JP2000500470A - Dihydropyrimidine and uses thereof - Google Patents

Abstract

(57) Abstract The present invention relates to dihydropyrimidine compounds that are selective antagonists of the human _α1A receptor. The present invention relates to a compound for treating intraocular pressure, inhibition of cholesterol synthesis, relaxation of the lower ureteral tissue, benign prostatic hypertrophy, impotence, cardiac arrhythmia, and any disease for which antagonism of the _α1A receptor is useful. Also relates to the use of. Further, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of the above compound and a pharmaceutically acceptable carrier.

Description

DETAILED DESCRIPTION OF THE INVENTION                     Dihydropyrimidine and uses thereof   This application is PCT International Application No. PCT / US95 / filed on November 16, 1995. 15025 is a continuation-in-part application, the contents of which are incorporated by reference. This application Throughout, various references are referenced in parentheses. Technology to which the present invention belongs In order to more fully describe the state of the field, the entire disclosure of these documents is referred to as references. And incorporated into the present application.                                Background of the Invention   The IUPHA nomenclature committee has traditionally identified receptor and ion channel lives. (Additional version) (Watson and Girlstone, 1995) "Α_1C"Subtype" and "α_1ANotation It has recently been approved for use as a name. The application and a table supporting the application And throughout the figure, α_1ANotation to indicate the receptor subtype Used. At the same time,_1AThe receptor described as α_1DAnd amended. The entire application Through this new nomenclature. Stable cell lines expressing these receptors As described herein, these cell lines are referred to under the American nomenclature (below). Deposited with the Can Type Culture Collection (ATCC).   Benign Prostatic Hyperplasia (BPH) is a benign prostate Prostatic tissue, also called thickening (Benign Prostatic Hypertrophy), grows like a nodule. It is a progressive disease that is characterized by greatness and obstructs the urethra. this As a result, increased urination frequency, nocturia, decreased urine output, difficulty starting urine output Or delay. When BPH becomes chronic, bladder smooth muscle hypertrophy and functional cost Combined with increased incidence of decompensated bladder and urinary tract infection obtain. Biochemical, histological and specific to prostate tumors that cause bladder drainage disorders The pharmacological properties are not yet known. However, the progress of BPH is a collection of elderly men It is considered an inevitable phenomenon for the party. Males over 70 BPH is observed in 70% of the cases. Currently, in the United States, as a treatment for BPH Can be selected Is surgery (Lepor, H., Urol. Clinics North Amer., 17, 651 (1990)). 40 More than 0,000 prostatectomy operations are performed annually (1986 data). By medicine It is clear that alternatives to surgery are eagerly needed. Surgery for BPH treatment Limitations include the morbidity, obstruction and inflammation symptoms of operating older men. This includes not only continuation or recurrence, but also the high cost of surgery.   α-adrenergic receptor (McGrath, et al. Med. Res. Rev., 9, 407-533, 1989) Are specific to the peripheral and central nervous systems on tissues and organs throughout the body It is a neuroreceptor protein. These receptors regulate many physiological functions. Switch, and therefore an important target for drug development . In fact, a number of alpha adrenergic drugs have been developed over the past 40 years. Examples include clonidine, phenoxybenzamine and prazosin (for treating hypertension) , Naphazoline (a nasal decongestant) and apraclonidine (apraclonidin) e) (Glaucoma treatment) is included. Alpha adrenergic drugs are divided into two distinct groups Can be divided into Norepinephrine, an endogenous neurotransmitter Agonists that mimic the receptor activating properties of Gonist)) and norepinephrine. Antagonists (phenoxybenzamine and prazosin are antagonists ). While many of these drugs are effective, they also have undesirable side effects. (Eg, clonidine causes dry mouth and sedation in addition to its antihypertensive effect) ).   Over the last 15 years, alpha-adrenergic receptors have been more accurately understood and And with the increase of in-depth research, those drugs have evolved. Before 1977, The existence of only one α-adrenergic receptor was known. 1977 and 19 During the 88 years, the central and peripheral nervous systems₁And α_TwoAt least Scientists acknowledge the existence of two alpha-adrenergic receptors Was done. Since 1988, new technologies in molecular biology have enabled the central nervous system and peripheral At least six α-adrenergic receptors throughout the nervous system: α_1A(New naming Mod), α_1B, Α_1D(New nomenclature), α_2A, Α_2BAnd α_2c(Bylund, DB, FASEB J., 6,832, (1992)). In many cases Which receptors regulate the body's physiological responses. Is positive Not exactly known. In addition, current alpha adrenergic drugs Is also not selective for α-adrenergic receptors. Many of these drugs Is disadvantageous due to poor selectivity for α-adrenergic receptors Side effects occur.   Since mid 1970, non-selective alpha antagonists have been treated to treat BPH. It has come to be. In 1976, M. Caine et al. (Brit. J. Urol., 48, 25 5 (1976)) that phenoxybenzamine, a non-selective α antagonist, H was reported to be useful in relieving symptoms. The drug is present on the prostate It may produce an effect by interacting with existing alpha receptors. Only However, the drug also causes significant side effects such as dizziness and asthenia, The chronic use of these to treat is significantly limited. further More recently, the alpha adrenergic antagonists prazosin and te Lazosin was also found to be useful for BPH treatment. But these drugs Things also cause adverse side effects. Recently, α_1AReceptor contracts human prostate smooth muscle (Gluchowski, C. et al., WO 94/10989, 1). 994; Forray, C. et al., Mol. Pharmacol. 45, 703, 1994). This finding, α_1AA Antagonists have few side effects and may be an effective drug for BPH treatment It indicates that. Further studies indicate that α_1AThe receptor is urethral smooth muscle Have been shown to be present in other lower urethral tissues such as ord et al. Br. J. Pharmacol., 114, 24P, (1995)).   The present invention relates to a cloned human α_1AIs a selective antagonist of the receptor It relates to a dihydropyrimidine compound. The present invention is intended to reduce intraocular pressure. The use of these compounds (Zhan, et al. Ophthalmol. Vis. Sci., 34 Abst. # 1133, 928, 1993), cholesterol synthesis (D'Eletto and Javitt, J. Cardiova). scular Pharmacol., 13 (Suppl. 2) S1-S4, 1989), benign prostatic hyperplasia, impotence Tsu (Milne and Wyllie, EP 0 459 666 A2, 1991), pain through the sympathetic nervous system (Campbell, WO92 / 14453, 1992), cardiac arrhythmia (S piers, et.al., J. Cardiovascular Pharmacol., 16,824-830, 1990) Use of these compounds for and α_1AReceptor antagonism may be useful Treat any disease Regarding use.                                Summary of the Invention   The present invention relates to human α_1ADihydropyrimidines are selective antagonists of the receptor For compounds. The present invention is directed to reducing intraocular pressure, inhibiting cholesterol synthesis, lower urethral tissue Treatment of benign prostate hyperplasia, impotence, cardiac arrhythmia, and alpha_1AAcceptance Use of the compounds for the treatment of any disease for which body antagonism may be useful Also concerns. The invention further provides a therapeutically effective amount of the above compound and a pharmaceutically acceptable A pharmaceutical composition comprising a carrier.                             Detailed description of the invention   The invention has the structure: Or Where M is the structure Has,     Where Y₁, Y_Two, Y_Three, Y_FourAnd Y_FiveIs each independently -H; linear or branched C₁-C₇Alkyl, monofluoroalkyl or polyfluoroalkyl; Or branched chain C_Two-C₇Alkenyl or alkynyl; C_Three-C₇Shiku Loalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or Cycloalkenyl; -F, -Cl, Br, or -I; -NO_Two; -N (R_Three)_Two; -N_Three; -CN;- OR_Three; -OCOR_Three; -COR_Three; -CON (R_Three)_Two; -N_Three; -CN; -OR_Three; -OCOR_Three; -C OR_Three; -CON (R_Three)_Two; Or -CO_TwoR_ThreeOr Y₁, Y_Two, Y_Three, Y_Four And Y_FiveAre on adjacent carbon atoms and both are methylenedioxy Make up the group;     Wherein R is independently -H; -F; linear or branched C₁-C₇Alkyl, monoflu Oloalkyl or polyfluoroalkyl; linear or branched C_Two-C₇Alkene Or alkynyl; -N (R_Three)_Two; -NO_Two; -CN; -CO_TwoR_Three;-( CH_Two)_pPO (OR_Three )_Two;-( CH_Two)_pPO (OR_Three)_Three; Or -OR_ThreeMay be;     Where R₁Is -H; -NO_Two; -CN; linear or branched C₁-C₇Alkyl, mono Fluoroalkyl or polyfluoroalkyl; linear or branched C_Two-C₇Al Kenyl or alkynyl; C_Three-C₇Cycloalkyl, monofluorocycloalkyl , Polyfluorocycloalkyl or cycloalkenyl; -N (R_Three)_Two; -OR_Three;- (CH_Two)_pOR_Three; -COR_Three; -CO_TwoR_Three; Or -CON (R_Three)_TwoMay be;     Wherein all p are independently integers from 1 to 7;     Where R_TwoIs -H; linear or branched C₁-C₇Alkyl, hydroxyalkyl , Alkoxyalkyl, aminoalkyl, monofluoroalkyl or polyfur Oroalkyl; straight or branched chain C_Two-C₇Alkenyl or alkynyl; C_Three-C₇ Cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl Or cycloalkenyl; C_Three-C_TenCycloalkyl-C₁-C_Ten-Alkyl, C_Three-C_Ten Cycloalkyl-C₁-C_Ten-Monofluoroalkyl or C_Three-C_TenCycloalkyl -C₁-C_Ten-Polyfluoroalkyl; -CN; -CH_TwoXR_Three, -CH_TwoX (CH_Two)_pNH R_Three,-(CH_Two)_nNHR_Three, -CH_TwoX (CH_Two)_pN (R_Three)_Two, -CH_TwoX (CH_Two)_pN_ThreeMa Or -CH_TwoX (CH_Two)_pNH CXR₇; -OR_ThreeMay be;     Here, all n are independently integers from 0 to 5, and p is as defined above. A cage;     Where each R_ThreeIs independently -H; linear or branched C₁-C₇Alkyl, monoflu Oloalkyl or polyfluoroalkyl; linear or branched C_Two-C₇Alkene Le or alkynyl; C_Three-C₇Cycloalkyl, monofluorocycloalkyl, Polyfluorocycloalkyl or cycloalkenyl;-(CH_Two)_pPO (OR₈)_Two; -(CH_Two)_pPO (OR₈)_Three; Or-(CH_Two)_pCOOR₈May be; Where R_FourIs the structure Has,     Where Z is C_Two-C₇Alkenyl or alkynyl; CH_Two; O; CO; CO_Two; C ONR_ThreeCO; CONR_Three; S; SO; SO_Two; Or NR_ThreeM is 0 or more and 3 Is an integer that is:     R_FiveAnd R₆Is independently -H; -F, -Cl, -Br, -I; -CO_TwoR_Three; -COR_Three ; -CON (R_Three)_Two; -CN; -NO_Two; -N (R_Three)_Two; -OR_ThreeA straight or branched chain C₁-C₇A Luquil, C₁-C₇Monofluoroalkyl, C₁-C₇Polyfluoroalkyl, C_Two-C₇ Alkenyl, C_Two-C₇Alkynyl, C_Three-C₇Cycloalkyl, or C_Three-C₇Shiku Where the alkyl, monofluoroalkyl, polyfur Oloalkyl, alkenyl, alkynyl, cycloalkyl or cycloalkenyl May be unsubstituted with -H, allyl or heteroallyl, or Allyl or heteroallyl may be -H, -F, -Cl, -Br, -I , -NO_Two, -CN, -N (R_Three)_Two, -OR_Three, -COR_Three, -CO_TwoR_Three, Or -CON ( R_Three)_TwoMay be unsubstituted or substituted; linear or Branched chain C₁-C₇Alkyl, monofluoroalkyl or polyfluoroalkyl, Straight or branched chain C_Two-C₇Alkenyl Or alkynyl, C_Three-C₇Cycloalkyl, monofluorocycloalkyl, May be trifluorocycloalkyl, or cycloalkenyl;     R₇Is -H; linear or branched C₁-C₇Alkyl, hydroxyalkyl, a Minoalkyl, alkoxyalkyl, monofluoroalkyl or polyfluoro Alkyl; straight or branched C_Two-C₇Alkenyl or alkynyl; C_Three-C₇Shiku Loalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or Cycloalkenyl; -CN; -CO_TwoR_Three; -COR_Three; -CON (R_Three)_Two; Or -OR_Threeso possible;     Where R₈Is -H; linear or branched C₁-C₇Alkyl, monofluoroal Killed or polyfluoroalkyl; linear or branched C_Two-C₇Alkenyl or Alkynyl; C_Three-C₇Cycloalkyl, monofluorocycloalkyl, polyfur Olocycloalkyl or cycloalkenyl;     Where R₉Is -H; -CN; linear or branched C₁-C₇Alkyl, monofluo Loalkyl or polyfluoroalkyl; linear or branched C_Two-C₇Alkenyl Or alkynyl; C_Three-C₇Cycloalkyl, monofluorocycloalkyl, Trifluorocycloalkyl or cycloalkenyl; -N (R_Three)_Two; -OR_Three;-( CH_Two)_p OR_Three; -COR_Three; -CO_TwoR_ThreeOr -CON (R_Three)_TwoMay be;     Where X is S; O; or NR_ThreeAnd;     Where B is -H; linear or branched C₁-C₇Alkyl, monofluoroalkyl , Polyfluoroalkyl, alkoxy, or thioalkyl; straight or branched C_Two-C₇Alkenyl; -SCH_TwoC₆H_FourOR_Three;-( CH_Two)_nC₆H_Five; -CH_TwoX (CH_Two)_nN HR_Three;-( CH_Two)_nNHR_Three; Or -OR_ThreeMay be; Or a pharmaceutically acceptable salt thereof.   In the present invention, allyl is benzyl, benzoyl, naphthyl, or phenyl. And heteroaryls include pyridyl, thiophenyl, furanyl, pyrazinyl , Piryl, naphthyl, indolyl, imidazolyl, benzflazanil, benzuf Ranyl, quinolyl, aminophenyl, benzimidazolyl or 2-keto-1-ben And zimidazolinyl.   The compounds of the present invention may comprise enantiomers, diastereomers, It may be present as an isomer, where two or more compounds are present to form a racemic mixture May be implemented.   Furthermore, the compounds of the invention are preferably at least 80% pure, more preferably Or 90% purity, and most preferably 95% purity.   The invention further relates to cis or trans isoforms of any of the compounds described herein. (+) Enantiomers are provided. The invention is also described herein. Provides (-) enantiomer that is a cis or trans isomer of any compound I do.   In one embodiment of the invention, the compound is (+)-6- (3,4-difluorophenyl) -1 -(N- [2- (4-cyano-4-phenyl-cyclohexylamino) ethyl]} carboxami De-5-methoxycarbonyl-4-methoxymethyl-2-oxo-1,2,3,6-tetrahydro Not a pyrimidine hydrochloride.   