipine. The bound radioligand is separated by filtration through GF/B filters using a cell harvester.

The compounds described above were assayed using cloned human alpha adrenergic receptors. The preferred compounds were found to be selective ~lc antagonists.
The binding affinities of compounds 13-17 are illustrated in the following table.

W097/42956 PCT~S97/08335 Binding affinities of compounds 13-17 at cloned human ~ld, ~lb and ~la receptors.

Example h~ld halb h~la pKi SEM n pKi SEM n pKi SEM n 13 6.14 0.02 3 6.21 0.09 3 9.74 0.02 3 14 6.46 0.04 3 6.59 0.08 3 9.68 0.05 3 6.01 0.03 3 6.33 0.06 3 9.41 0.09 3 16 6.24 0.06 3 6.37 0.06 3 9.54 o.og 3 17 6.17 0.04 4 6.32 0.06 4 8.99 0.12 4 h = human SUBSTITUTE SHEET(RULE 26) WO 97/42956 PCTrUS97/08335 ~N ~2 B = ~. 4-~eO-Ph Ph ~ ~ BW~ ~ ~ ~ R- ~ k H

R ~r'''~~~'X~2.E~r r 1 ~ E = OE. COO~e, COOEt E ~2Co3~ 4-Dio~ne ~ OC~
~Hz Scheme 1. General synthetic schemes f or the syn~hesis of the piperidine sidechains.

CA 02253862 l998-ll-09 W 097/42956 PCT~US97/08335 N

O
O =~
~ <

O p;'~

N 0~ ~, o h ~ ~ O
~ / ~ ~

=( x ¢ 9 CJ rq 0~ ~ ~ U
< ~
_. ( ~
> ~ r~
", E
N ~ O

n ~ h 0~ ~0 Z; ~ _~ 0 P:~ Z ~ ~ 0 U
0'~

O ~ N

O ~ <
0~ ~0 O L
r , ~ l r-~ Q 4 U

~ < ~ ~ E

~ ~ C_ o ~ rO ~"
o~

o r~ Z
. . .
,~ ~ r~

~ _~ ,..

r~

o=~ o '1 ;' t~ C~ 2 ~
0~ (z +~ ~Z +
O=~ _ 0~ ~
O _ ,.1 ~

E~- O

E
2 ~ N W

o ~ E

~ ( .o ~o ~o -- L~

o _ o ,~, o ~ 3 u U~

WO 97142956 rCT/US97108335 ~~'Ctt3~ ~0 ~ _~~--CN O~N~C~0 O O O O Piperidine. ~OI~c Isu~luranol ~ o ~ CX E~ ~ o~e O ¢
C

~~2 ~C o ~,~N~--N~

~07 ~ }, 0~ 0 ~--~-E o~'o 1. 4-Nitrophenyl chloro~ormate, NaHC~3, CH7Cl2, H20.
2. 3-[(4-Methoxycarbonyl-4-phenyl)piperidin-1-yl]propylamine.
3. 6N HCl.
. NaOH, Acetone.
5. DMAPECD, DMAP, NH3, CH2Cl2.

Scheme 4. Synthetic scheme for example 13.

W097l42956 PCT~S97/08335 ~3~ ~~ ~ C o o Plperidl~e. ~OAc ~ ~ ~enzene F

o O NH2 I F

~3 NallCO ~3--o J~ I--NH

F
o ~O ~N02 N one ~ ~ F

~ ~ N ~ O
F 4 ~ H o~f ~ F
O ~ O

H2N ~ ~ H
H O~'O
I

1. 4-Nitrophenyl chloroformate, DMAP, THF
2. 3-[(4-Methoxycarbonyl-4-phenyl)piperidin-1-yl]propylamine.
3. 6N HCl.
4. H2, Pd-C, MeOH.
5. DMAPECD, DMAP, NH40H, CH2Cl2.

Scheme 5. Synthetic scheme for example 14.

SUBSTITUTE SHEET (RULE 26) CA 02253862 lsss-ll-os W O 97/42956 PCT~US97/08335 ~ CN
HO ~ ~ OK 1) Na2CO3 ~nCl ~ ~ n-(CqHg)4N HSO4 ~ CN

N 2) 5OC12, ~eOH NNaOH, Toluene 81~ Bn 65 C N
~n ~ N
l)Conc. H2SO4. RT
2) ~eOH. ff ~ J

Bn 1) ~2~ Pd(OH)2/C.200 psi ~
2) 5r'~~'~'NH~OC ~ N
CO3~ DioIane.reflu I8) TFA.CH2C12.98%
Bn S

Scheme 6. Synthetic scheme for the preparation of 3-[4-(2-Pyridyl)-piperidin-1-yl]propylamine (Example 21 part d).

Sl~ 111 UTE SHEET (RULE 26) W O 971429S6 PCTrUS97/08335 O O F
OR NH2 1 ~ F
HN OCH3 3 ~ ,1 o ~ o ~ NOz 3 o ~ o N'~ OCH CH30 ~ ~~~-~N

o ~ Fo H

1. NaOAc, DMF.
2. 4-Nitrophenyl chloroformate, NaHCO3, CH2C12, H20.
3. 3-[(4-Pyridyl)-piperidin-1-yl]propylamine, CH2Cl2.
4. 6N HC1/THF.

