Background of the Invention The present invention concerns heterocyclic carbon compounds comprising 4-phenyl-1, 4-dihydropyridines having various aminoalkyl moieties connected via a cyanoguanidine group to the 3-position of the 4- phenyl ring. These compounds are NPY antagonists.

A substantial body of art has accumulated over the past two decades with respect to the 4-aryl-1, ,4-dihydropyridine class of compounds.

Syntheses of compounds in this category have been driven by their pharmacologic actions involving calcium channels rendering them useful for treating cardiovascular disorders such as ischemia and hypertension.

U.S. Patent 4,829,076 to Sziiagyi, et al. is an example of such substituted dihydropyridine derivatives, disclosing and claiming inter alia compounds of formula (1) as calcium antagonists for treating hypertension.

The closest art would be our previous work involving 4-(3-substituted- phenyl)- 1 ,4-dihydrQpyriciine derivatives having NPY antagonist properties.

These derivatives conform to structural formula (2).

In (2) B is either a covalent bond or the group -NH-. The symbol Z denotes hetaryl moieties, examples being piperidine or piperazine.

In U.S. Patent 5,554,621, Z is a fused ring or spiro-fused nitrogen heterocycle. In USSN 482,355, Z is a piperazinyl or homopiperazinyl moiety. Z is a piperidinyl or tetrahydropyridinyl moiety in USSN 639,968.

These reference compounds are easily distinguished from the compounds of the instant invention by virtue of the linking functional groups.

The cyanoguanidine linking moiety is a novel structural feature in the new compounds, connecting the side-chain to the 4-phenyl ring. A cyanoguanidine moiety has previously appeared in a different location in 4- phenyl-1, ,4-dihydropyridine derivatives.

Alker, et al. in J. Med. Chem., 1990, 33, 585-591 disclosed, inter alia, compounds of formula (3) having calcium antagonism activity.

As can be seen, these compounds differ structurally from the compounds of the present invention.

In summary, the prior art does not disclose nor suggest the unique combination of structural fragments which embody these novel dihydropyridine derivatives which possess good antagonist activity at NPY Y1 receptor sites while having reduced cardiovascular effects.

Summary and Detailed Description of the Invention The present invention comprises compounds of Formula (I), their pharmaceutically acceptable acid addition salts and/or their hydrates thereof. In the foregoing structural Formula (I), the symbols R'-R6, R10, n and Z have the following meanings.

R1 to R4 are independently selected from lower alkyl; R5 and R6 are independently selected from hydrogen and lower alkyl; n is an integer selected from 2 to 5; in which R7 and Re are independently selected from lower alkyl and lower alkanol ; the solid and broken line denote a single or double covalent bond; R9 is selected from hydrogen; lower alkyl; -CO2R1; (CH2)rnX and -(CH2)n-NR11R12 wherein m is zero or an integer from 1 to 3 and X is Cj cycloalkyl, naphthyl, and R13 can be lower alkyl, lower alkenyl, lower

alkoxy, hydrogen, halogen, hydroxy and dialkylamino. R11 and R12 are each lower alkyl or are taken together as a C35 alkylene chain or an ethyl-oxy-ethyl chain; and R10 is hydrogen or halogen.

The term "lower" refers to substituents such as alkyl or alkoxy that contain from one to four carbon atoms; and to alkenyl groups containing from two to four carbon atoms. R11 and R12 are independently selected from lower alkyl to give tertiary amine groups, or R" and R12 can be taken together as a propyl, butyl or pentyl chain, thereby giving a nitrogen- containing ring, or as an ethyl-oxy-ethyl chain, thereby giving a morpholinyl ring.

Preferred compounds are Formula (I) compounds wherein R1-R4 are methyl, R5 and R6 are hydrogen, Z is piperidine and R9 is selected from phenyl, naphthyl and cycloalkyl.

The compounds of the present invention can exist as optical isomers and both the racemic mixtures of these isomers as well as the individual optical isomers themselves are within the scope of the present invention.

The racemic mixtures can be separated into their individual isomers through well-known techniques such as the separation of the diastereomeric salts formed with optically active acids, followed by conversion back to the optically active bases.

As indicated, the present invention also pertains to the pharmaceutically acceptable non-toxic salts of these basic compounds.

Such salts include those derived from organic and inorganic acids such as, without limitation, hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, methanesulfonic acid, acetic acid, dichloroacetic acid, tartaric acid, lactic acid, succinic acid, citric acid, maleic acid, fumaric acid, sorbic acid, aconitic acid, salicyclic acid, phthalic acid, enanthic acid, and the like.

The Formula (I) compounds can be produced by utilizing the following processes. The range of Formula (I) compounds are obtained by selecting the appropriate starting materials for use in these processes.

General processes for synthesis of Formula (I) compounds are shown in

Schemes 1 and 2. The symbols R1-R10, n and Z are as previously defined.

The symbol R is lower alkyl.

Nearly all desired Formula (I) products can be synthetically derived from aniline intermediate of Formula (IV) and various Formula (V) intermediates. As shown in pathway A of Scheme 1, the aniline compound (IV) is converted to the isothiocyanate (III) by use of thiocarbonyldiimidazole.

Treatment of (Ill) with sodium cyanamide results in the sodium N- cyanoisothiourea salt (II) which can be reacted with various amines (V) to produce the Formula (I) products. An alternative approach is shown in pathway B wherein the isothiocyanate intermediate (III) is converted to the thiourea compound (X) which is converted to the carbodiimide compound (XI) using phosgene. Addition of sodium cyanamide provides the product (1).

Scheme 2 is used for synthesis of Formula (I) products in which R5 is lower alkyl. The aniline intermediate (IV) is acylated using trifluoroacetic anhydride to give compound (Vl) which is alkylated with an alkyl iodide, after nitrogen anion formulation with sodium hydride, to provide the monoalkylated aniline intermediate (XIV) following basic hydrolysis of (VII).

Reaction of (XIV) with the sodium N-cyanoisothiourea compound (IX) in the presence of HgCI2 yields the Formula (I) product wherein R5 is alkyl.

The Formula (IX) intermediate can be obtained from compound (V) by first treating with thiocarbonyldiimidazole and then with sodium cyanamide.

Formula (IV) intermediates are readily available via variations of the Hantzsch synthetic reaction applied to appropriate starting materials such as the nitrobenzaldehyde (VIII).