There is at least a 10-fold difference in selectivity, but those skilled in the art Provides an almost infinitely variable selectivity profile. Can understand. Each of these compounds is represented by α_1BAnd / or α_1DCompared to the receptor α_1AGiven that it has at least 10 times greater affinity for the receptor, Compounds having all of the combinations of selectivity obtained are also included in the scope of the present invention. it is conceivable that.   In a preferred embodiment of the present invention, andA compound selected from the group consisting of:   In one preferred embodiment for the compounds described herein, R_FourIs And p is 2, 3 or 4.   In one preferred embodiment for the compounds described herein, R_FourIs And p is 2, 3 or 4.   Further, the present invention provides the following structure Are also provided.   In one embodiment of the present invention, M is polyfluorophenyl and R_Fiveand R₆Is independently substituted or unsubstituted phenyl or pyridyl is there.   In a further embodiment of the present invention, R₁Is -CO_TwoCH_Three, -COCH_ThreeOr -C ONH_TwoAnd R_TwoIs CH_TwoOCH_Three, Methyl or ethyl; R₆Is H, -CN or Is CO_TwoCH_Three,.   The invention has the following structure: and A preferred embodiment having the following is provided. The invention has the following structure: Are also provided.   In another embodiment of the present invention, M is polyfluorophenyl and R_FiveIs replaced Substituted or unsubstituted phenyl or pyridyl.   The invention comprises a therapeutically effective amount of the above compound and a pharmaceutically acceptable carrier. Also provided are pharmaceutical compositions. The “therapeutically effective amount” in the present invention means that the compound is When administered to a patient suffering from an effective disease, the disease can be reduced, reduced, Is any amount of the compound that causes recovery. In some embodiments, the therapeutically effective The amount is about 0.01-500 mg per patient per day, preferably about 0.1-60 mg per day, Most preferably about 1-20 mg. In the practice of the present invention, a "pharmaceutically acceptable "A carrier" is any raw material known to those of skill in the art that is useful in formulating a pharmaceutical composition. It is a physical carrier.   In certain embodiments, the pharmaceutical carrier can be a liquid and the pharmaceutical composition is in the form of a solution possible. In another, equally preferred embodiment, the pharmaceutically acceptable carrier is a solid. Alternatively, the composition is in the form of a powder or a tablet. In a further embodiment, a pharmaceutical carrier Is a gel and the composition is in the form of a suppository or cream.   The present invention is a method of treating a patient afflicted with benign prostatic hyperplasia, comprising: Any one of the compounds described herein, which is effective in treating glandular hypertrophy, There is provided a method comprising administering to a patient. In addition, the present invention Provide compounds that do not reduce blood pressure in an amount effective to alleviate gonad enlargement Offer. In certain preferred embodiments, the compound is selected from the group consisting of lower urethral tissue, particularly If the urethral tissues are prostate smooth muscle, relax them before they Demonstrates efficacy in treating gonad hypertrophy.   Further, the present invention is a method of treating a patient suffering from increased intraocular pressure, comprising: Administering to a patient one of the compounds described herein that is effective in reducing elevation Providing a method comprising:   Further, the present invention provides a method for treating a patient suffering from a disease accompanied by an increase in blood cholesterol. A method effective to inhibit cholesterol synthesis, as described herein. A method comprising administering one of the compounds to a patient.   The present invention relates to α_1AMethods of treating diseases for which treatment with receptor antagonism may be effective Wherein one of the compounds described herein is effective in treating the condition. Also provided is a method comprising administering one to a patient.   Further, the invention is a method of treating a patient suffering from impotence, the method comprising: One of the compounds described herein, which is effective in treating impotence. A method comprising administering to a subject.   The present invention further provides a method of treating a patient suffering from pain through the sympathetic nervous system. As described herein, which is effective in treating pain through the sympathetic nervous system A method comprising administering one of the compounds to a patient.   The present invention is a method of treating a patient suffering from a cardiac arrhythmia, the method comprising: Administer one of the compounds described herein to a patient that is effective in treating arrhythmia. Providing a method comprising:   The present invention is a method of treating a patient afflicted with benign prostatic hyperplasia, comprising the steps of: A combination of a dactase inhibitor with an effective amount of the above to treat benign prostatic hyperplasia Also provided is a method comprising administering any of the compounds to a patient. Like Alternatively, the 5-α-reductase inhibitor is finasteride . α_1AThe amount administered to the patient together with the antagonist is about 0,0 per day per patient. 01-50 mg of finasteride. α_1AAdminister to patient with antagonist A preferred amount is about 0.2 to 10 mg finasteride per patient per day. α_1AA more preferred amount to administer to a patient with an antagonist is one day per patient Approximately 1 to 7 mg of finasteride. α_1APatient with antagonist The optimal amount to administer is about 5 mg finasteride per patient per day .   The present invention relates to a composition comprising finasteride and a pharmaceutically acceptable carrier. Pharmaceutical compositions comprising a therapeutically effective amount of any of the compound combinations described herein The product is also provided. In certain embodiments, the pharmaceutical composition comprises About 0.01 to 500 mg of any one of the compounds described herein, And finasteride in an amount of about 5 mg per patient per day. It is a combination of effective doses. A further preferred embodiment of the pharmaceutical composition comprises Any of the compounds described herein in an amount of about 0.1 to 60 mg per day One and finasteride in an amount of about 5 mg per patient per day, A combination of therapeutically effective amounts. The most preferred embodiment of the pharmaceutical composition is About 1-20 mg of any one of the compounds described herein per day And finasteride in an amount of about 5 mg per patient per day It is a combination of effective amounts.   Further, the present invention relates to a method for relaxing lower urethral tissue, wherein the lower urethral tissue is relaxed. An effective amount of one of the compounds described herein for relaxing the lower urinary tract Providing a method comprising contacting with a fabric. In one embodiment, the lower portion The urethral tissue is prostate smooth muscle. In one preferred embodiment, the compound is lower urine Does not concurrently lower blood pressure when effective in relaxing tract tissue.   The present invention is a method of relaxing the lower urethral tissue of a patient, the method comprising relaxing the lower urethral tissue. Administer to a patient an amount of any of the compounds described herein that is effective to slow down Providing a method comprising: In certain preferred embodiments, the compound is Without causing a drop in blood pressure, the lower urethral tissue is prostate smooth muscle.   Further, the present invention is a method of inhibiting contraction of prostate tissue, the method comprising: An effective amount of one of the compounds described herein is administered to the patient Providing a method comprising: In one preferred embodiment, the prostate The tissue is prostate smooth muscle and the compound does not combine with a decrease in blood pressure.   The present invention relates to the use of a compound as described herein for reducing intraocular pressure. A pharmaceutical composition for inhibiting cholesterol synthesis, a pharmaceutical composition for inhibiting cholesterol synthesis, Benign prostatic hyperplasia, impotence, cardiac arrhythmias and alpha_1AReceptor antagonism present To prepare a pharmaceutical composition for treating any disease that may be of use Provides use of. The present invention is intended to relax lower urethral tissue, particularly prostate smooth muscle. Use of a compound described herein to prepare a pharmaceutical composition for provide. The present invention further provides a pharmaceutical composition as described herein for preparing a pharmaceutical composition. The use of any compound that is effective in lowering intraocular pressure. Amount, an amount effective to inhibit cholesterol synthesis, as well as benign prostatic hyperplasia, Potents, cardiac arrhythmias and alpha_1AOptional where receptor antagonism may be useful Should be used in an amount effective to treat the disease, without concurrent lowering of blood pressure. provide.   The present invention relates to a medicine for lowering intraocular pressure and a method for inhibiting cholesterol synthesis. And benign prostatic hyperplasia, impotence, cardiac arrhythmias and α_1AReceptor In the preparation of a medicament for treating any disease for which antagonism may be useful Provide for the use of the compounds described herein. The present invention relates to a lower urethral set In the preparation of a medicament for the preparation of a medicament for relaxing tissue, especially prostate smooth muscle. There is provided the use of a compound as described herein in The present invention further provides Use of any of the compounds described herein in the preparation of a medicament, wherein Compound is effective in lowering intraocular pressure, effective in inhibiting cholesterol synthesis Effective amount, as well as benign prostatic hypertrophy, impotence, cardiac arrhythmias and α_1AReceptor In an amount effective to treat any disease for which antagonism may be useful Provide use that does not concurrently lower blood pressure.   The present invention inhibits cholesterol synthesis, a drug useful for lowering intraocular pressure Drugs useful for benign prostate hyperplasia, impotence, cardiac arrhythmias and α_1A Drugs useful for treating any disease for which receptor antagonism may be useful Wherein the active ingredient of the drug is any of the compounds described herein Provide the drug. Further, the present invention relates to a medicament as described herein, wherein An amount effective to reduce intraocular pressure, an amount effective to inhibit cholesterol synthesis, And benign prostatic hyperplasia, impotence, cardiac arrhythmias and α_1AReceptor antagonism Blood pressure in an amount effective to treat any disease that may be useful Provide a drug that does not cause concurrent decline.   The present invention relates to a drug useful for relaxing lower urethral tissue, particularly prostate smooth muscle. Thus, a drug wherein the active ingredient of the drug is any of the compounds described herein I will provide a. The present invention is also a drug useful for relaxing lower urethral tissue. Does not concurrently lower blood pressure in an amount effective to relax lower urethral tissue Provide such drugs.   The present invention relates to the (-) and (+) enantiomers of all the compounds of the present application described herein. Enantiomers are also provided. Included in the present invention are pharmaceutically acceptable salts and the present specification. Complexes with all compounds described in this publication. Salts include the following acids and salts Including but not limited to groups.   The following inorganic acids: hydrochloric, hydrofluoric, hydrobromic, hydroiodic, sulfuric and Boric acid. Organic acids; acetic acid, trifluoroacetic acid, formic acid, oxalic acid, malonic acid, succinic acid Acid, fumaric acid, tartaric acid, maleic acid, citric acid, methanesulfonic acid, trifluoro Romethanesulfonic acid, benzoic acid, glycolic acid, lactic acid and mandelic acid. below Inorganic bases; ammonia, hydroxyethylamine, and hydrazine. The following Machine base; methylamine, ethylamine, propylamine, dimethylamine, die Tylamine, trimethylamine, triethylamine, ethylenediamine, hydro Xylethylamine, morpholine, piperazine and guanidine. The present invention further provides In particular, hydrates and polymorphs of all compounds described herein )I will provide a.   In certain preferred embodiments, the pharmaceutical carrier can be a liquid and the pharmaceutical composition can be a solution. It can be in liquid form. In another similarly preferred embodiment, a 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. Further In embodiments, the compound is one of a pharmaceutically acceptable transdermal patch. It may be prescribed as a part.   Solid carriers include flavors, lubricants, solvents, suspending agents, fillers, glidants (g lidant), compression device, binder or tablet-disintegrati One or more substances that can act as ng agents) can be included. The encapsulant Is also good. In the case of a powder, the carrier is a finely divided solid, which is finely divided. It is a mixture with the active ingredient. For tablets, the active ingredient has the necessary compression properties It is mixed with the carrier in an appropriate ratio and is filled in the desired shape and size . Powder and Tablets preferably contain up to about 99% of the active ingredient. For example, a suitable solid phase Carriers include calcium phosphate, magnesium stearate, talc, sugar , Lactose, dextrin, starch, gelatin, cellulose, polyvinylpyrrolid , Low melting waxes, and ion exchange resins.   