Scheme 7. Synthetic scheme for example 15.

SUBST~TUTE SHEET (RULE 26) W O 97/42956 PCT~US97/08335 N ~

J~ HN 3 CH30 I~lN

~l-o ,--~ t~~

C}130 h ' ~

CH30J~';h h~
.

1. NaOAc, DMF.
2. 4-Nitrophenyl chloroformate, NaHCO3, CH2Cl2, H20.
3. 3-[(4-(2-Pyridyl)-piperidin-l-yl]propylamine, CH2Cl2.
4. 6N HCl/THF.

Scheme 8. Synthetic scheme for example 16.

~eO~ ~ J~d"f l ~J~ er~~

O k neo ~ ~ ~ tCE~n - Cl 21eO~ --~(CE~,~n N~

o O~e 1. (a) t-BuO~, DMF, 0~C; (b) TsOH.H2O, DMF, 100-120~C.
2 . NaH, THF, reflux.
3. 4-Methoxycar~onyl-4-phenylpiperidine, K2CO3, NaI, 1, 4-dioxane, reflux.

Sc~me 9. Synthetic scheme for example17.

CA 02253862 l998-ll-09 WO 97/42956 PCT~US97/08335 o a~ ~
o Z~ ~<0 \~/0~ 0=( ~0 V ~a ~Z
o~

~ ~ N
z ~C ~ ~ ' ~ O ~ J ~ ~

0~ ~ X

O ,~ O ~ o o~ ~o O U
o ~; ~Z C
0~ ~ m o~

Z
~ ~ ~

o _~
~; o~

S~ 111 UTE SHEET (RULE 26) CA 02253862 l998-ll-09 WO 97/42956 PCTrUS97/08335 O

h O ~ ~ ~

~
O
N

~; N

O ~ ~
_~_ ~ O

0_, O J

~~ ~
~= ~ oa( CA 02253862 l998-ll-09 W O 97/429S6 P ~ ~US97/08335 ~Z3:
~<
o~o ~ h ~ Z~

~Z~
Z~ ~ 0~ 0 ~_~z~ ~Z:~

0~ S
O ~
~0 ~ r S~ o U
~ ~ ~ '3 ~ s m m ~ '' O

SUBSTITUTE SHEET (RULE 26) O,, Z
~ C ~

_ _, =O ~
Z ' Z ~ ~
Cl r ~) 0~ ~ _ ~_ 0~ ~ O _4 d~

~ S o o o: o~ ~ Z
Z

o Z ~ ;~.
~_~; oz~
_)e U

CA 02253862 l998-ll-09 W O 97/42956 PCTrUS97/08335 C N ~

~ ~ a Z 0~~\o ~ ~ ~~

Z o ~ ~ N ~, O
~N X

~ N 5_1 ~0 ~ ~ ~D z ~ ~I N ~z~ .
oZ~~ ~ O

t l Z ~ U

SUBSTITUTE SHEET (RULE 26) CA 02253862 l998-ll-09 W O 97142956 PCTrUS97/08335 ~Z
~Z~
~ ~ z ~ ~ N ~

C
.~ ~

O~Z~o X

~)h ~C V ~J
~1 + ~ Z J

SI~ ITE SHEET (RULE 26) CA 02253862 lsss-ll-os W O 97/429S6 PCTrUS97/08335 O O 2 4-difluoro- ~ OBn HzN ~ NH
o~n Plperidine,HOAc ~ NaHCO3 F ~ EtOH, O ~ ~ 1. p-Nitrophenylchloroformate Ll 1 2. R ~+)-Phenethylamine 11 3 Separate diastereomers BnO ~ NH

(+) 1. p-Nitrophenyl-chloroformate ~ ~ F
2. a. R'NH2, THF ~\ ~ L IL,F
b. aq. HCl ~ ~ ~ 1. H2 / Pd-CO ~ O
BnO ~ N ~ N 2. NH3, EDC H2N ~ N N' N O 3. HCl / Et20 ~ N ~ O
( ) HCl R' = ~ N

CN
Scheme 14 (Cont.). Preparation Of example 22 (part-2) SU~,~ 111 lJTE SHEET (RULE 26) ~\ ~ + Z
o= O

0~ 0 ~ ~
,~ _I

, O 0 ~ ~ J~

:C ~
O
~ z ~ :r ~~~ '~
o~ o\ ~~
C
Z ~ ~, a~

X
~ ~ o Z ,.. , o o~ \o E
o=~ o s ~_/

SUBSTITUTESHEET(RULE26) CA 02253862 l998-ll-09 ~ -218-~0 _~0 $~

~o~ ~Z?

o~ o ~ ,¢ ~
,, ~

E
~o ~ o ~ -~

SUBSTITUTE SHEET ~RULE 26) CA 02253862 l998-ll-09 W O 97/42956 PCTrUS97/08335 ~ -219-~:~~
0~ 0 o O~
o Z

O O O C~;N
O \ Z

:~ t_) ~ N
Xo N ~J

N a;N
~ Z ~
O ~0 ~=~0 N ~ O =~ O

~0 ~

o=~ O ~ O O
O O

SUBSTITUTE SHEET (RULE 26) .