Scheme 3 R10 NO2 R100 NO2 methyl acetoacetate ¼ NH4OAcMeO2 CO2Me CHO M Me (Vlil) H (Xlla: Symmetrical) As seen in Scheme 3, (Xlla) is a symmetrical dihydropyridine compound. Unsymmetrical dihydropyridines, e.g. where R1wR4 and/or R2wR3, are readily prepared as in Scheme 4, using modified Hantzsch conditions starting with Knoevenagel adducts and appropriate amino crotonates.

Scheme 4 (Xllb: Unsymmetrical) A number of these starting materials and intermediate dihydropyridines are commercially available and/or described in the literature. Use of the Hantzsch reaction and its modifications would be known to one skilled in the synthetic chemical arts.

Reduction of nitrophenyldihydropyridines, e.g. (XII), using any of several standard reduction processes provides the starting Formula (IV) aniline intermediates used in the present invention.

Additional reaction intermediates and Formula (I) products can be prepared by appropriate modification of the foregoing synthetic schemes

and procedures. Additional examples and experimental procedures are provided infra.

The compounds of this invention demonstrate binding affinity at NPY Y1 receptors. This pharmacologic activity is assayed in SK-N-MC (human neuroblastoma) cell membranes using iodine-125-labeled I-PYY as a radioligand. The compounds of this invention had good binding affinities as evidenced by 1050 values being about 10 uM or less at NPY Y1 receptors.

Preferred compounds have IC50 values less than 100 nM and most preferred compounds have IC50 values of less than 10 nM. Although as a class, these types of dihydropyridines have significant affinity for a,-adrenergic receptors and/or Ca++ channels, the compounds of this invention possess much weaker affinities for a1 adrenergic receptors and Ca++ channels.

Pharmacologically, these compounds act as selective NPY antagonists at NPY Y1 receptor sites. As such, the compounds of Formula (I) are of value in the treatment of a wide variety of clinical conditions which are characterized by the presence of an excess of neuropeptide Y. Thus, the invention provides methods for the treatment or prevention of a physiological disorder associated with an excess of neuropeptide Y, which method comprises administering to a mammal in need of said treatment an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt, solvate or prod rug thereof. The term "physiological disorder associated with an excess of neuropeptide Y" encompasses those disorders associated with an inappropriate stimulation of neuropeptide Y receptors, regardless of the actual amont of neuropeptide Y present in the locale.

These physiological disorders include: disorders or diseases pertaining to the heart, blood vessels or the renal system, such as vasospasm, heart failure, shock, cardiac hypertrophy, increased blood pressure, angina, myocardial infarction, sudden cardiac death, congestive heart failure, arrythmia, peripheral vascular disease, and abnormal renal conditions such as impaired flow of fluid, abnormal mass transport, or renal failure; conditions related to increased sympathetic nerve activity for example, during or after coronary artery surgery, and operations and surgery in the gastrointestinal track;

cerebral diseases and diseases related to the central nervous system, such as cerebral infarction, neurodegeneration, epilepsy, stroke, and conditions related to stroke, cerebral vasospasm and hemorrhage, depression, anxiety, schizophrenia, dementia, seizure, and epilepsy; conditions related to pain or nociception; . diseases related to abnormal gastrointestinal motility and secretion, such as different forms of ileus, urinary incontinence, and Crohn's disease; abnormal drink and food intake disorders, such as obesity, anorexia, bulemia, and metabolic disorders; diseases related to sexual dysfunction and reproductive disorders such as benign prostatic hyperplasia and male erectile dysfunction; conditions or disorders associated with inflammation; . respiratory diseases, such as asthma and conditions related to asthma and bronchoconstriction; diseases related to abnormal homone release, such as leutinizing hormone, growth hormone, insulin and prolactin; sleep disturbance and diabetes.

There is evidence that NPY contributes to certain symptoms in these disorders: hypertension, eating disorders, and depression/anxiety; as well as circadian rhythms. Compounds of this invention are expected to be useful in treating these disorders as well as sleep disturbance and diabetes.

Selected compounds are tested further for their ability to block or stimulate NPY-induced feeding in test animals by intraperitoneal administration to the animal prior to inducing feeding behavior with NPY.

Taken together, these tests indicate that the compounds of this invention would be useful anorexiants and would function as anti-obesity agents with further use in various clinical eating disorders. Thus, another aspect of the

invention concerns a process for reducing food intake in an obese mammal or a mammal with an eating disorder. The process comprises systemic administration to such a mammal of an anorexiant-effective dose of a Formula (I) compound or a pharmaceutically acceptable acid addition salt and/or hydrate thereof.

On the basis of pharmacologic testing, an effective dose given parenterally could be expected to be in a range of about 0.05 to 1 mg/kg body weight and if given orally would be expected to be in the range of about 1 to 50 mg/kg body weight.

For clinical applications, however, the dosage and dosage regimen must in each case be carefully adjusted, utilizing sound professional judgment and considering the age, weight and condition of the recipient, the route of administration and the nature and gravity of the illness. Generally, the compounds of the instant invention will be administered in the same manner as for available anorexiant drugs such as Diethylpropion, Mazindol, or Phentermine and the daily oral dose would comprise from about 70 to about 1400 mg, preferably 500 to 1000 mg administered from 1 to 3 times a day. In some instances, a sufficient therapeutic effect can be obtained at lower doses while in others, larger doses will be required.

The term systemic administration as used herein refers to oral, buccal, transdermal, rectal, and parenteral (i.e. intramuscular, intravenous, and subcutaneous) routes. Generally, it will be found that when a compound of the present invention is administered orally, which is the preferred route, a larger quantity of reactive agent is required to produce the same effect as a smaller quantity given parenterally. In accordance with good clinical practice, it is preferred to administer the instant compounds at a concentration level that will produce effective anoretic effects without causing any harmful or untoward side effects. Similarly, the instant compounds can be administered to treat the various diseases, conditions, and disorders listed supra.