Liquid phase carriers include solutions, suspensions, emulsions, syrups, elixirs and tablets. Used in preparing pressurized compositions. Effectiveness The components are water, an organic solvent, a pharmaceutically acceptable liquid phase carrier such as a mixture of both, and Can be dissolved or suspended in a pharmaceutically acceptable oil or lipid . Liquid phase carriers include solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavors, suspending agents, Thickening agents, pigments, viscosity modifiers, stabilizers or osmotic pressure regulators, etc. Other suitable pharmaceutical additives can be included. For oral and parenteral administration Suitable examples of the liquid phase carrier include water (addition of the above-mentioned additives, for example, a cellulose derivative. Containing, preferably sodium carboxymethylcellulose solution), Coal (including monohydric and polyhydric alcohols such as glycols) And their derivatives, and oils such as fractionated coconut oil and pea. Nut oil). For parenteral administration, the carrier may be ethyl oleate. And oily esters such as isopropyl myristate oil Good. Sterile liquid carriers are useful in sterile liquid compositions for parenteral administration. Pressurized The liquid carrier for the composition may be a halogenated hydrocarbon or other pharmaceutically acceptable Compressed inert gas (propellent).   Liquid pharmaceutical compositions that are sterile solutions or suspensions can be administered, for example, intramuscularly, in the envelope. trathecal), can be used by dermal, intraperitoneal or subcutaneous administration Wear. Sterile solutions can also be administered intravenously. The compound is a sterile solid composition May be prepared as sterile water, saline or other suitable sterile and administered It may be dissolved or suspended at the time of administration using a possible solvent. The carrier needs and Inert binders, suspending agents, lubricants, flavors, sweeteners, preservatives, dyes and coatings May be included.   The compound may be, for example, sufficient saline or glucose to make the solution isotonic. , Bile salts, acacia, gelatin, sorbitan monooleate, poly Seo Rubate 80 (sorbitol and its anhydride copolymerized with ethylene oxide) Sterile solutions or suspensions containing other solutes or suspending agents, such as oleates Can be administered orally.   The compounds can also be administered orally, in either liquid or solid composition form. You. Compositions suitable for oral administration include pills, capsules, granules And solid forms such as tablets and powders, and solutions, syrups and elixirs Agents and suspensions are included. Forms useful for parenteral administration include sterile solutions, emulsions Liquid forms such as solutions and suspensions. Forms useful for parenteral administration include: Sterile solutions, emulsions and suspensions are included.   The optimal amount to be administered can be determined by those skilled in the art, It will vary with the mode of administration, and the progress of the condition. Patient age, body Other factors depending on the patient to be treated, including weight, sex, diet and time of administration. You will need to adjust the dose.   The present invention further provides metabolites of the compounds of the present invention. Metabolites of pharmaceutical compounds The in vivo activities and mechanisms of action of many enzymes required to produce It is well known. For example, ether is modified to alcohol, and ester is Estella. Amide modified by amidase and peptidase. Can be   Further, the present invention provides prodrugs of the compounds disclosed herein. . Knowing your metabolic activity will allow you to design prodrug compounds Comprising a compound of the invention when administered to a patient, such as a human. Expected to produce goods. For example, cyclohexylamino nitrogen is methyl, al Modified with various substituents such as canoyl, aroyl, or alkyl or Allyl carbamates may be formed, which when acted in vivo It is expected that endogenous enzymes will produce the compounds of the present invention. As mentioned above However, such modifications are merely exemplary and are not intended to limit the scope of the invention. Instead, such modifications and techniques are well known to those skilled in the art.   For treating the above disorders, the claimed compounds are therapeutically effective. The use of appropriate biological assays to determine certain possibilities is within the skill of the art. It will be easy to understand.   The present invention will be better understood from the experimental details that follow. However The skilled artisan will appreciate the specific methods and results being discussed It is to be understood that, to the extent required, it is merely illustrative of the invention as more fully described. It will be easily understood. Detailed description of the experiment For Examples 1-17, Scheme 1 provides a general synthesis for preparing compounds of the invention. Illustrates the scheme. Specific citations for the synthesis steps of Scheme 2-8 are as follows: It is included in the appropriate example below. All NMR data are 300 MHz GE Obtained using a QEPLUS NMR machine. Example 1 Cis-6- (3,4-difluorophenyl) -1- {N- [2- (cyano-4-phenyl-cyclohexyl) Lamino) ethyl]} carboxamino-5-methoxycarbonyl-4-methyl-2-oxo-1 , 2,3,6-tetrahydropyrimidine hydrochloride. Part-1 a) General preparation of 2- [4.cyano-4-allyl-cyclohexylamino] ethylamine Method (Scheme 2; Part-1). 4-cyclo-4-allyl-cyclohexanone (48.7 mm) in benzene (200 mL) ol), ethylenediamine (8.78 g, 146 mmol) and p-toluenesulfur A mixture of fonic acid (92 mg) was added to a Dean-Stark trap. And refluxed for 4 hours in order to remove the water formed. The solvent is evaporated and the residue is Redissolved in 60 mL of water and cooled to 0 ° C. Sodium borohydride (6. 45 g) were added in portions and the mixture was stirred at room temperature for 3 hours. Evaporate the solvent, Dissolve the residue in dichloromethane (300 mL) and wash with brine (3 × 500 mL) After drying (potassium carbonate), the solvent was evaporated to give a pale yellow viscous oil (90-95). %). The product is cis / trans different in a ratio of about 9: 1. Contains sexual body It was discovered. Chloroform / methanol / 2M ammonia in methanol Careful chromatography of this mixture using (100/10/5 to 100/20/10) Isomers that are in trans form with respect to amino and cyano groups by chromatography Some early fractions were obtained which were rich in. The late elution fraction contains amino groups and For the cyano group, it contained almost pure cis isomer. Part-2 b) Methyl 2-{(3,4-difluorophenyl) methylene} -3-oxobutyrate (Scheme 2 Step C). 3,4-Difluorobenzaldehyde (14.2 g, 0.1 mL) in benzene (150 mL). 1 mol), methyl acetoacetate (12.2 g, 0.105 mol), piperidine (0 . 430 g, 5 mmol) and acetic acid (0.30 g, 5 mmol). The mixture was stirred and refluxed for 8 hours using a Dean-Stark trap. Evaporates benzene The residue was dissolved in ethyl acetate (200 mL), brine (50 mL), saturated Potassium solution (50 mL) and saturated sodium bicarbonate solution one after another Washed. Dry the ethyl acetate solution (magnesium sulfate) and remove the solvent under reduced pressure. , And the residue was subjected to column chromatography (SiO 2_Two, EtOAc / hexane, 10%- 15%). The product, 2-{(3,4-difluorophenyl) methylene } -3-Methyl oxobutyrate was obtained as a yellow oil (0.98 g, 98.3%). Used in the next step without analyzing any features. c) 6- (3,4-difluorophenyl) -1,6-dihydro-2-methoxy-5-methoxycal Bonyl-4-methylpyrimidine (Scheme 2; Step D). 2-{(3,4-difluorophenyl) methylene} -3-oxobutyrate in DMF (30 mL) Chill (8.8 g, 36.6 mmol), O-methylisourea hydrogen sulfate (9.4 g) , 55 mmol), and NaHCO_Three(12.3 g, 0.146 mol) mixture Was stirred and heated at 70 ° C. for 16 hours. The mixture was cooled and EtOAc (30 0 mL) and washed with water (5 × 300 mL) and brine (300 mL) And dried (MgSO_Four)did. Evaporate the solvent and use the crude product as the gradient eluent. In xan Flash column on silica gel with 10% to 25% EtOAc solution Purification by chromatography gave the product as an oil (3.82 g, 20.2%). d) 6- (3,4-difluorophenyl) -1,6-dihydro-2-methoxy-5-methoxycal Bonyl-4-methyl-1-[(4-nitrophenyloxy) carbonyl] pyrimidine (Scheme 2; E). CH_TwoCl_Two6- (3,4-difluorophenyl) -1,6-dihydro-2-methoxy in (50 mL) C-5-methoxycarbonyl-4-methylpyrimidine (2.82 g, 9.52 mmol) And 4-dimethylaminopyridine (1.16 g, 9.52 mmol). 4-Nitrophenyl loroformate (1.82 g, 9.04 mmol) was added at 0-5 ° C. The mixture was allowed to reach the same temperature as room temperature. After 12 hours, the solvent was evaporated And the residue was purified by flash column chromatography (SiO_Two, EtOAc / hexane , 10% -15%) to give the product as white crystals (3.72, 84). . 7%); m. p. 172-174 ° C. e) 6- (3,4-difluorophenyl) -1,2,3,6-tetrahydro-2-oxo-5-methoxy Cicarbonyl-4-methyl-1- (4-nitrophenoxy) carbonylpyrimidine (ski Scheme 2; step F). 6- (3,4-difluorophenyl) -1,6-dihydro-2-methoxy in THF (200 mL) -5-methoxycarbonyl-4-methyl-1- (4-nitrophenoxy) carbonylpyrimidi (10 g) solution was stirred well at room temperature, and 6N hydrochloric acid aqueous solution (10 mL) was added. Added. Stirring was continued for 3 hours. The solvent was evaporated and the residue was dried under vacuum, white The product was obtained as a colored powder (9.7 g, 100%); m.p. p. 185-186 ° C. Part-3 f) cis-6- (3,4-difluorophenyl) -1- {N- [2- (4-cyano-4-phenyl-cycl) Rohexylamino) ethyl]} carboxamide-5-methoxycarbonyl-4-methyl-2- Oxo-1,2,3,6-tetrahydropyrimidine hydrochloride (Scheme 2; Step G). 5-Methoxycarbonyl-4-methyl-1,2,3,6-te in dichloromethane (50 mL) G Lahydro-2-oxo-6- (3,4-difluorophenyl) -1-[(4-nitrophenyloxy) ca Rubonyl] pyrimidine (500 mg, 1.15 mmol) and cis-2- [4-cyano- 4-phenyl-cyclohexylamino] ethylamine (351 mg, 1.5 mmol) The solution was stirred at room temperature for 12 hours. The solution was cooled with ice-cold 0.5N NaOH (2 × 10 mL) and dried over sodium sulfate. The solvent was evaporated under reduced pressure and the remaining The residue is flash chromatographed on silica gel (dichloromethane: MeOH : 2M ammonia in MeOH = 90: 8: 4), purified as white powder 0.55 g (87%) was obtained. The HCl salt is etherified with 1N HCl in ether. Prepared by treating the free base solution in. M. P. 172-174 ° C; C₂₉H₃₂N_FiveO_FourF_TwoCl 1.3H_TwoAnalytical theoretical value for O: 56.96; H, 5. 70; N, 11.45. Found: C, 57.10; H, 5.69; N, 11.12. Example 2 Cis-6- (3,4,5-trifluorophenyl) -1- {N- [2- (4-cyano-4-phenyl-cyclo Hexylamino) ethyl]}-carboxamido-5-acetyl-4-methoxymethyl-2- Oxo-1,2,3,6-tetrahydropyrimidine hydrochloride a) 3-{(3,4,5-trifluorophenyl) methylene} -2,4-pentanedione (ski System 2; Step C). 3,4,5.Trifluorobenzaldehyde (150 g) in benzene (150 mL). 6.2 mmol), 2,4.pentanedione (2.62 g, 26.2 mmol), pipet A mixture of lysine (0.430 g, 5 mmol) was charged with a Dean-Stark trap. The mixture was stirred and refluxed for 8 hours. The benzene was evaporated to give 2-{( 3,4,5-trifluorophenyl) methylene} -2,4-pentanedione is further purified Was used in the next step without any. b) 6- (3,4,5-trifluorophenyl) -1,6-dihydro-2-methoxy-5-acetyl L-4-Methylpyrimidine (Scheme 2; Step D). 2-{(3,4,5-trifluorophenyl) methylene} -2,4- in EtOH (400 mL) Pentandione (26.2 mmol), O-methylisourea hydrogen sulfate (3.22) g, 39.3 mmol), NaHCO_Three(6.6 g, 78.6 mmol) At 95-100 ° C for 6 hours. The mixture is filtered and the solid residue Was washed with ethanol (100 mL). The solvent is evaporated from the combined filtrates and the crude The product was used as a gradient eluent from 10% to 25% EtOAc in hexane. An oily substance produced by flash column chromatography on silica gel To give the product (2.80 g, 36%). c) 6- (3,4,5-trifluorophenyl) -1,6-dihydro-2-methoxy-5-acetyl- 4-methyl-1-[(4-nitrophenyloxy) carbonyl] pyrimidine (Scheme 2; E). CH_TwoCl_Two6- (3,4,5-trifluorophenyl) -1,6-dihydro-2-in (200 mL) Methoxy-5-acetyl-4-methylpyrimidine (2.8 g, 9.38 mmol) and To a solution of pyridine (10 mL) was added 4-nitrophenyl chloroformate (1. (886 g, 9.38 mmol) and the mixture is allowed to come to room temperature. Left. After 12 hours, the solvent is evaporated and the residue is flash column chromatographed. Raffy (SiO_Two, Dichloromethane / EtOAc, 10% -15%) The product was obtained as a white powder (4.0 g, 92%). d) 6- (3,4,5-trifluorophenyl) -1,2,3,6-tetrahydro-2-oxo-5-a Cetyl-4-methyl-1-[(4-nitrophenyloxy) carbonyl] pyrimidine (Scheme 2: Step F). 6- (3,4,5-trifluorophenyl) -1,6-dihydro-2-methoate in THF (100 mL) Xy-5-acetyl-4-methyl-1-[(4-nitrophenyloxy) carbonyl] pyrimidine ( 4.0 g (8.63 mmol), 6N hydrochloric acid aqueous solution (4 mL) was added at 0-5 ° C. The mixture was allowed to reach room temperature. After 2 hours, the solvent was evaporated and the product was Dry under vacuum. Obtain the title compound as a pure single compound for further purification Used for next step without (3.88 g, 100%). e) cis-6- (3,4,5-trifluorophenyl) -1- {N- [2- (4-cyano-4-phenyl- Cyclohexylamino) ethyl]}-carboxamide-5-acetyl-4-methoxymethyl 2-oxo-1,2,3,6-tetrahydropyrimidine hydrochloride (Scheme 2; Step G) . 6- (3,4,5-trifluorophenyl) -1,2,3,6-tetrahydro- in THF (10 mL) 2-oxo-5-acetyl-4-methyl-1-[(4-nitrophenyloxy) carbonyl] pirimi Gin (44.9 mg, 0.1 mmol) and cis-2- (4-cyano-4-phenyl-cycl) Rohexylamino) ethylamine (23.4 mg, 0.23 mmol) Stir at room temperature for 10 hours and evaporate the solvent. Redissolve the residue in dichloromethane (10 mL) Thaw, wash with ice cold 0.5N NaOH (2 × 5 mL), dry and evaporate solvent did. The residue was purified by thin-layer chromatography on preparative silica gel to give Form-Methanol-2M ammonia in methanol (100/2/1) as eluent To give the product as a white powder (53 mg, 88%). HCl The salt was prepared by treatment with 1N HCl in ether and was obtained as a white powder. A product was obtained. C₃₀H₃₂N_FiveO_ThreeClF_Three0.5CH_TwoCl_TwoTheoretical value for: C, 5 6.66; H, 5.30; N, 10.83. Found: C, 56.51; H, 5. 