W O 97/42956 PCTrUS97/08335 0~ ~
Z Z ~

~ o~ o Z ~
~

~o o o o~ ~

o ~ Oo ~ ~, ~ ,, . ~ ~
o ~ ~ ~

SUBSTITUTE SHEET (RULE 26) CA 02253862 l998-ll-09 W O 97/42956 PCTrUS97/08335 ~Y 0~ 0 O

O
O _, x a ~ ~, ~D
\
=~z~
f -- ~ E

~
V

,, o "

o o m SlJ~;~ ~ JTE SHEET (RULE 26) ,~ -222-~ Y
~Z X

k~ 0~ 0 ~Z:~ ~

o X~
O ~ V
~0=~ ~o > :~
~/ \~ Z:~ ~
_ ZX
0 ~ ~ A

O Vr~ ~

T- ,C a) Z~ ~ ~
L , ~ O
J X
Z~ Z

~z <~ E

¢ ~ ~ O
z G
SUBSTITUTE ''I ._t I (RULE 26) W097/429~6 PCT~S97/08335 O ~r O ~r O Ar R , J~" ~ h~) ~ --I
r - H,~ ~CO~Mc o ~~'~R ~J ~R
¦ 3 O ~r O O ~r ' ~ OM- RH

1~
O ~ O
~N~N ~ ~ OMe 1. (a) KtBuO, DMF; ~b) TsOH H2O, DMF, 100-110~C.
2. (a) NaH, THF, 1,S-dibromopentane; ~b) 4-Methoxycarbonyl-4-phenylpiperidine, K~.CO3, dioxane.
3. ~a) H2, PdtC, MeOH. (b~ CH3NH2, DMAPECD, CH2Cl2.
4. NaH, ClCO2Me, THF.
5. (a) H2, PdtC, MeOH. ~b) 3-~4-Methoxycarbonyl-4-phenylpiperidin-1-yl)propylamine, DMAPECD, CH2Cl2.

Sch-m~ 21 ~part-2). Synthetic scheme for examples 49, 50 and ~l.

~m~ PH~
~ (~) M~ldic ~ ç~ 2 Schem- 21 (part-1). Synthesis of ~S)-(-)-2-methyl-1,5-di~romopentane tThurkauf et al. J. Org. Chem. 1987, 52, 5466-5467).

W097/42956 PCT~S97/0~35 o .~, M~O~ O ~r ~ 40~

o ~, o 2 MbO ~ ~ ~ 3M~O ~ ~ .
~ ~ OH ~ ~ ~ ~

1. mCP3A, CH2C12-2. 4-(2-Pyridyl)piperidine, dioxane.
3. Oxalyl chloride, DMSO, CH2Cl2.

Sch~me 22. Synthetic scheme for examples 56 and 57 PCT~US97108335 H~3 Ek ~OH

O At O ~NO2 ~e OJ~N loJ~
O Ar O
N ~O
H ~-O~N ~O ~f N

H ~3 SchQmo 23. Synthetic scheme for example 59 W O 97/42956 PCTrUS97/08335 ~ ~ 3 ~ ~

Rl =H,F,CI,CH3 / 11 (~~
R2= 4-fluoro-1-methoxy,CH3 / R4~ N ~ N ~ ~ Br 4-methyl-1-methoxy, thiomethoxy, Cl, F / 11 L H

3~Rs ~ R3 = methyl, methoxymethyl Il 11 R4 = CH3, OCH3 R4~ ~NJ~N~~N~_ R5 = multifluoro H Q ~ ~N~2 2 ~
Rl ~ Rl ~ R2 1 . ~rCH2CH2CH2NE~OC
2. TFA ~--NH2 Scheme for the synthesis of examples 61-67.

SUBSTITUTE SHEET (RULE 26) W O 97/429S6 PCTrUS97/08335 Br ~ R O ~

N ~ O MeO ~ N ~ Br H H

A Ar O

MeO ~ N ~ N ~
or HN NAr N O R ~ XAr X = N, C-CN
Synthetic scheme for examples 68 and 69.

W 097/42956 PCT~US97/08335 F F

MeO~ Br ~ Br ~ Br N XX=Me, CH20Me N X R

HN ~ Ar O ~ F

MeO ~ N ~ N
Y = CN, Arl ~ N ~ X y Synthetic scheme for examples 7~72.

W 097142956 PCT~US97/08335 O ~ I
~D
,~
o~ E

~ ~Z~ i Z ~ C
~Z :~ o~ o + o LL o ~

I
O

SUBSTITUTE SHEET (RULE 26) W O 97/42956 PCTrUS97/08335 z I

~ O
,o ~ I

2~ ~~

m ~ ~ =~C
Z ~
E

I z ~~

O=( O
+

O ~Z

SU~S 111 UTE SHEET (RULE 26) CA 02253862 l998-ll-09 W O 97/42956 PCTtUS97tO8335 ~.~ ~

I~ ~ ~ ~ ~ T

.,C ~ O _ "~ O

C
r, ~ r~ ~

SUBSTITUTE SHEET (RULE 26) .