Therapeutically, the instant compounds are generally given as pharmaceutical compositions comprised of an effective anorectic amount of a compound of Formula I or a pharmaceutically acceptable acid addition salt thereof and a pharmaceutically acceptable carrier. Pharmaceutical

compositions for effecting such treatment will contain a major or minor amount, e.g. from 95 to 0.5% of at least one compound of the present invention in combination with the pharmaceutical carrier, the carrier comprising one or more solid, semi-solid, or liquid diluent, filler, and formulation adjuvant which is non-toxic, inert and pharmaceutically acceptable. Such pharmaceutical compositions are preferably in dosage unit forms; i.e., physically discrete units containing a predetermined amount of the drug corresponding to a fraction or multiple of the dose which is calculated to produce the desired therapeutic response. The dosage units can contain 1, 2, 3, 4, or more single doses, or, alternatively, one-half, one- third, or one-fourth of a single dose. A single dose preferably contains an amount sufficient to produce the desired therapeutic effect upon administration at one application of one or more dosage units according to the pre-determined dosage regimen usually a whole, half, third, or quarter of the daily dosage administered once, twice, three, or four times a day. Other therapeutic agents can also be present. Pharmaceutical compositions which provide from about 50 to 1000 mg of the active ingredient per unit dose are preferred and are conventionally prepared as tablets, lozenges, capsules, powders, transdermal patches, aqueous or oily suspensions, syrups, elixirs, and aqueous solutions. Preferred oral compositions are in the form of tablets or capsules and may contain conventional excipients such as binding agents (e.g. syrup, acacia, gelatin, sorbitol, tragecanth, or polyvinylpyrrolidone), fillers (e.g. lactose, sugar, maize-starch, calcium phosphate, sorbitol, or glycine), lubricants (e.g. magnesium stearate, talc, polyethylene glycol or silica), disintegrants (e.g. starch) and wetting agents (e.g. sodium lauryl sulfate). Solutions or suspensions of a Formula I compound with conventional pharmaceutical vehicles are generally employed for parenteral compositions such as an aqueous solution for intravenous injection or an oily suspension for intramuscular injection. Such compositions having the desired clarity, stability and adaptability for parenteral use are obtained by dissolving from 0.1% to 10% by weight of the active compound in water or a vehicle consisting of a polyhydric aliphatic alcohol such as glycerine, propyleneglycol, and polyethelene glycols or mixtures thereof. The polyethyleneglycols consist of a mixture of non- volatile, usually liquid, polyethyleneglycols which are soluble in both water and organic liquids and which have molecular weights from about 200 to 1500.

Description of the Specific Embodiments The compounds which constitute this invention and their methods of preparation will appear more fully from a consideration of the following examples which are given for the purpose of illustration only and are not to be construed as limiting the invention in sphere or scope. All temperatures are understood to be in degrees C when not specified.

The nuclear magnetic resonance (1H and '3C NMR) spectral characteristics refer to chemical shifts (6) expressed in parts per million (ppm) versus tetramethylsilane (TMS) as reference standard. The relative area reported for the various shifts in the proton NMR spectral data corresponds to the number of hydrogen atoms of a particular functional type in the molecule. The nature of the shifts as to multiplicity is reported as broad singlet (br s), singlet (s), multiplet (m), doublet (d), triplet (t) doublet of doublets (dd), quartet (q) or pentuplet (p). Abbreviations employed are DMSO-d6, (deuterodimethylsulfoxide), CDCI3 (deuterochloroform), and are otherwise conventional. The infrared (IR) spectral descriptions include only absorption wave numbers (cm~1) having functional group identification value. The IR determinations were generally employed using potassium bromide (KBr) as diluent. The elemental analyses are reported as percent by weight. Melting points were obtained using a Thomas Hoover capillary apparatus and are uncorrected. Mass spectra (m/z; MH+) and analytic HPLC (retention time and peak area %) data were obtained.

A. Preparation of Intermediates 1. Starting Dihydropyridines Example 1: General Procedure for the Preparation of Knoevenagel Adducts (Precursors to Asymmetric Dihydropyridines) As a general method, a mixture of 300 mmol each of 3- nitrobenzaldehyde and the requisite -keto ester was dissolved in 250 mL of toluene and piperidine (2.5 mL) and glacial HOAc (5 mL) were added. The solution was then allowed to reflux several h during which time the theoretical amount of H2O was removed by a Dean-Stark trap. The toluene

was then removed in vacuo and the resulting Knoevenagel products purified by flash chromatography (SiO2: EtOAc/Hex) or crystallization.

Example 2: General Method for the Preparation of Starting Dihydropyridines (XII) For symmetrical dihydropyridines (Xlla) the requisite -keto ester (126 mmol), a 3-nitrobenzaldehyde (63 mmol), and NH40Ac (95 mmol) were refluxed for several h in 150 mL of EtOH or i-PrOH using standard Hantzsch conditions. The crude reaction mixture was cooled to ambient temperature and the volatiles removed in vacuo. The symmetrical dihydropyridines were crystallized from EtOH or i-PrOH. Generally, for the asymmetrical dihydropyridines (Xllb), a mixture of the requisite Knoevenagel adduct (70 mmol) and an alkyl 3-aminocrotonate (70 mmol) was refluxed in i-PrOH overnight (24 h). The volatiles were then removed in vacuo and the crude products recrystallized from EtOH.

2. Aniline Intermediates of Formula (IV) Example 3: General Reductive Procedures for the Conversion of the Nitroarvl Dihydropyridines to the Anilines (IV) Catalytic Hydrogenation Method A. To a N2 solution of the nitro aromatic dihydropyridine (10 mmol) in 80 mL of EtOH, was added 0.5-1.0 g of 5% Pt on sulfided carbon and the resulting suspension shaken on a Parr Hydrogenation apparatus at room temperature under 60 psi of H2. After several h the reduction was usually complete as judged by theoretical H2 consumption. The suspension was then filtered through Celite and the filtrate concentrated in vacuo to give the anilines (IV). These were then purified by recrystallization or flash chromatography in the indicated solvents. In some of the examples the crude aniline derivatives were converted to a salt form and then recrystallized.

Iron Method B. In a 250-mL three-necked flask equipped with mechanical stirrer and reflux condenser was added a solution of NH4CI (64 mmol) in 50 mL of H2 iron powder (38 mg-atom, 325 mesh) and a solution of the nitro aromatic dihydropyridine (11 mmol) in 50 mL of MeOH. The resulting mixture was stirred at reflux for 6 h and then filtered through Celite

and rinsed with copious amounts of MeOH. The filtrate was partially concentrated in vacuo to yield an aq suspension, which was extracted with CH2CI2. The combined organic extracts were dried over Na2SO4, filtered, and the volatiles removed in vacuo to yield the crude anilines (IV). These were purified as above in the hydrogenation method.