12; N, 11.09. Example 3 (+)-Cis-5-carboxamide-6- (2,4-difluorophenyl) -1-{[2- (4-cyano-4- Phenyl-cyclohexylamino) ethyl]} carboxamido-4-ethyl-2-oxo-1 , 2,3,6-tetrahydropyrimidine hydrochloride. a) Benzyl 2-[(2,4-difluorophenyl) methylene] -3-oxopentanoate Scheme 2; Step C). Benzyl propionyl acetate (157 g, 0.758 mol) in benzene (1 L), 2,4-difluorobenzaldehyde (107.65 g, 0.758 mol), and The piperidinium acetate (5.49 g, 38 mmol) solution was stirred at room temperature for 96 hours. Was. The mixture was washed with water (2 × 100 mL), dried (magnesium sulfate), The solvent was evaporated under reduced pressure to recover the product as a pale yellow syrup (25 1.2 g). Used in the next step without further purification. b) 5- (benzyloxycarbonyl) -1,6-dihydro-2-methoxy-4-ethyl-6- (2,4 -Difluorophenyl) pyrimidine (Scheme 2; Step D). 2-[(2,4-difluorophenyl) methylene] -3-oxo in ethanol (800 mL) Benzyl pentanoate (80.0 g, 0.241 mol), O-methylisourea Misulfate (63.8 g, 0.362 mol, 1.5 eq.), NaHCO_Three(60. (48 g, 0.72 mol) was stirred at 60-70 ° C. for 20 hours. To room temperature After cooling, the mixture was filtered and the solid was washed with ethanol (200 mL). The solvent was evaporated from the combined filtrate, and the residue was subjected to column chromatography (SiO 2)._Two, E tOAc / hexane, 10% -30%) to give 5 as a pale yellow oil. -(Benzyloxycarbonyl) -1,6-dihydro-2-methoxy-4.ethyl-6- (2,4-difur (Orophenyl) pyrimidine was recovered (39 g, 42%).¹By H-NMR analysis This product was shown to be a mixture of amine / imine tautomers, This was used in the step. c) 5- (benzyloxycarbonyl) -4-ethyl-1,6-dihydro-2-methoxy-6- (2,4 -Difluorophenyl) -1-[(4-nitrophenyloxy) carbonyl] pyrimidine Team 2; Step F). CH_TwoCl_Two5- (benzyloxycarbonyl) -1,6-dihydro-2-methoate (200 mL) Xy-4-ethyl-6- (2,4-difluorophenyl) pyrimidine (22.5 g, 59.3) mmol) and 4- (N, N.dimethylamino) pyridine (9.3 g, 75.8 mmol) l) The solution of (1) was thoroughly stirred, and powdered 4-nitrophenyl chloroformate (1) was added. 5.3g, 75.8mmol) at 0 ° C. The reaction mixture is left at room temperature for 12 hours. Stir and add water (50 mL). Add pH of aqueous layer to 6N sodium hydroxide Was adjusted to 10-11. The dichloromethane layer was separated and dried (Na_TwoSO_Four) did. The solvent is evaporated under vacuum and the residue is purified by column chromatography (SiO_Two, Jig (Chloromethane / hexane, 20% -50%). The product was collected (32.0 g, 98%). d) 5- (benzyloxycarbonyl) -4-ethyl-1,6-dihydro-1- {N- [2-phenyl ) Ethyl]} carboxamide-2-methoxy-6- (2,4-difluorophenyl) pyrimidine ( Scheme 3; Steps C-1 and C-2). 5- (benzyloxycarbonyl) -4-ethyl-1,6-di in dichloromethane (200 mL) Hydro-2-methoxy-6- (2,4-difluorophenyl) -1-[(4-nitrophenyloxy) ca [Rubonyl] pyrimidine (32 g, 58.17 mmol) was added to a stirred solution of R-(+)-. α-Methylbenzylamine (9.16, 75.6 mmol) was added at room temperature. This The mixture was stirred for 12 hours, further diluted with dichloromethane (200 mL), Washed with N NaOH solution (2 × 60 mL). The organic layer is_TwoSO_FourDry on And filtered and the solvent was evaporated. The resulting mixture of diastereomers is purified by column chromatography. Chromatography (SiO_Two, 3% EtOAc in toluene). Dissolution The first product to emerge is (+)-5- (benzyloxycarbonyl) -4-ethyl-1,6-dihydrogen B-1- {N- [2-phenyl) ethyl]} carboxamide-2-methoxy-6- (2,4-difluoro Phenyl) pyrimidine (12.15 g, 38%). [α]_D= + 214 (100 mL CHCl_ThreeMedium, c = 1.5 g). e) (+)-5- (benzyloxycarbonyl) -1,6-dihydro-2-methoxy-4-ethyl-6- (2,4-Difluorophenyl) pyrimidine (Scheme 3; Step C-3). (+)-5 (benzyloxycarbonyl) -4-ethyl-1,6-dihydrogen in toluene (250 mL) Dro-1- {N- [2-phenyl) ethyl]} carboxamide-2-methoxy-6- (2,4-difluoro To a stirred solution of (phenyl) pyrimidine (11.15 g, 20.41 mmol) , 1,8-diazabicyclo [5,4,0] -undecane-7-ene (4.04 g, 26.53 mm ol) was added and the mixture was stirred at room temperature for 14 hours. The solvent is evaporated and the residue On silica gel using 3: 1 EtOAc / hexane as eluent Purified by column chromatography and (+)-5- (ben (Diloxycarbonyl) -1,6-dihydro-2-methoxy-4-ethyl-6- (2,4-difluorop (Enyl) pyrimidine was obtained (6.15 g, 78%). f) (+)-5- (benzyloxycarbonyl) -4-ethyl-1,6-dihydro-2-methoxy-6- (2,4- Difluorophenyl) -1-[(4-nitrophenyl-oxy) carbonyl] pyrimidine Scheme 2: Step E). CH_TwoCl_Two(+)-5- (benzyloxycarbonyl) -1,6-dihydro-2-in (200 mL) Methoxy-4-ethyl-6- (2,4-difluorophenyl) pyrimidine (4.1 g, 10. 62 mmol) and 4- (N, N-dimethylamino) pyridine (1.69 g, 13.8). 0 mmol) in a well stirred solution of solid 4-nitrophenyl chloroformate (2. 78 g, 13.80 mmol) were added at room temperature. The reaction mixture was stirred for 12 hours, Washed with 0.5N NaOH solution (2 × 50 mL). The organic layer is separated and dried (N a_TwoSO_Four)did. The solvent was evaporated and the residue was eluted with dichloromethane / hexane ( 20% -50%) by column chromatography on silica gel. Purified to give (+)-5- (benzyloxycarbonyl) -4-ethyl-1,6-dihydro-2-methoxy. 6- (2,4-difluorophenyl) -1-[(4-nitrophenyloxy) carbonyl] pirimi Gin (5.37 g, 92%) was obtained as a viscous oil. g) (+)-5-benzyloxycarbonyl-4-ethyl-1,2,3,6-tetrahydro-2-oxo SO-6- (2,4-difluorophenyl) -1-[(4-nitrophenyloxy) carbonyl] pirimi Gin (Scheme 4; Step A). (+)-6- (2,4-Difluorophenyl) -1,6-dihydride in dichloromethane (150 mL) 2-Methoxy-5-benzyloxycarbonyl-4-ethyl-1- (4-nitrophenoxy)- To a solution of carbonylpyrimidine (6.50 g, 11.81 mmol) was added ether ( 1N HCl in 50 mL) is added at room temperature and the mixture is stirred at room temperature for 12 hours did. The solvent was evaporated under reduced pressure and the residue was dried to give 6.31 g (1 00%). h) (+)-5- (benzyloxycarbonyl) -6- (2,4-difluorophenyl) -4-ethyl 2-oxo-1,2,3,6-tetrahydro-1- {N- [2- (4-cyano-4-phenyl-cyclohexyl Silamino) ethyl]} carboxamidopyrimidine (Scheme 4; Step B-1) . (+)-5-Benzyloxycarbonyl-4-ethyl-1,2,3,6-tetra in THF (20 mL) Hydro-2-oxo-6- (2,4-difluorophenyl) -1-[(4-nitrophenyloxy) cal Bonil ] Pyrimidine (537 mg, 1 mmol) and cis-2- (4-cyano-4-phenyl-cy Clohexylamino) ethylamine (281 mg, 1.2 mmol) was added at room temperature for 10 minutes. Stir for hours and evaporate the solvent. Redissolve it in dichloromethane (10 mL), Washed with ice-cold 0.5N NaOH (2 × 5 mL), dried and evaporated. The residue was purified by thin-layer chromatography on preparative silica gel as eluent. Use chloroform-methanol-2M ammonia in methanol (100/2/1). The product was obtained as a white powder (603 mg, 94%). i) (+)-6- (2,4-difluorophenyl) -4-ethyl-2-oxo-1,2,3,6-tetrahydride B-1- {N- [2- (4-cyano-4-phenyl-cyclohexylamino) ethyl]} carboxa Midopyrimidine-5-carboxylic acid (Scheme 4; Step B-2). MeOH (40 mL) and H_Two10% Pd-C in a mixture of O (8 mL) (100 m g) in a suspension of (+)-5- (benzyloxycarbonyl) -6- in methanol (10 mL). (2,4-difluorophenyl) -4-ethyl-2-oxo-1,2,3,6-tetrahydro-1- {N- [2 -(4-cyano-4-phenyl-cyclohexylamino) -ethyl]} carboxamidopyri A solution of thymidine (320 mg, 0.5 mmol) was added and the mixture was brought to 80 psi. For 6 hours. Filter the black suspension through a pad of celite , MeOH (2.0 L) and methanol / chloroform (1: 2, 200 mL). Washed thoroughly. The solvent was evaporated from the combined filtrate and the product (+)-cis-6- ( 2,4-difluorophenyl) -4-ethyl-2-oxo-1,2,3,6-tetrahydro-1- {N- [2- (4-cyano-4-phenyl-cyclohexylamino) -ethyl]} carboxamide pirimi Gin-5-carboxylic acid was recovered as a white solid (276 g, 98%). The product is Used in the next step without further purification. j) (+)-cis-5-carboxamide-6- (2,4-difluorophenyl) -1- {N- [2- (4- Cyano-4-phenyl-cyclohexylamino) ethyl]} carboxamido-4-ethyl-2 -Oxo-1,2,3,6-tetrahydropyrimidine hydrochloride (Scheme 4; Step B- 3). (+)-Cis-6- (2,4-difluorophenyl) -4-e in anhydrous dichloromethane (30 mL) Tyl-2-oxo-1,2,3,6-tetrahydro-1- {N- [2- (4-cyano-4-phenyl-cyclo Hexyl Amino) ethyl]} carboxamidopyrimidine-5-carboxylic acid (141 mg, 0.2 5 mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (71.3 mg, 0.372 mmol) and 4- (N, N-dimethylamino) pyridi (45.4 mg, 0.372 mmol) was stirred at room temperature for 2 hours. 40 % Aqueous ammonia (4090, 0.5 mL) was added to the mixture and stirring was Continued for hours. Dilute the mixture with 20 mL of dichloromethane and add saturated aqueous hydrochloric acid Washed with monium solution (3 × 10 mL). Dried (sodium sulfate) dichlorometh The solvent was evaporated from the tan solution, and chloroform / methanol / methanol Column chromatography on silica gel using 2M ammonia (100/2/1) in toluene Purification by chromatography gave the desired product as a white powder (120 m g, 88%); [α]_D= + 107 (c = 1.38 g, dichloromethane). HCl Salt treats free base in ether solution with 1N HCl in ether It was manufactured by MP 225-228 ° C; C₂₉H₃₃N₆O_ThreeF_TwoCl. 0.38H_Two O.0.19CH_TwoCl_TwoAnalytical value for: C, 57.47; H, 5.64; N, 13.75. Found: C, 57.80; H, 5.56; N, 13.37. Example 4 (+)-Cis-6- (3,4-difluorophenyl) -1- {N- [2- (4-cyano-4-phenyl-cyclo Hexylamino) ethyl]} carboxamide-5-methoxycarbonyl-4-methoxymeth Cyl-2-oxo-1,2,3,6-tetrahydropyrimidine hydrochloride Part 2 a) Methyl 2-[(3,4-difluorophenyl) methylene] -3-oxo-4-methoxybutyrate (Scheme 2; C). Methyl 4-methoxyacetoacetate (84.32 g, 0.57 g) in benzene (1.5 L) 7 mol), 3,4-difluorobenzaldehyde (82 g, 0.577 mmol), And a solution of piperidinium acetate (5.86 g, 0.068 mol) (Molecular sieves) (400 g) was added and the mixture was stirred at room temperature for 48 hours. . The molecular sieve was removed by filtration and the solvent was evaporated from the filtrate under reduced pressure. The residue Black Column chromatography on silica gel using chloroform / ethyl acetate (100: 3) Purification by chromatography afforded the product as an oil (67 g, 47%). this The product was a mixture of cis and trans isomers. b) 5-methoxycarbonyl-1,6-dihydro-2-methoxy-4-methoxymethyl-6- ( 3,4-Difluorophenyl) pyrimidine (Scheme 2: Step D). 2-[(3,4-difluorophenyl) methylene] -3-oxo- in ethanol (400 mL) Methyl 4-methoxybutyrate (7.50 g, 27.75 mmol), O-methylisourea -Hemisulfate (7.17 g, 41.63 mmol, 1.5 eq.) And sodium carbonate A suspension of thorium (6.99 g, 83.25 mmol, 3 eq.) At 50-55 ° C For 6 hours. The solvent is evaporated from the combined filtrate, and the residue is subjected to column chromatography. Fee (SiO_Two, EtOAc / hexane, 10-30%) to give 5-meth Xycarbonyl-1,6-dihydro-2-methoxy-4-methoxymethyl-6- (3,4-difluoro (Lophenyl) pyrimidine was obtained as a pale yellow oil (4.3 g, 47%). c) 5-methoxycarbonyl-4-methoxymethyl-1,6-dihydro-2-methoxy-6- (3 , 4-Difluorophenyl) -1-[(4-nitrophenylloxy) carbonyl] pyrimidine ( Scheme 3; Step B). CH_TwoCl_Two5-methoxycarbonyl-1,6-dihydro-2-methoxy-4 in (100 mL) -Methoxymethyl-6- (3,4-difluorophenyl) pyrimidine (4.3 g, 13.1 8 mmol) and 4- (N, N-dimethylamino) pyridine (2.09 g, 17.13) (mmol) in a well stirred solution, solid 4-nitrophenyl chloroformate ( (3.45 g, 17.13 mmol) at 0 ° C. The reaction mixture was cooled to room temperature for 12 hours. After stirring for an hour, the resulting solid was removed by filtration. The solvent is evaporated from the filtrate and the residue By column chromatography (SiO_Two, Dichloromethane / hexane, 20% -5 0%) to recover the product as a viscous oil (3.85 g, 59%). ). d) 5-methoxycarbonyl-4-methoxymethyl-1,6-dihydro-1- {N- [2-phenyl Ru) ethyl]} carboxamido-2-methoxy-6- (3,4-difluorophenyl) pyrimidi N Team 3; Steps C-1 and C-2). 5-methoxycarbonyl-4-methoxymethyl-1,6-dihydro in THF (140 mL) 2-methoxy-6- (3,4-difluorophenyl) -1-[(4-nitrophenyloxy) carbonyl [Pyrimidine (3.82 g, 7.77 mmol) in a stirred solution of R-(+)-α- Methylbenzylamine (1.13 g, 9.33 mmol, 1.2 eq.) At room temperature And stirring was continued for 12 hours. Evaporate the solvent and remove the residue by column chromatography. Graphy (SiO_Two, 10% -20% EtOAc in hexane) . The first product eluted is (+)-5-methoxycarbonyl-4-methoxymethyl-1,6- Dihydro-1- {N- [2-phenyl) ethyl]} carboxamide-2-methoxy-6- (3,4-diph (Ruorophenyl) pyrimidine (1.74 g, 44.5%) was obtained as an oil. [ α]_D= + 205.5 (100 mL CHCl_ThreeC in 5.1 g). e) (+)-5-methoxycarbonyl-1,6-dihydro-2-methoxy-4-methoxymethyl- 6- (3,4-Difluorophenyl) pyrimidine (Scheme 3; Step C-3). (+)-5-Methoxycarbonyl-4-methoxymethyl-1,6-dihydrogen in toluene (40 mL) Dro-1- {N- [2-phenyl) ethyl]} carboxamido-2-methoxy-6- (3,4-difluoro To a stirred solution of (phenyl) pyrimidine (1.74 g, 3.67 mmol) was added 1,8 -Diazabicyclo [5,4,0] -undecane-7-ene (0.250 g, 1.64 mmol) Was added and the mixture was stirred at 70-80 ° C for 1.5 hours. Evaporate the solvent and leave The residue is purified on silica gel as 9: 1 CHCl_ThreeWith EtOAc / EtOAc Purification by flash column chromatography, (+)-5-methoxycarbonyl-1,6 -Dehydro-2-methoxy-4-methoxymethyl-6- (3,4-difluorophenyl) pyrimidi Was obtained as a viscous oil (1.11 g, 92.5%). f) (+)-5-methoxycarbonyl-1,6-dihydro-2-methoxy-4-methoxymethyl- Chiral HPLC separation of 6- (3,4-difluorophenyl) pyrimidine (Scheme 3; Step A). 5-methoxycarbonyl-1,6-dihydro-2-methoxy-4-methoxymethyl-6- (3,4-di The racemate of fluorophenyl) pyrimidine can be purified by chiral HPLC [Chiral Cell (Chir alcel) OD 20 × 250 mm # 369-703-30604; λ254 nm; hexa Ethanol / ethanol 95/5 and 0.01% diethylamine; 60 per injection mg; retention time of desired enantiomer; 10.80 minutes, first enantiomer to elute (+)-5-methoxycarbonyl-1,6-dihydro-2 -Methoxy-4-methoxymethyl-6- (3,4-difluorophenyl) pyrimidine was obtained. g) (+)-5-methoxycarbonyl-4-methoxymethyl-1,6-dihydro-2-methoxy- 6- (3,4-difluorophenyl) -1-[(4-nitrophenyloxy) carbonyl] pyrimidi (Scheme 2; Step E). CH_TwoCl_Two(200 mL) of 1,6-dihydro-2-methoxy-4-methoxymethyl-6- (3, 4-difluorophenyl) pyrimidine (1.11 g, 3.4 mmol) and 4- (N, N-dimethylamino) pyridine (0.54 g, 4.42 mmol) was stirred well. To the solution was added 4-nitrophenyl dichloroformate (0.891 g, 4.42 m). mol) was added at room temperature. The solvent is evaporated and the residue is eluted on silica gel As CHCl_ThreeChromatography using / EtOAc (20% -50%) And purified by (+)-5-methoxycarbonyl-4-methoxymethyl-1,6-dihydrogen. 