W O 97/42gS6 PCTrUS97/08335 Z I

I 1~ ~Z I

0 1.)' O.
~ ~ E

~Z~ I y ~
C o~ ~ O
C I 1' o Z 21 E C

N , N
I; ~1 ,; .m ~z I Z Z I tr K t~: m c Z ~

~ZX ~ U~ ~

SUBSTITUTE SHEET (RULE 26) W O 97/42956 PCTtUS97tO8335 ~ /~ 0~

O o ~ I

0 1~ ~ ~Z I 0 ~' ~ o ~

E
Z~{~Z ~ ~ ~
Z .U~
O~ I ~ C
C

I E
Z ~Z

a~

O ~

~ ~ Z I
~ ~~
O ~ ~ ,0 S~Jt~:~ 111 IJTE SHEET (RULE 26) .

W O 97/42956 rcTrusg7/o8335 ~3 O \ _, Z a~
'~ ~
_ ~

X
. o ~Z_O' ~Z

x~ z ~Z= ~

Claims (52)

What is claimed is:
1. A compound having the structure:

or ;

wherein A is , , , , , , Or ;

wherein each of Y1, Y2, Y3, Y4 and Y5 is independently -H; straight chained or branched C1-C7 alkyl, monofluoroalkyl or polyfluoroalkyl;
straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; -F, -Cl, -Br, or -I; -NO2; -N3; -CN; -OR3, -OCOR3, -COR3, -CONHR3, -CON(R3)2, or -COOR3; or any two of Y1, Y2, Y3, Y4 and Y5 present on adjacent carbon atoms can constitute a methylenedioxy group;

wherein X is S; O; or NR3;

wherein R1 is -H; -NO2; -CN; straight chained or branched C1-C7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; -N(R3)2; -OR3; - (CH2)pOR3; -COR3; -CO2R3; or - CON (R3)2;

wherein R2 is -H; straight chained or branched C1-C7 alkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; C3-C10 cycloalkyl-C1-C10-alkyl, C3-C10 cycloalkyl-C1-C10-monofluoroalkyl or C3-C10 cycloalkyl-C1-C10-polyfluoroalkyl; - CN; - CH2XR3, - CH2X(CH2)pNHR3, - (CH2)nNHR3, - CH2X(CH2)pN(R3)2, -CH2X (CH2) pN3, or - CH2X(CH2) pNHCXR7; or - OR3;

wherein each p is independently an integer from to 7; wherein each n is independently an integer from 0 to 5;

wherein each R3 is independently -H; straight chained or branched C1-C7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;

wherein R4 is wherein Z' is (CH2)o, CO, (CH2)oCO, or CO(CH2)o;

wherein each V is independently O; S; CH2; CR5R7;
C(R7)2; or NR7;

wherein each m is independently an integer from 0 to 3; wherein o is an integer from 1 to 3;

wherein each R is independently -H; -F; straight chained or branched C1-C7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; -N(R3)2; -NO2; -CN; -CO2R3; or -OR3;

wherein R5 and R7 each independently may be -H; F;
Cl; Br; I; -COR3; -CO2R3; -CON (R3)2; -CN; -NO2;
-N(R3)2; -OR3; -SR3; -(CH2)p OR3; -(CH2)p SR3; straight chained or branched C1-C7 alkyl, aminoalkyl, carboxamidoalkyl; straight chained or branched C2-C7 alkenyl or alkynyl, or C3-C7 cycloalkyl or cycloalkenyl; wherein the alkyl, aminoalkyl, carboxamidoalkyl, alkenyl, alkynyl, cycloalkyl or cycloalkenyl may be substituted with one or more aryl or heteroaryl, wherein the aryl or heteroaryl may be substituted with -F, -Cl, -Br, -I, -NO2, -CN, -OR3, -SR3, C1-C3 alkyl, or carboxamido; aryl or heteroaryl, wherein the aryl or heteroaryl may be substituted with one or more -F, -Cl, -Br, -I, COR3, CO2R3, -CON (R3)2, -CN, -NO2, -N(R3)2, -OR3, -SR3, (CH2)o OR3, (CH2)o SR3; straight chained or branched C1-C7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl, C2-C7 alkynyl, C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; and wherein each R6 is independently -H; straight chained or branched C1-C7 alkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; or -OR3;

or a pharmaceutically acceptable salt thereof.
2. The compound of claim 1, wherein the compound comprises the (+) enantiomer.
3. The compound of claim 1, wherein the compound comprises the (-) enantiomer.
4. The compound of claim 1 having the structure:

5. The compound of claim 4, wherein Z' is CO and n is 0.
6. The compound of claim 5 having the structure:

7. A compound selected from the group consisting of:

and
8. A compound having the structure:

, or ;

wherein A is , , , , , , or ;

wherein each of Y1, Y2, Y3, Y4 and Y5 is independently -H; straight chained or branched C1-C7 alkyl, monofluoroalkyl or polyfluoroalkyl;
straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; -F, -Cl, -Br, or -I; -NO2; -N3; -CN; -OR3, -OCOR3, -COR3, -CONHR3, -CON(R3)2, or -COOR3; or any two of Y1, Y2, Y3, Y4 and Y5 present on adjacent carbon atoms can constitute a methylenedioxy group;

wherein X is S; O; or NR3;

wherein R1 is -H; -NO2; -CN; straight chained or branched C1-C7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyli -N(R3)2; -OR3; -(CH2)p OR3; -COR3; -CO2R3; or -CON(R3)2;

wherein R2 is -H; straight chained or branched C1-C7 alkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; C3-C10 cycloalkyl-C1-C10-alkyl, C3-C10 cycloalkyl-C1-C10-monofluoroalkyl or C3-C10 cycloalky-C1-C10-polyfluoroalkyl; -CN; -CH2XR3, -CH2X(CH2)p NHR3, -(CH2)n NHR3, -CH2X(CH2)p N(R3)2, -CH2X(CH2)p N3, or -CH2X(CH2)p NHCXR7; or -OR3;

wherein each p is independently an integer from 1 to 7; wherein each n is independently an integer from 0 to 5;

wherein each R3 is independently -H; straight chained or branched C1-C7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;

wherein R4 is or wherein Z is C2-C7 alkenyl or alkynyl; CH2; O; CO;
CO2; CONR3; S; SO; SO2; or NR3;

wherein Z' is (CH2)o, CO, (CH2)o CO, or CO(CH2)o;

wherein each D is independently CH2; O; S; NR3; CO;
or CS;

wherein W is C=O; C=NOR3; substituted or unsubstituted phenyl, pyridyl, thiophenyl, furanyl, pyrazinyl, pyrryl, naphthyl, indolyl, imidazolyl, benzfurazanyl, benzfuranyl or benzyimidazolyl, wherein the phenyl, pyridyl, thiophenyl, furanyl, pyrazinyl, pyrryl, naphthyl, indolyl, imidazolyl, benzfurazanyl, benzfuranyl or benzyimidazolyl is substituted with -H, -F, -Cl, -Br, -I, -NO2, -CN, straight chained or branched C1-C7 alkyl, straight chained or branched C1-C7 monofluoroalkyl, straight chained or branched C1-C7 polyfluoroalkyl, straight chained or branched C2-C7 alkenyl, straight chained or branched C2-C7 alkynyl, C3-C7 cycloalkyl, C3-C7 monofluorocycloalkyl, C3-C7 polyfluorocycloalkyl, C3-C7 cycloalkenyl, -N(R3)2, -OR3, -COR3, -CO2R3, or -CON(R3)2;

wherein each V is independently O; S; CH2; CR5R7;
C(R7)2; or NR7;

wherein each m is independently an integer from 0 to 3; wherein o is an integer from 1 to 3;

wherein each R is independently -H; -F; straight chained or branched C1-C7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; -N(R3)2; -NO2; -CN; -CO2R3; or -OR3;

wherein R5 is aryl or heteroaryl substituted with one or more of F; Cl; Br; I; COR3; CO2R3; -CON(R3)2;
CN; -NO2; -N(R3)2; - OR3, -SR3; (CH2)o OR3; (CH2)o SR3;
straight chained or branched C1-C7 alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained or branched C2-C7 alkenyl, C2-C7 alkynyl, C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;

wherein each R6 is independently -H; straight chained or branched C1-C7 alkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; or -OR3;

wherein R7 is aryl or heteroaryl substituted with one or more of F; Cl; Br; I; COR3; CO2R3; -CON(R3)2;

CN; -NO2; -N(R3)2; -OR3, -SR3; (CH2)o OR3; (CH2)o SR3;
straight chained or branched C1-C7 alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained or branched C2-C7 alkenyl, C2-C7 alkynyl, C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; and wherein R8 is -H; substituted or unsubstituted benzyl, benzoyl, phenyl, pyridyl, thiophenyl, furanyl, pyrazinyl, pyrryl, naphthyl, indolyl, imidazolyl, benzfurazanyl, benzfuranyl, benzimidazolyl or 2-keto-1-benzimidazolinyl, wherein the benzyl, benzoyl, phenyl, pyridyl, thiophenyl, furanyl, pyrazinyl, pyrryl, naphthyl, indolyl, imidazolyl, benzfurazanyl, benzfuranyl, benzimidazolyl or 2-keto-1-benzimidazolinyl is substituted with -H, -F, -Cl, -Br, -I, -NO2, -CN, straight chained or branched C1-C7 alkyl, straight chained or branched C1-C7 monofluoroalkyl, straight chained or branched C1-C7 polyfluoroalkyl, straight chained or branched C2-C7 alkenyl, straight chained or branched C2-C7 alkynyl, C3-C7 cycloalkyl, C3-C7 monofluorocycloalkyl, C3-C7 polyfluorocycloalkyl, C3-C7 cycloalkenyl, -N(R3)2, -OR3, -COR3, -CO2R3, or -CON(R3)2; substituted or unsubstituted straight chained or branched C1-C7 alkyl, monofluoroalkyl or polyfluoroalkyl; substituted or unsubstituted straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl or cycloalkenyl, wherein the alkyl, monofluoroalkyl, polyfluoroalkyl, alkenyl, alkynyl, cycloalkyl or cycloalkenyl is substituted with -H, phenyl, pyridyl, thiophenyl, furanyl, pyrazinyl, pyrryl, naphthyl, indolyl, imidazolyl, benzfurazanyl, benzfuranyl, benzimidazolyl, -N(R3)2, -NO2, -CN, -CO2R3, -OR3;