3. Formula (V) Diamine Intermediates Example 4: 4-(3-Methoxyphenyl)-1-piperidineethanamine A mixture of bromoacetonitrile (0.70 mL, 10 mmol), 4-(3- methoxyphenyl)piperidine (1.74 g, 9.1 mmol) and K2CO3 (1.3 g) in MeCN was stirred at room temperature for 3 days. The reaction mixture was partitioned between CH2CI2 and H2O, and the organic extract was dried (Na2SO4). The solvent was then removed in vacuo to afford [4-(3- methoxyphenyl)-1-piperidinyl] acetonitrile as an amber oil (2.03 g, 97%): MS (DCI) m/z231 (MH+). Anal. Calcd. for C14H18N2O 0.5 H2O: C, 70.27; H, 8.00; N, 11.71. Found: C, 70.12; H, 7.67; N, 11.87.

A solution of the analyzed amber oil (1.90 g, 8.26 mmol) in MeOH (50 mL) containing 30% aq. NH3 (10 mL) and Raney nickel was hydrogenated in a Parr apparatus at 50 psi for 2h. The catalyst was removed by filtration over Celite, and the solvent was then removed in vacuo from the filtrate to yield the desired compound as a pale blue oil (1.11 g, 58%). This material was subsequently reacted without further purification or characterization.

Example 5: N-Methyl-3-(4-phenyl- 1 -piperidinyl)propanamine A solution of 4-phenylpiperidine (480 mg, 3.0 mmol) and acrylonitrile (0.27 mL, 4.0 mmol) in MeCN (20 mL) was refluxed for 2h. Solvent was removed in vacuo to give 3-(4-phenyl-1 -piperidinyl)proparenitrile as a colorless oil (520 mg, 86%): MS (DCI) m/z215 (MH+). This oil was catalytically reduced in 99% yield to 4-phenyl-1-piperidinepropanamine by using the procedure given in Example 4.

A solution of this propanamine intermediate (5.45 g, 25 mmol) in ethyl formate (75 mL) was refluxed overnight. Solvent was removed in vacuo and the residue was taken up in CH2CI2 and chromatographed over silica

(CH2Cl2:MeOH, 7:3) with vacuum filtration to give N-[3-(4-phenyl-1- piperidinyl)propyl]formamide (5.54 g, 90%). This material (5.5 g, 22 mmol) was dissolved in anhydrous THF (50 mL) containing BH3Me2S (2.0 M in THF, 33 mL, 66 mmol) and refluxed overnight. The reaction mixture was then cooled, and was gradually quenched with MeOH (100 mL), followed by 3N HCI (100 mL). The resulting solution was refluxed overnight, and the solvent was then reduced in vacuo (to approximately 50 mL). This solution was made basic by the gradual addition of 20% NaOH, and then was extracted with CH2CI2. The organic extract was dried (Na2SO4), and the solvent was removed in vacuo. The residue was subjected to bulb-to-bulb vacuum distillation (Kugelrohr apparatus) to afford the title compound as a colorless oil (5.1 g, 100%). MS (DCI) m/z233 (MH+). 1H NMR (CDCI3) 6 7.22 (m, 5 H), 3.54 (s, 1 H), 3.06 (m, 2 H), 2.71 (m, 2 H), 2.48 (m, 6 H), 2.03 (m, 2 H), 1.77 (m, 6 H). Anal. Calcd. for C15H24N2e0.1 H2O: C,76.94;H, 10.42; N, 11.96. Found: C, 77.16; H, 10.80; N, 11.67.

4. Formula (IX) Isothiourea Sodium Salt Intermediates Example 6: 3-(4-phenyl-1-piperdinyl)propyl isothiocyanate A solution of 4-phenyl-1-piperidinepropanamine (Example 5 intermediate) (3.2 g, 14.7 mmol) and 1,1'-thiocarbonyldiimidazole (2.8 g, 15.7 mmol) in MeCN (100 mL) was stirred for 2 h. The reaction mixture was chromatographed by vacuum filtration over silica (MeCN) to furnish 1-(3- isothiocyanatopropyl)-4-phenylpiperidine as an amber oil which crystallized upon standing (1.25 g, 33%). mp 50-55 °C; MS (ESI) m/z261 (MH+); IR (KBr) 2113 cm-1. 1H NMR (CDCl3) 6 7.23 (m, 5 H), 3.63 (t, 2 H, J=6.3 Hz), 3.08 (m, 2 H), 2.55 (t, 2 H, J=7.2 Hz), 2.50 (m, 1 H), 2.15 (m, 2 H), 1.95 (t, 2 H, J=6. 9 Hz), 1.86 (m, 4 H). Anal. Calcd. for C16H20N2S#0,5 C2H3N: C, 66.28; H, 7.82; N, 12.08. Found: C, 66.68; H, 7.75; N, 12.22.

Example 7: N-Cyano-N'-[3-(4-phenyl-1 -pipendinyl)prnpyliisothiourna sodium salt Sodium ethoxide (1.1 M, prepared from 127 mg, 5.5 mmol sodium in 5.0 mL EtOH under a nitrogen atmosphere) was added to a solution of cyanamide (231 mg, 5.5 mmol) in 5.0 mL EtOH. To an aliquot (1.0 mL, 0.55 mmol) of this 0.55 M solution was added dropwise a solution of 1-(3-

isothiocyanatopropyl)-4-phenylpiperidine (120 mg, 0.55 mmol) in EtOH (5 mL). The mixture was briefly brought to a boil, and then was stirred at room temperature for 1 h. The solvent was removed in vacua, and the residue was triturated in Et2O and filtered to give the compound as a fine white solid (140 mg, 79%).

5. Scheme 1 Intermediates (II, III) Example 8: 1 4-Dihydro-4-[3-(isothiocyanato]phenyl)-2 .6-dimethyl-3 .5- pyridinedicarboxylic acid. dimethyl ester. hemihydrate (III) 1,4-Dihydro-4-(3-aminophenyl)-2,6-dimethyl-3,5-pyridinedicar boxylic acid, dimethyl ester (IV) (18.97 g, 60.0 mmol) in DMF (250 mL) was added via addition funnel to a solution of thiocarbonyldiimidazole (11.76 g, 60.0 mmol) in DMF (100 mL) over 2.0 h. The reaction was stirred an additional 30 min. H2O was added slowly resulting in a copious white precipitate. The precipitate was collected on a filter frit washed with H2O, and dried, to afford the compound as a white solid (16.1 g, 75%). mp 163-166 °C. 1H NMR <BR> <BR> (DMSO-d6)6 8. 98 (s,1 H),7.31(t,1 H,J=7. 7 Hz),7.17(m,2H),7.06(s,1 H), 4.88 (s, 1H), 3.55 (s, 6H), 2.27 (s, 6H); IR (KBr) 3314, 2122, 2086, 1681, 1654, 1222 cm1; MS (-ESI) 357 (MH). Anal. Calcd. for C18H18N2O4S.0.5 H2O: C, 58.84; H, 5.21; N, 7.63; S, 8.73. Found: C, 58.89; H, 5.04; N, 8.10; S, 8.73.