2-methoxy-6- (3,4-difluorophenyl) -1-[(4-nitrophenyloxy) carbo [Nyl] pyrimidine (1.30 g, 78%) was obtained as a viscous oil. [α]_D= + 2 62.2 (100 mL CHCl_ThreeIn c = 2.3 g). h) (+)-5-methoxycarbonyl-4-methoxymethyl-1,2,3,6-tetrahydro-2- Oxo-6- (3,4-difluorophenyl) -1-[(4-nitrophenyloxy) carbonyl] pi Limidine (Scheme 2; Step F). (+)-6- (3.4-Difluorophenyl) -1,6-dihydro- in dichloromethane (15 mL) 2-methoxy-5-methoxycarbonyl-4-methoxymethyl-1- (4-nitrophenoxy)- To carbonylpyrimidine (0.305 g, 0.60 mmol), ether (6 mL) IN HCl at room temperature was added and the mixture was stirred at room temperature for 12 hours. solvent Was evaporated under reduced pressure and the residue was dried to give 0.295 g (100 %) Of the product. Part-3 i) (+)-cis-6- (3,4-difluorophenyl) -1- {N- [2- (4-cyano-4-phenyl- Cyclohexylamino) ethyl]} carboxamido-5-methoxycarbonyl-4-meth Toximethyl-2-oxo-1,2,3,6-tetrahydropyrimidine hydrochloride (Scheme 2 Step G). (+)-5-Methoxycarbonyl-4-methoxymethyl-1, in dichloromethane (50 mL) 2,3,6-tetrahydro-2-oxy-6- (3,4-difluorophenyl) -1-[(4-nitrophen Niloxy) carbonyl] pyrimidine (0.850 g, 1.73 mmol) and cis -2- (4-cyano-4-phenyl-cyclohexylamino) ethylamine (0.567 g, (2.42 mmol) was stirred at room temperature for 12 hours. 0.5N ice-cooled NaOH (2 × 10 mL) and dried over sodium sulfate. Decompress the solvent And the residue is flash chromatographed on silica gel (dichloromethane). Purified by dichloromethane: MeOH: 2M ammonia in MeOH, 90: 8: 4) This gave 0.905 g (90%) as a white powder. The HCl salt is 1% in ether. Prepared by treating the free base of an ether solution with NHCl. White The powder was dried and recrystallized from anhydrous isopropanol. M. P. 233-235 ° C; [α]_D= + 131.16 (c = 0.735, MeOH); C₃₀H₃₄N_FiveO_FiveF_TwoC Analytical value for l: C, 58.30; H, 5.53; N, 11.06. Real Found: C, 57.91; H, 5.53; N, 11.10. Example 5 (+)-Trans-6- (3,4-difluorophenyl) -1- {N- [2- (4-cyano-4-phenyl-cy Clohexylamino) ethyl]} carboxamide-5-methoxycarbonyl-4-methoxy Cimethyl-2-oxo-1,2,3,6-tetrahydropyrimidine hydrochloride (Scheme 2: Step F). (+)-5-Methoxycarbonyl-4-methoxymethyl-1, in dichloromethane (50 mL) 2,3,6-tetrahydro-2-oxo-6- (3,4-difluorophenyl) -1-[(4-nitrophen Niloxy) carbonyl] pyrimidine (0.850 g, 1.73 mmol) and tiger 2- (4-cyano-4-phenyl-cyclohexylamino) ethylamine (0.567 g, 2.42 (mmol) was stirred at room temperature for 12 hours. This was ice-cooled with 0.5N NaOH ( 2 × 10 mL) and dried over sodium sulfate. Evaporate the solvent under reduced pressure The residue is flash chromatographed on silica gel (dichloromethane: Me OH: 2M ammonium in MeOH, 90: 8: 4) to give 0.90 5 g (90%) were obtained as a white powder. HCl salt is 1N HCl in ether Prepared by treating the free base of the ether solution used. C₃₀H₃₄N_FiveO_Five F_TwoAnal, calculated for Cl: C, 58.30; H, 5.53; N, 11.06. . Found: C, 57.99; H, 5.73; N, 11.20. Example 6 (-)-Cis-6- (3,4-difluorophenyl) -1- {N- [2- (4-cyano-4-phenyl-cyclo Hexylamino) ethyl]} carboxamide-5-methoxycarbonyl-4-methoxymeth Cyl-2-oxo-1,2,3,6-tetrahydropyrimidine hydrochloride a) (-)-5-methoxycarbonyl-4-methoxymethyl-1,6-dihydro-2-methoxy- 6- (3,4-difluorophenyl) -1-[(4-nitrophenyloxy) carbonyl] pyrimidi (Scale 2; step E). CH_TwoCl_Two(+)-5-Methoxycarbonyl-1,6-dihydro-2-methoxy in (20 mL) -4-methoxymethyl-6- (3,4-difluorophenyl) pyrimidine (1.167 g, 3 . 576 mmol) and 4- (N, N-dimethylamino) pyridine (0.655 g, 5 . 364 mmol) into a well stirred solution of powdered 4-nitroform chloroformate. Enyl (0.937 g, 4.65 mmol) was added at room temperature. Evaporate the solvent and Of the residue on silica gel using hexane / EtOAc (7/3%) as eluent. Was purified by column chromatography, using (-)-5-methoxycarbonyl-4-meth Xymethyl-1,6-dihydro-2-methoxy-6- (3,4-difluorophenyl) -1-[(4-nitro Rophenyloxy) carbonyl] pyrimidine (1.761 g, 100%) in viscous oil Obtained as quality. [α]_D= -335.3 (100 mL CHCl_Three(C in 1.0 = 1.0 g) . b) (-)-cis-6- (3,4-difluorophenyl) -1- {N- [2- (4-cyano-4-phenyl) Cyclohe Xylamino) ethyl]} carboxamide-5-methoxycarbonyl-4-methoxymethyl 2-oxo-1,2,3,6-tetrahydropyrimidine hydrochloride (Scheme 2; Step G and step F). (-)-5-Methoxycarbonyl-4-methoxymethyl-1, in dichloromethane (50 mL) 6-dihydro-2-methoxy-6- (3,4-difluorophenyl) -1-[(4-nitrophenyloxy Cis) carbonyl] pyrimidine (0.103 g, 0.21 mmol) and cis-2- (4- Cyano-4-phenyl-cyclohexylamino) ethylamine (0.059 g, 0.2 (51 mmol) was stirred at room temperature for 12 hours. It was ice-cooled with 0.5N NaOH ( 2 × 10 mL) and dried over sodium sulfate. Evaporate the solvent under reduced pressure , Flash chromatography on silica gel (dichloromethane: MeOH : 2M ammonia in MeOH, 90: 8: 4), purified as an oil 0.121 g was obtained. Dissolve it in THF (2 mL) and add 0.2 mL 6N H Treated with Cl and stirred at room temperature for 4 hours. Evaporate the solvent and dry the residue under vacuum The product was obtained as a white powder (130 mg, 100%). M. P. 220-2 22 ° C; [α]_D= .124.29 (c = 0.535, MeOH); C₃₀H₃₄N_FiveO_FiveF_TwoCl Analytical values for: C, 58.30; H, 5.53; N, 11.06. Measured value : C, 57.20; H, 5.57; N, 11.30. Example 7 (+)-Trans-6- (3,4-difluorophenyl) -1- {N- [2- (4- (2-pyridyl) -cyclo Hexylamino) ethyl]} carboxamide-5-methoxycarbonyl-4-methoxymeth Cyl-2-oxo-1,2,3,6-tetrahydropyrimidine hydrochloride a) 2- [4-allylcyclohexylamino] ethylamine (Scheme 2; Step A). 4-Allylcyclohexane (48.7 mmol) in benzene (200 mL) (i.e.4-2 -Pyridyl) -cyclohexanone) and ethylenediamine (8.78 g, 146 m mol) and p-toluenesulfonic acid (92 mg) Reflux in the trap for 4 hours to remove the water formed. The solvent is evaporated and the residue The meta Redissolved in knol (60 mL) and cooled to 0 ° C. On the other hand, borohydride Thorium (6.45 g) was added in portions and the mixture was stirred at room temperature for 3 hours. The solvent was evaporated and the residue was dissolved in dichloromethane (300 mL) and brine (3 × 5). 00 mL), dry (potassium carbonate) and evaporate the solvent to give a pale yellow viscous The product was obtained as an oil (90-95%). The product is pure and cis / Trans-isomer. Chloroform / methanol / Using 2M ammonia in methanol (100/10/5 to 100/20/10) Chromosome enrichment from this mixture by careful chromatography Some early fractions were obtained, including: The last eluted fraction is almost pure trans form It was an isomer. b) (+)-trans-6- (3,4-difluorophenyl-1- {N- [2- (4- (2-pyridyl) -cy Clohexylamino) ethyl]} carboxamide-5-methoxycarbonyl-4-methoxy Cimethyl-2-oxo-1,2,3,6-tetrahydropyrimidine hydrochloride (Scheme 2; Step G). (+)-5-Methoxycarbonyl-4-methoxymethyl-1,2,3,6-te in THF (10 mL) Trahydro-2-oxo-6- (3,4-difluorophenyl) -1-[(4-nitrophenyloxy) ca [Rubonyl] pyrimidine (49.1 mg, 0.1 mmol) and trans-2- (4- (2- Pyridylcyclohexylamino) ethylamine (30 mg, 0.136 mmol) Was stirred at room temperature for 12 hours. Wash with ice-cold 0.5N NaOH (2 × 5 mL) And dried over sodium sulfate. The solvent is evaporated under reduced pressure and the residue is evaporated on silica gel. To a white powder by preparative tlc (ethyl acetate: MeOH, 10: 1). mg (78%). HCl salt is an ether solution of 1N HCl in ether Prepared by treatment of the free base in. 180-184 ° C; [α]_D= + 187 (c = 0.65, methanol); C₂₉H₃₅N_FiveO_FiveF_TwoCl_Two.0.4CH_TwoCl_TwoAnalysis about Theory: C, 51.33; H, 5.43; N, 9.54. Found: C, 51.3 1; H, 5.43; N, 9.69. Examples 8 and 9 Cis-6- (3,4-difluorophenyl) -1- {N- [2- (4-phenylcyclohexylamino) D) Tyl]} carboxamide-5-methoxycarbonyl-4-methyl-2-oxo-1,2,3,6-tetra Lahydropyrimidine hydrochloride and Trans-6- (3,4-difluorophenyl) -1- {N- [2- (4-phenylcyclohexylurea) Mino) ethyl]} carboxamide-5-methoxycarbonyl-4-methyl-2-oxo-1,2,3 , 6-Tetrahydropyrimidine hydrochloride a) 2- [4-phenylcyclohexylimino] ethylamine (Scheme 5; Step A). 4-Phenylcyclohexanone (4.00 g, 22.9) in benzene (200 mL) 6 mmol) and ethylenediamine (1.66 g, 27.5 mmol) and p- A mixture of toluene sulfonic acid (437 mg) was placed in a Dean-Stark trap at 4 Reflux for hours and remove the water formed. Tlc analysis shows completeness of reaction Was. The solvent was evaporated and the product was used in the next step without further purification. b) cis-6- (3,4-difluorophenyl) -1- {N- [2- (4-phenylcyclohexyl) Amino) ethyl]} carboxamide-5-methoxycarbonyl-4-methyl-2-oxo-1,2 , 3,6--Tetrahydropyrimidine hydrochloride and Trans-6- (3,4-difluorophenyl) -1- {N- [2- (4-phenylcyclohexylurea) Mino) ethyl]} carboxamide-5-methoxycarbonyl-4-methyl-2-oxo-1,2,3 , 6-Tetrahydropyrimidine hydrochloride (Scheme 5; Step B). 5-methoxycarbonyl-4-methyl-1,2,3,6-tetra in dichloromethane (20 mL) Hydro-2-oxo-6- (3,4-difluorophenyl) -1-[(4-nitrophenyloxy) ca Rubonyl] pyrimidine (120 mg, 0.269 mmol) and 2- [4-phenylcy [Crohexylimino] ethylamine (69.8 mg, 0.33 mmol) Stirred at room temperature for 12 hours. The solvent was evaporated and the residue was re-dissolved in ethanol (10 mL). Dissolve and cool to 0 ° C. To this was added sodium borohydride (61 mg, 1.614). mmol) was added and stirring was continued for 2 hours. Evaporate the solvent and elute the residue Dichloro Use methane: MeOH: 2M ammonium in MeOH (100: 8: 4) And purified on preparative tlc silica gel. Isolate the two products and use the upper bun Is cis-6- (3,4-difluorophenyl) -1- {N- [2- (4-phenyl-cyclohexyl) Lamino) ethyl]} carboxamide-5-methoxycarbonyl-4-methyl-2-oxo-1 , 2,3,6-tetrahydropyrimidine (16 mg), the lower band was trans- 6- (3,4-difluorophenyl) -1- {N- [2- (4-phenylcyclohexylamino) methyl L]} carboxamide-5-methoxycarbonyl-4-methyl-2-oxo-1,2,3,6-tetra Hydropyrimidine (42 mg). The HCl salt is aerated with 1N HCl in ether. Prepared by treating the free base in tellurium solution. Example 8: cis isomer: M.P. P. 145-146 ° C; C₂₈H₃₃N_FourO_FourF_TwoCl 0.8H_Two Analytical theory for O: C, 58.24; H, 6.04; N, 9.70. Real Found: C, 58.13; H, 5.83; N, 9.50. Example 9: trans isomer: M.P. P. 156-157 ° C; C₂₈H₃₃N_FourO_FourF_TwoCl 0 .4CHCl_ThreeFor C: 55.85; H, 5.51; N, 9.1. 7. Found: C, 55.57; H, 5.76; N, 9.10. Example 10 Trans-6- (3,4-difluorophenyl) -1- {N- [2- (4-phenylcyclohexyl)- Methyl-amino] ethyl} carboxamide-5-methoxycarbonyl-4-methyl-2-oxo So-1,2,3,6-tetrahydropyrimidine hydrochloride (Scheme 5; Step C). Trans-6- (3,4-difluorophenyl) -1- {N- [2- (4-phenyl) acetone (10 mL) Enyl-cyclohexylamino) ethyl]} carboxamide-5-methoxycarbonyl- 4-methyl-2-oxo-1,2,3,6-tetrahydropyrimidine (60 mg, 0.114 m mol), methyl iodide (19.4 mg, 0.137 mmol, 1.2 eq.), and And a mixture of potassium carbonate (31.5 mg, 0.23 mmol) was stirred for 12 hours. And reflux, and the solids were removed by filtration. The solvent is evaporated from the filtrate and the residue is separated on silica. Flash chromatography on gel (dichloromethane: MeOH: MeOH 2M Ammo inside , 90: 8: 4) to give the product as an oil. HCl salt Is prepared by treatment of the free base in an ethereal solution with 1N HCl in ether. (14 mg). M. P. 140-142 ° C; C₂₉H₃₅N_FourO_FourF_TwoCl. 0.33 Hexane. 0.5 9CHCl_ThreeAnal. Anal. Found: C, 56.07; H, 5.99; N, 8.28. . Found: C, 56.37; H, 6.21; N, 7.90. Example 11 (+)-Cis-6- (3,4-difluorophenyl) -1- {N- [2- (4-methoxycarbonyl-4-f Enyl-cyclohexylamino) ethyl]} carboxamide-5-methoxycarbonyl- 4-methoxymethyl-2-oxo-1,2,3,6-tetrahydropyrimidine hydrochloride a) 2- [4-methoxycarbonyl-4-phenyl-cyclohexylamino] ethylami (Scheme 2; Step B). 2- [4-cyano-4-phenylcyclohexylamino] ethylamine (2.34 g, 10 m mol) and concentrated sulfuric acid (20 mL) was heated at 80-85 ° C. for 10 hours. Room it Cooled to warm, mixed with anhydrous methanol (200 mL) and refluxed for 20 hours. Dissolution The medium is evaporated, the residue is poured on ice (200 g) and 6N NaOH is added. This basified to pH 11. Extract with dichloromethane (4 × 125 mL) , Dried (potassium carbonate) and evaporated to give the product as an oil (2.1 g, 76%). This product is a pure mixture of cis and trans isomers there were. This was used in the next step without any further purification. b) (+)-cis-6- (3,4-difluorophenyl) -1- {N- [2- (4-methoxycarbonyl) -4-phenyl-cyclohexylamino) ethyl]} carboxamide-5-methoxycarbo Nyl-4-methoxymethyl-2-oxo-1,2,3,6-tetrahydropyrimidine hydrochloride Scheme 2; Step G). (+)-5-Methoxycarbonyl-4-methoxymethyl-1, in dichloromethane (15 mL) 2,3,6-tetrahydro-2-oxo-6- (3,4-difluorophenyl) -1-[(4-nitrophen Niloxy) carbonyl] pyrimidine (128 mg, 0.26 mmol) and 2- (4- Methoxycal Bonyl-4-phenylcyclohexylamino) ethylamine (70 mg, 0.26 m mol) was stirred at room temperature for 12 hours. It was ice-cooled with 0.5N NaOH ( 2 × 5 mL) and dried over sodium sulfate. Evaporate the solvent under reduced pressure, The residue is flash chromatographed on silica gel (dichloromethane: MeO H: 2M ammonia in MeOH, 90: 8: 4) to give a white powder. 78 mg (78%) were obtained. HCl salt is dissolved in 1N HCl in ether. It was prepared by treating the free base in the liquid. 112-114 ° C; [α]_D= + 136 (c = 0.55, CHCl_Three); C₃₁H₃₇N_FourO₇F_TwoCl.0.4CH_TwoCl_TwoAbout Analytical theoretical values: C, 55.05; H, 5.56; N, 8.18. Observed value: C, 55.05; H, 5.50; N, 8.16. Example 12 (+)-6- (3,4-difluorophenyl) -1- {N- [2- (4,4-diphenyl-cyclohexyla Mino) ethyl]} carboxamide-5-methoxycarbonyl-4-methoxymethyl-2-oxo So-1,2,3,6-tetrahydropyrimidine hydrochloride a) 2- [4,4-diphenylcyclohexylamino] ethylamine (Scheme 2; Step A). 