, or ;

or a pharmaceutically acceptable salt thereof.
9. The compound of claim 8 having the structure:

10. The compound of claim 9 having the structure:

11. The compound of claim 10 having the structure:

wherein V is selected from CR5R7 or NR7 and p is selected from 1-3.
12. The compound of claim 11, wherein the compound is selected from the group consisting of:

and
13. A compound having the structure:

or ;

wherein A is , , , , , , or ;

wherein each of Y1, Y2, Y3, Y4 and Y5 is independently -H; straight chained or branched C1-C7 alkyl, monofluoroalkyl or polyfluoroalkyl;
straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; -F, -Cl, -Br, or - I; -NO2; -N3; -CN; -OR4, -OCOR4, -COR4, -CONHR4, -CON(R4)2, or -COOR4; or any two of Y1, Y2, Y3, Y4 and Y5 present on adjacent carbon atoms can constitute a methylenedioxy group;

wherein X is S; O; or NR4;

wherein B is -H; straight chained or branched C1-C7 alkyl, monofluoroalkyl, polyfluoroalkyl, alkoxy or thioalkyl; straight chained or branched C2-C7 alkenyl; - SCH2C6H4OR4, -(CH2)n C6H5; -CH2X(CH2)n NHR4;
-(CH2)n NHR4; or -OR4;

wherein R1 is -H; -NO2; -CN; straight chained or branched C1-C7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; -N(R4)2; -OR4; -(CH2)p OR4; -COR4;
-CO2R4; or -CON(R4)2;

wherein R2 is -H; straight chained or branched C1-C7 alkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; C3-C10 cycloalkyl-C1-C10-alkyl, C3-C10 cycloalkyl-C1-C10-monofluoroalkyl or C3-C10 cycloalkyl-C1-C10-polyfluoroalkyl; -CN; -CH2XR4, -CH2X(CH2)p NHR4, -(CH2)n NHR4, -CH2X(CH2)p N(R4)2, -CH2X(CH2)p N3, or -CH2X(CH2)p NHCXR7; or -OR4;

wherein each p is independently an integer from 1 to 7; wherein each n is independently an integer from 0 to 5;

wherein R3 is , or wherein Z is C2-C7 alkenyl or alkynyl; CH2; O; CO;
CO2; CONR4; S; SO; SO2; or NR4;

wherein Z' is (CH2)o, CO, (CH2)o CO, or CO(CH2)o;

wherein each D is independently CH2; O; S; NR4; CO;
or CS;

wherein W is C=O; C=NOR4; substituted or unsubstituted phenyl, pyridyl, thiophenyl, furanyl, pyrazinyl, pyrryl, naphthyl, indolyl, imidazolyl, benzfurazanyl, benzfuranyl or benzyimidazolyl, wherein the phenyl, pyridyl, thiophenyl, furanyl, pyrazinyl, pyrryl, naphthyl, indolyl, imidazolyl, benzfurazanyl, benzfuranyl or benzyimidazolyl is substituted with -H, -F, -Cl, -Br, -I, -NO2, -CN, straight chained or branched C1-C7 alkyl, straight chained or branched C1-C7 monofluoroalkyl, straight chained or branched C1-C7 polyfluoroalkyl, straight chained or branched C2-C7 alkenyl, straight chained or branched C2-C7 alkynyl, C3-C7 cycloalkyl, C3-C7 monofluorocycloalkyl, C3-C7 polyfluorocycloalkyl, C3-C7 cycloalkenyl, -N(R4)2, -OR4, -COR4, -CO2R4, or -CON(R4)2;

wherein each V is independently O; S; CH2; CR5R7;
C(R7)2; or NR7;

wherein each m is independently an integer from 0 to 3; wherein o is an integer from 1 to 3;

wherein each R is independently -H; -F; straight chained or branched C1-C7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; -N(R4)2; -NO2; -CN; -CO2R4; or -OR4;

wherein each R4 is independently -H; straight chained or branched C1-C7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;

wherein R5 is aryl or heteroaryl substituted with one or more of F; Cl; Br; I; COR3; CO2R3; -CON(R3)2;
CN; -NO2; -N(R3)2; -OR3, -SR3; (CH2)o OR3; (CH2)o SR3;
straight chained or branched C1-C7 alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained or branched C2-C7 alkenyl, C2-C7 alkynyl, C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;

wherein each R6 is independently -H; straight chained or branched C1-C7 alkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; or -OR4;