Example9:4-[3-[[(cyanomino)mercaptomethyl]amino]phenyl]-1 1,4-dihydro- 2.6-dimethyl-3.5-pyridinedicarboxylic acid. dimethyl ester. sodium salt (II) Cyanamide (2.52 g, 60 mmol) in EtOH (50 mL) was added to a solution of sodium (1.38 g, 60 mmol) in EtOH (150 mL). The isothiocyanate (Example 8) (17.9 g, 50 mmol) in EtOH (150 mL) was then added to the sodium cyanamide solution via an addition funnel. After the addition was complete, the reaction was brought to a brief boil and then allowed to stir for 1.0 h. at room temperature. The mixture was then concentrated and the residue triturated with EtOAc to provide the compound as a yellow solid <BR> <BR> (22.6g,100%).1HNMR(DMSO-d6)# 9.05 (s,1H),7.51(s,1H), 7.35(d,1H, J=8.0 Hz), 6.98 (t, 1H, J=8.0 Hz), 6.65 (d, 1H, J=8.0 Hz), 4.84 (s, 1H), 3.57 (s, <BR> <BR> 6H),2.27(s,6H).13C NMR(DMSO-d6)8186.5,167.4,147.4,145.7,140.1,

127.4,121,2,119.8, 118.7,117.6,101.2,50.6, 38.0,18.1; IR (KBr) 2159cm- 1.

6. Schmem 2 Intermediates (VI, VII, XIV) Example 10: 1 ,4-Dihydro-2,6-dimethyl-4-[3-[(trifluoroacethyl)amino]phenyl ]- 3.5-pyridinedicarboxylic acid. dimethyl ester (Vl) A solution of 1 ,4-dihydro-4-(3-aminophenyl)-2,6-dimethyl-3,5- pyridinedicarboxylic acid, dimethyl ester (IV) (10.0 g, 31.6 mmol) in CH2CI2 (500 mL) containing pyridine (2.8 mL, 35 mmol) was cooled to 0 °C.

Trifluoroacetic anhydride (4.7 mL, 33 mmol) was then added dropwise, and the resulting mixture was stirred at room temperature for 2 h, resulting in a thick suspension. A white solid was collected by filtration and dried in an Abderhalden apparatus for 2 h to afford the compound (9.58 g, 74%). This material was not characterized, but was directly converted to (VII).

Example 11: 1 ,4-Dihydro-2,6-dimethyl-4-[3- [methyl(trifluoroacetyl)amino]phenyl]-3,5-pyridinedicarboxyl ic acid. dimethyl ester (VII) To a solution of compound (VI) (Example 10) (2.06 g, 5.0 mmol) in DMF (20 mL) under N2 was added NaH (60% mineral oil dispersion, 240 mg, 6.0 mmol). This mixture was stirred for 10 min, followed by the addition of Mel (0.60 mL, 10 mmol). The reaction mixture was stirred for lh, and then was quenched with H2O (100 mL). A precipitate readily formed, which was collected by filtration and rinsed with H2O. The resulting solid was taken up in CH2CI2, dried (Na2SO4), and the solvent was removed in vacuo to furnish the compound as a light amber solid (1.91 g, 90%). mp 184-186 °C; MS (ESI) m/z425 (MH+). 1H NMR (DMSO-d6) 6 8.92 (s, 1 H), 7.34 (t, 1H, J=7.8 Hz), 7.19 (m, 2H), 7.09 (s, 1H), 4.87 (S, 1H), 3.52 (s, 6H), 3.25 (s, 3H), 2.26 (s, 6H). Anal. Calcd. for C20H2tF3N2Os0. 2 H2O: C, 55.84; H, 5.02; N, 6.52. Found: C, 55.84; H, 4.96; N, 6.24.

Example 12: 1 ,4-Dihydro-2,6-dimethyl-4-[3-(methylamino)phenyl]-3,5- pyridinedicarboxylic acid. dimethyl ester (XIV) A solution of compound (VII) (Example 11) (1.67 g, 3.92 mmol) in EtOH (30 mL) and 1 N NaOH (30 mL) was heated to reflux, and then was cooled and extracted with CH2CI2. The organic extract was dried (Na2SO4), and the solvent was removed in vacuo to afford the compound as a pale yellow solid (1.11 g, 86%). mp 182-184 °C; MS (ESI) m/z 329 (MH+). tH NMR (DMSO-d6) 6 8.78 (s, 1 H), 6.91 (t, 1 H, J=7. 8 Hz), 6.33 (m, 2H), 6.26 (d, 1H, 8. 1 Hz), 5.45 (q, 1H, J=5.1 Hz), 4.82 (s, 1H), 3.56 (s, 6H), 2.60 (d, 3H, J=5.1 Hz), 2.25 (s, 6H).