4,4-diphenylcyclohexanone (2.5 g) and ethyl ether in benzene (200 mL) A mixture of tylenediamine (10 g) and p-toluenesulfonic acid (100 mg) was added. Reflux for 4 hours in a Dean-Stark trap to remove the water formed. solvent Was evaporated and the residue was redissolved in methanol (60 mL) and cooled to 0 ° C. This To this, sodium borohydride (2 g) is added in portions and the mixture is left at room temperature for 3 hours. While stirring. The solvent was evaporated and the residue was redissolved in dichloromethane (300 mL) Wash with brine (3 × 500 mL), dry (potassium carbonate) and evaporate the solvent A colorless, viscous oil was obtained (2.94 g, 100%).¹This raw material was analyzed by H-NMR. The product was shown to be pure. It is then processed without any further purification. Used in Tep. b) (+)-6- (3,4-difluorophenyl) -1- {N- [2- (4,4-diphenylcyclohexene) Silamino) ethyl]} carboxamide-5-methoxycarbonyl-4-methoxymethyl- 2-oxo-1,2,3,6-tetrahydropyrimidine hydrochloride (Scheme 2; Step G) . (+)-5-Methoxycarbonyl-4-methoxymethyl-1,2,3,6-te in THF (15 mL) Trahydro-2-oxo-6- (3,4-difluorophenyl) -1-[(4-nitrophenyloxy) Carbonyl] pyrimidine (125 mg, 0.245 mmol) and 2- (4,4-diffe Nylcyclohexylamino) ethylamine (125 mg, 0.446 mmol) The solution was stirred at room temperature for 12 hours. It was ice-cooled with 0.5N NaOH (2 × 5 m L) and dried over sodium sulfate. The solvent is evaporated under reduced pressure and the residue On silica gel by flash chromatography (dichloromethane: MeOH: Purified by 2M ammonia in MeOH, 90: 8: 4), 147 mg (92% ) Was obtained as a white powder. The HCl salt is prepared by 1N HCl in ether. Prepared by treating the free base in an ether solution. 160-162 ° C; [α]_D= + 184 (c = 0.68, methanol); C₃₅H₃₉N_FourO_FiveF_TwoCl. 0.19CH_Two Cl_Two: C, 61.68; H, 5.79; N, 8.18. Found: C, 62.8 2; H, 5.87; N, 8.37. Example 13 (+)-Cis-6- (3,4-difluorophenyl) -1- {N- [2- (4-cyano-4- (2-fluorophen Nyl) -cyclohexylamino) ethyl]} carboxamide-5-methoxycarbonyl-4 -Methyl-2-oxo-1,2,3,6-tetrahydropyrimidine hydrochloride (Scheme 2; G). (+)-6- (3,4-difluorophenyl) -1,6-dihydro-5-methoxycarbonyl-4-methyl 1- (4-nitro) phenoxycarbonyl-2-pyrimidine (60 mg, 0.138 m mol), cis-2- [4-cyano-4- (2-fluorophenyl) cyclohexylamino] e Mixture of tylamine (50 mg, 0.19 mmol) and methylene chloride (4 mL) Was stirred at room temperature overnight. After washing with 1N NaOH solution, the organic layer was concentrated, By preparative TLC (eluent: 10/1 ethyl acetate / 2M ammonia in methanol) The title compound was obtained as a yellow foam in 41% yield (32 mg): D CIMS, m / z = 570 (MH⁺). Free salt with 1 equivalent of 1M HCl in ether Processing groups Afforded the HCl salt as an off-white solid: mp 172-176 ° C. [α]_D= 11 4.7 (1.9 mg / mL MeOH). C₂₉H₃₀F_ThreeN_FiveO_FourHCl 0.5CHCl_ThreeNitsu Analytical theoretical values: C, 53.22; H, 4.77; N, 10.52. Measured value: C, 53.34; H, 4.77; N, 10.45. Example 14 (+)-Cis-6- (3,4-difluorophenyl) -1- {N- [2- (4-cyano-4- (2-pyridyl) -cy Clohexylamino) ethyl]} carboxamide-5-methoxycarbonyl-4-methoxy Cimethyl-2-oxo-1,2,3,6-tetrahydropyrimidine hydrochloride (Scheme 2; Step G). (+)-6- (3,4-difluorophenyl) -1,6-dihydro-5-methoxycarbonyl-4-meth Xymethyl-1- (4-nitro) phenoxycarbonyl-2-pyrimidone (50 mg, 0.1 mg). 107 mmol), cis-2- [4-cyano-4- (2-pyridyl) cyclohexylamino] e Mixture of tyramine (40 mg, 0.164 mmol) and methylene chloride (4 mL) Was stirred at room temperature overnight. After washing with a 1N NaOH solution, the organic layer was concentrated. By preparative TLC (eluent: 10/1 ethyl acetate / 2M ammonia in methanol) Purification gave the title compound as a yellow oil in 50% yield (31 mg): CIM S, m / z = 583 (MH⁺). Treat the free base with 2 equivalents of 1M HCl in ether. The HCl salt was obtained as an off-white solid: m.p. p. 148-152 ° C. [α]_D = 110.9 (1.65 mg / mL MeOH). C₂₉H₃₂F_TwoN₆O_Five.2 HCl 0.65 CHCl_ThreeAnalytical value for: C, 48.58; H, 4.76; N, 11.4. 6. Found: C, 48.30; H, 4.87; N, 11.20. Example 15 Cis-6- (3,4-difluorophenyl) -1- {N- [3- (4-cyano-4-phenyl-cyclohexyl Silamino) propyl]} carboxamide-5-methoxycarbonyl-4-methyl-2-oxo So-1,2,3,6-tetrahydropyrimidine hydrochloride. a) General description of 3- [4-cyano-4-allylcyclohexylamino] propylamino Production method a) 3- [4-cyano-4-phenylcyclohexylamino] propylamine (Scheme 6, step A). 4-Cyano-4-phenylcyclohexanone (5.0 g, 25 mL) in benzene (50 mL) . 09 mmol) and 1,3-diaminopropane (5.58 g, 75.3 mmol). Dean-Stark trap with a mixture of and p-toluenesulfonic acid (23 mg) And refluxed for 4 hours in order to remove the water formed. The solvent is evaporated and the residue is (40 mL) and cooled to 0 ° C. This includes sodium borohydride (6.45 g) was added in portions and the mixture was stirred at room temperature for 3 hours. Solvent Evaporate and dissolve the residue in dichloromethane (300 mL) and brine (3 × 500 mL), dried (potassium carbonate) and evaporated to a pale yellow viscous oil. The product was obtained as quality (4.5 g, 72%).¹The product is pure by H-NMR And was found to contain the cis / trans isomer in a ratio of about 4: 1. . b) cis-6- (3,4-difluorophenyl) -1- {N- [3- (4-cyano-4-phenyl-cycl) Rohexylamino) propyl]} carboxamide-5-methoxycarbonyl-4-methyl- 2-oxo-1,2,3,6-tetrahydropyrimidine hydrochloride (Scheme 6; Step B) . 5-Methoxycarbonyl-4-methyl-1,2,3,6-tetra in dichloromethane (50 mL) Hydro-2-oxo-6- (3,4-difluorophenyl) -1-[(4-nitrophenyloxy) cal Bonyl] pyrimidine (0.500 g, 1.15 mmol) and 3- [4-cyano-4-fu [Enylcyclohexylamino] propylamine (0.371 g, 1.49 mmol ) Was stirred at room temperature for 12 hours. It was ice-cooled with 0.5N NaOH (2 × 1 0 mL) and dried over sodium sulfate. The solvent was evaporated under reduced pressure and the The residue is flash chromatographed on silica gel (dichloromethane: MeO H: 2M ammonia in MeOH, 90: 8: 4), purified as a white powder 0.570 g (87.6%) of the product was obtained. HCl salt is 1N HCl in ether Prepared by treating the free base solution in ether solution with 1. M.p.16 3-165 ° C; C₃₀H₃₄N_FiveO_FourF_TwoCl.1.2H_TwoAnalytical theoretical value for O: C, 5 7.77; H, 5.88; N, 11, 23. Found: 57.65; H, 5.71. N, 11.20. Example 16 (+)-Cis-1.3-{[4- (3,4-difluorophenyl) -2,5-dioxo-1,2,3,4,5,7-hex Sahydro-4H-furo [3,4-d] -pyrimidine-3-carbonyl] amino} -ethyl- (4-sia No-4-phenylcyclohexyl) amine ・ hydrochloride a) (+)-6- (3,4-difluorophenyl) -1,6-dihydro-2-oxo-5-methoxy-ca Rubonyl-4-bromomethyl-1-[(4-nitrophenyloxy) carbonyl] pyrimidine ( Scheme 7; Step A). (+)-6- (3,4-difluorophenyl) -1,6-dihydro-2-me in 5 mL of chloroform Toxi-5-methoxycarbonyl-4-methyl-1-[(4-nitrophenyloxy) carbonyl ] Pyrimidine (1.5mmol, 0.66g) Of chloroform (1.5 mmol, 0.09 mL) in chloroform at 0 ° C. The solution was allowed to return to room temperature for 1.5 hours. The solvent is removed in vacuo and the residue Clean the residue again with CHCl_Three(20 mL) and washed with brine. Separate the organic layer and add N a_TwoSO_FourAfter drying over, filtering and removing the solvent in vacuo, 0.81 g of (+)-6- (3,4-difluorophenyl) -1,6-dihydro-2-oxo-5-methoxycarbonyl-4-bu Lomomethyl-1-[(4-nitrophenyloxy) carbonyl] pyrimidine in yellow foam As obtained. Used in the next step without any purification. b) (+)-4- (3,4-difluorophenyl) -2,5-dioxo-1,2,4,5,6,7-hexahydride B-Cyclopentapyrimidine-3-carboxylic acid-4-nitrophenyl ester (Scheme 7; Step B). (+)-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 an oil bath for 3 hours (oil bath temperature 130 ° C. The resulting brown residue was washed with CHCl_ThreeAnd washed with (+)-4- (3,4-difluoro Nyl) -2,5-dioxo-1,2,4,5,6,7-hexahydrocyclopentapyrimidine-3-cal Boronic acid-4-nitrophenyl ester was obtained as a light brown solid without further purification In the next step Used (crude product amount, 0.51 g). c) (+)-cis-1-3-{[4- (3,4-difluorophenyl) -2,5-dioxo-1,2,3,4,5,7 -Hexahydro-4H-furo [3,4.d] -pyrimidine-3-carbonyl] amino} -ethyl- (4- Cyano-4-phenylcyclohexyl) amine hydrochloride (Scheme 7; Step C). (+)-4- (3,4-Difluorophenyl) -2,5-dioxo-1,2,4,5,6, in THF (5 mL) 7-hexahydro-cyclopentapyrimidine-3-carboxylic acid-4-nitrophenyles Ter (86 mg, 0.20 mmol) and cis-2- (4-cyano-4-phenylcyclo) A solution of hexylamino) ethylamine (70 mg, 0.3 mmol) was added at room temperature to 12 Stirred for hours. It was separated by preparative tlc (ethyl acetate / methanol, 90:10). Purification on Lycagel afforded 91 mg (85%) as a white powder. HCl salt Prepared by treating the free base in ether solution with 1N HCl in Was. [Α]_D= + 102 (c = 0.75, MeOH); C₂₈H₂₇N_FiveO_FourF_TwoCl.0.38 CH_TwoCl_Two: C, 56.41; H, 4.80; N, 11.59. Obtained value: C, 56 . 80; H, 4.96; N, 11.29. Example 17 (+)-Cis-6- (3,4-difluorophenyl) -1- [4- (4-cyano-4-phenyl-cyclohex Silamino) butyl] -5-methoxycarbonyl-2,4-dimethyl-1,6-dihydropyrim Gin hydrochloride (Scheme 8). To a suspension of NaH (50 mg, 60% dispersion in mineral oil) in THF (7 mL) was added TH 6- (3,4-difluorophenyl) -1,6-dihydro-5-methoxycarbonyl in F (8 mL) 2,4-dimethylpyrimidine (0.32 g, 1.14 mmol) and HMPA (0 . 205 g, 1.14 mmol) at 0 ° C. 15 minutes later, 1,4-di Bromobutane (0.47 mL, 4.0 mmol) was added. Reaction mixture for 10 minutes Reflux for a while. The solid was removed by filtration. After removing the solvent, the residue is Chromatography on silica gel (eluent: ethyl acetate), 44% yield Afforded the product as a yellow oil (0.2 g). 1- (4-bromobutyl) -6- (3,4-difluorophenyl) -1,6-dihydro-5-methoxyca Rubonyl-2,4-dimethylpyrimidine (0.1 g, 0.43 mmol), cis-4-sia No-4-phenylcyclohexylamine (0.18 g, 0.9 mmol), potassium carbonate (0.3 g, 2.1 mmol), sodium iodide (65 mg, 0.43 mmol) A mixture of 1) and acetone (6 mL) was refluxed overnight. After removing solids and solvent The residue was purified by preparative TLC (eluent: 100/20 v / v ethyl acetate-2 in methanol). M ammonia) and the product as a combination of diastereomers, The product was obtained in a yield of 0.23 g. HPLC separation (column: Chiralcel OD20) × 250 mm; eluent: 60/40 / 0.1, hexane / 2-propanol / die ) Gave the pure title compound as a yellow oil: DCIMS , M / z = 535 (MH⁺). Treat the free base with 2 equivalents of 1M HCl in ether This afforded the HCl salt as a white solid: mp 169-172 ° C. [α]_D= 68.6 (2.2 mg / mL MeOH). C₃₁H₃₆F_TwoN_FourO_Two2HCl 0.9CHCl_Three For C: 53.59; H, 5.48: N, 7.84. Measured value : C, 53.61; H, 5.67; N, 7.81. In the general synthetic schemes cited here, appropriately substituted starting materials were used. It is speculated that additional compounds would be synthesized. Example 18 (+)-6- (3,4-difluorophenyl) -1- {N- [2- (4-cyano-4-phenylcyclohexyl -1-ylamino) -ethyl]} carboxamide-5-methoxycarbonyl-4-hydroxy Methyl-2-oxo-1,2,3,6-tetrahydropyrimidine. (+)-6- (3,4-difluorophenyl) -1- {N- [2- (4-cy) in dichloromethane (8 mL) Ano-4-phenylcyclohex-1-ylamino) -ethyl]} carboxamide-5-methoate Xycarbonyl-4-methoxymethyl-2-oxo-1,2,3,6-tetrahydropyrimidine ( (0.108 g, 0.184 mmol) in a well stirred solution. The boron bromide solution was added dropwise at -78 ° C and the cooling bath was removed. Its mixing After stirring at room temperature for 4 hours, methanol (5 mL) was added to terminate the reaction. Remove the solvent and remove Of the residue on silica gel for preparative use as chloroform / methanol / meta By thin-layer chromatography using 2M ammonium in ethanol (95/4/1). And purified. Compounds migrating earlier (Rf = 0.6, CHCl_Three: CH_ThreeO H: CH_Three2M NH in OH_ThreeSilica gel plate eluted using (25: 2: 1) TLC above) is (+)-6- (3,4-difluorophenyl) -1- {N- [2- (4-cyano-4-f Enylcyclohex-1-ylamino) ethyl]} carboxamide-5-methoxycarbo Nyl-4-bromomethyl-2-oxo-1,2,3,6-tetrahydropyrimidine, Converted to the hydrochloride salt by treatment with 1N HCl in water (10 mg); MH + = 6 30; P. 225-227 ° C; [α]_D= + 126 (c = 0.115, MeOH ); C₂₉H₃₁N_FiveO_FourF_TwoCl_Two.0.2CH_TwoCl_TwoTheoretical value for C: 51.2 8; H, 4.63; N, 10.24. Found: C, 51.40; H, 4.58; N, 10.12. Second compound (Rf = 0.5, CHCl_Three: CH_ThreeOH: CH_ThreeO 2MNH in H_ThreeTL on silica gel plate eluted with (25: 2: 1) C) is converted to (+)-6- (3,4-difluorophenyl) -1- {N- [2- (4-cyano-4-phenyl-cycl) Rohex-1-ylamino) ethyl]} carboxamide-5-methoxycarbonyl-4-hydr Roxymethyl-2-oxo-1,2,3,6-tetrahydropyrimidine (45 mg); NH + = 568; C₂₉H₃₁N_FiveO_FiveF_Two.0.35CH_TwoCl_TwoAnalytical value for: C, 59. 02; H, 5.35; N, 11.72. Found: C, 58.93; H, 5.50. N, 11,68. Example 19 (+)-6- (3,4-difluorophenyl) -1- {N- [2- (4-cyano-4-phenylcyclohexyl -1-ylamino) ethyl]} carboxamido-4-methoxymethyl-2-oxo 1,2,3,6- Tetrahydropyrimidine-5-carboxylic acid. a) Benzyl 2-[(3,4-difluorophenyl) methylene] -3-oxo-4-methoxybutyrate . Benzyl 4-methoxyacetoacetate (84 g, 0.37 mol) in benzene (1 L) , 3,4-difluorobenzaldehyde (52.5 g, 0.37 mmol), pipet acetate A molecular sieve (400 g) was added to a solution of ridinium (1.58 g, 2.63 mmol). Was added and the mixture was stirred at room temperature for 48 hours. The molecular sieve is removed by filtration And filter The solvent was evaporated from the liquid under reduced pressure. Use chloroform / ethyl acetate (100: 3) The residue was purified by column chromatography on silica gel The final product was obtained (118 g, 91%). NMR showed that the product was in cis form. And a mixture of trans isomers. b) 5-benzyloxycarbonyl-1,6-dihydro-2-methoxy-4-methoxymethyl- 6- (3,4-difluorophenyl) pyrimidine. 2-[(3,4-difluorophenyl) methylene] -3-oxo- in ethanol (400 mL) Benzyl 4-methoxybutyrate (60 g, 0.181 mol), O-methylisourea Misulfate (46.77 g, 0.271 mol, 1.5 eq.), Sodium carbonate (53 . 25 g, 0.634 mol, 3.5 eq.) Suspension at 50-55 ° C. for 6 hours. Stirred. The solvent is evaporated from the combined filtrate and the residue is purified by column chromatography. (SiO_Two, EtOAc / hexane, 10% -30%) and purified by Xycarbonyl-1,6-dihydro-2-methoxy-4-methoxymethyl-6- (3,4-difluoro (Lophenyl) pyrimidine was obtained as a pale yellow oil (24.7 g, 35%). c) 5-benzyloxycarbonyl-4-methoxymethyl-1,6-dihydro-2-methoxy- 6- (3,4-difluorophenyl) -1-[(4-nitrophenyloxy) carbonyl] pyrimidi N. CH_TwoCl_Two(100 mL) in 5-benzyloxycarbonyl-1,6-dihydro-2-methoxy Ci-4-methoxymethyl-6- (3,4-difluorophenyl) pyrimidine (12 g, 29 m mol) and pyridine (10 mL) were pulverized into a well-stirred solution. 