wherein R7 is aryl or heteroaryl substituted with one or more of F; Cl; Br; I; COR3; CO2R3; -CON(R3)2;
CN; -NO2; -N(R3)2; -OR3, -SR3; (CH2)o OR3; (CH2)o SR3;
straight chained or branched C1-C7 alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained or branched C2-C7 alkenyl, C2-C7 alkynyl, C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; and wherein R8 is -H; substituted or unsubstituted benzyl, benzoyl, phenyl, pyridyl, thiophenyl, furanyl, pyrazinyl, pyrryl, naphthyl, indolyl, imidazolyl, benzfurazanyl, benzfuranyl, benzimidazolyl or 2-keto-1-benzimidazolinyl, wherein the benzyl, benzoyl, phenyl, pyridyl, thiophenyl, furanyl, pyrazinyl, pyrryl, naphthyl, indolyl, imidazolyl, benzfurazanyl, benzfuranyl, benzimidazolyl or 2-keto-1-benzimidazolinyl is substituted with -H, -F, -Cl, -Br, -I, -NO2, -CN, straight chained or branched C1-C7 alkyl, straight chained or branched C1-C7 monofluoroalkyl, straight chained or branched C1-C7 polyfluoroalkyl, straight chained or branched C2-C7 alkenyl, straight chained or branched C2-C7 alkynyl, C3-C7 cycloalkyl, C3-C7 monofluorocycloalkyl, C3-C7 polyfluorocycloalkyl, C3-C7 cycloalkenyl, -N(R4)2, -OR4, -COR4, -CO2R4, or -CON(R4)2; substituted or unsubstituted straight chained or branched C1-C7 alkyl, monofluoroalkyl or polyfluoroalkyl; substituted or unsubstituted straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl or cycloalkenyl, wherein the alkyl, monofluoroalkyl, polyfluoroalkyl, alkenyl, alkynyl, cycloalkyl or cycloalkenyl is substituted with -H, phenyl, pyridyl, thiophenyl, furanyl, pyrazinyl, pyrryl, naphthyl, indolyl, imidazolyl, benzfurazanyl, benzfuranyl, benzimidazolyl, -N(R4)2, -NO2, -CN, -CO2R4, -OR4;

, or ;

or a pharmaceutically acceptable salt thereof.
14. The compound of claim 13, wherein the compound comprises the (-) enantiomer.
15. The compound of claim 13, wherein the compound comprises the (+) enantiomer.
16. The compound of claim 13 having the structure:

17. The compound of claim 16 having the structure:

18. The compound of claim 17, wherein the compound is selected from the group consisting of:

and
19. A compound having the structure:

or ;

wherein A is , , , , , , or ;

wherein each of Y1, Y2, Y3, Y4 and Y5 is independently -H; straight chained or branched C1-C7 alkyl, monofluoroalkyl or polyfluoroalkyl;
straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; -F, -Cl, -Br, or -I; -NO2; -N3; -CN; -OR4, -OCOR4, -COR4, -CONHR4, -CON(R4)2, or -COOR4; or any two of Y1, Y2, Y3, Y4 and Y5 present on adjacent carbon atoms can constitute a methylenedioxy group;

wherein X is S; O; or NR4;

wherein B is -H; straight chained or branched C1-C7 alkyl, monofluoroalkyl, polyfluoroalkyl, alkoxy or thioalkyl; straight chained or branched C2-C7 alkenyl; - SCH2C6H4OR4; -(CH2)n C6H5; -CH2X(CH2)n NHR4;
-(CH2)n NHR4; or -OR4;

wherein R1 is -H; -NO2; -CN; straight chained or branched C1-C7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; -N(R4)2; -OR4; -(CH2)p OR4; -COR4;
-CO2R4; or -CON(R4)2;

wherein R2 is -H; straight chained or branched C1-C7 alkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; C3-C10 cycloalkyl-C1-C10-alkyl, C3-C10 cycloalkyl-C1-C10-monofluoroalkyl or C3-C10 cycloalkyl-C1-C10-polyfluoroalkyl; -CN; -CH2XR4, -CH2X(CH2)p NHR4, -(CH2)n NHR4, -CH2X(CH2)p N(R4)2, -CH2X(CH2)p N3, or -CH2X(CH2)p NHCXR7; or -OR4;

wherein each p is independently an integer from 1 to 7; wherein each n is independently an integer from 0 to 5;
wherein R3 is wherein Z' is (CH2)o, CO, (CH2)o CO, or CO(CH2)o;

wherein each V is independently O; S; CH2; CR5R7;
C(R7)2; or NR7;

wherein each m is independently an integer from 0 to 3; wherein o is an integer from 1 to 3;

wherein each R is independently -H; -F; straight chained or branched C1-C7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; -N (R4)2; -NO2; -CN; -CO2R4; or -OR4;

wherein each R4 is independently -H; straight chained or branched C1-C7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;

wherein R5 and R7 each independently may be -H; F;
C1; Br; I; -COR3; -CO2R3; -CON (R3)2; -CN; -NO2;
-N(R3)2; -OR3; -SR3; -(CH2)p OR3; -(CH2)p SR3; straight chained or branched C1-C7 alkyl, aminoalkyl, carboxamidoalkyl; straight chained or branched C2-C7 alkenyl or alkynyl, or C3-C7 cycloalkyl or cycloalkenyl; wherein the alkyl, aminoalkyl, carboxamidoalkyl, alkenyl, alkynyl, cycloalkyl or cycloalkenyl may be substituted with one or more aryl or heteroaryl, wherein the aryl or heteroaryl may be substituted with -F, -Cl, -Br, -I, -NO2, -CN, -OR3, -SR3, C1-C3 alkyl, or carboxamido; aryl or heteroaryl, wherein the aryl or heteroaryl may be substituted with one or more -F, -Cl, -Br, -I, COR3, CO2R3, -CON(R3)2, -CN, -NO2, -N(R3)2, -OR3, -SR3, (CH2)o OR3, (CH2)o SR3; straight chained or branched C1-C7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl, C2-C7 alkynyl, C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; and wherein each R6 is independently -H; straight chained or branched C1-C7 alkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; or -OR4;