7. Formula (I) Products Example 13: 4-[3-[[(Cyanoimino)[[3-[4-phenyl-1 - piperidinyl]propyl]amino]emethyl]methylamino]jphenyl]-1 .4-dihydro-2 .6- dimethyl-3.5-pyridinedicarboxylic acid. dimethyl ester (Synthesis via Scheme 2.) To a solution of N-cyano-N'-[3-(4-phenyl-1- piperidinyl)propyl]isothiourea sodium salt (IX) (115 mg, 0.35 mmol) and the aniline intermediate (XIV) from Example 12 (115 mg, 0.35 mmol) in THF (7 mL) at 0 °C was added HgCI2 (95 mg, 0.35 mmol). The reaction mixture was then refluxed for 3 h. After cooling to room temperature, H2O (1 mL) was added, and the mixture was stirred for 30 min. A gray precipitate was collected by filtration, and rinsed with CH2CI2, the organic extract was dried (Na2SO4), and the solvent was removed in vacuo. The residue was subjected twice to flash chromatography (silica gel, MeOH:CH2Cl2, 4:96) to afford the compound as a white solid (15 mg, 4.5%). mp 85-90 °C; MS (ESI) m/z 599 (MH+); 1H NMR (CDCI3) 8 7. 30 (m, 8 h), 6.98 (d, 1 H, J=7.8 Hz), 6.91 (s, 1 H), 5.29 (br s, 1 H), 5.09 (s, 1 H), 3.67 (s, 6 H), 3.63 (m, 2 H), 3.47 (m, 2 H), 3.37 (s, 3 H), 3.00 (m, 2 H), 2.73 (m, 4 H), 2.45 (s, 6 H), 2.38 (m, 1 H), 2.26 (m, 2 H), 2.03 (m, 2 H); 13C NMR (CDCI3) # 168.2, 150.4, 146.8, 130.6, 129.0, 128.0, 127.4, 127.0, 124.9, 124. 1, 117. 3, 102. 3, 54. 1, 51.4, 51. 3, 40. 8, 40. 3, 39. 9, 38. 9, 30. 4, 25. 4, 19. 3. HRMS (FAB) Calcd. for C34H43N6O4 (MH+): m/z 599.3346. Found: 599.3362.

Example 14: General Procedure for the Scheme 1 Synthesis of Formula (I) Products Under a N2 atmosphere, HgCI2 (0.27 g, 1.0 mmol) was added to a cooled (0 °C) suspension of the dihydropyridine aniline derivative (IV) (1.0 mmol), and a diamine (V) (1.5 mmol) in THF (25 mL). The reaction mixture was stirred for 3 h while warming to room temperature. The reaction was then quenched with H2O (0.2 mL), and was stirred overnight. The resulting black precipitate was removed by vacuum filtration over Celite, and CH2CI2 (25 mL) was added to the filtrate. This solution was extracted twice with 1 N NaOH (25 mL), the organic extract was dried (Na2SO4), and the solvent was removed in vacuo. The crude product was generally flash chromatographed, over silica gel with the indicated eluent, to afford the target Formula (I) compound. By this method, the following Formula (I) products were prepared.

Example 15: 4-[3-[[(Cyanokimino)[[2-[4-(3-methoxyphenyl)-1 piperidinyl]ethyl]amino]methyl]amino][henyl]-1,4-dihydro-2,6 -dimethyl-3,5- pyridinedicarboxylic acid. dimethyl ester The compound was isolated as a beige solid (33%) after purification by flash chromatography (CH2CI2:MeOH, 99:1). mp 116-121 °C, 1H NMR (DMSO-d6) 8 8.92 (s, 1H), 7.18-7.10 (m, 3H), 6.92 (d, 2H, J=7.6 Hz), 6.83- 6.74 (m, 3H), 4.90 (s, 1 H), 3.74 (s, 3H), 3.52 (s, 6H), 3.34 (s, 6H), 3.00 (d, 2H, J=10.5 Hz), 2.26 (s, 6H), 2.09 (t, 2H, 11. 4 Hz), 1.74-1.56 (m, 3H); 13C NMR (DMSO-d6)# 167.3,159.3,158.5, 148.6,147.8,146.0, 137.6,129.3,138.4, 123.2, 121.9, 120.8, 118.8, 117.4, 112.5, 111.4 101. 2, 56. 9, 54. 8, 53. 5, 50.7,41.7, 39.2, 38.3, 32.8, 18.2. HRMS Calcd. for C33H41N6O5(MH+): 601.3139 Found: 601.3147.

Example 16: 4-[3-[[(Cyanoimino)[[4-[4-(3-methoxyphenyl)-1- pipendinyl]butyl]amino]methyl]amino]phenyl]-1 .4-dihydro-2 6-dimethyl-3. 5- pyridinedicarboxylic acid. dimethyl ester hydrate The compound was isolated as a yellow oil (32%) after purification by <BR> <BR> flashchromatography(CH2CI2:MeOH, 99:1). 1H NMR(DMSO-d6)# 8.91 (d, 2H, J=8.0 Hz); 7.25-7.14 (m, 3H), 7.04 (s, 1H), 6.98 (d, 1H, J=7.9 Hz), 6.90 (d, 1 H, J=7.7 Hz), 6.80-6.74 (m, 3H), 4.89 (s, 1 H), 3.80 (s, 3H), 3.56 (s, 6H),

3.34 (s, 8H), 3.22 (d, 2H, J=5.5 Hz), 3.04 (bs, 2H), 2.27 (s, 6H), 1.74 (m, 3H), 1.51 (bs, 2H); $C NMR (DMSO-d6) # 167.3, 159.3, 157.9, 148.5, 145.9, 137.6, 129.3, 128.4, 123.1, 121.7, 120.7, 118.8, 117.3, 112.4, 111.4,101.1, 89.3,54.9, 53.5, 50.7, 41.3, 38.3, 26.8, 18.2, Anal. Calcd for C35H44N6O5#1.6 H2O: C, 63.93; H, 7.24; N, 12.78. Found: C, 63.82; H, 6.99; N, 12.84.

Example 17: 4-[3-[[(Cyanomino)[[3-(4-phenyl-1 - piperidinyl) propyl]aminol]methyl]amino]phenyl]-1 4-dihydro-2. .6-dimethyl- 3 .5-pyridinedicarboxylic acid. dimethyl ester hydrate The compound was isolated as an airy off-white solid (72%) after purificationbyflashchromatography(CH2CI2:MeOH, 99:1). mp 131- 135 °C. Anal. Calcd for C33H40N6O4#1.0 H2O: C, 65.76; H, 7.02; N, 13.94.

Found: C, 65.59; H, 6.91; N, 13.84.

Example 18: 4-[3-[[(Cyanoimino)[[3-[4-(3-methoxyphenyl)-1 - piperidinyl]propyl]amino]methyl[amino]phenyl]- 4-dihydro-2. 6-dimethyl- 3.5-pyridinedicarboxylic acid. dimethyl ester. hydrochloride salt. dihydrate The compound was isolated as an ivory solid (58%) after purification by flash chromatography (CH2CI2:MeOH, 20:1). The product was characterized as the HCI salt: mp 135 °C. Anal. Calcd for C34H42N6O5#HCI#2.0 H2O: C, 59.44; H, 6.89; N, 12.27. Found: C, 59.33; H, 6.47; N, 12.05.