4-Nitrophenyl chloroformate (8.69 g, 43 mmol) was added at 0 ° C. Anti The reaction mixture was stirred for 12 hours at room temperature, the solvent was evaporated from the filtrate and the residue was Matography (SiO_Two, Dichloromethane / hexane, 20% -50%) To give the product as a foam (14.2 g, 86%). d) (+)-5-benzyloxycarbonyl-4-methoxymethyl-1,6-dihydro-1- {N- [ (2-phenyl) ethyl]} carboxamide-2-methoxy-6- (3,4-difluorophenyl) Pyrimidine. 5-benzyloxycarbonyl-4-methoxymethyl-1,6-dihydrogen in THF (120 mL) Dro-2-methoxy-6- (3,4-difluorophenyl) -1-[(4-nitrophenyloxy) cal R-(+)-was added to a stirred solution of [bonyl] pyrimidine (6 g, 10.5 mmol). α-Methylbenzylamine (1.8 g, 5 mmol) was added at room temperature, and the mixture was stirred for 12 hours. Continued for hours. The solvent is evaporated and the residue is purified by column chromatography (SiO_Two, (10-20% EtOAc in hexane). First major to elute Product is (+)-5-benzyloxycarbonyl-4-methoxymethyl as an oil. 1,6-dihydro-1- {N- [2-phenyl) ethyl]} carboxamide-2-methoxy-6- (3 , 4-Difluorophenyl) pyrimidine (2.1). e) (+)-5-benzyloxycarbonyl-1,6-dihydro-2-methoxy-4-methoxymeth Tyl-6- (3,4-difluorophenyl) pyrimidine. (+)-5-benzyloxycarbonyl-4-methoxymethine in dichloromethane (200 mL) Tyl-1,6-dihydro-1- {N- [2-phenyl) ethyl]} carboxamide-2-methoxy-6- A solution of (3,4-difluorophenyl) pyrimidine (2 g, 3.5 mmol) was stirred. To this, 1,8-diazabicyclo [5,4,0] -undecane 7-ene (0.6 mL) was added, The mixture was stirred at room temperature for 12 hours. The solvent is evaporated and the residue is used as eluent. Flash column on silica gel with 30-40% EtOAc in xane Purified by chromatography, (+)-5-benzyloxycarbonyl-1,6-dihydrido Ro-2-methoxy-4-methoxymethyl-6- (3,4-difluorophenyl) pyrimidine (1.25 g, 86%) as a neutral oil. f) (+)-5-benzyloxycarbonyl-4-methoxymethyl-1,6-dihydro-2-methoate Xy-6- (3,4-difluorophenyl) -1-[(4-nitrophenyloxy) carbonyl] pyri Midin. CH_TwoCl_Two(+)-5-benzyloxycarbonyl-1,6-dihydro-2-methoate (20 mL) Xy-4-methoxymethyl-6- (3,4-difluorophenyl) pyrimidine (125 g, 3 . 0 mmol) was stirred sufficiently, and powdered 4-nitro chloroformate was added to the solution. Phenyl (1 g, 5 mmol) was added at room temperature. The solvent is evaporated and the residue is CHCl as eluent_ThreeOn silica gel with / EtOAc (20% -50%) No kara (+)-5-benzyloxycarbonyl-4-methoxy Cimethyl-1,6-dihydro-2-methoxy-6- (3,4-difluorophenyl) -1-[(4-nitro [Phenyloxy) carbonyl] pyrimidine was obtained as a viscous oil (1.70 g). , 86%). [α]_D= + 200 (100 mL CHCl_ThreeC = 1.215 g). g) (+)-6- (3,4-difluorophenyl) -1- {N- [2- (4-cyano-4-phenylcyclo) Hex-1-ylamino) -ethyl]} carboxamide-5-benzyloxycarbonyl-4- Methoxymethyl-2-oxo-1,2,3,6-tetrahydropyrimidine (cis isomer). (+)-6- (3,4-difluorophenyl) -1,6-dihydro-2-methoxy in THF (5 mL) -5-benzyloxycarbonyl-4-methoxymethyl-1- (4-nitrophenoxy) -carbo Nylpyrimidine (0.100 g), and 2- [4-cyano-4-phenylcyclohexyl-1 A solution of [-yl] aminoethylamine (0.05 g) was stirred at room temperature for 12 hours. to this In contrast, 6N HCl (0.5 mL) was added and stirring was continued for 2 hours. Steam solvent Evolved and the residue was mixed with dichloromethane (10 mL) and ice cold 0.5 N Na Washed with OH (2 × 10 mL) and dried over sodium sulfate. Evaporate the solvent under reduced pressure And the residue was flash chromatographed on silica gel (dichloromethane). Purified by methane: MeOH: 2M ammonia in MeOH, 90: 8: 4) 0.12 g of the product was obtained as a white powder. NMR shows that the purified product is pure It was shown to be. Then proceed to the next step without any further characterization Used in. h) (+)-6- (3,4-difluorophenyl) -1- {N- [2- (4-cyano-4-phenylcyclo) [Hex-1-ylamino) -ethyl]} carboxamido-4-methoxymethyl-2-oxo-1, 2,3,6-tetrahydropyrimidine-5-carboxylic acid. (+)-6- (3,4-Difluorophenyl) -1- {N in methanol / water (9/1, 10 mL) -[2- (4-Cyano-4-phenylcyclohex-1-ylamino) ethyl]} carboxamide -5-benzyloxycarbonyl-4-methoxymethyl-2-oxo 1,2,3,6-tetrahydro To a solution of pyrimidine (120 mg) was added 10% palladium on activated carbon (20 mg). Was added and the mixture was hydrogenated at 125 psi for 4 hours. Tlc analysis of reactants Showed the completeness of the reaction. The catalyst is removed by filtration and the solvent is evaporated. , Pale yellow powder (86 mg); m.p. p. 188-191 ° C; C₂₉N₃₁N_FiveO_FiveF_Two 0.5H_TwoAnalytical theory for O: C, 60.41; H, 5.59; 15. Found: C, 60.28; H, 5.62; N, 12.34. Example 20   Specific embodiments of the oral compositions of the compounds of the present invention are described herein. 100 mg of one of the compounds Formulated with lactose fine enough to give a total amount of 80-590mg . Pharmacological profile of compounds against the cloned human adrenergic receptor. Lofir   For the selected compounds of the invention, the six cloned human α-1 and Binding affinity for α-2 receptor subtype and L-type calcium channel It was measured. The protocols for these experiments are shown below. α₁Protocol for determining antagonist potency   The activity of compounds on various human receptors selectively expresses this receptor Determined in vitro using a cultured cell line. Human α-adrenaline shown below Cloned cDNA or clonin encoding an agonistic receptor Genomic DNA or a structure containing both genomic DNA and cDNA These cell lines were prepared by transfecting the structures. α_1DHuman adrenergic receptor   Contains 150 bp of 5 'untranslated sequence (5'UT) and 300 bp of 3' untranslated sequence (3'UT) α_1D(1719bp) coding region with polylinker modified eukaryotic cell Cloned into the BamHI and ClaI sites of the current vector pCEXV-3, J.HR.   The construct includes a partially overlapping human lymphocyte genomic clone and hippocampal cDN. A ligation of the A clone was included. The 5 'sequence is a 1.2 kb SmaI-XhoI genomic fragment ( For subcloning, instead of the SmaI site from the internal insert, The 3 'sequence is 1.3 kb Xh oI- ClaI cDNA fragment (ClaI site is a vector polylinker Those of them). Plasmid α1A / EXJ (a plasmid containing the α1A receptor gene) The current vector (former nomenclature)) and the plasmid pGCcos3neo (aminoglycoside) Plasmid containing the transferase gene) using the calcium phosphate method And stable co-transfection into LM (tk-) cells. A cell line was obtained. The cells contain 25 mM glucose, 10% calf calf serum, 100% Units / ml penicillin g, and 100 μg / ml streptomycin sulfate Dulbecco's Modified Eagle's Medium (GIBCO, Grand Island, NY) ) In a controlled environment (37 ° C, 5% CO_Two) And developed as a monolayer. Next Next, clones stable with respect to the resistance to the antibiotic G-418 (1 mg / ml) were selected. To collect the membrane,^ThreeH] The ability to bind prazosin is described below. (See "Radioligand binding assay").   Human α used herein_1DThe cell line expressing the receptor was identified as L-α_1A(Old nomenclature ) Of the Budapest Treaty on the International Recognition of the Deposit of Microorganisms in Patent Procedures As per regulations, 12301 Rockwell, Rockville, Maryland, United States 20852 Deposited at the American Type Culture Collection in London Drive. Hi G α_1DThe cell line expressing the receptor is given ATCC Accession No. CRL11138. Obtained and deposited on September 25, 1992. α_1BHuman adrenergic receptor   200 base pairs and 5 'untranslated sequence (5'UT) and 600 base pairs of 3' untranslated sequence (3 ' Α including UT)_1BOf the entire coding region (1563 bp) of the eukaryotic expression vector pC It was cloned into the EcoRI site of EXV-3. The construct is a brainstem from λZapII ligating the full length of the cDNA containing the EcoRI fragment into an expression vector Was out. Stable cell lines were selected as described above. The cell line used herein is L -α_1BBudapest Article on International Recognition of Deposit of Microorganisms for Patent Procedure 12301 Parc Rockville, Maryland, United States 20852, pursuant to the provisions of Deposited at Clone Drive's American Type Culture Collection . The cell line, L-α_1BReceived ATCC accession number CR11139 on September 29, 1992 I got it. α_1AHuman adrenergic receptor:   Contains 400 bp of 5 'untranslated sequence (5'UT) and 200 bp of 3' untranslated sequence (3'UT) α_1APCEXV-3 in which the entire coding region (1401 bp) is modified with a polylinker Cloned into the KpnI site of the eukaryotic expression vector EXJ. . The construct contains three overlapping fragments, a 5 '0.6 kB HincII genomic clone. , A 1.8 EcoRI hippocampal cDNA clone in the middle and a 3 '0.6 kb PstI genomic clone. It included ligation of muclones. The hippocampus cDNA clone is HincII and PstI sites at the 5 'and 3' ends, respectively, were made available for ligation. In addition, it overlaps with the 5 'and 3' genomic clones. Each is a vector (ie, 5 'and 3' KpnI sites of the fragment, obtained from pBluescript) and 3 'untranslated sequence The full length of the clone was cloned into the KpnI site of the expression vector using Was. Stable cell lines were selected as described above. Human α as used herein_1AReceptor A stable cell line that expresses L-α_1c(Old nomenclature), the microorganism in the patent procedure Under the provisions of the Budapest Treaty on the International Recognition of Deposits, 852 Rockwill, Maryland 12301 American Thai at Park Lane Drive Deposited at the Pu Culture Collection. Human α_1AThe cell expressing a receptor The cell system was assigned accession number CR11140 on September 25, 1992. Radioligand binding assay   The transfected cells were scraped from the culture flask and 5 ml of 5 mM Place in Tris-HCl, 5 mM EDTA, pH 7.5 and break cells by sonication broke. The cell lysate is centrifuged at 4 ° C. for 5 minutes at 1000 rpm, and the supernatant is centrifuged at 4 ° C. for 20 minutes. And centrifuged at 30,000 xg. 50 mM Tris-HCl, 1 mM MgCl_TwoAnd 0.1% Asco The precipitate was suspended in rubic acid pH 7.5. Α to the membrane preparation of LM (tk-) cells₁Ann Tagonist [^ThreeH] Prazosin (0.5 nM, specific activity 76.2 Ci / mmol) Performed in a volume of 0.25 ml and incubated at 37 ° C. for 20 minutes. Non-specific binding is 10 μM Of phentolamine. The reaction was performed using a cell harvester. Stopped by filtering through a / B filter. Inhibition experiments usually consist of 7 Computer with non-linear regression curve fitting consisting of test compound at twice the concentration -Analysis was performed using the program to obtain Ki values. α_TwoHuman adrenergic receptor   α_TwoΑ for receptor₁To determine the potency of an antagonist, α_2A, Α_2BYou And α_2CLM (tk-) stably transfected with the gene encoding the receptor A cell line was used. α_2AThe cell line expressing the receptor is L-α_2A199 Deposited with ATCC Accession No. CRL11180 on November 6, 2002. α_2BExpressing the receptor The cell line used is L-NGC-α_2BATCC reception on October 25, 1989 Deposited under the number CRL10275. α_2CThe cell line expressing the receptor is L-α_2CAnd life On November 6, 1992, it was deposited under ATCC accession number CRL11181. All of Cell lines are subject to the provisions of the Budapest Treaty on the international recognition of deposits of microorganisms in patent proceedings. 12321 Parklaw, Rockville, MD 20852, USA Deposited at the American Type Culture Collection at N Drive. cell Lysate was prepared as described above (see radioligand binding assay). Suspended in M glycylglycine buffer (pH 7.6 at room temperature). Equilibrium competitive binding assay Is [^ThreeH] Raoulscine (0.5 nM) for non-specific binding Was determined by incubating with 10 μM phentolamine. Was. The bound radioligand is passed through a GF / B filter using a cell harvester. And separated by filtration. Α for calcium channel₁Determination of antagonist activity   Basically, Glossman and Ferry (Methods in Enzymology 109: 513-550,1 985) to the membrane fragment of rat myocardium.^ThreeH] Nitrendipine competitive In binding assays, α₁Determine potency of antagonist did. Briefly, tissue is minced into 0.1 mM phenylmethylsulfonate. Homogenized in 50 mM Tris-HCl (pH 7.4) containing lufluoride. 100 The homogenate was centrifuged at 0 g for 15 minutes, and the resulting supernatant was centrifuged at 45,000 g for 15 minutes. Was. The 45,000 g precipitate was suspended in a buffer and centrifuged a second time. [^ThreeH] Nito A sample of membrane protein was incubated at 37 ° C for 30 minutes in the presence of rangepin (1 nM). Nonspecific binding was determined in the presence of 10 μM nifedipine. Combined Radioligand is filtered through a GF / B filter using a cell harvester Separated by   The compounds described above are used to clone the cloned human alpha adrenergic receptor and Assay was performed using a calcium channel. Preferred compounds are α_1ASelective a It turned out to be an antagonist. The compound described herein is a rat L-form It was found that it also showed a weak binding affinity for calcium channels. Compound 2 The α-adrenergic receptor binding affinities of ５5, 7, 11, 13 and 14 are shown in the table below. It is shown in FIG.   In part 1 of the general synthetic scheme, an optionally substituted cycloalkanone is Reflux with diaminoalkane to give the corresponding (cycloalk-1-yl) amino Noalkylimine, NaBO_FourWhen treated with (cycloalk-1-yl ) An aminoalkylamine is obtained. In Part 3, we will look at 1-[(4-nitrophenyl) Add the diamine to the [oxycarbonyl] pyrimidine to obtain the final product. Cyclohexene Although sanone is shown, the method extends from cyclobutanone to cyclooctanone. The same applies to substituted cycloalkanones. further, Replacing the diaminoalkane of part 1 with an aminoalkanol gives the An ester is obtained instead of the mid. In the scheme below, for clarity, Diaminoalkanes are shown as either ethyl, propyl or butyl, Any suitable alkyl, branched alkyl or as shown in Scheme 1. A substituted alkyl may be used, where R is as defined in the specification. It is.   