or a pharmaceutically acceptable salt thereof.
20. A pharmaceutical composition comprising a therapeutically effective amount of the compound of claim 1 and a pharmaceutically acceptable carrier.
21. The pharmaceutical composition of claim 20 wherein the amount of the compound is an amount from about 0.01 mg to about 500 mg.
22. The pharmaceutical composition of claim 21 wherein the amount of the compound is from about 0.1 mg to about 60 mg.
23. The pharmaceutical composition of claim 22 wherein the amount of the compound is from about 1 mg to about 20 mg.
24. The pharmaceutical composition of claim 20, wherein the carrier is a liquid and the composition is a solution.
25. The pharmaceutical composition of claim 20, wherein the carrier is a solid and the composition is a tablet.
26. The pharmaceutical composition of claim 20, wherein the carrier is a gel and the composition is a suppository.
27. The pharmaceutical composition of claim 20, wherein the compound additionally does not cause a fall in blood pressure at dosages effective to alleviate benign prostatic hyperplasia.
28. A method of treating a subject suffering from benign prostatic hyperplasia which comprises administering to the subject an amount of the compound of claim 1 effective to treat benign prostatic hyperplasia.
29. A method of claim 28, wherein the compound additionally does not cause a fall in blood pressure at dosages effective to alleviate benign prostatic hyperplasia.
30. The method of claim 29, wherein the compound effects treatment of benign prostatic hyperplasia by relaxing lower urinary tract tissue.
31. The method of claim 30, wherein lower urinary tract tissue is prostatic smooth muscle.
32. A method of treating a subject suffering from high intraocular pressure which comprises administering to the subject an amount of the compound of claim 1 effective to lower intraocular pressure.
33. A method of treating a subject suffering from a disorder associated with high cholesterol which comprises administering to the subject an amount of the compound of claim 1 effective to inhibit cholesterol synthesis.
34. A method of treating a disease which is susceptible to treatment by antagonism of the .alpha.1A
receptor which comprises administering to the subject an amount of the compound of claim 1 effective to treat the disease.
35. A method of treating a subject suffering from impotency which comprises administering to the subject an amount of the compound of claim 1 effective to treat impotency.
36. A method of treating a subject suffering from sympathetically mediated pain which comprises administering to the subject an amount of the compound of claim 1 effective to treat sympathetically mediated pain.
37. A method of treating a subject suffering from cardiac arrhythmia which comprises administering to the subject an amount of the compound of claim 1 effective to treat cardiac arrhythmia.
38. A method of treating a subject suffering from benign prostatic hyperplasia which comprises administering to the subject an amount of the compound of claim 1 effective to treat benign prostatic hyperplasia.
39. The method of claim 38, wherein the compound effects treatment of benign prostatic hyperplasia by relaxing lower urinary tract tissue.
40. The method of claim 39, wherein lower urinary tract tissue is prostatic smooth muscle.
41. A method of treating a subject suffering from benign prostatic hyperplasia which comprises administering to the subject an amount of the compound of claim 1 in combination with a 5 alpha-reductase inhibitor effective to treat benign prostatic hyperplasia.
42. The method of claim 41, wherein the 5-alpha reductase inhibitor is finasteride.
43. A method of treating a subject suffering from benign prostatic hyperplasia which comprises administering to the subject an amount of the compound of claim 1 in combination with a 5 alpha-reductase inhibitor effective to treat benign prostatic hyperplasia.
44. The method of claim 43, wherein the 5-alpha reductase inhibitor is finasteride.
45. A pharmaceutical composition comprising a therapeutically effective amount of the compound of claim 1 in combination with a therapeutically effective amount of finasteride and a pharmaceutically acceptable carrier.
46. The pharmaceutical composition of claim 45 wherein the compound is present in an amount from about 0.01 mg to about 500 mg and the therapeutically effective amount of the finasteride is about 5 mg.
47. The pharmaceutical composition of claim 46 wherein the compound is present in an amount from about 0.1 mg to about 60 mg and the therapeutically effective amount of finasteride is about 5 mg.
48. The pharmaceutical composition of claim 47 wherein the compound is present in an amount from about 1 mg to about 20 mg and the therapeutically effective amount of finasteride is about 5 mg.
49. A method of relaxing lower urinary tract tissue which comprises contacting the lower urinary tract tissue with an amount of the compound of claim 1 effective to relax lower urinary tract tissue.
50. The method of claim 49, wherein the lower urinary tract tissue is prostatic smooth muscle.
51. A method of relaxing lower urinary tract tissue in a subject which comprises administering to the subject an amount of the compound of claim 1 effective to relax lower urinary tract tissue.
52. The method of claim 51, wherein the lower urinary tract tissue is prostatic smooth muscle.
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