Example 19: 4-[3-[[(Cyanoimino)[[3-[4-cyclophenyl-1- piperidinyl]propy]amino]methyl]amino]phenyl]-1,4-dihydro-2,6 -dimethyl- 3 .5-pyridinedicarboxylic acid. dimethyl ester. hemihydrate The compound was isolated as a yellow solid (47%) after purification by flash chromatography (CH2CH2:MeOH, 6:1). The product was characterized as the HCI salt: mp 171-178 °C. Anal. Calcd for C33H46N6O4#HCI#1.5H2O: C, 60.58; H, 7.70; N, 12.85. Found: C, 60.38; H, 7.34; N, 12.70.

Example 20: 4-[3-[[(Cyanoimino)[[3-[4-phenyl-1- piperidinyl]propyl]methylamino]mentyl]amino]phenyl]-1 .4-dihydro-2 .6- dimethyl-3,5-pyridinedicarboxylic acid. dimethyl ester The crude product was taken up in CH2CI2, from which a precipitate formed. Filtration afforded the product as a light amber solid (30%): mp 135-145 °C (sintered); MS (ESI) m/z599 (MH+); IR (KBr) 2181 cm1. Anal.

Calcd. for C34H42N6O4 O 0. 6 CH2Cl2: C, 63.97; H, 6.70; N, 12.94. Found: C, 63.93; H, 6.48; N, 13.11.

Example 21: 4-[3-[[(Cyanoimino)[[3-[4-phenyl-1- piperidinyl]-propyl]methylamino]methyl]amino]-4-fluorophenyl ]-1 .4-dihydro- 2.6-dimethyl-3.5-pyridinedicarboxylic acid. dimethyl ester Following the schemes and procedures described supra, 4-fluoro-3- nitrobenzaldehyde was carried trough to 1,4-dihydro-4-[(4-fluoro-3- isothiocyanato)phenyl]-2,6-dimethyl-3,5-pyridine dicarboxylic acid, dimethyl ester and then converted into the corresponding N-cyanoisothiourea salt by treatment with an equivalent amount of sodium cyanamide in EtOH. The salt was not purified, but was dried and used in the subsequent HgCI2 mediated coupling with intermediate (V) to produce the title compound (I) which was isolated as a dried foam (150 mg, 47%) after flash column chromatography (silica gel, CH2CI2:MeOH, 10:1). 1H NMR (CDCI3) 67. 45 (br. s, 1H), 7.24 (m, 1H), 7.18 (m, 1H), 7.15-7.05 (m, 5H), 6.95 (t, 1H, J=9.3Hz), 6.19 (br. 2H), 4.97 (s, 1 H), 3.60 (s, 6H), 3.46 (m, 2H), 3.00-2.96 (m, 3H), 2.52 (m, 4H), 2.34 (s, 6H), 2.04 (m, 3H), 1.82-1.69 (m, 4H), 1.51 (m, 2H). Anal. Calcd. for C33H39F1N6O4.1.4 H2O: C, 63.12; H, 6.71; N, 13.38. Found: C, 63.46; H, 6.52; N, 12.94.

Example 22: 4-[3-[[(Cyanoimino)[[3-[4-(3-methyoxyphyenyl)-1 - <BR> <BR> piperidinyl]propyl]methylamino]methyl]amino]-4-fluorophenyl] -1 .4-dihydro- 2,6-dimethyl-3,5-pyridinedicarboxylic acid. dimethyl ester Following the same procedure as for Example 21, the cyanoisothiourea salt was converted into the desired product (I) via coupling with the appropriate diamine (V). The compound was isolated as a dried foam (52%) after flash column chromatography (silica gel, CH2CI2:MeOH, <BR> <BR> 10:1): 1HNMR(CDCl3) # 7.36 (br.s,1H),7.2-6.8(m,5H),6.7-6.5(m,3H),6.4

(br. s 1H), 4.97 (s, 1H), 3.79 (s, 3H), 3.63 (s, 6H), 3.45 (m, 2H), 2.97-2.93 (m, 2H), 2.48 (m, 2H), 2.34 (s, 6H), 2.0 (m, 2H), 1.6-1.8 (m, 5H), 1.6-1.4 (m, 2H).

Anal. Calcd. forC34H42F1N6O50.75H2O: C, 63.19; H, 6.63; N, 13.01. Found: C, 62.82; H, 6.37; N, 13.42.

A number of additional Formula (I) compounds were prepared using combinatorial, parallel synthesis chemical techniques. Intermediates of Formula (II) the sodium N-cyanoisothiourea salts, could be stored and reacted in a combinatorial fashion with various Formula (V) diamines and mercuric chloride to provide Formula (I) products.

Example 23: General Procedure for Combinatorial Synthesis of Formula (I) Products Simultaneous reactions were performed using 19 diamines (V). A diamine (V) (0.20 mmol), the sodium N-cyanoisothiourea salt (II) (0.30 mmol) and HgCI2 (0.082 g, 0.30 mmol) were placed into individual 15 mL reaction vials equipped with a stir bar. THF (4 mL) was added to each vial.

The vials were closed with Teflon lined screw caps and the resulting suspensions were stirred at room temperature for 1 h. The reaction mixtures were vacuum filtered through 8 mL Bond Elut cartridges containing Celite.

A Varian Vac Elut SPS 24 was used and each effluent was collected in a 16 x 100 mm test tube. THF (2 mL) was used to complete the transfer to the Celite bed. An aliquot (0.05 mL) of each THF effluent was diluted in MeOH (0.2 mL) and analyzed by analytical HPLC and LC-MS. The remainder of each THF effluent was evaporated using a Savant Speed Vac. Samples that were> 80% pure by HPLC were not further purified by preparative HPLC. To remove any residual HgC12, such samples were partitioned between EtOAc (4 mL) and H2O (3 x 2 mL) and then the organic layer was evaporated to give the Formula (I) products. Samples < 80% pure by HPLC were subjected to automated preparative HPLC. The MeOH portion of the fractions was evaporated using the Speed Vac. The resulting aq. solutions were treated with aq. Na2CO3 (0.7 mL, 2 M) and then extracted with EtOAc (8 mL). The organic layers were washed with aq. Na2CO3 (2.7 mL, 0.5 M) and then H2O (3 x 2 mL). Two aliquots (0.05 mL each) of these organic solutions were removed for final product HPLC and MS analysis. The remainder of the organic solutions were then transferred to tared 16 x 100 mm test tubes and evaporated using the Speed Vac to give the product.