In Part 2 of the general synthetic scheme, O-methylisourea (R "" = OMe) When used in Step D, several different 2-substitutes on dihydropyrimidine are produced. It is important to note that In particular, primary amines (ie, NH_TwoR_Three ) Can be added to 2-methoxypyrimidine to give 2-aminopyrimidine. There Is ethanethiol if R "" = OMe is replaced by 4-methoxybenzylthiol And treatment of the product with TFA to afford 2-thioxodihydropyrimidine May be able to produce.   By replacing 1,4-dibromobutane with other dibromoalkanes, To produce alkyl-linked cycloalkylamine derivatives of hydropyrimidine Similar compounds, including branched compounds, may be produced.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) A61P 27/02 A61K 31/00 627A A61K 31/505 31/505 31/506 601 31/519 606 C07D 491 / 048 C07D 491/048 (81) Designated countries EP (AT, BE, CH, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE), OA ( BF, BJ, CF, CG, CI, CM, GA, GN, ML, MR, NE, SN, TD, TG), AP (KE, LS, MW, SD, SZ, UG), UA (AM, AZ) , BY, KG, KZ, MD, RU, TJ, TM), AL, AM, AT, AU, AZ, BA, BB, BG, BR, BY, CA, CH, CN, C , CZ, DE, DK, EE, ES, FI, GB, GE, HU, IL, IS, JP, KE, KG, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MD, MG, MK, MN, MW, MX, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK, TJ, TM, TR, TT, UA, UG, US, UZ , VN (72) Inventor Nagurasunum, Danaparan, United States 07446, New Jersey, Ramsey, Island Avenue 450, Apartment 74 (72) Inventor Wong, WY United States, New Jersey 07102, Newark, Columbia Street 34 (72) Inventor Miao, Shaw W United States, New Jersey 08820, Edison, Prestwick Way 295 (72) Inventor Paten, Iker er United States, Pennsylvania 19438, hard Leesville, Country bi-menu-lane 1401 (72) inventor guru butterfly skiing, Charles United States, New Jersey 07470, Wayne, Chopin drive 153

Claims (1)

[Claims]   1. Construction: Or Where M is the structure    Where Y₁, Y_Two, Y_Three, Y_FourAnd Y_FiveAre each independently —H; straight-chain or branched C₁ -C₇Alkyl, monofluoroalkyl or polyfluoroalkyl; linear or Is branch C_Two-C₇Alkenyl or alkynyl; C_Three-C₇Cycloalkyl, monoflu Olocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;- F, -Cl, -Br, or -I; -NO_Two; -N (R_Three)_Two; -N_Three; -CN; -OR_Three; -OCOR_Three; -COR_Three; -CON (R_Three)_Two; -N_Three; -CN; -OR_Three; -OCOR_Three; -COR_Three; -CON (R_Three )_TwoOr -CO_TwoR_ThreeOr Y₁, Y_Two, Y_Three, Y_FourAnd Y_Five2 in One is on an adjacent carbon atom and both make up a methylenedioxy group;     Wherein R is independently -H; -F; linear or branched C₁-C₇Alkyl, monofluo Loalkyl or polyfluoroalkyl; linear or branched C_Two-C₇Alkenyl Or alkynyl; -N (R_Three)_Two; -NO_Two; -CN; -CO_TwoR_Three;-( CH_Two)_pPO (OR_Three)_Two;- (CH_Two)_pPO (OR_Three)_Three; Or -OR_ThreeMay be;     Where R₁Is -H; -NO_Two; -CN; linear or branched C₁-C₇Alkyl, monoph Fluoroalkyl or polyfluoroalkyl; linear or branched C_Two-C₇Alkene Or alkynyl; C_Three-C₇Cycloalkyl, monofluorocycloalkyl, Trifluorocycloalkyl or cycloalkenyl; -N (R_Three)_Two; -OR_Three;-( CH_Two )_pOR_Three; -COR_Three; -CO_TwoR_ThreeOr -CON (R_Three)_TwoMay be;     Wherein all p are independently integers from 1 to 7;     Where R_TwoIs -H; linear or branched C₁-C₇Alkyl, hydroxyalkyl, Alkoxyalkyl, aminoalkyl, monofluoroalkyl or polyfluoro Loalkyl; straight or branched C_Two-C₇Alkenyl or alkynyl; C_Three-C₇Shiku Loalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or Cycloalkenyl; C_Three-C_TenCycloalkyl-C₁-C_Ten-Alkyl, C_Three-C_TenShiku Lower alkyl-C₁-C_Ten-Monofluoroalkyl or C_Three-C_TenCycloalkyl-C₁ -C_Ten-Polyfluoroalkyl; -CN; -CH_TwoXR_Three, -CH_TwoX (CH_Two)_pNHR_Three, -(CH_Two)_nNHR_Three, -CH_TwoX (CH_Two)_pN (R_Three)_Two, -CH_TwoX (CH_Two)_pN_Three, Or- CH_TwoX (CH_Two)_pNHCXR₇; Or -OR_ThreeMay be;     Here, all n are independently an integer of 0 or more and 5 or less, and p is as defined above. Is;     Where each R_ThreeIs independently -H; linear or branched C₁-C₇Alkyl, monofluoro Alkyl or polyfluoroalkyl; linear or branched C_Two-C₇Alkenyl or Is alkynyl; C_Three-C₇Cycloalkyl, monofluorocycloalkyl, polyfur Orocycloalkyl or cycloalkenyl;-(CH_Two)_pPO (OR₈)_Two;-( CH_Two)_p PO (OR₈)_Three; Or-(CH_Two)_pCOOR₈May be; Where R_FourIs the structure Has,     Where Z is C_Two-C₇Alkenyl or alkynyl; CH_Two; O; CO; CO_Two; C ONR_ThreeCO; CONR_Three; S; SO; SO_Two; Or NR_ThreeM is 0 or more and 3 Is an integer that is:     R_FiveOr R₆Is independently -H; -F, -Cl, -Br, -I; -CO_TwoR_Three; -COR_Three;- CON (R_Three)_Two; -CN; -NO_Two; -N (R_Three)_Two; -OR_ThreeLinear or branched C₁-C₇Alkyl , C₁-C₇Monofluoroalkyl, C₁-C₇Polyfluoroalkyl, C_Two-C₇Al Kenil, C_Two-C₇Alkynyl, C_Three-C₇Cycloalkyl, or C_Three-C₇Cycloa It can be alkenyl; wherein said alkyl, monofluoroalkyl, polyfluoro Alkyl, alkenyl, alkynyl, cycloalkyl or cycloalkenyl is , -H, allyl or heteroallyl may be unsubstituted or substituted. Allyl or heteroallyl is -H, -F, -Cl, -Br, -I, -N O_Two, -CN, -N (R_Three)_Two, -OR_Three, -COR_Three, -CO_TwoR_ThreeOr -CON (R_Three)_Twoso Unsubstituted or substituted; linear or branched C₁- C₇Alkyl, monofluoroalkyl or polyfluoroalkyl, linear or Branch C_Two-C₇Alkenyl or alkynyl, C_Three-C₇Cycloalkyl, monofluor Rocycloalkyl, polyfluorocycloalkyl, or cycloalkenyl. Can;     R₇Is -H; linear or branched C₁-C₇Alkyl, hydroxyalkyl, amino Alkyl, alkoxyalkyl, monofluoroalkyl or polyfluoroalkyl Kill; straight or branched C_Two-C₇Alkenyl or alkynyl; C_Three-C₇Cycloal Kill, monofluorocycloalkyl, polyfluorocycloa Alkyl or cycloalkenyl; -CN; -CO_TwoR_Three; -COR_Three; -CON (R_Three)_Two; TAHA-OR_ThreeMay be;     Where R₈Is -H; linear or branched C₁-C₇Alkyl, monofluoroalkyl Or polyfluoroalkyl; linear or branched C_Two-C₇Alkenyl or alk Nil; C_Three-C₇Cycloalkyl, monofluorocycloalkyl, polyfluorocyclo Loalkyl or cycloalkenyl;     Where R₉Is -H; -CN; linear or branched C₁-C₇Alkyl, monofluoroa Alkyl or polyfluoroalkyl; linear or branched C_Two-C₇Alkenyl or Alkynyl; C_Three-C₇Cycloalkyl, monofluorocycloalkyl, polyfluor Rocycloalkyl or cycloalkenyl; -N (R_Three)_Two; -OR_Three;-( CH_Two)_pOR_Three;- COR_Three; -CO_TwoR_Three; Or -CON (R_Three)_TwoMay be;     Where X is S; O; or NR_ThreeAnd;     Where B is -H; linear or branched C₁-C₇Alkyl, monofluoroalkyl, Polyfluoroalkyl, alkoxy or thioalkyl; linear or branched C_Two-C₇ Alkenyl; -SCH_TwoC₆H_FourOR_Three;-( CH_Two)_nC₆H_Five; -CH_TwoX (CH_Two)_nNHR_Three ;-( CH_Two)_nNHR_Three; Or -OR_ThreeMay be; Or a pharmaceutically acceptable salt thereof.   2. 2. The compound of claim 1, wherein the compound contains the (+) enantiomer. object.   3. 2. The compound of claim 1, wherein the compound comprises the (-) enantiomer. object.   4. The compound is and2. The compound of claim 1 selected from the group consisting of:   5. 5. The compound of claim 4, wherein R_FourBut, And p is 2, 3 or 4.   6. The compound of claim 5, wherein R_FourBut A compound that is   7. 7. The compound of claim 6, wherein the structure is: A compound having the formula:   8. The compound of claim 7, wherein M is polyfluorophenyl and R_FiveIs placed Compounds that are substituted or unsubstituted phenyl or pyridyl.   9. 9. The compound of claim 8, wherein R₁Is -CO_TwoCH_Three, -COCH_ThreeOr -C ONH_TwoAnd R_TwoIs -CH_TwoOCH_Three, Methyl or ethyl; and R₆Is H,- CN or CO_TwoCH_ThreeA compound that is   10. The compound of claim 6, wherein the compound is: and A compound selected from the group consisting of:   11. 11. The compound of claim 10, wherein said compound is the (+) enantiomer. Compound.   12. 11. The compound of claim 10, wherein the compound is the (-) enantiomer. Compound.   13. 7. The compound of claim 6, wherein the structure is:A compound having the formula:   14． 14. The compound of claim 13, wherein M is polyfluorophenyl and R_Five Is a substituted or unsubstituted phenyl or pyridyl.   15. 15. The compound of claim 14, wherein the compound is A compound that is   16. 16. The compound of claim 15, wherein said compound is the (+) enantiomer. Compound.   17． 16. The compound of claim 15, wherein said compound is the (-) enantiomer. Compound.   18. Comprising a therapeutically effective amount of the compound of claim 1 and a pharmaceutically acceptable carrier. Pharmaceutical compositions.   19. 20. The pharmaceutical composition of claim 18, wherein the amount of said compound is about 0.01-500 mg. A pharmaceutical composition which is an amount.   20. 20. The pharmaceutical composition of claim 19, wherein the amount of said compound is about 0.1-60 mg. A pharmaceutical composition which is:   21. 21. The pharmaceutical composition of claim 20, wherein the amount of said compound is in an amount of about 1-20 mg. Certain pharmaceutical compositions.   22. 20. The pharmaceutical composition of claim 18, wherein said carrier is a liquid and said composition is A pharmaceutical composition which is a solution.   23. 20. The pharmaceutical composition of claim 18, wherein said carrier is solid and said composition is A pharmaceutical composition which is a tablet.   24. 20. The pharmaceutical composition of claim 18, wherein said carrier is a gel, and wherein said composition is Pharmaceutical compositions that are suppositories.   25. 20. The pharmaceutical composition of claim 18, wherein said compound is a pharmaceutically acceptable agent. A pharmaceutical composition formulated as part of a transdermal patch.   26. A method of treating a patient suffering from benign prostatic hyperplasia, comprising the steps of: Administering to the patient an amount of the compound of claim 1 effective to treat large. How to be.   27. 27. The method of claim 26, wherein the amount is effective to reduce benign prostatic hyperplasia. Wherein the compound does not cause a decrease in blood pressure.   28. 28. The method of claim 27, wherein said compound relaxes lower urethral tissue. And how to be effective in the treatment of benign prostatic hyperplasia.   29. 29. The method of claim 28, wherein the lower urethral tissue is prostate smooth muscle. .   30. A method of treating a patient suffering from increased intraocular pressure, A method comprising administering to a patient an effective amount of a compound of claim 1.   31. A method to treat patients suffering from diseases with elevated blood cholesterol And providing the compound of claim 1 in an amount effective to inhibit cholesterol synthesis to the patient. Administering to the subject.   32. α_1AA method for treating a disease for which treatment with receptor antagonism may be effective. Administering to the patient an effective amount of the compound of claim 1 to treat the disease. A method comprising:   33. A method of treating a patient suffering from impotence, comprising: Administering to the patient an effective amount of the compound of claim 1 to treat the disease. Way.   34. A method of treating a patient suffering from pain through the sympathetic nervous system, comprising: Administering to the patient an effective amount of the compound of claim 1 for treating pain through the sensory nervous system. A method comprising:   35. A method of treating a patient suffering from a cardiac arrhythmia, the method comprising: Administering to the patient an effective amount of the compound of claim 1 to treat the disease. Way.   36. A method of treating a patient suffering from benign prostatic hyperplasia, comprising the steps of: 5α-reductor An effective amount of a compound according to claim 1 for treating benign prostatic hyperplasia together with a lipase inhibitor. Administering a substance to a patient.   37. 37. The method of claim 36, wherein said 5-α-reductase inhibitor is finastere. How to be a ride.   38. Combination of a therapeutically effective amount of the compound of claim 1 with finasteride. And a pharmaceutically acceptable carrier.   39. 39. The pharmaceutical composition of claim 38, wherein the composition comprises about 0.01-500 mg of the compound and about A pharmaceutical composition comprising 5 mg finasteride.   40. 39. The pharmaceutical composition of claim 38, wherein about 0.1-60 mg of the compound and about 5 m A pharmaceutical composition comprising g finasteride.   41. 40. The pharmaceutical composition of claim 38, wherein about 1-20 mg of the compound and about 5 mg. A pharmaceutical composition comprising finasteride.   42. A method of relaxing the lower urethral tissue, wherein the lower urethral tissue is relaxed. Contacting an effective amount of the compound of claim 1 with lower urethral tissue. Way.   43. 43. The method of claim 42, wherein the lower urethral tissue is prostate smooth muscle. .   44. 44. The method of claim 43, wherein the compound does not reduce blood pressure.   45. A method of relaxing the lower urethral tissue of a patient, wherein the lower urethral tissue is relaxed. Administering to the patient an effective amount of the compound of claim 1 to cause the compound to become effective. .   46. 46. The method of claim 45, wherein the lower urethral tissue is prostate smooth muscle. .   47. 47. The method of claim 46, wherein said compound does not reduce blood pressure.   48. A method of inhibiting prostate tissue from contracting, wherein the prostate tissue is contracted. Administering to the patient an amount of the compound of claim 1 which is effective to inhibit Way   49. 49. The method of claim 48, wherein said prostate tissue is prostate smooth muscle.   50. 50. The method of claim 49, wherein said compound does not reduce blood pressure.   51. 43. The method of claim 42, wherein the compound relaxes lower urethral tissue. The method administered with inasteride.