As can be seen, the desired Formula (I) product may be obtained by appropriate selection of Formula (IV) and (V) starting materials (e.g.

Scheme 1) or Formula (XIV) and (IX) starting materials (e.g. Scheme 2).

Other modifications of reactants and procedures to produce these products would be known to one skilled in the art of organic chemical synthesis.

Some additional examples of Formula (I) products are contained in Tables 1,2 and 3.

Tabel 1: Formula (I) Products<BR> Z is Piperidine Ex. R10 n Y R9 % Yield Mol. Formula Mp °C M/Z MH+ 24 H 3 H CH2Ph 53 C34H41N6O4 indistinct 597 25 H 2 H Ph 62 C34H42N8O4 160-165 - 26 H 4 H Ph 54 C32H38N6O4 100-105 - 27 H 3 H 2-MeOPh 56 C38H46N6O9 indistinct - 28 H 3 H 3-HOPh 36 C33H40N6O5 115-120 - Ex. R10 n Y R9 % Yield Mol. formula Mp °C M/Z MH+ 29 H 3 H 4-FPh 39 C33H39FN6O4 105-110 - 30 H 3 H 1-naphthyl 66 C37H43N6O4 - 635 31 H 3 H 3-Me2NPh 73 C35H45N7O4 110-115 - 32 H 3 OH 4-MePh 60 C34H42N6O5 143-155 - 33 H 3 OH 4-FPh 49 C33H39FN6O5 118-128 - 34 H 3 CO2Me Ph 31 C35H42N6O6 - 643 35 H 3 CN Ph 46 C34h39N7O4 - 608 36 4-F 3 CO2Me Ph 42 C35H41FN6O6 - 661 37 4-F 3 CN Ph 58 C34H38FN7O4 - 628 38 4-F 3 H t-Bu 68 C31H43FN6O4 - - 39 H 3 H 3-IPh 38 C33H39IN6O4 - - 40 H 3 H H 50 C37H36N6O4 - 509 41 H 3 H Me 41 C28H38N6O4 - 523 52 H 3 H Et 53 C29H40N6O4 - 537 Ex.R10nVR9%YieldMol.FormulaMp0CM/ZMH+ 43H3 H Pr 77 C30H42N604 - 551 44H3Hi-Pr21C30H42N6O4-551 45H3HNMe24C2gH41N7O4-552 46 H 3 H t-Bu 24 C1H44N6O4 - 565 47H3HCH2NMe233CaoH43N7O4-566 48 H 3 H 23 C31H43N7O4 - 578 49H3HCH2CH2NMe218C31H45N7O4-580 9f9II23 C32H45N7O4 - 592 ---------------------592 52 H 3 H No 23 C31H43N7O5 - 594 (u 53H3HI9 N32C33H47N704-606 Ex.R10nYR0%YieldMol.FormulaMp0CM/ZMH+ 54H3H234C32H45N705-608 55H 3 H 44 C33H47N7O5 - 622 o Rable 2: Formula (I) Products<BR> Z is Tetrahydropyridine Ex. R10 n R9 % Yield Mol. formula Mp °c M/Z MY+ 56 H 3 4-MePh 45 C34H41N6O4 114-124 597 57 H 3 4-FPh 53 C33H37FN6O4 - - 58 H 3 1-naphthyl 11 C37H40N6O4 - 633 Table 3: Formula (I) Proudcts<BR> Z is Piperazine Ex. R10 n R9 % Yield Mol. formula Mp °C M/Z MY+ 59 H 3 c-hexyl 39 C32H45N7O4 - 592 68 H 3 Et 60 C28H39N7O4 127-132 - 61 H 3 n-Pr 86 C29H41N7O4 115-120 62 H 3 i-Pr 85 C29H41N7O4 145-150 - 63 H 3 c-Pr 42 C29H39N7O4 115-120 - Ex. R10 n R9 % Yield Mol. Formula Mp °C M/Z MH+ 64 H 3 n-Bu 92 C30H43N7O4 135-140 - 65 H 3 i-Bu 97 C39H44N7O4 155-160 566 66 H 3 t-Bu 33 C30H43N7O4 110-115 - 67 H 3 CH2C-Pr 93 C30H41N7O4 145-150 - 68 H 3 c-pentyl 97 C31H43N7O4 150-155 - 69 H 3 CO2t-Bu 79 C31H43N7O6 115-120 - 70 H 3 Ph 69 C32H40N7O4 90-95 586 71 H 3 4-FPh 80 C32H39N7O4 95-100 604 72 H 3 3-MeOPh 82 C33H42H7O5 110-115 616 73 H 3 3-Me2NPh 54 C34H44N8O4 130-140 - 74 H 3 3-HOPh 40 C32H39N7O5 110-120 - 75 4-F 3 c-hexyl 56 C32H44N7O4 - 76 H 3 H 59 C26H35N7O4 105-110 - Scheme 1 General Processes for Compound (I) Synthesis A. 10 R10R NH2NH2 qthiocarbonyldiimidazole~R'Ncs R1 0 0o2R4thiocarbonyidiimidazoleR102tCo2R4 R2R3RNN, R3 HH (IV)(III) sodium cyanamide n10R10 6NH/(NRz(CH2)H 0N(HnZNY;NCN R1041 R1 OACo2R4R02 c02R4 IN/R3R6NH-(CH2)n'I RN R3RazzR6NH(CH2)n-R H(V)H (V) (I)(11) Scheme 1 General Processes for Compound (I) Synthesis (continued) B. R10HH NI NyN(H2) H2N-(cH2) n-z T (111) (XV) R102tc3O2R4 RR3 H (X) phosgene R10 N=C=N (CH2)nN--(CH2),,-Z 0 sodiumR102co2R4 (I)<cyanamideIR2 R3 H x Scheme 2 General Processes for Product (I) with R5#H R'ORIOR10 NH2NHCOCF, NR5cocF3 io))co24tfl'afIUnOyn9etCR10NaHR10 Co2R4 Nan ~coR4 co2R4 M R3N R3 R-I 2 R3 HH H (IV)(Vl)(Vll) OoH CN s R10N'CN f NR/NH (CH2) nZiNHRs co2R4 cN R102 co4 R1O11HR'O,CyR I R3 SNa (IX)H (I)(XIV)